SAMJ Vol 106, No 9 (2016) by HMPG

SEPTEMBER 2016 PRINT EDITION

GUEST EDITORIAL Mitigating high-altitude illness DEBATE Cannabis â&#x20AC;&#x201C; where are we now? CME Functional neurosurgery (part 2) IN PRACTICE Human brucellosis in South Africa CASE REPORT Neonatal tetanus associated with a common skin infection RESEARCH The South African child death review pilot Effects of diabetes on health-related quality of life at a tertiary hospital

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SEPTEMBER 2016

FROM THE EDITOR

The cannabis debate: Let’s do the research B Farham

PRINT EDITION

ACTING EDITOR Bridget Farham, BSc (Hons), PhD, MB ChB

ANNOUNCEMENT 5

New article submission protocol: SAMJ goes live with Editorial Manager

GUEST EDITORIAL

EDITOR’S CHOICE

Recognising and mitigating the risk of altitude-related illness R Hofmeyr, W Meyer, M James, R De Decker

EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR ASSOCIATE EDITORS Q Abdool Karim, A Dhai, N Khumalo, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman HMPG CEO AND PUBLISHER Hannah Kikaya | Email: hannahk@hmpg.co.za

DEBATE 11

Psychoactive substances: Position statement on harm reduction D J Stein, E Manyedi, for the Executive Committee of the Central Drug Authority

Position statement on cannabis: A step forwards D J Stein, E Manyedi, for the Executive Committee of the Central Drug Authority

Adding to the cannabis debate: Comment on various Central Drug Authority papers K Scott

Clarifying the position statements of the Central Drug Authority Executive Committee D J Stein, E Manyedi, for the Executive Committee of the Central Drug Authority

CORRESPONDENCE

Social justice and research using human biological material: A right to respond S Mahomed, M Nöthling Slabbert, M S Pepper

The potential danger of journal summary services T Freeth

20 20 22 22

IZINDABA Cutting-edge ZAR120 million boost for SA’s surgical skills ‘Shamed’ Durban doctor claims ZAR20 million Two fatalities in Durban’s multiple hospital strikes Give us peer-educators, not nurses, say sex workers

EDITORIAL Child deaths in South Africa: Lessons from the child death review pilot S Mathews, L J Martin, D Coetzee, C Scott, Y Brijmohun

CME

GUEST EDITORIAL Functional neurosurgery (part 2) J M N Enslin

ARTICLES Surgical management of movement disorders J M N Enslin

Surgical management of pain S J Rothemeyer, J M N Enslin

MANAGING EDITORS Ingrid Nye Claudia Naidu TECHNICAL EDITORS Emma Buchanan Paula van der Bijl NEWS EDITOR Chris Bateman | Email: chrisb@hmpg.co.za PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Carl Sampson CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za JOURNAL ADVERTISING Charles William Duke Reneé Hinze Ladine van Heerden Azad Yusuf ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574 SAMA website: www.samedical.org Journal website: www.samj.org.za

IN PRACTICE 37

CLINICAL UPDATE Recipes for obstetric spinal hypotension: The clinical context counts D G Bishop, R N Rodseth, R A Dyer

‘Getting under our skin’: Introducing banked allograft skin to burn surgery in South Africa N L Allorto, A D Rogers, H Rode

MEDICINE AND THE LAW Improving the recording of clinical medicolegal findings in South Africa R Jina, J M Kotzé

CLINICAL ALERT Invasive carbapenem-resistant Enterobacteriaceae infection at a paediatric hospital: A case series O O Malande, A du Plessis, D Rip, C Bamford, B Eley

September 2016, Print edition

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For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) www.pharmadynamics.co.za Amloc 5 mg. Each tablet contains amlodipine maleate equivalent to 5 mg amlodipine. Reg. No.: RSA S3 38/7.1/0183. NAM NS2 06/7.1/0011. BOT S2 BOT 0801198. Amloc 10 mg. Each tablet contains amlodipine maleate equivalent to 10 mg amlodipine. Reg. No.: RSA S3 38/7.1/0147. NAM NS2 06/7.1/0012. BOT S2 BOT 0801199. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 25 November 2011. 1) IMS, MAT unit sales, December 2015. 2) Dahlof B, Sever PS, Poulter NR, et al. for the Ascot investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906. 3) Nissen SE, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: A randomised controlled trial. JAMA 2004;292:2217-2226. 4) Department of health website: http//www.doh.gov.za - Accessed 10/03/2016. ACD271/04/2016.

Human brucellosis in South Africa: Public health and diagnostic pitfalls J M Wojno, C Moodley, J Pienaar, N Beylis, L Jacobsz, M P Nicol, J Rossouw, C Bamford

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CASE REPORTS Sirolimus-induced lymphoedema K G Motse, M J Mashabane

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Neonatal tetanus associated with skin infection M Maharaj, N Dungwa

RESEARCH The South African child death review pilot: A multiagency approach to strengthen healthcare and protection for children* S Mathews, L J Martin, D Coetzee, C Scott, T Naidoo, Y Brijmohun, K Quarrie

A cross-sectional study of socioeconomic status and cardiovascular disease risk among participants in the Prospective Urban Rural Epidemiological (PURE) Study* B A Egbujie, E U Igumbor, T Puoane

The histological significance of atypical glandular cells on cervical cytology: Experience at Groote Schuur Hospital, Cape Town, South Africa* L D Hoffman, H-T Wu

Missed appointments among rifampicin-resistant tuberculosis (RR-TB) patients at a decentralised RR-TB outpatient clinic in Johannesburg, South Africa* R Gajee, K Schnippel, N Mthupha, B Muzah, R H Berhanu

Effects of diabetes mellitus on health-related quality of life at a tertiary hospital in South Africa: A cross- sectional study* R Daya, Z Bayat, F J Raal

A follow-up study of a large group of children struck by lightning* L M A Silva, M A Cooper, R Blumenthal, N Pliskin

*Full article available online only.

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September 2016, Print edition

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SEPTEMBER 2016 (WEB ONLY)

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VOL. 106 NO. 9

SAMJ SUBSCRIPTION RATES Local subscriptions ZAR 1 368.00 p.a. Foreign subscriptions ZAR 3 108.00 p.a. Single copies ZAR114.00 local, ZAR 259.00 foreign

The following articles appear in the full, online issue only: 843

CORRESPONDENCE

844

‘50 for 50’: A celebration of 50 years of cancer research at the International Agency for Research on Cancer global conference in Lyon, France C Taljaard, C Y Wright

IN PRACTICE

867

CLINICAL UPDATE A biobank to support HIV malignancy research for sub-Saharan Africa J W Schneider, M Sanderson, D Geiger, M Nokta, S Silver

870

CRISPR-Cas: Revolutionising genome engineering S A Nicholson, M S Pepper

874

MEDICINE AND THE LAW Postoperative care: From a legal point of view, whose responsibility is it? D J McQuoid-Mason

891

CASE REPORTS Three cases of intentional isoniazid overdose – a life-threatening condition D F Stead, C R Mason

893

Primary ethmoid sinus squamous cell carcinoma in a young adult man N Goncalves, L A Burnell, S Motakef, P C Modi

Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit.

Effects of oestrogen on prepubescent children F Daubenton

RESEARCH 933

The PAWPER tape and the Mercy method outperform other methods of weight estimation in children at a public hospital in South Africa V G Georgoulas, M Wells

940

What are the communication skills and needs of doctors when communicating a poor prognosis to patients and their families? A qualitative study from South Africa L L Ganca, L Gwyther, R Harding, M Meiring

Subscriptions: Tel. 012 481 2071 Email: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE Health and Medical Publishing Group (Pty) Ltd Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 Tel. 012 481 2069 Email: dianes@hmpg.co.za EDITORIAL OFFICE Suite 11, Lonsdale Building, Lonsdale Way, Pinelands, 7405 Tel. 021 532 1281 | Cell. 072 635 9825 Email: publishing@hmpg.co.za Please submit all letters and articles for publication online at http://www.editorialmanager.com/samj © Copyright: Health and Medical Publishing Group (Pty) Ltd, a subsidiary of the South African Medical Association Use of editorial material is subject to the Creative Commons Attribution – Non-commercial Works Licence. http://creativecommons.org/licenses/by-nc/3.0 Printed by TANDYM PRINT

SEPTEMBER 2016 PRINT EDITION

GUEST EDITORIAL Mitigating high-altitude illness

Background photo: Cannabis plants grown for medical marijuana | Reuters/Baz Ratner

DEBATE Cannabis – where are we now? CME Functional neurosurgery (part 2) IN PRACTICE Human brucellosis in South Africa

Hexagon photos: Effects of altitude | Ekashustrova; Fatalities in strikes | AIDS 2016; Lightning strike | mishooo; Child deaths | Joanna Dorota

September 2016, Print edition

CASE REPORT Neonatal tetanus associated with a common skin infection RESEARCH The South African child death review pilot Effects of diabetes on health-related quality of life at a tertiary hospital

FROM THE EDITOR

The cannabis debate: Let’s do the research My father, who died 4 years ago at the age of 85, was a deeply conservative man. He was a district officer and then a colonial policeman in what was then Northern Rhodesia. When we left in the early 1960s he trained as a solicitor in England and had a predominantly criminal practice. He encountered substance abuse, in all its forms, in all areas of his career. He always believed that the so-called drugs of abuse – including cannabis – should be legalised and subject to the same regulation as alcohol and tobacco. His reasoning came from constant contact with those affected by illegal drugs. He strongly believed that as long as drugs such as cannabis were illegal – and, importantly, unregulated – there would be criminal activity associated with their supply and use. Like most sensible people, he could see that the ‘war on drugs’ was ineffective and causing untold misery to many while bringing immense wealth to a few. Importantly, he also believed that this criminalisation of use and supply led to people who might otherwise have led normal lives landing up as criminals. His opinion was revolutionary for his time and not shared by many of his contemporaries. I have to say that I have always agreed with him. The recent debate in the SAMJ around the legalisation of cannabis[1,2] is timely given the slow pace of attempts at legalising cannabis for medicinal use and also for personal use in different parts of the world. I am not going to get involved in the minutiae of this particular debate, which continues in this current issue.[3-6] Read carefully, the two positions largely converge, both towards the position of legalising cannabis use and supply, albeit with slightly differing opinions on how and when to do this. Having said that, I must congratulate the Central Drug Authority, as a governmental advisory body, for going on record in a public forum to push for a shift in direction in this key area. Given the free – despite regulation – supply and use of tobacco and alcohol, both indisputably seriously harmful, the caution with which people are approaching the legalisation of cannabis is interesting. But perhaps it is the very knowledge of the harms associated with alcohol and tobacco that is, probably unconsciously, informing this caution? Which brings me to my point. Cannabis will eventually be legalised more widely, at least for medicinal use. However, as pointed out in a recent article in the Medical Journal of Australia,[7] ‘cultivation of cannabis for medicinal and scientific purposes needs considered management before it is rolled out as a therapeutic good’. What this article states is that the anecdotal reports from people with intractable illnesses who have had symptomatic benefit from cannabis need further research. Australia’s federal parliament has recently amended their narcotic drugs act to allow controlled cultivation of cannabis for medicinal and scientific purposes. In the USA the Drug Enforcement Administration (DEA) announced that it would reach a decision on the legal status of cannabis by July this year, which it is hoped will

lower the hurdles that scientists in the USA currently have to jump to do research into cannabis.[8] Both the DEA and the Australian Medical Association – and I am sure most sensible people – believe that we need more research into cannabis. At present medical use of cannabis is illegal in South Africa, but it is widely used by ‘alternative practitioners’ who claim to cure a variety of cancers and other serious diseases. I regularly receive emails letting me know where I can access medicinal cannabis locally, and I know of one so-called ‘healer’ in my local community who was recently arrested for possession of large quantities of medicinal cannabis (to the dismay of those in my leafy suburb who decry the drug lords in our neighbouring informal settlements!). The usual arguments apply – it is ‘natural’ so cannot be harmful, and the anecdotes of efficacy abound. But at present we have few or no data on the indications, efficacy, safety or dose range of cannabinoids. We also – because there is no regulation and control – have no confirmation that drug constituents are consistent and of high reproducible quality. We don’t know how to store the drug to ensure stability, or exactly how it should be prescribed. Given that cannabis is already easily available and will almost certainly be legally available in the not-too-distant future, and that people are already using it ‘medicinally’, this research is urgently needed and should not be held up in the debates around the harms or otherwise of the substance. And, in this spirit, I would urge government (and large corporates that are involved in selling that truly harmful substance, alcohol) to step up and provide the funds that are needed for research into cannabis – and substance abuse in all its forms. Bridget Farham

Acting Editor ugqirha@iafrica.com 1. Stein D. Position statement on cannabis. S Afr Med J 2016;106(6):569-570. DOI:10.7196/SAMJ.2016. v106i6.10863 2. Scott K. Comment on the Central Drug Authority’s position statement on cannabis. S Afr Med J 2016;106(6):545-546. DOI:10.7196/SAMJ.2016.v106i6.11036 3. Stein D, Manyedi E. Psychoactive substances: Position statement on harm reduction. S Afr Med J 2016;106(9):836. DOI:10.7196/SAMJ.2016.v106i9.11223 4. Stein D, Manyedi E. Position statement on cannabis: A step forwards. S Afr Med J 2016;106(9):837. DOI:10.7196/SAMJ.2016.v106i9.11222 5. Scott K. Adding to the cannabis debate: Comment on various Central Drug Authority papers. S Afr Med J 2016;106(9):838-839. DOI:10.7196/SAMJ.2016.v106i9.11270 6. Stein D, Manyedi E. Clarifying the position statements of the Central Drug Authority Executive Committee. S Afr Med J 2016;106(9):840. DOI:10.7196/SAMJ.2016.v106i9.11283 7. Martin JH, Bonomo YA. Medicinal cannabis in Australia: The missing links. Med J Aust 2016;204(10):371-373. DOI:10.5694/mja16.00234 8. Rutkin A. DEA mellowing out on cannabis would make medical research easier. New Scientist 2016, April. https://www.newscientist.com/article/2084036-dea-mellowing-out-on-cannabis-would-makemedical-research-easier/ (accessed 12 August 2016).

S Afr Med J 2016;106(9):833. DOI:10.7196/SAMJ.2016.v106i9.11354

New article submission protocol: SAMJ goes live with Editorial Manager The Health and Medical Publishing Group is pleased to announce that the SAMJ will be moving to the Editorial Manager article submission and management system. In light of the need for a more efficient, intuitive, customisable and stable platform for online manuscript processing, HMPG selected Editorial Manager, used by major publishers/journals such as The Lancet, Springer, Nature, Wolters Kluwer and BMC. Editorial Manager describes itself as the industry leader for cloud-based manuscript submission and peer-review tracking for scholarly journals, reference works and other publications. It offers great configurability, enabling us to design a workflow system that is automated, supportive and integrated. The new submission and tracking system will be in effect from 1 September 2016. New instructions for authors will be made available on the SAMJ website. The SAMJ Editorial Manager system can be accessed on the internet (www.editorialmanager.com/samj). Alternatively, visit the SAMJ website to access a link that will direct you to the Editorial Manager system. Authors will be required to register a profile on the system. More information on the registration process can be found on the SAMJ Editorial Manager site. All manuscripts submitted before 1 September 2016 will be reviewed and processed on the current SAMJ OJS platform. The HMPG team will do its best to make the move as seamless as possible; any queries can be directed to the Managing Editor, Claudia Naidu (claudian@hmpg.co.za).

September 2016, Print edition

GUEST EDITORIAL

Recognising and mitigating the risk of altitude-related illness only approach 6 kPa (Fig. 1). This is less than half of the sea level value, despite ade quate acclimatisation. Values <3 kPa have been recorded in healthy climbers on Everest.[9] The only reliable preventive measure to combat HAI is a slow rate of ascent to altitude, allowing adequate time for physiological acclimatisation. While most healthy indi viduals can acclimatise up to 5 500 m, HAI can be induced in any individual if the rate of ascent is sufficiently rapid. Contrary to common beliefs, youth, physical and aerobic fitness, gender and previous ascent to high altitudes offer no protection.[7] Medications such as acetazolamide (Diamox) may hasten acclimatisation, but still require a suitably slow ascent profile to have a protective effect.[3] Numerous evidence- and consensus-based guidelines for safe ascent rates and acclimatisation exist,[8,10,11] but are not uniformly applied.[5] Typically, above 3 500 m, an increase in sleeping altitude of ≤500 m/day is recommended,

with a rest day for each 3 - 4 days’ climb. The old climber’s adage ‘climb high, sleep low’ may confer an advantage, but this has not been proven in the literature. While most of the world’s highest peaks lie deep within wilderness areas and require a lengthy trek to reach (and therefore time for acclimatisation), Kilimanjaro is a particularly important exception. As the world’s highest free-standing mountain, it allows rapid ascent from the surrounding lowlands (<700 m). Conversely, the absence of requirement for technical climbing skills to gain the 5 895 m summit, combined with the allure of one of the Seven Summits, draws >30 000 aspirant summiteers every year – many of whom have never before experienced extreme altitudes. While the trekking distances required make reaching the summit in 3 - 4 days easily achievable, acclimatising to nearly 6 km above sea level cannot occur in such a short time. Itineraries of 4 - 5 days have rates of AMS >75%,[4] while

Metres above sea level

9 000

Alveolar partial pressure of oxygen (kPa)

Minimum ascent rate (days)

Everest

Extreme altitude

8 848 m 8 000

Aconcagua 6 961 m

7 000

Very high altitude

6 000 Kilimanjaro 5 895 m 5 000

Mont Blanc 4 808 m

4 000 Thabana Ntlenyana 3 482 m

High altitude

The recent tragic and widely publicised death of South African (SA) celebrity Gugu Zulu on Mount Kilimanjaro has drawn significant public interest and speculation about the risks of high-altitude trekking and climb ing.[1] It has also demonstrated numerous myths and misconceptions with regard to safe high-altitude ascents among not only the lay public, but also medical professionals. Kilimanjaro is of particular relevance, as it has a very high incidence of altitude-related illnesses.[2-5] Regardless of the details of the Zulu tragedy, a great number of southern Africans undertake treks on Kilimanjaro each year. We have a responsibility to improve understanding and access to medically sound advice for prospective adventurers, and to encourage tour operators to plan and market adventure activities that mitigate the risks to participants. While the proportional composition of the atmosphere remains remarkably consistent, ambient pressure decreases logarithmically with ascent, causing a corresponding decrease in the partial pressure of oxygen (PO2).[6] The physiological effects of altitude are predominantly due to the resultant hypoxia and hypo baria. High altitude is defined as >1 500 m above sea level, where the phy sio logical effects of altitude may first be consistently observed, but pathological consequences are very rare.[7] At this level, the alveolar partial pressure of oxygen (PAO2) is ~10 kPa, compared with the sea level value of 13 kPa. It is worth noting that large areas of SA, including the extensive metropolitan areas in Gauteng, therefore qualify as highaltitude areas. Above 3 500 m is referred to as very high altitude, above which immediate compensatory mechanisms no longer suffice, acclimatisation over time is required, and the incidence of acute high-altitude illness (HAI) due to rapid ascent increases dramatically. This can include the syndrome complex known as acute mountain sickness (AMS), or the more severe and life-threatening conditions, high-altitude cerebral or pulmonary oedema (HACE or HAPE). While uncommon, cases have occurred in the Drakensberg mountains (authors’ experience). Altitudes >5 500 m are referred to as extreme altitudes. Exposure to these levels without gradual acclimatisation will almost certainly result in severe illness.[8] At the top of Kilimanjaro (5 895 m, barometric pressure ~47 kPa), atmospheric air has a PO2 of only 9.4 kPa and the alveolar gas equation predicts that even with maximal hyperventilation and hypocarbia, the PAO2 can

3 000 Drakensberg 3 000 m 2 000

Johannesburg 1 760 m

1 000

Table Mountain 1 084 m

11 13

Sea level

Fig. 1. Relative heights of well-known African and international peaks in comparison to Kilimanjaro, with approximate PAO2 values and minimum duration of safe ascents (drawing by the authors, PAO2 values calculated).

