Inside: Drug窶電rug interactions; screening for depression
RCSI The evolutionary basis of human disease
Volume 8: Number 1. 2015 ISSN 2009-0838
smj Royal College of Surgeons in Ireland Student Medical Journal
RCSI DEVELOPING HEALTHCARE LEADERS WHO MAKE A DIFFERENCE WORLDWIDE
Acknowledgements Thank you to RCSI Alumni for their continued support to us as students – providing career advice, acting as mentors, enabling electives and research, and supporting the publication of the RCSIsmj since its inception in 2008. We, as today’s generation of students and tomorrow’s generation of alumni, are very grateful for this ongoing support. A special thanks to Professor David Smith for the time and encouragement he has given to the RCSIsmj Ethics Challenge. We would also like to thank the Dean, Professor Hannah McGee, for her sponsorship, and Margaret McCarthy in the Dean's Office for her constant endorsement and assistance. The RCSIsmj was extremely privileged to have a number of professors and clinicians involved in this year's journal club. We would like to thank the following for their support of, and participation in the journal club, and to express our appreciation of the time, knowledge and expertise they shared with us: Doctor Patrick Dicker Doctor Mark Murphy Professor David Smith Professor Arnold Hill Professor Seamus Sreenan Professor Noel G. McElvaney Professor Fergal Malone Professor Naomi McCallion Professor Fergal O'Brien
RCSIsmjcontents Royal College of Surgeons in Ireland Student Medical Journal
4 4
Editorial Director’s welcome
RCSI Ethics Challenge
Executive Committee Director Editor-in-Chief Senior Editor
Melissa Schorr Natalie Achamallah Mohit Butaney
5 6
Peer Review Director
Rachel Green
Original articles
Assistant Peer Review Director
Ian Elliott
10
Senior Staff Writer
Hailey Carroll
14 19 23
Staff Writers Poornima Jayadev Menon Gurtej Singh Daniel O’Reilly Peer Review Team Mark Abel Nadia Al-Bader Carina Bee Rimpy Cheema Carling Cheung Alex Kasman Kimberly Ng Corey Nixon Simran Ohson Sarah Pradhan Aashna Sood Nadine Straka Stephanie Tung Zachary Wikerd Matthew Wong Executive Secretary Stephen Kenny Education Director Stephen Tsoukas Education Officers Shane Carr Amelia Reid Public Relations Maria Mikail Tessa Weinberg Koh Pei Ying Webmasters Stephen Tsoukas Rebecca Jagoo
RCSIsmj Ethics Challenge 2015/2016 RCSIsmj Ethics Challenge winner 2014/2015
Demographic and symptomatic predictors of incomplete bolus transit in patients with ineffective oesophageal motility Prevalence and risk factors for modified prescriptions in an Irish community pharmacy Prevalence of haemoglobinopathies in the diabetic population served by Connolly Hospital Tissue is the issue: is margin re-excision rate following breast-conserving surgery a good quality measure?
Case reports 28 32 36
An unexpected tumour The hidden dangers of drug–drug interactions Recognition and management of rumination syndrome in the paediatric population
Review articles 39 42
Anthropometric screening for obesity in the Asian adult population Premature ejaculation: current and evolving treatments
Staff reviews 48 52 56 61
Culture, criteria and clinicians – dissecting discrepancies in the prevalence of attention deficit hyperactivity disorder The evolutionary basis of human disease Melatonin and cancer: it’s nothing to yawn at Warming up to therapeutic hypothermia
Perspectives 66 69 72 75
Popular neurocience: the new frontier, or an exercise in misdirection? Staying Lean Letting the gen(i)e out of the bottle? Genetic testing for mental illness The doctor will tweet you now: medicine in the social media age
Elective report 79
Asylum seeker healthcare in France: one month with the PASS Programme
Travel briefs 81 82 83 84
A phenomenal experience Impressions of Bahrain Too good to be true? Beneath Mount Everest
Alumni spotlight 85
A view of the “war” from afar
Book review 87
An Act of Love by Marie Fleming with Sue Leonard
JOURNALISM CONTENT DESIGN
The Malthouse, 537 NCR, Dublin 1. T: 01-856 1166 F: 01-856 1169 www.thinkmedia.ie Design: Tony Byrne, Tom Cullen and Ruth O’Sullivan Editorial: Ann-Marie Hardiman and Paul O’Grady
Abstracts 88 89 90
Methicillin-resistant Staphylococcus aureus in Connolly Hospital, Dublin: evaluation of clinical features, molecular epidemiology and risk factors to improve patient outcomes The CQUIN dementia screening protocol for acute hospital patients aged 75 and over: compliance and feasibility in a UK hospital The effect of epidural insertion on blood pressure and cardiotocography
Please email comments to editorsmj@rcsi.ie, join our Facebook page, or follow us on Twitter @RCSIsmj to discuss journal articles. Submissions to submissionssmj@rcsi.ie Volume 8: Number 1. 2015 | Page 3
RCSIsmjeditorial and director’s welcome On learning and leadership “The mission of RCSI's research strategy is to improve human health through translational research ... We promote innovative research that leads to improved diagnostics, therapeutics and devices; tackles important healthcare delivery issues; informs policy and clinical practice and enhances the quality of education of healthcare professionals.” RCSI Institute of Research Mission Statement – www.rcsi.ie/research The Royal College of Surgeons in Ireland has recently undergone a rebranding campaign. As part of this campaign, a brief mission statement was added to all RCSI communications. You will notice it at the bottom of the website, on all printed publications (including this one), and in the signature of every email you get from the RCSI: “Developing healthcare leaders who make a difference worldwide.” This year’s issue of the RCSIsmj is filled with the work of students who are fulfilling this mission statement, both here in Ireland and in a global context. Aislinn Killian proposes economic strategies that may benefit HSE spending, and Michael Bravo offers insights into social media’s potential as an educational tool for patients and healthcare professionals alike. Reviews by Gurtej Singh, Poornima Menon and Corey Nixon alert us to new and evolving therapies for conditions ranging from acute trauma to cancer. We also explore the work that RCSI students are doing abroad: Lisa McNamee discusses her work with asylum seekers in France, and in our new ‘Travel briefs’ section, several students reflect on time spent in Nepal, Bahrain, Cuba and Argentina. In her prizewinning ethics essay, Julia Ciurria explores medical tourism and the plight of potential organ donors in developing nations. Worldwide leadership, however, is not restricted to work done outside
Ireland; it also encompasses cognisance of globalisation and awareness of the changing needs of our patients here in Dublin. Stephan Grundy discusses the utility of HbA1c screening in patients with haemoglobinopathies, and Naomi O’Sullivan questions current anthropometric screening for cardiovascular risk and its applicability in Asian populations. Finally, in this year’s alumni spotlight, class of 2010 RCSI graduate Daniel Joyce reflects on his training in Ireland and offers his perspective on current challenges facing trainee doctors. I hope you will find this issue informative and inspirational as you continue on your educational journey. As we do our best to muddle through our day-to-day responsibilities as students, be they preparing for anatomy card signings, memorising biochemical pathways, or mastering cranial nerve exams, it can feel impossible to imagine that we have any power to make a difference. The pages of this journal are filled with evidence of our enthusiasm for learning and leading, and our capability to do so, each in our own way.
Natalie Achamallah Editor-in-Chief RCSIsmj 2013-2014
Director’s welcome It is with great pride and excitement that I welcome you to the 2015 edition of the RCSI Student Medical Journal. Every year we are overwhelmed by the quantity and quality of submissions from the student body, and this year is no exception. It is always a challenge to go through the process of selecting and editing the best articles for each edition, and we are so appreciative of the hard work and enthusiasm of our authors. Similarly, each year when it comes time to select new staff we are inundated with exceptional applicants, and it is with great effort that we carefully build our team. I am equally grateful to this year’s staff members, who have once again gone above and beyond with their dedication and discipline. I am confident that you will be inspired and impressed by the work of our peers, and hope that you find this edition both informative and enjoyable. Over the years, the RCSIsmj has continued to grow and evolve as an educational tool. In addition to the familiar print format, we have initiated an increasingly popular journal club, now in its third successful year. A sincere and heartfelt thank you is due to our superb education team members, who have gone to great lengths to organise and co-ordinate these sessions throughout the year. They have provided fantastic opportunities for students to be exposed to research, and to be Page 4 | Volume 8: Number 1. 2015
involved in the discussion and presentation of scientific works. Participants interact in an intimate setting with experts in their fields. We have been wonderfully fortunate to have the enthusiastic support of the RCSI staff in these endeavours, including that of both Professor of Surgery Arnold Hill and Professor of Medicine Noel G. McElvaney. As my involvement in the RCSIsmj comes to an end, I am excited for the next generation and confident as I hand over the reins. I have no doubt that the RCSIsmj will continue to provide a platform for student publication and opportunities to develop leadership and teamwork skills, as well as encouraging involvement and interest in medical research.
Melissa Schorr Director, RCSIsmj 2014-2015
RCSIsmjprize
Ethics Challenge 2015/2016 THE USE OF UNTESTED DRUGS IN THE TREATMENT OF THE EBOLA VIRUS The case In 2014, the World Health Organisation (WHO) endorsed the use of untested Ebola interventions on patients infected with the disease.1 A small American company, Mapp Biopharmaceutical, has been testing a vaccine called ZMapp on animals, but no one knows whether it is safe or effective in humans. Only a handful of doses are available and scaling up production to thousands of doses could take months. In a press conference, Marie-Paule Kieny, Assistant Director-General of the WHO, said: “[There has been] unanimous agreement among the experts that in the special circumstances of this Ebola outbreak it is ethical to offer unregistered treatments”. The expert panel believed2 that the extent of the outbreak and the high case fatality rate outweighed concerns about the side effects of untested treatments.
Who to treat A second question has arisen regarding the equitable distribution of a vaccine: two white American medical missionaries were given two doses of ZMapp and have improved. A Spanish victim also received
ZMapp but died. Why were they chosen instead of Africans? Apparently, it is regarded as good practice to treat ‘first responders’ first because of a social responsibility to help those who help others. “These were people who had volunteered to put themselves in harm’s way to help people who were affected by this,” bioethicist G. Kevin Donovan of Georgetown University Medical Center in Washington told USA Today.3 “It’s not unreasonable for them to have the expectation that we would try to help them”.
Questions 1. Do you think it is ethical to give patients an untested drug for the treatment of a disease like Ebola? 2. Do you think it is ethical to give an untested drug to healthcare professionals first? 3. If you agree that healthcare professionals should receive the drug first, what ethical criteria should be used to decide which healthcare professionals receive the drug?
References 1. Kupferschmidt K. Using experimental drugs and vaccines against Ebola is ethical, WHO panel says. [Internet] Available from: http://news.sciencemag.org/africa/2014/08/using-experimental-drugs-an d-vaccines-against-ebola-ethical-who-panel-says. 2. World Health Organisation. Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD). Summary of the panel discussion. [Internet] Available from:
http://www.who.int/mediacentre/news/statements/2014/ebola-ethical-rev iew-summary/en/. 3. Weintraub K. Experimental Ebola therapies raise ethical questions. [Internet] Available from: http://www.usatoday.com/story/news/nation/2014/08/07/ebola-serum-et hical-issues/13731363/.
This is the seventh instalment of the RCSIsmj Ethics Challenge. The editorial staff would like to congratulate Julia Ciurria on her winning essay in the 2014/2015 Ethics Challenge. Please see page 6 for her submission. We invite students to submit an essay discussing the ethical questions raised in the scenario presented. Medical ethics is an essential aspect of the medical curriculum and we hope to encourage RCSI students to think critically about ethical situations that arise during their education and subsequent careers. All essays will be reviewed by a faculty panel of experts and the winning essay will be published in the 2016 print edition of the RCSIsmj. The deadline for submission of entries will be the same as the general submission deadline for the 2016 edition of the RCSIsmj. Please visit our website at www.rcsismj.com for specific dates. Please contact us at editorsmj@rcsi.ie with any questions or concerns.
Submission guidelines Please construct a lucid, structured and well-presented discourse for the issues raised by this scenario. Please ensure that you have addressed all the questions highlighted and discuss these ethical issues academically, making sure to reference when necessary. Your paper should not exceed 2,000 words. Your essay will be evaluated on three major criteria: 1. Ability to identify the ethical issues raised. 2. Fluency of your arguments. 3. Academic quality with regard to depth of research, appropriateness of references and quality of sources. Good luck! The winning entry will be presented with a prize at the launch of the ninth issue.
Volume 8: Number 1. 2015 | Page 5
RCSIsmjethics challenge ETHICS CHALLENGE WINNER 2014/2015
To sell and buy a kidney
One functioning kidney to save a life! Potential donors will be morally and financially rewarded. Donors will receive
$10,000 plus medical care.
Julia Ciurria RCSI medical student
Introduction
The ethics of organ sales
This year’s RCSIsmj Ethics Challenge put forth the case of Ben, a 29-year-old husband and father of three living in the Philippines. Both he and his wife are underpaid factory workers who hope to shelter their children from the same socioeconomic fate. Being of good health and aware of the inherent dangers of surgery, Ben considers selling one of his kidneys to make his children’s education a financial reality.1 This essay first discusses the ethics of organ sales using the framework of the four pillars of bioethics – autonomy, beneficence, non-maleficence and justice2 – then proposes alternative methods for increasing the pool of available organs for transplant.
Autonomy It is the right of the competent patient to decide the direction of his or her care, bar causing harm to him or herself or others.2 Studies largely indicate that living kidney donation is safe and without increased risk of end-stage renal disease.3 Thus, proponents of organ sales argue that for the preservation of autonomy we must permit competent patients to sell their kidneys if they wish to do so,4,5 as it does not violate either of these caveats. Few take issue with the donation of organs, but the selling of organs elicits strong resistance. In both cases the body is subject to the same surgical procedure, suggesting that it
Page 6 | Volume 8: Number 1. 2015
RCSIsmjethics challenge is the actual act of selling the organ, not its removal per se, that is seen to be debasing to the body.6,7 Those opposed to organ sales insist that it is in fact damaging to the individual and to others: it is considered both an affront to human dignity and exploitative of the individual.7,8 Preserving human dignity The Kantian definition of human dignity describes people as not merely a means to an end, but an end in themselves.6 The removal of organs for profit directly contradicts this principle in two ways. Firstly, it violates the concept of the body as dignified in its wholeness. The selling of organs is an existential issue as much as it is an ethical one, calling into question our understanding of the human body’s seemingly paradoxical state of acting as a whole and as a sum of interchangeable parts.6,9 The second Kantian objection is to the commoditisation of the body,6 which treats the person as a mere means. These concerns suggest that the sale of organs is more than just a matter of binary moral terms – should or shouldn’t – but a question of the relationship of the body to the human condition. Exploitation of the organ vendor The 2008 Declaration of Istanbul explicitly condemns transplant commercialism and calls for protection of the world’s poorest members, who are vulnerable to organ trafficking.10 Yet proponents of an organ market contend that the right of the vendor to sell his or her kidney should be protected, as long as the decision is free of coercion. Because abject poverty is the historical motivator for organ sales, one may question whether someone living under these conditions is truly able to avoid coercion. Critics suggest that vendors are often poorly informed or unable to comprehend the full extent of the procedure and its long-term health implications.8 Competency is considered to be the capacity to make decisions,2 irrespective of whether those decisions are consistent with the wishes of family or physicians. Yet both the vendor and the buyer are desperate; without purchasing a kidney the patient will die, and without selling a kidney the vendor is subjected to further poverty, risking death. Can either party, simply by virtue of circumstance alone, truly be considered immune from coercion? While some argue that extremes of poverty render the patient unfit to make such choices, others reject this idea wholeheartedly,5,8 arguing that this mentality reflects unacceptable paternalism. Still, the question of coercion remains prominent in the debate. Concerning autonomy, perhaps less frequently considered is the transplant surgeon.8 Has she the right to refuse surgical intervention in the case of a paid donor? For the medical profession, to operate within a legal organ market is to morally condone the practice of organ sales. The right of the patient to receive medical intervention must be counterbalanced by the physician’s right to refuse to perform said intervention. The autonomy of the physician cannot be compromised in deference to the patient’s desires.
Beneficence The physician has an obligation to act in the patient’s best interest. An organ market would give moribund patients on waiting lists access to organs. Consider Iran, where kidney sales are legal. Remarkably, there was no waiting list for kidney transplant ten years after establishing a compensated donation system.11 However, the vendor is a patient too, and his welfare must be considered. In Iran, there is documented long-term donor dissatisfaction,12 as psychological and emotional distress, compounded by social stigmatisation, is reported.13,14 This suggests that physician beneficence requires fully considering the long-term welfare of the donor. Non-maleficence The physician is not to harm the patient, and if harm cannot be avoided, the benefits must outweigh the risks. There is risk inherent in any surgery, and kidney transplant is no different. However, we morally permit familial relatives to donate their kidneys. If we concede that the benefits of organ donation outweigh the harms in this case, this should remain true regardless of whether there is accompanying compensation to the donor.8 As such, the act of harvesting an organ for sale may not inherently violate primum non nocere. Justice Organ sale may be defended for its utilitarian value,8 that is, the greatest benefit to the greatest amount of people. Permitting organ sales would increase the pool of available organs, whereas forbidding it would strip vendors and their families of a means of economic improvement.15,16 To satisfy deontological and utilitarian justice, proponents say that fair distribution of procured organs would be required, which could be accomplished through regulation of organ sales. However, it is argued that if organ sales are legitimised as a source of income, society no longer has the moral responsibility to provide alternative socioeconomic welfare to its poorest members.8,17 Selling a kidney may become expected from the poor before other financial aid is offered to them.
The development of an ethical organ market What would an ethical organ market look like and is it realistically achievable? Consider the sale of other human tissue, such as gametes. In Ireland, there is currently no specific legislation surrounding egg donation, but the 2009 Medical Council guidelines state that donations “should be altruistic and non-commercial”.18 In fact, the majority of nations have made financing egg donation illegal.19 Those nations that allow it have adapted varying degrees of compensation ranging from reimbursement for medical costs to outright purchasing of eggs.19 According to Satz, an ethical market cannot tolerate excessive harm to the vendor or society, ignorance of the vendor as to his or her actions and/or product, or vulnerability of either the vendor or purchaser.20 The potential for harm in a legal organ market largely depends on the ability of governments to regulate Volume 8: Number 1. 2015 | Page 7
RCSIsmjethics challenge it. In spite of the Declaration of Istanbul, organ sales occur, and refusal to legalise this practice leaves it unregulated. It is argued that the creation of an organ market would allow for both legal and medical safeguards to be put in place.21 A legitimate organ market could assuage fears of vendors having no legal remit if denied their pay, and no access to proper medical care both preand postoperatively; both scenarios are harsh realities of the current ‘black market’ state of organ sales. A legalised organ market would also allow for a waiting period for would-be vendors to reconsider their choice to sell and to re-evaluate their circumstances.21 To accomplish this, a monopsony has been proposed; that is, a single legitimate purchasing body would exist to set prices for organs, ensure equitable distribution of organs, and monitor adequate healthcare for both donor and recipient.21,22 In the case of the United Kingdom, the National Health Service has been recommended to act as the purchasing body.22 Theoretically, this would prevent vendors from receiving inadequate financial compensation, bar the wealthy from monopolising organ purchases, and allow for better patient prognosis by improving cross-matching, screening for infectious diseases, and ensuring legitimate operating facilities.21,22 Furthermore, the market would be confined to a specific geopolitical region, such as the European Union, to prevent the exploitative use of developing nations as organ reservoirs.21,22 However, even if such a market existed and could prevent extortion from the world’s poorest, it would not protect the catchment’s poorest.8 For example, in Iran the majority of vendors are the uneducated poor.23 Common sense suggests that financial incentive would attract vendors from the lowest socioeconomic class and purchasers from the highest. The exploitation would simply be shifted from the poorest of the world to the poorest of that particular circumscribed market.7
Increasing the organ pool Presumed consent Evidence suggests that European countries with presumed consent (PC) carry out up to 31% more kidney transplants than countries that employ an opt-in donation system, owing to increased cadaveric donations from those who have not documented their preference.24 Moreover, PC would increase the number of young donors with organs more suitable for transplant. Younger patients are less likely to address their donor preference; many of these individuals would choose to donate their organs posthumously but fail to make their wishes clearly known and legally documented. An opt-in system denies these patients the opportunity to do so.24 While PC is generally associated with increased donation in European countries, there is wide variation outside of this region.25 A country’s wealth and predominant religio-cultural mores influence donor attitudes. For nations such as those in Latin America, authorising PC actually decreases organ donations.26 Great Britain has rejected PC legislation outright on the grounds of “potential to undermine the concept of donation Page 8 | Volume 8: Number 1. 2015
as a gift, to erode trust in [health] professionals and the government”.27 An alternative to PC, mandated choice, requires an individual to declare their donor status.28 It is speculated that this policy would increase the donor pool simply because when forced to choose a donor status, some people would choose to become donors who would not have considered doing so otherwise.28 The question remains whether this increase in the donor pool would be sufficient to relieve the organ deficit. Encouraging posthumous donation A controversial suggestion is to increase available organs by relaxing restrictions on posthumous donors, specifically those who are older or diabetic.28,29 Others believe that there should be greater encouragement from governments, hospitals and advocacy groups for both living and posthumous donation.10 However, it can be argued that using moral incentive to increase pressure on people to become organ donors is perhaps no less ethically suspect than providing monetary incentive. Moreover, fostering favourable attitudes towards organ donation does not necessarily translate into higher posthumous donation rates in practice.30 To increase the likelihood of posthumous donation, people should be “supported to make a confident and informed decision”.30 This involves facilitating dialogue with both family and physician.30 Improving renal care It is possible that the answer to organ shortages does not lie in increasing the organ pool. Focus on “advancement of clinical and basic science research”,10 including improvements in donor kidney preservation, timelier cross-matching, new immunotherapy techniques to prevent rejection, improved dialysis and increased access to treatment, would decrease the number of both failed transplants and failing kidneys. Reorienting health services to practice preventive medicine, such as obesity and hypertension reduction, would decrease the organ deficit by decreasing organ failure.8,31 Many view strengthening research in organ cloning and molecular therapies that prevent kidney tissue damage8 as far more ethically permissible than developing organ markets.
Concluding remarks Revisiting the specific case of Ben, like so many others the motivation to sell his kidney is to alleviate his family’s circumstance of poverty. It is misguided at best to believe that a one-time financial compensation for his kidney will translate into lasting improvements for him and his family’s well-being. The root causes of poverty are manifold and complex; an organ market would not change the socioeconomic background that forced Ben into his current circumstance. It would seem that developing a legal organ market would only serve to benefit those desiring an organ, not the many desperate enough to elect to put a price tag on their organs. However, the particularities of each nation must be taken into account when making this decision.
RCSIsmjethics challenge The complexities surrounding organ sales and the development of an organ market are compounded by the fact that it is illegally occurring in the background of this ethical debate. Many who advocate for organ sales do so simply because of the current reality of grossly under-resourced transplant services and organ trafficking. Changing legislation surrounding posthumous organ
donation has had variable success internationally, leading many to embrace medical advancement in renal care and transplant quality as a means to relieve the organ deficit. That being said, a review of the statistics of international transplant waiting lists warrants decision-making bodies to immediately tackle this issue with new fervour.
References 1. RCSIsmj Editors. Ethics Challenge 2014/2015. Royal College of Surgeons Student Medical Journal 2014;7(1):5. 2. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. Oxford University Press, 2009. 3. Ibrahim HN, Foley R, Tan L et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360(5):459-69. 4. Friedman EA, Friedman AL. Payment for donor kidneys: pros and cons. Kidney Int. 2006;69(6):960-2. 5. Cherry MJ. Why should we compensate organ donors when we can continue to take organs for free? A response to some of my critics. J Med Philos. 2009;34(6):649-73. 6. Jecker NS. Selling ourselves: the ethics of paid living kidney donation. Am J Bioeth. 2014;14(10):1-6. 7. Marino IR, Cirillo C, Cattoi A. Ethical market in organs. Market of organs is unethical under any circumstances. BMJ. 2002;325(7368):835. 8. Hippen B, Ross LF, Sade RM. Saving lives is more important than abstract moral concerns: financial incentives should be used to increase organ donation. Ann Thorac Surg. 2009;88(4):1053-61. 9. Zwart H. The donor organ as an ‘object a’: a Lacanian perspective on organ donation and transplantation medicine. Med Health Care Philos. 2014;17(4):559-71. 10. Steering Committee of the Istanbul Summit. Organ trafficking and transplant tourism and commercialism: the Declaration of Istanbul. Lancet 2008;372(9632):5-6. 11. Ghods AJ. Ethical issues and living unrelated donor kidney transplantation. Iran J Kidney Dis. 2009;3(4):183-91. 12. Ghods AJ, Savaj S. Iranian model of paid and regulated living-unrelated kidney donation. Clin J Am Soc Nephrol. 2006;1(6):1136-45. 13. Zargooshi J. Quality of life of Iranian kidney “donors”. J Urol. 2001;166(5):1790-9. 14. Koplin J. Assessing the likely harms to kidney vendors in regulated organ markets. Am J Bioeth. 2014;14(10):7-18. 15. Radcliffe-Richards J, Daar AS, Guttmann RD et al. The case for allowing kidney sales. International Forum for Transplant Ethics. Lancet 1998;351(9120):1950-2. 16. Matas AJ. The case for living kidney sales: rationale, objections and concerns. Am J Transplant. 2004;4(12):2007-17. 17. Rivera-Lopez E. Organ sales and moral distress. J Appl Philos. 2006;23(1):41-52.
18. Busardò FP, Gulino M, Napoletano S et al. The evolution of legislation in the field of medically assisted reproduction and embryo stem cell research in European Union members. BioMed Res Int. 2014;2014:307160. doi: 10.1155/2014/307160. Epub 2014 Jul 24. 19. Kenney NJ, McGowan ML. Egg donation compensation: ethical and legal challenges. Medicolegal and Bioethics. 2014;4:15-24. 20. Satz D. Why Some Things Should Not Be for Sale: The Moral Limits of Markets. Oxford University Press; USA, 2010. 21. Harris J, Erin C. An ethically defensible market in organs. BMJ. 2002;325(7356):114-5. 22. Erin CA, Harris J. An ethical market in human organs. J Med Ethics. 2003;29(3):137-8. 23. Hippen BE. Organ sales and moral travails: lessons from the living kidney vendor program in Iran. CATO Policy Analysis Series 2008(614). 24. Ugur ZB. Does presumed consent save lives? Evidence from Europe. Health Econ. 2014 Oct 2. doi: 10.1002/hec.3111. [Epub ahead of print] 25. Rithalia A, McDaid C, Suekarran S et al. Impact of presumed consent for organ donation on donation rates: a systematic review. BMJ. 2009;14;338:a3162. doi: 10.1136/bmj.a3162. 26. Dominguez J, Rojas JL. Presumed consent legislation failed to improve organ donation in Chile. Transplant Proc. 2013;45(4):1316-7. 27. NHS. The potential impact of an opt out system for organ donation in the UK. An independent report from the Organ Donation Taskforce. 2008. Available from: http://www.odt.nhs.uk/pdf/the-potential-impact-of-an-opt-out -system-for-organ-donation-in-the-UK.pdf. 28. Saunders J. Bodies, organs and saving lives: the alternatives. Clin Med. 2010;10(1):26-9. 29. Baskin-Bey ES, Kremers W, Stegall MD et al. United Network for Organ Sharing’s expanded criteria donors: is stratification useful? Clin Transplant. 2005;19(3):406-12. 30. Rockloff M, Hanley C. The default option: why a system of presumed consent may be effective at increasing rates of organ donation. Psychol Health Med 2014;19(5):580-5. 31. Jafar TH. Organ trafficking: global solutions for a global problem. Am J Kidney Dis. 2009;54(6):1145-57.
Volume 8: Number 1. 2015 | Page 9
RCSIsmjoriginal article
Demographic and symptomatic predictors of incomplete bolus transit in patients with ineffective oesophageal motility Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:10-13.
Abstract
Sarah Pradhan1 Michelle Buresi2 Milli Gupta2 Michael Curley2 Lynn Wilsack2 Christopher N. Andrews2 1RCSI medical student 2Cumming School of Medicine,
University of Calgary, Canada
Page 10 | Volume 8: Number 1. 2015
Introduction: Ineffective oesophageal motility (IOM) describes a non-specific manometric pattern of peristaltic failure.1 It is a common abnormality, affecting as many as 61% of patients undergoing manometry for query oesophageal motility disorders.2 IOM is also known as hypotensive (<30mmHg) oesophageal contractions;3 bolus clearance is impaired by low amplitude and ineffective pressure waves. Oesophageal contractions with â&#x2030;Ľ30mmHg amplitudes are required to effectively propel food.4 IOM is defined as ineffective or non-transmitted, failed contractions (<30mmHg) occurring in at least 20% of swallows. Methods: A retrospective chart review of patients referred to a regional gut motility centre in Canada who were then diagnosed with IOM was performed. Multiple linear regression analysis was used to determine demographic predictors of incomplete bolus clearance, including gender, age and primary complaint. Results: A total of 230 patients (130 females, 100 males; mean age, 51.7 years; range, 18-82.3 years) with a diagnosis of IOM were included. Primary presenting complaints included dysphagia (33.9%), and heartburn and reflux (33%). Decreasing proportions of peristaltic contractions correlated significantly with decreased bolus transit. Conversely, higher intrabolus pressure correlated significantly with incomplete bolus transit. Intrabolus pressure serves as an indicator of outflow obstruction, and forces resisting peristalsis and incomplete bolus transport.5 Gender was not significant but increasing age was associated with less incomplete bolus transit. Conclusion: Dysphagia was the most common symptom reported by patients with IOM, followed by heartburn and reflux. Other demographic factors should be evaluated for their effect on bolus transit.
RCSIsmjoriginal article
FIGURE 1: Normal manometric swallow (left) vs. ineffective swallow (right).
Introduction Ineffective oesophageal motility (IOM) describes a non-specific manometric pattern of peristaltic failure.1 It is a common abnormality, affecting as many as 61% of patients undergoing manometry for query oesophageal motility disorders.2 IOM is also known as hypotensive oesophageal contractions;6 pressure waves are of low amplitude and ineffective, thus impairing bolus clearance. IOM has been defined as ineffective or non-transmitted, failed contractions occurring in at least 20% of swallows but not fitting diagnostic criteria for any other oesophageal motility disorder.7 Commonly reported symptoms include non-cardiac chest pain, dysphagia, heartburn, acid reflux7 and cough.1 Unfortunately, there is very limited information regarding the cause and natural history of this disorder, except that it “reduces the effectiveness of bolus transit through the oesophagus”.8 Pressure waves in the distal oesophagus in IOM, even if peristaltic, are low amplitude and ineffective (<30mmHg), thus impairing bolus clearance.1 In a 2006 study by Cho et al.,9 factors found to most significantly affect bolus transit included amplitude of the oesophageal pressure waves and normal peristalsis. Dysphagia is the most frequent symptom occurring in patients with incomplete bolus transit.4 In healthy volunteers, nearly all manometrically normal contractions lead to complete bolus transit. However, information regarding bolus transit in IOM patients is mixed. A small 2011 study showed that all IOM patients included in the study had incomplete bolus transit.10 Other studies have found that IOM in which ≥50% of swallows are ineffective is more frequently associated with abnormalities in bolus transit.11 In 2004, Tutuian et al. found that almost one-third of IOM patients included in the study showed normal bolus transit.12 Thus, a diagnosis of IOM does not necessarily predict complete or incomplete bolus transit. IOM likely has a number of aetiologies. In patients with gastro-oesophageal reflux disease (GORD), 20-50% present with IOM, making it the most prevalent oesophageal motor disorder associated with GORD.7 A hypotensive lower oesophageal sphincter (LOS) is frequently observed in patients with GORD, and is also associated with IOM.13 Increased acid reflux and subsequent chronic acid exposure in GORD may weaken musculature in the distal oesophagus, resulting in hypocontractility.7 IOM has also been associated with reflux oesophagitis.13 In animal models with acid-induced oesophagitis, inflammatory mediators have been found to impair acetylcholine release and directly inhibit smooth muscle contraction, reducing the force of contraction and impairing peristalsis.3 IOM has been responsive to prokinetic drugs such as metoclopramide, which supports impaired cholinergic stimulation as the
main defect.1 After taking edrophonium, an acetylcholinesterase inhibitor, approximately half of patients suffering from severe IOM reverted to mild IOM or normal peristalsis.1 This further suggests that cholinergic stimulation can improve oesophageal motility in those with preserved neuromuscular structure.1 However, there is currently no proven treatment for hypotensive oesophageal contractions and no drug can dependably increase the magnitude of peristaltic contraction in the oesophagus.7 Non GORD-related IOM has been associated with increased oesophageal muscle thickness when compared to controls and GORD-related IOM.14 Dysphagia was a more common symptom in patients with thicker oesophageal musculature;14 the increased wall thickness results in obstruction. Other proposed secondary causes of IOM include infiltrative disease such as amyloidosis, connective tissue diseases such as scleroderma, and the use of medication with anticholinergic effects.3 Diagnosis is made by oesophageal manometry, which measures intraluminal pressure changes within the oesophagus during swallows. The manometry procedure consists of inserting a high-resolution catheter via the naris following topical xylocaine anaesthesia administration. The upper and lower oesophageal sphincter pressures (UOS and LOS) and oesophageal motor function are assessed in response to at least ten 5mL saline swallows. Impedance rings on the catheter measure intraluminal bolus transit in conjunction with the manometrically detected oesophageal contractions via pressure changes. Incomplete bolus transit is diagnosed if “bolus exit is not identified at any one of the three distal impedance measuring sites – 15, 10 and 5cm above the lower oesophageal sphincter” in each swallow.15 The aim of this preliminary, hypothesis-generating study is to evaluate predictors of incomplete bolus transit in patients diagnosed with IOM.
Methods A retrospective exploratory chart review was undertaken with the approval of the University of Calgary Conjoint Health Research Ethics Board. All patients referred to a regional gut motility centre for evaluation of symptoms potentially due to oesophageal motility disorders were included. All subjects were clinically assessed by a gastroenterologist, who obtained a detailed history including the patient’s primary complaints, other pertinent symptoms and demographic information. Based on differential diagnoses, patients were referred to undergo manometry and pH impedance procedures were performed in query of a possible oesophageal motility disorder. Informed consent was obtained from all patients included in the study for chart review, health record review and/or future contact. Volume 8: Number 1. 2015 | Page 11
RCSIsmjoriginal article Confidentiality was ensured and maintained throughout the study. After completion of the manometry and impedance procedures, numerical data was converted into Clouse plots, visual graphs that â&#x20AC;&#x153;illustrate the physiology of contractile co-ordination and the mechanics associated with bolus transitâ&#x20AC;? (Figure 1).16 These were viewed in ManoView 3.0 and analysed by an attending gastroenterologist, who confirmed each patientâ&#x20AC;&#x2122;s diagnosis and generated a manometry report including test findings and a discussion of primary presenting complaint. All patients who were diagnosed with IOM were included in the study, regardless of comorbid conditions, and there were no exclusion criteria. These reports were retrieved from a manometry database and the information was used to compile an oesophageal motility database. Data was analysed using IBM SPSS Statistics Version 21 with multiple linear regression analysis to determine predictors of incomplete bolus clearance, including gender and age, as well as primary complaints. To examine which manometric variables best predicted the percentage of swallows with incomplete bolus transit for any given patient, a multiple linear regression was performed using selected variables, and adjusted for age, gender and presenting primary symptom. All tests were two-sided and significance was set at the 95% level.
Results A total of 230 patients (130 females, 100 males; mean age, 51.7 years; range, 18-82.3 years) with a diagnosis of IOM were included in the study. Primary presenting complaints included dysphagia (33.9%), heartburn and reflux (33%), chest pain (11.7%), other (10.9%) such as globus sensation (feeling of having a mass, or fullness in the throat, when none is present), and vomiting and cough (8.7%). There were four patients (1.7%) whose symptom information was missing. Many patients had more than one symptom; however, there were no significant differences in baseline characteristics across primary symptom groups (data not shown). Decreasing proportions of peristaltic contractions correlated significantly with decreased bolus transit, meaning a higher percentage of incomplete bolus transit. The multiple regression model fit was highly significant (F=10.14, 9 df, p<0.001) with an adjusted r square of 0.373. Similarly, higher intrabolus pressure correlated significantly with higher percentages of incomplete bolus transit. Gender was not significant but increasing age was associated with less incomplete bolus transit. The mean percentage of swallows exhibiting incomplete bolus transit was 60.009%. The remainder of the manometric variables, seen in Tables 1 and 2, were not significantly associated with incomplete bolus transit.
Table 1: Manometric findings.
Age (years) LOS basal mean pressure (mmHg) LOS mean residual pressure (mmHg) LOS relaxation (%) Peristaltic oesophageal motility (%) Simultaneous oesophageal motility (%) Failed oesophageal motility (%) Oesophageal mean wave amplitude (mmHg) Oesophageal mean wave duration (s) Incomplete bolus clearance (%) Incomplete bolus transit time (s) Mean distal contractile integral (mmHg) Intrabolus pressure at LOS relaxation (mmHg)
Mean
Std. error of the mean
N value
51.682 27.097 4.767 86.613 44.496 8.291 47.257 55.63 3.56 60.009 5.52 771.14 -1.30
0.9674 1.1422 0.3371 2.5249 1.6817 0.9916 1.8241 1.730 0.053 2.0944 0.276 52.775 0.344
230 230 230 230 230 230 230 219 219 227 60 168 140
Table 2: Statistical error reporting for manometric findings. Variable
(Constant) Female Age (years) LOS basal mean pressure (mmHg) LOS mean residual pressure (mmHg) Peristaltic oesophageal motility (%) Oesophageal mean wave amplitude (mmHg) Oesophageal mean wave duration (s) Mean distal contractile integral (mmHg) Intrabolus pressure at LOS relaxation (mmHg)
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Unstandardised co-efficients
Standardised co-efficients
95.0% confidence interval for B
B
Std. error
Beta
Sig. W
Lower bound
Upper bound
129.232 -6.511 -0.430 -0.225 -1.069 -0.634 -0.173 0.128 0.004 1.832
16.680 4.400 0.154 0.156 0.656 0.092 0.187 3.333 0.008 0.783
-0.102 -0.211 -0.135 -0.177 -0.524 -0.146 0.003 0.100 0.237
0.141 0.006 0.151 0.106 0.000 0.355 0.969 0.572 0.021
96.230 -15.216 -0.734 -0.533 -2.367 -0.815 -0.542 -6.466 -0.011 0.283
162.234 2.193 -0.126 0.083 0.229 -0.453 0.196 6.722 0.019 3.380
RCSIsmj original article Discussion Based on the apparent variability in the status of bolus transit in IOM, it is beneficial to determine both demographic and symptomatic determinants of incomplete bolus clearance in this subset of patients. Symptomatic findings of this study are consistent with previous literature. Although a significant correlation was found between decreasing proportions of peristaltic contractions and decreased bolus transit, stronger relationships between predictors of incomplete bolus transit in IOM patients may be found with a larger sample size. Although IOM is a relatively under-researched area with little information available regarding cause and implications, this study sets a foundation for further research. The commonest symptomatic complaints as expressed by patients with IOM can now be applied in a clinical setting as a tool to determine whether patients who are diagnosed with other oesophageal disorders may in fact have co-existing disorders such as IOM. The value of manometry as a diagnostic tool has also been highlighted in this study; it provides information about pressure changes and functionality of the oesophagus without the use of radiation. It should be performed in patients complaining of dysphagia or reflux of query oesophageal pathology. Oesophageal disorders such as GORD, which tend to coincide with IOM, are high prevalence, which certainly warrants further exploration. The
proposed aetiologies of IOM have also influenced drug research, which has shown promising results towards resolution of this disorder. The findings of this preliminary study propose a basis for investigation of other demographic factors that should be evaluated for their effect on bolus transit, such as the presence of connective tissue disorders like scleroderma, or the effect of certain medications that may affect motility, both of which are known to affect gut motility in nonspecific ways.3,7
Conclusion IOM describes a pattern of vague, non-specific oesophageal dysfunction that does not fit diagnostic criteria for any other oesophageal motility disorder. In this study, peristalsis predicted effective bolus transit, and the patient-reported symptoms of incomplete bolus transit were consistent with previous literature. Prior literature reports many likely aetiologies of IOM, along with discrepancies regarding whether IOM predicts complete or incomplete bolus transit. Overall, our findings show promise, and contribute to knowledge regarding this disorder. These findings not only provide insight into demographic factors surrounding IOM, but also emphasise the need for increased use of manometry in a clinical setting. They reveal a need for further research into IOM in order to help relieve patients of symptoms and improve their daily lives.