September 2016, Print edition

An open letter to South Africa’s healthcare service providers

Thank you… As a healthcare professional, you protect the health and wellbeing of thousands of patients, and many of those whom you tirelessly care for are members of GEMS. Thank you for the many new lives you have brought into the world and into the GEMS family in the past decade. Thank you for guiding and nurturing thousands of GEMS babies through their formative years and the childhood illnesses that are part of growing up. Thank you for being the helping hand that dispenses care to our older members in their twilight years. Thank you for being the voice that offers hope to those afflicted by dreaded diseases and terminal illness. Our commitment to you… As healthcare practitioners you are a scarce and precious resource, you are the backbone of our healthcare delivery system. Without you we could not provide accessible, affordable quality care to our members. We want you to know that we acknowledge and appreciate your tireless efforts in ensuring that our members receive quality healthcare.

A word of concern… It is with great concern that we have noted an increasing trend among a small group of seemingly unscrupulous healthcare practitioners who do not view healthcare as a precious resource, often using the funds that are at the disposal of our members in a wasteful and abusive manner. This is done without due consideration to the sustainability of GEMS or that of the broader South African healthcare industry.

Tough action from GEMS… In honouring the true ethos of this proud profession and the sacrosanct doctor/patient relationship, we caution the small minority of healthcare practitioners who are responsible for such wasteful practices. Those who abuse member and Scheme funds are guilty of the unacceptable practice of fraud.

If this describes you, you may stop reading now, unless you are so committed to your profession that you, yourself, would want to assist us to bring to book those who are bringing our proud profession into disrepute.

There is a smaller group of individuals who do not uphold the values of their profession, do not care for our members as we do and do not uphold the sanctity of life. These are individuals who are motivated by greed. The sustainability of the South African healthcare industry carries little weight in their hearts and minds.

For these reasons, in the coming months, the Scheme will be introducing a number of additional managed care and forensic interventions and will be taking a tough stance on waste, misuse of member benefits and particularly fraud.

Yours in health Dr Gunvant (Guni) Goolab Principal Officer: GEMS

Working towards a healthier you

GEMS111

In line with our values of honesty and transparency we thought it fair to alert those who are abusing GEMS’s resources to desist from any practice that will endanger the sustainability of the Scheme, thereby harming our members, our valued healthcare professionals and the greater South African healthcare system.

GUEST EDITORIAL

HACE incidence has been reported as 18%.[2] Indeed, consensus statements in the wilderness medical literature indicate that ascents of <7 days carry very high risks.[10] In contrast to this lies the commercial imperative: every day on Kilimanjaro incurs additional guiding, porter, camping, national park and rescue fees, all of which create a perverse incentive to hurry, imposed by the almighty dollar. This is further compounded by the pressure placed on the guides by companies and climbers alike, for whom summit success is paramount. It is important to recognise that AMS symptoms are nonspecific (headache, nausea, vomiting, gastrointestinal upset, fatigue and poor sleep) and mimic common conditions such as influenza.[12] HAI is very rare below 2 500 m, but any new symptoms occurring after ascent above 3 500 m should be presumed to be altitude related until proven otherwise. Mild AMS can be managed by temporarily halting ascent, simple analgesia and hydration. Moderate to severe AMS (or any evidence of HACE or HAPE) should result in immediate descent until symptoms subside. Adherence to these simple guidelines should minimise the risk of an altitude-induced death. Mountaineers on expeditions on remote peaks traditionally make provision for the risk of altitude illness by allowing time for acclimatisation, and carrying suitable supplies for treatment if such illness should occur. While medication and descent are the mainstay of altitude illness, supportive therapy with supplemental oxygen and portable hyperbaric chambers can be lifesaving, especially in cases where descent is delayed or impossible owing to weather or logistical difficulties. Despite the relative accessibility of Kilimanjaro, and while many tour operators claim to offer their services, the varying level of medical skills and number of groups spread across the mountain make availability questionable. Reliance on helicopter rescue in this region, even without the limits of altitude, weather, and darkness, is inadvisable. Historically, mountaineering expeditions have been medically supported by recreational mountaineers who are doctors and who may have very varied backgrounds and medical skills. In recent times, however, the importance of providing high-quality, evidence-based practice in wilderness, remote and austere settings has driven the development and rapid growth of the disciplines and formal education in wilderness, expedition and extreme medicine.[13] Examples include the Fellowship of the Academy of Wilderness Medicine (FAWM)[14] under the auspices of the Wilderness Medical Society (WMS), and the Diploma in Mountain Medicine (DiMM),[15] under the auspices of the International Climbing and Mountaineering Federation (UIAA). As practice has evolved, published standards for the education, skills and proficiencies of expedition medics have emerged.[16,17] Until very recently, these educational opportunities have not been available in SA. Currently, however, internationally accredited training courses are being offered, and a Wilderness and Expedition Medicine Society of Southern Africa (WEMSSA) has been formed. Owing to the accessibility and popularity of climbing Kilimanjaro and other African peaks, practitioners should recognise the significant risks of very high altitude ascents and refer participants to accepted guidelines and expedition or altitude experts. Doctors wishing to serve as expedition medics should undertake formal training and obtain experience in the field, whether their role is voluntary or for remuneration. Large or specialist groups (such as charity events) are encouraged to request the services of an experienced and qualified expedition doctor, who can oversee planning, screening, equipment

and the health of participants on the expedition. Finally, the medical fraternity should continue to advocate that individuals do not shy from the health benefits to be gained from the wilderness, while promoting adequate acclimatisation for high-altitude adventures and actively campaigning against itineraries placing participants at heightened risk. Ross Hofmeyr Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town; and WildMedix, Cape Town, South Africa Walther Meyer WildMedix, and Venture Forth International, Cape Town, South Africa Mike James Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Rik De Decker Division of Paediatric Cardiology, University of Cape Town, and Red Cross War Memorial Childrenâ&#x20AC;&#x2122;s Hospital, Cape Town, South Africa; and International Commission for Alpine Rescue, Kloten, Switzerland Corresponding author: R Hofmeyr (ross.hofmeyr@uct.ac.za) 1. South African rally driver Gugu Zulu dies on Kilimanjaro. BBC News Online, 18 July 2016. http://www. bbc.com/news/world-africa-36823937 (accessed 10 August 2016). 2. Karinen H, Peltonen J, Tikkanen H. Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania: An observational study. High Alt Med Biol 2008;9(4):301-306. DOI:10.1089/ham.2008.1008 3. Davies AJ, Kalson NS, Stokes S, et al. Determinants of summiting success and acute mountain sickness on Mt Kilimanjaro (5 895 m). Wilderness Environ Med 2009;20(4):311-317. DOI:10.1580/1080-6032-020.004.0311 4. Jackson SJ, Varley J, Sellers C, et al. Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro. High Alt Med Biol 2010;11(3):217-222. DOI:10.1089/ham.2010.1003 5. Shah NM, Windsor JS, Meijer H, Hillebrandt D. Are UK commercial expeditions complying with wilderness medical society guidelines on ascent rates to altitude? J Travel Med 2011;18(3):214-216. DOI:10.1111/j.1708-8305.2011.00511.x 6. James MF, Hofmeyr R, Grocott MP. Losing concentration: Time for a new MAPP? Br J Aneasth 2015;115(6):824-826. DOI:10.1093/bja/aev151 7. Gallagher SA, Hackett PH. High-altitude illness. Emerg Med Clin North Am 2004;22(2):329-355. DOI:10.1016/j.emc.2004.02.001 8. Hackett PH, Roach RC. High-altitude illness. N Engl J Med 2001;345(2):107-114. DOI:10.1056/ NEJM200107123450206 9. Grocott MP, Martin DS, Levett DZ, et al. Arterial blood gases and oxygen content in climbers on Mount Everest. N Engl J Med 2009;360(2):140-149. DOI:10.1056/NEJMoa0801581 10. Luks AM, McIntosh SE, Grissom CK, et al. Wilderness Medical Society practice guidelines for the prevention and treatment of acute altitude illness: 2014 update. Wilderness Environ Med 2014;25(4 Suppl):S4-S14. DOI:10.1016/j.wem.2014.06.017 11. Imray C, Wright A, Subudhi A, Roach R. Acute mountain sickness: Pathophysiology, prevention, and treatment. Prog Cardiovasc Dis 2010;52(6):467-484. DOI:10.1016/j.pcad.2010.02.003 12. Roach R, Bartsch P, Hackett PH, Oelz O. The Lake Louise acute mountain sickness scoring system. In: Wood S, Roach RC, eds. Hypoxia and Molecular Medicine. Burlington, VT: Queen City Printers, 1993:272-274. 13. Imray CH, Grocott MP, Wilson MH, Hughes A, Auerbach PS. Extreme, expedition, and wilderness medicine. Lancet 2015;386(10012):2520-2525. DOI:10.1016/S0140-6736(15)01165-4 14. Wilderness Medical Society. Fellowship in the Acadamy of Wilderness Medicine 2016. http://www. wms.org/fawm/ (accessed 10 August 2016). 15. International Climbing and Mountaineering Federation/International Commission for Alpine Rescue/ International Society for Mountain Medicine. UIAA Diploma in Mountain Medicine 2016. http:// theuiaa.org/mountain-medicine-diploma.html (accessed 10 August 2016). 16. Mellor A, Dodds N, Joshi R, et al. Faculty of Prehospital Care, Royal College of Surgeons Edinburgh guidance for medical provision for wilderness medicine. Extrem Physiol Med 2015;4(1):22. DOI:10.1186/s13728-015-0041-x 17. Kupper T, Nies I, Jillebrandt D, Milledge JS, Basnayt B. Official Standards of the UIAA Medical Commission, vol. 8: Model Contract for Health Care on Trekking and Expeditions for Doctors. Bern, Switzerland: International Mountaineering and Climbing Federation (UIAA), 2008:8.

S Afr Med J 2016;106(9):834-835. DOI:10.7196/SAMJ.2016.v106i9.11389

September 2016, Print edition

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EDITOR’S CHOICE

CME: Functional neurosurgery (part 2)

This month’s CME includes the final two articles that review functional neurosurgical topics: surgery for movement disorders, where deep brain stimulation (DBS) forms a major part, and surgical management of pain. These articles make it clear that neurosurgery forms a central part of the management of patients with common disabilities such as severe pain and movement disorders that are refractory to medical management. Appropriate referral and a thorough work-up by a multidisciplinary team are required, and these complex disorders should not be managed in isolation. Owing to the invasive nature of surgery for functional neurosurgical pathology, care is needed to confirm that the medical management of the patient has been properly done and that all medical options have been exhausted. Certain conditions such as Parkinson’s disease must, however, be referred to a unit with the ability to perform DBS early on, as there are studies showing that patients that receive DBS early in their disease process have much better outcomes than those who wait for periods longer than 10 years.

Invasive carbapenem-resistant Enterobacteriaceae (CRE) infection at a paediatric hospital

Invasive infection caused by CRE, first documented in the late 1990s, has become a serious global public health problem. Resistance to carbapenems may result from several mechanisms, including alteration of outer membrane permeability due to loss of porins, upregulation of efflux systems together with extended-spectrum β-lactamases, or commonly the production of carbapenemases. Publications from the USA, Europe, Asia and the Middle East have begun to describe CRE infection in children, but there have been none from Africa. A retrospective study at Red Cross War Memorial Children’s Hospital (RCWMCH) in Cape Town[1] describes a series of cases of CRE at a paediatric hospital and documents the clinical and microbiological experience of children with invasive CRE infection in South Africa (SA). The first invasive CRE infection at RCWMCH was recorded in November 2012. A further 9 children developed invasive infection caused by CRE during the study period, 1 in 2013, 3 in 2014 and 5 in 2015. This is one of the very first studies to report on the outcome of invasive CRE infection among children in an African setting. Since the first invasive CRE infection was diagnosed in November 2012, there has been a steady increase in the annual number of cases. The emergence of CRE infection to some extent follows a change in the empirical antibiotic policy for hospital-acquired sepsis. Until randomised control trials define optimal treatment strategies, CRE infection in children with severe underlying disease such as those described in this case series must be treated with combination anti biotic therapy to optimise outcomes.

The South African child death review (CDR) pilot

In 2014, more than 40 000 children died in SA.[2] Although under-5 mortality declined from 56 deaths per 1 000 live births in 2009 to 41 per 1 000 in 2013,[3] SA has not met the Millennium Development Goal to reduce under-5 mortality by two-thirds. The under-5 child mortality rate in 2014 was 39 per 1 000, with most of these deaths preventable.[2] Importantly, neonatal and infant deaths accounted for a large proportion of under-5 deaths. Recent trends show that the reduction in under-5 deaths has plateaued.[4] In order to reduce child mortality further to meet the

sustainable development goals, it is critical to understand causes of death and associated factors. Mathews et al.[5] describe the SA CDR pilot, the pattern of child deaths reviewed and the factors associated with these deaths. CDR teams were established at two pilot sites, Salt River mortuary (Western Cape Province) and Phoenix mortuary (KwaZulu-Natal Province). All child deaths were reviewed by a multidisciplinary team at the pilot sites for the period 1 January 2014 - 31 December 2014. This is the first CDR process for SA, and the formation of multiagency teams to review child deaths at the two pilot sites provided invaluable insights into out-of-hospital deaths. The death notification system has been criticised for lacking completeness of child death data, misclassification and miscoding cause of death.[4] The CDR has shown the potential to increase accuracy in determining causes of death and to reduce undetermined or ill-defined causes to complement the Child Healthcare Problem Identification Programme (Child PIP) audit of in-hospital child deaths. Furthermore, the CDR process, through the review and co-ordinated response to the investigation and management of suspected abuse and neglect cases, facilitated an increase in identification of such cases, while the involvement of a child protection agency allowed for supporting families in crisis and protecting other children at risk in the family.

A follow-up study of a large group of children struck by lightning

On 11 November 1994, 26 preadolescent girls, 2 adult supervisors and 7 dogs were sleeping in a tent in in a rural part of the Northern Province of SA when the tent was struck by lightning. Four of the girls and 4 of the dogs were killed. The adults were unharmed, but all but 3 of the children suffered significant injuries. No follow-up studies have been done to date on such a large group of people, especially children. The initial report[6] concentrated on physical sequelae such as burns, cataracts and macular holes, skull fractures and tympanic membrane rupture, and did not investigate symptoms of pain, weakness or more subjective clinical findings. Silva et al.[7] have investigated the long-term problems that the surviving girls continue to experience as a consequence of the 1994 lightning incident, including neuropsychological issues, mood symptoms and chronic pain. The most prevalent long-term issue was impaired vision. Consistent with previous studies, 20% of participants reported persisting irritability, mood swings, emotional reactivity and feelings of guilt. Depression and anxiety were reported by 30% of the sample, higher than the reported incidence in SA. The fact that the girls still keep in contact with one another via social media demonstrates the impact the 1994 lightning incident had on their respective lives. BF 1. Malande OO, du Plessis A, Rip D, Bamford C, Eley B. Invasive carbapenem-resistant Enterobacteria ceae infection at a paediatric hospital: A case series. S Afr Med J 2016;106(9):877-882. DOI:10.7196/ SAMJ.2016.v106i9.11028 2. Statistics South Africa. Mortality and Causes of Death in South Africa, 2014: Findings from Death Notification. Pretoria: SSA, 2015. 3. Hall K, Meintjes H. Demography of South Africa’s children. In: De Lannoy A, Swartz S, Lake L, Smith C, eds. The South African Child Gauge 2015. Cape Town: Children’s Institute, University of Cape Town, 2015. 4. Nannan N, Dorrington R, Laubscher R, et al. Under-5 Mortality Statistics in South Africa: Shedding some Light on the Trends and Causes 1997 - 2007. Cape Town: South African Medical Research Council, 2012. 5. Mathews S, Martin LJ, Coetzee D, et al. The South African child death review pilot: A multiagency approach to strengthen healthcare and protection for children. S Afr Med J 2016;106(9):895-899. DOI:10.7196/SAMJ.2016.v106i9.11234 6. Carte AE, Anderson RB, Cooper MA. A large group of children struck by lightning. Ann Emerg Med 2002;39(6):665-670. DOI:10.1067/mem.2002.124438 7. Silva LMA, Cooper MA, Blumenthal R, Pliskin N. A follow-up study of a large group of children struck by lightning. S Afr Med J 2016;106(9):929-932. DOI:10.7196/SAMJ.2016.v106i9.10564

September 2016, Print edition

DEBATE

Psychoactive substances: Position statement on harm reduction

The recent special session of the United Nations General Assembly on drugs was timely for several reasons. It is clear that the ‘war on drugs’ has failed – a singular focus on supply reduction does not work. Worldwide, there have been ongoing changes in the legal status of alcohol, tobacco, marijuana and other psychoactive substances or drugs, as states attempt to develop balanced strategies of supply reduction, demand reduction and harm reduction. There is increasing emphasis on the importance of implementing evidence-based policies to address the significant morbidity and mortality associated with the use of alcohol, tobacco, marijuana and other psychoactive substances.[1-4] Psychoactive substances are subject to several international and national conventions and laws that have emphasised the importance of the ‘war on drugs’ and supply reduction. At the same time, it is increasingly clear that evidence-based, balanced policies are needed, which address the important differences between alcohol, tobacco, marijuana and other psychoactive substances or drugs.[5] The Prevention of and Treatment for Substance Abuse Act 70 of 2008 speaks to the National Drug Master Plan, which emphasises a range of strategies for addressing the excessive use of alcohol, tobacco, marijuana and other psychoactive substances. Supply reduction refers to policing efforts to curb the manufacture and distribution of alcohol, tobacco, marijuana and other psychoactive substances or drugs. Demand reduction refers to preventive efforts to decrease their demand. Harm reduction refers to policies and interventions to reduce the harmful consequences of alcohol, tobacco, marijuana and other psychoactive substance use. Focusing on harm reduction does not indicate that risky behaviours in general, and the use of psychoactive substances or drugs in particular, are welcomed. This approach is based rather on the scientific evidence on what works to improve public health and reduce social harms when tobacco, alcohol, marijuana and other psychoactive substances are already being used.[6,7] Not all psychoactive substance use is harmful, although alcohol, tobacco, marijuana and other psychoactive substances are associated with a spectrum of potential harms to individuals and to society.[5] Extrapolating from international knowledge, it is clear that in South Africa (SA) alcohol is the most harmful substance in use, in view of its links with physical illness, mental illness, interpersonal violence and crime. Tobacco is also extremely harmful to individuals and costly for society because of its link with lung cancer and other medical conditions. Marijuana has been associated with many harmful effects, as have a range of other substances. Therefore, evidence-based policies and interventions must address the individuals and communities involved, the drugs being consumed and the environment in which this occurs.[8] Fortunately, growing evidence shows that specific policies and interventions can reduce the potential harms associated with the continued use of psychoactive substances.[6,7] For example, there is considerable evidence that brief psychotherapies are useful for treating sufferers from alcohol, tobacco, marijuana and other drug dependence. Primary care clinicians should screen for abuse and provide evidencebased interventions where indicated.[9] Other efficacious interventions for reducing harm in people with alcohol, tobacco, marijuana, opioid and other drug use include medication-assisted treatment and needle and syringe programmes.[10,11] Providing such interventions requires the work of many stakeholders; skills must be developed, medications and human resources made available, and health systems strengthened.

Recommendations

• The National Drug Master Plan emphasises the importance of an integrated approach to supply reduction, demand reduction and harm reduction strategies for combating alcohol, tobacco, marijuana and other psychoactive substance use and abuse in SA.

•

For any substance, the balance between these three strategies and the approach taken should be evidence-based. Data from other countries show that alcohol causes the most individual and societal harm. It is therefore essential to put particular efforts into implementing evidence-based policies and interventions for alcohol harm reduction. This should address upstream drivers of alcohol use, as well as prevention and intervention. Efforts to reduce harm have been poorly resourced in SA and, given the enormous profits of the liquor industry, there is a need and obligation for its greater involvement in local harm reduction efforts. Local school survey data suggest high rates of experimentation with alcohol, tobacco, marijuana and other drugs during early adolescence. Evidence-based interventions, including a strong focus on harm reduction, are needed in this age group, which comprises a large proportion of South Africans. There is little evidence that focusing on supply reduction via criminalisation is effective in reducing alcohol, tobacco, marijuana and other substance abuse. There are insufficient data showing that the commercialisation of such entities is safe, particularly when it is not accompanied by rigorous supply, demand and harm reduction strategies. Evidence-based approaches that reduce harm from continued and chronic use of alcohol, tobacco, marijuana and other substances (particularly among vulnerable groups such as adolescents and people with mental disorders) deserve greater attention and additional resources. These include psychotherapy and medicationassisted therapy for individuals, and addressing the structural drivers of continued psychoactive substance use. Mental, neurological and substance use disorders contribute significantly to SA’s burden of disease. There must be more research attention and a greater focus of clinical resources on this area.

Dan J Stein

Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa dan.stein@uct.ac.za

Eva Manyedi

School of Nursing, Faculty of Agriculture, Science and Technology, North-West University, Mahikeng, South Africa For the Executive Committee of the Central Drug Authority (Carol du Toit, Dan Stein, David Bayever, Eva Manyedi, Johlene Ntwana, Lethiwe Ndlovu, Mogotsi Kalaemodimo, Moses Gama, Pelmos Mashabela, Peter Ucko) 1. Chisholm D, Doran C, Shibuya K, Rehm J. Comparative cost-effectiveness of policy instruments for reducing the global burden of alcohol, tobacco and illicit drug use. Drug Alcohol Rev 2006;25(6):553565. DOI:10.1080/09595230600944487 2. Mosher JF, Yanagisako KL. Public health, not social warfare: A public health approach to illegal drug policy. J Public Health Policy 1991;12(3):278-323. DOI:10.2307/3342844 3. Drucker E. Drug prohibition and public health: 25 years of evidence. Public Health Rep 1999;114(1):1429. DOI:10.1093/phr/114.1.14 4. Babor TF. Linking science to policy: The role of international collaboration and problem-focused integrative reviews. Addiction 2015;110(Suppl 2):40-46. DOI:10.1111/add.12911 5. Nutt DJ, King LA, Phillips LD, Independent Scientific Committee on Drugs. Drug harms in the UK: A multicriteria decision analysis. Lancet 2010;376(9752):1558-1565. DOI:10.1016/S01406736(10)61462-6 6. Anderson P, Chisholm D, Fuhr C. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet 2009;373(9682):2234-2246. DOI:10.1016/S01406736(09)60744-3 7. Jones L, Hughes K, Atkinson AM, Bellis MA. Reducing harm in drinking environments: A systematic review of effective approaches. Health Place 2011;17(2):508-518. DOI:10.1016/j. healthplace.2010.12.006 8. Van Beek I. Harm reduction – an ethical imperative. Addiction 2009;104(3):342-343, discussion 345346. DOI:10.1111/j.1360-0443.2008.02418.x 9. Babor TF, McRee BG, Kassebaum PA, et al. Screening, Brief Intervention, and Referral to Treatment (SBIRT): Toward a public health approach to the management of substance abuse. Subst Abuse 2007;28(3):7-30. DOI:10.1300/j465v28n03_03 10. Aspinall EJ, Nambiar D, Goldberg DJ, et al. Are needle and syringe programmes associated with a reduction in HIV transmission among people who inject drugs: A systematic review and metaanalysis. Int J Epidemiol 2014;43(1):235-248. DOI:10.1093/ije/dyt243 11. Timko C, Schultz NR, Cucciare MA, et al. Retention in medication-assisted treatment for opiate dependence: A systematic review. J Addict Dis 2016;35(1):22-35. DOI:10.1080/10550887.2016.1100960

S Afr Med J 2016;106(9):836. DOI:10.7196/SAMJ.2016.v106i9.11223

September 2016, Print edition

DEBATE

Position statement on cannabis: A step forwards

Dr Scott’s response[1] to our position statement[2] enables us to clarify our views to health professionals and the public. We agree with Dr Scott on several points. There is an increasing evidence-based consensus that policy on alcohol, tobacco, cannabis and other substances should move from the ‘war on drugs’ towards a science-based public health approach (as was successful locally in addressing tobacco use).[3] We agree that various substances differ in their associated costs and harms and that globally alcohol is a far more harmful substance than cannabis.[4] We also agree that an approach to substances that emphasises harm reduction and human rights is also key, and that new local policies and programmes are urgently needed, given the enormous burden of disease caused by alcohol, tobacco, cannabis and other substance use.[5] Our position statement was developed with these in mind! We have also submitted to this journal a position statement on harm reduction[6] to emphasise the importance of this approach to alcohol, tobacco, cannabis and other substance use from a public health perspective. Nevertheless, important clarifications on questions of science, substance use regulation and local politics are also needed. Dr Scott claims that our scientific view has ‘confirmation bias’ in that we selectively present evidence on the harms of cannabis. However, we drew on rigorous published systematic reviews in discussing its harms and benefits. While we accept that alcohol is a harmful agent and that cannabis may have health benefits, systematic reviews routinely confirm that cannabis use is harmful for certain aspects of health. Research on its health benefits remains sparse to date, with more research needed to establish safe dosages. Health professionals and the public must understand what the scientific literature indicates and the individual and public health problems associated with the use of tobacco, alcohol, cannabis and other psychoactive substances. Awareness of the potential medicinal uses of psychoactive agents is also important, as is the need for further research in this area. Our position statement made these points and we trust that health professionals will be persuaded by the relevant systematic reviews. Dr Scott starkly contrasts prohibition and legal regulation and argues that decriminalisation is merely a form of prohibition. Our more nuanced view is that a broad spectrum of legislation is consistent with the harm reduction approach. The evidence base indicates that decriminalisation can contribute to improved public health (Dr Scott mentions Portugal, but does not mention this finding in that context) and that legal regulation does not necessarily stamp out criminal activity (consider the illegal trade of alcohol in South Africa (SA)). [7] Decriminalisation may be an achievable step locally for cannabis but does not preclude additional types of regulation for a range of drugs over time, based on evidence of what works to improve public health and to reduce harm. We hope that policy allows research on cannabis and other drugs for medicinal purposes, that when people use psychoactive substances measures are made available to prioritise safety (e.g. needle exchange), and that medication-assisted treatment is made widely available. At the same time, we are cognisant of not wanting policy to lead simply to ‘Big Tobacco’ being joined by ‘Big Marijuana’[8] – there is insufficient evidence this would be a gain for public health. Regarding politics, it is important to emphasise that our position statement was authored by members of the Executive Committee of the Central Drug Authority (CDA). The broader CDA contains

many civil servants representing different government departments and reporting to their ministers, each of whom may have different positions on aspects of policy related to alcohol, tobacco, cannabis and psychoactive substance use. For example, some departments are focused on adhering to the international agreements that SA has signed to outlaw drugs. We also know that there may be different positions within government about the value of putting more pressure on the liquor industry to support harm reduction efforts and of doing so from a public health perspective. As advisors to government, our goal is to emphasise an evidence-based and balanced approach. We hoped that a public position statement would be welcomed by health professionals and the public as a progressive and pragmatic step to address SA’s massive public health problem from alcohol, tobacco, cannabis and other psychoactive substance use. We did not expect that our position statement would be accepted by those wishing to continue a ‘war on drugs’, or by those who support immediate commercialisation of all psychoactive sub stances in SA. Our science-based public health approach attempts to take a balanced and pragmatic step forward. As more data become available and political will is found to develop new policies and programmes to improve public health and advance harm reduction with respect to the use of alcohol, tobacco, cannabis and other psychoactive substances, we hope that the CDA Executive Committee will reassess its position on the best way forward. In the interim, we call on health professionals, civil society and the public to join the move away from the ‘war on drugs’ and towards a public health approach. While our position statement could lead to a focus on the issue of cannabis decriminalisation, in line with a public health approach and the profile of our burden of disease, we request health professionals and civil society to also focus on the urgency for harm reduction measures in the area of alcohol, tobacco and opioid use. Dan J Stein

Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa dan.stein@uct.ac.za

Eva Manyedi

School of Nursing, Faculty of Agriculture, Science and Technology, North-West University, Mahikeng, South Africa For the Executive Committee of the Central Drug Authority (Carol du Toit, Dan Stein, David Bayever, Eva Manyedi, Johlene Ntwana, Lethiwe Ndlovu, Mogotsi Kalaemodimo, Moses Gama, Pelmos Mashabela, Peter Ucko) 1. Scott K. Comment on the Central Drug Authority’s position statement on cannabis. S Afr Med J 2016;106(6):545-546. DOI:10.7196/SAMJ.2016.v106i6.1103 2. Stein D, for the Executive Committee of the Central Drug Authority. Position statement on cannabis. S Afr Med J 2016;106(6):569-570. DOI:10.7196/SAMJ.2016.v106i6.10863 3. Reddy P, James S, Sewpaul R, et al. A decade of tobacco control: The South African case of politics, health policy, health promotion and behaviour change. S Afr Med J 2013;103(11):835-840. DOI:10.7196/samj.6910 4. Nutt DJ, King LA, Phillips LD, Independent Scientific Committee on Drugs. Drug harms in the UK: A multicriteria decision analysis. Lancet 2010;376(9752):1558-1565. DOI:10.1016/S01406736(10)61462-6 5. Ellis GFR, Stein DJ, Thomas KGF, Meintjes EM. Substance Use and Abuse in South Africa: Insights from Brain and Behavioural Sciences. Cape Town: University of Cape Town Press, 2012. 6. Stein D, Manyedi E, for the Executive Committee of the Central Drug Authority. Psychoactive substances: Position statement on harm reduction. S Afr Med J 2016;106(9):836. DOI:10.7196/ SAMJ.2016.v106i9.11223 7. Goncalves R, Lourenco A, Silva SN. A social cost perspective in the wake of the Portuguese strategy for the fight against drugs. Int J Drug Policy 2015;26(2):199-209. DOI:10.1016/j.drugpo.2014.08.017 8. Richter KP, Levy S. Big marijuana – lessons from big tobacco. N Engl J Med 2014;371(5):399-401. DOI:10.1056/NEJMp1406074

S Afr Med J 2016;106(9):837. DOI:10.7196/SAMJ.2016.v106i9.11222

September 2016, Print edition

DEBATE

Adding to the cannabis debate: Comment on various Central Drug Authority papers

Definition of legal regulation

This contribution addresses the following documents published in this and a previous edition of the SAMJ: • The Central Drug Authority (CDA)’s position paper on cannabis[1] • The CDA’s position paper on harm reduction[2] • The CDA’s response[3] to the editorial[4] commenting on the CDA’s position statement on cannabis. As there is considerable overlap between the contents of the above documents, this article tries to avoid covering all the arguments put forward both in these documents and in the author’s comment[4] on the CDA’s position statement on cannabis. Instead, it sets out to inform medical professionals and civil society why the incorporation of illicit drugs into the existing regulatory framework of drug control is the only holistic way to implement comprehensive harm reduction measures and bring an end to the ‘war on drugs’.

Harm reduction

Most of the CDA’s recommendations in respect of a more humanistic approach to harm reduction should be supported. It is to be hoped that its increasingly progressive attitude to drug issues will give the medical profession a dominant role in policy-making within the structures of the CDA, in parliament and in other decision-making forums. For too long the criminal justice system has had an overriding influence on the way governments have created harmful drug laws and the manner in which these laws have been implemented. Drug use should be primarily a public health issue, not a criminal one. Illicit drug use is classified as a crime, but since it is victimless, it should not be a crime at all. The consumption of illicit psychoactive drugs should be no more a crime than the use of tobacco or alcohol.

The United Nations Conventions on drugs

The CDA’s call for more evidence before it will back the implementation of legal regulation, as well as its advocacy for the continued adherence to the harmful, irrational and outdated United Nations (UN) Single Convention on Drugs of 1961[5] (and related conventions), needs to be addressed. The UN Convention on Psychotropic Substances, 1971[6] classifies a range of psychotropic drugs into four main schedules depending on their perceived harmfulness – the scheduling of a psychotropic drug determines the degree to which it is controlled. Those drugs considered to have medicinal value are allocated different schedules to those that are deemed to have none. Examples of the drugs that occupy the latter schedules are cannabis, methamphetamine and LSD. The glaring omission from these comprehensive lists is the most harmful drug of all, alcohol. Excluding alcohol from the UN schedules has more to do with political expediency and alcohol’s culturally sanctioned status than concern for its addiction potential or harmfulness.

Legal regulation is a rational, humanistic alternative to the war on drugs

The only holistic, proven and rational way to deal with the undesirable consequences of the human penchant to use psychoactive substances[7] is to legalise these drugs and include them in the flexible framework known as ‘legal regulation’. Legal regulation is a wellknown and widely applied legal and administrative process that most countries use to tax and control the production, distribution and sale of prescription drugs, alcohol, tobacco and other drugs.

‘Legalisation’ and ‘legal regulation’ differ. While legalisation is merely a process that makes something that is illegal legal, legal regulation provides a regulatory framework that governs the production, supply and use of drugs – any activity outside this framework remains prohibited. A widely held misconception is that legal regulation is a radical idea; it is therefore sometimes characterised as a ‘liberalisation’ or ‘relaxation’ of the law. However, it is in fact the opposite; it is about bringing the drug trade within the law – with strict controls that are impossible to impose when prohibition prevails. Legal regulation certainly does not imply a free-for-all that makes drugs available to anyone, anywhere and at any time. Instead, legal regulation enables governments to control where drugs are grown, manufactured and sold, and who can access them. It also allows the authorities to monitor and specify the quality, strength and composition of the products in the marketplace, something that is impossible to do under the laws of prohibition. Although legal regulation is an imperfect system of drug control, it is far preferable to the total prohibition of any drug, and preferable to its milder version, decriminalisation. This was clearly demonstrated by the fiasco of the 1920s/1930s alcohol prohibition laws in the USA and their subsequent repeal. At present, almost every country (apart from a few where the prohibition of alcohol still exists) uses a variation of legal regulation to control the trade and use of alcohol products. Prior to their signing of the UN’s Single Convention on Drugs in 1961, most countries included cannabis, opium and other drugs in this effective, adaptable framework. Since 1961, the 185 countries that signed the Convention have been expected to implement its irrational and harmful rules, which exclude two of the most harmful psychoactive drugs, alcohol and tobacco.[8,9] That an extremely harmful drug such as alcohol can be regulated, controlled and taxed, with a relatively low background level of crime associated with its production and trade, stands in stark contrast to the trillion-dollar international illicit drug industry that is dominated by organised crime syndicates, contributes nothing to a state’s fiscus and costs the global community billions of dollars annually. Anyone who takes a dispassionate view of this obvious state of affairs cannot but agree that legal regulation is far preferable to prohibition.

Aims of legal regulation

The legal regulation of ‘recreational’ psychoactive drugs strives to protect the young and vulnerable by controlling their availability, and to educate the public about their potential harms. It aims to reduce crime by diverting the profits currently generated and retained by the illicit drug trade to the state fiscus. This tax revenue could finance education, rehabilitation, medical services and support effective, humanistic crime-fighting initiatives, and provide for other expenses associated with the regulation of recreational drugs. Public health relating to these products would be improved by ensuring that products are pure and standardised, and through the provision of health education and other pertinent information. Legal regulation provides a way to protect human rights by abolishing unjust laws that discriminate against those who use psychoactive substances for recreational and medicinal purposes, removing the fear of prosecution. Existing laws make it virtually impossible to control any of the links in the illicit drug supply chain. At present, anyone of any age can buy drugs – drug dealers don’t ask for ID! Under a system of legal regulation, many activities, such as sales to minors, would remain illegal and subject to sanctions. Proponents of legal regulation generally support the implementation of improved, stricter controls over legal drugs such as alcohol, tobacco and other recreational drugs.

September 2016, Print edition

DEBATE

However, for legal regulation to be optimally effective it needs to be complemented by improvements in public health, drug use edu cation, and addiction prevention and treatment. Society also needs to focus attention on the underlying psychosocial causes of addiction such as mental illness, adverse childhood experiences, poverty, inequality and social exclusion. The change to legal regulation from the current status need not happen overnight. It may be cautious, phased in and adapted according to the results. If policies do not work, they may be revisited and, where necessary, changed. Although legal regulation alone will not solve the many problems related to either currently legal or illicit drugs, it provides a far better alternative to the existing crime and social problems caused by drug prohibition. Local and global experience over the past 100 years demonstrates that prohibition cannot achieve these aims, and in fact actively undermines them. Legal regulation does what the war on drugs has failed to do. If properly implemented, it could decrease drug use among children, foster harm reduction measures in drug users, reduce the stigmatisation of addicts, curtail infectious disease transmission, dramatically reduce drug-related deaths, control the quality, sale and availability of drugs, substantially decrease drug-related criminal activity, reduce the profits of organised crime, lessen the opportunity for corruption among law enforcement officials, lower the cost of law enforcement and reduce prison populations.[10] It also allows for the more effective implementation of drug education programmes and drug-related health services.