References 1. Sifrim D, Fornari F. Non-achalasic motor disorders of the oesophagus. Best Pract Res Clin Gastroenterol. 2007;21(4):575-93. 2. Leite LP, Johnston BT, Barrett J, Castell JA, Castell DO. Ineffective esophageal motility (IEM): the primary finding in patients with
10. Burgess NG, Wyeth JW. An audit of combined multichannel intraluminal impedance manometry in the assessment of dysphagia. J Gastroenterol Hepatol. 2011;26(Suppl. 3):79-82. 11. Blonski W, Vela M, Safder A, Hila A, Castell DO. Revised criterion for
nonspecific esophageal motility disorder. Dig Dis Sci.
diagnosis of ineffective esophageal motility is associated with more
1997;42(9):1859-65.
frequent dysphagia and greater bolus transit abnormalities. Am J
3. Patterson WG, Raj MD, Goyal RK, Habib FI. Esophageal motility disorders. GI Motility Online. 2006; Part 1. doi:10.1038/gimo20. 4. Tutuian R, Castell DO. Combined multichannel intraluminal impedance
Gastroenterol. 2008;103(3):699-704. 12. Tutuian R, Castell DO. Clarification of the esophageal function defect in patients with manometric ineffective esophageal motility: studies
and manometry clarifies esophageal function abnormalities: study in 350
using impedance-manometry. Clin Gastroenterol Hepatol.
patients. Am J Gastroenterol. 2004;99(6):1011-9.
2004;2(3):230-6.
5. Ren J, Massey BT, Dodds WJ, Kern MK, Brasseur JG, Shaker R et al. Determinants of intrabolus pressure during oesophageal peristaltic bolus transport. Am J Physiol. 1993;264(3 Pt 1):G407-13. 6. Bulsiewicz WJ, Kahrilas PJ, Kwiatek MA, Ghosh SK, Meek A, Pandolfino JE.
13. Fornari F, Callegari-Jacques SM, Scussel PJ, Madalosso LF, Barros EF, Barros SG. Is ineffective oesophageal motility associated with reflux oesophagitis? Eur J Gastroenterol Hepatol. 2007;19(9):783-7. 14. Kim JH, Rhee PL, Son HJ, Song KJ, Kim JJ, Rhee JC. Is all ineffective
Esophageal pressure topography criteria indicative of incomplete bolus
esophageal motility the same? A clinical and high-frequency
clearance: a study using high-resolution impedance manometry. Am J
intraluminal US study. Gastrointest Endosc. 2008;68(3):422-31.
Gastroenterol. 2009;104(11)2721-8.
15. Tutuian R, Castell DO. Esophageal multichannel intraluminal
7. Richter JE. Oesophageal motility disorders. Lancet. 2001; 358:823-8.
impedance testing. UptoDate. Available from:
8. Conklin J, Pimentel M, Soffer E. Color Atlas of High Resolution Manometry.
http://www.uptodate.com/contents/esophageal-multichannel-intralu
New York; Springer Science+Business Media, 2009. 9. Cho YK, Choi MG, Park JM, Oh JH, Paik CN, Lee JW et al. Evaluation of esophageal function in patients with esophageal motor abnormalities
minal-impedance-testing?source=search_result&search=Esophageal+m ultichannel+intraluminal+impedance+testing.&selectedTitle=1~7. 16. Pandolfino J, Roman S. High resolution manometry: an atlas of
using multichannel intraluminal impedance esophageal manometry.
esophageal motility disorders and findings of GERD using esophageal
World J Gastroenterol. 2006;12(39):6349-54.
pressure topography. Thorac Surg Clin. 2011;21(4):465-75.
Volume 8: Number 1. 2015 | Page 13
RCSIsmjoriginal article Prevalence and risk factors for modified prescriptions in an Irish community pharmacy
Abstract
Samuel Obasi1 Alan Tinsley2 Frank Doyle3 1RCSI School of Pharmacy 2McCabeâ&#x20AC;&#x2122;s Pharmacy 3Division of Population Health
Sciences (Psychology), RCSI
Background: Despite a dearth of knowledge on the causes of prescribing errors in medical practice, and the rates of prescribing errors among certain patient groups, little Irish research exists to address this issue. One possible reason for this is that the analysis of prescription modification is not part of the recognised job description of a pharmacist. Aims: To investigate the prevalence, nature and risk factors for prescription modifications in an Irish community pharmacy. Methods: A cross-sectional study was performed to examine prescriptions dispensed in an Irish community pharmacy over a period of five weeks. Results: In total, 866 prescriptions were examined. The overall prevalence of prescribing errors and prescription modifications was 17.9% (155), with a mean of 31 modifications per week. Prescription only medicines (POM) comprised 94.8% (147) of the modifications, of which 87% (128/147) were prescription errors requiring a simple clerical clarification before dispensing could occur. The remaining 13% (19; average of 3.8 per week) were prescribing faults with potential clinical consequences if left unaltered. Half (51%) of all POM modifications occurred through consultation with the patient or their representative. The following factors were associated with increased risk of POM modifications: being a female patient (OR=1.605, 95% CI 1.104-2.333, p=0.013); and, being prescribed drugs in the following therapeutic areas â&#x20AC;&#x201C; musculoskeletal (OR=1.906, 95% CI 1.023-3.551, p=0.042), and genitourinary system and sex hormones (OR=3.691, 95% CI 2.255-6.042, p<0.001). Subsequent multivariate analysis confirmed these as significant independent risk factors for POM modifications. Conclusions: The majority of prescribing errors modified involved non-serious clerical errors. However, an average of 3.8 POM prescriptions with potential clinical consequences were modified weekly. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:14-18.
Page 14 | Volume 8: Number 1. 2015
RCSIsmjoriginal article Introduction
Methods
Medicines should be prescribed only when they are necessary, and in all cases the benefit of administering the medicine should be considered in relation to the risk involved; these guidelines are stated in the British National Formulary, as well as being common sense to practitioners.1 Even so, large-scale studies in the US2 and the UK3 by the Institute of Medicine (IOM) and the UK General Medical Council (GMC), respectively, have shown that medication errors, the most common of which are prescribing errors,4 are common in practice. Jeffrey Aronson, a clinical pharmacologist based in Oxford University, devised a method for classifying incorrect prescriptions as either faults or errors based on psychological theory. Aronson’s definitions aim to explain errors rather than merely describing them.5 Prescribing faults concern the decision-making process in writing a prescription (e.g., dose too high or low, or drug allergy or contraindication), while prescription errors concern the act of writing the prescription (e.g., absence of drug strength or number of tablets).5 Prescription modifications, on the other hand, are interventions that prevent error occurrence and can be made through contact with the doctor about a query, checking the patient’s medication history, or interviewing the patient or their representative.6 They are required when there is a reduction in the probability of treatment being timely and effective, or an increase in the risk of harm to the patient when compared to generally accepted practice.7 The 2012 PRACtICe study carried out by the GMC found that one in 20 prescriptions contained a prescribing or monitoring error, affecting one in eight patients, with severe errors (a score greater than 7 on a scale numbered from zero to 10) found in one in 550 prescription items.3 Another UK study, the 2009 EQUIP study, looked at the causes of prescribing errors by foundation trainee doctors, and reported a mean of 8.9 errors per 100 medication orders.8 These proportions may be even higher in Ireland. In 2013, more than 20 million prescriptions were filled in Ireland for over 60 million medical items, including medicines and medical devices.9 In 2009, Sayers et al. found that 12.4% (491) of the prescriptions written by 28 general practitioners in Galway and Donegal contained one or more prescribing errors.10 Much of the Irish research available has concentrated on the incidence or prevalence of prescribing errors. Several of these have focused on errors more common in specific patient groups (e.g., patients over 65 years) or in certain therapeutic classes of drugs.11,12,13,14 There is, however, a gap in the literature with regard to studies that simultaneously take into account patient-, drug- and prescriber-related factors that contribute to prescription modifications as a result of prescribing errors. Large-scale studies have been conducted in the US, the Netherlands and the UK to assess community pharmacy interventions intended to reduce prescribing errors, but data in this field is lacking thus far in Ireland.6,15,16 Such research will provide a fuller picture of the risk factors for prescribing errors and prescription modifications in an Irish context, which may lead to new strategies aimed at reduction.
Study design A cross-sectional study was performed to examine prescriptions dispensed in a community pharmacy in Leinster over a period of five weeks in winter 2012. All prescriptions were included and each was checked for prescribing errors by the supervising pharmacist. This included medications, as well as other healthcare products such as diabetes test strips, bandages, and needles. Inclusion criteria were based on the need for prescription modification.7 The following were excluded from modification because of their lack of potential impact on patient care: address incorrect or absent; medical scheme data incorrect or absent; incorrect package size; product not in stock; unit of dosage or package specified incorrectly (e.g., mL instead of g); generic substitution; or, legal prescription requirements (e.g., for controlled drugs). Where there were two or more reasons given for a modification, the most relevant reason was selected based on the highest risk of harm to the patient. Classification of prescription items Prescribed items were classified according to guidelines set out in the Irish Medicinal Products Regulations, as prescription only medicines (POM), over-the -ounter medicines (OTC) or non-medicines. All medicines were classified into therapeutic groups using the Anatomical Therapeutic Chemical (ATC) classification given by the WHO Collaborating Centre for Drug Statistics Methodology.17 During the data management process, prescribing errors were divided into two groups as per Aronson: prescription errors and prescribing faults.5 Data collection and analysis Data collected from eligible prescriptions included: the date the prescription in question was dispensed by the pharmacy; the therapeutic group of the prescribed drug; the age and gender of the patient; a description of the nature of the prescription (printed or handwritten, POM, OTC medicine or non-medicine); a description of the prescriber (the patient’s own GP or another physician); and, a description of the modification type, if any was made. Descriptive statistics were used to determine the prevalence of POM modifications, and logistic regression was used to estimate the association between prescription characteristics and modification. Multivariate logistic analysis was then performed combining the significant univariate predictors, to determine their independence or otherwise.
Results Descriptive statistics Over the five-week study period, 1,303 prescriptions were collected by the pharmacy and 66% (866) were analysed. Those excluded were collected on the days the supervising pharmacist was absent. Of the 866 prescriptions included, 17.8% (155) were modified, 94.8% (147) of which were due to Volume 8: Number 1. 2015 | Page 15
RCSIsmjoriginal article Table 1: Analysis of prescriptions. All prescriptions (n=866)
Modified prescriptions n (%) (n=155)
Non-modified prescriptions n (%) (n=711)
Prescription only medicine (POM)
796 (92%)
147 (94.8%)
649 (91.2%)
Over-the-counter medicine (OTC)
42 (4.8%)
6 (3.9%)
36 (5.1%)
Non-medicine
28 (3.2%)
2 (1.3%)
26 (3.7%)
Age, mean (SD)
43.01 (21.9)
40.15 (22.82)
43.64 (21.71)
Female
490 (56.6%)
99 (63.9%)
391 (55%)
Handwritten prescriptions
263 (30.4%)
55 (35.5%)
208 (29.2%)
Own doctor/prescriber
725 (83.7%)
133 (85.8%)
592 (83.3%)
Drug-related factors
Patient-related factors
Prescriber-related factors
ATC class nervous system
37
ATC class anti-infectives for systemic use
32
ATC class genitourinary system and sex hormones
24
ATC class respiratory system
17
ATC class dermatologicals
14
Other ATC classes
13
ATC class musculoskeletal system
10 0
5
10
15
20
25
30
35
40
POM prescription
FIGURE 1: Therapeutic classes where POM modifications occurred with greater frequency. POMs. The mean age of patients whose prescriptions required modification was 40.15 years and the majority were women (63.9%). Printed prescriptions accounted for 64.5% (100), while prescriptions written by the patient’s own doctor or prescriber accounted for 85.8% (133) (Table 1). Nature of prescription modifications The numbers of modified OTC (3.9%) and non-medicine prescriptions (1.3%) were too small for statistical analysis; as such, only POM modifications were considered further. POM modifications occurred with greater frequency in the following therapeutic classes: nervous system (ATC code N); anti-infectives for systemic use (ATC code J); genitourinary system and sex hormones (ATC code G); respiratory system (ATC code R); dermatologicals (ATC code D); and, musculoskeletal system (ATC code M) (Figure 1). The majority (87%; 128) of the POM Page 16 | Volume 8: Number 1. 2015
modifications concerned a prescription error where clarification of an insufficiently written prescription was needed (e.g., omitted drug dose), while the other 13% (19) were prescribing faults (e.g., dose too high). POM modifications after consultation with a patient or proxy, where the pharmacist identified a need for clarity, accounted for the greatest number of interventions. In 51% (75) of cases, the pharmacy consulted the patient or their proxy, either to clarify the doctor’s intentions or to establish their knowledge or need for additional medicines information. In 30% of cases (44), modifications of POM prescriptions were made after consultation with the prescriber or the prescriber’s assistant. These included instances where a drug was either out of stock or unavailable in Ireland, or where the strength or dose of a medicine was omitted. The remaining 19% (28) were made based on the patient’s medical history (e.g., where a contraindication/allergy was present).
RCSIsmjoriginal article Table 2: Univariate and multivariate risk factors for prescription modification. Multivariate
Univariate Modified POM prescriptions (n=147, 100%)
Odds ratio (OR)
95% I (df)
p value
ATC-code N
37 (25.2%)
1.098
0.762-1.578
0.619
ATC-code J
32 (21.8%)
1.033
0.701-1.523
0.870
ATC-code G
24 (16.3%)
3.691
2.255-6.042
<0.001
ATC-code R
17 (11.6%)
1.463
0.932-2.298
0.098
ATC-code D
14 (9.5%)
1.169
0.646-2.116
0.606
ATC-code M
10 (6.8%)
1.906
1.023-3.551
0.042
Age, mean (SD) (n=139)
39.6 (22.4)
0.993
0.985-1.001
0.081
Female
99 (67.3%)
1.605
1.104-2.333
0.013
Handwritten
50 (34.0%)
1.247
0.855-1.818
0.253
Own doctor/prescriber
125 (85.1%)
1.142
0.697-1.872
0.598
Modified POM prescriptions (n=147, 100%)
Odds ratio (OR)
95% I (df)
p value
24 (16.3%)
3.531
2.095-5.952
<0.001
10 (6.8%)
2.408
1.248-4.645
0.009
99 (67.3%)
1.595
1.073-2.372
0.021
Drug related factors
Patient-related factors
Prescriber-related factors
Univariate and multivariate risk factors for prescription modification Univariate analysis identified two therapeutic drug classes that exhibited significantly higher rates of POM modifications: the genito-urinary system and sex hormones therapeutic drug class (ATC code G), where modifications were almost three times more likely than in other therapeutic classes (OR=3.691, 95% CI [2.255-6.042], p<0.001), and the musculoskeletal system therapeutic class (ATC code M) (OR=1.906, 95% CI [1.023-3.551], p=0.042) (Table 2). Gender was also found to be a significant risk factor for POM modifications, with female patients significantly more likely to have their prescriptions modified (OR=1.605, 95% CI [1.104-2.333], p=0.013) than male patients. Multivariate analysis showed that these remained strong independent risk factors for POM modifications. Prescriber-related factors such as handwritten or typed prescriptions and the source of the prescription (patient’s own doctor/other prescriber) were not significant. This result was unusual but not unexpected, as low numbers of patients (16.2%; 141 of 866) in this study utilised a doctor or prescriber other than their own. Patient’s age was also not significant.
Discussion In this study, the overall prevalence of prescription modifications was 17.9%. As a measure of modification rate this is very high, especially when compared to results reported in similar studies performed in the US, the Netherlands by Buurma et al., and the UK. These reported modification rates of 3.8% (102) from 2,690 prescriptions, 4.3% (2014) from 47,374 prescriptions, and 0.75% (1,500) from 201,000 prescribed medical items, respectively.6,15,16 Differences in national healthcare programmes – for example the use of electronic prescribing, which has been associated with much lower error rates than handwritten prescriptions18 – in the US, the UK and the Netherlands, may partly account for this difference in modification rates. In this study, there were far fewer modifications
of prescribing faults than there were of prescription errors, meaning that the majority of modifications were of errors that were unlikely to cause patient harm. There was a 2.2% (19 of 866) modification rate when it came to these prescribing faults, representing a mean of 3.8 POM prescribing faults in the pharmacy per week. In contrast, there was a 14.8% modification rate for prescription errors, a mean of 25.6 POM prescription errors in the pharmacy per week. Drugs from the nervous system therapeutic class made up the highest source of POM modifications in this study, which is consistent with previous studies such as Buurma et al.15 However, these results differ with regard to finding significant associations between drugs in both the genitourinary system and sex hormones therapeutic drug class and POM modifications. Our findings regarding drugs in the genitourinary system and sex hormones therapeutic class (ATC code G) were unexpected, as our literature review did not flag this drug class. It is important to mention that the majority of modifications for this drug class concerned clarifications about directions for use, where they were either missing or incomplete. One possible reason for the incompleteness of the dose directions may be due to patients being already familiar with how to use their medicines. In this regard, individual experience about what constitutes a prescribing error may also have had consequences on error detection in this study. There was also a significant association between POM modifications and female gender. This was at odds with our literature review, where associations between gender and prescribing errors were either insignificant15 or found to be higher in male patients.3,19 A number of factors may account for this finding; for example, all concerned drugs in the genitourinary system and sex hormones therapeutic drug class in this study were oral contraceptives. However, multivariate analysis shows both gender and drugs with ATC code G to be independent variables. Volume 8: Number 1. 2015 | Page 17
RCSIsmjoriginal article We found that printed prescriptions had a reduced frequency of errors, consistent with results by Buurma et al.15 Most of our (51%) POM modifications were made based on consultation with the patient or their proxy. In contrast, Warholak and Rupp reported that the majority (64.1%) of their modifications were made based on consultation with the prescriber.6 The biggest limitation in this research was regarding study design. As the research was cross-sectional, causality could not be inferred. Also, our study was conducted in just one pharmacy and may not be generalisable to others. We found a mean prescribing error rate of 17.9 errors per 100 prescriptions, corresponding to an average of 31 prescribing errors per week; a comparatively higher rate than that reported in the GMC PRACtICe study and the EQUIP study,3,8 but within the range (12.4-27%) that has been reported across various healthcare settings in Ireland.10,11,20
prescriptions with potential clinical consequences were modified weekly. Most were resolved through consultation with the patient or their representative, or checking the patient’s medical history, more so than through contact with the doctor or the prescriber. This study is important because it is the first Irish article that shines a light on the little-acknowledged phenomenon of prescription modification. Patient factors like female gender, as well drug factors such as the therapeutic class of drugs (e.g., genitourinary and sex hormones therapeutic class and musculoskeletal therapeutic class) have implications for the probability of prescription modifications, which suggests that focus must be put on ways to mitigate errors arising from patients and prescriptions that fit that profile. Pharmacists and community pharmacies play a pivotal role in preventing prescribing errors. This study also illustrates the critical role that patient involvement can play in the prescribing process with
Conclusion
regard to harm prevention and improved compliance. Future research should build upon this study and explore modification boundaries that should be removed or installed to advance patient safety.
The majority of prescribing errors modified in this study involved non-serious clerical errors. However, an average of 3.8 POM
References 1. Joint Formulary Committee. BNF 67. London; BMJ Group and Pharmaceutical Press, 2014. 2. Kohn LT, Corrigan JM, Donaldson MS (eds.). To Err is Human – Building a Safer Health System. Washington; National Academies Press, 2000. 3. Avery T, Barber N, Ghaleb M et al. Investigating the prevalence and causes of prescribing errors in general practice: The PRACtICe Study. Nottingham: General Medical Council, 2012. 4. Bates DW, Cullen DJ, Laird N et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA. 1995;274(1):29-34. 5. Aronson JK. Medication errors: definitions and classification. Br J Clin Pharmacol. 2009;67(6):599-604. 6. Warholak TL, Rupp MT. Analysis of community chain pharmacists’ interventions on electronic prescriptions. J Am Pharm Assoc (2003). 2009;49(1):59-64. 7. Dean B, Barber N, Schachter M. What is a prescribing error? Qual Health Care. 2000;9(4):232-7. 8. Dornan T, Ashcroft D, Heather H et al. An in depth investigation into causes of prescribing errors by foundation trainees in relation to their medical education. EQUIP study. London; General Medical Council, 2009. 9. Health Service Executive. Health Service Executive Annual Report and Financial Statements 2013. Dublin; HSE, 2014. 10. Sayers YM, Armstrong P, Hanley K. Prescribing errors in general practice: a prospective study. Eur J Gen Pract. 2009;15(2):81-3. 11. Ryan C, O’Mahony D, Kennedy J, Weedle P, Byrne S. Potentially inappropriate prescribing in an Irish elderly population in primary care. Br J Clin Pharmacol. 2009;68(6):936-47.
Page 18 | Volume 8: Number 1. 2015
12. Gallagher P, Barry P, O’Mahony D. Inappropriate prescribing in the elderly. J Clin Pharm Ther. 2007;32(2):113-21. 13. Hamilton H, Gallagher P, Ryan C, Byrne S, O’Mahony D. Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalised patients. Arch Intern Med. 2011;171(11):1013-9. 14. Relihan EC, Ryder SA, Silke B. Profiling harmful medication errors in an acute Irish teaching hospital. Ir J Med Sci. 2012;181(4):491-7. 15. Buurma H, De Smet PA, van Den Hoff OP, Egberts AC. Nature, frequency and determinants of prescription modifications in Dutch community pharmacies. Br J Clin Pharmacol. 2001;52(1):85-91. 16. Hawksworth GM, Corlett AJ, Wright DJ, Chrystyn H. Clinical pharmacy interventions by community pharmacists during the dispensing process. Br J Clin Pharmacol. 1999;47(6):695-700. 17. Anonymous. Guidelines for ATC classification and DDD assignment 2012. Oslo: WHO Collaborating Centre for Drug Statistics Methodology, 2012. 18. Kaushal R, Kern LM, Barron Y, Quaresimo J, Abramson EL. Electronic prescribing improves medication safety in community-based office practices. J Gen Intern Med. 2010;25(6):530-6. 19. Kopp BJ, Erstad BL, Allen ME, Theodorou AA, Priestley G. Medication errors and adverse drug events in an intensive care unit: direct observation approach for detection. Crit Care Med. 2006;34(2):415-25. 20. Bates K, Beddy D, Whirisky C, Murphy M, O’Mahony JB, Mealy K. Determining the frequency of prescription errors in an Irish hospital. Ir J Med Sci. 2010;179(2):183-6.
RCSIsmjoriginal article Prevalence of haemoglobinopathies in the diabetic population served by Connolly Hospital Abstract Introduction: Small shifts in glycaemic control are associated with significant effects on clinical complications in patients with diabetes. Measurement of glycosylated haemoglobin, called HbA1c, is well established as the gold standard for measurement of long-term glycaemic control. However, variations in haemoglobin may alter the validity of HbA1c. Aim: To determine the percentage of HbA1c tests performed on patients with haemoglobinopathies at Connolly Hospital, with consideration of the possible need for fructosamine measurement in those patients. Methods: A retrospective chart review covering all patients tested for HbA1c at Connolly Hospital between January 1, 2014, and July 1, 2014. Results: Some 28 patients out of a total of 3,920 (0.71%) were automatically flagged in laboratory records as demonstrating abnormal haemoglobins upon HbA1c measurement, with 36 HbA1c tests in total (including repeats on individuals) run on these patients over the study period. Nine (four female, five male) had previous records of specific haemoglobin screening tests, all of which were consistent with sickle cell trait. Conclusion: The number of patients having HbA1c tested at Connolly Hospital who have haemoglobinopathies warrants interpreting their HbA1c results with caution. It is worth considering the need to perform fructosamine measurements regularly in house as an alternative. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:19-22.
Introduction
Stephan Grundy1 Dr Seamus Sreenan2 1RCSI medical student 2Connolly Hospital,
Blanchardstown
Small shifts in glycaemic control are associated with significant effects on clinical complications in patients with diabetes. Measurement of glycosylated haemoglobin, called HbA1c, is well established as the gold standard for measurement of long-term glycaemic control. The proportion of haemoglobin (Hb) in HbA1c is normally the most accurate indicator of blood sugar levels over the preceding three months. Diabetic retinopathy, microalbuminuria and diabetic nephropathy are known to increase greatly with relatively minor HbA1c increases, and modest reductions in HbA1c have been associated with significant reductions in microvascular complications.1,2 Knowledge of HbA1c level, therefore, is a crucial element in managing diabetes. However, its reliability is not absolute, as it is dependent on the assumption of a normal (120-day) erythrocyte lifespan and metabolism.3,4,5 The question of HbA1câ&#x20AC;&#x2122;s reliability has become
increasingly important with its adoption as the primary tool for diagnosing diabetes and monitoring glycaemic control. Although HbA1c generally provides a good indicator of patient response to treatment, it is not necessarily accurate in all patients or populations. Some patients demonstrate a glycation gap: HbA1c levels inconsistent with clinical presentation, blood glucose/home monitoring results, or glycated plasma protein levels. The reason for this gap is not fully understood; several physiological variables, including erythrocyte lifespan, are implicated to various degrees.6 The close association between the glycation gap and diabetic nephropathy7 suggests that discrepancies between measured HbA1c and non-Hb-based methods of measurement are clinically important. Of particular interest is the usefulness of HbA1c screening in patients with globin chain defects such as sickle cell trait and thalassaemias. Patients with these conditions inherit either one or two incorrect Volume 8: Number 1. 2015 | Page 19
RCSIsmjoriginal article Table 1: Mean HbA1c levels recorded. Overall population
49.6
Women with haemoglobinopathies
58.9
Women without haemoglobinopathies
54.5
Men with haemoglobinopathies
62.7
Men without haemoglobinopathies
63.4
Table 2: Full blood count results for female patients with (available for 7/11) and without (available for 6/10) haemoglobinopathies. Data are means for each group. Results highlighted in bold are below the reference ranges. Test
Haemoglobinopathies
No haemoglobinopathies
Connolly Hospital reference range
Unit
RBC
4.35
4.48
3.88-4.99
x 1012/L
Hb
11.74L
12.13
11.8-14.8
g/dL
PCV
0.347L
0.360
0.360-0.440
L/L
MCV
79.81L
81.36L
82.0-98.0
fL
MCH
27.03L
28.32
27.3-32.6
Pg
MCHC
33.83
34.02
31.6-34.9
g/dL
RDW
14.886
14.5
9.9-15.5
%
MPV
9.77
9.56
7.4-10.0
fL
Table 3: Full blood count results for male patients with (available for 13/17) and without (available for 4/14) haemoglobinopathies. Data are means for each group. All means for the male patients were within reference ranges. Test
Haemoglobinopathies
No haemoglobinopathies
Connolly Hospital reference range
Unit
RBC
5.06
4.82
4.32-5.66
x 1012/L
Hb
13.83
13.77
13.3-16.7
g/dL
PCV
0.414
0.401
0.390-0.500
L/L
MCV
82.21
87.07
82.0-98.0
fL
MCH
27.41
29.45
27.3-32.6
Pg
MCHC
33.34
33.83
31.6-34.9
g/dL
RDW
14.5
14.075
9.9-15.5
%
MPV
9.5
9.75
7.4-10.0
fL
copies of the globin gene with a range of effect on normal Hb levels. Hb variances may alter the normal glycosylation process. The specific effect of sickle cell trait (meaning the patient is heterozygous for the sickle cell mutation) on the accuracy of HbA1c as a reflection of serum glucose levels is uncertain. The increased erythrocyte turnover seen with haemoglobinopathies is known to decrease glycosylation time.3 Abnormal Hb may also directly disrupt HbA1c measurement by chromatography.4,5 The chief alternative method of glycaemic control evaluation is by fructosamine testing. Rather than Hb, fructosamine levels show the degree of glycation of serum proteins, chiefly albumin. However, while fructosamine, c-fructosamine (corrected for serum albumin) and HbA1c show similar error rates in identifying glycaemic control levels, HbA1c has proven to be a slightly better discriminator.8 Fructosamine is a less costly test, but measures blood glucose over a shorter duration (two weeks versus three months for HbA1c), and therefore must be performed more often than HbA1c. Even so, it may provide more accurate measurements for patients with haemoglobinopathies, as it does not depend on a normal erythrocyte lifespan. In previous decades, the presence of a patient population with Page 20 | Volume 8: Number 1. 2015
haemoglobinopathies was not an issue in Irish healthcare. However, the enhanced ethnic diversity of Irelandâ&#x20AC;&#x2122;s twenty-first century population offers a range of new challenges to the Irish medical community. As well as maintaining a high awareness of the genetic conditions common among the native Irish population, we must also consider conditions prevalent in Africa and the Middle East such as thalassaemias and sickle cell anaemia. The consequences of inaccurate blood glucose monitoring in these populations are potentially severe. Underestimation may prevent sufficient treatment, whereas overestimation may lead to excessively aggressive treatment. The goals of this study were to determine the approximate percentage of haemoglobinopathies among diabetic patients in a Dublin hospital, and to evaluate the potential benefit of fructosamine measurements for these patients.
Methods The study population consisted of all patients receiving HbA1c testing at Connolly Hospital over a six-month period, as identified by laboratory records. This included Diabetic Day Clinic patients, hospital patients, and GP patients whose blood samples were sent in for HbA1c testing. The
RCSIsmjoriginal article total number of individuals tested was 3,920: 1,786 female, 2,099 male, and 35 gender unrecorded. The total group’s average age was 57. Patients with haemoglobinopathies were identified by automatic laboratory flagging on HbA1c test results. The results of full blood counts were noted if available. Gender, age, HbA1c, patient location and date of testing were recorded for all individuals. When a patient was tested more than once in the study’s time period, values used were from the most recent test. Connolly Hospital currently uses the blood count reference ranges for Caucasians only in determining laboratory standard values.9 It was considered optimal to match control groups by age, sex and race, due to the question of apparent physiological variances in haematocrit (HCT), Hb and mean cell volume (MCV) between the Caucasian and African populations.10,11 As laboratory records in Connolly Hospital at this time do not always include ethnic origin, and approximately half of the people tested were GP patients for whom personal data beyond these records was unavailable, it was impossible to achieve exact confirmation of a racial match for the control group in all cases. All of those patients in both the haemoglobinopathy and control groups for whom ethnic data was available were identified as being of Nigerian origin. The control groups were definitively matched by age and sex. HbA1c testing was performed at Connolly Hospital by means of high-performance liquid chromatography (HPLC) two-phase elution, using a Menari HA-8160 HbA1c auto-analyser. Reversed phase partition chromatography elutes all fractions up to stable HbA1c (P1, P1, HbF, labile and stable HbA1c); this is followed by ion exchange chromatography, eluting the remaining fractions (A0, A2, and others appearing in the S/C window). The presence of Hb variants is automatically noted. Analysis on the Menari HA-8160 is not directly affected by the presence of Hb C or Hb S.12
Results Twenty-eight patients with definite haemoglobinopathies were identified (17 men, 11 women), constituting 0.71% of the total patient population tested for HbA1c at Connolly Hospital in the designated period. A group of 28 age- and gender-matched controls was selected. Four of the 11 female patients identified with haemoglobinopathies had Hb screening records showing results consistent with sickle cell trait; for one of these, the possibility of α-thalassaemia (HbA2 + 3.5%, HbF + 1.7%) was also noted. The other seven were flagged for haemoglobinopathy without details. Five of the 17 male patients flagged with haemoglobinopathies had Hb screening records, all consistent with sickle cell trait. Average age for the female population with haemoglobinopathies who received HbA1c tests at Connolly within the study’s time period was 42; average age for the male population was 52. Age ranges for both genders were largely limited to a ten-year spread, with few outliers. Mean HbA1c levels for each group are given in Table 1. Two female patients with haemoglobinopathies also had single fructosamine tests performed. The results of these were 354mol (equivalent of HbA1c 73mmol/mol; compared to measured HbA1c of 65mmol/mol one week later), and 316mol (equivalent of HbA1c 61.7mmol/mol, compared to measured HbA1c of 86mmol/mol at the same time). Both discrepancies suggest an inaccurate HbA1c reading, although the different time
periods covered by the two methods make it impossible to confirm a glycation gap from single readings. Overall, women with haemoglobinopathies had lower average red blood cells (RBC), Hb, packed cell volume (PCV), mean cell haemoglobin (MCH), and MCV than the women without, and a higher mean platelet volume (MPV) (Table 2); men with haemoglobinopathies demonstrated higher RBC, Hb and PCV, with lower MCV and MPV than men without (Table 3). However, these differences were fairly minor, and given the small study populations, are likely not significant.
Discussion For the purposes of this study those haemoglobinopathies that were tested for and identified were consistent with sickle cell trait (the heterozygous form of the mutation) rather than sickle cell anaemia (the more severe form, homozygosity for the aberrant globin chain). Therefore, it is unsurprising that the differences between RBCs, Hb, PCV, MCV and MPV in the haemoglobinopathy and control groups were not great. The chief finding of interest was the unexpectedly high proportion of patients with haemoglobinopathies among those tested. Ireland’s most recent national census (2011) identified the overall “Black or Black Irish-African” population as 1.28% of the total population;13 the most recent final report (2006) showed Nigeria as the predominant country of origin (16,300), with a slightly larger total for the rest of Africa collectively (19,026).14 Approximately 25% of Nigerian adults have the sickle cell trait.15 The national prevalence of diabetes mellitus in Nigeria in 2010 was recorded as 3.8%, with a higher prevalence in urban regions (7.9%); overall, African prevalence is estimated at 3.9%.16 Assuming the highest possible prevalence of both diabetes and sickle cell trait in the African/African-descent population in the catchment area served by Connolly, approximately 0.31% of the collective population in that area should be expected to display sickle cell trait. The population with both sickle cell trait and diabetes, then, would only be expected to be 0.025%. The possibility that the patients flagged for haemoglobinopathy for whom no haemoglobinopathy screening was carried out (seven of 11 women, 12 of 17 men) actually carried a thalassaemia trait must not be ignored. However, adding the expected figures on patients with both sickle cell anaemia and diabetes to the maximum possible thalassaemia trait carrier percentages (44% altogether in Africa with the highest prevalence in North Africa),17,18 would still yield only an expected overall diabetic patient total of approximately 0.14%, as contrasted to the overall total of 0.7% that was actually demonstrated. There are many possible explanations for this discrepancy. Type II diabetes comprises >90% of diabetes cases in Africa,16 and all patients in both haemoglobinopathy and control groups in this study for whom records were available were diagnosed with type II diabetes. This condition typically has an insidious onset, and is suspected to be significantly underdiagnosed even in the Western world. It is therefore possible that the African figures are very much understated. Not all patients who are tested for HbA1c are by definition diabetic, although the high HbA1c means shown here indicate a high frequency of probable diabetes among the study population. The question of whether a Western urban environment might increase the likelihood of a person of African descent developing diabetes is beyond the scope of this study, although it might prove a fruitful issue to explore in the future. Volume 8: Number 1. 2015 | Page 21
RCSIsmjoriginal article Conclusion Blood glucose levels are the primary guide to diabetes management, directing medication and dosage selection, and providing feedback regarding treatment response. While home blood glucose monitoring is an important part of the patient’s role in controlling diabetes, the combination of daily variables and the difficulty of ensuring consistent adherence means that this method is insufficiently reliable in terms of ongoing evaluation. Accurate longer-term measurements have been demonstrated to provide more reliable results regarding glycaemic control: thus far, HbA1c is the chief method that has been investigated. The most recent NICE guidelines for the management of type II diabetes (2009, CG37) specifically recommend that: “When HbA1c monitoring is invalid (because of disturbed erythrocyte turnover or abnormal haemoglobin type), estimate trends in blood glucose control using one of the following: fructosamine estimation, quality-controlled plasma glucose profiles, [or] total glycated haemoglobin estimation (if abnormal haemoglobins)”.19 This study demonstrated a prevalence of just below 1% of abnormal Hbs in patients undergoing HbA1c testing at Connolly Hospital. There are significant potential dangers of both overestimating and underestimating glycaemic control. Considering the concerns of
inaccuracy in the diagnosis of diabetes when HbA1c is used for this purpose, it is prudent, in patients with these conditions, to consider supplementing or replacing HbA1c with non-Hb-dependent means of measurement. This would avoid the risks of inaccurate diagnosis, under-treatment, or excessively aggressive glycaemic control. Fructosamine should be considered as an alternative tool for consistent blood glucose monitoring. Further consideration regarding alternate measurements for the rapidly-increasing Irish population with haemoglobinopathies and/or investigating alternate HbA1c targets for diabetes diagnosis and monitoring in these patients may be beneficial. The population served by Connolly Hospital who have both haemoglobinopathies and diabetes, for whom it would be optimal to institute regular fructosamine testing, is numerically sufficient to indicate that it would be worthwhile to be able to perform fructosamine testing in house.
Acknowledgements I am grateful for the ongoing guidance and assistance of Professor Seamus Sreenan, the staff of the Diabetes Day Centre at Connolly Hospital, and the personnel of the Connolly Hospital haematology laboratory.
References 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86. 2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose
9. Bain BJ. Blood Cells: A Practical Guide (4th ed.). Hoboken; Wiley-Blackwell, 2006. 10. Bain B. A Beginner’s Guide To Blood Cells. Hoboken; Wiley-Blackwell, 2003: ch.4, Table 4.2. 11. Beutler E, West C. Hematologic differences between African-Americans
control with sulphonylureas or insulin compared with conventional
and whites: the roles of iron deficiency and α-thalassemia on
treatment and risk of complications in patients with type 2 diabetes
hemoglobin levels and mean corpuscular volume. Blood.
(UKPDS 33). Lancet. 1998;352(9131):837-53. 3. Bhat VS, Dewan KK, Krishnaswamy PR. Diagnostic dilemma of HbA1c detection in presence of a hemoglobinopathy: a case report. Indian J Clin Biochem. 2011;26(1):91-5. 4. Smaldone A. Glycemic control and hemoglobinopathy: when A1c may not be reliable. Diabetes Spectr. 2008;21(1):46-9. 5. Nasir NM, Thevarajah M, Yean CY. Hemoglobin variants detected by hemoglobin A1c (HbA1c) analysis and the effects on HbA1c measurements. Int J Diabetes Dev Ctries. 2010;30(2):86-90. 6. Cohen RM, Smith EP. Frequency of HbA1c discordance in estimating blood glucose control. Curr Opin Clin Nutr Metab Care. 2008;11(4):512-17. 7. Cohen RM, Holmes YR, Chenier TC, Joiner CH. Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy. Diabet Care. 2003;26:1163-67. 8. Horn FG, Ettinger B, Lin MJ. Comparison of serum fructosamine vs glycohemoglobin as measures of glycemic control in a large diabetic population. Acta Diabetol. 1998;35(1):48-51.
Page 22 | Volume 8: Number 1. 2015
2005;106(2):740-5. 12. NGSP. Factors that interfere with HbA1c test results. [Internet] Updated September 2014. Available from: http://www.ngsp.org/factors.asp. 13. Central Statistics Office. 2011: CD27. [Internet] Available from: http://www.cso.ie/px/pxeirestat/Statire/SelectVarVal/saveselections.asp. 14. Central Statistics Office. Census 2006: Non-Nationals Living In Ireland. Dublin; Stationery office, 2008:36. 15. Akinyanju OO. A profile of sickle cell disease in Nigeria. Ann N Y Acad Sci. 1989;565:126-36. 16. Hall V, Thomsen RW, Henriksen O, Lohse N. Diabetes in Sub Saharan Africa 1999-2011: epidemiology and public health implications. A systematic review. BMC Public Health 2011;11:564. 17. Kotila TR, Adeyemo AA, Mewoyeka OO, Shokunb WA. Beta thalassaemia trait in western Nigeria. Afr Health Sci. 2009;9(1):46-8. 18. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008;86(6):480-7. 19. NICE. NICE guidelines (CG87). May 2009: section 1.35. [Internet] Available from: http://www.nice.org.uk/guidance/cg87/chapter/1-guidance#glucose-control-levels.
RCSIsmjoriginal article Tissue is the issue: is margin re-excision rate following breast-conserving surgery a good quality measure? Abstract
Chigozie Igwe1 James Murphy2 Maurice Murphy2 Gerrard Oâ&#x20AC;&#x2122;Donoghue2 1RCSI medical student 2Waterford University Hospital
Introduction: Breast-conserving surgery (BCS) with radiotherapy is an equivalent treatment to mastectomy for early-stage breast cancer in terms of survival, with improved patient satisfaction. The optimum margin width and rate of margin re-excision has been controversial. We aimed to evaluate the appropriateness of this treatment, and to examine the rate of margin re-excision or conversion to mastectomy following initial BCS. Methods: A retrospective study of patients treated at University Hospital Waterford for invasive or pre-invasive breast disease between January 2011 and December 2013 was performed. Demographics, tumour characteristics and outcomes were compared for patients receiving BCS and radiotherapy versus mastectomy. Results: Of 350 breast cancer patients undergoing surgery, 202 (57.7%) were treated with BCS, as compared to 148 (42.3%) who underwent mastectomy. Of the 202 BCS patients, close margins were found in 33 (16.3%) and positive margins in 28 (13.9%) patients. In the mastectomy group, these numbers were 38 (25.7%) and 15 (10.1%), respectively. Re-excision of margins with or without axillary clearance was later performed in 16.3% of the BCS group and 13.4% went for mastectomy. Discussion: The rates of positive margins and margin re-excision following BCS in this study are consistent with international standards. The indications for margin re-excision, and the method of pathological analysis used, may uncover potential solutions to improve the re-operation rate after BCS. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:23-27.