Examples of effective legal regulation

Alcohol Sweden’s alcohol laws provide an example of the ways in which a specific country can adapt legal regulation to its own requirements. Its laws allow the private sector to produce and sell products with an alcohol concentration of less than 3.5%. Products with an alcohol concentration above that level can be purchased only from a limited number of state-owned liquor stores. That South Africa (SA) and other countries regulate the use, production, sale and advertising of alcohol and tobacco in different ways demonstrates the flexibility conferred by legal regulation. Tobacco In contrast to the rise in the consumption of illicit drugs, the global use of tobacco has been declining steadily.[11] This reduction is being achieved without blanket bans or criminalising smokers. Rather, it is the result of programmes that include appropriate education, advertising constraints and stricter market regulation, only possible because tobacco is a legal product. Cannabis The legalisation of cannabis in US states such as Colorado demon strates how easy it is to incorporate a previously illicit substance into the framework of legal regulation. In Spain, cannabis social clubs[12] have been in existence for over a decade. These clubs are non-commercial organisations of cannabis users who grow, cultivate and share enough cannabis of good quality to meet their personal needs. This type of consumer-focused, non-profit model could easily be incorporated into legal regulation structures. It would also allay the fears of the CDA and others that legalising cannabis would open the doors for imagined commercial entities such as ‘Big Cannabis’ (cf. ‘Big Tobacco’) to arise and dominate the market. Levels of drug use are often equated with levels of drug harm, but the vast majority of drug use is non-problematic.[13-15] Rather

than narrowly focusing on reducing use, policy should seek to reduce overall harm. Although decriminalisation mitigates the harms experienced by drug users, unlike legal regulation, it does not address the extensive damage and suffering caused by the massive criminal structures that dominate the drug trade. We have a choice: the drug trade can be controlled either by criminals or governments. Legal regulation is the only substantiated, holistic and humanistic way to deal with the issues relating to the health benefits and harms of recreational and other drugs, their social impact and the vast crime networks that the current laws help to sustain. With its seemingly endless search for more and more evidence and its call for an end to the war on drugs, it is hoped that the CDA will move away from confirmation bias that emphasises the pharmacological harms of illicit drugs over the widespread damage caused by the current drug laws themselves. Instead, it should acknowledge that the evidence it claims to be looking for is to be found in the laws and extensive experience of most countries’ efforts to manage currently licit psychoactive drugs such as alcohol, tobacco and prescription drugs. Continuing to prevaricate by emphasising the dangers of drugs (over and above the best solutions for dealing with the wider drug issues) gives the CDA’s political masters the opportunity to use that unbalanced ‘evidence’ to promote an agenda that runs counter to the CDA’s new progressive approach to drug law reform. Let us not forget that it was less than a decade ago that the SA government tried to further its own perverse agenda by prejudicially emphasising and exaggerating the adverse effects of the antiretroviral drug nevirapine to severely restrict its use in the fight against HIV/ AIDS. It took a non-medical non-governmental organisation, the Treatment Action Campaign, to force the government to provide this effective drug.[16] Those of us in the medical profession, especially those working in academic and government structures, need to avail ourselves of all the evidence pertaining to the public health, criminal and social effects of the current drug laws and ensure that this time we are the ones who speak the full truth to power. Keith Scott

Simon’s Town, Cape Town, South Africa zscottz@gmail.com 1. Stein D, for the Executive Committee of the Central Drug Authority. Position statement on cannabis. S Afr Med J 2016;106(6):569-570. DOI:10.7196/SAMJ.2016.v106i6.10863 2. Stein D, Manyedi E, for the Executive Committee of the Central Drug Authority. Psychoactive substances: Position statement on harm reduction. S Afr Med J 2016;106(9):836. DOI:10.7196/ SAMJ.2016.v106i9.11223 3. Stein D, Manyedi E, for the Executive Committee of the Central Drug Authority. Position statement on cannabis: A step forwards. S Afr Med J 2016;106(9):837. DOI:10.7196/SAMJ.2016.v106i9.11222 4. Scott K. Comment on the Central Drug Authority’s position statement on cannabis. S Afr Med J 2016;106(6):545-546. DOI:10.7196/SAMJ.2016.v106i6.11036 5. United Nations. Single Convention on Narcotic Drugs, 1961. New York: UN, 1961. 6. United Nations. Convention on Psychotropic Substances, 1971. New York: UN, 1971. 7. Crocq M. Historical and cultural aspects of man’s relationship with addictive drugs. Dialogues Clin Neurosci 2007;9(4):355-361. 8. Nutt DJ, King LA, Phillips LD, Independent Scientific Committee on Drugs. Drug harms in the UK: A multicriteria decision analysis. Lancet 2010;376(9752):1558-1565. DOI:10.1016/s0140-6736(10)61462-6 9. Lachenmeiera D, Rehm J. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Sci Rep 2015;5:8126. DOI:10.1038/srep08126 10. Goga K. The drug trade and governance in Cape Town. Pretoria: Institute for Security Studies, 2014:263. 11. World Health Organization. Global Report on Trends in Tobacco Smoking 2000 - 2025. Geneva: WHO, 2015. 12. Alonso M. Cannabis Social Clubs in Spain. Amsterdam: Transnational Institute, 2011. 13. Robins L, Helzer J, Davis D. Narcotic use in Southeast Asia and afterward. An interview study of 898 Vietnam returnees. Arch Gen Psychiatry 1975;32(8):955-961. 14. Clarke H, Soneji N, Ko D, Yun L, Wijeysundera D. Rates and risk factors for prolonged opioid use after major surgery: Population based cohort study. BMJ 2014;348:g1251. DOI:10.1136/ bmj.g1251 15. Mann J. British drugs survey 2014: Drug use is rising in the UK – but we’re not addicted. The Guardian Newspaper, 5 October 2014. 16. Constitutional Court of South Africa. Case CCT 8/02. Johannesburg: Constitutional Court of SA, 2002.

S Afr Med J 2016;106(9):838-839. DOI:10.7196/SAMJ.2016.v106i9.11270

September 2016, Print edition

DEBATE

Clarifying the position statements of the Central Drug Authority Executive Committee

It is remarkable that Dr Scott begins his response[1] to our rebuttal[2] of his earlier editorial[3] by stating that his paper ‘tries to avoid covering all the arguments put forward’ by us. Indeed, our impression is that he has merely repeated the position in the earlier editorial, that he uses rhetorical devices to distort our views, and that he ignores the key points we have made. First, Dr Scott repeats his statement that our position statement suffers from confirmatory bias, and fails to address the evidence base on harms and benefits of drugs that we cite. He distorts our views by drawing an analogy between our citations of this evidence base and past misconceptions about antiretrovirals. We think that other clinicians will agree that the point made in our rebuttal – that substances are associated with well-researched harms, as well as with potential benefits – cannot simply be ignored. Second, Dr Scott again laments the various United Nations (UN) conventions, and the harms associated with current drug laws. He distorts our views by accusing us of supporting the UN conventions and failing to recognise harms associated with current drug laws. However, as we stated in our rebuttal, the intention of our position statements is precisely to bring attention to and advocate for harm reduction, both with respect to cannabis and more generally, as a key public health approach to addressing tobacco, alcohol and other substance use. Third, Dr Scott again draws a stark contrast between prohibition and legal regulation, criticising decriminalisation as merely a form of prohibition. He distorts our views by assuming that we stand wholly for prohibition. In our rebuttal we emphasised that a broad range of regulatory options lie between decriminalisation and

commercialisation, noting that decriminalisation is merely one practical step in the right direction. The evidence indicates that ‘Big Cannabis’ is not an imaginary construct that can simply be ignored. Nevertheless, we would note, as we did in our earlier rebuttal, some overlap between our position and Dr Scott’s. We seem to agree on a public health approach to the regulation of tobacco, alcohol and other substances, on a focus on harm reduction rather than a ‘war on drugs’, and on the recognition that alcohol is the most widely used and harmful substance in the South African context and so deserving of particularly careful regulation. We hope that many clinicians, as well as members of the public, will also find common ground on these issues. Dan J Stein

Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa dan.stein@uct.ac.za

Eva Manyedi

S Afr Med J 2016;106(9):840. DOI:10.7196/SAMJ.2016.v106i9.11283

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CORRESPONDENCE

Social justice and research using human biological material: A right to respond

The potential danger of journal summary services

To the Editor: This communication refers to an article by Jordaan[1] titled ‘Social justice and research using human biological material: A response to Mahomed, Nöthling-Slabbert and Pepper’, which appeared in the July 2016 SAMJ. The original article[2] to which Jordaan refers and has responded was first published in the South African Journal of Bioethics and Law in 2013 and is titled ‘The legal position on the classification of human tissue in South Africa: Can tissues be owned?’ We note with great concern that Jordaan’s response was published in the SAMJ, 3 years after the publication of our original article, which he refers to as a ‘recent’ article. We would like to correct this misinformation, as our original article is in fact not recent. Because of the lapse in time, and the fact that Jordaan’s response was published in a different journal, readers of the SAMJ may not have a comprehensive understanding of the content of our original article. Furthermore, as authors of that article we were not provided, as one would expect in terms of editorial practice and ethics, with an opportunity to respond to Jordaan, or even notified that his article was going to appear in your journal. In his response, Jordaan has clearly misinterpreted the issues we raise regarding ownership of human tissues, a matter that has been debated extensively in the academic sphere for some time. Jordaan has chosen, very selectively and most likely deliberately, to pick on certain aspects of our original article and question the credibility of our opinions, to which we are fully entitled. A critique provided in a staccato fashion, without considering the aims and arguments purported in our original article as a whole, can only be flawed. Furthermore, the allegations and conclusions that Jordaan has reached in his response are unjustified and do not function to further academic debate on the ethical and legal issues that we considered. There are, however, certain aspects that Jordaan has pointed out in his response that we do appreciate in the spirit of academic discourse. His overall intention was to highlight our alleged weak and unconvincing arguments. However, it is our opinion that your omission, as Editor, to provide us with the opportunity to respond to Jordaan’s article in the same issue is not conducive to healthy academic discussion and debate. We are quite sure that the intention of an established journal like the SAMJ is to uphold the principles of editorial ethics and academic professionalism. As the original authors of the article to which Jordaan has responded, we hereby wish to inform you that we reserve our right to reply. A full response will be submitted to your journal in due course.

To the Editor: On 29 April, NEJM Journal Watch published a summary[1] of a recent trial of single-dose dexamethasone for acute asthma compared with the current standard of 5-day prednisone. Unfortunately the one-line opening paragraph of the summary (which was the only line in the email alert) stated the opposite of the actual outcome of the trial. The one-line summary stated: ‘A randomized trial suggests that the regimens may be equivalent.’ The study[2] was designed as a noninferiority trial and dexamethasone in fact failed (albeit narrowly) to meet the prespecified parameters of non-inferiority. In the current environment where medical practitioners are bombarded by data, it is likely that many would read the oneline summary without reading the full summary, let alone the original article. It is even conceivable that practitioners around the world might change their practice on the basis of this oneline summary, especially with the summary promoted as ‘practice changing’ on the website. NEJM Journal Watch’s reported global monthly readership is half a million;[3] the concomitant pressures of drug company direct marketing are significant; and the fact that studies have shown equivalence between 5 days of predni sone and two doses of dexamethasone could easily be confused with this result. There are potentially grave consequences from such a practice change: the raw data from the study yield an NNH (number needed to harm) of 43 for using single-dose dexamethasone instead of 5-day prednisone. This is a worrying statistic for a condition that is both common and potentially lethal, especially when one notices that the study’s loss to follow-up (an attempted phone call at 2 weeks) was nearly twice as high in the dexamethasone group as in the prednisone group. Adherence is clearly the appeal of a single-dose regimen, but it should be pointed out that, besides the factor of script fulfillment, prednisone adherence was in fact intrinsically controlled for in the study. And, in my particular context and through most of the rest of Africa where discharge medicines are provided free by the state and are often dispensed directly from emergency departments, script fulfillment is a minor aspect of adherence challenges.

Department of Jurisprudence, College of Law, University of South Africa mahoms1@unisa.ac.za

The author is an independent general practitioner involved in a pilot public-private partnership between the Western Cape Department of Health and various NGOs in facilitating equitable access to primary care for individuals with intellectual, physical and psychiatric disabilities. He has no conflicts of interest with either the outcome of the referenced research or the journal summary service cited.

M Nöthling Slabbert

Timo Freeth

S Mahomed

Cape Town, South Africa timofreeth@gmail.com

College of Law, University of South Africa

M S Pepper

Institute for Cellular and Molecular Medicine, South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, and Department of Immunology, Faculty of Health Sciences, University of Pretoria, South Africa 1. Jordaan DW. Social justice and research using human biological material: A response to Mahomed, Nöthling-Slabbert and Pepper. S Afr Med J 2016;106(7):678-680. DOI:10.7196/SAMJ.2016.v106i7.10552 2. Mahomed S, Nöthling-Slabbert M, Pepper MS. The legal position on the classification of human tissue in South Africa: Can tissues be owned? S Afr J Bioethics Law 2013;6(1):16-20. DOI:10.7196/SAJBL.258

S Afr Med J 2016;106(9):841. DOI:10.7196/SAMJ.2016.v106i9.11379

1. Pallin DJ. Acute asthma: Single-dose dexamethasone vs 5-day prednisone. NEJM Journal Watch, 2016. http://www.jwatch.org/na41200/2016/04/29/acute-asthma-single-dose-dexamethasone-vs-5-dayprednisone?query=etoc_jwhospmed&jwd=000101389940&jspc=IM (accessed 3 May 2016). 2. Rehrer MW, Liu B, Rodriguez M, et al. A randomized controlled trial of single dose dexamethasone versus 5 days of oral prednisone in acute adult asthma. Ann Emerg Med 2016; 14 April, ePub ahead of print. DOI:10.1016/j.annemergmed.2016.03.017 3. NEJM Journal Watch Information. NEJM Journal Watch, 2016. http://www.jwatch.org/about/journalwatch (accessed 26 May 2016).

S Afr Med J 2016;106(9):842. DOI:10.7196/SAMJ.2016.v106i9.11088

September 2016, Print edition

ETHICS FOR ALL 2016

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IZINDABA

Cutting-edge ZAR120 million boost for SA’s surgical skills A ZAR120 million state-of-the-art surgical skills simulation laboratory opened on the Tygerberg campus of Stellenbosch University (SU) this July, replicating realtime theatre scenarios and turbo-boosting healthcare for the entire sub-Saharan region. It is geared to train 1 200 physicians in its first year of operation. Described by Prof. Nico Gey van Pittius, vice-dean of research at SU, as ‘set to revolutionise training in sub-Saharan Africa’, the laboratory houses eight fully simulated theatre operating stations, ‘dry’ and ‘wet’ capacity, a 100-seat lecture theatre and a virtual intensive care unit – all complemented and connected by versatile and breakthrough audiovisual capabilities. In the laboratory, which goes by the university acronym of the Sunskill Laboratory, surgical registrars in all disciplines, seasoned surgeons and primary care practitioners, nurses and related healthcare professionals will acquire and hone routine to gold-standard, high-end, niche skills. Van Pittius said the laboratory would promote the increase of cross-disciplinary work, tapping into uncharted areas of research, while his neurosurgery division chief and colleague, Prof. Ian Vlok, enthused about the savings in theatre time and cost, the safe acceleration of learning and improved patient outcomes. ‘We have to be accountable for the skillsets that come out of here. Basic surgical skills and proper, appropriate anatomical knowledge will be minimum entrance quali fications – the last thing we want to create is a bunch of loose cannons,’ he stressed.

Tygerberg neurosurgeon Prof. Ian Vlok demonstrates possible procedures on a ZAR1 million human dummy.

Vlok leads the three-man neurosurgical team at Tygerberg Hospital that initiated the collaboration with sponsor Medtronic, a top global surgical equipment supplier. Medtronic’s MD for Africa, Mr Peter Fuller, said the ZAR120 million equipment costs would be ‘amortised’ over the long term. Vlok said specialist training had always demanded a delicate balance between gaining surgical experience and not putting patients’ health at risk in order to do so. On 26 July, just 6 days after the launch, 40 international neurosurgeons converged on the laboratory to conduct intensive training ses-

sions that included the most advanced keyhole surgery, showcasing equipment ranging from ZAR1million human dummies able to replicate human functions and disease symptoms to endoscopes, high-definition surgical microscopes, image-guided navigation equipment and surgery-enhan cing computed tomography scanners. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2016;106(9):847. DOI:10.7196/SAMJ.2016.v106i9.11333

‘Shamed’ Durban doctor claims ZAR20 million A Durban doctor who was summarily marched out of his hospital in full view of patients and colleagues and later suspended, with his provincial health MEC pillorying him on a departmental website for allegedly refusing to treat a car-crash victim, this June sued his employers for ZAR20 million. Dr Shaheen Seedat, a senior doctor at Mah at ma Gandhi Hospital in Phoenix, issued the letter of demand to the KwaZulu-

Natal (KZN) Department of Health in midJune after being ‘wrongfully’ accused of failing to clinically assess a severely injured young man, Riveshan Tandather, aged 19, who was brought to the hospital on 11 July last year. Tandather later died. Seedat was reportedly called over to intervene in a ‘signover’ dispute between an emergency services staffer and hospital staff. The aggrieved ambulanceman laid the complaint.

September 2016, Print edition

KZN MEC for health, Sibongiseni Dhlomo, ordered a probe headed by Dr Henry Sunpath, posting on his department’s website: ‘I am appalled by the manner in which a [man who was] critically injured in a motor vehicle accident was dealt with.’ Seedat’s suspension was lifted in October after an internal enquiry cleared him. Five witnesses, including three doctors and nurses who were on duty on the day, plus an expert witness, testified.

IZINDABA

However, the matter was then ‘escalated’ to the Health Professions Council of South Africa, which Seedat’s attorney Mervyn Sigamoney described as ‘absurd’. He said his client had ‘not laid a hand’ on the deceased. The internal disciplinary hearing should never have taken place, as there was no case to answer, and had fully exonerated his client. No one in authority had yet apologised to Seedat who suffered hugely negative media exposure that left him

a patient pariah. Dr Sunpath (a co-respondent in the civil proceedings) proceeded ‘recklessly’ against Dr Seedat, ‘knowing’ he was not the treating doctor. Sigamoney said he suspected that ‘another agenda is at play here’, and warned that the amount claimed could climb if the authorities continued to play hardball. ‘My client’s career is compromised and the taxpayer gets punished,’ he added. Samuel Mkhwanazi, the provincial health department’s spokesman,

said it was ‘government policy not to comment on such matters’. Sigamoney said Dr Seedat was frog-marched out of the hospital, in full view of the public and other professionals. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2016;106(9):848. DOI:10.7196/SAMJ.2016.v106i9.11334

Two fatalities in Durban’s multiple hospital strikes Two strikers, believed to be cleaners, died in a confrontation with security guards at King Edward VIII Hospital on 14 July, following the non-implementation of a legal amendment rendering certain non-timebased temporary hospital staff permanent employees. The South African Public Service Union (SAPSU) vowed on 16 June to extend its week-long protest, demanding that temporary workers employed for longer than 3 months at government institutions be given permanent jobs. The strikes affected Mahatma Gandhi, King Dinizulu and King Edward VIII hospitals. The pre-dawn killing involved security guards and an allegedly armed cleaner who approached them at the

hospital. The cleaner and a colleague were shot, one body being found by police at the scene and another nearby. Speaking at a press briefing on 16 June, the interim secretary-general of the union, Moses Tsotetsi, said the legal section in dispute was the amendment to Section 198 of the Labour Relations Act (Act 66 of 1995), which dealt with temporary workers. He said the law, which was officially signed in, needed enforcing, with no bargaining council involvement. ‘Workers are unwilling to back down – they’re tired,’ he said. Many of those affected were security guards and cleaners younger than 40, and legally entitled to a salary of between ZAR5 000 and ZAR6 000, plus benefits. This would

increase to the level of government employees after 18 months. While it was not their intention to impact on essential health services, they had to fight for their rights and were consulting lawyers. Led by former COSATU secretary-general Zwelinzima Vavi, SAPSU protestors marched to the Durban City Hall to deliver a memo to KwaZulu-Natal (KZN) premier Willies Mchunu. A spokesman for the KZN health department was unavailable. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2016;106(9):849. DOI:10.7196/SAMJ.2016.v106i9.11335