Volume 8: Number 1. 2015 | Page 23
RCSIsmjoriginal article Introduction In Ireland, approximately 650 women die each year from breast cancer, accounting for 16% of cancer deaths in women. Based on the 2013 annual report of the National Cancer Registry, 2,767 cases of breast cancer are newly diagnosed every year, contributing a total of approximately 16% of the total registered cancers in females – just below that of non-melanoma skin cancer at 21%.1,2 Of the 27 countries in the EU, although female breast cancer incidence and mortality in Ireland is ranked the sixth and third highest, respectively, the Irish mortality/incidence ratios are the same as that found for the EU overall, with two deaths for every 10 women diagnosed.1 Records for the earliest surgical intervention for breast cancer date as far back as the first century AD.3 However, the modern era of surgical treatment for breast cancer was ushered in by William Stewart Halsted – professor of surgery at Johns Hopkins University – who pioneered and popularised the now commonly known ‘radical mastectomy’. This procedure involves the clearance of the breast tissue with the overlying skin, the pectoralis muscles, and all axillary lymph nodes. Since the introduction of Halsted’s procedure at the end of the 19th century, modern clinical trials have demonstrated that the use of a less extensive procedure is equally effective in treating breast cancer when performed with adjuvant radiotherapy.2,4 Breast-conserving surgery (BCS) is a less radical procedure, defined by the International Consensus Conference as “... complete removal of the breast tissue with a concentric margin of surrounding healthy tissue performed in a cosmetically acceptable manner (lumpectomy), usually followed by radiation therapy”.5 BCS aims to match the oncologic results of mastectomy while preserving aesthetics, and comparison studies have found it to be equivalent, with both procedures having negligible risk of major adverse events.6,7 BCS in conjunction with appropriate adjuvant therapy is now the mainstay of treatment for women presenting with early stage invasive cancer.6 It requires a balance between conservation of aesthetics and removal of sufficient tissue to achieve negative margins in order to avoid local recurrence and the need for further surgeries.8 Although margin status post BCS provides a strong prognostic factor for local recurrence, there was until recently no general consensus among surgeons on the optimum margins to be achieved for the lowest probability for recurrence.9 This was due to the fact that optimal negative margins had not yet been addressed in randomised trials.10 Measures of surgical performance for BCS are difficult to establish as it is generally considered a low-risk procedure. Surgical oncological outcomes are typically based on 30-day morbidity and mortality rates; however, due to the low rates associated with breast procedures, there are no measures consistently and reliably used to evaluate low-risk breast procedures, and therefore, few comparisons of surgical outcomes among breast surgeons at present.11,12,13 The need for re-excision surgery has been used as a measure of quality, but its scope is limited due to the variable circumstances under which BCS and re-excision is offered among surgeons, including Page 24 | Volume 8: Number 1. 2015
purely for cosmesis. These factors, in addition to clinical variables (patient age, tumour type, imaging, etc.), can bias the rate of re-excision and mastectomy. It is also important to consider that surgeons who prefer wider excision margins would have lower re-excision rates.14,15,16 The aim of this study was to retrospectively examine the rate of margin re-excision and conversion to mastectomy following initial BCS in patients with non-metastatic invasive or intraductal carcinoma of the breast, and to consider the appropriateness of the indications for each of these.
Methods A retrospective review of a prospectively maintained database of patients treated at University Hospital Waterford for invasive or pre-invasive breast disease was performed. Ethical approval was not required as the study was part of an audit cycle. The data was obtained through patients’ electronic records from a validated pathology, radiology, and medical decision-making (MDM) report archive. Patients with histologically proven invasive or pre-invasive breast disease, either through a core biopsy (>95%) or at operation between January 2011 and December 2013, were included. The study was restricted to females. Patients with known metastases were excluded. Those patients who had initial surgeries performed outside the institution and patients with breast cancer who were not treated surgically were also excluded.
Data collection Patient demographics, date of diagnosis, and date and type of first and subsequent breast and nodal procedures were recorded (Table 1). Clinical, radiological and pathological assessment documented the following: tumour type, grade, nodal burden, receptor status, presence of proliferation indices (Ki67), evidence of vascular and lymphovascular invasion, and TNM stage. Positive and close margins were defined as tumour on ink and tumour within 1mm of ink, respectively. The rate of margin re-excision or mastectomy following initial BCS was analysed via SPSS software (version 19).
Results Of the 350 patients included in the review, 202 (57.7%) had BCS and 148 (42.3%) had mastectomies. The median age for the BCS group (51.8 years) was slightly younger than for the mastectomy group (60 years). The distributions of tumour type, grade and receptor status were similar between groups. A larger proportion of the mastectomy group (9.5%) were stage T3/4, corresponding to tumours >50mm in the greatest dimension with or without extension to the chest wall and/or to the skin, compared to 1% of the BCS group.17 Among the BCS group, 68.9% were node negative compared to 43.9% in the mastectomy group. Patients with metastatic disease were excluded. In the BCS group, 58.9% of tumours were excised with clear margins as compared to 64.2% in the mastectomy group (Tables 2 and 3). Of those remaining, 16.3% in the BCS group and 25.7% in
RCSIsmjoriginal article Table 1: Histological features and demographic data. Patient and tumour characteristics:
BCS group No. (n=202)
% 100*
Mastectomy group No. % (n=148) 100*
Age, years
Median (range)
Tumour type
Infiltrating ductal
165
85.2
111
79.9
Infiltrating lobular
19
9.8
24
17.3
Infiltrating other
9
4.7
4
2.9
Tumour grade
51.8 (26.8-90.4)
60 (30-86)
I
3
1.6
3
2.2
II
118
63.1
90
67.2
III
66
35.3
41
30.6
DCIS
DCIS present
147
72.8
109
73.7
Receptor status
oestrogen/progesterone+
179
88.6
131
88.5
HER2+
28
13.9
12
8.1
Initial surgery axilla
T stage
N stage
Sentinel lymph node biopsy
171
84.7
94
63.5
Axillary clearance
17
8.4
50
33.8
None
14
6.9
6
4.1
Tis
2
1.0
4
2.7
T1
96
49.5
50
33.8
T2
94
48.5
79
53.4
T3/T4
2
1.0
14
9.5
NO
131
68.9
65
43.9
N1
48
25.3
51
34.5
N2
7
3.7
20
13.5
N3
4
2.1
5
3.4
* Missing values excluded in % calculation the mastectomy group had close margins (tumour <1mm from ink) and 13.9% of the BCS group and 10.1% of the mastectomy group had positive margins (tumour touching ink). The total need for further surgery following BCS was 29.7% (60/202). Of these, 16.3% had re-excision of margins with or without axillary clearance and 13.4% had mastectomy with or without axillary clearance.
Discussion The demographic data presented here highlight possible confounding factors for (comparable) success rates of BCS and mastectomy. Patients who opted for BCS were more likely to be T1 staged, whereas those who had mastectomies were far more likely to be stage T3/T4. In the BCS group, 68.9% were node negative compared to 43.9% in the mastectomy group. Patients with less Volume 8: Number 1. 2015 | Page 25
RCSIsmjoriginal article Table 2: Margins obtained from breast-conserving surgery. No. (n = 202)
% 100*
Margin status
Clear Close (tumour <1mm from ink) Positive (tumour touching ink)
119 33 28
58.9 16.3 13.9
Procedures to improve margins
Re-excision of margins Re-excision of margins + axillary clearance Mastectomy Mastectomy + axillary clearance
28 5 18 9
13.9 2.5 8.9 4.5
*Missing values in % calculations Table 3: Margin status for initial mastectomy treatment.
Margin status Clear Close (tumour <1mm from ink) Positive (tumour touching ink)
advanced disease were more likely to fall into the BCS group, which may explain the outcome. Of those patients who received BCS and later required further surgery, 33.3% of those who had mastectomies (9/27) also required axillary clearance, as opposed to 15.2% of those who had re-excision of margins (5/33). This is consistent with the likelihood that those requiring mastectomies had more advanced disease. The definition of a negative margin and the benefit of a wider margin is often a debate in breast surgery. Variability in outcomes in the BCS group may be attributable to surgeons who prefer wider excision margins and thus have lower re-excision rates. Based on a systematic review of 33 studies, SSO-ASTRO (Society of Surgical Oncology and the American Society for Radiation Oncology) guidelines recommended â&#x20AC;&#x153;no ink on tumourâ&#x20AC;? as the standard for an adequate margin in patients undergoing BCS.18 Data collected in future studies should examine the proportions of tumours with clear, close and positive margins in the re-excision versus mastectomy groups. However, in cases where more tissue is initially removed, mastectomy and breast reconstruction may later be done for cosmetic purposes. The rate of re-intervention, including re-excision of margins and mastectomy, following BCS (29.7%) is comparable to international standards (27%).19 Patients in the BCS group were also younger than those in the mastectomy group. Younger patients may be more likely to opt for BCS for cosmetic reasons, which have been shown to be very important in determining satisfaction, especially in those presenting with early stage breast cancer.20,21 BCS may also preserve the impression of normality, both in feeling and in perception by others.22,23 It is important to attempt to quantify the Page 26 | Volume 8: Number 1. 2015
No.
%
(n=148) 95 38 15
100 64 26 10
quality of life of patients undergoing these procedures in order to better understand their impact. The retrospective nature of this study is a major limitation, as this subjects it to selection bias as well as well as a lack of data that could potentially help in better characterising these patient populations, their tumours, and the medical decisions. It is particularly unclear whether patients underwent any sort of adjuvant or neo-adjuvant therapy that could potentially have impacted on the results of this study. The indications for margin re-excision, and the method of pathological analysis, may uncover potential solutions to improve the rate of reoperation after BCS. Specific clinical circumstances that might impact on decisions need to be evaluated at an institutional level due to the potential variability of the medical practitioners, as well as the patient population. In the age of personalised medicine, factors such as tumour pathology, immunohistochemical markers, genetics, and other such predictive assays need to be evaluated in order to better select patients who would respond well to BCS as compared to those who require mastectomies. This cohort of patients and tissue provides a valuable source to be able to achieve this goal for our population. It would also be important to follow these patients to assess for factors such as the need for potential second re-excision and the overall long-term impact of the treatment in this population.
Conclusion When compared to mastectomy, patients who undergo BCS show higher quality of life and satisfaction with their decision. Hence BCS with adjuvant therapy is more acceptable to the majority of patients
RCSIsmjoriginal article with breast cancer.20,21 This highlights the issue concerning BCS and quality of life. A patient with breast cancer who opts for mastectomy would not need further re-excision surgery, while those who undergo BCS may need further excisions, which may cause substantial amounts of stress (physical, emotional and economic). A considerable number of patients choose to have a mastectomy as their second re-excision surgery, thereby avoiding the potential risk of any further surgery.24,25,26
BCS is considered to have maximum benefits when there are adequate margins at the initial surgery while retaining as much breast tissue as possible for cosmesis. When these margins are not met, additional surgery is advocated.
References 1.
National Cancer Registry Ireland. Cancer in Ireland 2013: Annual Report
cancer treated with breast conservation therapy. Am J Surg.
http://www.ncri.ie/publications/statistical-reports/cancer-ireland-2013-an
2002;184(5):383-93.
nual-report-national-cancer-registry. 2.
4.
15. Azu M, Abrahamse P, Katz SJ, Jagsi R, Marrow M. What is an adequate
American Society of Clinical Oncology. Progress & Timeline. [Internet]
margin for breast-conserving surgery? Surgeon attitudes and correlates.
Available from:
Ann Surg Oncol. 2010;17(2):558-63.
www.cancerprogress.net/timeline/major-milestones-against-cancer. 3.
14. Singletary SE et al. Surgical margins in patients with early-stage breast
of the National Cancer Registry. [Internet] Available from:
16. Taghian A, Mohiuddi M, Jagsi R, Morrow M. Current perceptions
Ellis H. The treatment of breast cancer: a study in evolution. Ann R Coll
regarding surgical margin status after breast-conserving therapy: result of
Surg Engl. 1987;69(5):212-15.
a survey. Ann Surg. 2005;241(4):629-39.
Harvey AM. Early contributions to the surgery of cancer: William S. Halsted, Hugh H. Young and John G. Clark. Johns Hopkins Med J. 1974;135:399-417.
17. American Joint Committee on Cancer. Breast Cancer Staging (7th ed.). [Internet] 2009. Available from: https://cancerstaging.org/references-tools /quickreferences/Documents/BreastMedium.pdf. 18. Moran MS, Scnitt SJ, Giuliano AE et al. SSO-ASTRO consensus guidelines
5.
Schwartz GF, Veronesi U, Clough KB et al. Consensus Conference on Breast Conservation. Seminars in Breast Disease. Milano, 2005:178-85.
on margins for breast conserving surgery with whole breast irradiation in
6.
Fisher B, Anderson S, Bryant J et al. Twenty-year follow-up of a
stage I and II invasive breast cancer. Ann Surg Oncol. 2013. Doi:
randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. 7.
N Engl J Med. 2002;347(16):1233-41.
randomized trial comparing breast-conserving therapy with mastectomy:
Finks JF, Osborne NH, Birkmeyer JD. Trends in hospital volume and
European Organization for Research and Treatment of Cancer 10801
operative mortality for high-risk surgery. N Engl J Med. 2011;364(22):2128-37. 8.
Margenthaler JA, Gao F, Klimberg VS. Margin index: a new method for prediction of residual disease after breast-conserving surgery. Ann Surg Oncol. 2010;17:2696-701.
9.
10.1245/s10434-014-3481-4. 19. Van Dongen JA, Voogd AC, Fentiman IS et al. Long term results of a
Holland PA, Gandhi A, Knox WF et al. The importance of complete excision in the prevention of local reoccurrence of ductal carcinoma in situ. Br J Cancer. 1998;77:110-4.
10. Kreike B, Hart AA, van de Velde T et al. Continuing risk of ipsilateral breast relapse after breast conserving therapy at long term follow-up. Int J Radiat Oncol Biol Phys. 2008;71:1014-21. 11. Houssaimi N, Macasskill P, Marinovich ML et al. Meta-analysis of the impact of surgical margins on local recurrence in women with early stage
trial. J Natl Cancer Inst. 2000;92(14):1143-50. 20. Janz NK, Mujahid M, Lantz PM et al. Population-based study of the relationship of treatment and sociodemographics on quality of life for early stage breast cancer. Qual Life Res. 2005;14(6):1467-79. 21. Janz NK, Mujahid M, Hawley ST et al. Racial/ethnic differences in quality of life after diagnosis of breast cancer. J Cancer Surviv. 2009;3(4):212-22. 22. Pockaj BA, Degnim AC, Boughey JC et al. Quality of life after breast surgery: what have we learned and where should we go next? J Surg Oncol. 2009;99(7):447-55. 23. Rowland JH, Desmond KA, Meyerowitz BE, Belin TR, Wyatt GE, Ganz PA. Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors. J Natl Cancer Inst. 2000;92(17):1422-9. 24. Veronesi U, Luini A, Galimberti V, Zurrida S. Conservation approaches for
invasive breast cancer treated with breast conserving therapy. Eur J
management of stage Iâ &#x201E;II carcinoma of the breast: Milan Cancer Institute
Cancer. 2010;46:3219-32.
trials. World J Surg. 1994;18(1):70-5.
12. Moo TA, Choi L, Culpepper C et al. Impact of margin assessment method on positive margin rate and total volume excised. Ann Surg Oncol. 2014;21:86-92. 13. Silverstein MJ, Lagios MD, Groshen S et al. The influence of the margin
25. McCahill LE, Single RM et al. Variability in reexcision following breast conservation surgery. JAMA. 2012;307(5):467-75. 26. De la Rochefordiere A, Abner AL, Silver B, Vicini F, Recht A, Harris JR. Are cosmetic results following conservative surgery and radiation therapy for
width on local control of ductal carcinoma in situ of the breast. Cancer
early breast cancer dependent on technique? Int J Radiat Oncol Biol
Res. 1999;340(19):1455-61.
Phys. 1992;23(5):925-31.
Volume 8: Number 1. 2015 | Page 27
RCSIsmjcase report An unexpected tumour
FIGURE 1: 14cm left ovarian mass suspicious for malignancy (right side of image) and 6cm right ovarian mass below the uterus (left side of image).
Abstract A 47-year-old Caucasian woman from Dublin presented to the gynaecology clinic in Beaumont Hospital with a six-month history of progressively worsening, irregular, heavy intermenstrual bleeding and abdominal discomfort. She also had severe pelvic pressure symptoms. On palpation, she had a firm, tender pelvic mass. A transabdominal pelvic ultrasound scan showed a 10x6cm mass that was determined to be a uterine fibroid. The patient was scheduled for total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO). At laparotomy, a large, irregular, nodular left ovarian mass and smaller right ovarian mass were discovered. Incidentally, the appendix was found to be grossly abnormal in appearance and distorted due to an irregular mass. Histology revealed a primary mixed adenocarcinoma and goblet cell neuroendocrine carcinoma of the appendix with ovarian metastases. Mixed adenocarcinoma and neuroendocrine tumours of the appendix are extremely rare, aggressive, and difficult to diagnose due to their nonspecific presentation. Few of these tumours have been reported in the literature and thus the standard of management and prognosis have not yet been established. The management of the few cases that have been published generally includes right hemicolectomy due to the invasiveness of the tumour. In this case, diagnosis was not made until a laparotomy intended to remove a uterine fibroid revealed an unexpected tumour. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:28-31.
Introduction
Janelle Wilkinson RCSI medical student
Page 28 | Volume 8: Number 1. 2015
Uterine fibroids, or leiomyomas â&#x20AC;&#x201C; smooth muscle tumours of the myometrium â&#x20AC;&#x201C; are the most common benign tumours in women of reproductive age.1 Although their pathogenesis is not clear, there is evidence that oestrogen accentuates their growth, as they rarely appear before menarche and regress after menopause.1
These tumours occur in more than 30% of women between the ages of 40 and 60, and prevalence increases with age.2 Risk factors include prolonged oestrogen exposure, for example in the cases of early menarche and nulliparity, with some evidence of influence by caffeine and alcohol intake.1
RCSIsmjcase report
FIGURE 2: Grossly abnormal appendix with 4cm diameter mass found on laparotomy (lower left).
The majority of women with uterine fibroids have no symptoms; however, in symptomatic patients the most common presenting symptom is abnormal uterine bleeding, especially menorrhagia.1 They may also present with non-cyclical pelvic pain, pelvic pressure and infertility.1 In some cases, uterine fibroids may present with mass effect. Rarely, they can become large enough to mimic pregnancy, with weights over 11.4kg.3 These are difficult to treat due to their atypical presentations, although they can cause severe pelvic discomfort, urinary tract obstruction, and small bowel obstruction, and often require surgery due to the discomfort and severity of symptoms.2 The diagnostic investigation of uterine fibroids typically involves transabdominal ultrasound due to its accessibility and low cost; however, transvaginal scans are also ideally performed.1 Magnetic resonance imaging (MRI) is the most sensitive modality (88-93%) in cases where there is doubt as to the origin of the pelvic mass.1 Standard management of symptomatic uterine fibroids includes short-term pharmacological management with triptorelin, a gonadotropin-releasing hormone (GnRH) agonist, or a selective progesterone receptor modulator (SPRM) such as ulipristal acetate.1 For more definitive, curative treatment, surgical management includes hysterectomy, or myomectomy in cases of desired preserved fertility.1 Newer, minimally invasive procedures such as uterine artery embolism and other ablation procedures are good treatment options for women without a desire for future fertility, but who wish to retain their uterus.1
Case report A 47-year-old Caucasian woman from Dublin presented to the gynaecology clinic in Beaumont Hospital with a six-month history of progressively worsening irregular, heavy intermenstrual bleeding and abdominal discomfort. She had no post-coital bleeding or dyspareunia, and no urinary or bowel symptoms. Both of her children were born by spontaneous vaginal delivery, and she had a tubal ligation five years prior to presenting. Her last smear test in 2014 was normal. Other past medical history includes haemochromatosis, which is managed by haematology in Beaumont. On physical examination the patient was found to have a firm, tender palpable mass arising from the pelvis reaching the umbilicus. Bimanual examination was consistent with fibroids. A subsequent transabdominal ultrasound scan was done, which showed a 10x6cm mass appearing to arise from the uterus, with similar echogenicity to a fibroid. Both ovaries were said to be normal in appearance. The left ovary was difficult to visualise and, on subsequent transvaginal ultrasound scan, it was said to be unremarkable. Due to her pelvic discomfort and irregular bleeding, the patient was scheduled for a total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO). Further imaging with pelvic MRI was advised but her surgery was scheduled prior to her scan date. She was commenced on ulipristal acetate three months prior to surgery in an attempt to reduce the size and vascularity of the fibroid. One week prior to surgery, she had no relief of pelvic Volume 8: Number 1. 2015 | Page 29
RCSIsmjcase report Table 1: A literature review of four cases of neuroendocrine carcinoma of the appendix. Case no.
Authors
Year
Patient age and gender
Preoperative diagnosis
Operation
Pathological diagnosis
1
Thomas et al.
2006
70, M
Malignant caecal polyp
Right hemicolectomy
MANEC
2
Couvelard
2010
–
–
?MANEC
3
Tanaka et al.
2012
53, M
Postoperative ileus
Ileocaecal resection
MANEC
4
Tomioka et al.
2013
53, F
Acute appendicitis
Ileocaecal resection
NEC
5
This case
2014
47, F
Uterine fibroids
Right hemicolectomy Total abdominal hysterectomy and bilateral salpingooophorectomy
MANEC
MANEC: mixed adenoneuroendocrine carcinoma. NEC: neuroendocrine carcinoma. Data derived from Tomioka K et al. pressure symptoms. On palpation in the pre-assessment room, the fibroid had not reduced in size and was believed to have increased in size. At laparotomy, the uterus was found to be normal in size – the mass that was thought to be originating from the uterus was actually a 14cm heterogeneous, irregular, nodular left ovarian mass. A 6cm right ovarian mass was also discovered. Both had changes suspicious for malignancy (Figure 1). Unexpectedly, the appendix was incidentally found to be grossly abnormal in appearance, distorted by a solid, spiral mass approximately 4cm in diameter at the distal end (Figure 2). A TAH-BSO was performed with an infra-colic omentectomy. Because of the appendiceal mass, a colorectal surgeon was consulted intraoperatively for an opinion and he performed a right-sided hemicolectomy due to abnormal-looking surrounding bowel. The patient recovered well and was discharged on day five postoperatively. Sectioning through the left and right ovarian tumour showed a haemorrhagic centre with a surrounding tan, firm area. Histology of the appendiceal and ovarian masses revealed a primary mixed adenocarcinoma and goblet cell neuroendocrine carcinoma of the appendix that had metastasised to the ovaries, uterine serosal surface and local lymph nodes. Microscopic tumour was also detected in the omentum (TNM staging score: T3N2M1). The patient was referred to the oncology team and will be commenced on a folinic acid, fluorouracil, and oxaliplatin chemotherapy regimen. She is for staging computed tomography scan shortly.
Discussion Neuroendocrine tumours (NETs), historically called carcinoid tumours, are rare neoplasms of neuroendocrine cells. A rare Page 30 | Volume 8: Number 1. 2015
subtype, appendiceal tumours account for only 4.8% of gastrointestinal NETs and have an annual incidence of 0.15-0.6 per 100,000.4,5 Although NETs of the appendix are extremely rare, they represent the most common neoplasms of the appendix, accounting for 80% of all appendiceal neoplasms.4 They are most commonly found incidentally on appendectomy.6 Although appendiceal NETs have long been thought to be benign, recent evaluation has revealed that malignant subtypes exist, which are more aggressive.7 Mixed adeno-neuroendocrine carcinoma (MANEC) of the appendix represent a rare subset of appendiceal NET with an incidence of 0.01-0.05 per 100,000.4 There are only four reported cases of MANEC of the appendix on Pubmed as of this writing. In every case, the non-specific clinical presentation made its identification particularly challenging.5 Preoperative diagnoses in the literature included malignant caecal polyps, postoperative ileus, acute appendicitis, and uterine fibroids in this case (Table 1).5,8,9,10 The sole reason the appendiceal MANEC was diagnosed in this case was due to abdominal discomfort experienced by the patient due to metastatic ovarian masses. She did not have any gastrointestinal symptoms to suggest the possibility of a gastrointestinal pathology. The patient’s age, premenopausal state, presentation of abnormal uterine bleeding, pelvic discomfort and pelvic mass seeming to originate from the uterus favoured the more common diagnosis of a uterine fibroid. Due to the malignant characteristics of the ovarian masses, the abnormal-looking appendix warranted surgical review, as there is a well-established link between ovarian cancer and appendiceal metastases.11 Presentation of primary appendiceal goblet cell carcinoma (GCC) with ovarian metastases is unusual, and in this case is most likely a
RCSIsmjcase report reflection of the advanced stage of the disease.4 In a retrospective and prospective follow-up study at the Mayo Clinic in 2006, 70% of patients with GCC presented with appendicitis-mimicking symptoms, 25% with right lower quadrant pain, 16% with bowel obstruction, and 14% incidental.12 A total of 50% of female patients had stage IV cancer with ovarian metastases on initial presentation.12 European Neuroendocrine Tumor Society (ENETS) guidelines note that one-third of appendiceal GCCs may be asymptomatic, and an incidental finding on surgery for other reasons.4 Thus, appendiceal GCCs have non-specific presentations and advanced stages can be unknowingly widely metastasised at initial diagnosis. In this case, the patient had evidence of mixed adenocarcinoma and goblet cell neuroendocrine carcinoma on histology. Owing to the adenocarcinoma component, the tumour had a more aggressive course than classical carcinoid tumours, and was more likely to metastasise to regional lymph nodes and the ovaries.4 According to the ENETS consensus guidelines, approximately 10% of appendiceal GCCs present with widespread distant metastases to the liver, ovaries and peritoneum at diagnosis.4 While localised cases have a reasonably good survival rate (five-year survival rate 50-80%), the few cases that present with distant metastases have a poor prognosis (five-year survival rate <20%).4 The early stages of appendiceal GCC have a similar prognosis to appendiceal NET; however, due to the adenocarcinoma component, the prognosis of advanced stages of appendiceal GCCs tend to more closely approximate those of colonic-type adenocarcinoma.4 Due to the lack of case studies on appendiceal MANEC, the definitive surgical management has not yet been established. In this case, the patient underwent a right-sided hemicolectomy due to the grossly abnormal appearance of the bowel surrounding the appendix. Similarly, management of all previously reported cases of appendiceal MANEC has involved either an ileocaecal resection or
References 1. Khan AT, Shehmar M, Gupta JK. Uterine fibroids: current perspectives. Int J Womens Health. 2014;6:95-114. 2. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;15:1503-8. 3. Moris D, Vernadakis S. Giant uterine leiomyoma mimicking pregnancy. Mayo Clin Proc. 2014;89:53-4. 4. Pape UF et al. ENETS Consensus Guidelines for the Management of Patients with Neuroendocrine Neoplasms from the Jejuno-Ileum and the Appendix including Goblet Cell Carcinomas. Neuroendocrinology. 2012;95(2):135-56. 5. Tomioka K et al. Primary neuroendocrine carcinoma of the appendix: a case report and review of the literature. Anticancer Res. 2013;33(6):2635-8. 6. Ploenes T, Borner N, Kirkpatrick CJ, Heintz A. Neuroendocrine tumour, mucinous adenocarcinoma and signet-ring cell carcinoma of the appendix: three cases and review of literature. Indian J Surg. 2013;75(Supp.1):299-302.
right-sided hemicolectomy.4,13 Best course of treatment for confirmed ovarian metastases with primary GCC has not yet been determined; however, bilateral salpingo-oophorectomy has been suggested for all female patients diagnosed with MANEC due to the propensity of the tumour to spread to the ovaries.4 In cases of distant metastases, a chemotherapy regimen including 5-fluorouracil (e.g., FOLFOX) has been shown to be effective in at least 50% of cases of stable disease.4 The consensus for follow-up is three- to six-month interval staging in cases of metastatic disease, as well as gastrointestinal follow-up due to the high co-incidence (up to 48%) of other gastrointestinal tumours in these patients.4
Conclusion NETs of the appendix represent a rare subset of malignancies with variable, non-specific presentations. They are often diagnosed on pathology postoperatively. MANEC presents a particularly difficult diagnostic challenge as it is more aggressive, owing to the adenocarcinoma component, and masses are often found incidentally on surgical procedures for other pathologies. Patients may present with localised symptoms of distant metastases. Our unusual case demonstrates that patients with seemingly typical gynaecological symptoms may ultimately have a rare, unexpected underlying pathology. Further in-depth case studies and information are required on mixed adenoneuroendocrine carcinoma of the appendix in order to expand the knowledge of its unique clinical course, develop an appropriate standard of management, and improve prognosis of the disease.
Acknowledgements I would like to sincerely thank Dr Paul Byrne, Consultant Obstetrician and Gynaecologist, and Dr Tara Rigney, Registrar Obstetrician and Gynaecologist, for their contributions to this case report, as well as for their permission to publish the case.
7. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934-59. 8. Thomas RE, Maude K, Rotimi O. A case of intussuscepted neuroendocrine carcinoma of the appendix. World J Gastroenterol. 2006;12:971-3. 9. Couvelard A. Appendicular pathology. Mixed endocrine carcinoma with poorly differentiated large cell component. Ann Pathol. 2010;30:124-9. 10. Tanaka S et al. A case of appendiceal mixed adenoneuroendocrine carcinoma after appendectomy. Jpn J Gastroenterol Surg. 2012;45:1121-8. 11. Kokanali MK, Guzel AI, Erkilinc S, Tokmak A, Topcu HO, Gungor T. Risk factors for appendiceal metastasis with epithelial ovarian cancer. Asian Pac J Cancer Prev. 2014;15:2689-92. 12. Pham TH, Wolff B, Abraham SC, Drelichman E. Surgical and chemotherapy treatment outcomes of goblet cell carcinoid: a tertiary cancer center experience. Ann Surg Oncol. 2006;13:370-6. 13. Bak M, Asschenfeldt P. Adenocarcinoid of the vermiform appendix. A clinicopathologic study of 20 cases. Dis Colon Rectum. 1988;31:605-12.
Volume 8: Number 1. 2015 | Page 31
RCSIsmjcase report The hidden dangers of drug–drug interactions
Abstract
Rachel MacCann
RCSI medical student
Antiretroviral medications have the potential to produce serious drug interactions by interfering with the hepatic cytochrome P450 cascade. Ritonavir, a protease inhibitor, is a known CYP450 inhibitor that is commonly used in the treatment of HIV infection. Iatrogenic Cushing’s syndrome is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs that result in hypothalamic-pituitary-adrenal axis suppression. It is well documented in HIV-infected patients receiving inhaled steroids in combination with a ritonavir-containing antiretroviral regimen. This case describes a 45-year-old man with HIV who suffered an unintentional severe reaction between his HIV treatment and fluticasone while participating in an asthma research trial. He presented with classical Cushing’s features, as well as a decline in his respiratory health. Biochemical tests confirmed iatrogenic Cushing’s syndrome and clinical symptoms resolved after stopping ritonavir and tapering down the levels of corticosteroid with eventual discontinuation. Poor outcomes in these cases can be attributed to miscommunication and a lack of clear medical guidelines, as well as the fear of disclosure among patients with sensitive diagnoses. This case highlights the importance of taking a full and thorough drug history, and the risks associated with polypharmacy in patients. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:32-35.
Page 32 | Volume 8: Number 1. 2015
RCSIsmjcase report Background
Table 1: Clinical manifestations and findings in Cushing’s syndrome.
In 2014, 379 people were newly diagnosed in Ireland as having HIV. This is an 11% increase from the year before and gives a rate of 7.5 per 100,000 population. Treatment of HIV involves a therapy called HAART (highly active anti-retroviral therapy), which is a combination of medicines that aims to stop the virus replicating in the body and allow the immune system to recover. The current anti-retroviral classes include nucleoside analogues, nucleotide analogues, non-nucleoside analogues and protease inhibitors. These drugs can be used in combination to provide more powerful treatment. Ritonavir, a protease inhibitor (PI), is a potent inhibitor of the hepatic cytochrome P450 3A4 (CYP3A4) isozyme and is used at low doses to boost the levels of other PIs for the treatment of HIV infection.1 Because of its action on liver enzymes, which metabolise several medications, ritonavir also has the potential to produce serious drug interactions. For example, use with inhaled or intranasal corticosteroids can result in iatrogenic Cushing’s syndrome (Table 1) with a decreased CD4 cell count.2 Cushing’s syndrome describes the signs and symptoms associated with prolonged exposure to inappropriately high levels of the hormone cortisol. The hypothalamic-pituitary-adrenal (HPA) axis controls the release of cortisol, and exogenous use of steroids such as glucocorticoids can suppress the HPA axis, leading to elevated cortisol levels. This case report illustrates an unanticipated drug interaction, which occurred while a patient was undergoing treatment with HAART for HIV infection. The importance of taking a full drug history to prevent such an interaction is discussed, as is how to manage such a case if an interaction has occurred. The outcome highlights the importance of communication in the medical profession, and the dilemmas and dangers related to nondisclosure of sensitive diagnoses.
Clinical features
Irritability, anxiety and emotional disturbance Moon facies Osteoporosis Cardiac hypertrophy (hypertension) Buffalo hump Obesity Adrenal tumour or hyperplasia Thin, wrinkled skin Abdominal striae Decreased libido in males Muscle weakness Purpura Skin ulcers
Laboratory findings
Elevated haematocrit and white cell count with eosinopenia Hypokalaemia, hypochloraemia and alkalosis Glycosuria and elevated 24-hour 17-hydroxy corticoids
X-ray findings
Osteoporosis: marked in pelvis and spine Skull: enlargement of the pituitary fossa Chest: widening of superior mediastinum and bronchogenic carcinoma
Diagnostic tests
Dexamethasone suppression test Metopirone (metyrapone) test Synacthen test Insulin tolerance test
Table 2: Patient’s baseline medications. Medication
Class
Indication
Route
Dose
Lopinavir
PI
HIV
PO
400mg BD
Ritonavir
PI
HIV
PO
100mg TDS
Tenofovir/emtricitabine
NRTI
HIV
PO
T OD
Trimethoprim/sulfamethoxazole
Combination antibiotic
PCP prophylaxis
PO
960mg OD
Salbutamol
Bronchodilator
Asthma
INH
100 PRN
Tiotropium bromide
Bronchodilator
COPD
INH
5mcg OD
Diltiazem
Calcium channel blocker
Hypertension
PO
60mg TDS
Calichew
Calcium supplement
Osteoporosis
PO
T OD
Tramadol
Analgesic
Chronic pain
PO
50mg TDS
Risedronate
Bisphosphonate
Osteoporosis
PO
3mg once weekly
PI = protease inhibitor; NRTI = nucleoside reverse trascriptase inhibitor; HIV = human immunodeficiency virus; PO = orally; od = once daily; bd = twice daily; tds = three times daily. Volume 8: Number 1. 2015 | Page 33
RCSIsmjcase report The case A 45-year-old Irish man with a background history of HIV was admitted to James Connolly Hospital, Blanchardstown, where he was treated for exacerbation of COPD and three compression fractures of his vertebrae. Five weeks later, he presented to Beaumont Hospital with facial swelling, oedema and a significant functional decline. Since his discharge from Blanchardstown, he reported decreased mobility and fatigue associated with leg weakness; his legs would buckle beneath him and he had suffered from several falls. He found it difficult to get up out of bed and move around, for which he at first used a walking aid to help his mobility but had since been confined to a wheelchair. He did not report any sensory abnormalities, facial weakness, swallowing disturbances, diplopia, or urinary or bowel symptoms. Over the same time period he experienced increasing shortness of breath and frequency of his cough, which was productive of brown mucus. He found simple tasks such as turning in bed exhausting and recently had to give up work. When he tried to wean himself off his steroids his respiratory symptoms got worse. On examination, he was noted to have moon facies, severe shortness of breath, fatigue and proximal muscle weakness, all suggestive of Cushingâ&#x20AC;&#x2122;s syndrome. A random cortisol test and 24-hour urinary free cortisol confirmed this diagnosis. He was subsequently admitted as an inpatient for further work-up. Because of his background history of HIV, he was referred to the infectious diseases team following admission. Past medical history was signficant for HIV, first diagnosed in 2005, for which he was started on a HAART regimen in 2009. This included Kaletra (lopinavir/ritonavir) and Truvada (tenofovir/emtricitabine) once daily (od) (Table 2). His most recent CD4+ T-cell count was 188 and his HIV viral load was <40 copies/mL, and he was commenced on co-trimoxazole for PCP prohlyaxis due to his low CD4+ count. He had a lifelong history of asthma for which he had never been hospitalised but for which he described poor compliance with his medications. He had had frequent chest infections over the past several years and was diagnosed with emphysema in 2010. History was also significant for hepatitis C, atrial fibrillation, depression, eczema and atopic dermatitis. There was no previous surgical history. The patient was an ex-smoker with a 30 pack year history, an ex-intravenous drug user and did not drink alcohol. He had to give up work because of his decreased mobility, which had a significant impact on his quality of life. On exam, there were no signs of peripheral lipo-atrophy or central lipo-accumulation, which would have suggested HAART-associated lipodystrophy associated with PIs. His random cortisol result was abnormally low at 12 (ref range 105-260) and so a synacthen test was not performed. 3 It was agreed that his adrenal suppression was secondary to a high dose of steroids. Further tests showed that he had a low testosterone level at 4.9mmol/L with an LH of 2 and FSH of 7.3. Page 34 | Volume 8: Number 1. 2015
Neurological examination and electromyography were consistent with proximal myopathy. The most likely explanation was that the patient must have had ongoing exposure to high systemic levels of exogenous corticosteroids, yet he denied the intake of oral steroids and had a history of poor compliance with his asthma medications. Further questioning revealed that six months earlier, the patient had enrolled in an asthma drug trial in Beaumont Hospital. The aim of this trial was to improve compliance in asthma patients. A Seretide diskus (fluticasone/salmeterol) was added to his pro re nata (PRN) salbutamol and he was asked to monitor his peak flow readings over a three-month period. He remarked that it was during this time period that he developed the Cushingoid features, and that the experimenters noted in his fourth and final trial visit that he had shown marked deterioration. However, because of his respiratory symptoms he continued to use the Seretide diskus after completion of the study as part of his asthma treatment regime. Based on this history it was concluded that the patient had suffered a significant interaction between ritonavir and the fluticasone contained in the Seretide diskus. His HAART regimen was then changed from Kaletra and Truvada to Kivexa (abacavir/lamivudine) one tablet od and raltegravir 400mg bd to remove the interaction. Hydrocortisone was given for physiological cover, to be gradually reduced every month; slow discontinuation was necessary to avoid precipitation of adrenal crisis. He was also started on risedronate, and continued on his pain medication for osteoporosis and fractures. Three months after his admission the patient was seen at the outpatients clinic for follow-up. He had a slightly reduced Cushingoid appearance and improved muscle tone. Repeat testosterone levels were 11.7mmol/L and he was considered a candidate for testosterone replacement. A repeat of his cortisol day curve showed an adequate response and a lower dose of hydrocortisone was continued. The patient has been monitored closely over the past several months as an outpatient with weekly visits, and as of ten months after his initial presentation had shown improved muscle tone. He is currently on very low dose hydrocortisone, to eventually be discontinued.