Give us peer educators, not nurses, say sex workers Using peer educators to enrol sex workers into healthcare programmes is far superior to persuasion via traditional healthcare workers, who are seen as prejudiced and lacking understanding, Médecins Sans Frontières (MSF) research presented to a scientific forum at the University of the Witwatersrand last month shows. The MSF research at two Mozambican sites in the Malawi-Beira transport corridor between January 2014 and June 2015 enrolled 1 810 sex workers to explore communitybased testing strategies. Peer educators were able to reach out to their peers and gain trust, enrolling 1 461 sex workers in Tete and 349 in Beira, most of them from Zimbabwe, with a minority from Malawi. A full 59% of those

in Tete and 54% of the Beira cohort were HIV-positive, with HIV positivity increasing with age (29 - 43% for age 18 years and younger, and around 78% by 35 years and older). There was a good response to testing, in spite of stigma and prevention challenges which included retention for retesting (24% traced for follow-up a year later) and sex workers experiencing prejudice and being undervalued by non-sex workers on the MSF team. The aim was to keep HIV-negative sex workers HIV-negative, to link HIV-positive sex workers to HIV care and treatment, and to provide community outreach via HIV testing and counselling, female and male condoms, lubricants, retesting and sexually

September 2016, Print edition

transmitted infection and family planning services. The team facilitated integrated, friendly services (antiretroviral drugs and viral load testing) plus in-country and crossborder referrals. Integrating peer educators into the MSF outreach programme proved pivotal. Presenter Dr Humberto Jassitene expres sed excitement at the new South African HIV guidelines, which recommend pre-exposure prophylaxis for sex workers, something he hoped to emulate ‘very soon’. Chris Bateman chrisb@hmpg.co.za S Afr Med J 2016;106(9):850. DOI:10.7196/SAMJ.2016.v106i9.11336

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EDITORIAL

Child deaths in South Africa: Lessons from the child death review pilot South Africa (SA) has not met the child mortality target for the Millennium Development Goals, despite having invested substantially in programmes and policies to achieve these targets. The scale-up of the prevention of mother-to-child transmission programmes reduced HIV transmission from mother to child, but this has not been sustained owing to limitations in community-based child health services.[1] Child mortality has declined, but has now plateaued.[2] Children continue to die from preventable and treatable causes of death.[3] Current data sources are incomplete, and do not provide information on deaths occurring out of health facilities. [1] The child death review (CDR) pilot explores the pattern of child deaths and informs prevention strategies to improve child survival in SA. In this editorial we draw on the conclusions of the CDR pilot,[4] where multiagency teams were established to investigate non-natural and unexpected deaths referred to two mortuary sites in order to strengthen child health and protection response systems and to prevent child deaths. Strategies to improve child survival have mainly focused on under-5 deaths, yet our CDR pilot has shown that deaths throughout childhood require attention. The following patterns of child mortality were identified: (i) infanticide in the neonatal period; (ii) acquired natural causes (in particular lower respiratory tract infection (LRTI)) during infancy; (iii) child abuse- and neglect-related deaths in children aged <5 years; (iv) road traffic deaths, in particular deaths of pedestrians, as children become older; and (v) homicide and suicide in the older age group (15 - 17 years). The CDR investigates each child death using a set of questions that include the medical factors together with the social contributors to each child’s death, particularly in sudden unexpected and injury-related deaths. This process requires an understanding of the context or environment in which each death occurred, including factors at each level – individual (biological and psychological), family, social, cultural, health and social welfare system – that influence access to care and the care the child received.[5] The neonatal period is well documented as a period of great risk, particularly for preterm infants. We show that preterm infants are at increased risk of dying from LRTIs during the post-neonatal period once they have been discharged home, especially during winter. We have argued[6] that as the state has invested substantially in the care of preterm infants during the neonatal period, it is imperative that research be conducted to identify why these infants die once out of hospital from seemingly preventable natural causes. Social circumstances such as poor living conditions intersect with limited support for mothers and suboptimal quality of community-based services, making preterm infants vulnerable to death from preventable infections such as LRTIs. Although SA has a strategy to re-engineer primary healthcare (PHC) through ward-based PHC outreach teams, its impact is currently limited because of a low healthcare worker-topopulation ratio and lack of training.[1] A purely biomedical approach to reduce such deaths is therefore inadequate, and our CDR process highlights the need to consider social and behavioural influences in combination with health systems factors.[4] Interviews with families performed as part of the CDR process have revealed a large number of cases where infants with no previous medical history of note were apparently well and were fed and put to bed, but later found dead. This recurring pattern of ‘fed, bed, dead’ is a grave concern. These deaths are mainly due to LRTI, and while some cases are associated

with preterm birth, a number of infants have no identifiable risk factors. It appears that many caregivers are unaware of symptoms and signs in infants that require urgent medical attention. This clearly warrants further research into the clinical aspects of LRTI in order for clinical management of infants to be evidence based. The population of infants dying from natural causes out of hospital and admitted to the Forensic Pathology Service (FPS) in the Western Cape presents a cohort that could provide invaluable insights, which has been noted in previous recent research.[7,8] At present, limited capacity restricts the ability to perform complete detailed postmortem examinations (including full microbiological, virological, biochemical and genetic analyses) of these natural deaths. The early neonatal period was shown to be a period of increased risk of deaths resulting from abandonment and injury. This finding is supported by the national child homicide study showing that SA had one of the highest reported rates of neonaticide globally.[9] Neonaticide is the killing of a newborn within the first 6 days of life, and infanticide the killing of a child in the first year of life. Both these acts are a form of child abuse, whether the killing was deliberate or the death due to a deliberate omission of care, e.g. when a baby is abandoned without care, protection or supervision.[9] Infanticide or abandonment of a newborn is far more common than the CDR pilot suggests, as many infants are ‘dumped’ in sewers, refuse dumps and dirt bins, and the pilot only identified remains brought to a mortuary. Despite SA’s liberal termination of preganancy legislation and the availability of community-based contraception services, it would appear that we are not meeting the needs of large numbers of women. We need to examine maternal and mental health services for pregnant women and determine the appropriate support services required by women in communities to decrease infanticide. Child deaths related to abuse and neglect deaths were common in the under-5 age group, highlighting the vulnerability of young children to violence and neglect in the home. Physical violence under the guise of discipline is common in SA, and regarded as an acceptable parenting practice.[10] Banning corporal punishment in the home is the first step towards making the home safer for children, and should be a priority in conjunction with primary prevention interventions to reduce the risk of children being exposed to violence in the home. Parenting programmes that enhance the parent-child relationship and reduce harsh parenting practices have been shown to be effective in SA.[11] Enhancing current parenting practices and support systems for families through the early identification of vulnerable families is critical to prevent fatal child abuse. The contribution of neglect to child mortality, and in particular sudden unexpected deaths of infants (SUDIs), is difficult to determine accurately, and this has also been highlighted internationally. The CDR process, through a multiagency review and co-ordinated response to the investigation and management of suspected abuse and neglect cases, facilitated an increase in the identification of child deaths from neglect. The biological cause of death on its own in a SUDI is unable to provide the full picture of the circumstances leading to the child’s death, and the Road To Health booklet, supporting health data and the social circumstances, together with an investigation into the care of the child, provided us with a better understanding of the context in which children are dying. Legally, sudden unexpected deaths must be referred to the nearest FPS (mortuary) for a medicolegal investigation.[12] The difference

September 2016, Print edition

EDITORIAL

between referral patterns of natural deaths at the two sites in our pilot has raised concern with regard to SUDIs and the need to create awareness on the part of medical colleagues and communities of the definition of a SUDI as an unnatural death.[4] This difference may well extend beyond the two pilot sites and be a much wider occurrence throughout provinces. Anecdotally, the experiences of the forensic pathologists involved in this study suggest that referrals of SUDI cases to the FPS occur much more commonly in the Western Cape than in KwaZulu-Natal. From personal experience (LJM serves as a member of the National Forensic Pathology Service Committee) and involvement in national mortality-based studies of two of the authors (SM and LJM), it is suggested that the Western Cape referral pattern is different from the national referral pattern in that most SUDIs are not referred to the FPS, but declared as natural deaths by medical practitioners in the community, and are therefore never brought to the attention of the health surveillance system.[13,14] A concern is the potential for child homicides, in particular deaths from neglect, to remain undetected. This may also place other children in the family at risk. Injury deaths among older children (10 - 17 years) are a concern. In our review there were 11 suicides (7% of the non-natural deaths), including two 9-year-old children. Deliberate self-harm and suicide in children aged <10 years is unusual, establishing the intent of the child after their death is impossible, and the death could be related to other factors.[15] Not much is known about suicides in this young age group, and understanding the underlying risk factors for young children is critical to inform interventions to prevent such deaths. Homicide due to interpersonal violence was the leading cause of injury death in this pilot, and mainly affected young men. Preventing male-on-male violence is critical in the context of high levels of crime and violence in many communities, where children are exposed to violence on a daily basis both in their homes and in the community. Boys in particular are exposed to adverse childhood experiences such as neglect, harsh parenting and abuse, and this contributes to the shaping of violent masculinities.[16] Multipronged evidence-based prevention strategies to strengthen families and equip parents with the skills to use positive discipline may reduce such pathways. The CDR has shown the potential to increase the accuracy of ascertaining causes of death in children and to reduce undetermined or ill-defined causes, to complement the Child Healthcare Problem Identification Programme (Child PIP) audit of in-hospital child deaths. It improves our ability to identify cases of abuse and neglect so that appropriate action may be taken, and also the circumstances that place children at high risk so that strategies can be put in place to minimise this risk. Data collected from the CDR process are an important barometer for the wellbeing of children in our society, and the study reported on in this issue[4] portrays a grim reality. There is clearly a lack of understanding and awareness regarding the definitions of unnatural deaths according to the Regulations for Forensic Pathology practice, and all stakeholder agencies need to disseminate the requirements and mandates of the statutory obligations of healthcare practitioners. These agencies include the national and provincial departments of health responsible for the FPS, as well as the clinical managers of health services, the National Prosecuting Authority, the Department of Justice (inquest magistrates and prosecutors) and the South African Police Service.

Shanaaz Mathews Children’s Institute, Faculty of Health Sciences, University of Cape Town, South Africa Lorna J Martin Division of Forensic Medicine and Toxicology, Faculty of Health Sciences, University of Cape Town, South Africa David Coetzee Health Impact Assessment, Western Cape Department of Health, Cape Town, and School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Chris Scott Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa Yasheen Brijmohun Forensic Pathology Services, KwaZulu-Natal Department of Health, Durban; and Department of Forensic Medicine, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Corresponding author: S Mathews (shanaaz.mathews@uct.ac.za) 1. Doherty T, Kroon M, Rhoda N, Sanders D. Ending preventable child deaths in South Africa: What role can ward-based outreach teams play? S Afr Med J 2016;106(7):672-674. DOI:10.7196/SAMJ.2016. v106i7.10790 2. Chopra M, Daviaud E, Pattinson R, Fonn S, Lawn JE. Saving the lives of South Africa’s mothers, babies, and children: Can the health system deliver? Lancet 2009;374(9692):835-846. DOI:10.1016/S01406736(09)61123-5 3. Nannan N, Dorrington R, Laubscher R, et al. Under-5 Mortality Statistics in South Africa: Shedding Some Light on the Trends and Causes 1997-2007. Cape Town: South African Medical Research Council, 2012. 4. Mathews S, Martin L, Coetzee D, et al. The South African child death review pilot: A multi-agency approach to strengthen healthcare and protection for children. S Afr Med J 2016;106(9):895-899. DOI:10.7196/SAMJ.2016.v106i9.11234 5. Sidebotham P, Fraser J, Covington T, et al. Understanding why children die in high-income countries. Lancet 2014;384(9946):915-927. DOI:10.1016/S0140-6736(14)60581-X 6. Velaphi S, Rhoda N. Reducing neonatal deaths in South Africa – are we there yet, and what can be done? S Afr J Child Health 2012;6(3):67-71. DOI:10.7196/SAJCH.493 7. Groenewald P, Bradshaw D, Neethling I, et al. Linking mortuary data improves vital statistics on cause of death of children under five years in the Western Cape Province of South Africa. Trop Med Int Health 2016;21(1):114-121. DOI:10.1111/tmi.12624 8. Reid AE, Hendricks MK, Groenewald P, Bradshaw D. Where do children die and what are the causes? Under-5 deaths in the Metro West geographical service area of the Western Cape, South Africa, 2011. S Afr Med J 2016;106(4):359-364. DOI:10.7196/SAMJ.2016.v106i4.10521 9. Abrahams N, Mathews S, Martin LJ, Lombard C, Nannan N, Jewkes R. Gender differences in homicide of neonates, infants, and children under 5 y in South Africa: Results from the crosssectional 2009 National Child Homicide Study. PLoS Med 2016;13(4):e1002003. DOI:10.1371/ journal.pmed.1002003 10. Seedat M, van Niekerk A, Jewkes R, Suffla S, Ratele K. Violence and injuries in South Africa: Prioritising an agenda for prevention. Lancet 2009;374(9694):1011-1022. DOI:10.1016/S01406736(09)60948-X 11. Wessels I, Ward CL. A ‘best buy’ for violence prevention – evaluating parenting skills programmes. SA Crime Quarterly 2015;54:17-28. DOI:10.4314/sacq.v54i1.2 12. Republic of South Africa. Regulations to the National Health Act 61 of 2003. Pretoria: Government Gazette, 2007. http://www.saflii.org/za/legis/consol_reg/nha61o2003rangnr636590.pdf (accessed 8 May 2016). 13. Matzopoulos R, Prinsloo M, Pillay-van Wyk V, et al. Injury-related mortality in South Africa: A retrospective descriptive study of postmortem investigations. Bull World Health Organ 2015;93:303313. DOI:10.2471/BLT.14.145771 14. Mathews S, Abrahams N, Jewkes R, Martin LJ, Lombard C. The epidemiology of child homicides in South Africa. Bull World Health Organ 2013;91:562-568. DOI:10.2471/BLT.12.117036 15. Sidebotham P, Fraser J, Fleming P, Ward-Platt M, Hain R. Patterns of child death in England and Wales. Lancet 2014;384(9946):904-914. DOI:10.1016/S0140-6736(13)61090-9 16. Mathews S, Jewkes R, Abrahams N. ‘I had a hard life’: Exploring childhood adversity in the shaping of masculinities among men who killed an intimate partner in South Africa. Br J Criminol 2011;51(6):960-977. DOI:10.1093/bjc/azr051

S Afr Med J 2016;106(9):851-852. DOI:10.7196/SAMJ.2016.v106i9.11382

September 2016, Print edition

CME

GUEST EDITORIAL

Functional neurosurgery (part 2) This month’s CME includes the final two articles that review functional neurosurgical topics, i.e. surgery for movement disorders,[1] where deep brain stimulation plays a major role, and surgical management of pain.[2] From these articles, which give an overview of the respective topics, it is clear that neurosurgery forms a central part of the management of patients with common disabilities, such as severe pain and movement disorders that are refractory to medical management. Patients need appropriate referral and a thorough work-up that involves a multidisciplinary team. These complex disorders should not be managed in isolation. Owing to the invasive nature of surgery for functional neuro surgical pathology, care is needed to confirm that the medical management of the patient has been done thoroughly and that all medical options have been exhausted. Patients with conditions such as Parkinson’s disease must, however, be referred to a unit where deep brain stimulation can be performed early on in the disease process, as some studies show that patients who are subjected to this technique early have a much better outcome than those who wait >10 years. The biopsychosocial model in medicine is often seen to correspond to a general practitioner’s approach. A holistic approach is especially important in managing complex pain syndromes. Treating the biological aspects of pain only, will lead to heartache for both physician and patient and to failure of therapy. Chronic pain leads to psychological problems and often to significant social impairment. All of these need to be taken into account for the successful management of the patient. Pain management requires a stepwise increase in pharmacological interventions, starting with paracetamol and followed by cyclo-oxygenase-2 (COX-2) inhibitors. If there is still no improvement, opioids are added, followed by pain-modification agents such as tricyclic antidepressants and some selective anticonvulsants. Throughout the treatment process, adjuncts to medication should be employed, such

as psychotherapy, electrotherapy as used by physiotherapists, and play and music therapy. These contribute a great deal to modifying the patient’s experience of pain. When pain is refractory to all these modalities, surgical management becomes an option. The neuro surgeon then uses modulating devices such as spinal cord stimulators, peripheral nerve stimulators, and lesioning techniques, which interrupt the afferent pathway. Spinal canal catheters effecting direct drug delivery to the spinal receptors are often beneficial in spinerelated pain syndromes. The take-home message from the four CME articles,[1-4] – a small window into the practice of the functional neurosurgeon – is that multidisciplinary units are needed to manage these complex pathologies of epilepsy, pain, spasticity and movement disorders. The general practitioner is an essential part of this team, and knowledge of the stepwise escalatory approach to care is vital to appropriate and early referrals. J M N Enslin Division of Neurosurgery, Red Cross War Memorial Children’s Hospital, and Constantiaberg Mediclinic, Cape Town, South Africa enslin@functionalneurosurgery.co.za 1. Enslin JMN. Surgical management of movement disorders. S Afr Med J 2016;106(9):854-857. DOI:10.7196/SAMJ.2016.v106i9.11355 2. Rothemeyer SJ, Enslin JMN. Surgical management of pain. S Afr Med J 2016;106(9):858-860. DOI:10.7196/SAMJ.2016.v106i9.11366 3. Enslin JMN, Fieggen AG. Surgical management of spasticity. S Afr Med J 2016;106(8):753-756. DOI:10.7196/SAMJ.2016.v106i8.11225 4. Enslin JMN, Rothemeyer SJ, Fieggen AG. Surgical management of epilepsy. S Afr Med J 2016;106(8):757760. DOI:10.7196/SAMJ.2016.v106i8.11194

S Afr Med J 2016;106(9):853. DOI:10.7196/SAMJ.2016.v106i9.11372

September 2016, Print edition

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Surgical management of movement disorders J M N Enslin, BPhysT, MB ChB, FCNeurosurgery (SA), MMed (Neurosurg) Division of Neurosurgery, Red Cross War Memorial Children’s Hospital, and Constantiaberg Mediclinic, Cape Town, South Africa Corresponding author: J M N Enslin (enslin@functionalneurosurgery.co.za)

Movement disorders are usually treated by neurologists, and appropriately so. The first-line management of all conditions that are grouped together as movement disorders (e.g. Parkinson’s disease, dystonia, essential tremor) is with medication and, in some, with rehabilitative strategies, such as occupational therapy, physiotherapy and even psychotherapy. In general, if these strategies fail or have undesirable consequences, surgery would become an option. Intramuscular injection of botulinum toxin is also very useful in the focal dystonias, such as writer’s cramp, and in the occupation-specific dystonias, such as musician’s dystonia or hairdresser’s dystonia. The limiting factor is the total safe dosage allowed. One cannot inject every muscle involved in all four limbs in a patient with generalised dystonia. This has led to surgery being offered as therapy in certain cases where there have previously not been any alternatives. Surgery does not offer curative procedures for movement disorders, but long-term control with medication is possible, often with significant reduction or complete cessation of symptoms. S Afr Med J 2016;106(9):854-857. DOI:10.7196/SAMJ.2016.v106i9.11355

Disability from movement disorders is often seen as par for the course in the ageing process. It is the price paid by those who are lucky enough to grow old. There are, however, also young patients who develop Parkinson’s disease (PD) and dystonia and have to discontinue their profession owing to a severely disabling tremor or task-specific dystonia, such as writer’s cramp or musician’s dystonia. In this group of patients, especially, awareness about surgical options to alleviate disability caused by their movement disorder is of the utmost importance. Surgical procedures performed for movement disorders are classically divided into two categories (Table 1).