Discussion Research clearly advises against the co-administration of fluticasone with ritonavir.4 In 2002, GlaxoSmithKline performed a pharmacokinetic clinical study5 in healthy subjects to evaluate the effects of several CYP3A4 inhibitors, including ritonavir, on systemic concentrations of intranasal fluticasone. In this study, the area under the concentrationâ&#x20AC;&#x201C;time curve (AUC) was increased 350-fold for serum fluticasone levels, and plasma cortisol levels were found to be decreased by 86%. As a consequence of this trial and numerous case reports,2 the combination of ritonavir with fluticasone was considered to be relatively contraindicated in 2007. It is critical to collect a thorough medication history in patients
RCSIsmjcase report exhibiting signs and symptoms of unexplained Cushing’s syndrome. Lipodystrophy caused by some antiretroviral medications shares some overlapping features with iatrogenic Cushing’s syndrome (e.g., central obesity, weight gain and dorsocervical fat pad) and so distinction between the two conditions is necessary. Despite this, similar cases continue to occur. This can be ascribed to a lack of guidance regarding medical management of those with HIV and other medical problems such as asthma or other infections. Another predominant factor is the fear of disclosure by patients on HIV medications to doctors other than those managing their antiretroviral medications. When dealing with HIV patients who also have asthma/emphysema, recommendations about treatment include: 1. Change the antiretroviral regimen to one that does not inhibit the CYP3A4 isozyme. 2. Substitute the inhaled/intranasal corticosteroid with another safer, non-interacting corticosteroid such as beclomethasone.6 As with this patient, those diagnosed with Cushing’s syndrome should be initiated on oral steroid replacement and this should gradually be tapered down. Adrenal function recovery may take nine to 12 months7 and serum cortisol levels can be checked every four to six weeks to reassess the need for ongoing steroid replacement therapy. Interestingly, this drug–drug interaction is not limited to inhaled corticosteroids. Cushing’s syndrome has been reported when injectable (e.g., triamcinolone8) and topical corticosteroids9 were used in conjunction with CYP3A4 inhibitors. Therefore, this is a potential risk for patients on PIs who are chronically using corticosteroids via any route. This
adds to the importance of checking for drug–drug interactions when prescribing. When dealing with sensitive medical issues such as HIV treatment management, the responsibility of the doctor is twofold: to educate the patient about the importance of their treatments and possible side effects; and, to ensure that the patient experiences a safe, non-judgmental health service. This responsibility tends to fall to the infectious disease specialist, with whom the patient may have a closer relationship. The prevention of dangerous drug interactions requires patient education and disclosure of all medications. The problem of disclosure can only be mitigated with a reduction in the stigma associated with HIV. Patients shouldn’t be afraid to tell the doctors they encounter that they are being treated for HIV. Knowledge of this problem should encourage us to challenge ourselves in our practice and change the way we perceive certain conditions. This case prompted a research study into the use of other drugs, particularly inhaled corticosteroids, by all patients on ritonavir in the HIV clinic in Beaumont. A screening tool was developed to identify ‘at-risk’ patients and to promote better communication between doctors and patients.
Conclusion The drug−drug interaction between corticosteroids, especially fluticasone, and PIs is significant and deserves close attention and evaluation. Timely communication among all prescribing physicians for a given patient is indicated in order to proactively detect significant interactions before they manifest themselves clinically. Most importantly, patients who are prescribed ritonavir should be counselled about potential interactions with inhaled and intranasal steroids, and should consult with a pharmacist or physician specialising in HIV prior to taking these agents.
References 1. Abbott Laboratories, editor. Norvir Package Insert. North Chicago, IL: 2012. Available from: http://wwwrxabbottcom/pdf/norvirtab_pipdf. 2. Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors. HIV Med. 2013;14(9):519-29. 3. Jenkins D, Forsham PH, Laidlaw JC et al. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med. 1955;18:3-14. 4. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9:389-96. 5. GlaxoSmithKline. GlaxoSmithKline (GSK) clinical study register. Available at: http://www.gsk-clinicalstudyregister.com.
6. Boyd SD, Hadigan C, McManus M, Chairez C, Nieman LK, Pau AK et al. Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone. J Acquir Immun Defic Syndr. 2013;63(3):355-61. 7. Hopkins RL, Leinung MC. Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin North Am. 2005;34:371-84, ix. 8. Schwarze-Zander C, Klingmüller D, Klümper J, Strassburg CP, Rockstroh JK. Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature. Infection. 2013;41(6):1183-7. 9. Ermis B, Ors R, Tastekin A, Ozkan B. Cushing’s syndrome secondary to topical corticosteroids abuse. Clin Endocrinol (Oxf.). 2003;58:795-6.
Volume 8: Number 1. 2015 | Page 35
RCSIsmjcase report Recognition and management of rumination syndrome in the paediatric population
Abstract
Simran Ohson RCSI medical student
Rumination syndrome is a commonly misdiagnosed condition that presents similarly to gastro-oesophageal reflux disease. It has a higher prevalance in paediatric populations with cognitive delay and requires an elaborate multidisciplinary approach to management. A 13-year-old boy presented to a Dublin childrenâ&#x20AC;&#x2122;s hospital with a four-year history of postprandial belching and reflux, on a background history of Down syndrome and autism spectrum disorder. The patient had become increasingly emotionally agitated by the episodes. He had also experienced significant weight loss over the previous year. Management through a standard gastro-oesophageal reflux disease approach was unsuccessful. Bloods, imaging and endoscopy were all normal. No abdominal masses were detected. The patient was diagnosed with rumination syndrome and admitted as an inpatient for multidisciplinary management. A percutaneous endoscopic gastrostomy (PEG) tube was inserted and feeds commenced, which led to slight weight gain. The patient was discharged for home feeding and a follow-up appointment with occupational therapy. Rumination syndrome in populations with cognitive delay requires a uniquely tailored approach to diagnosis and treatment. Standard treatment involves diaphragmatic retraining exercises, which are difficult to teach, or fundoplication, which is not always curative. Therefore, new approaches using biofeedback and pharmacological therapy should be explored for use in paediatric populations with cognitive delay. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:36-38.
Page 36 | Volume 8: Number 1. 2015
RCSIsmjcase report Introduction Rumination syndrome is a rare condition commonly misdiagnosed as gastro-oesophageal reflux disease (GORD). It is characterised by episodes of recurrent postprandial regurgitation, which may be followed by rechewing or reswallowing of the regurgitated food.1 Although rumination syndrome is relatively rare in the general population, prevalence is between 6 and 10% in children with cognitive impairment.2 Diagnosis requires an exclusion of bulimia nervosa and GORD, with average time to diagnosis ranging from 21 to 77 months.2 Therefore, it is an important differential to consider in children with cognitive delay in order to avoid unnecessary investigations and prevent severe impairments to growth. This case demonstrates the complexity of diagnosis and management of rumination syndrome.
Case presentation A 13-year-old boy presented to the gastrointestinal outpatient clinic (OPC) at Our Lady’s Children’s Hospital (OLCH) in Dublin, Ireland, for re-evaluation following a four-year history of reflux and recurrent belching. He had a background history of Down syndrome, autism spectrum disorder (ASD) and learning difficulties. The patient was initially referred to OLCH by his GP in 2012 with a two-year history of progressive chronic regurgitation, leading to a two-centile drop in weight. The regurgitation began as a series of postprandial belching episodes and evolved to a reflux of food contents. The reflux only occurred postprandially and was not accompanied by retching. It was infrequently associated with vomiting, which was not projectile in nature and contained no blood or bile. No major infections preceded the onset of the reflux. The patient was initially diagnosed with GORD, but symptoms did not subside after treatment with lansoprazole (15mg) for one year. The symptoms continued to worsen and in the year prior to presentation there was a progressive reduction in appetite and a noticeable increase in mood swings and irritability. Relevant past medical history included chronic constipation since birth, managed by Movicol PRN. All immunisations were up to date. Examination revealed a distressed child making cooing noises and repeatedly chewing on his thumb. Abdominal muscles
were tense but a mass was palpable in the left lower quadrant consistent with stool due to constipation. Endoscopy and barium swallow were performed and did not show any evidence of inflammatory, anatomical or neoplastic pathology underlying the regurgitation, and metabolic blood panels were unremarkable. Diagnoses of rumination syndrome and aerophagia secondary to ASD were made in the gastrointestinal OPC.
Management and outcome The patient was admitted for observation and evaluation by a multidisciplinary team consisting of a gastroenterologist, occupational therapist, psychologist and physiotherapist. A percutaneous endoscopic gastrostomy (PEG) tube was inserted and feeds were commenced at 35mL/h. Following one week of care, the patient tolerated feeds well and they were gradually increased to 50mL/h. At this point he was discharged home for pump feeding through the PEG.
Discussion While rumination syndrome is poorly understood, the pathogenesis is believed to be due to a learned, but unintentional, dysfunction in the abdominal musculature in response to food in the stomach. The aetiology is related to a viral or psychosocial stressor that alters vagal nerve sensation and abdominal muscle function.2 In response to food, the abdominal muscles paradoxically contract and overpower the lower oesophageal sphincter, refluxing gastric contents into the oesophagus and mouth. Diagnosis is made using the ROME III criteria (Table 1). While this patient met all three major criteria for rumination syndrome, there was a long delay in diagnosis, which may be attributed to a lack of awareness of this condition and the lengthy process inherent to a diagnosis of exclusion. Treatment of rumination syndrome is primarily behavioural. Diaphragmatic breathing retraining exercises are effective in most paediatric populations.4 However, they can be difficult to adopt, since the prevalence is greatest in children with cognitive delay, and communication is commonly an issue. Instead, these patients are managed using PEG tube feeds and pharmacological symptom control. Baclofen has been shown to be successful in
Table 1: Rome III Diagnostic Criteria for rumination syndrome.* 1. a. b. c.
Repeated painless regurgitation and rechewing or expulsion of food that: begins soon after ingestion of a meal; does not occur during sleep; and, does not respond to standard treatment for gastro-oesophageal reflux.
2. No retching. 3. No evidence of an inflammatory, anatomic, metabolic, or neoplastic process that explains the subject’s symptoms. *Criteria fulfilled for the last three months with symptom onset at least six months prior to diagnosis.
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RCSIsmjcase report curative instead of symptom relieving. In a recent study, patients were given live visual feedback of their abdominothoracic muscles via electromyography, and were able to restore normal voluntary function of the diaphragm and anterior abdominal muscles, thus eliminating rumination episodes.7 Biofeedback has proven beneficial for children with autism but future study is required to demonstrate efficacy in children with other forms of cognitive delay.8 In the case of our patient, biofeedback could prove to be an effective treatment and allow avoidance of unnecessary surgery. The lengthy diagnostic period for rumination syndrome can put a massive stress on the family of a child with cognitive delay. Not only does the failure of medical therapy result in persistent reflux and belching, but it also results in a failure to thrive, which further halts the childâ&#x20AC;&#x2122;s development and growth. The child is also subjected to invasive diagnostic procedures to rule out other causes, resulting in many lengthy hospital stays, which impact on their ability to go to school and overall quality of life.
Conclusion
controlling symptoms in both paediatric and cognitively impaired populations, but it does not have any effect on overall disease remission.5 In refractory cases in adult populations, Nissen fundoplication has resulted in full resolution of symptoms.6 However, recent opinion suggests that the operation does not correct the underlying physiological abnormalities; therefore, symptoms may return.1 New biofeedback regimens are being investigated, which could serve to replace the current treatments, especially as they can be
It is important to consider the difficulties in diagnosis of rumination syndrome, especially as it is a diagnosis of exclusion and presents with symptoms similar to GORD. Rumination syndrome should be placed higher in the differential and considered at an earlier stage in patients with cognitive disability and gastro-oesophageal reflux refractory to treatment. Most importantly, the prolonged diagnosis procedure can be taxing and distressing to both the patient and the family. Appropriate management should always include a multidisciplinary approach, including social support for the family. Recent opinion suggests that the lower rates of success with fundoplication do not outweigh its risks; therefore, conservative management with biofeedback should be considered before surgical intervention. This approach can help to reduce the burden of rumination syndrome on the families, and subsequently result in greater outcome measures and control of symptoms.
References 1. Kessing BF, Smout AJ, Bredenoord AJ. Current diagnosis and management of the rumination syndrome. J Clin Gastroenterol. 2014;48(6):478-83. 2. Mousa HM, Montgomery M, Alioto A. Adolescent rumination syndrome. Curr Gastroenterol Rep 2014;16(8):1-6. 3. Appendix A: Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. Am J Gastroenterol 2010;105(4):895. 4. Chitkara DK, Van Tilburg M, Whitehead WE. Teaching diaphragmatic breathing for rumination syndrome. Am J Gastroenterol. 2006;101:2449-52. 5. Blondeau K, Boecxstaens V, Rommel N, FarrĂŠ R, Depeyper S, Holvoet L et al. Baclofen improves symptoms and reduces postprandial flow events in patients with rumination and supragastric belching. Clin Gastroenterol Hepatol. 2012;10(4):379-84.
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6. Oelschlager BK, Chan MM, Eubanks TR, Pope CE 2nd, Pellegrini CA. Effective treatment of rumination with Nissen fundoplication. J Gastrointest Surg. 2002;6(4):638-44. 7. Barba E, Burri E, Accarino A, Malagelada C, Rodriguez-Urrutia A, Soldevilla A et al. Biofeedback-guided control of abdominothoracic muscular activity reduces regurgitation episodes in patients with rumination. Clin Gastroenterol Hepatol. 2015;13(1):100-6.e1. [Epub 2014 Apr 24]. 8. Quill KA. Instructional considerations for young children with autism: the rationale for visually cued instruction. J Autism Dev Disord. 1997;27(6):697-714.
RCSIsmjreview Anthropometric screening for obesity in the Asian adult population Abstract The prevalence of obesity in the Asia-Pacific region is rising rapidly to meet levels observed in Western populations. The impact of obesity is significant on both the patient and the affected national health systems, increasing morbidity and mortality associated with cardiovascular disease and diabetes. However, prevention programmes may slow the development of the obesity epidemic. In order to be effective, these programmes must target correctly identified, at-risk individuals. Anthropometric measurements such as body mass index (BMI), waist-to-height ratio (WHtR) and waist circumference (WC) are practical and inexpensive indices for identifying overweight and obese patients. There is growing concern that the widely recommended BMI cut-offs may not be universally applicable across all populations. In light of this, the current BMI cut-offs must be reviewed and WHtR and WC must be given greater consideration when designing primary prevention programmes for Asian populations, particularly as recommended guidelines are frequently based predominantly on data from European and North American regions. This means that the guidelines currently being used by healthcare providers simply may not be relevant to Asian patients. These patients may be incorrectly stratified into a given weight category that could result in missed opportunities to prevent serious health problems such as hypertension and diabetes. Clearly, there is a need to reassess the current guidelines and explore indices that are most suitable for this population. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:39-41.
Obesity as a global trend
Naomi O’Sullivan RCSI medical student
As of 2008, the World Health Organisation (WHO) recognises more than 1.4 billion adults worldwide as overweight and at least 500 million as obese.1 Traditionally a predominantly Western disease, obesity – defined as a condition of abnormal or excessive fat accumulation in adipose tissue – is rapidly increasing to epidemic proportions on a global scale. In recent years it has seen a dramatic rise in developing and newly developed nations in the Asia-Pacific region (specifically Japan, China and Malaysia). For instance, in 1994 the prevalence of obesity in the US was 19-24%, compared to a mere 0.8% in China for the same time period.2 However, in 2011 this figure had risen dramatically to 37-42% in some regions of China.3 Clearly, Asian nations are catching up with the trend. This is likely due to decreasing levels of physical activity, dietary changes that occur with Westernisation, and stresses associated with an urban society. Recent immigration trends make this shift an issue that also concerns Ireland.
According to data from the Irish census in 2011, 18,000 residents identified themselves as being of Chinese ethnicity, an increase from 16,500 in 2006. Over the same time period there was an 87% increase in the number of residents identifying themselves as being from an Asian background other than Chinese.4
The burden of obesity Obesity increases the risk of morbidities and mortalities, including hypertension and cardiovascular disease (CVD), diabetes mellitus, stroke and respiratory disease.5 Studies have estimated that ≥75% of hypertension (defined as systolic pressure of ≥140mmHg or diastolic pressure of ≥90mmHg) can be attributed directly to obesity, and that weight loss is effective in lowering blood pressure.6,7,8,9 The increasing prevalence of obesity in the Asian population is paralleled by skyrocketing prevalence of hypertension; this number has been estimated at Volume 8: Number 1. 2015 | Page 39
RCSIsmjreview 27.2% of adults aged 35 to 74 years in China alone.10 Obesity is also a known risk factor for stroke, the second leading cause of deaths and leading cause of long-term disability worldwide.6,11,12 In 2005, 5.7 million deaths were attributed to stroke. This is projected to rise to 6.5 million in 2015, with the majority of these deaths occurring in low to middle income countries such as China.11
Anthropometric screening for obesity Given the increasing diversity of the Irish population, and the demonstrated association between obesity and chronic disease, Irish healthcare providers need to be aware that current screening protocols being used in their practices may not be adequate for all patients. Classically at-risk individuals have been identified via anthropometric measurements such as body mass index (BMI) and waist circumference (WC). However, there is growing concern as to whether these measurements are universally applicable across all populations. Anthropometry is the study of the measurement of the human body in terms of the dimension of bone, muscle and adipose tissue. Cut-off points for BMI, waist-to-height ratio (WHtR) and WC can aid in absolute risk assessment, determining type and intensity of treatment needed, and monitoring for the effects of treatment.2 Of these, BMI is the most widely recommended, but there is growing evidence that it may not be the most effective index in screening for cardiometabolic risk.2,13 Body mass index In 2000, the WHO standardised classification of overweight and obese based on the use of BMI, equal to weight in kilograms divided by height in metres squared (kg/m2) (Table 1).1,2 It is a simple index, largely independent of height, that has long been considered a predictor of morbidity and mortality due to chronic disease.14 Table 1: WHO BMI classifications. Category
BMI (kg/m2)
Level of risk
Underweight Normal range Overweight Obese class I Obese class II Obese class III
<18.5 18.5-24.9 25.0-29.9 30.0-34.9 35.0-39.9 ≥40.0
Low Average Increased Moderate Severe Very severe
These classifications are intended for international use, with guidelines suggesting weight loss interventions when BMI reaches 25kg/m2. However, they are based on data from Western European or American populations, and therefore may not be appropriate for all ethnic groups. The mean BMI is 26.19kg/m2 in the UK and 22.86kg/m2 in China.1,2,15 By the above definition, 8-15% of Caucasians are considered to be obese compared to only 2.2-4.8% of ethnically Chinese Hong Kong people.16 This does not reflect the prevalence of obesity-related disease, which raises the question of whether inappropriately high cut-offs have resulted in an Page 40 | Volume 8: Number 1. 2015
underestimation of obesity and its related risks.7 The WHO recently proposed the following additional trigger points for public health action in the Asian population: ≥23kg/m2 representing increased risk and ≥27.5kg/m2 representing high risk.7 In other words, in the Asian population there exists an increased risk of developing hypertension at a BMI that is still deemed to be within the healthy range as defined by the WHO.17 Although BMI has classically been the most widely used indicator of weight status, it is not without its limitations. Firstly, BMI does not account for variations in body fat distribution. This is significant, as the location of excess adiposity is a strong determinant of cardiometabolic risk.18 Additionally, BMI does not distinguish between overweight due to muscle versus fat accumulation. In order to avoid faulty risk approximation, BMI should not be used as a universal measure of obesity as a risk factor for disease.19 Waist circumference WC is a simple and accurate method of assessing a patient’s abdominal fat.13 WC correlates closely with BMI and total body fat, and is associated with cardiovascular disease (CVD) risk factors independent of BMI.19 Risk stratification by WC is biased by height, and cut-off points cannot be used universally across gender or race.20 Bei Fan et al. (2002) showed that when WC was kept below 85cm for men and 80cm for women in the Chinese population, it could prevent 47-58% of clustering of risk factors.21 Meanwhile, optimal WC cut-off values for Taiwanese were defined as 80.5cm for men and 71.5cm for women.22 As a comparison, the WHO identifies Caucasian Europeans being at increased risk at WC of ≥94cm in men and ≥80cm in women.1,2 Waist-to-height ratio The simplest proposed method for anthropometric measurement may be WHtR, which only involves one variable. Waist circumference reflects abdominal obesity and is subject to change with weight loss and gain. Height may be considered to be constant when referring to an adult; its inclusion in the ratio makes WHtR applicable in populations with a wide range of heights. WHtR is significantly associated with all CVD risk factors to a greater extent than BMI.22 Individuals with normal BMI but high WHtR are at greater risk than those with low WHtR, indicating that it may be able to identify risk in individuals who would otherwise be classified as “healthy”.24 WHtR is also more easily applied across ethnicities and sexes. A value of 0.5 is applicable to both men and women regardless of race as an action level to identify at-risk patients with increased CVD risk. WHtR, therefore, provides a simple message that clinicians can easily illustrate to patients: “keep your waist circumference to less than half your height”.25
Conclusion Obesity places enormous financial burdens on both the affected individuals and governments funding their healthcare. In 2009, Finkelstein and colleagues reported that, in the US, compared with normal weight patients, obese patients incur 46% greater inpatient costs, 27% more physician visits and 80% increased spending on prescription drugs.26 While more studies need to be conducted in
RCSIsmjreview Asian populations, Reinhold and colleagues reported in 2011 that annual spending in China due to overweight and obesity may be as high as 7.4 billion US dollars.27 The indirect effects of obesity generate substantial costs through work absenteeism, reduced productivity, increased mortality before retirement and decreased years of disability-free life.28 A Chinese case study in 2005 demonstrated that the indirect effects of obesity accounted for 8.73% of gross national product.29 With Asian populations following the rising obesity trends in Western populations, it can be reasonably assumed that the
economic impact of obesity will also continue to escalate. BMI may have been the classical anthropometric index used to detect obesity but it is time to consider using WHtR as the primary screening tool in the Asian population. Continuing to use the existing guidelines may fail patients who do not match the traditional Western physique, leaving them at risk of death due to largely preventable causes. Considering Irelandâ&#x20AC;&#x2122;s changing demographics, it is time for practitioners to explore alternative anthropometric indices for identifying obesity.
References 1. World Health Organisation. Obesity and overweight Fact sheet No. 311 [updated August 2014 and cited Nov 2014] Available from: http://www.who.int/mediacentre/factsheets/fs311/en/. 2. World Health Organisation. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series [updated 2000 and cited Dec 3 2013]. Available from: http://libdoc.who.int/trs/WHO_TRS_894.pdf. 3. Shi XD. Prevalence of obesity and associated risk factors in Northeastern China. Diabetes Res Clin Pract. 2011;91:389-94. 4. Central Statistics Office. This is Ireland, Highlights from Census 2011 Part 1 [Updated March 2012 and cited 4 February 2015]. Available from: www.cso.ie/en/census/census2011reports/. 5. Bray GA. Obesity in adults: Health hazards. UpToDate [updated December 2014 and cited February 2015]. Available from: www.uptodate.com. 6. Wilson PWF. Overview of the possible risk factors for cardiovascular disease. UpToDate [updated Sept 2014 and cited Nov 2014]. Available from: www.uptodate.com. 7. Krauss R, Winston M, Fletcher B. Obesity: impact on cardiovascular disease. Circulation. 1998;98:1472-6. 8. Zalesin KC. Impact of obesity on cardiovascular disease. Endocrine Metab Clin North Am. 2008;37:663-84. 9. Garrison RJ, Kannel WB, Stokes J 3rd. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med. 1987;16:234-51. 10. Hu D, Xie J, Fu P et al. Central rather than overall obesity is related to diabetes in the Chinese population: the InterASIA Study. Obesity. 2007;15:2809-16. 11. Gill T. Epidemiology and health impact of obesity: an Asia Pacific perspective. Asia Pac J Clin Nutr. 2006;15:3-14. 12. Rosamond W et al. Heart disease and stroke statistics committee and stroke statistics subcommittee. Circulation. 2008;117:e25-e146. 13. National Heart Lung and Blood Institute. Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in adults: The Evidence Report [updated September 1998 and cited 2013
16. Ko GTC, Chane JCN, Cockram CS. Simple anthropometric indexes and cardiovascular risk factors in Chinese. Int J Obesity. 1997;21:995-1001. 17. World Health Organisation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363:157-63. 18. Blair D, Habicht JP, Sims EA, Sylwester D, Abraham S. Evidence for an increased risk for hypertension with centrally located body fat and the effect of race and sex on this risk. Am J Epidemiol. 1984;119:526-40. 19. Schneider H. The predictive value of different measures of obesity for incident cardiovascular events and mortality. J Clin Endocrinol Metab. 2010;95:1777-85. 20. Misra A, Wasir JS, Vikram NK. Waist circumference criteria for the diagnosis of abdominal obesity are not applicable uniformly to all populations and ethnic groups. Nutrition. 2005;21:969-76. 21. Bei Fan Z. Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults: study on optimal cutoff points of body mass index and waist circumference in Chinese adults. Asia Pacific J Clin Nutr. 2002;11:685-93. 22. Lin W-Y. Optimal cut-off values for obesity: using simple anthropometric indices to predict cardiovascular risk factors in Taiwan. Int J Obesity. 2002;26:1232-8. 23. Hsieh SD, Yoshinage H. Abdominal fat distribution and coronary heart disease risk factors in men: waist/height ratio as a simple and useful predictor. Int J Obes Relat Metab Disord. 1995;19:585-9. 24. Ashwell M, Gibson S. Waist to height ratio is a simple and effective obesity screening tool for cardiovascular risk factors: analysis of date from the British National Diet and Nutrition Survey of adults aged 19-64 years. Obes Facts. 2009;2:97-103. 25. Ashwell M, Hsieh SD. Six reasons why the waist-to-height ratio is a rapid and effective global indicator for health risks of obesity and how its use could simplify the international public health message on obesity. Int J Food Sci Nutr. 2005;56:303-7. 26. Finklestein EA. The lifetime medical cost burden of overweight and
December 3]. Available from: www.ncbi.nlm.gov/books/NBK2004.
obesity: implications for obesity prevention. Obesity. 2008;16:1843-8.
14. Norgan NG. Population differences in body composition in relation to
27. Reinhold T, Schultzendorf A, Muller-Riemenschneider. Economic consequences
the body mass index. Eur J Clin Nutr. 1994;48:10-25. 15. Philip J, Leach R, Kalamara E, Shayeghi M. The worldwide obesity epidemic. Obesity Research. 2001;9:228-33.
of overweight and obesity in Asia-Pacific. Eur J Int Med. 2011;3:3-9. 28. Wang C. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815-25.
Volume 8: Number 1. 2015 | Page 41
RCSIsmjreview Premature ejaculation: current and evolving treatments
Abstract
Corey Nixon RCSI medical student
Despite having been recognised and documented for over 300 years, there have been shockingly few treatments developed for premature ejaculation (PE). Once viewed as the result of psychoanalytical internal conflicts and treated primarily via behavioural therapies, the focus of PE treatment since the 1990s particularly has shifted towards pharmacological intervention. Prior to 2009, off-label drugs such as selective serotonin reuptake inhibitors (SSRIs), opioids and topical anaesthetics were the treatments of choice. Dapoxetine, the first licensed drug for PE, entered the market in 2009 and has since triggered great interest in the field. New research on PE prevalence has revealed that 2.3% to as high as 82.6% of some male populations are stricken with PE. This newly realised market has prompted researchers to explore many novel techniques, drugs and surgeries to combat PE. This review aims to describe and compare the various old, new and evolving therapies used for patients with premature ejaculation and discuss how these therapies may reduce the anxiety and depression that often co-occur with PE. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:42-47.
Page 42 | Volume 8: Number 1. 2015
RCSIsmjreview Introduction Premature ejaculation (PE) is a complex ejaculatory dysfunction that is considered to be the most prevalent sexual dysfunction in post-pubescent men.1,2,3,4 Although this dysfunction has been known for many decades, the first unified evidence-based definition of lifelong and acquired PE was published in June 2014 by the International Society for Sexual Medicine (ISSM). This definition includes: a) nearly or always ejaculating within one minute of vaginal penetration (lifelong), or a clinically significant decrease in intravaginal ejaculatory latency time (IELT) to three minutes or less (acquired); b) an inability to delay ejaculation in nearly or all attempts at intravaginal intercourse; and, c) characterisation by marked distress or negative consequences.5 Lifelong PE occurs with nearly all attempts at intercourse from the first sexual experience. Acquired PE begins after a known period without PE and occurs due to medication, complication of surgery or a stressor. The 2014 ISSM definition suggests that men with an IELT less than three minutes are very likely to have PE, either acquired or lifelong. Both types of PE invade what many would view as the most intimate and personal part of their lives â&#x20AC;&#x201C; sex. PE is a very serious disease, involving psychological, social and relationship aspects of the patientâ&#x20AC;&#x2122;s well-being, leading to greatly reduced quality of life. By recognising and treating PE, the other aspects of well-being damaged by PE may be made either easier to manage or corrected altogether.
Diagnostic measures Clinically, PE is diagnosed on the basis of self-reported estimates and diagnostic tools, while research studies mostly rely on direct measurement of IELT. Self-reporting in community healthcare is variable across cultures and age groups,6 and diagnostic questionnaires have been shown to be problematic for over-diagnosing PE.7 Throughout the literature, many diagnostic tools have been developed to adapt to cultural differences, to allow community physicians to accurately diagnose PE. No one standard diagnostic tool has been universally accepted.8 However, a three-minute self-reported IELT has been found to be sufficient for diagnosis of acquired PE.5 Due to the sensitive nature of the condition, and the previously ambiguous definition of PE, many men have been treated based on self-reported dysfunction and sexual distress. Clinical trials use stopwatch-measured IELT in an attempt to eliminate bias for data analysis; however, it has been shown in a previous study that estimated IELT and stopwatch IELT are very similar.9 Inevitably, diagnosing this sexual dysfunction is very difficult because it is rooted in personal performance often intertwined with anxiety and embarrassment.
Prevalence Many papers cite PE as the most prevalent sexual dysfunction in men,1,2,3,4,10,11 but the number reported range anywhere between 2.3 and 82.6% depending on ethnicity, study design, definition used and type of PE studied.3,6,7,12 Difficulties in accurately assessing prevalence, including inconsistent definition and the self-reported nature of diagnosis, are further compounded by the fact that many men with probable PE have never consulted a physician (according to one questionnaire survey of 12,000 men over Europe and the United States).6 Further public attention and education about this important topic will
theoretically lead to more men consulting their physicians for appropriate treatment. With the introduction of the ISSM definition, it is hoped that new studies will find the true prevalence of PE.
Causes of PE Ejaculation is known to involve the neurotransmitter serotonin (5-HT). Many receptor subtypes are implicated but only pro-ejaculatory receptors 5-HT1a and anti-ejaculatory receptors, 5-HT1b and 5-HT2c, have been studied in PE.13,14,15,16 The current belief is that either heightened sensitivity of the 5-HT1a receptor, decreased sensitivity of the 5-HT1b and 5-HT2c receptors, or a combination of both, is responsible for PE.16 PE is often also associated with frustration and disappointment, which compounds an already difficult issue.17,18 Corona et al.18 show that many patients with PE exhibit symptoms of anxiety disorders as well, suggesting that anxiety could be a cause or result of PE rather than strictly organic dysfunction. In addition to anxiety, many men and women also have an expectation that both partners should orgasm in intercourse, but in PE, these expectations are almost never met. As a result, one study questionnaire showed that nearly 20% of women had previously ended relationships specifically due to PE.17 With relationship issues stemming from underperformance, anxiety is further propagated, which possibly worsens the dysfunction.18 Clearly, these psychological factors play a role, but the pathogenesis of PE appears to be multifactorial and further research in this field will help to elucidate the mechanisms at work.
Behavioural therapy for PE PE was traditionally managed via behavioural therapies such as the sensate focus, squeeze technique and start-stop techniques, but nowadays pharmacological therapy dominates treatment.10,19 While many of these behavioural therapies are still available, they are generally impractical because they require high patient motivation to be effective and lose efficacy after cessation.10 Inevitably, behavioural therapies are being forgotten as new and effective drug therapies become the norm.
Selective serotonin reuptake inhibitors Although they are not currently labelled for this indication, selective serotonin reuptake inhibitors (SSRIs) including paroxetine, fluoxetine, fluvoxamine, sertraline and citalopram are both well tolerated and effective in treating both lifelong and acquired PE.20 Their once-daily (OD) use, however, comes with moderate side effects, including reduced libido and anejaculation (Table 1). Paroxetine has been shown to be the most effective SSRI for PE based on mean increase in IELT (Table 1), with only one study showing paroxetine to be inferior compared to other SSRIs.21 However, long-term use of SSRIs has been shown to have unfavourable effects on male fertility, such as negatively affecting sperm structure and count, and men are thus advised to exercise caution, particularly when attempting to conceive.22 Regardless, if the patient chooses to pursue OD SSRIs to treat their PE, paroxetine appears to be the best researched, best tolerated solution, and offers the greatest results.23,24,25,26,27 A major milestone in the treatment of PE has been the licensing of the SSRI dapoxetine for as needed (PRN) use in premature ejaculation. Since 2009, it has been approved for PE in men aged 18-64 years by the Volume 8: Number 1. 2015 | Page 43
RCSIsmjreview Table 1: Comparison of current drugs used in PE treatment. Drug
Drug class
Drug latency
Mean IELT increase from
Paroxetine
OD SSRI
>1 day of dosage
<3 min. baseline (min.)
Most common side effects
1.0-7.624,25,26,27,34
Nausea, diarrhoea, headache,25 anejaculation and reduced libido27
Sertraline
OD SSRI
>1 day of dosage
2.0-3.252,53
Dizziness, reduced libido52
Citalopram
OD SSRI
>1 day of dosage
2.8-3.954,55
Nausea, dry mouth, loss of appetite54
Fluoxetine
OD SSRI
>1 day of dosage
1.8-3.256,57
Reduced libido, reduced penile rigidity57
Dapoxetine
On-demand SSRI
1.4-2.0 hours58
1.0-4.5 (30mg)35,58 1.6-3.1 (60mg)58
Nausea, dizziness, headache, somnolescence30
Nausea, headache, palpitation, flushing24,35
Sildenafil, Tadalafil, Mirodenafil
PDE5i
2 hours24
With SSRI: 2.9-3.924,34,35
Clomipramine
Tricyclic antidepressant
Taken OD36 or 4-6 hours21
1.1 (20mg OD)36 3.3 (30mg OD)36 2.0-2.5 (25mg on demand)21
Dry mouth, nausea, fatigue21,36
Somnolence, pruritis, headache, dizziness37,60
Tramadol hydrochloride
Opioid analgesic
2-3 hours37,59
1.4-20.6226,37,59
Topical anaesthetic
0.5-1 hour38
2.0-10.038,39,40,41
Prilocainelidocaine mixture
Erectile dysfunction, burning sensation of partnerâ&#x20AC;&#x2122;s genitals38,40,41
SS cream
Topical anaesthetic
1 hour42
9.642
Mild burning sensation and pain of the penis42
Abbreviations: OD, once daily; SSRI, selective serotonin reuptake inhibitor; PDE5I, phosphosdiesterase 5 inhibitor.
European Medicines Agency (EMA) and over 60 countries, and is the most prescribed drug designated for PE, though it has yet to be approved by the FDA.28 Dapoxetine has received acclaim for being an effective oral medication that acts quickly after administration. Whereas other oral medications take multiple doses to reach full effectiveness (Table 1), dapoxetine gives one- to three-minute IELT increases in most PE patients within about 30 minutes post ingestion.29,30,31 The pharmacokinetic profile of dapoxetine is also desirable given that it is rapidly absorbed and quickly eliminated with a half-life of 1.4 hours.32 Though it is more convenient Page 44 | Volume 8: Number 1. 2015
and possibly safer for the patient, it produces less effective IELT extension than the OD SSRIs. Also, during three phase 3 trials of dapoxetine, 24-122 of 710 patients discontinued the study due to adverse effects (Table 1) compared to 1-8 of 357 in placebo groups.30 Regardless of its possibly poorer IELT results, the use of dapoxetine is increasing in place of other medications.33 Given its specific approval for PE and its good pharmacokinetic profile, physicians are able to responsibly prescribe an EMA-approved, quick fix for PE patients. If tolerated, dapoxetine can be both effective and convenient while possibly avoiding persistent issues associated with long-term once-daily dosing.
RCSIsmjreview Alternative medications Phosphodiesterase 5 (PDE5) inhibitors are sometimes used in conjunction with SSRI therapy, typically with paroxetine24,34 and dapoxetine,35 for synergistic effect. They are rarely used as monotherapy for PE patients without comorbid erectile dysfunction (Table 1). A tricyclic antidepressant typically prescribed for its off-label benefits in treating PE is clomipramine. Its efficacy is notably worse than paroxetine and citalopram except at its highest dose (Table 1). While clomipramine is well tolerated by patients, it is similar in efficacy but less convenient than dapoxetine, and has poorer efficacy than non-dapoxetine SSRIs.21,36 It is typically considered by physicians as an alternative in patients who are intolerant of SSRIs. Tramadol hydrochloride, first developed as an analgesic in Germany in the late 1970s, is an opioid that also exhibits norepinephrine and serotonin reuptake inhibition.37 While tramadol increased IELT from 1.6-33.5 minutes26,37 depending on dosage in two clinical trials, one study revealed that all 300 treated PE patients experienced pruritus and somnolence, and many also experienced headaches and dizziness.37 Despite its possibly greater efficacy, tramadol hydrochloride may have no place in prescription due to adverse events. Prilocaine-lidocaine topical anaesthetics, which exist both as creams and sprays, take effect in 30-60 minutes, providing convenient on-demand use for the patient.38,39 In addition to convenience, they have also been found to be more efficacious than dapoxetine though similar to non-dapoxetine SSRIs. Multiple studies have identified one major drawback to treatment with topical anaesthetics; in some men it leads to erectile dysfunction, which ultimately defeats the purpose.38,39,40,41 Furthermore, a condom is needed to prevent adverse effects to the sexual partner.38,39,41 SS cream, a herbal anaesthetic gaining popularity in the Asia-Pacific region, is similar to prilocaine-lidocaine in terms of convenience and efficacy, but shows decreased prevalence of erectile dysfunction (8/530 men).42 Both of these topical anaesthetics are good options for men who either have difficulty taking oral medication or prefer direct application.
experience a burning sensation after application.46 Given the current data, RTX has little role in a market already dominated with more convenient, less painful and universally effective treatments.
Non-pharmacological management Pelvic floor muscle physiotherapy Pelvic floor muscle physiotherapy (PFMP), a combination of physio-kinesiotherapy, electro-stimulation and biofeedback, has been shown to be an effective non-pharmacological therapy for men with PE. In a 12-week study period, men increased their IELT from baseline 0.53 to 2.4 minutes, although five of 40 were unresponsive.47 PFMP has a decreased efficacy compared to SSRIs, tramadol and clomipramine, but the side effects of this therapy are virtually non-existent. With further revision of methods, PFMP may become first choice for treatment given its therapeutic potential and minimal side effects compared to pharmacological treatments. Surgical interventions There are currently two options for surgical treatment of PE: hyaluronic acid penile injections (HAPI) and surgical resection of penile dorsal nerves (SRDN). HAPI, a relatively new procedure, involves direct injection of hyaluronic acid into the glans penis to decrease its sensitivity. It has shown a 3.1- to 4.9-minute increase in IELT at six months48,49,50 and a 4.5-minute increase at five years post operation.49 This increase in IELT is higher compared to most SSRIs (Table 1), but also has the benefit of permanence. No side effects, complications or deformities were reported in any of the three trials. SRDN increased mean IELT by 2.4-2.7 minutes as measured shortly after the procedure, but long-term events were not recorded.50,51 Paraesthesia and numbness of the penis were reported in nine of 45 subjects in one trial.50 These surgical interventions have the potential to provide a long-term treatment for PE that is not dependent on daily medication.