Pathophysiology of movement disorders

To understand the principles behind the surgical management of movement disorders, we first need to review the basic physiology of movement. This is a complex topic and a detailed discussion is beyond the scope of this article, but a brief overview is given. Human movement is the end result of a complex, orchestrated and masterfully executed interaction of sensory feedback, modulation and action. Human movement is planned in the frontal lobes and is strongly linked to the need for reward. At the most primitive level, one performs an action to achieve an award. Four cerebral areas are involved in human movement: • primary motor cortex: e.g. sending the message via the corticospinal tracts to a limb • secondary motor cortex (supplementary motor area): planning of movement

Table 1. Possible surgical procedures for treating movement disorders Lesioning procedures

Neuromodulation

Stereotactic lesioning of basal ganglia and/or thalamic targets

Deep brain stimulation

Selective peripheral denervation of specific muscles

Intrathecal baclofen therapy

• prefrontal cortex: adding emotional influ ence to our movements • cingulate gyrus.

all the abovementioned nuclei in controlling movements.

There are also subcortical structures involved in movement: • basal ganglia: thalamus, globus pallidus and subthalamic nucleus (STN) • cerebellum: ‘fine tuning’ of all movement takes place here • white matter tracts: corticospinal tract, reticulospinal tracts and afferent tracts, e.g. spinothalamic.

PD occurs more commonly in patients of 55 - 65 years of age and it is estimated that up to 2% of people >60 years old will develop the condition.[2] PD is characterised by the clinical triad of bradykinesia, resting tremor and postural instability.[3] Some of the associated features are bradymemia (slowness of thoughts), bradyphrenia and gait abnormalities, such as festination (shuffling gait).[3] Also note that PD has associated non-motor symptoms. These are mostly resistant to all surgical interventions and include cognitive impairment, mood disturbances, sleep disturbances and even autonomic disorders.[4] These non-motor symptoms often cause most dysfunction in previously high-performing individuals with PD. Care and support should therefore not be solely fixated on the movements or tremors, but a holistic multidisciplinary approach is essential. DBS of the STN was recommended for patients with PD by the American Academy of Neurologists in 2006.[5] The GPi is also a therapeutic target, but is best reserved for patients with PD where rigidity is the main feature.[5] Ideal candidates for DBS are those with pre-operative good motor response to levodopa therapy during their ‘on period’.[6] DBS has been shown to reduce the ‘off time’

The basal ganglia and cerebellum form part of a complex circuit controlled by positive and negative feedback loops.[1] There is a network of connectivity between the thalamic nulei, cerebellum, STN and globus pallidus, which modifies and refines our actions. Dopamine plays an important role as the main neuro transmitter substance in this network. The physiological effect of lesioning or deep brain stimulation (DBS) on these nuclei is still unknown, but the most likely explanation is that the damping effect of PD is alleviated by high-frequency stimulation of the STN, while the inverse happens in dystonia, where stimulation of the globus pallidus interna (GPi) dampens the abnormal tone and movements. Much research is being done worldwide, with some units using viral tractography mapping studies that show the interconnectedness of

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Parkinson’s disease

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in patients and the need for medication, and improve dyskinesia and motor function.[4] The ideal candidates for DBS are summarised in Table 2. The reason for waiting for 5 - 6 years of symptomatic PD before considering DBS, is to allow ample time for excluding differential diagnoses such as other neurodegenerative diseases; also, most patients develop motor fluctuations and dyskinesias only after this time period.[7] There is, however, good evidence to support the early use of DBS in patients with motor fluctuations caused by PD.[8] Patients experience good resolution of these effects and therefore must be referred for surgical treatment options early in the disease. It is important to note that there is no benefit with regard to the non-motor effects, and there is some concern related to suicide risk, which is slightly higher after surgery. This may be due to the motor disability being relieved, but not the mood disturbances.[9]

Dystonia

Dystonia forms part of the complex of disorders that present with abnormal movements. It is classified into focal and generalised dystonia and further into primary and secondary causes. The mainstay of focal dystonia is local intramuscular injection with botulinum toxin, which causes local paralysis of the injected muscle fibres.[10] This can allow the patient with focal types of dystonia, such as musician’s cramp or cervical torticollis, to have normalised movements of their hands or neck, depending on the pathology and the selected injection sites. Botulinum toxin is effective for 5 - 6 months, and usually requires repeated injections to control the disability. In long-standing cases of focal dystonia, such as spasmodic cervical torticollis, selective peripheral denervation of the sternocleidomastoid muscle, trape zius and splenius capitis muscles in the neck can lead to significant improvement in the torticollis (the Bertrand procedure). In focal dystonia of the hand some authors report very good long-lasting effects with contralateral lesioning of the ventral oralis anterior nucleus of the thalamus.[11] Taira, from Japan,[11] is renowned for having the patient awake during the procedure, with his/her musical instrument in the theatre, and asks the patient to perform a musical piece that would elicit their dystonia, while he is performing the surgical procedure. By doing this he confirms the therapeutic effect and avoids any damage to the surrounding internal capsule. Stereotactic placement of a DBS electrode in these thalamic nuclei, or in the GPi, has a similar effect, with the added benefit of removal if there are any side-effects and the ability to modify the stimulation parameters.

Table 2. Ideal PD patient for DBS Adequate brain imaging that excludes alternative diagnosis No cognitive impairment and motivated patient and family Realistic expectations regarding the potential outcome of DBS Duration of PD >5 years Proof of dopamine responsiveness (at least 30% improvement in motor score with dopamine) Problematic dyskinesia and motor fluctuations despite optimal medical therapy Disabling medication-resistant tremor Good medical health No atypical parkinsonism ≤80 years of age

Generalised dystonia of genetic cause (specifically DYT1 abnormality) is the most responsive to DBS. Patients with DYT1 dystonia do extremely well after DBS; consequently, it is currently the first-line therapy. DBS is expensive, but if the cost v. benefit analysis is taken into account there is significant functional gain for the patient, with long-term financial savings with regard to hospitalisation and chronic medication for funders. There is also major functional improvement and freedom of movement with the surgical management of dystonia patients.

Essential tremor

Essential tremor is one of the most common movement disorders and affects up to 5% of the general population.[12] It may affect people from all age groups (most commonly the elderly) and has a strong familial predilection, with an autosomal-dominant inheritance pattern.[12] Essential tremor is most often of a postural nature and is absent at rest. There is a clear exaggeration of this tremor with anxiety and stress, relieved by alcohol use.[13] Medical management forms the mainstay of treatment (beta-blockers, gabapentin and other anticonvulsants).[13] Once functional ability and quality of life are severely impaired by the tremor and it is refractory to medical treatment, DBS of the ventral intermediate nucleus of the thalamus is an option. Lesioning of the same nucleus (thalamotomy) may also be considered, with the drawback that the procedure is not reversible and may be associated with permanent neurological deficits after surgery. Up to 90% of patients experience a significant reduction in the number of tremors in their upper limbs and in the severity of the tremors.[13] All patients who are candidates for DBS or lesioning procedures to treat their movement disorder need to undergo some basic blood tests, including a coagulation profile. This will reduce the risk of potentially catastro phic haemorrhagic complications. Generally, patients undergo brain imaging, magnetic resonance imaging (MRI) being the most

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useful. This is used to merge the stereotactic imaging and to exclude cerebral lesions and severe cerebral atrophy, which may be contraindications to DBS. Imaging also excludes differential diagnoses, such Wilson’s disease – a dystonic condition treatable with medication rather than surgery.

Surgical workflow

The procedure is performed in one of two ways by most centres. Two different techniques are used to confirm the placement of the electrode in the chosen target. Fig. 1 summarises the procedures. The most common technique uses micro-electrode recording (MER) to confirm placement of the electrode. With this technique, a very thin electrode monitors the electrical activity at an individual neuronal level as it is passed through the brain parenchyma. The STN and GPi have characteristic electrical waveforms that are readily recognised by experienced neurosurgeons and neurophysiologists. Accuracy is therefore confirmed on a physiological level and the best electrode position is chosen during the surgical procedure. The same electrode can be used for stimulation, thereby checking for side-effects and unplanned effects on nearby structures, such as the optic tract or the internal capsule. Repositioning is then possible, during which the patient needs to be awake. Fig. 2 is an intraoperative image of this procedure. It may be difficult to perform in the elderly and younger children with dystonia, where the abnormal movements are so violent that the patient cannot be kept still in the head frame. Another approach, and the one I prefer, is to perform the entire procedure under general anaesthesia. The patient has the stereotactic frame applied, a stereotactic MRI brain scan is performed, and the target planning is done while the patient is anaesthetised. Once the planning has been done, the frame is applied over the frame base (Fig. 3) and the procedure is performed. Two burr holes are made behind the hairline and the electrodes are placed directly on the selected target. After placement of both electrodes a stereotactic MRI scan is

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MER verified

Imaging verified General anaesthesia Stereotactic frame applied

Awake patient Stereotactic frame applied

Stereotactic MRI performed

Stereotactic CT brain performed

No merging necessary Merging of CT to pre-operative MRI

Stereotactic guidance frame applied in theatre

DBS electrodes placed to co-ordinates

DBS electrodes placed with MER guidance

Stereotactic MRI done to confirm placement

Most suitable electrode and trajectory chosen

Electrode position changed if not on target

IPG implanted and connector leads tunnelled

Duration: 5 - 8 hours

Duration: 2.5 - 3.5 hours

Fig. 1. Workflow of DBS summary, illustrating the difference between the two techniques (MER = micro-electrode recording; CT = computed tomography; MRI = magnetic resonance imaging; IPG = implantable pulse generator).

Fig. 2. The neurosurgical team placing the DBS electrode in a patient who is awake. The stereotactic frame is in situ on the patient’s head.

Fig. 3. A patient in the MRI head coil with stereo tactic base and fiducial box on the head.

performed again and imaging verification is done to confirm the position of the electrode in the chosen target (Fig. 4). If the placement is accepted, the implantable pulse generator (IPG) is inserted in theatre; if not, the electrode is first repositioned and then the procedure is completed. Frame-based stereotaxis is still the

gold standard worldwide – the patient is fitted with a stereotactic frame that is bolted to the head – but there are some units that perform frameless stereotactic techniques. The IPG is implanted in a subcutaneous pocket that is usually created on the left side of the chest wall. In very cachectic patients

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the IPG can be implanted in the submuscular plane to prevent skin breakdown over the device. The two electrodes are tunnelled under the skin to connect the implanted electrodes to the IPG – similar to a ventri culoperitoneal shunt placement. The day after surgery the IPG is activated and a stepwise approach is used to test for side-effects and beneficial effects at a range of settings. The results of this initial screening procedure are used by the team to decide on the settings to be used when treating the patient. Stereotactic lesioning techniques use the same workflow as described above, the only differences being that patients should not be operated on under anaesthesia and a radiofrequency electrode is placed stereotactically to the target in the basal ganglia. Once the target is reached, a stimulation pulse is used to check for side-effects and confirm the therapeutic effect. If there is no risk of damaging vital structures, such as the internal capsule, then a radiofrequency pulse is used to create a thermic lesion in the target nucleus. This leads to permanent disease modification by interrupting the intricate feedback mechanisms that have been discussed above.

Follow-up

Once the DBS procedure has been performed, follow-up of patients is the same as in those who do not qualify for DBS as treatment of their movement disorder. Patients tend to improve if they are kept on low doses of their medication, even if symptoms are well controlled without medication. In PD, for example, it is important to remember that DBS does not treat the non-motor effects of the disease, and the psychological and autonomic components are controlled by medication as before. However, the benefit is that dosages can be lowered to levels that cause fewer side-effects. Two types of IPGs (pacemakers) are used: rechargeable and non-rechargeable. The advantage of the former is that it only needs replacement every 9 - 15 years, depending on the manufacturer’s specifications and the specific stimulation settings used (higher voltages at longer pulse width put more strain on the battery than inverse settings). The non-rechargeable implant will require replacement every 3 - 5 years, again depending on the settings used and the condition treated. Patient factors mostly determine which of the two types are used. Dependable caregivers or patients with a reliable electricity supply in their home will easily cope with the required once-weekly recharging session that is done with a magnetic recharging device that is placed, and kept, over the

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Fig. 4. Screenshot of a postoperative MRI scan showing the location of the electrode in the GPi bilaterally ((C) yellow arrow). The red dot ((C) green arrow) is the planned location that is superimposed on the postoperative image. This electrode is in the perfect location in the GPi. (A) Coronal section, (B) sagittal section, and (C) axial section of DBS electrodes.

IPG for ~2 hours, allowing it to recharge. In doubtful circumstances or unreliable patients, the non-rechargeable option is fail safe. Changing of the IPG requires another operation, which is associated with higher wound infection rates than the primary surgery. This is the major reason for opting for a rechargeable device if financial and social circumstances allow. DBS for dystonia differs from that for PD and essential tremor in one major way: the therapeutic effect of DBS in patients with dystonia has a slow onset, while in PD and essential tremor the effect is immediate. It is important that the patient with dystonia and their family realise this before the procedure, otherwise they are very disappointed and believe that the therapy was unsuccessful. Some units in Europe inform the patient that it will take months for the DBS to start working (personal experience), but in general there is at least some therapeutic effect in most patients in the first month after initiating the stimulation. Most patients experience a therapeutic effect within 6 months of the implantation. I prefer to switch on the stimulation device the day after surgery, but many surgeons rather wait a few days.

The rationale behind the waiting period is to allow for the slight swelling that is caused by the small electrode in the GPi or the STN to dissipate so that the effect of stimulation can be evaluated in isolation, without the lesioning effect playing a role in patient improvement. The effect of the lesioning procedures, such as pallidotomy (lesioning in the globus pallidus) or subthalamic nucleotomy (lesioning in the STN), is immediate and permanent in most instances. However, even in these procedures, the therapeutic effect of globus pallidus lesioning will take time to manifest.

Summary

Surgical management of movement disorders becomes an option only when appropriate medical management has been exhausted and the patient’s functioning and quality of life are impaired because of the disease. The abovementioned three diseases form the bulk of movement disorders treated by neurosurgeons, but currently targets for DBS are increasing by the month. Modern functional neurosurgeons treat pain conditions (e.g. cluster headaches) and psychiatric diseases (e.g. anorexia nervosa, major depres-

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sive disorder and obsessive compulsive disorder) with DBS and lesioning techniques. Certain conditions, especially psychiatric diseases where the cingulate gyrus is the target, lend themselves to lesioning rather than DBS. Therefore, lesioning techniques that have been performed since the mid1900s still play an important role in modern neurosurgery. It is generally agreed that surgery for movement disorders must only be performed in specific centres, where a multidisciplinary team is involved in the pre-operative work-up and the postoperative management of the patient. Neurosurgeons with special skills and aptitude for this type of work are needed; therefore, there are not many units in South Africa that offer this specialised service. Early referral is needed and more needs to be done to inform patients, their families and the medical fraternity of the surgical options for treating movement disorders. 1. Bajwa JA, Johnson MD, Vitek JL. Pathophysiology of dystonia. In: Lozano AM, Gildenberg PL, Tasker RR, eds. Textbook of Stereotactic and Functional Neurosurgery. Heidelberg: Springer, 2009:1779-1801. 2. Tanner CM, Aston DA. Epidemiology of Parkinson’s disease and akinetic syndromes. Curr Opin Neurol 2000;13(4):427-430. DOI:10.1097/00019052-200008000-00010 3. Lang AE, Lozano AM. Parkinson’s disease. N Engl J Med 1998; 339(15):1044-1053. DOI:10.1056/nejm199810083391506 4. Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: The NMSQuest study. Move Disord 2006;21(7):916-923. DOI:10.1002/mds.20844 5. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66(7):983-995. DOI:10.1212/01. wnl.0000215250.82576.87 6. Kazumata K, Antonini A, Dhawan V, et al. Preoperative indicators of clinical outcome following stereotaxic pallidotomy. Neurology 1997;49(4):1083-1090. DOI:10.1212/wnl.49.4.1083 7. Tan EK, Jancovic J. Patient selection for surgery for Parkinson’s disease. In: Lozano AM, Gildenberg PL, Tasker RR, eds. Textbook of Stereotactic and Functional Neurosurgery. Heidelberg: Springer, 2009:1529-1539. 8. Schuepbach WMM, Rau J, Knudson K, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med 2013;368(7):610-622. DOI:10.1056/NEJMoa1205158 9. Benabid AL, Mitrofanis J, Chabardes S, et al. Subthalamic nucleus stimulation for Parkinson’s disease. In: Lozano AM, Gildenberg PL, Tasker RR, eds. Textbook of Stereotactic and Functional Neurosurgery. Heidelberg: Springer, 2009:1603-1631. 10. Persaud A, Garas G, Silva S, et al. An evidence-based review of botulinum toxin (Botox) applications in non-cosmetic head and neck conditions. JRSM Short Report 2013;4(2):1-9. DOI:10.1177/2042533312472115 11. Taira T, Hori T. Stereotactic ventrooralis thalamotomy for taskspecific focal hand dystonia (writer’s cramp). Stereotact Funct Neurosurg 2003;80(1-4):88-91. DOI:10.1159/000075165 12. Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Move Disord 1998;13(1):5-10. DOI:10.1002/mds.870130105 13. Nazzaro JM, Lyons KE, Pahwa R. Management of essential tremor. In: Lozano AM, Gildenberg PL, Tasker RR, eds. Textbook of Stereotactic and Functional Neurosurgery. Heidelberg: Springer, 2009:1743-1757.

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Surgical management of pain S J Rothemeyer,1 MB ChB, FCNeurosurgery (SA); J M N Enslin,2 BPhysT, MB ChB, FCNeurosurgery (SA), MMed (Neurosurg) Department of Neurosurgery, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Division of Neurosurgery, Red Cross War Memorial Children’s Hospital, and Constantiaberg Mediclinic, Cape Town, South Africa

1 2

Corresponding author: J M N Enslin (enslin@functionalneurosurgery.co.za)

Severe and intractable pain is one of the most difficult and challenging neurological conditions to deal with and to treat. The entity is not entirely well understood, and the afflicted patients often have significant concomitant neuropsychological problems that obscure the physical issue at hand. Physicians also do not fully understand what pain is. In a sense all pain is neural in origin. From a therapeutic perspective, pain is divided into visceral (dull and poorly localised owing to enteric sensory receptors) and somatosensory (more discreet and localised – often owing to nociceptors being stimulated) pain. It is detected by nociceptors, i.e. sensory reseptors with the ability to interpret and transmit noxious stimuli. Treatment options include medication, physical therapy and psychotherapy. The availability of sophisticated new medication, such as pregabalin, augments the medical arm of therapy. If these therapies fail, and with a thorough multidisciplinary approach involving carefully screened cases, surgery may form part of the management. Generally, surgical pain management is divided into neuromodulative (enhancing physiological control of the pain system) and neurodestructive (lesioning and destroying the defined pain generator in the central nervous system) surgery. Complex pain management should not focus on cure as the only outcome. Patients often experience pain for years before considering surgery; it would therefore be unwise to expect an immediate cure. Careful psychological support and evaluation is of the utmost importance. This article gives an overview of the neurosurgical management of pain. S Afr Med J 2016;106(9):858-860. DOI:10.7196/SAMJ.2016.v106i9.11366

To understand the management of pain, it is important to focus on some basic aspects of pain physiology. A detailed explanation of this topic is, however, beyond the scope of this article. Neuropathic pain is described as ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’.[1] The Kyoto Protocol of the International Association for the Study of Pain (IASP) defined pain as follows: ‘Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.’[1] The pain can be peripheral or central (depending on whether the peripheral nervous system or central nervous system is involved).[1] In 1986, the World Health Organization (WHO) first published its ‘pain ladder’[2] approach to the management of pain. Even in severe or complex pain management algorithms, these steps are still followed. The first step includes the use of paracetamol or a nonsteroidal anti-inflammatory drug (NSAID). If these do not relieve the pain, then adjunctive drugs are added, such as anticonvulsants (gabapentin or pregabalin) or a tricyclic antidepressant (amitriptyline). Further severe pain requires the addition of an opiate (e.g. morphine).[2] Patients with pain that does not respond to this ladder approach, should be referred to a specialist pain management centre. The multidisciplinary team should ideally consist of an anaesthetist with a special interest in pain management,

social worker, psychologist, psychiatrist, physiotherapist, occupational therapist and functional neurosurgeon.[3] Various other ancillary therapeutic methods, such as musical therapy and play therapy, are often also involved and may aid in managing complex pain.

Pathophysiology

Pain is defined as a nociceptive and emotional response to a lesion or a disease that affects the somatosensory system.[1] This system comprises the brain and the areas in the brain that are intricately involved with our sensory experience of our surroundings – the thalamus and its nuclei that act as major relay centres for the information transferred to the sensory cortex

from all the receptive organs in our bodies. This information is transmitted to the thalamus and the rest of the central nervous system via long white matter tracts in the spinal column and brainstem (spinothalamic and reticulothalamic tract). The peripheral nerves act as afferent pathways for neural messages from the nociceptive receptors to the spinal cord, and the efferent pathways that relay the messages to react to the stimulus.[4] Fig. 1 is a schematic illustration of a cross-sectional cut through the spinal cord.[4] In this article, the reader is referred back to this illustration to understand the surgical techniques used to manage pain. Pain is caused by nociceptor activation by noxious stimuli (chemical, mechanical or temperature) that initiate a cascade of

Dorsal columns Rexed laminae Dorsal roots

Corticospinal tract Dorsal ganglion Spinothalamic tract

Ventral root

Ventral

Fig. 1. Sketch of an axial cut through the spinal cord and nerve roots, illustrating the ganglion and the different white and gray matter sections involved in pain surgery.[4]

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neurotransmitter substances, which lead to an electrical potential change in nerve fibres. Pain is transmitted via thick, myelinated A (β and δ)-fibres, as well as thin, unmyelinated C-fibres. Pain can therefore be ‘gated’ by using this two-fibre process to one’s advantage. There are certain therapies, such as transcutaneous electrical nerve stimulation (TENS) and other physiotherapeutic activities, which cause stimulation of the A-fibres, thereby blocking the slower C-fibres and modulating pain. Central neural injury involves injury to any part of the central nervous system from the dorsal root entry zone (DREZ) second-order neurons up to the sensory cortex, i.e. somewhere along the path of the spinoreticulothalamic system. This was historically called ‘central pain’. In cases of such pain, it has been shown that thalamic neurons have an abnormal, spontaneous high-frequency discharge pattern, firing in bursts. This may be the reason why deep brain stimulation (DBS) of the thalamus and motor cortex stimulation are effective to treat central pain.[5,6] Neural injury can be traumatic (blunt, such as crushing; or sharp, such as cutting), avulsive (e.g. brachial plexus injuries); chemical; electrical; or thermal. Regardless of the mechanism, damaged primary afferent neurons undergo similar changes. The injured nerves are sensitised and discharge spontaneously. They may become hypersensitive to noradrenaline, which contributes to the complex regional pain syndrome. As the damaged nerve attempts to regenerate, the regenerating sprouts may produce ectopic discharges. Demyelinated nerve fibres have ‘ephaptic’ electrical transmission, where adjacent fibres activate each other. Isolated demyelinated axons can generate reflected

neural impulses, which move in directions opposite to normal electrical flow; this may cause the ‘buzzing’ feeling some people experience with pain.[4] Peripheral nerve injuries can affect function up to the point of termination in the dorsal horn (Fig. 1) – these abnormal primary neurons sprout and colonise new areas within the dorsal horn. Injured afferent neurons produce different neuropeptides to the ones they normally produce. Injured dorsal root neurons discharge at higher frequencies and more spontaneously than normally.

Surgical techniques

The physician should ensure that treatable causes of the pain have been carefully identified and excluded. Examples include temporomandibular joint disorder, dental disease, malocclusion causing facial pain (incorrectly labelled as trigeminal neuralgia), nerve compression syndromes (carpal tunnel syndrome is the most common), and radicular arm or leg pain of spinal origin (e.g. degenerative cervical spondylotic changes causing burning arm or hand pain). Neuropathic pain should be considered a diagnosis of exclusion, arrived at after diligent, careful screening of a patient. Once pain is confirmed to be refractory to all medical therapy and adjuncts such as music therapy, physiotherapy, and cognitive behavioural therapy, the pain team should consider surgery. The techniques available in the surgical management of pain are summarised in Table 1.[5-12] Surgery can help in the management of pain in the following ways: • by modulating neural function:[5-8] TENS, spinal cord stimulation (SCS), motor cortex stimulation (MCS), and DBS

Table 1. Possible surgical therapies for managing complex pain Lesional procedures

Neuromodulation

Other

• Dorsal root entry zone lesioning • Dorsal rhizotomy • Dorsal root ganglionectomy • Rhizolysis of nerve ganglion • Neurectomy • Stereotactic radiosurgery • Percutaneous radiofrequency gangliolysis • Mechanical balloon gangliolysis • Image-guided tractotomy and nucleotomy • Cordotomy • Midline myelotomy

• Spinal cord stimulation • Peripheral nerve stimulation • Motor cortex stimulation • Cranial nerve stimulation • Deep brain stimulation

• Intrathecal medical therapy • Microvascular decompression

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• by destroying neural function:[12,13] avulsing the afflicted nerve(s), e.g. DREZ lesioning, myelotomy, tractotomy, cingulotomy, or thalamotomy, in the hope of removing the short-circuited, dysfunctional paingenerating nerves from the normal neural system, or interrupting the feedback pathway to the brain. A single injured nerve can be freed up, and the neuroma scar resected. Multiple peripheral nerves may be treated similarly, but rather than operating and injuring several functional nerves, multiple nerves are often treated non-invasively with electrical modulation, using TENS or SCS, located either at the corresponding spinal segment or the DREZ. Similarly, craniofacial pain syndromes, such as trigeminal neuralgia, are successfully treated by moving the pulsating artery that compresses the mandibular nerve in the cerebellopontine angle with microvascular decompression or, in the absence of an offending artery, performing a blockade of the trigeminal ganglion with balloon compression or glycerol rhizolysis.[10,11] If the injury occurs distal to the dorsal root ganglion (DRG) (Fig. 1) – a major relay for sensory/pain input – and it is intact, then reversible modulation more central to the DRG, such as SCS or intrathecal morphine therapy, is possible.[7,9] SCS activates the inhibitory effect of large primary afferent neurons in the dorsal columns, damping the incoming pain signal. If the DRG is injured, it causes corresponding injury to the dorsal columns and renders them unusable to modulation by SCS;[5] any modulation target is then selected ‘deeper’ to this level, e.g. the contralateral thalamus or motor cortex. DREZ lesioning is chosen for plexus or root lesions where the root(s) or plexus has been avulsed from the spinal cord and the DREZ relay cells are hyperactive, which contributes to the pain.[13] DREZotomy is also useful in managing spasticity.[13,14] More central, destructive procedures such as cordotomy and midline myelotomy of the spinal cord are reserved for patients in whom sensory loss is already present (e.g. after complete spinal cord injury) and who experience severe autonomic abnormalities or spasticity. In cases of spinal cord injury, pain is frequently a confounding factor. The physician must always rule out pain caused by ongoing mechanical instability (bony, ligamentous or both). Such pain could be classified as: radicular, segmental (at the level of the injured cord), infrasegmental, or visceral. DREZ lesioning is offered if the injury involves the dorsal columns. If these are intact, SCS is

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suggested. It is important to be sure that the underlying instability or mechanical compression has been dealt with before other therapies are considered.[9] Cerebral causes of pain are rare, but do occur. Peripheral tech niques, such as DREZ lesioning, will not be effective in these cases. A classic example is thalamic pain caused by stroke (DejerineRoussy syndrome), where MCS (sited over the opposite motor cortex) is offered. It is thought to inhibit overactive relay neurons in the thalamus.[5] Long-standing, severe pain is often associated with comorbid disease and spasticity. The comorbidities should be treated aggres sively and therapy for spasticity, such as DREZ lesioning or intrathecal baclofen therapy, can be used with great success to improve the quality of life and improve function.[14] It is important to reiterate at this stage that the patient should be treated – not only his/her pain.

Conclusion

Neuropathic pain is complex and difficult to diagnose and treat. A multidisciplinary team, with expert management and decisionmaking, is key. Surgical treatment is one of the last resorts after maximal dose medical and other therapies have failed, and should be tailored to the type and anatomical level of neural injury. Surgery may be declined to patients who have comorbid psychosis, refractory depression or other conditions. Be aware that patients with chronic pain often self-medicate with elaborate regimens and may be using medications affecting coagulation (aspirin, NSAIDs, and herbal or homeopathic medication). Such self-medication must be screened

out before suggesting any form of surgery, as bleeding in the central nervous system could have devastating effects. Modulation is preferable to ablation, as the former is reversible. However, the surgical technique should be individualised to every case. Time and thought should be given to getting to know the patient and their social and psychological circumstances. Chronic pain management should not be treated in the ‘stampede’ clinics that mostly fill our hospital passages. A caring and unhurried approach is needed with the aid of a multidisciplinary team. 1. Loeser JD, Treede RD. The Kyoto protocol of IASP Basic Pain Terminology. Pain 2008;137(3):473-477. DOI:10.1016/j.pain.2008.04.025 2. World Health Organization.WHO’s Pain Relief Ladder. www.who.int/cancer/palliative/painladder/en/ (accessed 4 August 2016). 3. The British Pain Society. Guidelines for Pain Management Programmes for Adults. London: Churchill House, 2013. 4. Ingram S. Physiologic anatomy of nociception. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:3-11. 5. Sindou M, Maarrawi J, Mertens P. Motor cortex stimulation. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:366-379. 6. Kalia SK, Hamani C, Rezai A, Lozano AM. Deep brain stimulation for chronic pain. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:380-392. 7. Linderoth B, Meyerson BA. Spinal cord stimulation: Mechanisms of action. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:319-333. 8. Harsh V, Viswanathan A. Peripheral nerve stimulation. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:349-353. 9. Tavanaiepour D, Levy RM. An overview of the rational use of intrathecal analgesic therapies. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:393-407. 10. Burchiel K. Microvascular decompression for trigeminal neuralgia. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:425-433. 11. Luther N, Kondziolka D, Lunsford LD. Percutaneous retrogasserian glycerol rhizolysis. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:470-475. 12. Cleary DR, Cetas JS. Overview of destructive neurosurgical procedures for pain. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:521-528. 13. Sindou M. Dorsal root entry zone lesions. In: Burchiel K, ed. Surgical Management of Pain. New York: Thieme, 2015:576-594. 14. Enslin JMN, Fieggen AG. Surgical management of spasticity. S Afr Med J 2016;106(8):753-756. DOI:10.7196/SAMJ.2016.v106i8.11225

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CLINICAL UPDATE

Recipes for obstetric spinal hypotension: The clinical context counts D G Bishop,1 MB ChB, FCA; R N Rodseth,2 MB ChB, FCA, MMed, Cert Crit Care, MSc, PhD; R A Dyer,3 MB ChB, FCA, PhD erioperative Research Group, Department of Anaesthetics, Edendale Hospital, Pietermaritzburg, South Africa, and School of Clinical Medicine, P College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa 2 Perioperative Research Group, Department of Anaesthetics, Grey’s Hospital, Pietermaritzburg, South Africa, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa; and Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio, USA 3 Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: D G Bishop (davidgbishop@gmail.com)

Hypotension following obstetric spinal anaesthesia remains a common and important problem. While recent research advances have brought us closer to the perfect recipe for the obstetric spinal anaesthetic, these advances have not been translated into practical guidelines able to reduce the unacceptable number of fatalities that occur in environments where resources are limited. In South Africa, more than half of anaesthetic deaths are still related to spinal hypotension. A gap exists between the ‘perfect recipe’, developed from a clinical context rooted in resource-rich research environments, and its application and performance in real-world resource-poor environments – conditions experienced by more than 75% of the world’s population. This review attempts to define this knowledge gap and proposes a research agenda to address the deficiencies. S Afr Med J 2016;106(9):861-864. DOI:10.7196/SAMJ.2016.v106i9.10877

Hypotension following obstetric spinal anaesthesia remains a com mon and important problem. Recent advances, including better inci dence delineation,[1] improved understanding of haemodynamics[2,3] and growing clarity on vasopressor choice,[4] have brought us closer to the recipe for the perfect obstetric spinal anaesthetic – the elusive ‘Holy Grail’.[5] Unfortunately, in many resource-limited environments these advances have not been adopted. This may be related to con cerns about generalisability, in part due to known anatomical and physiological differences in populations and minor differences in the studied recipes, and in part to the context in which they are applied. Research advances have not been translated into practical guidelines able to reduce the unacceptable number of fatalities that occur in resource-limited environments. In South Africa (SA) the 2011 - 2013 National Committee for Confidential Enquiry into Maternal Deaths (NCCEMD)[6] reported that more than half of all anaesthetic deaths were still related to spinal hypotension. A gap exists between the ‘perfect recipe’, developed from a clinical context rooted in resourcerich research environments, and its application and performance in

real-world resource-poor environments – conditions experienced by more than 75% of the world’s population.[7] This review attempts to define this knowledge gap and proposes a research agenda to address the deficiencies.

Context is king – the importance of the clinical environment

Why is it necessary to distinguish between differing clinical contexts? There are marked differences in the availability of staff, equipment, drugs and infrastructure across different levels of the health sector. This is tacitly acknowledged by the reluctance to implement some research findings in resource-poor environments. Management strategies need to be adapted to match available clinical skill, drug availability, monitoring capabilities and patient profile. To frame further discussion, we propose a classification of three contexts that potentially require different clinical approaches (Table 1). Resource-poor clinical contexts are limited on multiple fronts. For example, poorer staffing ratios are compounded by a lack of

Table 1. Suggested definitions of clinical context in obstetric anaesthesia Clinical context

Personnel

Equipment

Health system

Resource rich

Dedicated senior anaesthetist with obstetric expertise

Invasive monitoring, full anaesthetic facilities and infusion pumps

Well-assessed and triaged, hydrated and optimised patients. Modern theatres, recovery facilities and good staffing ratios

Resource constrained

Dedicated junior anaesthetist, lacks experience, slower reaction times

Basic monitoring (NIBP/ECG/SpO2) in all cases, anaesthesia machine, infusion pumps usually available

Intermittent-level care – may be dehydrated patients, unrecognised comorbidity. Overloaded systems with delays in accessing theatres

Resource poor

Part-timer/nurse, lack of experience, slower reaction times, divided attention

NIBP, SPO2 in most cases, Ambu bag and oxygen available. No infusion pumps. Inconsistent drug and sundry supply

Not reliably assessed and managed preoperatively. Undetected pathology more likely. Poor theatre design and no recovery facility

NIBP = non-invasive blood pressure; ECG = electrocardiogram; SpO2 = peripheral capillary oxygen saturation.

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expertise and training. The responsible doctor does not necessarily have an understanding of the principles of anaesthesia, and the job is often allocated by default to the doctor or nurse who is unable to perform the surgery. This is further complicated by a lack of available equipment (such as electrocardiographic monitoring) and inconsistent drug supplies. Vasopressor choice is often dictated by availability rather than preference. In addition, the attending doctor is frequently required to perform more than one function, often as both obstetrician and anaesthetist, and will be making rapid assessments of patients in multiple locations in the lead-up to surgery. This increases the likelihood of missing significant obstetric and medical comorbidities and significant dehydration in patients presenting to theatre. Attending doctors may need to administer the initial anaesthetic and also conduct the surgery, being required to monitor the anaesthetic either directly while operating or via a nurse. This scenario applied in 7% of the anaesthetic deaths analysed in a recent national report.[8] The anaesthetist may have very limited experience of general anaesthesia for caesarean section (CS) and therefore inappropriately administer spinal anaesthesia in cases where general anaesthesia is indicated. Management strategies must therefore be tailored to a low-expertise environment with poorly prepared patients and a lack of anaesthetic vigilance. Theoretically, simple preventive strategies such as fixed, low-dose vasopressor infusions may minimise the need for rapid clinician intervention and therefore hold an advantage over strategies highly reliant on clinician intervention.

The SA context

The SA health system includes hospitals from all three contexts. Tertiary hospitals are often well staffed and well equipped, while district-level hospitals, especially in the rural setting, suffer from staffing and equipment deficiencies. Even at regional level, the number of CSs performed outstrips the number of trained anaesthesia providers, creating a relatively resourceconstrained environment. [6] In the Saving Mothers report for 2011 - 2013,[6] three out of every four mothers who died as a result of direct anaesthetic causes received spinal anaesthesia, with ‘small district hospitals contributing disproportionately to anaesthetic related maternal deaths’. This pattern is unusual, as mortality rates generally tend to increase in more specialised centres owing to greater case complexity. In SA this pattern is reversed, with 56% of all deaths occurring in district hospitals, 35% in the regional centres and 8% in the tertiary centres. [6] The majority of women who died in district-level hospitals received a spinal anaesthetic. This pattern has been noted in previous reports,[8] where 64% of all spinal deaths were related to severe uncorrected hypotension. Although the exact case fatality rate for spinal v. general anaesthesia is unknown because denominator data are incomplete, the total number of anaesthetic deaths in SA is increasing, particularly in the group who receive spinal anaesthesia. [6] This represents an area where relatively simple interventions may result in significant changes.

The clinical context and current obstetric evidence

Research on obstetric spinal hypotension has largely been performed under highly standardised research conditions, which do not reflect the broader SA context. There is an intense focus on management of patients by senior clinicians, usually in elective rather than emergency cases and often incorporating highly specialised invasive monitoring. This is a requirement

for high-quality research, where sophisticated methods elucidate an underlying mechanism and are then translated into simple clinical interventions. However, given that these interventions will be applied in a significantly different context, they must still be tested in the real-world setting. While SA has continued to produce internationally recognised research, a gap exists between the research context and the reality of the SA public health sector. There is a need to translate critical research into pragmatic management strategies that target a specific clinical context, and then test these strategies in that environment.

Relevant current literature

Over the past 10 years, significant progress has been made in defining and predicting hypotension, and describing haemodynamic changes during spinal anaesthesia for CS. These insights have all contributed to the development of the current state-of-the-art recipe. We will discuss each of these aspects in turn, focusing on clinical context gaps.

Incidence and definition

The incidence of obstetric spinal hypotension varies according to the definition applied.[1] Klohr et al. [1] found across 63 publi cations that the incidence of spinal hypotension was 27% when defined as a systolic blood pressure (SBP) <70% of baseline, but that it increased to 39% using an SBP of <75% of baseline. Up to 80% of spinal anaesthetics in obstetrics require the use of a vasopressor to treat hypotension. [9] Most of these studies came from resource-rich environments, and there are few studies that look at this incidence in resource-constrained environments. It is reasonable to assume that the incidence and severity of hypotension could be significantly higher in the latter setting. This is important because the NCCEMD process does not address the ‘near-misses’, and therefore does not quantify the true extent of the problem.