Conclusion Evolving treatments An alpha-1 adrenoreceptor antagonist, silodosin, has shown positive results in a pilot clinical trial with a mean IELT increase of 2.3 minutes.43 However, like other alpha-1 antagonists it carries the risks of postural hypotension, dizziness and anejaculation43 and should not be used in patients at previous risk of hypotension. DA-8031, a novel SSRI, has shown some positive results in rat models.44 It has also been shown to peak in plasma concentration within an hour,45 so it may be another convenient on-demand drug for PE. For patients with redundant prepuce (not circumcised), a new topical application solution called resiniferatoxin (RTX) has been shown to increase IELT by 3.26 minutes. However, treating with RTX requires the glans penis to be soaked for 30 minutes to take effect, and all subjects
PE is a complex disorder, given its psychological and biological nature along with its tendency to be variably self-reported by men. PE may stem from a neurobiological dysfunction, but ultimately invades many aspects of these patientsâ&#x20AC;&#x2122; lives, causing anxiety and frustration in those afflicted. It can damage or even break up the patientsâ&#x20AC;&#x2122; intimate relationships with their partners. Therapies to increase IELT can improve quality of life and may even reduce performance anxiety, allowing these men to engage in normal sexual relationships. Treatment has evolved from solely behavioural therapy to a wide variety of pharmacological, surgical and physical therapies. Promising treatments are emerging to fill the void of available licensed treatments for premature ejaculation and may rival dapoxetine in treating this very important condition. Volume 8: Number 1. 2015 | Page 45
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46. Shi B, Li X, Chen J, Su B, Li X, Yang S et al. Resiniferatoxin for treatment of lifelong premature ejaculation: a preliminary study. Int J Urol. 2014;21(9):923-6. 47. Pastore AL, Palleschi G, Fuschi A, Maggioni C, Rago R, Zucchi A et al. Pelvic floor muscle rehabilitation for patients with lifelong premature ejaculation: a novel therapeutic approach. Ther Adv Urol. 2014;6(3):83-8. 48. Littara A, Palmieri B, Rottigni V, Iannitti T. A clinical study to assess the effectiveness of a hyaluronic acid-based procedure for treatment of premature ejaculation. Int J Impot Res. 2013;25(3):117-20. 49. Kwak TI, Jin MH, Kim JJ, Moon DG. Long-term effects of glans penis augmentation using injectable hyaluronic acid gel for premature ejaculation. Int J Impot Res. 2008;20(4):425-8. 50. Kim JJ, Kwak TI, Jeon BG, Cheon J, Moon DG. Effects of glans penis augmentation using hyaluronic acid gel for premature ejaculation. Int J Impot Res. 2004;16(6):547-51. 51. Zhang G-X, Yu L-P, Bai W-J, Wang X-F. Selective resection of dorsal nerves of penis for premature ejaculation. Int J Androl. 2012;35(6):873-9. 52. Xu G, Jiang H-W, Fang J, Wen H, Gu B, Liu J et al. An improved dosage regimen of sertraline hydrochloride in the treatment for premature
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56. Arafa M, Shamloul R. A randomized study examining the effect of 3 SSRI on premature ejaculation using a validated questionnaire. Ther Clin Risk Manag. 2007;3(4):527-31. 57. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B. Effect of SSRIs antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol. 1998;18(4):274-81. 58. McMahon CG. Efficacy of dapoxetine in the treatment of premature ejaculation. Clin Med Insights Reprod Heal. 2011;5:25-39. 59. Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA. Tramadol HCL has promise in on-demand use to treat premature ejaculation. J Sex Med. 2008;5(1):188-93. 60. Malonne H, Sonet B, Streel B, Lebrun S, De Niet S, Sereno A et al. Pharmacokinetic evaluation of a new oral sustained release dosage form of tramadol. Br J Clin Pharmacol. 2003;57(3):270-8.
compound for premature ejaculation, on male rat sexual behavior. Int J Urol. 2014;21(3):325-9.
Volume 8: Number 1. 2015 | Page 47
RCSIsmjstaff review Culture, criteria and clinicians – dissecting discrepancies in the prevalence of attention deficit hyperactivity disorder
Abstract
Hailey Carroll RCSI senior staff writer
Consideration of social factors is key to understanding and assessing under- and over-treatment of attention deficit hyperactivity disorder (ADHD), as they play a large role in presentation, diagnosis and management strategy. The lower prevalence of ADHD in Ireland, as compared to other countries, is an example of the varied rates of the disease around the world. Is this because, here in Ireland, the symptoms of ADHD are viewed as a behavioural problem? Variable diagnostic rates are in part unavoidable, as ADHD diagnoses are made based on behaviour alone. The use of different diagnostic criteria may result in a lower diagnostic ‘bar’, which manifests as a generally higher prevalence of ADHD as more are likely to fit its less rigid diagnostic criteria. Similarly, prescribing patterns, and thus treatment protocols, for children with ADHD vary greatly. This article discusses these issues and how they fit into the Irish context. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:48-51.
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RCSIsmjstaff review Introduction Attention deficit hyperactivity disorder (ADHD) is a childhood onset disease with a variety of clinical symptoms: inability to focus, overactivity, difficulty controlling behaviour, or a combination of these.1 As a result the child’s behaviour may present as inappropriate for his or her age and development. Since its inclusion in the 1994 DSM IV, the number of children newly diagnosed with ADHD each year continues to rise exponentially.2 Though the global prevalence of ADHD has increased significantly since that time, great variation exists from country to country; reports from the United States put this number at 11%, much higher than reported rates from Africa (8.5%) and Europe (4.6%).3,4 This has led to questions and concerns among the public, in the media, and between healthcare professionals. Some are as simple as “why?” and others more controversial: “is ADHD really a disease?” Even if these answers were clear, questions regarding treatment of ADHD would remain. The approach to management varies from country to country, and includes varying degrees of pharmacological therapy and behavioural intervention, either alone or in combination. Pharmacological treatment of ADHD generally comes under the most scrutiny and its use is impacted by a variety of societal and political factors. A major concern among the public, media and healthcare professionals is the potential that ADHD is being over-diagnosed, and by extension over-treated.5,6 In Ireland, the prevalence of ADHD is reported at between 1 and 3%, well below the international and European averages.2 Although Ireland is not the only country with a lower than average prevalence of ADHD, the exact reasons for the difference are not understood. Is this because Irish physicians do not recognise the symptoms of the disease — or is there a different diagnostic ‘bar’ in Ireland? Perhaps there are Irish cultural factors that discourage patients and their families from presenting with the symptoms? Conversely, are other countries suffering from over-diagnoses of the disease? Providing answers to these questions is essential in order to ensure optimal care for Irish children.
Standard diagnostic criteria Variable diagnostic rates are in part unavoidable, as ADHD diagnoses are made based on behavioural criteria alone. This is compounded by the use of different diagnostic criteria; clinicians in some countries primarily use the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition, or DSM-V, as a guideline for ADHD diagnosis, whereas others, including Ireland, are guided primarily by the International Classification of Diseases, 10th Revision, or ICD-10.7 To fit a diagnosis of ADHD, the DSM-V requires that a child must “exhibit at least six symptoms from either or both the inattention criteria and/or hyperactivity-impulsivity criteria”.8 The ICD-10 offers both a different name (hyperkinetic disorder) and diagnostic criteria for
the same condition. To meet these criteria, impaired attention and overactivity should be persistent and pervasive across different settings, such as home, clinic and classroom. Additionally, the child must exhibit at least three attention problems, at least three activity problems, and meet further criteria that show an abnormality of age and attention for his or her developmental age.9 This lower diagnostic bar in countries where diagnosing clinicians are guided by the DSM-V’s criteria may manifest as a generally higher prevalence of ADHD in children, as more are likely to fit its less rigid diagnostic criteria. In addition to the use of different criteria, the staff involved in clinical decision-making across healthcare contexts can influence diagnostic patterns. Certain health systems place greater emphasis on engaging a multidisciplinary team to aid in the diagnosis and treatment of a child with ADHD. Due to the need for more people to be in agreement, this approach potentially results in fewer diagnoses.10 This can be explained by more variables that are introduced with each additional clinician, including his or her perception of the condition and assessment method used. These factors, in combination with differing diagnostic criteria, make comparing prevalence rates of ADHD as a whole difficult. However, even among all these variables, countries that use the DSM-V diagnostic criteria have far greater reported prevalence rates.11
Management strategies The first line pharmacological treatment for ADHD in children is stimulant medication, most commonly methylphenidate and amphetamine.12,13,14 Their mechanism of action is to increase the concentration of the monoamines dopamine and norepinephrine in the synaptic cleft by blocking their reuptake into the presynaptic neuron.15 Stimulants have a significant side effect profile, which includes increased heart rate and blood pressure, headaches, sleeping problems, tiredness, decreased appetite, and – especially problematic in the paediatric population – possible effects on height and weight trajectories. In 3-6% of children treated, use of stimulants may lead to more serious neurological or psychiatric side effects including psychotic symptoms and mood disorders.12,16 Due to these potential adverse effects, stimulant use in children is frequently debated despite being generally well tolerated in practice. Comparatively little controversy surrounds the use of behavioural and psychosocial therapies, as they are generally viewed as non-damaging. They may be, however, difficult to access to the extent that they are needed. The development of such services can range from non-existent, or available only in large cities, to well-established, depending on the psychiatric service and culture of a particular country.14 Research on the efficacy of pharmacological versus psychosocial therapy has turned up variable results, but there is large support for multimodal treatment, which incorporates both, as superior to either alone. Some guidelines for clinical practice specifically
Volume 8: Number 1. 2015 | Page 49
RCSIsmjstaff review recommend that ADHD should be managed via joint use of psychoeducation, psychotherapy and pharmacotherapy.12,17 Internationally, prescribing patterns, and thus treatment protocols for children with ADHD, vary greatly. A longitudinal study of Canadian children found that being prescribed a stimulant medication for ADHD was significantly predicted by core ADHD symptoms, as well as demographics such as being male, low maternal immigration, and immigrant status.12 One of the most reliable predictive factors regarding the incidence of prescribed psychostimulants is economical; per capita gross domestic product (GDP) heavily predicts the prescription rate and use of ADHD medication across all countries. However, three countries in particular – the United States, Canada, and Australia – had higher than predicted use. The United States exceeded predicted expenditures by 594%.11 To investigate this trend further, recent studies have looked at prescribing patterns for ADHD medications across Europe. In 2014 Caci et al. found a significant difference in the type of therapy received by children with ADHD across European countries; 5% of children in Italy received medication alone compared to 33% in the Netherlands and the UK. To put this in context, in the United States nearly 60% of children with ADHD receive pharmacological therapy.3,7 Differences were also seen in the proportions of patients receiving multimodal therapy or behavioural therapy alone. Interestingly, despite the specific difference in prescribing rates, there was no significant difference in satisfaction with treatment between countries.3
Cultural influence Cultural mentality can be a large driving force in the recognition and management of psychiatric illness. Perspectives on children diagnosed with a psychological condition vary dramatically around the world. Some countries have very strong ‘anti-psychiatry’ and ‘anti-medication’ values.14 Culture does not simply impact on diagnostic and management practices in the healthcare context; it may also play a role in a parent seeking care for a symptomatic child. Some cultures consider the symptoms consistent with ADHD a behavioural problem that does not require treatment. In cultures where a psychiatric diagnosis is looked upon unfavourably, parents are reluctant to seek help for children who may be struggling due to underlying ADHD; parents do not want to label their child as deviant or having a pathological disorder. Conversely, where ADHD is commonly diagnosed and treated pharmacologically, parents may be driven by the idea of a ‘quick fix’ for a child who may not actually require intervention.11
The Irish context In Ireland, as in many countries, stigma and lack of mental health literacy act as major barriers to seeking help for psychiatric difficulties.18 Perhaps this is why the published rate of ADHD in Ireland is far lower than the international average.2
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It is estimated that the prevalence of childhood psychiatric disorders is actually far higher than published numbers, but that only one in 20 affected children are receiving mental healthcare.18 ADHD in Ireland is a particularly unsettled condition, without a clear place among diagnosing clinicians in the health service. ADHD activism groups, led mostly by parents of children who are affected by the disease, perceive themselves as “battling against perceptions put forward in the popular media that ADHD is a consequence of bad parenting and dysfunctional family relationships”.19 Paediatricians in the UK and the US consider ADHD a core component of their casework, whereas the Irish situation is less clear.18 The Health Service Executive (HSE) outlines the process for being diagnosed with ADHD in Ireland on its website – describing a lengthy process that is likely to involve the child’s general practitioner, a period of watchful waiting, followed by a referral to a child or adult psychiatrist, a paediatrician, or the mental health service for children and young people.20 The Child and Adolescent Mental Health Service (CAMHS) is, despite the promise of its title, an underdeveloped, overworked service. Referrals to CAMHS are generally met with long waiting lists, which ultimately delay diagnosis and treatment of childhood psychiatric disorders including ADHD.10,18 A 2001 survey of Irish paediatricians found that 30% of respondents’ caseload was management of ADHD. The overwhelming majority of this cohort believed that they should be involved in assessment, and to a lesser extent, treatment, of childhood psychiatric disorders. More than half also expressed interest in additional training. Interestingly, of this group 45% reported that they used treatments other than medication.21 In a later survey of paediatricians, child psychiatrists and GPs in a selected catchment area for the Dublin CAMHS programme, ADHD medications, overwhelmingly methylphenidate, were reported to be the most frequently prescribed psychiatric medication.19 Overall, this picture suggests a role for further training, both in the prescribing and use of stimulant medication, and in behavioural therapies.
Conclusion Consideration of social factors is key to understanding and assessing under- and over-treatment of ADHD, as they play a large role in presentation, diagnosis and management strategy. The lower prevalence of ADHD in Ireland, as compared to other countries, is just an example of the varied rates of the disease around the world. Is this because, here in Ireland, the symptoms of ADHD are viewed as a behavioural problem? Have cultural drivers and anti-psychiatry sentiments deterred parents from seeking help for their children, or clinicians from administering a diagnosis? Or, is the difference explained by the lack of a concrete diagnostic process, compounded by the
RCSIsmjstaff review stricter diagnostic criteria Ireland uses in concordance with the ICD-10? Ultimately, there is a need for a more effective, streamlined, and attentive process for diagnosing and treating children with ADHD in Ireland. Data from cross-sectional, retrospective, and follow-up studies indicate that children and youths with ADHD are at risk of developing other psychiatric difficulties in childhood, adolescence and adulthood, including antisocial behaviour, and mood, anxiety and substance use disorders.22
Regardless of reasons for the possible under- or over-treatment of the disease, its long-term impacts are substantial. It is essential to further investigate this issue so that clinicians are not doing a disservice to children in Ireland: no matter which box they tick or criteria they fulfill – primum non nocere.
References 1.
2.
PubMed Health. Attention deficit hyperactivity disorder. [Internet]
hyperactivity disorder medication use: population-based longitudinal
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002518/.
study. Br J Psychiatry. 2014;205(4):291-7.
Quinlan A. Is Attention Deficit Hyperactivity Disorder (ADHD) really a
hyperactivity disorder (ADHD) in children with comorbid tic disorders.
<http://www.irishexaminer.com/lifestyle/healthandlife/parenting/is-attent
Cochrane Database Syst Rev. 2011;(4):CD007990. doi:
Caci H et al. Daily life impairments associated with self-reported childhood/adolescent attention-deficit/hyperactivity disorder and
ADHD: social context and recent trends. Psychiatr Serv. 2011;62(5):459-64. catecholamine systems and behaviour. Annu Rev Pharmacol Toxicol.
2014. Available from:
1993;33:639-77. adolescent and adult patient beliefs and attitudes impact treatment?
Graf WD, Miller G, Nagel SK. Addressing the problem of ADHD
Patient Prefer Adherence. 2014;8:1317-27. al. Long-acting medications for the hyperkinetic disorders. A systematic
Goldman LS et al. Diagnosis and treatment of
review and European treatment guideline. Eur Child Adolesc Psychiatry.
Council on Scientific Affairs, American Medical Association. JAMA. 1998;279(14):1100-7. Hodgkins P, Sasane R, Meijer W. Pharmacologic treatment of attention-deficit/hyperactivity disorder in children: incidence, prevalence,
8.
2006;15(8):476-95. 18. O’Keefe N, McNicholas F. Paediatricians’ views on their role in the assessment and management of ADHD and autism. Ir Med J. 2011;104(9):282-4. 19. Edwards C. Spatialising the contentious politics of ADHD: Networks and
and treatment patterns in The Netherlands. Clin Ther.
scalar strategies in health social movement activism. Health Place.
2011;33(2):188-203.
2014;29:52-9.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, D.C.; American Psychiatric Association, 2013.
9.
17. Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J et
2014;14(5):569-81. attention-deficit/hyperactivity disorder in children and adolescents.
7.
16. McCarthy S. Pharmacological interventions for ADHD: how do
dhd.html?_r=0. medication as neuroenhancements. Expert Rev Neurother. 6.
15. Seiden LS, Sabol KE, Ricaurte GA. Amphetamine: effects on
Friedman R. A Natural Fix for A.D.H.D. The New York Times. 31 October http://www.nytimes.com/2014/11/02/opinion/sunday/a-natural-fix-for-a
5.
10.1002/14651858.CD007990.pub2. 14. Hinshaw S et al. International variation in treatment procedures for
experiences of diagnosis and treatment: Results from the European Lifetime Impairment Survey. Eur Psychiatry. 2014;29(5):316-23. 4.
13. Pringsheim T, Steeves T. Pharmacological treatment for attention deficit
disease? Irish Examiner. 26 May 2013. Available from: ion-deficit-hyperactivity-disorder-adhd-really-a-disease-232119.html>. 3.
12. Galera C et al. Clinical and social factors associated with attention deficit
(Accessed on 2014 February 24). Available from:
World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva; World Health Organisation, 1992.
10. McNicholas F. Safe and judicious paediatric psychotropic prescribing. Ir
20. Health Service Executive. ADHD. Available from: http://www.hse.ie/eng/health/az/A/ADHD/Diagnosing-ADHD.html. 21. McNicholas F. Psychotropic prescribing practices of paediatricians in the UK. Child Care Health Dev. 2001;27(6):497-508. 22. Heiligenstein E, Guenther G, Levy A, Savino F, Fulweiler J. Psychological and academic functioning in college students with attention deficit hyperactivity disorder. J Am Coll Health. 1999;47(4):181-5.
Med J. 2014;107(2):41-3. 11. Lang H, Scheffler R, Hu T. The discrepancy in attention deficit hyperactivity disorder (ADHD) medications diffusion: 1994-2003 – A global pharmaceutical data analysis. Health Policy. 2010;97(1):71-8.
Volume 8: Number 1. 2015 | Page 51
RCSIsmjstaff review The evolutionary basis of human disease
Abstract
Daniel Oâ&#x20AC;&#x2122;Reilly RCSI medical student
Natural selection is the driving force behind evolution and describes how traits become fixed in a population due to their tendency to produce reproductive success. An understanding of this process and how it relates to our own species, Homo sapiens, can help us to better understand why many medical conditions occur. Natural selection acts over many generations in order to elicit an effective and stable change in phenotype. In contrast, in the space of just a few generations our environment has changed almost completely. This leads to a mismatch between the internal and external milieu. Evolution is the closest thing to a grand unifying theory in biology, has implications in all areas based in biological science and, as illustrated through this paper, has the potential to inform us about the aetiology of disease and our potential to treat it. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:52-55.
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RCSIsmjstaff review Introduction Theodosius Dobzhansky famously declared: “Nothing in biology makes sense except in the light of evolution”.1 Despite this, medical students, biomedical researchers and clinicians rarely consider the importance of evolution in their respective fields. Natural selection is the driving force behind evolution and describes how traits become fixed in a population due to their tendency to produce reproductive success. An understanding of this process and how it relates to our own species, Homo sapiens, can help us to better understand why many medical conditions occur.2 By understanding that natural selection is a slow process, that traits that benefit us in one circumstance may be deleterious in another, and that the evolutionary process values reproductive fitness over individual fitness, we create a model in which we can better understand the aetiology of human illness and consider possible interventions. We can also connect diseases from apparently disparate fields under one conceptual umbrella, which can aid us in furthering research.2
Disease as a consequence of modern lifestyle Evolution is a slow process. Natural selection acts over many generations in order to elicit an effective and stable change in phenotype. In contrast, in the space of just a few generations our environment has changed almost completely. This leads to a mismatch between the internal and external milieu.3 In developed countries, calorie-dense food is readily available and exposure to a wide range of pathogens is at its lowest ebb since any point in human history. However, rather than eliminating disease burden in modern society this has simply resulted in a shift towards chronic disease caused by long-term calorific excess and imbalanced immune response. Thrifty genes and the ‘Out of Africa’ hypothesis Modern evolutionary theory states that Homo sapiens emerged as a species from either the African continent directly or from very recent emigrants. This means that for the vast majority of our time on this planet we lived in environments not dissimilar to the modern African savannah. This theory – referred to as the recent single origin hypothesis (‘Out of Africa’ hypothesis) – helps to explain many unique features of man relative to his great ape cousins; bipedal gait, relative hairlessness and large numbers of sweat glands have distinct advantages in the hot, open spaces in which early man would have searched for food.4 Today’s African savannah lacks in fast food restaurants what it boasts in biological diversity, and so we must assume that this was also true at the dawn of modern humans. The corresponding lack of access to calorie-dense, sweet or fatty foodstuffs meant it was advantageous for our ancestors to eat large quantities when they came upon them (beehives, fruit trees, successful hunts) and so this trait was selected for. Additionally, individuals who could better lay down fat stores ahead of periods of famine (possessing so called ‘thrifty genes’) would also gain a survival advantage.5 Fortunately, we no longer live in an environment where we must
strain against the elements in order to maintain body weight; however, the combination of our ancestral sweet tooth and fat deposition promotes the development of the global epidemic of overweight and obesity seen today. Metabolic syndrome is characterised by increased insulin resistance, abdominal obesity, dyslipidaemia and hypertension. Interestingly, parallels can be drawn between this pathological state in man and the physiology of animals that undergo long periods of relative calorie deficit, such as hummingbirds and hibernating mammals. This suggests that the metabolic syndrome is an extreme consequence of the natural selection of individuals best equipped for fat storage. Unfortunately, this trait leaves them maladapted to modern life.6 The hygiene hypothesis The steady increase in chronic inflammatory disease in the developed world7 may be partially explained by the hygiene hypothesis, which states that excessively clean environments lead to a tendency for our immune system to overreact to self-antigens. Numerous epidemiological studies suggest that children who are raised in less sterile environments, for example with a larger number of siblings, who attend crèches or were raised in the countryside, have a lower tendency towards atopy, or allergic and autoimmune illness.8 The cellular biology behind this counter-intuitive idea is thus. For most of human evolution we have co-evolved with both pathogens and commensals (‘old friends’), which helped to balance our immune system by direct modulation and tolerance. Once we eliminate these from our environment, our immune system loses its point of reference and becomes imbalanced, acting on self-antigens to produce disease. An imbalance between Th1/Th2 cells is traditionally considered the culprit, where Th1 cells are implicated in cell-mediated autoimmune conditions (type I diabetes mellitus) and Th2 cells in antibody-driven pathologies (asthma).8 Helminths (worms) are one of the most important pathogens in generating correct immune response for a number of reasons: (1) they have considerable ability to elicit immunoregulatory circuits; (2) they produce chronic infections from childhood; and, (3) they contribute to the virulence of other pathogens. The importance of immunoglobulin E (IgE) in both allergy and helminth infections also supports their central role in the production of tolerance.9 In short, natural selection of elements of the immune system that protected against lethal infections is now maladaptive, as exposure to these pathogens is not as commonplace in the modern environment.
Natural selection as a balancing act Evolution balances the costs of a particular trait against the benefits that it confers upon the individual. Often a trait that is massively beneficial in one sense can be immensely costly in a number of others; provided it produces a net positive in survival and reproduction, it will spread and eventually become a fixed feature in the species.2 Volume 8: Number 1. 2015 | Page 53
RCSIsmjstaff review
The advantages of being bipedal A good example of this in man is a bipedal gait, or walking on two legs as opposed to four. This practically species-defining trait emerged somewhere between six and eight million years ago, with evidence of at least habitual bipedalism seen in the Australopithecus Spp., some of our earliest ancestors.10 Shifts in the environment in early evolution resulted in a reduction of woodland and an increase in open grassland; our arboreal ancestors had to traverse longer distances on the ground than they previously had. Doing so by ‘knuckle walking’, as seen in modern chimpanzees (Pan troglodytes) was extremely energy costly. Individuals who could walk upright (a more efficient way of locomotion over open spaces) gained a selective advantage by needing less food to survive.11 This is how our ancestors moved from brachiation (or swinging through trees) and knuckle walking to habitual bipedalism, and finally the upright posture we utilise today. Other fringe benefits of bipedalism probably helped to set the trait in the species; collecting fruit, utilising tools and hunting became easier and more energy efficient, allowing our early ancestors greater access to calories than their competitors.12 The move from a quadruped to a bipedal gait was not without consequence on human anatomy. The human foot is drastically different from our Hominidae cousins with our great toe (hallux) permanently adducted and directed anteriorly with a distinct arch — features that promote force dissipation and store elastic energy during walking. The lower limb is longer than the forelimbs to increase the leverage it possesses.10 However, perhaps the two most important changes that result in disease in modern man is the co-optation of the subvertical backbone for vertical locomotion and the shortening of the anteroposterior distance between the sacrum and the acetabulum in the pelvis.10,13 Our long history of chronic back pain Back pain is one of the most common problems a doctor is likely to encounter in practice; it is a significant cause of morbidity globally and a major cause of missed work days.14 Humans suffer from more back pain than any other species as a consequence of Page 54 | Volume 8: Number 1. 2015
having retained a quadruped spine but adopting a biped gait. A number of minor modifications to our spines allow us to cope with the 90º change in gravity vector. We possess curvatures in both the cervical and lumbar regions, which help to dissipate the force going through them. We also have more lumbar vertebrae than other great apes, but they are shorter to produce greater support.13 Nevertheless, the spine remains based on a quadruped design, meaning that back pain remains a problem in Homo sapiens.13 The obstetric dilemma Humans, in part because of their bipedal gait, are almost uniquely difficult to bring into the world. Human labour is slow and dangerous when compared with the great apes, which is often illustrated by the fact that humans are the only animals that seek help in labour instead of isolation.12 Effective bipedal gait requires anterior displacement of the sacrum to stabilise the spine and multiple changes in pelvic architecture, which affects parturition. The resulting decrease in pelvic outlet diameter is especially problematic in modern humans as compared with our predecessors (with the exception of possibly Homo neanderthalensis) because of encephalisation, or our large cranial capacity.15 The end result is considerable sexual dimorphism in the shape of pelvises. In order to support childbirth in addition to walking upright, the female pelvis has acquired the ‘gynoid’ shape beloved of obstetricians and anatomists alike.12 As a result of encephalisation human babies are born comparatively early and require a greater level of nurturing (secondary altriciality).12 Despite this cost, the benefits of upright gait and larger brain size outweigh the risks of difficult childbirth. This may also be responsible for many of the social characteristics of our species. Increased child rearing requires greater co-operation and larger social groups.
Reproductive success is paramount in evolution A common misunderstanding of evolution is that natural selection is concerned with survival (‘survival of the fittest’). This is not truly the case; in fact, reproduction determines which traits
RCSIsmjstaff review are passed on. While this may correlate with survival (the longer you live the greater the chance you will reproduce) the two are not necessarily interlinked.2 Disposable soma Organisms are expensive structures to maintain from a bioenergetics point of view; they fly in the face of thermodynamics, acting as discrete, organised packets of chaotic chemical reactions for the duration of their lifespan. In spite of this organisms survive for a reasonably long time in good condition, with the body repairing most insults without much difficulty (scratches, bumps, bruises, etc.). So why does it stop? Why does the body cease to repair as well as we get older? Why does our hair go grey, our skin lose its elasticity and our joints get painful? Surely allowing our bodies to fall into a state of disrepair is a failing in natural selection.16 Fortunately for the theory of evolution (but unfortunately for us) this is not the case. Evolution values reproduction over all else. When the value of a reproductive entity in propagating genes becomes less than the energetic cost of homeostasis a process of senescence begins. This ‘disposable soma’ hypothesis suggests that ageing – despite occurring in a relatively predictable fashion – is not a programmed process but a slow deterioration influenced by environment, fecundity and genes. This also helps us to understand why genetic engineering has yet to indefinitely extend life in even the simplest organisms: it’s simply not in our genes.16 Despite recent biomedical advances, the diseases of
ageing will likely be relevant to clinical practice for the foreseeable future. Traits that are beneficial in our reproductive prime are selected for preferentially, as they are the genes which are passed on to our offspring. Traits that are harmful in later life may be preserved provided they confer an advantage in reproduction, a principle known as pleiotropic antagonism. Although no specific gene has been identified that acts in such a manner, it makes sense that metabolic resources would be optimally spent in the reproductive years of life rather than being ‘wasted’, from an evolutionary sense, in our twilight.16
Final thoughts Although this article has focused mainly on human macro-evolution, micro-evolutionary processes that occur in cancer and microbial pathogens are of equal importance to human health and disease. The iatrogenic selection pressures placed on microbes and cancer cells alike produce the refractory and resistant disease we have become familiar with in a post-antibiotic/classical chemotherapeutic medical landscape.17,18 Evolution is the closest thing to a grand unifying theory in biology. ‘Darwin’s dangerous idea’ has implications in all areas based in biological science and, as has been illustrated through this paper, has the potential to inform us about the aetiology of disease and our potential to treat it. By understanding natural selection and the processes that produce these diseases, we come one step closer to developing effective therapies, as well as a better understanding of how we became what we are today.
References 1. 2.
Dobzhansky T. Nothing in biology makes sense except in the light of
10. Latimer, B. The Perils of Being Bipedal. Ann Biomed Eng. 2005;33:3-6.
evolution. Am Biol Teach. 1973;35:125-9.
11. Foley RA, Elton S. Time and energy: the ecological context for the
Varki A. Nothing in medicine makes sense, except in the light of evolution. J Mol Med (Berl). 2012;90:481-94.
3.
Nesse RM, Williams GC. Evolution and the origins of disease. Sci Am.
evolution of bipedalism. In: Strasser E (ed.). Primate Locomotion: recent advances. New York; Plenum Press, 1998:419-33. 12. Wittman AB, Wall LL. The evolutionary origins of obstructed labour:
1998;279:86-93.
bipedalism, encephalisation, and the human obstetric dilemma. Obstet
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Tattersall I. Human origins: Out of Africa. PNAS. 2009;106:16018-21.
Gynaecol Surv. 207;62:739-48.
5.
Chakravarthy MV, Booth FW. Eating, exercise, and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol. 2004;96:3-10.
6.
Johnson RJ et al. Redefining metabolic syndrome as a fat storage condition based on studies of comparative physiology. Obesity (Silver Spring). 2013;21:659-64.
7. 8.
Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases.
muscular properties of the trunk – implications for human low back pain. Pathophysiology. 2005;12:233-42. 14. Hoy D et al. A systematic review of the global prevalence of low back pain. Arthritis Rheum. 2012;64:2028-37. 15. Weaver TD, Hublin J-J. Neandertal birth canal shape and the evolution of human childbirth. Proc Natl Acad Sci USA. 2009;106:8151-6.
Autoimmun Rev. 2003;2:119-25.
16. Kirkwood TBL. Understanding the odd science of aging. Cell. 2005;120:437-47.
Sironi M, Clerici M. The hygiene hypothesis: an evolutionary perspective.
17. Heng HHQ et al. The evolutionary mechanism of cancer. J Cell Biochem.
Microbes Infect. 2010;12:421-7. 9.
13. Schilling N, Arnold D, Wagner H, Fischer MS. Evolutionary aspects and
Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the hygiene hypothesis. Science. 2001;296:490-4.
2010;109:1072-84. 18. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74:417-33.
Volume 8: Number 1. 2015 | Page 55
RCSIsmjstaff review Melatonin and cancer: itâ&#x20AC;&#x2122;s nothing to yawn at
Abstract
Gurtej Singh RCSIsmj staff writer
Sleep plays a vital role in health and well-being. Melatonin, a hormone secreted from the pineal gland, is integral to sleep induction and maintenance. Melatonin secretion increases after the onset of darkness, peaks in the middle of the night, and gradually falls during the second half of the night. Exogenous preparations are widely marketed in the treatment of jet lag and insomnia. Melatoninâ&#x20AC;&#x2122;s actions extend beyond sleep induction and include complex signalling pathways that induce cell protection, inhibit angiogenesis, and stimulate endogenous immunomodulators. Recent studies have indicated that women who work night shifts (and therefore have decreased levels of melatonin) are at an increased risk of breast cancer. Researchers have begun to exploit this association by supplementing chemotherapeutic and supportive cancer therapies with melatonin and have had largely positive results. However, the majority of trials are by a single group of researchers and external validation is needed. Initial results from the Cancer Treatment Centers of America (CTCA) and National Cancer Institute (NCI) have been positive. Further studies should investigate the long-term side effects of melatonin treatment. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:56-60.
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RCSIsmjstaff review Introduction Humans spend approximately one-third of their lives sleeping. Sleep is observed in all animals in some form and likely has a vital evolutionary relevance.1 Despite this universality, sleep is a poorly understood phenomenon. Once described by Elizabethan dramatist Thomas Dekker as “…the golden chain that ties health together,”2 it has always been understood to have a role in our physical and mental well-being. But how? The normal sleep-wake cycle is regulated by melatonin, a hormone secreted from the pineal gland.3 The man who discovered it was also the first person to examine its clinical use: Dr Aaron Lerner. In 1975 he self-administered intravenous melatonin for five days.4 He described feeling “relaxed” and “sleepy”. Melatonin is now widely marketed as a sleep aid and used in the treatment of jet lag.5 Melatonin may also play other roles in health and well-being; it is a potent antioxidant and protects cells from free radical damage.6 Melatonin secretion increases after the onset of darkness, peaks in the middle of the night (between 2.00am and 4.00am), and gradually falls during the second half of the night. Exposure to light at night can effectively eliminate the nocturnal rise in melatonin; decreased melatonin levels have been demonstrated in shift-workers exposed to night-time.7 This phenomenon has been proposed as an explanation for shift-workers’ increased risk of cancer.8 The data surrounding the link between night shifts and cancer is somewhat conflicting. Many of these studies are retrospective in design and prove correlation, not causation.9,10 However, therapeutic studies have demonstrated the oncostatic effects of melatonin.11,12,13,14 Using melatonin in the treatment of neoplasms represents an interesting shift in medical oncology and has exciting therapeutic implications. The purpose of sleep is unknown, but perhaps, through the action of melatonin, sleep prevents cancer?
Understanding the pathophysiology Melatonin, ‘the hormone of darkness’, is known to regulate the circadian rhythm and sleep cycle by binding to suprachiasmatic receptors. In addition to this role, it is also thought to bind to intracellular receptors found in the central nervous system and peripherally, which leads to multiple downstream effects. In general, melatonin seems to influence second messenger cascades, which vary depending on the cell type. In leukocytes, stimulation results in the generation of reactive oxygen species (ROS), which then act as second messengers. The ROS signal downstream molecules to sustain the transcription of genes that are involved in survival-promoting effects, many of which are found in the mitochondria. During metabolic cell stress, it is hypothesised that melatonin protects cells by producing ROS, which increase mitochondrial membrane stability and preserve their energy-producing function. The homeostatic effect of melatonin extends to environmental stressors, accelerated metabolism and ageing.15
A series of receptor-independent mechanisms may explain melatonin’s pleiotropic effects. Melatonin has been shown to directly stimulate the activity of several antioxidant and detoxification enzymes, thereby preventing the accumulation of DNA damage during oxidative stress, while also stimulating transcription of protection and repair genes.16,17 Its oncostatic effects can be attributed to its stimulatory potential on lymphocytes, monocytes/macrophages, and natural killer (NK) cells, as well as promoting granulocyte and B lymphocyte survival.18 Because NK cells are effective against a variety of tumour types, notably leukaemias and lymphomas, the enhancement of NK cell activity by melatonin may have considerable significance for therapeutic applications.19 Both physiologic and pharmacologic concentrations of melatonin result in protective effects, although the mechanisms are not fully understood. Melatonin may also play a significant role in decreasing angiogenesis, an important mediator of tumour progression.20,21,22 Exogenous melatonin has been shown to decrease the activity of hypoxia-inducible factor 1 (HIF-1).22 Researchers at Henry Ford Hospital23 evaluated the action of melatonin on angiogenesis in oestrogen receptor negative breast cancer in vitro and in vivo using cell and mouse models, respectively. Mice in a treatment group received pharmacologic doses of melatonin for 21 days. At the end of the 21-day treatment, researchers used single photon emission computed tomography (SPECT) to determine whether melatonin therapy effectively reduced the size of implanted human breast cancer or impacted the formation of new blood vessels in the mice. Based on SPECT findings, the treatment group had significantly smaller tumours and less vascular growth compared to the control group.23 This study highlights the exciting therapeutic potential of melatonin in the treatment of cancer. In vitro and rodent studies have several limitations specific to studies of melatonin and cancer. Rats are nocturnal creatures and, although they demonstrate a serum level peak in melatonin during the night, it is fairly low compared to that in humans.24 Additionally, neoplasm formation is surprisingly different between humans and rodents.25 Inbred strains of mice have a high incidence of spontaneous malignant tumours, but also of spontaneous tumour regression.26 Similarly, in vitro studies are not reflective of human cell physiology. Cells are kept in conditions with variable temperature, electrolyte concentration, and extracellular matrix contents.27 Therefore, although in vitro and rodent studies can highlight important pathophysiological effects of melatonin, they are poor adjuncts to the complex human physiology and provide only limited evidence.
Making the link between shift work and cancer Between 1992 and 2013, at least 20 different epidemiologic studies have investigated the link between sleep, melatonin and oncogenesis.28 Many of these focus on the correlation between cancer and night shift work; however, several limitations have been found with this model. Generally, there has been a lack of Volume 8: Number 1. 2015 | Page 57
RCSIsmjstaff review
consistency in defining exposure to light at night. Potential confounding factors, such as socioeconomic status, number of children, body mass index, and smoking and alcohol consumption are typically not well controlled for.29 Additionally, studies rarely account for individual factors that may modify the impact of shift work, especially chronotype.30 Chronotype – or diurnal preference – can be defined as a patient’s preference for activity during the daytime compared to the night-time, and may be related to genetic polymorphisms.31 It may also have a role in explaining individual differences in melatonin levels. Most studies that examine the relationship between melatonin and neoplasia have focused on its antiproliferative effects on breast cancer. Though melatonin is implicated in a variety of cancer types, it has an additional role in specifically decreasing oestrogen receptor expression on breast cells and decreasing turnover of breast epithelial cells.32 One of the first large studies of this effect was carried out in 1996 by Tynes et al.,10 who investigated the incidence of breast cancer in 2,619 female Norwegian radio and telegraph operators with potential exposure to light at night. The authors observed no association for women aged 50 years or less, but reported an increased breast cancer risk among postmenopausal women aged over 50 years (odds ratio [OR] 4.3; 95% CI 0.7-26).10 In 2001, Schernhammer et al. from Harvard University investigated the relationship between night shift work and breast cancer in nurses.9 Participants were asked for the number of years they had worked rotating night shifts. A moderate increase in breast cancer risk was observed among the women who worked for 15-29 years on rotating night shifts (RR=1.08, 95% CI 0.90-1.30), and this further increased among women who worked for 30 or more years (RR=1.36; 95% CI 1.04-1.78). The assessment of exposure to light at night was an important limiting factor in this study, as was the fact that no information was given regarding the actual number of nights worked per Page 58 | Volume 8: Number 1. 2015
month.9,33 Schernhammer et al.34 followed up their 2001 study by using novel techniques to measure urinary melatonin levels in the same cohort of registered nurses and correlate this with breast cancer risk. Melatonin’s major urinary metabolite, 6-sulfatoxymelatonin (aMT6s), is closely correlated with peak plasma melatonin levels during the previous night.35 The study found a statistically significant inverse association between first morning aMT6s level and breast cancer risk ([OR]=0.62, 95% CI 0.41-0.95; p=0.004). In 2013 a highly publicised case-control study by Grundy et al.36 showed a twofold risk of breast cancer in women doing more than 30 years’ shift work, with no association at shorter periods of exposure. Interestingly, this study recorded a lifetime occupational history from each participant and was able to capture the proportion of day, evening and night shifts for each job, allowing jobs with both a rotating and permanent night shift pattern to be captured. This study addressed several limitations of previous research by including a cohort with a wide range of occupations, oestrogen receptor status, and important potential confounding variables such as body mass index, smoking history and reproductive history. Future epidemiologic studies should assess shift work characteristics such as regular versus irregular shifts, time schedules for each shift and intensity of light exposure.
Exploiting melatonin as a therapeutic agent Numerous clinical trials have attempted to address the impact of exogenous melatonin therapy on solid tumours.11,12,13,14 One of the earliest studies, published in 1994 by Lissoni et al.,11 investigated exogenous melatonin in the treatment of unresectable brain metastasis versus supportive care alone. Survival at one year and mean survival time were significantly higher in patients treated with melatonin than in those who received supportive care alone. Additionally, metabolic and
RCSIsmjstaff review infective complications from supportive medications (steroids and anticonvulsants) were significantly lower in the melatonin treatment group. Ten years later, the same research group13 investigated the five-year survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin. The percentage of tumour regression was significantly higher in patients treated with chemotherapy and melatonin versus chemotherapy only (17 of 49 versus 9 of 51, p<0.05). Additionally, the chemotherapeutic regimen was substantially better tolerated in patients treated with melatonin. Specifically, melatonin significantly reduced the percentage of neurotoxicity (2 of 49 versus 9 of 51, p<0.01), thrombocytopenia (1 of 49 versus 7 of 51, p<0.01), and weight loss greater than 10% (3 of 49 versus 21 of 51, p<0.001). In a 2005 systematic review of randomised controlled trials (RCTs), melatonin was found to reduce the risk of death at one year (RR: 0.66, 95% CI: 0.59â&#x20AC;&#x201C;0.73, p<0.56), an effect that was consistent across melatonin dose and type of cancer. The researchers concluded that the substantial reduction in risk of death, low adverse events reported, and low costs related to this intervention suggest great potential for melatonin in treating cancer.37 A significant limitation was the lack of independent verification, as the same network of investigators, Lissoni et al., conducted all 10 of the included trials. This may not necessarily bias the results, but warrants scepticism, especially in the presence of largely positive results. A further two38,39 recent systematic reviews have reported an improvement in tumour remission, one-year survival, and alleviation of radiochemotherapy-related side effects with melatonin treatment, although seven out of the eight included trials were by the same investigators, Lissoni et al. This may affect the credibility of the results to some extent. Trials that are currently underway at the Cancer Treatment Centers of America (CTCA) and National Cancer Institute (NCI) may address these concerns.37 At the time of publishing this article, the CTCA40 had released an abstract examining the effect of evening (PM) melatonin on the survival of patients with advanced non-small cell lung cancer. Analyses revealed better survival for those patients
receiving PM melatonin (p=0.04, RR of death 0.454). Sleep quality was enhanced and quality of life declined less rapidly when PM melatonin was given.40 Some studies investigating the salutary effects of melatonin and cancer yield negative results. Del Fabbro et al.41 investigated the effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia in a double-blind, placebo-controlled trial. They found that in cachectic patients with advanced lung or gastrointestinal cancer, oral melatonin 20mg at night did not improve appetite, weight or quality of life compared to placebo.
Conclusion Sleep is a complex physiologic state that is poorly understood. Melatonin plays a role in sleep induction and maintenance, and disruption of its secretion can lead to negative downstream effects. Exogenous melatonin is widely marketed in the treatment of jet lag and insomnia as it decreases time to sleep onset, increases sleep efficiency, and increases total sleep time.5 The importance of sleep has been highlighted by recent studies, which have found a link between night shifts and increased prevalence of cancer. Melatonin levels have been implicated as a mitigator of tumourigenesis, both as an antioxidant and as an anti-angiogenesis agent. Researchers have begun to exploit this association and studies have reported positive results in trials where melatonin was added to chemotherapeutic or supportive cancer therapies. These findings are, however, preliminary, and should be interpreted with caution. At the time of this publishing the vast majority of positive trials had been conducted by the same group of researchers. These findings require validation from other centres. That said, initial results from Cancer Treatment Centers of America (CTCA) and the National Cancer Institute (NCI) have generally been positive. Once a sleep aid to be taken before long air trips, melatonin is now a potentially cancer-fighting agent with exciting therapeutic potential. This new and exciting role for melatonin may hint at at least one of sleepâ&#x20AC;&#x2122;s purposes. Perhaps Thomas Dekker was correct, and the maxim true: good sleep actually is a staple of good health.
References 4. 1.
Srinivasan V, Spence WD, Pandi-Perumal SR, Zakharia R, Bhatnagar KP, Brzezinski A. Melatonin and human reproduction: shedding light on the
Supplementum. 1978;13:339-47. 5.
Sutton J. Words of Wellness: A Treasury of Quotations for Wellbeing (2nd
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Rodriguez C, Mayo JC, Sainz RM et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36(1):1-9.
Xie L, Kang H, Xu Q et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-7.
ed.). Hay House, 1991. 3.
Arendt J. Jet-lag and shift work: (2). Therapeutic use of melatonin. J R Soc Med. 1999;92(8):402-5.
darkness hormone. Gynecol Endocrinol. 2009;25(12):779-85. 2.
Lerner AB, Nordlund JJ. Melatonin: clinical pharmacology. J Neurol Transm
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Siegel JM. Sleep viewed as a state of adaptive inactivity. Nat Rev Neurosci. 2009;10(10):747-53.
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Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk
24. Arendt J. Melatonin and the Mammalian Pineal Gland. Springer, 1995.
of breast cancer. J Natl Cancer Inst. 2001;93(20):1557-62.
25. Anisimov VN, Ukraintseva SV, Yashin AI. Cancer in rodents: does it tell us
Schernhammer ES, Laden F, Speizer FE et al. Rotating night shifts and risk of breast cancer in women participating in the nursesâ&#x20AC;&#x2122; health study. J Natl Cancer Inst. 2001;93(20):1563-8.
10. Tynes T, Hannevik M, Andersen A, Vistnes AI, Haldorsen T. Incidence of breast cancer in Norwegian female radio and telegraph operators. Cancer Causes Control. 1996;7(2):197-204. 11. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A
about cancer in humans? Nat Rev Cancer. 2005;5(10):807-19. 26. Tillmann T, Kamino K, Mohr U. Incidence and spectrum of spontaneous neoplasms in male and female CBA/J mice. Exp Toxicol Pathol. 2000;52(3):221-5. 27. Hartung T, Daston G. Are in vitro tests suitable for regulatory use? Toxicol Sci. 2009;111(2):233-7. 28. Kamdar BB, Tergas AI, Mateen FJ, Bhayani NH, Oh J. Night-shift work
randomized study with the pineal hormone melatonin versus supportive
and risk of breast cancer: a systematic review and meta-analysis. Breast
care alone in patients with brain metastases due to solid neoplasms.
Cancer Res Treat. 2013;138(1):291-301.
Cancer. 1994;73(3):699-701. 12. Lissoni P, Paolorossi F, Tancini G et al. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br Journal Cancer. 1996;74(9):1466-8. 13. Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003;35(1):12-5. 14. Lissoni P, Brivio F, Fumagalli L et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res. 2008;28(2b):1377-81. 15. Luchetti F, Canonico B, Betti M et al. Melatonin signaling and cell protection function. FASEB J. 2010;24(10):3603-24. 16. Manda K, Ueno M, Anzai K. AFMK, a melatonin metabolite, attenuates x ray induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res. 2007;42(4):386-93. 17. Sliwinski T, Rozej W, Morawiec-Bajda A, Morawiec Z, Reiter R, Blasiak J. Protective action of melatonin against oxidative DNA damage: chemical inactivation versus base-excision repair. Mutat Res. 2007;634(1-2):220-7. 18. Miller SC, Pandi PSR, Esquifino AI, Cardinali DP, Maestroni GJM. The role of melatonin in immuno-enhancement: potential application in cancer. Int J Exp Pathol. 2006;87(2):81-7. 19. Currier NL, Sun LZY, Miller SC. Exogenous melatonin: quantitative
29. Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES. Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer. 2005;41(13):2023-32. 30. Bhatti P, Mirick DK, Davis S. Invited commentary: Shift work and cancer. Am J Epidemiol. 2012;176(9):760-3; discussion 764-5. 31. Gamble KL, Motsinger-Reif AA, Hida A et al. Shift work in nurses: contribution of phenotypes and genotypes to adaptation. PloS One. 2011;6(4):e18395. 32. Stevens RG. Electric power use and breast cancer: A hypothesis. Am J Epidemiol. 1987;125(4):556-61. 33. Dahlgren K. Long-term adjustment of circadian rhythms to a rotating shiftwork schedule. Scand J Work Environ Health. 1981;7(2):141-51. 34. Schernhammer ES, Hankinson SE. Urinary melatonin levels and postmenopausal breast cancer risk in the Nursesâ&#x20AC;&#x2122; Health Study cohort. Cancer Epidemiol Biomarkers Prev. 2009;18(1):74-9. 35. Baskett JJ, Cockrem JF, Antunovich TA. Sulphatoxymelatonin excretion in older people: relationship to plasma melatonin and renal function. J Pineal Res. 1998;24(1):58-61. 36. Grundy A, Richardson H, Burstyn I et al. Increased risk of breast cancer associated with long-term shift work in Canada. Occup Environ Med. 2013;70(12):831-8. 37. Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39(4):360-6. 38. Seely D, Wu P, Fritz H et al. Melatonin as adjuvant cancer care with and
enhancement in vivo of cells mediating non-specific immunity. J
without chemotherapy: a systematic review and meta-analysis of
Neuroimmunol. 2000;104(2):101-8.
randomized trials. Integr Cancer Ther. 2012;11(4):293-303.
20. Park SY, Jang WJ, Yi EY et al. Melatonin suppresses tumor angiogenesis by
39. Wang YM, Jin BZ, Ai F et al. The efficacy and safety of melatonin in
inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res.
concurrent chemotherapy or radiotherapy for solid tumors: a
2010;48(2):178-84.
meta-analysis of randomized controlled trials. Cancer Chemother
21. Dai M, Cui P, Yu M, Han J, Li H, Xiu R. Melatonin modulates the expression of VEGF and HIF-1 alpha induced by CoCl2 in cultured cancer cells. J Pineal Res. 2008;44(2):121-6. 22. Park JW, Hwang MS, Suh SI, Baek WK. Melatonin down-regulates HIF-1 alpha expression through inhibition of protein translation in prostate cancer cells. J Pineal Res. 2009;46(4):415-21. 23. Jardim-Perassi BV, Arbab AS, Ferreira LC et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PloS One. 2014;9(1):e85311.
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Pharmacol. 2012;69(5):1213-20. 40. Lis CG, Levin RD, Grutsch JF et al. Effect of evening melatonin on the survival of patients with advanced non-small cell lung cancer (ANSCLC). J Clin Oncol. 2014;32(Suppl; abstr e19068). 41. Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. J Clin Oncol. 2013;31(10):1271-6.
RCSIsmjstaff review Warming up to therapeutic hypothermia Abstract Sudden cardiac arrest (SCA) occurs when an individual’s cardiac muscle fibres fail to beat synchronously to produce a pulse. Despite improvements in resuscitation since the 1950s, post-arrest prognosis remains poor from a neurological standpoint. Therapeutic hypothermia has been demonstrated to mitigate the anoxic brain injury that occurs during cardiac arrest. An element of post-cardiac arrest care guidelines since 2002, it is the only intervention that has been shown to improve neurological recovery.1 This paper examines the historical use of therapeutic hypothermia, delineates invasive and non-invasive methods of induction, discusses the debate surrounding the optimal temperature for cooling, and introduces ongoing research into this exciting field. Royal College of Surgeons in Ireland Student Medical Journal 2015;(8)1:61-65.
The ABCs of sudden cardiac arrest
Poornima Menon RCSI medical student
Sudden cardiac arrest (SCA), which is responsible for the death of approximately 5,000 people each year in Ireland, describes the failure of cardiac muscle fibres to beat synchronously to produce a pulse.2 When the heart fails to beat effectively, blood is not circulated to the body and the brain. In the event of SCA, cardiopulmonary resuscitation (CPR) may achieve return of spontaneous circulation (ROSC). CPR involves the use of closed cardiac massage, airway and ventilation support, defibrillation (in ventricular fibrillation and ventricular tachycardia) and drug therapy. The rate of ROSC following CPR varies from 18.3% to 43.8%, and is highly dependent on factors such as the age of the patient, the aetiology of the cardiac arrest, the time to commence CPR, the presence of skilled emergency medical personnel, and the initial rhythm on ECG.3,4 Five minutes of anoxia during cardiac arrest is sufficient to cause cerebral injury.5 Therefore, even if ROSC is achieved, 80% of patients who initially survive a cardiac arrest remain in a coma, 40% enter a persistent vegetative state and 80% die within one year.5 In 1958, CPR pioneer Dr Peter Safar published ABC of Resuscitation, a book that has played a critical role in shaping modern day CPR training and, in turn, reducing the mortality rates associated with SCA. The resuscitative steps described by him extended beyond the letter C, to the letter H – hypothermia – for cerebral resuscitation.6 Following ischaemic neuronal injury, elevated concentrations of excitatory neurotransmitters such as glutamate and aspartate lead to neuronal death by toxicity. Hypothermia may inhibit their
FIGURE 1: Safar’s prophetic ABCDEFGHI of resuscitation.7 release, in addition to increasing the release of neurotrophins, acting on astroglial cells to maintain neuronal integrity, inhibiting apoptotic neuronal death, and stimulating angiogenesis in ischaemic areas.8 At a physiological level, cooling results in decreased intracranial pressure, reduced brain metabolism, lower oxygen consumption and, therefore, decreased cerebral blood flow. This decreases the severity of reperfusion injury following ROSC.8 Furthermore, hypothermia reduces the inflammatory response occurring after brain injury.9
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RCSIsmjstaff review Table 1: Two decisive 2002 RCTs provide evidence for TH. Author
Sample
Methods
Results
Bernard et al.22
77 comatose patients with out-of-hospital cardiac arrest with initial rhythm of ventricular fibrillation.
Cooled to 33°C for 12 hours with ice packs, and then actively rewarmed.
Good outcome defined as discharged home or to a rehabilitation facility.
Cooling commenced in field by paramedics.
Good outcome: 49% of patients in the hypothermia group and 26% in the normothermia group (p=0.046) Statistically insignificant difference in mortality rates between two groups (p=0.145)
Hypothermia After Cardiac Arrest (HACA) study group21
275 comatose patients, with ROSC within 60 minutes of cardiac arrest, with initial rhythm of ventricular fibrillation or ventricular tachycardia.
Cooled to 32-34°C for 24 hours with a cooling mattress, with passive rewarming afterwards. Ice packs applied if target temperature not obtained within four hours.
Neurological outcome at six months measured on Pittsburgh cerebral performance scale. Favourable outcome defined as category 1 or 2 (good recovery or moderate disability). There was a 14% absolute risk reduction in mortality (NNT = 7) and a 16% improvement in cerebral performance (NNT= 6) for patients treated with hypothermia.
Early beginnings of the letter H The use of therapeutic hypothermia (TH) dates back as far as 1500 BC as detailed in the Edwin Smith Papyrus, the oldest known surgical textbook; ancient Egyptians used cooling for control of acute hemorrhage.10 In more modern clinical medicine, Russian physicians resuscitated cardiac arrest patients by covering them with snow, and Canadian physician William Osler demonstrated that cold baths reduced mortality in patients suffering from typhoid fever in the 1800s.11,12 Despite these early uses, an American neurosurgeon, Dr Temple Fay, is regarded as the father of modern TH.13 In an attempt to stop cancer cells multiplying in the body, he lay 150 pounds of ice chips over the body of a sedated patient. At that time (1938), survival below a body temperature of 35°C was believed to be impossible; when the patient’s blood pressure and pulse effectively disappeared after core temperature dropped to 32°C for 24 hours, this belief seemed to be confirmed. Astonishingly, within a few hours of rewarming, the patient returned to consciousness with no recollection of the events. Among scepticism and even shock, Dr Fay continued to perform trials on “refrigeration” and provided a tremendous amount of knowledge detailing the physiological effects of induced hypothermia on the body.13 Others followed Dr Fay’s lead. In the 1950s, Dr Bill Bigelow and his colleagues used hypothermia during cardiac surgery to slow down cellular processes, which offered surgeons more time to operate before the organs became hypoxic.14 Around the same time Rosomoff and Gilbert demonstrated that TH reduced cerebral oxygen consumption, blood flow and metabolic rate.15 By 1959, hypothermia was being used routinely for head and spinal cord injuries in addition to cardiac surgeries.12 After Benson et al. found that cooling could ameliorate some of the hypoxic damage caused to the central nervous system post cardiac arrest, TH began to make its way into CPR guidelines.16 In 1964, Dr Peter Safar incorporated TH into the first published algorithm on Page 62 | Volume 8: Number 1. 2015
cardiopulmonary resuscitation; he recommended cooling comatose patients within 30 minutes of ROSC (Figure 1).7 Its adoption into CPR recommendations did not mean that TH was without problems. Moderate hypothermia (28°C-32°C) was thought to be most effective; however, this temperature often induced cardiac irritability and ventricular fibrillation. This difficulty, in addition to higher rates of infection, hyperglycaemia and coagulopathies in patients who received cooling, resulted in the discontinuation of TH by most clinicians until its renaissance in the early 1990s.8,12
Resuscitation of therapeutic hypothermia Skilled CPR personnel and increased availability of defibrillators in the 1990s meant that early resuscitation from cardiac arrest was achievable. Despite this, the poor neurological prognosis for patients post ROSC compelled researchers to hunt for a therapy that would alleviate the ischaemia arising during cardiac arrest. Randomised controlled trials showed no improvement in neurological outcome from pharmacological agents such as thiopental, corticosteroids, lidoflazine and nimodipine.17,18,19,20 A number of small clinical trials conducted at this time, supported by previous animal studies, showed that mild hypothermia at a temperature of 34-36°C could lead to improvements in cerebral performance post ROSC.8 In 2002, the Advance Life Support Task Force of the International Liaison Committee on Resuscitation (ILCOR) published guidelines recommending hypothermia as a treatment for unconscious adult patients who are survivors of ventricular fibrillation arrests, following the publication of two decisive randomised controlled trials (RCTs)21,22 (Table 1).23 The significance of the neurological benefit demonstrated in the trials, despite their small sample size, prompted hospitals to immediately utilise TH as part of their post-cardiac arrest care protocol. The 2010 American Heart Association (AHA) guidelines continued to
RCSIsmjstaff review Table 2: Kim et al. 2009 study. Sample
Methods
Results
1,359 comatose patients with ROSC, with initial rhythms of ventricular fibrillation and ventricular tachycardia.
Randomisation to standard care or to pre-hospital cooling. Pre-hospital cooling: infusion with up to 2L of 4°C saline as soon as possible after ROSC. Both groups received hospital cooling.
Pre-hospital cooling decreased mean core temperature by 1.2°C in patients with ventricular fibrillation and by 1.3°C in patients without ventricular fibrillation, by hospital arrival. Pre-hospital cooling resulted in a one-hour reduction in time to achieve a temperature of less than 34°C. No difference in mortality or neurological prognosis between two groups. Number needed to harm through pre-hospital cooling = 20 patients.
support TH, by recommending earliest possible induction of it for unconscious adult survivors of cardiac arrest, irrespective of their initial cardiac rhythm, although a later study showed no benefit from mild therapeutic hypothermia in non-shockable rhythms.1,24 The AHA guidelines’ affirmation of TH’s neuroprotective effects prompted clinicians to wonder whether it would be beneficial to commence hypothermia even earlier, if possible in the pre-hospital setting. Paramedics in Ireland and abroad began using ice packs and iced intravenous fluids to induce hypothermia following resuscitation of patients who had suffered a cardiac arrest, although there weren’t any studies to support this practice.25,26 This practice was discouraged, in 2014, after Kim et al. published an RCT that demonstrated an increased incidence of rearrests in the field, increased pulmonary oedema on the first chest x-ray, and increased diuretic use associated with the use of pre-hospital cooling, with no corresponding improvement in survival or neurological status (Table 2).27
How to cool a human Both invasive and non-invasive methods exist for induction of TH. Surface cooling is typically achieved using circulating cold air or water blankets, or using ice packs. These methods are cheap and widely used, but may be cumbersome, often have variable cooling rates, and increase the risk of overcooling.28 To avoid systemic complications of global hypothermia, collars fitted around the patient’s neck cool blood flowing through the carotid arteries to the brain. However, the majority of studies conducted to assess the efficacy of surface cooling of the head in adults have failed to show efficacy.29 Transnasal evaporation is an effective method of pre-hospital intra-arrest cooling that reduces the time necessary to achieve hypothermia in hospital.30 Significant cooling of the nasal passages and the brain is achieved by spraying a liquid coolant-oxygen mixture into the nasal cavity, where it rapidly evaporates.30 Invasive methods of inducing hypothermia involve intravenous (IV) infusion of cold fluids. IV fluids are a fast, safe and efficacious method of inducing hypothermia; however, they must be supplemented with other surface cooling methods for maintenance.31 Devices that
circulate temperature-adjusted saline through an IV line based on the patient’s temperature are available, such as the Alsius CoolGard 3000 device with Icy catheter (Zoll Medical Corporation; Massachusetts, USA); however, these are very expensive.32 Extracorporeal circulation cooling devices allow for rapid induction of cooling, oxygenation of blood during resuscitation, and speedy delivery of intravenous drugs. These machines have been shown to be effective but their use is limited by the availability of the device.33
Is cooler really better? Cooling to 32-34°C (as recommended by the 2010 AHA guidelines) induces bradycardia and hypotension. At this temperature patients are more prone to infections and are unable to mount a fever response.34 In order to prevent shivering, they require sedation and paralytics – both of which hinder neurological examination and prognostication.35 The 2013 Targeted Temperature Management (TTM) trial, published in the New England Journal of Medicine, randomised 950 comatose patients with ROSC following an out-of-hospital cardiac arrest, regardless of initial rhythm, to temperatures of either 33 or 36°C for 28 hours.36 The results of this landmark trial showed no difference in mortality or neurological outcome between the two groups. There were, however, higher rates of hypokalaemia and serious adverse effects in the group maintained at a temperature of 33°C. The results of this study shocked the medical community. Critics of the trial suggested that a temperature of 33°C conferred additional neurological benefits that the study did not have sufficient power to detect. Furthermore, after 28 hours of cooling, the hypothermia group was actively rewarmed from 33°C to 36°C in six hours, faster than in all previous trials. Some clinicians argued that rapid rewarming may have negated the benefits of the therapeutic hypothermia.37 This absence of benefit at 33°C compared to 36°C challenges our understanding of the physiological benefit of TH. Could the avoidance of hyperthermia be more important than the induction of hypothermia? Post-cardiac arrest patients commonly develop pyrexia due to infections – for example, aspiration pneumonia – which is associated with poor prognosis.38,39 Further trials may also address the possibility of a dose-response relation between hypothermia and Volume 8: Number 1. 2015 | Page 63
RCSIsmjstaff review the degree of brain injury. Patients who have more severe neurological injury might require deeper hypothermia, while others might only need temperature management.40 In December 2013, the ILCOR published a statement advising clinicians to continue cooling TH patients to 32-34°C until a formal consensus is reached regarding the optimal temperature.41 Since then, Dr Stephen Bernard (who conducted one of the two 2002 landmark trials) has called for the guidelines to be changed to 36°C in a BMJ editorial.42 Some hospitals have put Dr Bernard’s suggestions into action; in Ireland, Cork University Hospital has revised its guidelines for hypothermia post cardiac arrest to a temperature of 36°C for 28 hours.43 In this period of uncertainty, UptoDate advises clinicians to cool patients to 36°C if they have moderate coma (some motor response) and no malignant EEG changes or cerebral oedema on CT brain. For patients with deep coma, malignant EEG patterns, or cerebral oedema on CT brain, they recommend cooling to 32-34°C, as this lower temperature might provide greater benefit.44
Conclusion TH is not a new concept; physicians have been cooling their patients to one end or another since ancient Egyptian times. TH has, however, enjoyed a revival in the last 15 years. Numerous exciting studies have altered clinical practice, and new techniques for cooling patients have been developed. Still, many questions remain unanswered. It is
unclear whether mild hypothermia offers any additional neuroprotective benefits post cardiac arrest. There is conflicting evidence as to whether pre-hospital or intra-arrest cooling offers any advantage. Three ongoing studies may further our understanding of this mysterious field. The Rapid Infusion of Cold Normal Saline (RINSE) trial (Australia) and the Pre-hospital Resuscitation Intra-Nasal Cooling Effectiveness Survival Study (PRINCESS) trial (California), are assessing cold saline infusions and transnasal evaporative cooling, respectively, to determine whether cooling prior to ROSC, during CPR on the field, improves outcome compared to standard care.45,46 In another trial – the Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT) trial (Pittsburgh) – trauma victims who have suffered cardiac arrest and failed resuscitative attempts will be rapidly cooled to below 10°C with an aortic flush. The aim is to preserve their organs for long enough to enable resuscitative surgery and delayed resuscitation with cardiopulmonary bypass. We eagerly await the results from these revolutionary studies.47 The story of targeted temperature management serves to illustrate how modern clinical practice is based on evidence-based medicine. It also illustrates that as future clinicians we should always be open to reinventing old therapies and constantly evaluating the benefit provided by current best practice.
References 1. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M et al. Part 9: post-cardiac arrest care: American Heart
9. Bro-Jeppesen J, Kjaergaard J, Wanscher M, Nielsen N, Friberg H, Bjerre M et al. The inflammatory response after out-of-hospital cardiac arrest is not
Association Guidelines for Cardiopulmonary Resuscitation and Emergency
modified by targeted temperature management at 33°C or 36°C.
Cardiovascular Care. Circulation.
Resuscitation. 2014;85(11):1480-7.
2010;122(18 Suppl.3):S768-86. 2. HSE. Sudden Cardiac Death Task Force Report. 2013 [Accessed 2014 November 7]; Available from: http://www.hse.ie/eng/services/Publications/topics/Heart/Sudden_Cardiac _Death_Task_Force_Report.html. 3. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012;307(11):1161-8. 4. Gräsner JT, Meybohm P, Lefering R, Wnent J, Bahr J, Messelken M et al. ROSC after cardiac arrest – the RACA score to predict outcome after out-of-hospital cardiac arrest. Eur Heart J. 2011;32(13):1649-56. 5. Madl C, Holzer M. Brain function after resuscitation from cardiac arrest. Curr Opin Crit Care. 2004;10:213-7. 6. Kochanek PM, Drabek T, Tisherman SA. Therapeutic hypothermia: the Safar vision. J Neurotrauma. 2009;26(3):417-20. 7. Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc. 1964;54:629-35. 8. Karnatovskaia LV, Wartenberg KE, Freeman WD. Therapeutic hypothermia
10. Tisherman SA (ed.). Therapeutic Hypothermia (Molecular and cellular biology of critical care medicine). Springer, 2005. 11. Varon J, Sternbach G. Cardiopulmonary resuscitation: lessons from the past. J Emerg Med. 1991;9:503-7. 12. Varon J, Acosta P. Therapeutic hypothermia: past, present and future. Chest. 2008;133(5):1267-74. 13. Alzaga AG, Salazar GA, Varon J. Resuscitation great. Breaking the thermal barrier: Dr. Temple Fay. Resuscitation. 2006;69(3):359-64. 14. Kermode-Scott, B. Wilfred G Bigelow. BMJ. 2005;330(7497): 967. 15. Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol. 1954;179(1):85-8. 16. Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use of hypothermia after cardiac arrest. Anesth and Analg. 1959;38:423-8. 17. Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med. 1986;314:397-403. 18. Jastremski M, Sutton-Tyrell K, Vaagenes P, Abramson N, Heiselman D, Safar P. Glucocorticoid treatment does not improve neurologic recovery
for neuroprotection: history, mechanisms, risks, and clinical applications.
following cardiac arrest. Brain Resuscitation Clinical Trial I Study Group.
Neurohospitalist. 2014;4(3):153-63.
JAMA. 1989;262:3427-30.
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RCSIsmjstaff review 19. Brain Resuscitation Clinical Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of
33. Soga T, Nagao K, Kikushima K, Watanabe K, Tachibana E, Mukoyama T et al. Mild therapeutic hypothermia using extracorporeal cooling
comatose survivors of cardiac arrest. N Engl J Med.
method in comatose survivors after out-of-hospital cardiac arrest.
1991;324:1225-31.
Circulation 2006;114:II-1190.
20. Roine RO, Kaste M, Kinnunen A, Nikki P, Sarna S, Kajaste S.
34. Perbet S, Mongardon N, Dumas F, Bruel C, Lemiale V, Mourvillier B et
Nimodipine after resuscitation from out-of-hospital ventricular
al. Early-onset pneumonia after cardiac arrest: characteristics, risk
fibrillation: a placebo-controlled, double-blind, randomized trial.
factors and influence on prognosis. Am J Respir Crit Care Med.
JAMA. 1990;264:3171-7. 21. Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-56. 22. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63. 23. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck WG, Billi J et al.; International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest: an advisory statement by the
2011;184(9):1048-54. 35. Blondin NA, Greer DM. Neurologic prognosis in cardiac arrest patients treated with therapeutic hypothermia. Neurologist. 2011;17(5):241-8. 36. Nielsen N, Weterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C et al.; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-206. 37. Polderman KH, Varon J. We should not abandon therapeutic cooling after cardiac arrest. Crit Care. 2014;18(2):130. 38. Gebhardt K, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC;
advanced life support task force of the International Liaison
Post Cardiac Arrest Service. Prevalence and effect of fever on outcome
Committee on Resuscitation. Circulation. 2003;108:118-21.
following resuscitation from cardiac arrest. Resuscitation.
24. Dumas F, Grimaldi D, Zuber B, Fichet J, Charpentier J, Pène F et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation. 2011;123(8):877-86. 25. Kim F, Olsufka M, Nichol G, Copass MK, Cobb LA. The use of pre-hospital mild hypothermia after resuscitation from out-of-hospital cardiac arrest. J Neurotrauma. 2009;26(3):359-63. 26. Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ et al.; for the Rapid Infusion of Cold Hartmanns (RICH) Investigators. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010;122(7):737-42. 27. Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T et al.
2013;84(8):1062-7. 39. Leary M, Grossestreuer A, Iannacone S, Gonzalez M, Shofer FS, Povey C et al. Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest. Resuscitation. 2013;84(8):1056-61. 40. Rittenberger JC, Callaway CW. Temperature management and modern post-cardiac arrest care. N Engl J Med. 2013;369(23):2262-3. 41. ILCOR. Targeted temperature management following cardiac arrest: an update. [Internet] 2013. Available from: http://www.ilcor.org/data/TTM-ILCOR-update-Dec-2013.pdf. 42. Bernard S. Inducing hypothermia after out of hospital cardiac arrest. BMJ 2014;348:g2735. 43. HSE. Cork University Hospital. Guidelines for hypothermia post cardiac arrest. [Internet] Available from:
Effect of prehospital induction of mild hypothermia on survival and
http://www.emed.ie/Cardiovascular/_img/Hypothermia_Post_Cardiac_
neurological status among adults with cardiac arrest: a randomized
Arrest_Revised_20140610.pdf.
clinical trial. JAMA. 2014;311(1):45-52. 28. Merchant RM, Soar J, Skrifvars MB, Silfvast T, Edelson DP, Ahmad F et
44. UpToDate. Overview of sudden cardiac arrest and sudden cardiac death. Available from:
al. Therapeutic hypothermia utilization among physicians after
http://www.uptodate.com/contents/overview-of-sudden-cardiac-arrest
resuscitation from cardiac arrest. Crit Care Med. 2006;34(7):1935-40.
-and-sudden-cardiac-death.
29. Straus D, Prasad V, Munoz L. Selective therapeutic hypothermia: a
45. Deasy C, Bernard S, Cameron P, Jacobs I, Smith K, Hein C et al.; RINSE
review of invasive and noninvasive techniques. Arq Neuropsiquiatr.
investigators. Design of the RINSE trial: the rapid infusion of cold
2011;69(6):981-7.
normal saline by paramedics during CPR. BMC Emerg Med.
30. Glencorse M. A review of the pre-ROSC intranasal cooling effectiveness study. Journal of Paramedic Practice. 2011;3(6):291-7. 31. Kliegel A, Janata A., Wandaller C, Uray T, Spiel A, Losert H et al. Cold
2011;11:17. 46. Nordberg P, Taccone FS, Castren M, Truhlár A, Desruelles D, Forsberg S et al. Design of the PRINCESS trial: pre-hospital resuscitation
infusions alone are effective for induction of therapeutic hypothermia
intra-nasal cooling effectiveness survival study (PRINCESS). BMC
but do not keep patients cool after cardiac arrest. Resuscitation.
Emerg Med. 2013;13:21.
2007;73(1):46-53. 32. Resuscitation Central. Cooling techniques. [Internet] Post Resuscitation
47. Tisherman S, Kochanek P. EPR-CAT: Emergency preservation and resuscitation for cardiac arrest from trauma. Available from:
Care 2010. [Accessed 2015 February 2]. Available from:
http://www.ccm.pitt.edu/research/projects/epr-cat-emergency-preserv
http://www.resuscitationcentral.com/hypothermia/cooling-techniques/.
ation-and-resuscitation-cardiac-arrest-trauma.
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RCSIsmjperspective
Popular neuroscience: the new frontier, OR AN EXERCISE IN MISDIRECTION? Seeing is believing when it comes to neuroimages, but is this necessarily a good thing? NATALIE ACHAMALLAH explores the issues.
“People often accept inaccurate explanations because they feel right.”1 Functional neuroimages made their popular debut in a 1983 Vogue magazine article. The headline, ‘High-tech breakthrough in medicine: new seeing-eye machines… look inside your body, can save your life’ was accompanied by a graphic of three brilliantly coloured brains labelled “NORMAL,” “SCHIZO,” and “DEPRESSED”. By presenting the images this way, the magazine’s editors condensed a great deal of cultural content about concepts of human nature into concrete and distinct categories. Placing them next to each other asked the viewer to see their differences as the essential characteristics of the labels that describe them. With no other explanatory text, this display insisted that there are at least three kinds of brain. Viewers were persuaded to equate person with brain, brain with scan, and scan with diagnosis.2 We tend not to question the effect neuroimages have on us because there is something intuitively right about a machine being able to show us the difference between schizophrenic brains, depressed brains and normal brains. They seem to provide an objective way to distinguish ‘them’ (the mentally abnormal) from ‘us’. Without our Page 66 | Volume 8: Number 1. 2015
realising it, the position of these images against each other compels us to see one as negative and the other as positive. When presented with both, we align the positive with the ideal.2
The ‘seductive details’ effect In all areas, not just neuroscience, humans are fairly inept at understanding explanations and reasoning about them in a sophisticated way. For example, we tend to rate longer explanations as more expert, failing to recognise circularity of arguments.1 When we believe scientific explanations, it is often because we find them intuitively satisfying, not because we understand them and judge them as accurate. Perhaps this is why neuroscience information is so attractive; the perception of a basis in rational science may lead us to uncritically accept any explanation containing neuroscience information, even if it is irrelevant to the logic of the explanation.3,4 To test this assumption, cognitive neuroscientists Weisberg et al. examined the influence of neuroscience information on people’s judgments of explanations. Three groups of subjects – novices, neuroscience students, and neuroscience experts – were given brief descriptions of psychological phenomena. These were followed by
RCSIsmjperspective an explanation of the phenomenon that did or did not contain irrelevant neuroscience information. The inclusion of neuroscientific details caused novices and students to judge explanations more favourably than the exact same explanations without the neuroscientific component.3 This may be because of the ‘seductive details’ effect – presenting readers with interesting but irrelevant details diverts their attention from important generalisations or gaps in logic.
Seeing is believing Because of their visual component, neuroimages are even more epistemically compelling than a statement of the information they represent. The authority of brain scans is a direct result of the fact that they are visual objects, in accordance with the belief that for something to be true it must be seen.5,6 These images are especially influential because they provide physical ‘proof’ of cognitive processes that previously were only understandable in abstract and indirect terms.7 Brain scans also tend to be equated with the idea of expert knowledge; their use as representations of brain activity confers a great deal of scientific credibility on studies of cognition.8 In a study done by McCabe et al., the use of neuroimages positively influenced ratings of the associated research as compared with identical articles accompanied by no images, bar graphs, or topographical maps representing regional activation.7 Other studies indicate that the more concrete and ‘brain-like’ the image, the more credibility it has. Keehner and Mayberry, for example, asked naïve readers to judge the soundness of scientific reasoning in a series of reports that were accompanied by representations of neuroimaging data. These readers perceived brain images that appeared highly three-dimensional and object-like as more convincing than other representations of the same data.9
Looking into the mind Coverage of brain scanning, specifically functional magnetic resonance imaging (fMRI), in the print media, suggests an overall optimism for the neurotechnology frontier. Articles that are not explicitly positive tend to be neutral, with very few articles expressing criticism of neuroimaging methods. This unbridled optimism for neuroimaging technology no doubt shapes public expectations regarding the future of psychiatry.10 These expectations, unfortunately, are based on misinterpretation of a relatively new and poorly understood set of technologies for ‘knowing’ the brain. Misinterpretation of neuroimaging research is at least in part a function of poor engagement of the public by researchers; the many translational processes involved in producing brain scans are rarely discussed.6 Functional neuroimaging techniques measure surrogate signals whose spatial specificity and temporal response are subject to physical and biological constraints.11 Their correlation with actual activity is assumed, and the fact that the nature of the activity may be excitatory, inhibitory, direct, modulatory, etc., is all but ignored. fMRI, for example, measures levels of activity in areas of neural tissue by measuring blood flow to them.12 This requires the
assumption that greater blood flow to an area during the activity indicates that area’s involvement – which is not necessarily true.11 A review by Racine et al. showed that fewer than one-third of articles directed at the public offered any explanation whatsoever of what fMRI actually achieves.13 Another, by O’Connell et al., concluded that “41% of media articles gave little or no technical detail of the neuroimaging methods; this was particularly notable in articles on marketing (77%) and diagnosis (73%)”. Journalists, who are not trained in interpretation of neuroimaging studies, may also unknowingly distort the conclusions drawn by researchers.14 For most people, popular media is the primary means of acquiring information about neuroimaging. Therefore, it is no wonder that so much confusion exists about the technology and its capabilities.
Neuroimaging: the new frontier? Media portrayals of neuroimaging compel us to wonder whether it will eventually be possible for employers, juries, parole boards, or law enforcement to examine our brains in order to answer questions such as: Are you prone to depression? How neurotic are you? To whom are you sexually attracted? How do you feel about other races? What scares you? Have you abused illegal drugs?15 These questions suggest that neuroimaging is a new form of mind-reading, with the ability not only to see thoughts but to create pictures of them based on physiological, neurochemical processes.14,16 In the commercial sector, neuromarketing (the use of brain scans to gauge the attractiveness of products to potential consumers) has already become a common practice.17,18,19,20 It is no wonder that the public has begun to assign brain scans the future potential to do just about anything, and to speculate about their utility in employment decisions, military biosecurity (especially their use as lie-detecting agents), and judgment of guilt in court cases.14 Although the use of brain scans in courtrooms is not uncommon, their admittance as evidence has been and continues to be controversial. In the 1982 trial of John Hinckley Jr, attorneys attempted to introduce brain scans to the case for the defence after his attempted assassination of Ronald Reagan. Expert witnesses objected to showing the scans to the jury; radiologists brought in to testify claimed that: “…one had to be trained to be able to read a radiological image. Why should the jury see the image? Because then they will eventually decide on what they think the image looks like”.2 What use could it be to show a jury composed of lay people images that demand considerable interpretive skill and training for technicians and specialists before they can reliably be used for diagnosis?21
Proceeding with caution… In 1997 Life magazine said of MRI that it “allows us to see, and to know ourselves in ways unthinkable a century ago”.22 Over two decades later the promise of what images of the brain may be able to tell us about the mind still seems irresistible. When news media and medical dramas portray neuroimaging as authoritative technology that can make vague diagnoses definitive, we are Volume 8: Number 1. 2015 | Page 67
RCSIsmjperspective inclined to believe them. Imaging appeals to our affinity for reductionist explanations of cognitive phenomena, and offers us a promise of certainty.6 Researchers continue to explore new and controversial potential uses for neuroimaging; a 2013 study by Peterson et al. examined fMRIs of minimally conscious patients, looking for patterns that may aid in end-of-life clinical decision-making. In their discussion the authors state: “...despite scepticism regarding the precise clinical and diagnostic application of fMRI, popular demand and legal precedence may undercut any preventive arguments advanced by the medical ethics community…”23 Gabrielle Samuel identifies this as ethically problematic; it suggests that popular demand supersedes the actual capabilities of a technology when determining its value. Popularity reflects the promotion of a medical innovation, a phenomenon known as “the sociology of expectations”.24,25 Discussion of new technology often includes optimistic speculation
about its future applications – ‘hype’ – which may be exaggerated by researchers to generate interest and sufficient public support to ensure further development.24,26 If neuroimaging has the potential to improve health and economic prospects, it is no wonder that it generates so much media interest and public curiosity, even if these applications are not yet scientifically validated. This fascination makes us susceptible to misdirection, making the use of brain scans in the public sphere risky and ethically fraught.5 Findings may be distorted, either by the media or by scientists, in hopes of gaining public interest, reputation or commercial gain.27 Perhaps researchers should be more discerning about their introduction of images to the public through the media. After all, even if they have the expert knowledge to distinguish good neuroscience from bad, they must not assume that those outside of the discipline will be as discriminating.3
References 1.
Trout JD. Seduction without cause: uncovering explanatory neurophilia.
15. Farah MJ, Wolpe PR. Monitoring and manipulating brain function: new
Trends Cogn Sci. 2008;12(8):281-2.
neuroscience technologies and their ethical implications. Hastings Cent
2.
Dumit J. Picturing Personhood: Brain Scans and Biomedical Identity.
Rep. 2004;34(3):35-45.
3.
Weisberg DS, Keil FC et al. The seductive allure of neuroscience
in disorders of consciousness challenges current diagnostic and public
explanations. J Cogn Neurosci. 2008;20(3):470-7.
understanding paradigms. Am J Bioeth. 2008;8(9):13-15.
Princeton, NJ; Woodstock, Princeton University Press, 2004.
4.
O’Connor C, Joffe H. How has neuroscience affected lay understandings of personhood? A review of the evidence. Public Underst Sci. 2013;22(3):254-68.
5.
Roskies AL. Neuroimaging and inferential distance. Neuroethics 2008;1:19-30.
6.
Joyce KA. Magnetic appeal: MRI and the myth of transparency. Ithaca, NY; Cornell University Press, 2008.
7.
McCabe DP, Castel AD. Seeing is believing: the effect of brain images on judgments of scientific reasoning. Cognition. 2008;107(1):343-52.
8. 9.
16. Racine E, Bell E. Clinical and public translation of neuroimaging research
17. McClure SM, Li J et al. Neural correlates of behavioral preference for culturally familiar drinks. Neuron. 2004;44(2):379-87. 18. Koenigs M, Tranel D. Prefrontal cortex damage abolishes brand-cued changes in cola preference. Soc Cogn Affect Neurosci. 2008;3(1):1-6. 19. Murphy ER, Iles J et al. Neuroethics of neuromarketing. J Con Behav. 2008;7:293-302. 20. Schaefer M, Knuth M et al. Striatal response to favorite brands as a function of neuroticism and extraversion. Brain Res. 2011;1425:83-9. 21. Prasad A. Making images/making bodies: visibilizing and disciplining
Johnson D. ‘How do you know unless you look?’: brain imaging,
through magnetic resonance imaging (MRI). Sci Technol Hum Val.
biopower and practical neuroscience. J Med Humanit. 2008;29(3):147-61.
2005;30(2):291-316.
Keehner M, Mayberry L, Fischer MH. Different clues from different views: the role of image format in public perceptions of neuroimaging results. Psychon Bull Rev. 2011;18(2):422-8.
10. Racine E, Waldman S et al. Contemporary neuroscience in the media. Soc Sci Med. 2010;71(4):725-33. 11. Logothetis NK. What we can do and what we cannot do with fMRI. Nature. 2008;453(7197):869-78. 12. Logothetis NK, Pfeuffer J. On the nature of the BOLD fMRI contrast mechanism. Magn Reson Imaging. 2004;22(10):1517-31. 13. Racine E, Bar-Ilan O et al. fMRI in the public eye. Nat Rev Neurosci. 2005;6(2):159-64. 14. O’Connell G, De Wilde J et al. The brain, the science and the media. The
22. Joyce K. Appealing images: magnetic resonance imaging and the production of authoritative knowledge. Soc Stud Sci. 2005;35(3):437-62. 23. Peterson A, Naci L, Weijer C et al. Assessing decision-making capacity in the behaviorally nonresponsive patient with residual covert awareness. AJOB Neuroscience. 2013;4(4):3-14. 24. Samuel G. ‘Popular Demand’ – constructing an imperative for fMRI. AJOB Neuroscience. 2013;4(4):17-18. 25. Brown N, Webster A. New Medical Technologies and Society. Cambridge, UK; Polity Press, 2004. 26. Brown N. Hope against hype – accountability in biopasts, presents and futures. Social Studies. 2003;16(2):3-21. 27. Wardlaw JM, O’Connell G et al. ‘Can it read my mind?’ – What do the
legal, corporate, social and security implications of neuroimaging and
public and experts think of the current (mis)uses of neuroimaging? PLoS
the impact of media coverage. EMBO Rep 2011;12(7):630-6.
One. 2011;6(10): e25829.
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RCSIsmjperspective
Staying Lean AISLINN KILLIAN explores the possible advantages of implementing Lean Sigma principles in the HSE.
By the end of 2014 the Irish Health Service Executive (HSE) is set to run a deficit of €500 million for the year. This is despite the additional €200 million in funding the service received at the end of 2013.1 The increased expenditure has been attributed to a rise in demand for health services, fueled by factors such as an ageing population, expensive medical technology, and a reduced tax base as a consequence of the recession.2 The global picture is not dissimilar, with healthcare services around the world struggling under the strain of austere government policies. The most detrimental consequence is the effect on the patient experience as hospitals are plagued with delays, inefficiencies and waste.3 In the search for a sustainable solution, two techniques have gained attention in healthcare policy: Lean and Six Sigma. Both were developed in relation to manufacturing: Lean focuses on reducing waste and improving flow through, and Six Sigma uses statistical tools to reduce variation and defects.3 In the last decade several countries, including the UK, have applied a combined Lean and Six Sigma approach (referred to as Lean Sigma) to their public health systems. Many have recorded improvements in waiting times and elimination of waste.4 In 2010 the Department of Health in Ireland announced its intention to start applying Lean reform principles to the HSE. Since then, Lean methods have been piloted in selected hospitals and wards, and have achieved good results.5 However, four years on, implementation of Lean principles in the HSE has barely moved past the pilot stage, and the use of Six Sigma techniques never properly began.5 Given the increasing demand for healthcare and the mounting pressure to deliver high quality care for less, sustainable application of Lean Sigma principles on a national scale is of significant interest.
What is Lean Sigma? Lean principles were popularised by Toyota Motor Corp, who first implemented them in their production lines in the 1950s.6 Since then, Toyota’s ‘Just In Time’ policy has focused on using raw materials as soon as they arrive in the factory in order to use “what is needed, when it is needed, and in the amount needed”.7 This production plan reduces waste and inefficiency, which is the cornerstone of Lean.6,7 This is accomplished through value stream mapping; each step of a process is mapped out to determine value, a process that highlights the non value-added steps so that they can be removed or adjusted and flow through the system can be improved (Figure 1).6 4–58 days
CURRENT STATE GP
0–11 days
1–9 days
HOSP
2–8 days
REGISTRATION
1–36 days
SORT
1–14 days
TRIAGE
0–5 days
SORT/APPOINT
ENDOSCOPY
1–7 days
ENDOSCOPY BOOKED
FUTURE STATE GP
0–3 days
0–11 days
HOSP
0–5 days
REGISTRATION
BEFORE: UP TO 90 DAYS
SAME DAY
SORT / TRIAGE / SORT/APPOINT
AFTER: UP TO 26 DAYS
0–3 days
ENDOSCOPY
1–4 days
ENDOSCOPY BOOKED
FIGURE 1: Value stream mapping according to Lean principles. Registration, Triage and Booking Process image. Source: http://www.scotland.gov.uk/Publications/2008/03/20155232/27. Volume 8: Number 1. 2015 | Page 69
RCSIsmjperspective In the 1980s Motorola pioneered Six Sigma principles in an effort to reduce defects in its production line. Six Sigma uses the DMAIC (Define, Measure, Analyse, Improve, and Control) framework and other statistical tools to examine and quantify variations produced in a process. By detecting and eliminating sources of error, the quality of the end product can be improved.6 In healthcare, as in manufacturing, it is now acknowledged that Lean and Six Sigma principles can be combined to maximise results. In 2005 the NHS Institute for Innovation and Improvement presented a report documenting the successful reduction in waiting times in the NHS after applying Lean and Six Sigma strategies together. Lean strategies create the optimal environment to reduce waste and improve flow, and Six Sigma helps to quantify problems, to identify sources of defect, and to provide evidence-based solutions. Together they can create "rapid transformational improvement at lower cost".6
Lean Sigma in healthcare Lean Sigma is said to have the potential to transform healthcare in equal measure to its transformation of the automotive industry.8 Small studies have found improvements in patient flow through a radiology department,9 outpatient waiting times, inpatient hospital stay,10 and surgical inventory costs4 where Lean Sigma principles have been implemented. Systematic reviews have also demonstrated successes in a surgical setting11 and in acute inpatient care.12 Despite overall improvements, the heterogeneity of the studies included increases the risk of bias. Lean Sigma implementation in healthcare is a recent idea, and thus most studies lacked adequate sample sizes and long-term follow-up. To date, a limited number of Irish studies have been done. The University Hospital Limerick compared data from hip fracture patients in the orthopaedic ward pre and post implementation of Lean Sigma to identify bottlenecks in the system. A lengthy delay was noted between sending for the first surgical patient of the day to be brought to theatre and their actual arrival. Addressing this delay resulted in an earlier mean theatre start time and an increase in daily theatre usage by 38 minutes. An additional 12% of patients received surgery in less than 24 hours from admission. The study also reported a one-day reduction in post-op stay, which was attributed to the new procedural change in theatre, as well as other strategies implemented to speed up referral times in the Emergency Department.13 Another HSE initiative of note is the Productive Ward, developed by the NHS with the aim of empowering frontline staff by increasing their responsibility. Specifically, it requires nurses to examine each process in the ward to identify inefficiencies, then come up with their own solutions. Preliminary HSE studies have reported increased direct patient care and cost savings.5 Though these results are promising, both the Productive Ward study and the University of Limerick study concluded that in
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order to gain more sustainable improvements from Lean Sigma, the HSE needs to make a commitment to change on a larger scale. This means introducing Lean Sigma principles to all HSE hospitals and involving all levels of staff.5,13
Continuous improvement For many organisations, 'going Lean' involves hiring external technical experts to identify and solve their procedural problems.15 This method may provide short-term gains but it does not create the environment for continuous improvements. For Lean Sigma to be implemented in a sustainable manner in the HSE, there needs to be empowerment and greater accountability of employees, and a shift in structure of the health services towards a customer-centric organisation. A recent article by McKinsey, a consulting company, referred to creating the environment for continuous improvement as the "soft" side of Lean, which is separate from the "hard" process of identifying technical faults. The article discussed the need for involvement of all employees, as each employee will have a unique interaction with the system and will therefore be able to provide different perspectives on how to improve. Part of this process includes helping employees to develop a greater understanding of the patient experience, so that suggestions on how to improve the system can be made with the patient in mind. One tactic suggested by McKinsey is to have employees follow patients from admission to discharge so that they develop an understanding of what patients go through.15 McKinsey also recommended tracking team performance to be measured against key performance indicators. Leaders of healthcare systems in the US and Europe have found that collecting and publicising performance data â&#x20AC;&#x201C; for example the number of patients treated in a month by a team â&#x20AC;&#x201C; has helped to engage and motivate employees.15 In Ireland the Department of Health's 'Money Follows the Patient' policy, introduced in 2014, is a step in the right direction. This policy reforms the hospital funding system so that money is allocated based on the cost per treatment carried out by the hospital, as opposed to giving a block grant. The cost of each treatment is determined by a central pricing office and takes into account factors such as patient age and the complexity of the treatment. Lack of competition and perverse incentives are seen as challenges to implementing Lean Sigma; however, these can be overcome by strategies that motivate employees.16 The HSE is no different to other parts of the public sector; its funding is independent of patient satisfaction. Employeesâ&#x20AC;&#x2122; salaries are fixed as per the HSE pay scheme, which does not allow for variations based on individual performance. Compounding the problem is the possibility that if public sector employees suggest a cost-saving method, it may in fact result in a budget cut to their area. These factors combined make for an apathetic work environment.15
RCSIsmjperspective This problem may be mitigated by appropriate incentive programmes, which have been shown to improve morale and productivity.15 Employees must have a central role in programme design, and both they and the organisation at large should benefit.15,16 Gain sharing arrangements have also had positive results; under the guidance of McKinsey, an unnamed European government reinvested savings delivered by one aircraft maintenance unit across the whole defence department, which resulted in the sharing of technical knowledge across units and an ultimate saving of €12 million in one year.15
it is possible to identify the exact areas that are inefficient and wasteful. This allows for evidence-based solutions, which will improve the quality of care and ultimately reduce costs. The current economic constraints are set to continue for several years and demand on the healthcare system will continue to rise. Lean Sigma has shown results when applied to healthcare systems abroad and it is beginning to produce results in Ireland. Lean Sigma is a long-term project; difficulties in its application to the public sector should be recognised and a culture of continuous improvement, with motivated employees, needs to be promoted. Lean Sigma has the potential to deliver high quality care in an efficient and cost-effective manner.
Conclusion Lean Sigma at its core is about delivering a high quality product to the customer. In healthcare patients are the customers, and the focus needs to placed back on them. The pressure to reduce costs has shifted the balance away from the patient, yet by mapping out and analysing each step of the patient experience,
References 1.
Wall M. New estimates suggest HSE will face deficit of €450m-€500m for the year. Irish Times, Oct 2014. Available from: http://www.irishtimes.com/business/new-estimates-suggest-hse-will-facedeficit-of-450m-500m-for-the-year-1.1877337 (accessed 31 Oct 2014).
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Health Service Executive. National Service Plan 2014. HSE, Dec 2013: Pg 2. Available from: http://www.hse.ie/eng/services/Publications/corporate/serviceplan2014/n
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Laureani A, Brady M, Antony J. Applications of Lean Six Sigma in an Irish
ahead of print] 12. Glasgow J, Scott-Caziewell J, Kaboli P. Guiding inpatient quality improvement: a systematic review of Lean and Six Sigma. Jt Comm J Qual Patient Saf. 2010;36:533-40. 13. McNamara R, Butler A, Baker C et al. Use of lean principals to improve
doi:10.1108/lhs-01-2012-0002.
flow of patients with fractured neck of femur – the HOPE Study. Ir Med J.
HSE. The Productive Ward: Releasing Time to Care (TM) Quality
2014;107(3):70-2.
Improvement Initiative. 2014. (Accessed 2014 Oct 31). Available from:
14. White M, Wells J, Butterworth T. Implementation of releasing time to
http://www.hse.ie/productiveward/.
care – the productive ward. J Nurs Manag. 2013. DOI:
National Health Service. Lean Sigma (1st ed.). NHS Institute of
10.1111/jonm.12069.
Innovation and Improvement, 2005. (Accessed 2014 Oct 31). Available from: http://www.institute.nhs.uk/images//documents/FinalVersionLeanSigmaD ec11Orlandopresentation.pdf.
15. McKinsey & Company. A leaner public sector. McKinsey 2014. (Accessed 2014 Oct 31). Available from: http://www.mckinsey.com/insights/public_sector/a_leaner_public_sector. 16. Audier A, Sanders U, Winslade P. More Than Lean. 2010. (Accessed 2014
Toyota-global.com. Toyota Global Site | Just-in-Time. 2014. (Accessed
Oct 31) Available from:
2014 Oct 31). Available from:
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http://www.toyota-global.com/company/vision_philosophy/toyota_prod uction_system/just-in-time.html. 8.
2013;148:1050. 11. Mason S, Nicolay C, Darzi A. The use of Lean and Six Sigma methodologies in surgery: a systematic review. Surgeon. 2014;Sep 1. pii:
hospital. Leadership in Health Services. 2013;26:322-37.
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program using Lean Six Sigma in a veterans affairs hospital. JAMA Surg.
S1479-666X(14)00102-4. doi: 10.1016/j.surge.2014.08.002. [Epub
tions_management_july_2007.pdf (accessed 31 Oct 2014).
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Quality Initiative 1. Radiographics. 2010;30:309-15. 10. Gayed B, Black S, Daggy J et al. Redesigning a joint replacement
ationalserviceplan2014.pdf (accessed 31 Oct 2014). Six Sigma. (1st ed.). NHS 2007. Available from:
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Aakre K, Valley T, O'Connor M. Quality Initiatives: Improving Patient Flow for a Bone Densitometry Practice: Results from a Mayo Clinic Radiology
Westwood N, Silvester K. Eliminate NHS losses by adding Lean and some http://www.institute.nhs.uk/images//documents/westwood_article_opera
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9.
ore_than_lean_raising_quality_public_services/. 17. Department of Health Ireland. Money Follows the Patient. Dublin: Department of
Manos A, Slatter M, Alukal G. Make healthcare lean. Quality Progress.
Health Ireland, 2014. (Accessed 2014 Oct 31) Available from:
2006;39(7):24-30.
http://health.gov.ie/future-health/structural-reform-2/money-follows-the-patient/.
Volume 8: Number 1. 2015 | Page 71
RCSIsmjperspective
Letting the gen(i)e out of the bottle? GENETIC TESTING FOR MENTAL ILLNESS AMELIA REID explores the facts, and the ethics, around screening for depression.
Introduction Anyone watching science headlines in September 2014 may have read about a new blood test that allows clinicians to “diagnose clinical depression as easily as they check cholesterol”.1 This byline, and others, appeared in response to a study out of Northwestern University2 that evaluated a panel of biomarkers in patients with major depressive disorder (MDD). This was heralded in print media as a breakthrough that seemed to answer the diagnostic dilemma facing psychiatry today. “Blood test spots adult depression… a new blood test is the first objective scientific way to diagnose major depression in adults…”3,4 These claims may be exaggerating the actual findings of the Northwestern study, but they still force us to ask ourselves: were such a test widely available, would the populace at large be keen, or at least willing, to entertain mass screening? In a 2010 Australian study, researchers found that there was “strong interest in predictive Page 72 | Volume 8: Number 1. 2015
genetic testing for susceptibility to depression”.5 Another group, based on in-depth interviews with 21 members of families with a “high density of bipolar disorder”, reported expressed interest in prenatal or predictive testing, depending, however, on the level of certainty involved.6 In short, there appears to be support from many groups for genetic testing for individuals with psychiatric illnesses. Although concerns remain surrounding confidentiality, and employment and insurance discrimination, there has been significant interest among adult patients for genetic testing for conditions such as depression and schizophrenia.7 Reasons cited included access to genetic counselling and early psychological intervention.8 Research efforts to identify the offending genes in a multiplicity of disorders are integral to the advance of evidence-based therapeutics and medical care. But this quest is not a value-free pursuit. Practical
RCSIsmjperspective barriers to using genetic information – which is often expressed in probabilities – to inform diagnosis and treatment may be superseded by ethical challenges to individual and family senses of well-being or threat. These ethical dimensions of genetic counselling become central in deciding whether to test or, having done so, what to do with the information gained. Mass genetic screening is not a new idea in and of itself; in most countries, newborns are screened routinely for phenylketonuria (PKU), congenital hypothyroidism, cystic fibrosis and a range of disorders associated with inborn errors of metabolism. In the US, genetic screening varies by state, with New York, for instance, screening for HIV. However, no country, as yet, screens for genetic susceptibility to psychiatric illness.
‘The depression gene’ Depression is a distressingly common disease – in Ireland 300,000 people experience depressive illness at any given time9 – and yet we know very little about its pathophysiology compared with other chronic and multifactorial diseases such as diabetes. Several theories of the neurobiology of depression have been postulated including dysfunction of the limbic system, decreased monoamine production in the brain, decrements in brain-derived neurotrophic factors (growth factors that regulate brain plasticity), and a dysfunctional hypothalamic-pituitary-adrenal axis with an increase in serum glucocorticoid concentrations.10 Although several genes have been implicated in the onset or likelihood of developing mental illnesses, the most promising thus far is the serotonin (5-HT) transporter gene. Serotonergic neurotransmission is associated with many physiological functions such as sleep, appetite, and depressed mood and anxiety.11 Beginning with a 2003 study by Caspi et al.,12 there has been an increasing body of evidence to support the role of the 5-HT transporter in the prediction of MDD. A functional polymorphism in the promoter region (known as 5-HTTLPR) has been associated with an increased risk of depression – although precisely how much is unclear.11 A great deal of focus has been placed on the interaction between the gene and the effects of the environment and stressful life events.13 Although environments cannot alter gene sequences, they can alter gene expression; the epigenetic explanation has been invoked to explain why some people with the gene will have a major depressive disorder in their lifetime, and others will not. Just as stressors influence genes, genes may influence stressors. Some studies have suggested that individuals without the 5-HTTLPR show a bias for processing positive affective material and selectively avoiding negative affective material.13 This means that people may process stressful life events differently, and that certain people, given allelic variation, are possibly more ‘resilient’ and less susceptible to emotional disorders.14
even after gene/environment interactions are accounted for. For instance, monozygotic twins may be raised in the same way, by the same parents and in the same environment, and yet be discordant for the symptoms of depression. They also point out that some genes confer an increased risk if inherited from one parent, but not the other. Even if a wholly genetic cause for depression were established, its utility in mass screening would be undercut by unpredictable symptoms and variable combination with other psychiatric disorders. This would present a diagnostic conundrum, for example in a patient who tested positive at birth and much later suffered grief following a family member’s death. The presentation likely would not fit the classical picture of depression, and yet with a positive test result on record it nevertheless may be treated as such.16
Born this way In spite of the difficulties, it can be argued that there are benefits to be gained from testing for a gene – even if only predispositional – for depression, such as increasing the dialogue about mental health between health professionals and patients. Screening presents an opportunity for mental health professionals to discuss signs and symptoms with parents and families, as well as how to deal with the disease should it arise. For these benefits to be meaningful, the predictive validity or power of the tests would need to be communicated clearly to the parents by genetic counsellors. It has been suggested, perhaps optimistically, that identifying a biogenetic cause or further medicalising of depression (or mental health more generally) might reduce the stigma around mental illness; depressed people cannot be blamed for symptoms, if the cause is in their DNA and therefore beyond their control.5 In actuality, however, studies have shown that there is a tenuous link between biogenetic explanations and stigma. In fact, medicalisation might actually increase stigma by causing people to view the disease as more serious and potentially unavoidable.17 This has the potential to propagate shame and fear of being labelled as depressed by families, in workplaces and in social relationships more broadly. Fear of discrimination is especially pertinent to mandatory genetic testing. Mass newborn screening for non-psychiatric conditions has been problematic in this regard in the past. In some parts of America in the 1970s, testing positive for a genetic disorder did not stop children from attending school – but refusing a genetic test did.18 This contributed to a fear that genetic testing would mean a decrease in an individual’s right to privacy, and concerns about how the information gathered in genetic tests was being stored and used.18,19 These concerns are magnified significantly when the test in question involves a sensitive, potentially stigmatising condition.
Costs: financial and non Nature + nurture + ? Development of depression is still not so straightforward as nature-plus-nurture, however. Mill and Petronis15 have identified many epidemiological peculiarities that are still largely unexplained,
Mass newborn screening for inborn errors of metabolism is a cost-saving measure in the long term; testing provides information necessary to delay or even prevent the onset and severity of these diseases.20 The same cannot said for psychiatric illness. Monitoring Volume 8: Number 1. 2015 | Page 73
RCSIsmjperspective every child who tests positive over the course of their lifetime, identifying when symptoms are severe enough to warrant intervention, and deciding what treatment or treatments will be offered (knowing that these may or may not be effective) is unlikely to be a cost-effective process.14 This would be particularly so if it were found that only a small number of individuals who test positive for the gene actually develop depression over the course of their lifetime. This raises a further quandary for those who test negative but still develop depression in later life: will their illness somehow be deemed less serious or less legitimate than those who tested positive for a predispositional gene? Should they receive the same treatment as those who have tested positive, and should funding for their treatment be allocated in the same way?
Just because we can… does that mean we should? On the matter of the Northwestern blood test, the Huffington Post proclaimed definitively: “A blood test for depression shows the illness is not a matter of will…”4 This rhetoric suggests to readers that in the near future, psychiatric illnesses may be added to a panel of mass genetic screening tests such as those for PKU and
congenital hypothyroidism. However, depression is different from these conditions in a number of ways. It is diagnosed with a degree of subjectivity, such that the patient fulfills a range of criteria and displays symptoms that disrupt their normal social and occupational functioning.13 It can present at any stage in life (although often in adolescence), and affects females more than males.11 In a practical sense, detection at screening may confer no benefit to development of the disease or prognosis.14 In the absence of proven mechanisms linking genetic susceptibility to MDDs, it is hard to argue that a genetic test would have much, if any, clear predictive value or clinical utility. Testing positive may label a person as ill, creating stigma that is felt throughout adult life, and create anxiety about having children and passing on the offending gene. The very existence of genetic information about psychiatric conditions gives rise to the possibility that employers or insurers might demand it. While the media hyperbole around the study conducted by Northwestern University promised far more than the authors claimed, the day might come when a predisposition to mental illness can be predicted with some certainty. But the question will remain – just because we can, should we?
References 1.
Firger J. New blood test could be first to detect clinical depression. CBS News. [Internet] 16 September 2014. Available from: http://www.cbsnews.com/news/first-blood-test-for-clinical-depression/.
2.
Redei E, Andrus B, Kwansy M, Seok J, Cai X, Ho J et al. Transcriptomic
SJ, Oostra BA et al. Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry. 2008;13:772-85. Influence of life stress on depression: moderation by a polymorphism in
Haelle T. Blood Test Spots Adult Depression: Study. [Internet] WebMD
the 5-HTT gene. Science. 2003;301:386-9. Mental Disorders (5th ed.). Washington DC; American Psychiatric
dult-depression-study.
Association, 2013.
Almendrala A. A blood test for depression shows the illness is not a Available from: http://www.huffingtonpost.com/2014/09/16/blood-test-depression_n_5 826592.html. Wilde A, Meiser B, Mitchell P, Schofield P. Public interest in predictive genetic testing, including direct-to-consumer testing, for susceptibility to
6.
epigenetic perspective. Mol Psychiatry. 2007;12:799-814. 16. Kleinman A. Culture, bereavement and psychiatry. Lancet. 2012;379(9816):608-9. 17. Kvaale E, Gottdiener W, Haslam N. Biogenetic explanations and stigma: a meta-analytic review of associations among laypeople. Soc Sci Med. 2013;96:95-103.
Bowman D, Studdert D. Newborn screening cards: a legal quagmire. Med J Aust. 2011;194:319-22. Meiser B, Mitchell PB, McGirr H, Van Herten M, Schofield PR. Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study. Soc Sci Med. 2005;60:109-18.
9.
Pediatrics 2001;107(6):1451-5. 15. Mill J, Petronis A. Molecular studies of major depressive disorder: the
Wilhelm K, Meiser B, Mitchell PB, Finch AW, Siegel JE, Parker G et al. Br J Psychiatry. 2009;194:404-10.
8.
14. Committee on Bioethics. Ethical issues with genetic testing in pediatrics.
major depression: preliminary findings. Eur J Hum Genet. 2010;18:47-51. Issues concerning feedback about genetic testing and risk of depression. 7.
13. American Psychiatric Association. Diagnostic and Statistical Manual of
http://www.webmd.com/depression/news/20140916/blood-test-spots-a
matter of will. [Internet] The Huffington Post, 16 September 2014.
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12. Caspi A, Sugden K, Moffitt T, Taylor A, Craig I, Harrington H et al.
doi: 10.1038/tp.2014.66. 2014. Available from:
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2008;455:894-902. 11. Lopez-Leon S, Janssens A, Gonzalez-Zuloeta Ladd AM, Del-Favero J, Claes
biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy. Transl Psychiatry. 2014;4:e442. 3.
10. Krishnan V, Nestler E. The molecular neurobiology of depression. Nature.
Department of Social Protection Ireland. Depression. [Internet] Available from: http://www.welfare.ie/en/downloads/protocol1.pdf.
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18. Fulda K, Lykens K. Ethical issues in predictive genetic testing: a public health perspective. J Med Ethics. 2006;32:143-7. 19. Goldenberg A, Sharp R. The ethical hazards and programmatic challenges of genomic newborn screening. JAMA. 2012;307:461-71. 20. Carroll A, Downs S. Comprehensive cost-utility analysis of newborn screening strategies. Paediatrics. 2006;117:287-95.
RCSIsmjperspective MICHAEL BRAVO looks at the pleasures and pitfalls of social media use for medical personnel.
The doctor will tweet you now: MEDICINE IN THE SOCIAL MEDIA AGE
The advent of Mark Zuckerberg’s Facebook just over 10 years ago ushered in the second digital age, bringing with it new ways to interact – sharing status updates, writing blogs, or sharing photos or videos.1 Websites like Facebook, Instagram and Twitter, collectively termed ‘social media’, have been used for everything from organising social revolution, to tracking flu outbreaks, or predicting election outcomes.1 Social media have unreservedly affected all facets of daily life, extending even to healthcare, where there has been a meteoric rise in adoption. In the last year, 34% of people have used social media (e.g., Facebook, Twitter, Instagram) to get information about a health issue.2 The ubiquity of social media and the endless possibilities it provides require doctors to embrace it and prepare themselves for
patients who use it. Thus, physicians and physicians in training must understand their role in the online community, and how they can adopt positive social media practices. This means understanding how they can use social networks to interact with other doctors and with their patients, and the potential dangers they face in doing so.
How can fellow physicians interact? The internet has long been an accepted forum for patients to research and discuss medical issues; up to 24% of Americans first turn to the internet for information about their symptoms or diagnoses.2,3,4 Until recently, physicians have rarely had the same opportunity to discuss medical issues with their peers. Volume 8: Number 1. 2015 | Page 75
RCSIsmjperspective Peer-to-peer physician communication In the last five years, a number of physician-only platforms have begun to allow more candid interaction by requiring members to provide their medical credentials.5,6 Networks like Sermo and Doximity allow doctors to crowd source diagnoses, create polls, follow compensation trends, earn continuing medical education credits, or simply network to discuss similar interests.6 A recent study showed that social network advocacy for a particular serum assay test was more influential than published studies. This suggests that peer recommendation has significant sway in promoting clinical practice change.7 This is particularly interesting in light of how many physicians use peer-to-peer (P2P) communication; a 2013 survey of AMN Healthcare, a physician staffing company, found that 48% of physicians used online sites for professional networking and peer recommendations.8 Issues surrounding P2P physician interaction Physicians are trained to safeguard patient confidentiality, but may let their guard down in seemingly harmless environments. In a 2003 study, conversations that compromised patient confidentiality were overheard by observers in 12% of elevator rides in a Toronto hospital.9 When the opportunity to also share video and images emerges, opportunity to cause a confidentiality breach is increased. Katie Duke, a nurse featured on reality TV show New York Med, shared a picture she captioned ‘Man vs. 6 Train’ on Instagram. It depicted the refuse from supplies used while attempting to revive a man who fell in front of an New York City subway train. No personal information was displayed in the image, but she was fired at the end of her shift for breaking hospital rules; the treatment could be linked to newspaper publications that had released the man’s name.10 The Stevenson and Peck criteria, first published in 2011, help physicians to decide what should and should not be shared online, as well as helping them to assess their social media actions generally. They originated from T.A. Cavanagh’s Double-Effect Reasoning Model, which focuses on “doing good and avoiding evil” when making difficult moral decisions (Table 1).11 Translated into practice, this means removing any identifying information when writing a case to share on social media. The author should write in a respectful tone, with the intent to stimulate understanding or empathy, without intent to harm, and ensure that the physician’s self-interest is not above the patient’s (e.g., posting to release frustration or provide humour).12 While these criteria seem relatively straightforward, in practice they sometimes prove more difficult than one might expect. In a study of over 250 medical blogs, 42% of entries were patient cases, and 17% of these contained enough information to identify the patient.13
How can doctors interact with patients online? Patients as friends and followers Social media also provides a new method by which to interact with patients. Dr Jennifer Dyer, a paediatric endocrinologist in Ohio, uses social media to connect with her patient population, especially teenagers who avoid email or phone calls.14 Some practices have Page 76 | Volume 8: Number 1. 2015
Table 1: T.A. Cavanagh’s Double-Effect Reasoning Model criteria. 1. The act considered separately from its unintended harmful effects is in itself not wrong. 2. The agent intends only good and does not intend harm as an end or as a mean. 3. The agent reflects upon their relevant duties, considering accepted norms, and takes due care to eliminate or alleviate any foreseen harm through their act. (Consider: security of communication, patient’s consent, ability to identify patient, potential audience, professional reputation and responsibilities, tone.)11 established their own closed-system social media platforms that help patients to monitor treatment, change prescriptions, or ask questions about their symptoms.15,16 The potential for interaction is not limited to professional accounts; one study recently showed that 34.5% of practising physicians had received a friend request to their personal accounts.17 Fewer physicians have extended the friend request themselves (5%); however, up to 14% of physicians do social media searches on their patients.15 Patient outreach with social media Connecting with patients via social media opens the possibility of using telemedicine to provide additional levels of care remotely, for example by sharing images or videos of the disease or symptom. Up to 7% of US physicians have used video chat to interact with patients, which is of particular interest for physicians who service large rural populations where face-to-face consultation is not always feasible.18,19 Telemedicine can also be used by international relief organisations to contact medical specialists for consultation.20 Social media can also serve patient education. Individual physicians, medical organisations or hospitals can promote accurate, specific health information to combat the multitude of erroneous information online. The Mayo Clinic, world-renowned hospital and medical research institute, has one of the most active Twitter feeds in the healthcare social media sphere, publishing new studies, holding Q&A sessions with experts, and discussing medical conditions in an accessible way.21,22 Preventing problems with patients Despite their benefits, online ‘friendships’ can create secondary relationships with patients that may compromise professionalism. Shared pictures, status updates and background information seem innocent, but they may influence care.23 For example, if a physician sees photos of a patient smoking, when they have previously reported being a non-smoker, should this be discussed at the next consultation? Might this compromise a patient’s insurance status if the information is added to the chart? Alternatively, the patient
RCSIsmjperspective might see postings on the physician’s profile that introduce doubt in their ability to provide appropriate care, such as photos from nights out, postings from personal friends, or other biographical information such as religion (particularly relevant to providing consultations about end of life care or abortion). Dr Jake Varghese, a family physician in the US, was questioned by a patient about his choice of a fast food restaurant because of a posting on Facebook.13,24,25
How can online presence be perceived? Venting and frustration in social media Engaging in social media requires physicians to balance their roles as anonymous internet users and respected members of the community. The materials they post are subject to the scrutiny of patients and potential patients. Some material posted online may be considered differently because of personal or generational differences.26 Furthermore, the ‘viral’ nature of controversial posts may inspire activism by completely unrelated parties. After one patient’s chronic tardiness to her prenatal appointments, Dr Amy Dunbar complained to her friends on Facebook.27 “She is now three hours late for her induction,” quipped Dunbar. “May I show up late to her delivery?” The post was picked up by a Facebook group composed of expectant mothers, who promptly filed complaints with her hospital, demanding that she be fired.27 While there was no breach of privacy, this post seriously damaged Dr Dunbar’s reputation. While venting frustrations about patients may be cathartic and comforting when other healthcare providers empathise, the potential risk of violating patient confidentiality, coupled with the response of the online community, might make it more trouble than it is worth. Medical students: protecting future careers Medical students (for whom it would be typical to have a robust personal online presence) are particularly susceptible to long-term ramifications of social media use. Residency programme directors may use social media networks to ‘vet’ applicants; over one-third have ranked applicants lower because of their postings online.28 Group memberships, photos, wall
posts and comments are used as methods of determining the candidate’s professionalism.29 Students have responded by locking down their privacy details, but even this does not guarantee protection.30 Perceived anonymity online may encourage users to write or post things they otherwise would not, termed the “online disinhibition effect”.31 For some, being linked to ‘anonymous’ postings may have disastrous consequences. Male students in the Faculty of Dentistry at Dalhousie University in Halifax, Nova Scotia, created a ‘private’ Facebook group that involved sexually explicit discussions about female classmates, including posts about the use of chloroform and a poll about “hate” sex.32 One member revealed the group to one of the targets and helped her file a complaint to the university.33 Thirteen involved students were suspended from clinical duties, indicating that they will be ineligible for graduation.33
Conclusions Social media networks provide new opportunities in medicine. They create forums by which to interact with other physicians, consult with patients, extend services to inaccessible areas, and educate patients with evidence-based medical information. However, there are a number of obstacles that can compromise a doctor’s ethics and professionalism. Most major bodies that represent physicians, including the Canadian, American, British and Irish medical associations, have issued guidelines for social media use.34,35,36,37 These guidelines include recommendations for establishing and maintaining professional social media accounts, including how to check security settings, and encourage physicians to be proactive to correct misinformation about themselves that they may find online. Of paramount importance is respecting the strict confidentiality inherent to the patient–physician relationship, while maintaining an online presence that allows frank and earnest discussion to promote good medical practices. Professionals who are committed to these ideals will not only enrich their own patients’ treatment, they will have a positive impact on patients whose healthcare providers learn from their communicated experience.
References 1.
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Williams LC. How the Facebook decade changed the world, for better and
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Fox, S. How do we know that social media is important to health care?
for worse. [Internet]. [Place unknown]: Think Progress; 2015 [cited January
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Fox S. The Social Life of Health Information, 2011 [Internet]. Washington DC: Pew Research; 2011 [cited 2015 January 11]. Available from:
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Wicks P, Massagli M, Frost J, Brownstein C, Okun S, Vaughan T et al.
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Sermo [Internet]. New York: Sermo; 2015 [cited 2015 January 11]. Available from: http://www.sermo.com.
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Doximity [Internet]. San Mateo: Doximity; 2015 [cited 2015 January 11]. Available from: http://www.doximity.com.
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Weiss CH, Poncela-Casasnovas J, Glaser JI, Pah R, Persell SD, Baker DW et al. Adoption of a high-impact innovation in a homogeneous population. Phys Rev X. 2014;4(4):041008.
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AMN Healthcare. 2013 Survey of Social Media and Mobile Usage by Healthcare Professionals. San Diego; AMN Healthcare, 2013:28.
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Vigod SN, Bell CM, Bohnen JMA. Privacy of patients’ information in hospital lifts: observational study. BMJ. 2003;327:1024-5.
10. Neporent L. Nurse firing highlights hazards of social media in hospitals [Internet] 2014 [cited 2015 January 11]. Available from: http://abcnews.go.com/Health/nurse-firing-highlights-hazards-social-mediahospitals/story?id=24454611. 11. Stevenson SE, Peck LA. I am eating a sandwich now: intent and foresight in the Twitter age. J Mass Media Ethics. 2011;26:56-65. 12. Chretien KC, Kind T. Social media and clinical care – ethical, professional, and social implications. Circulation. 2013;127:1413-21. 13. Greysen SR, Chretien KC, Kind T, Young A, Gross CP. Physician violations of online professionalism and disciplinary actions: a national survey of state medical boards. JAMA. 2012;307:1141-2. 14. Otto MA. Social media facilitate medical communication: experts debate risks and benefits of engaging in Twitter, Facebook, texting, and blogs. Rheumatology News. 2011;44(2):55. 15. Jent JF, Eaton CK, Merrick MT, Englebert NE, Dandes SK, Chapman AV et al. The decision to access patient information from a social media site: what would you do? J Adolesc Health. 2011;49:414-20. 16. Hawn C. Take two aspirin and tweet me in the morning: how Twitter, Facebook, and other social media are reshaping health care. Health Aff (Millwood). 2009;28:361-8. 17. Bosslet GT, Torke AM, Hickman SE, Terry CL, Helft PR. The patient doctor
23. Guseh JS II, Brendel RW, Brendel DH. Medical professionalism in the age of online social networking. J Med Ethics. 2009;35:584-6. 24. Mathews AW. Should doctors and patients be Facebook friends? The Wall Street Journal. 2013 February 4. 25. Lagu T, Greysen SR. Physician, monitor thyself: professionalism and accountability in the use of social media. J Clin Ethics. 2011;22:187-90. 26. Chretien KC, Farnan JM, Greysen SR, Kind T. To friend or not to friend? Social networking and faculty perceptions of online professionalism. Acad Med. 2011;86:1545-50. 27. Levitt A. Amy Dunbar: tardiness-hating OB/GYN now most reviled St. Louisan on Facebook [Internet]. DailyRFT; 2013 [cited 2015 January 22]. Available from: http://blogs.riverfronttimes.com/dailyrft/2013/02/amy_dunbar_facebook_ob gyn.php. 28. Go PH, Klaassen Z, Chamberlain RS. Attitudes and practices of surgery residency program directors toward the use of social networking profiles to select residency candidates: a nationwide survey analysis. J Surg Educ. 2012;69(3):292-300. 29. Schulman CI, Kuchkarian FM, Withum KF, Boecker FS, Graygo JM. Influence of social networking websites on medical school and residency selection process. Postgrad Med J. 2013;89:126-30. 30. Strausberg MB, Djuricich AM, Carlos WG, Bosslet GT. The influence of the residency application process on the online social networking behaviour of medical students: a single institutional study. Acad Med. 2013;88(11):1707-12. 31. Suler J. The online disinhibition effect. Cyberpsychol Behav. 2004;7(3):321-6. 32. CBC News. Dalhousie University probes misogynistic student ‘Gentleman’s Club’ [Internet]. Dec 17, 2014 [cited 2015 Jan 22]. Available from: http://www.cbc.ca/news/canada/nova-scotia/dalhousie-university-probes-mi sogynistic-student-gentlemen-s-club-1.2873918?cmp=rss. 33. Blatchford C. Dalhousie dentistry students paying a heavy price for
relationship and online social networks: results of a national survey. J Gen
victimless thoughtcrimes [Internet]. Jan 12, 2015 [cited 2015 Jan 12].
Intern Med. 2011;26:1168-74.
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18. Terry K. Telemedicine reduces rural health disparities, says UnitedHealth [Internet]. 2011 [cited 2015 January 15]. Available from: http://www.informationweek.com/mobile/telemedicine-reduces-rural-health -disparities-says-unitedhealth/d/d-id/1099233. 19. Manhattan Research. Seven percent of US physicians use video chat to communicate with patients [Internet]. 2011 [cited 2015 January 11].
http://news.nationalpost.com/2015/01/12/christie-blatchford-dalhousie-den tistry-students-paying-a-heavy-price-for-victimless-thoughtcrimes/. 34. Canadian Medical Association. Social media use [Internet]. 2014 [cited 2014 Oct 24]. Available from: https://www.cma.ca/En/Pages/social-media-use.aspx. 35. American Medical Association. Opinion 9.124 – Professionalism in the Use of Social Media [Internet]. 2014 [cited 2014 Oct 24]. Available from:
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atient-online-video-conferencing.
36. British Medical Association. Using social media: practical and ethical
20. TDR: a time to live or die? [Editorial]. Lancet. 2012;379:1562.
guidance for doctors and medical students [Internet]. 2014 [cited 2014 Oct
21. @MayoClinic. Wrist fractures: Treatment decisions not always
24]. Available from:
straightforward. #HealthLetter http://mayocl.in/1Do0uSG. 30 Jan 2015. [Tweet] Available from: https://twitter.com/MayoClinic/status/561366260802678784. 22. Wheeler CK, Said H, Prucz R, Rodrich RJ, Mathes DW. Social media in plastic
http://bma.org.uk/-/media/Files/PDFs/Practical%20advice%20at%20work/Et hics/socialmediaguidance.pdf. 37. Irish Medical Organisation. IMO Position Paper on Social Media [Internet]. 2014 [cited 24 Oct 2014]. Available from:
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RCSIsmjelective report
Asylum seeker healthcare in France: ONE MONTH WITH THE PASS PROGRAMME LISA MCNAMEE spent a month at Dupuytren Hospital in Limoges, a centre that provides healthcare services to asylum seekers and French residents without documents.
Imagine you’re a Syrian refugee, recently arrived in France having fled a brutal war and the destruction of your home. You have very little French and no English, and your ulcerative colitis medication has run out. As an asylum seeker, you are likely entitled to medical treatment in France via the PASS (Permanences d’accès aux soins de santé/Permanent Access to Health Care) programme, but only if you can get a special form filled out by the local civil service office (Prefecture). Enrolling in PASS is a long, bureaucratic process, characterised by intermittent access to translators and a lack of multilingual staff. Your situation is further complicated by an overcrowded living situation, a lack of food security and little money.
The PASS programme In France, ‘universal’ healthcare is offered via the Carte Vitale – a card that is brought to the GP or specialist in order to access free or very reduced cost healthcare. Patients then pay an upfront fee directly to the doctor, which is subsequently refunded by the State. The majority of French citizens are issued a Carte Vitale when they turn 16 via the social security system; however, those who don’t have a bank account, a permanent address or an identity card may fall through the cracks. As a new arrival in France, one cannot access
healthcare through the Carte Vitale system for a minimum of three months. The PASS is a bridging health provision service for those who don’t qualify for mainstream access, mainly for asylum seekers and undocumented migrants. Enrollment isn’t automatic; each case is separately evaluated by a civil servant (not a medic). It’s a confusing system, with many levels of healthcare entitlement, all of which have similar sounding names.
Dupuytren Hospital Dupuytren Hospital is based in Limoges, a small city in the Limousin region of west-central France. Its name comes from the French verb ‘Limoger,’ which means ‘to be banished to Limoges’ – it was a punishment to be sent there as a civil servant in the past. Now, its train stations, parks and overwhelmed housing services are home to another group of banished people: asylum seekers and undocumented migrants. These patients come with a mixture of languages and cultures, translation of which complicates their medical care. Within our service at Dupuytren, there were two main types of entitlement, which gave patients access to different levels of healthcare, but whose issuance seemed to be at the whim of the local bureaucrat. Volume 8: Number 1. 2015 | Page 79
RCSIsmjelective report Denial of care/resources
Appropriate facilities/precautions for medical staff
Resource allocation for asylum seekers is a contentious, constantly evolving political issue in France. A recent change in French law meant that certain treatments, including chemotherapy, are no longer available to migrants. Prior to 2014, immigrants to France could apply for treatments that were available in their home country but inaccessible to them there for reasons such as cost or distance. Due to a recent policy change, however, any treatment that exists in a person’s country of origin can be denied to them in France regardless of its accessibility. While I was placed in Limoges, two Georgian women who were undergoing chemotherapy treatment in the Paris PASS programme were suddenly denied further treatment by the local administrators. Both had appointments booked by their doctors within the district hospital, but were phoned by hospital administrators a few days beforehand to say that their entitlements had changed under French law and they no longer qualified. The only dental care available under the PASS scheme is tooth extraction. This means that a painful tooth requiring only a small filling might be pulled unnecessarily; we were unable to refer to a dentist for any other service. This was difficult to explain to patients and was one of the more upsetting restrictions on the care we could offer in the clinic. Other services somewhat arbitrarily ignored by the scheme were ophthalmologic and psychiatric services.
I began my placement just as Ebola was starting to hit the headlines in the summer of 2014. A large proportion of our patients came from north and west Africa, parts of the world where France has a colonial history. We would examine young patients from Guinea who were acutely unwell without protective gear, checking their temperatures and hoping they didn’t have a fever. As many people arrive in France and go directly to the PASS services, Ebola transmission was a conceivable risk. When my supervising doctor raised this concern with other hospital staff she was told that ‘as there was no directive from Paris re: Ebola, no protective gear was deemed necessary at this time’.
Cultural barriers Every day at Dupuytren brought new challenges. Several of the cases I saw were extremely complex, and relationships between our patients and other hospital staff were often fraught. One woman told her doctor that she was being verbally abused at home, and that her husband was preventing her from leaving the house. He had taken her passport and hidden it to ensure that she would not fly back to her family in Algeria. During the consultation, I talked to the husband in the anteroom to keep him from interfering with the consultation or listening to his wife’s complaints. The case was brought to the PASS social worker’s attention, who dismissed the issue as ‘cultural’ and not worth intervening in because the husband and wife involved were Algerian. Another patient had left an extremely violent situation in his home country, where he had been forced into killing his younger siblings to save his own life. Though he had fled his home and travelled to Europe for a better life, his living conditions in France were so poor that he was now considering returning home. Experiences such as his, and those of countless others, were very difficult to contextualise. Working with a poor and transient population came with many non-medical difficulties (on top of the language barrier). Patients could not afford bus fare to the hospital, which is several kilometres outside of the main town. Single use bus passes were distributed by the PASS social worker, but she often ran out of these by the end of the month. Patients who were left without often missed appointments because they simply couldn’t get there. Page 80 | Volume 8: Number 1. 2015
Conclusion My education to date at the RCSI has emphasised holistic care of the patient, but this placement brought it into sharp focus. The time I spent in France was hugely rewarding, offering a varied and interesting caseload, many clinical signs to see and chances to practice my history and examination skills in three languages – some, it has to be said, much better than others. I encountered multi-drug resistant TB, HIV, and hepatitis C frequently. It was not uncommon to find multiple serious, undiagnosed illnesses in the same patient. Most also had psychological issues due to what they had left behind in their own country, the hardships of living on the streets of France, or both. The lack of access to counsellors, dentists, and often even food and adequate housing, were huge issues. Trying to treat an insulin-dependent diabetic who has nothing to eat at home is a not uncommon scenario in this patient cohort. My supervising doctor was frustrated with the lack of progress made in her year at the programme. The next logical step, in her eyes, is the expansion of the programme to better integrate with local charitable organisations. For example, SOS Racisme aids asylum seekers with food and accommodation. These alliances may be the only way to improve the overall quality of life of patients in the foreseeable future. Very little data is collected on the resources available to each individual PASS service. My team developed an online survey to evaluate what the average PASS service had access to, in an attempt to make a case for improved availability of necessary hospital resources. Huge variations were discovered between facilities offered by each local PASS office; some were very well equipped and supported by the attached hospital, while others only had one part-time intern doctor available. Prior to this experience, I felt that the EU’s healthcare allocation for asylum seekers was adequate, if restricted. The next appropriate step should be to examine the differences in service provision between neighbouring EU countries, for example France, Ireland and the UK. Significant and quantifiable differences between them may highlight the need to improve the provision of appropriate healthcare and reveal methods by which to do so. In any case, the current French system needs to be systematically and independently evaluated, and the significant gaps in service provision addressed.
RCSIsmjtravel brief
A phenomenal experience TAYYAUB MANSOOR spent some time working in the Hospital Pediatrico Dr H Notti, in Mendoza, Argentina. Mendoza and Hospital Notti Mendoza is a city of just over 115,000 people lying east of the Andes Mountains. Its paediatric population is served by the Hospital Pediatrico Dr H Notti, a public children’s hospital. Hospital Notti is a two-storey building covering an area of about 36,000 square metres, containing 300 beds and a staff of over 1,000 people. It is the only large-scale paediatric hospital in Mendoza and provides care not only for the city but also the larger province of Mendoza, a total population of over 200,000 children. Some families travel as far as 300km to avail of its services.
Surgery There are four operating theatres assigned for elective surgery: one for gastrointestinal surgeries, one for neurosurgery and orthopaedic cases, one for burns and trauma, and one for other general surgeries. Common procedures include laparoscopic cholecystectomies, tonsillectomies and cryptorchidectomies. Cholecystectomies are surprisingly common, which is perhaps in part explained by the rising obesity epidemic among children.1 All other abdominal surgeries, including diaphragmatic hernia, pyloric stenosis and appendicectomy, are performed using a traditional open approach. Although the laparoscpic approach is associated with lower wound complication rates, limitations in surgical experience restrict its use to cholecystectomies and gynaecological cases.2
Burns and trauma Burn injuries were also commonplace in Hospital Notti – burns are a leading cause of lost disability-adjusted life-year (DALY) in low and middle income countries. Commonly, these injuries occur at home where poor design in both the housing and cooking appliances increase risk for open fire accidents. The WHO estimates that child mortality from burn injuries is
more than seven times higher in low and middle income countries where prevention strategies have not been adequately implemented.3
Neurosurgery With the neurosurgical team, I also saw lumbar punctures, craniotomies and placement of ventriculoperitoneal (VP) shunts. One patient, a little girl born two months premature, had a severe form of spina bifida – myeloschisis – in which neural tissue is exposed to the outside world. Repair involves a risky surgery during which the neural plate is closed, and tissue and muscle are sutured over the exposed segment. The surgery was successful, but the doctors grimly explained to the parents that their child’s outcome would likely be poor; she had already developed hydrocephalus, and complications of the surgery such as leg paralysis and incontinence are common.
Reflections Going to Argentina for my medical elective was a phenomenal learning experience. I was able to experience a different culture, meet new people, and I had the opportunity to see a variety of procedures. I also witnessed firsthand the difficulties, such as lack of access to laparoscopic surgeries, which may affect hospitals in developing countries. Sadly, simple complications such as infection are prevalent at Hospital Notti due to lack of infection control programmes.4 For example, a two-month-old baby developed an infection shortly following placement of a VP shunt, which then had to be surgically removed and re-placed into her internal jugular vein. Another baby with an extra-ventricular drain (EVD) developed a massive subdural empyema with significant mass effect evident in her CT scan. Overall, my experience in Mendoza has given me a deeper insight into the differences that can exist in the healthcare system across borders, one that I won’t forget anytime soon.
References 1. Bonfrate L, Wang DQ-H, Garruti G, Portincasa P. Obesity and the risk and prognosis of gallstone disease and pancreatitis. Best Pract Res Clin Gastroenterol. 2014;28(4):623-35. 2. Sola JE, Neville HL. Laparoscopic vs open pyloromyotomy: a systematic review and meta-analysis. J Pediatr Surg. 2009;44(8):1631-7.
3. World Health Organisation. World Health Organisation Burns Fact Sheet. Available from: http://www.who.int/mediacentre/factsheets/fs365/en/. 4. Rosenthal VD, Guzman S, Crnich C. Device-associated nosocomial infection rates in intensive care units of Argentina. Infect Control Hosp Epidemiol. 2004;25(3):251-5.
Volume 8: Number 1. 2015 | Page 81
RCSIsmjtravel brief
Impressions of Bahrain JUSTIN MING ZHENG MA joined students at the RCSI-Medical University of Bahrain for an elective trip.
The RCSI-Medical University of Bahrain is in Busaiteen, a small town on the Muharraq island in the Arabian Gulf. Since it was founded in 2004, the RCSI has offered the unique opportunity for students to spend a semester (either JC3 or IC2) in an exchange programme to the alternative campus. On my arrival, I was warmly welcomed by the student council as they gave us a tour of what would be our campus for the next four months. It was truly state of the art, with an incredible multifunctional sports hall and a newly furbished clinical laboratory. I was touched by the friendliness of the student body and they helped me settle down in no time.
trained in Ireland, giving a sense of familiarity and consistency, while the addition of other local lecturers complemented the learning experience as they added their own style. Perhaps the greatest difference was how anatomy is taught, where plastic models are used instead of cadavers and practical sessions are more self directed. Though models are not as realistic and detailed, they have fewer variables and are much easier to access. Self-directed practical sessions encourage students to work together in a problem-based approach. Ultimately, I found that it is up to the student, and the effort put into anatomy sessions determines how much is taken out of them.
Students, professors, classes
Culture
On the first day of lectures I was surprised to find that classes were smaller compared to those in Dublin. Each year has only 150 students, mostly from Gulf Cooperation Council countries like Kuwait and Qatar, with a small mix of international students. I quickly realised, however, that I rather enjoy the small class size. It was easier to meet people, and the professors are able to give more attention to each student. To welcome us they even brought us around the city to introduce us to some local cuisines. A smaller class size in each year also meant that there were more opportunities to connect with students from higher years, creating a strong community atmosphere in the college. The structure of lectures is more or less identical to Dublin, as a close communication is kept between the two. Most lecturers were
On my arrival I noticed that everywhere I looked, men and women were dressed in the traditional dishdasha or wearing a hijab, respectively; I felt extremely out of place with my sport shorts and t-shirt. I quickly learned more about local customs, tried out Middle Eastern foods and even picked up one or two Arabic words! I also had the chance to visit neighbouring places like the UAE, Oman and Kuwait, giving me the chance to understand the rich history and enjoy the unique scenery of the Middle East.
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Concluding thoughts Going to Bahrain was truly an amazing experience. It was challenging, keeping up with lectures while adapting to a new environment, but the reward was great. I learned as much about myself as I learned about the practice of medicine.
RCSIsmjtravel brief
Too good to be true? ANNIKA GALLAGHER and SENAN O’CONNELL explored the acclaimed Cuban health service. In August 2012 an article appeared in The Irish Times about the Cuban healthcare system, evaluating their acclaimed first-world service on a third-world budget.1 In the article, Cuba – a small island isolated geographically from the Central American landmass, and economically from the overshadowing United States – was shown to have the rarest of things: a modern day health system success story. During our Senior Selected Component in third year we had the opportunity to observe the workings of Cuban healthcare as visiting medical students.
Another world Cuba itself seems to be in a time warp. Little or no internet access, limited opportunities for personal enterprise and difficulties in accessing basic materials are common. Despite these limitations, it’s also a society that looks after all of its members. A history of constrained resources has forced Cuba to develop creative solutions to healthcare expenses. For example, international trade restrictions necessitated the formation of a native pharmaceutical industry to provide for the population’s needs. A strong political commitment to health has been noted.2
A foundation in primary care The Cuban healthcare system consists of a four-tiered structure, composed of GP/nurse facilities (consultorios), polyclinics, general hospitals and specialised referral hospitals. The foundation of this system is based on primary care. Annual visits by the doctor to each household in the consultorio’s district include general medical check-ups, as well as inspection for sanitation and education efforts (for example a discussion about standing water and the spread of dengue fever). Consultarios also hold clinics that are attended by specialists such as paediatricians and obstetricians, thus avoiding referrals. Family doctors we encountered concurred that this level of local care is the foundation underpinning national healthcare outcomes. Polyclinics, described as the ‘traffic light’ of the system, provide a full range of primary care services, including urgent coronary
and respiratory care, dentistry, laboratory facilities, minor operative procedures and rehabilitation. Only after polyclinic options were exhausted would patients be referred to general or specialised hospitals.
Success stories Prevention and promotion are two key pillars in community-oriented primary care. Targeted promotion strategies in Cuba have led to postnatal immunisation uptake rates for one-year-old children at close to 100%, according to UNICEF figures. Similarly, sexual health campaigns have proved effective with HIV levels of 0.1%.3 Media outlets have been utilised as a source of promotion through television and radio campaigns. Health promotion posters are commonplace, giving guidelines on matters such as salt intake, cancer risk factors and smoking. In fact, the only advertisements to be seen are either pro-revolutionary or health promotion. There was certainly merit in studying the Cuban Primary Healthcare Service. In the current global economy, as countries struggle with tightened health budgets and ageing populations, the Cuban system provides a model of efficient allocation of resources in a financially constrained environment. Whether it would be as successful elsewhere remains to be seen, but aspects of it such as the strong emphasis on prevention and promotion, along with the polyclinic system, may be universally applicable.
References 1. Gorry, C. The Cuban Experience: Better health on a budget? The Irish Times, August 14, 2012. 2. Pagliccia N, Alvarez Perez A. The Cuban experience in public health: does political will have a role? Int J Health Serv. 2012;42(1):77-94. 3. UNICEF. Statistics. [Internet] [Accessed May 2013] Available from: http://www.unicef.org/infobycountry/cuba_statistics.html.
Volume 8: Number 1. 2015 | Page 83
RCSIsmjtravel brief
Beneath Mount Everest MAY-ANH NGUYEN and JONATHAN MARKOVICH found their expectations challenged in Nepal. Last August, we spent a month as the only two foreigners in Bharatpur town, located in the Chitwan District of Nepal. Our host family welcomed us with the customary side-to-side nod and with more dal bhat than our appetites could handle. We volunteered at the College of Medical Sciences Teaching Hospital (CMS), a relatively small and cramped building on the edge of the Chitwan jungle.
obtained off the streets without a prescription at a relatively low cost, leading to the possibility of rising antibiotic resistance in Nepal. We also learned a little bit about how the healthcare system functioned in Nepal. Like the United States, it is a private pay-per-service system with some governmental subsidisation. However, there is no such establishment as health insurance; patients are often refused or discontinued service because of their inability to pay.
Confounding expectations As Nepal is a developing nation, we expected that the majority of patient admissions would be related to infectious diseases. On our first day in the emergency department, however, we were surprised to find this assumption to be false. The prevalence of cardiovascular disease in Nepal is 33.9%; however, only 8.5% of Nepalis receive treatment.1 Surprisingly, at CMS the issue was not one of inadequate resources; the cardiac care facilities were brand new and comparable to Western standards. Available treatment options included international gold standard treatments such as coronary angioplasties using drug-eluting stents. During our cardiology placement the only reminder that we were in Nepal was the friendly cockroach in the cath lab! As we spent more time with the team, it became evident that the source of the issue was the inability of most local Nepalis to recognise early symptoms of cardiac events. Patients typically presented to the hospital in later stages of myocardial infarction. We speculated that early diagnosis and thereby better outcomes could possibly be achieved by allocating resources to increase public awareness about cardiovascular disease.
Paediatric problems The time we spent with the paediatrics team aligned more closely with our preconceived notions of medicine in economically disadvantaged countries like Nepal. The predominant reason for admission to the NICU was neonatal sepsis, either as a complication of prematurity or inadequate sanitary measures intrapartum. Afternoons on the paediatric wards were filled with the cries of children plagued by transmissible diseases. Antibiotics could be Page 84 | Volume 8: Number 1. 2015
Warmth and resourcefulness Nepal captured our hearts with its picturesque landscape and the warmth of its culture, and the CMS constantly impressed us through its staff’s resourcefulness and commitment to betterment. The time we spent there opened our eyes to the realities of a weak healthcare system but also left us optimistic about its capacity for improvement. Fittingly, we took an Everest mountain flight at the end of our journey. We were overcome with awe sitting in that rickety plane; it’s impossible not to feel very vulnerable in contrast to the world’s highest peak. Medicine itself was once faced with such insurmountable challenges as conquering Mt Everest. Looking down upon the summit, we reflected on how far humanity has come in its triumph and that the outlook for medicine is brighter than ever. Along our ascent, we must always remember to look down to remind ourselves of how fortunate we are to have the means to make it that far, and that there are still others at the base that we can help.
Reference 1. Sharma SK, Ghimire A, Radhakrishnan J, Thapa L, Shrestha NR, Paudel N et al. Prevalence of hypertension, obesity, diabetes, and metabolic syndrome in Nepal. Int J Hypertens. 2011;2011:821971. doi: 10.4061/2011/821971. Epub 2011 April 19.
RCSIsmjalumni spotlight
A view of the “war” from afar DANIEL JOYCE, a graduate of the RCSI class of 2010, offers a view on the plight of the graduate hospital doctor in Ireland. A 2013 article in this journal outlined the data describing the reasons for the exodus of doctors from Irish shores.1 This article is intended to be a disruptive and honest, but not unduly critical, personal reflection on the enormous challenges facing the physician workforce in Ireland. Astonishingly, Ireland continues to train outstanding doctors in the harshest of environments, but I fear that, for Irish people, those days are numbered.
Youthful enthusiasm I graduated from the RCSI in 2010 and began working as an enthusiastic intern at a Dublin hospital in pursuit of a dream to be a surgeon in Ireland. Equipped with an exceptional education from the RCSI, I anticipated a year in which I would apply and capitalise on my newfound knowledge. Naïve excitement was promptly extinguished upon the realisation that I had signed up for a job that largely involved completing tasks that no one else wanted or was willing to do. There is, of course, some education to be had in service, and indeed many of the jobs that junior house staff perform are crucial for good patient care, but for the most part they are not educational. While it’s almost four years since I roamed the halls looking for the ever elusive ECG machine, I still remember the fear that a patient might need an imaging study or some other test, since it invariably involved (metaphorically) promising one’s firstborn as an enticement. Grown men and women would emerge from radiology or endoscopy suites crying, bearing figurative war wounds from the struggle to obtain tests that their patients needed. The caregivers that inflicted these war wounds are good conscientious people, but at least then it seemed that hostility was the only effective gatekeeper to prevent their overstretched departments from overload and meltdown. To quote the current Minister for Health, Dr Leo Varadkar – it was “a war on all fronts”.
Leaving the battlefield A battlefield, albeit a metaphorical one, is not a safe learning environment, and with that in mind I made the fateful decision to purchase a one-way ticket to the United States. I do not write this piece with any disdain for the magnificent, committed physician educators that populate our broken healthcare system. I count several of them as close mentors and friends. Indeed, I sought their advice, and the vast majority subtly but candidly supported my
decision to seek training in the US, albeit with the warning that it would be challenging to come back after training. The decision was easy. I could never risk becoming terminally engaged in the snipe hunt that was and still is in many ways the postgraduate medical training system in Ireland. To my great surprise many of my American interviews consisted of leaders in surgery promoting their programmes to candidates, hoping to entice the best to come and realise their dreams at their institutions. It was a strange experience, since at the time entry to higher specialist training in Ireland was portrayed as something reserved not only for the most gifted of candidates, but for those who demonstrated a level of self-sacrifice that might be expected of an eternally indentured servant.
Is a 48-hour week wise? To the credit of the physician leaders in our postgraduate training bodies, there has been considerable progress in streamlining the training process, but I regret to say that there has been no ceasefire on the frontline that is the hospital system. From the outside, at least, it appears that the Irish healthcare system is disintegrating. There seems to be only one measure of success: the number of patients on trolleys in the nation’s emergency rooms. This of course is a gross oversimplification and does not do justice to the efforts of those who are striving to deliver world-class care in areas such as the HSE National Cancer Control Programme. Nonetheless, this is the impression that both current and expatriate doctors have and it needs to be changed. The hostile and downright unacceptable environment in which Irish NCHDs live and work has led to a certain level of understandable militancy in their ranks. Instead of focusing on their career development and education, they have been left with no choice but to resort to industrial action to vindicate their rights and those of their patients. Though by no means do I support the current unsafe working hour arrangements, I do not think the sole focus on reaching the much-revered 48-hour working week is wise. I imagine such a statement will generate much criticism from my colleagues, but I do not think that the 48-hour work week in itself supports education or the best clinical outcomes. It is of course enshrined in EU legislation, and on that front is frequently hijacked by the HSE to avoid paying well-earned overtime. NCHDs have justifiably seized it as a key end point in their negotiations with the HSE, but I fear it might be a case of cutting off the nose to spite the face. The case is Volume 8: Number 1. 2015 | Page 85
RCSIsmjalumni spotlight complex, but I firmly believe that a competent surgeon cannot be trained in a realistic timeframe while working 48 hours per week. In truth, few trainees are or ever will be truly European Working Time Directive (EWTD) compliant and the pursuit of its rigid implementation may be the wrong focus in the pursuit of a world-class postgraduate medical education and, indeed, optimal patient care. The implementation of the 80-hour work week in the United States has not generated the expected safety gains, and may in fact be associated with a trend towards worse outcomes for patients and little to no improvement in resident well-being or certifying exam scores.2 To this end, the American Board of Surgery is sponsoring the Flexibility In duty hour Requirements for Surgical Trainees trial (FIRST). This randomised controlled trial will examine patient outcomes (death or serious morbidity composite) as the primary end point. I do not support unregulated work hours as there is ample evidence to demonstrate the deleterious effects of fatigue on performance;3 however, the fixation on the 48-hour work week is neither practical nor evidence based. Nor do I believe that EWTD compliance in Irish postgraduate medical training is possible, practical or even desirable. Fair, flexible and appropriately remunerated working hours that respect the need for sleep and one’s personal and family life are the way forward.
It’s all about the money? Monetary compensation is a factor in the current difficulties with recruiting top talent to Irish shores. Many NCHDs leave Ireland to pursue specialised fellowships and never return, since their skills and knowledge are highly sought after in the US, Canada, Australia and beyond. Some may view this as an abandonment of duty and a lack of patriotism, driven by a sense of entitlement and narcissism. I would argue that the desire to receive reasonable compensation after ten to 15 years’ training is neither greedy nor selfish. Many new consultants find themselves over 15 years into their working life, laden with debt accumulated during years of six-monthly moves, and with young families to support. Regardless of how one views the salaries commanded by doctors, they are a highly mobile profession and are voting with their feet. Rather than viewing salaries as an opportunity to strip cost from the healthcare system, they should be viewed as solid investments in human infrastructure and capital. Higher salaries alone are not a successful measure to retain key staff, but they do play a role. I am not advocating that
the Government should recklessly open the coffers to lure doctors from afar, but they must realise that the retention of world-class doctors is not an inexpensive endeavour. Salary does play a small but significant role in the recruitment and retention of NCHDs and consultants; however, it alone is not a solution. Irish NCHDs’ remuneration is for the most part far in excess of that in the United States and it is by no means preventing the current exodus of Irish doctors. Rather, the ‘package’ is broken. Training in Ireland requires one to dispense with the dreams that drove so many of us to study medicine. One commentator referred to NCHD recruitment as a process of finding individuals willing to “wear white coats and fill gaps”. Many of my classmates who are now specialist registrars tell me anecdotes that support this notion. Protected training time is seen as a foreign concept that has no real meaning in the day-to-day “war” described by the Minister for Health. Creativity and innovation are stifled by the constant battle to provide patients with safe care in an environment where the emphasis is on the absolute number of trolleys in emergency room corridors. The current people strategy in the HSE – replacing emigrating doctors with migrant doctors from Asia and Africa – may seem to alleviate the problem in numeric terms. Time has, however, shown that these doctors are, like their Irish counterparts, unwilling to work in the often harsh conditions without the prospect of ongoing career development. They too are leaving. It is not a question of whether one is Irish or otherwise; physicians are unwilling to fight this “war” in the current working conditions.
Winning the war I am sure it is only a matter of time before the Minister for Health or the HSE assembles another taskforce to examine the current manpower crisis in the health service. This is not necessary, since the problems have been outlined for almost a decade now. The HSE’s own 2007 Medical Education, Training and Research Strategy emphatically declares that “in promoting best practice in medical education and training, the HSE will ensure that the inevitable service pressures will not undermine or derail the delivery of the HSE’s medical education and training work plan”.4 A successful path forward will require the political elite to develop a persistent sense of urgency that extends beyond trolley numbers and waiting lists. It will also require an even greater engagement by physicians, nurses and all caregivers to lead the change from a trolley-centric system to patient- and caregiver-driven healthcare.
References 1. Chalikonda L. Why are Irish doctors emigrating? RCSIsmj. 2013;6(1):93-8.
4. Fitzgerald MX. Medical Education, Training & Research [online]. Dublin,
2. Philibert I, Nasca T, Brigham T, Shapiro J. Duty-hour limits and patient
Health Service Executive, 2007. [Accessed 2015 January 2] Available from:
care and resident outcomes: can high-quality studies offer insight into
http://www.hse.ie/eng/services/publications/corporate/etr/Medical_Educa
complex relationships? Ann Rev Med. 2013;64:467-83.
tion,_Training_Research_HSE_Strategy.pdf.
3. Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature. 1997;388(6639):235.
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RCSIsmjbook review An Act of Love by Marie Fleming with Sue Leonard
Reviewed by Hailey Carroll, senior staff writer Paperback: 304 pages Publisher: Hachette Books Ireland Published: 2014 ISBN: 978-1444791228 Who should decide when you are allowed to die? This is a hotly debated question and many parties are sure they have the ‘right’ answer: politicians and legislators arguing that it is a decision for the Government, controversial physicians blurring – and sometimes crossing – the ever-moving line, and patients pleading with both that the choice should be theirs. An effort to project an often drowned out voice in this delicate, yet desperately important, argument, An Act of Love by the late Marie Fleming with Sue Leonard is a poignant, powerful memoir. Marie was diagnosed with multiple sclerosis (MS) in her mid-thirties and subsequently became a hero to the MS community in Ireland. She was a spokeswoman for those suffering from life-limiting illnesses during her journey to change Irish legislation surrounding assisted suicide and the right to die.
The choice to decide when to die MS is a frightening and disabling disease – the course is progressive, the symptoms debilitating, and the prognosis poor. The immune system attacks the myelin sheaths surrounding the fibres of the central nervous system, leaving plaques, which interrupt the transmission of messages to the rest of the body. For Marie, MS took hold bit by bit, stage by stage over 24 years, eventually leaving her wheelchair bound and lacking physical independence. Despite the physical impact as the disease progressed, she maintained a strong conviction: that it was her choice to dictate how and when her life would end. Marie wanted to be the one to decide when she had had enough. With the support of her family and her partner Tom Curran, Marie contemplated the conundrum posed by her death: how does
someone who no longer has the ability to walk or feed herself take her own life? The law in Ireland strictly states that all acts surrounding suicide must only involve the person themselves, an impossibility for a woman who would lack the ability to commit the act when the time came. Trapped in her body by a disease that gave her the ability neither to choose how to live nor how to die, Marie sought an answer in the form of new legislation. She took a case against the Irish State to the High Court, fighting courageously not only for herself but for all who would come after her.
Lessons in humanity Marie Fleming lost her court case, but lived to complete her memoir. The story of her journey not only highlights the arguments for and against assisted suicide from different perspectives, it also offers invaluable lessons about humanity that are crucial for healthcare practitioners to understand. An Act of Love ‘demedicalises’ the medical, reminding us through Marie’s inner dialogue that we are also patient advocates – providing treatment for diseases that are so much greater than the sum of their symptoms. Just before Marie passed away peacefully in her home, Tom asked the publishers to rush print a single copy of her book. The first (and at that point only) copy was hand delivered the day after she died and placed in her coffin to be buried with her. Regardless of your familiarity with the case, or your views on this hotly debated issue, An Act of Love is a must read; Marie Fleming and her story embody the true spirit of humanity and the resilience of the Irish people. Volume 8: Number 1. 2015 | Page 87
RCSIsmjabstract Methicillin-resistant Staphylococcus aureus in Connolly Hospital, Dublin: evaluation of clinical features, molecular epidemiology and risk factors to improve patient outcomes Mark Abel1
FIGURE 1: PFGE gel banding pattern for 13 isolates plus lambda ladder markers.
Niall Stevens2 Eoghan Oâ&#x20AC;&#x2122;Neill3 1RCSI medical student 2RCSI Clinical Microbiology 3Connolly Hospital, Blanchardstown
Introduction
Results
Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of healthcare-associated infection (HCAI); these bacteria now account for 22.8% of staphylococcal bloodstream infections in Ireland. In addition to causing significant patient morbidity and mortality, this rapidly escalating problem costs the Irish health system over â&#x201A;Ź23 million per year.1,2,3 Connolly Hospital Blanchardstown (CHB), Dublin, has implemented a policy in which all inpatients who are in hospital for more than 30 days are screened monthly for MRSA colonisation. This study examined the clinical features, molecular epidemiology and risk factors for acquiring MRSA at Connolly Hospital over a 24-month period.
Patient risk factors such as old age, underlying chronic illness, previous and prolonged healthcare contact, non-intact skin, surgery during admission and antibiotic exposure were found to be among the risk factors for MRSA acquisition. An evaluation of the CHB MRSA screening programme showed that only 53% of patients had been screened every month as required by the protocol. PFGE of the isolates showed eight clonal groups. All were related either by ward or date of isolation, suggesting cross-transmission within and across wards.
Methods The Infection Prevention and Control Team data on MRSA colonisation and infection at CHB was used to generate a list of patients identified at routine monthly screening over a two-year period. These 43 medical charts were reviewed for clinical features, risk factors, antibiotic exposures and outcomes. Swabs from colonised patients were obtained from the laboratory and re-cultured, along with eight reference strains representing major circulating staphylococcal cassette chromosome mec (SCCmec) types. Pulsed field gel electrophoresis (PFGE) was performed on all clinical isolates, and the eight reference strains and their restriction patterns compared to determine genetic relatedness of strains isolated across hospital wards.
Conclusion The results of this study demonstrate a need for improved compliance with the CHB MRSA screening policy. A patient MRSA screening tracking record has been established to ensure that monthly screens are not missed. Genetic testing of isolates has also highlighted the problem of cross-transmission. In addition to reducing healthcare costs, strategies that improve hand hygiene and antimicrobial stewardship can have a significant impact on both patient outcomes and quality of life.
Acknowledgments We would like to thank the staff of the Department of Clinical Microbiology, Royal College of Surgeons in Ireland, and the Infection Prevention and Control Team, Connolly Hospital Blanchardstown, for their support in this study. This work is supported by the Health Research Board Ireland through a Summer Student Scholarship (Grant SS/2012/6).
References 1. Pfizer. Methicillin-resistant Staphylococcus aureus (MRSA) In Ireland:
3. European Centre for Disease Prevention and Control. Surveillance Report:
Addressing the issues. Dublin: Pfizer, 2010. [Internet] [cited 2012 August
Antimicrobial resistance surveillance in Europe 2012 [Internet]. Stockholm:
20]. Available from:
European Centre for Disease Prevention and Control, 2012 [cited 2014
www.pfizer.ie/UserFiles/File/news.../MRSA_Report_FINAL.pdf.
Nov 03]. Available from:
2. Health Protection Surveillance Centre. EARS-Net Report, Quarters 1-2 2014 [Internet] Dublin: Health Protection Surveillance Centre, 2014. [cited 2014 Nov 03]. Available from: http://www.hpsc.ie/A-Z/MicrobiologyAntimicrobialResistance/ EuropeanAntimicrobialResistanceSurveillanceSystemEARSS/EARSSSurveillanc eReports/2014Reports/File,14686,en.pdf.
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http://www.ecdc.europa.eu/en/publications/Publications/antimicrobial-resi stance-surveillance-europe-2012.pdf.
RCSIsmjabstract The CQUIN dementia screening protocol for acute hospital patients aged 75 and older: compliance and feasibility in a UK hospital Stephen Klaus1 Sarah T Pendlebury DPhil FRCP2 1RCSI medical student 2NIHR Oxford Biomedical Research
Centre and Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford
Introduction It has been estimated that only 42% of people in England who have dementia have been formally diagnosed.1 In an attempt to better identify and manage dementia in the hospital setting, the Department of Health, England, introduced mandatory cognitive screening via the Commissioning for Quality and Innovation (CQUIN) process for all emergency admission patients over the age of 75 remaining in hospital for >72 hours. The Oxford University Hospitals (OUH) implemented the cognitive screen to include the following four items: 1) the 10-point Abbreviated Mental Test Score (AMTS);2,3 2) presence or absence of known dementia; 3) clinical diagnosis of delirium; and, 4) a question regarding subjective memory complaint.1 The authors aimed to evaluate the clinical utility and feasibility of this screening protocol.
Methods Consecutive older patients aged >75 years admitted to one acute medical team were prospectively administered the OUH cognitive screen over a five-week period in March-May, 2013. Completion rates at admission for the four items indicated by the screening protocol were recorded. The research team then reviewed patients for whom the screening protocol was not complete in order to measure feasibility of completion.
patient review by the research team, AMTS completion rate rose to 77%; the remaining 23% of patients were unable to answer questions, primarily due to acute illness (e.g., agitation, reduced level of consciousness). Completion of the dementia and delirium questions rose to 100% and 90%, respectively, although only 47% were asked the memory question.
Conclusion The majority of patients were able to undertake the AMTS, indicating that it is feasible for use in the acute setting. The admitting teams performed reasonably well in administering the AMTS, but completed the questions on dementia and delirium in less than half of cases, even though this was feasible in nearly all patients. Our findings highlight the need for ongoing education and cyclical audit to increase compliance, particularly in the identification and recording of dementia and delirium.
References 1. Department of Health [UK]. Using the Commissioning for Quality and Innovation (CQUIN) Payment Framework: Guidance on New National Goals for 2012-13. 2012.
Results Of 134 eligible patients (mean age Âą SD 84.5 Âą 5.9, 51% women), 94 (69%) had a completed AMTS by the admitting team. A total of 61 (45%) had a completed dementia question (item 2), 60 (44%) had a completed delirium question (item 3) and only 27 (25%) had been asked about subjective memory complaint (item 4). After
2. Hodkinson HM. Evaluation of a mental test score for assessment of mental impairment in the elderly. Age Ageing. 1972;1(4):233-8. 3. Jitapunkul S, Pillay I, Ebrahim S. The Abbreviated Mental Test: its use and validity. Age Ageing. 1991;20(5):332-6.
Volume 8: Number 1. 2015 | Page 89
RCSIsmjabstract The effect of epidural insertion on blood pressure and cardiotocography Daire Nevin Maguire RCSI medical student
Background Epidural anaesthetics are associated with maternal hypotension; the relative risk is estimated at 18.23.1 Reduction in maternal blood pressure (BP) is the result of sympathetic blockade, dilatation of maternal vasculature, and decreased venous return. Decreased utero-placental perfusion affects foetal heart rate as detected by cardiotocography (CTG). There is conflicting evidence as to whether epidurals increase rates of intervention and operative delivery secondary to non-reassuring CTG.2,3
Objective To investigate if epidural insertion increased obstetric intervention rates secondary to CTG abnormalities where there was a significant reduction in maternal BP.
Study design Retrospective analysis was carried out of the medical records of 96 healthy patients in a city hospital in Waterford, Ireland. Inclusion criteria were patients with no pertinent medical conditions, on continuous CTG monitoring with a normal CTG prior to epidural insertion, with no known foetal abnormalities, and where vaginal delivery was anticipated. A significant reduction in maternal BP was designated as systolic reduction greater than 30 and diastolic reduction greater than 15, or any BP reading below 90/60. CTG and BP readings were reviewed for two hours post insertion, and course throughout labour was noted. CTG changes requiring registrar or consultant presence, any subsequent intervention (foetal blood sampling [FBS] or operative delivery), and any significant reductions in maternal BP were identified and recorded.
agents were used: chirocaine, marcaine, lignocaine and L-bupivacaine. No emergency caesarean sections were required within two hours of epidural insertion. However, 21.9% of patients exhibited a significant drop in BP one hour post insertion, and 6.2% required obstetric review within two hours due to CTG abnormalities. The chirocaine group had six (19.3%) cases of significantly reduced BP and one case (3.2%) requiring obstetric review and FBS. The L-bupivacaine group had 14 cases (26.4%) of significant BP reduction of which five (9.4%) required obstetric review and four (7.5%) required FBS. The two remaining groups did not require any intervention.
Conclusion Epidural insertion was not shown to be significantly associated with CTG abnormalities requiring subsequent obstetric review. Of note, all patients requiring obstetric intervention in this cohort also exhibited significantly decreased maternal BP.
References 1. Anim-Somuah M, Smyth RM, Jones L. Epidural versus non-epidural or no analgesia in labour. Cochrane Database Syst Rev. 2011;7;(12):CD00331. 2. Leighton BL, Halpern SH. The effects of epidural analgesia on labor, maternal, and neonatal outcomes: a systematic review. Am J Obstet Gynecol. 2002;186(5 Suppl. Nature):S69. 3. American Society of Anesthesiologists Task Force on Obstetric Anesthesia. Practice guidelines for obstetric anesthesia: an updated report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia. Anesthesiology. 2007;106(4): 843-63.
Findings There was no standard protocol for epidural insertion. Four anaesthetic Page 90 | Volume 8: Number 1. 2015
Cartoon by Eoin Kelleher, RCSI Class of 2014.
RCSI editorsmj@rcsi.ie submissionssmj@rcsi.ie www.rcsismj.com.
smj Royal College of Surgeons in Ireland Student Medical Journal