Prediction of obstetric spinal hypotension

Avoiding spinal hypotension is important for maternal and fetal safety as well as for maternal comfort, since even minor degrees of hypotension are associated with an increased incidence of intraoperative nausea and vomiting. [10] The prediction of obstetric spinal hypotension has received considerable attention and has recently been the subject of review in a local journal.[11] While a number of practical predictors such as body mass index, maternal age and baseline heart rate have shown potential, results have been conflicting and applied predominantly to elective patients. Autonomic indices such as heart rate variability have also shown promise, [12] but have yet to be translated into a practical clinical tool. Given the high incidence of hypotension,[1,9] research in this area should focus on predicting which patients will have severe hypotension, where outcomes relating to maternal and fetal safety are more likely to be affected. We need simple clinical parameters that identify highrisk patients and can be coupled to preventive strategies or earlier referral to specialist centres. There are no scoring systems in daily use addressing this need.

Haemodynamic changes under spinal anaesthesia

The dominant mechanism behind obstetric spinal hypotension is a reduction in arterial sympathetic tone,[2,3,13,14] although venodilatation probably also plays a role. This hypotension results in an increased heart rate,[3] although a small proportion of patients may respond with hypotension and bradycardia.[15] Better understanding of the

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mechanism of hypotension has led to clinical management moving from a fluid-based strategy towards a vasopressor-based prophylactic strategy supported by fluid co-loading.[16] One study proposed that heart rate may be ‘the best surrogate indicator of cardiac output during spinal anesthesia for cesarean delivery’.[2] This is of particular relevance to the resource-poor setting, where targeting simple surrogate outcomes such as heart rate could be explored for practical implementation in clinical guidelines.

in a number of higher-risk groups, including women undergoing unplanned CS, has not been well elucidated. They went on to state that ‘titrated phenylephrine infusions co-administered with crystalloid should now be recommended for prophylaxis against spinal hypotension’.[16] However, because the context of the research is very specific, it is not clear how to implement this in differing environments.

The choice of vasopressor

Strategies to combat hypotension on a pharmacological basis can be divided into ‘reactive’ or ‘preventive’ approaches. Reactive approaches generally involve early and aggressive treatment with fluid and a vaso pressor bolus in response to a significant decrease in blood pressure. Implicit in these strategies is a vigilant anaesthetist with adequate experience in the field. Many guidelines offer the choice of ephedrine or phenylephrine as the vasopressor, including the National Institute for Health and Care Excellence (NICE)[23] and SA guidelines.[24] These recommendations reflect caution in applying conclusions drawn from research on elective CS in healthy women to the urgent CS in women with comorbidity in different clinical environments. The NICE clinical guidelines for CS[23] state that ‘Women who are having a CS under regional anaesthesia should be offered intravenous ephedrine or phenylephrine, and volume pre-loading with crystalloid or colloid to reduce the risk of hypotension occurring during CS.’ They further recommend that ‘intravenous ephedrine or phenylephrine should be used in the management of hypotension during CS’. One guideline in the UK recommends that anaesthetists should ‘only consider phenylephrine infusion for elective CS and if they have received training in equipment and the technique’. For emergency cases, a bolus technique is recommended.[18] 2004 SA recommendations[24] state that ‘the standard first line and very safe vasopressor is ephedrine’, although later Essential Steps in the Management of Obstetric Emergencies (ESMOE) informal recommendations allow for either ephedrine or phenylephrine to be used. No mention is made of prophylactic vasopressor infusions. It is evident that despite overwhelming evidence for the benefit of prophylactic phenylephrine infusions in elective patients, clinicians are reluctant to implement these findings even in the resource-rich setting in which the research was performed. This was highlighted more than 6 years ago, but continues to be a concern.[17]

In recent years there has been a move towards using phenylephrine as the agent of choice in treating obstetric spinal hypotension.[4] Despite prevailing evidence, practice has been slow to change even in settings with similar resources to those in which the research was conducted. [17] In an excellent editorial, Smiley[17] questioned the reluctance of anaesthetists to embrace the use of phenylephrine and offered several explanations for this. One reason put forward was that the choice is not perceived as ‘being quite a life and death issue’. This argument could be advanced in resource-rich settings where a dedicated anaesthetist is available to respond quickly and appropriately to a decrease in blood pressure, but it may not apply to a less ideal context. Experienced anaesthetists potentially respond more rapidly to signals such as patient symptoms and heart rate, but this cannot be relied upon in settings where there is no dedicated anaesthetist. Preventive strategies that reduce the need for rapid intervention should have important advantages in this context. Prophylactic strategies have not been adopted in SA because of concerns about feasibility in resource-constrained hospitals and about safety in the hands of inexperienced clinical staff, a concern echoed in international guidelines.[18] This concern may be unfounded, given that simple strategies such as fixed-rate, low-dose phenylephrine infusions have a low complication rate and provide improved haemodynamic stability and are therefore particularly suited to the inexperienced anaesthetist. Also, it is only by effective prophylactic use of vasopressors that maternal symptoms due to spinal hypotension can be prevented.

Vasopressor management strategies

Modern strategies for combating obstetric spinal hypotension employ a combination of fluid and a vasopressor. The recommended first-line agent is phenylephrine,[4] with the notable exceptions being the patient who responds to spinal anaesthesia with bradycardia and hypotension, or has undiagnosed cardiac disease and unexpectedly requires positive inotropy. Recent literature has moved the debate from the choice between ephedrine and phenylephrine to the manner in which phenylephrine should be given. This reflects an acceptance of phenylephrine as the drug of choice. Initial work using high phenylephrine infusion rates (100 µg/min) and aggressive fluid co-loading showed that hypotension could be almost eliminated, but at the cost of reactive hypertension.[10,19] Subsequent work with lower-dose phenylephrine infusions supported prophylactic infusions as part of routine CS.[14] Further dose-finding studies suggested that a range of 25 - 50 µg/min seemed to give the most benefit with the fewest side-effects.[20,21] Haemodynamic studies also suggested that targeting the baseline heart rate may be the best way to maintain cardiac output during phenylephrine administration.[2] A recent systematic review concluded that prophylactic phenyl ephrine infusions reduced maternal hypotension, nausea and vomi ting without altering other relevant maternal or neonatal outcomes. [22] The setting of this work is elective CS in healthy patients, in ideal clinical conditions. In a recent editorial, Butwick et al.[16] noted that the potential impact of phenylephrine infusions

Current guidelines

Closing the gap

It is clear that there is a gap between the research clinical context and the application of research to the resource-poor context. In order to close this gap, we need to develop and test models in a broader context and acknowledge the need for context-sensitive management strategies. Table 2 offers some hypothetical contextsensitive guidelines and the rationale for these approaches. These recipes need to be refined and tested with pragmatic studies that evaluate the ability of institutions in differing contexts to achieve success with differing guidelines in resource-limited areas, by conducting well-designed, multicentre studies. In SA this could be accomplished through the establishment of an obstetric anaesthesia research group focused on large pragmatic clinical trials aimed at improving maternal safety during CS. Such a network could be established rapidly by making use of existing structures such as the South African Obstetric Anaesthesia Special Interest Society, the ESMOE and the South African Perioperative Research Group. This network should set national priorities for obstetric anaesthesia research and focus on the SA context. Research centres could be established in resource-limited areas, where potential interventions could be tested in small pilot trials preceding large national pragmatic

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Table 2. Suggested vasopressor recipes based on clinical context Context

Presumption

Fluids

Vasopressor

Notes

Resource rich

Patients hydrated and well assessed, vigilant senior anaesthetist

Co-load

Phenylephrine infusion (start at 50 µg/ min), titrate to effect

Good evidence-based research Target near-normal baseline heart rate and blood pressure

Resource constrained

May be fluid deficit, unrecognised pathology, junior anaesthetist

Consider preload, administer co-load

Phenylephrine infusion (25 µg/min) Titrate if experienced, otherwise run at fixed rate: bolus intermittently and discontinue if reactive hypertension

Applied from research-setting data Good theoretical basis, requires testing in real-world setting

Resource poor

May be fluid deficit and unrecognised pathology, junior anaesthetist, divided attention

Preload/ rehydrate and co-load

Phenylephrine (500 µg) or ephedrine (50 mg) in first litre of crystalloid – run freely then convert to bolus strategy

Lack of evidence for this approach Requires study prior to application

Table 3. Proposed perioperative research agenda for obstetric spinal hypotension Need

Rationale

Validate traditional predictors of spinal hypotension in context and continue to explore novel predictors with practical applicability

Early identification of high-risk patients a priority, enabling appropriate resource allocation via referral and potentially different management strategies

Develop a robust scoring system to identify mothers at risk of hypotension following spinal anaesthesia for CS, using these predictors Develop easily available novel scoring tools (such as the obstetrics shock index) Comparison of a prophylactic vasopressor infusion with a treatment bolus strategy for the management of hypotension following spinal anaesthesia for CS

Safe practical ways to utilise the current knowledge base in resource-poor settings should be tested

Develop simple methods of applying prophylactic vasopressor infusion strategies in resource-poor environments Research the principle of targeting heart rate for the prevention and treatment of hypotension: initially in the academic setting, and then apply to regional centres

Newer techniques first studied in controlled, strictly protocol-driven studies before testing in other contexts

Develop an obstetric research network in SA and agree on a research framework and pathway

Co-ordinating research will enable bigger, multicentre trials, while drawing on experience from established centres

trials. A proposed research agenda for such a programme is outlined in Table 3.

Conclusion

In recent years there have been significant advances in the field of obstetric anaesthesia. High-quality research has outlined the mechanism, described the haemodynamic changes and refined the management of obstetric spinal hypotension. However, there is a gap between this knowledge base and its implementation in real-world settings outside the research environment. We need to acknowledge this gap, and focus on contextualising research findings in a pragmatic fashion. This is best achieved through innovative, collaborative research, starting in academic centres, and applying the findings in the context of limited-resource environments. 1. Klohr S, Roth R, Hofmann T, Rossaint R, Heesen M. Definitions of hypotension after spinal anaesthesia for caesarean section: Literature search and application to parturients. Acta Anaesthesiol Scand 2010;56(7):909-921. DOI:10.1111/j.1399-6576.2010.02239.x 2. Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009;111(4):753-765. DOI:10.1097/ALN.0b013e3181b437e0 3. Langesaeter E, Dyer RA. Maternal haemodynamic changes during spinal anaesthesia for caesarean section. Curr Opin Anaesthesiol 2011;24(3):242-248. DOI:10.1097/ALN.0b013e31818a401f 4. Dyer RA, Biccard BM. Ephedrine for spinal hypotension during elective caesarean section: The final nail in the coffin? Acta Anaesthesiol Scand 2012;56(7):807-809. DOI:10.1111/j.1399-6576.2012.02719.x 5. Macarthur A. Solving the problem of spinal-induced hypotension in obstetric anesthesia. Can J Anaesth 2002;49(6):536-539. DOI:10.1007/BF03017377 6. Pattinson RC, ed. Saving Mothers 2011-2013: The Sixth Report of the National Committee for Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: Government Printer, 2014. 7. Reed A, Mumba JM, Dyer R. A spotlight on obstetric anesthesia in the developing world: Finally getting the attention it deserves. Anesth Analg 2015;120(6):1179-1181. DOI:10.1213/ANE.0000000000000722 8. Rout CC, Farina Z. Anaesthesia-related maternal deaths in South Africa: Chapter Seven of the 5th Saving Mothers Report 2008-2010. South Afr J Anaesth Analg 2012;18(6):281-301. DOI:10.1080/22 201173.2012.10872868

9. Rout CC, Rocke DA. Prevention of hypotension following spinal-anesthesia for cesarean-section. Int Anesthesiol Clin 1994;32(2):117-135. DOI:10.1097/00004311-199400000-00010 10. Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section. Br J Anaesth 2004;92(4):469474. DOI:10.1093/bja/aeh088 11. Bishop DG. Predicting spinal hypotension during caesarean section. South Afr J Anaesth Analg 2014;20(4):170-173. DOI:10.1080/22201181.2015.959336 12. Chamchad D, Arkoosh VA, Horrow JC. Using heart rate variability to stratify risk of obstetric patients undergoing spinal anesthesia. Anesth Analg 2004;99(6):1818-1821. DOI: 10.1213/01. ANE.0000140953.40059.E6 13. Sharwood-Smith G, Drummond GB. Hypotension in obstetric spinal anaesthesia: A lesson from preeclampsia. Br J Anaesth 2009;102(3):291-294. DOI:10.1093/bja/aep003 14. Langesaeter E, Rosseland LA, Stubhaug A. Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: A randomized, double-blind comparison of low-dose versus high-dose spinal anesthesia with intravenous phenylephrine or placebo infusion. Anesthesiology 2008;109(5):856-863. DOI:10.1097/ALN.0b013e31818a401f 15. Kinsella SM, Lohmann G. Supine hypotensive syndrome. Obstet Gynecol 1994;83(5):774-788. 16. Butwick AJ, Columb MO, Carvalho B. Preventing spinal hypotension during caesarean delivery: What is the latest? Br J Anaesth 2015;114(2):183-186. DOI:10.1093/bja/aeu267 17. Smiley RM. Burden of proof. Anesthesiology 2006;111(3):470-472. DOI:10.1097/ALN.0b013e3181b16466 18. Mayer J, Jackson G. Hypotension Management in Obstetric Regional Anaesthesia. Reading, UK: Royal Berkshire Trust, 2015. 19. Ngan Kee WD, Khaw KS, Ng FF. Prevention of hypotension during spinal anesthesia for cesarean delivery: An effective technique using combination phenylephrine infusion and crystalloid cohydration. Anesthesiology 2005;103(4):744-750. 20. Allen TK, George RB, White WD, Muir HA, Habib AS. A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine for hemodynamic support during spinal anesthesia for cesarean delivery. Anesth Analg 2010;111(5):1221-1229. DOI:10.1213/ANE.0b013e3181e1db21 21. Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg 2010;111(5):12301237. DOI:10.1213/ANE.0b013e3181f2eae1 22. Heesen M, Kolhr S, Rossaint R, Straube S. Prophylactic phenylephrine for caesarean section under spinal anaesthesia: Systematic review and meta-analysis. Anaesthesia 2014;69(2):143-165. DOI:10.1111/anae.12445 23. National Institute for Health and Care Excellence (NICE). Caesarean section. NICE guidelines [CG132]. Published November 2011, last updated August 2012. https:www.nice.org.uk/guidance/ cg132 (accessed 25 July 2016). 24. Dyer RA, Rout CC, Kruger AM, van der Vyver M, Lamacraft G, James MF. Prevention and treatment of cardiovascular instability during spinal anaesthesia for caesarean section. S Afr Med J 2004;94(5):367-372.

Accepted 11 April 2016.

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CLINICAL UPDATE

‘Getting under our skin’: Introducing banked allograft skin to burn surgery in South Africa N L Allorto,1 FCS (SA), MMed; A D Rogers,2 FC Plast Surg (SA), MMed; H Rode,3 FCS (SA), FRCS, MMed dendale Hospital Burn Service, Pietermaritzburg; and Department of Surgery, School of Clinical Medicine, College of Health Sciences, E Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 2 Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto; and Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Canada 3 Burn Unit, Red Cross War Memorial Children’s Hospital, Cape Town; and Division of Paediatric Surgery, Department of Surgery, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: A D Rogers (alandavid.rogers@sunnybrook.ca)

Deceased donor skin possesses many of the properties of the ideal biological dressing, and a well-stocked skin bank has become a critically important asset for the modern burn surgeon. Without it, managing patients with extensive burns and wounds becomes far more challenging, and outcomes are significantly worse. With the recent establishment of such a bank in South Africa, the challenge facing the medical fraternity is to facilitate tissue donation so that allograft skin supply can match the enormous demand. S Afr Med J 2016;106(9):865-866. DOI:10.7196/SAMJ.2016.v106i9.10852

Burn injury remains a severely neglected epidemic in South Africa (SA), despite the magnitude of the problem. This has been described by a number of authors, and there is a shift towards addressing the deficits.[1-6] The recent establishment of the first allograft skin bank in SA is potentially a tremendous stride towards moving in line with basic international burn care standards. Experience globally has shown that besides centralising burn care into regional multidisciplinary burn centres, the ready availability of deceased donor allograft skin has been the single most important strategy to reduce both mortality and morbidity.[7-14] The gold standard for managing burn injuries remains excision and autografting using split-skin grafts.[7,11] This skin is either meshed (to obtain greater surface area) or unmeshed (obligatory for hands and faces), depending on the recipient site, but requires available donor sites. Expansion ratios are seldom achieved: 2:1 does not gain 100% more skin coverage, for instance. Since certain areas are unsuitable as donor sites, >50% burns may require repeated harvesting. Because donor sites heal by secondary intention, these areas require considerable physiological resources to heal, and several weeks before they are available for reharvest.

In addition, prolonged surgical interventions have been shown to increase the likelihood of intraoperative hypothermia, blood loss and other complications. As a result, when faced with a major burn, surgeons preferably excise and cover all areas with allograft as soon as possible. Once this is achieved, the patient will regain physiological equipoise, and autograft cover is no longer such an urgent priority, but can be performed in a staged, more effective manner.[8-11] Allograft is also an excellent ‘test of the wound bed’. If the skin ‘takes’, it is probable that the autograft will also take, therefore reducing the likelihood of autograft loss and optimising the critical resource that is the patient’s donor sites. Further debridement can then be performed in sections where the allograft failed to adhere, for instance where debridement was inadequate, or in the presence of infection, fat necrosis, haematoma or seroma.[5-8] Although the most important indication is undoubtedly in the context of the major burn, there are a number of other scenarios where an allograft may contribute substantial value in clinical practice (Table 1).[9,11] Figs 1 - 3 demonstrate the advantage of sheet grafting a dorsal hand burn after debridement, prior to

Table 1. Major indications for deceased-donor allograft Indication

Benefits and application

Major burn

Staged application at debridement, and staged removal when autograft or dermal substitute is to be placed Alexander (sandwich) technique:[12] the application of widely meshed autograft covered by allograft

Small burn injury

Uncertain depth of excision Infection, e.g. burn wound cellulitis Hand and facial burns to optimise sheet autograft take (Figs 1 - 3)

Necrotising soft-tissue infection

Test the wound bed prior to autografting

Exfoliative skin conditions, e.g. toxic epidermal necrolysis

Avoid repeated and painful dressing changes Biobrane is regarded as the first line for this indication

Neoplasm

After excision, awaiting confirmation of adequate margins by pathology service

Complex wound from any cause

Test the wound bed prior to autografting

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Fig. 1. Removal of sheet allograft; areas marked where further debridement is necessary.

Fig. 2. Wound bed after selected further debride ment.

autografting, to optimise graft take, reduce scarring and therefore optimise function. Burn surgeons will only be able to take advantage of this strategy if there are adequate stores of skin, and this will require a significant alteration in the referral system of tissue donors, improved knowledge of the referral process on the part of healthcare professionals, and their participation in it, and the fostering of a culture of tissue dona tion in our society.[11,14,15] Despite declining surgical numbers, organ transplantation is well established in SA;[14,15] in fact, it is internationally acclaimed. Tissue donation, however, is largely unknown as far as the general public and medical fraternity is concerned, with only corneal donation receiving some, albeit insufficient, attention. The few published data in this area locally focus on legal considerations.[15] No effective system exists in state hospitals for the referral of potential tissue donors, and tissue (and organ) donations are predominantly derived from private hospitals. Although attitudes towards tissue donation are generally positive when information is provided, individuals are frequently reluctant to consider donating

the organs of a relative if they do not know that person’s donation preference.[14] It is apparent that campaigns need to be initiated that are inclusive of organs and tissue, and that target both the private and state healthcare sectors. There needs to be a collaborative effort to develop systems in hospitals for referral of tissue donors to the tissue bank (for skin, cornea, bone and heart valves), facilitation of education in all institutions, as well as a national campaign to create awareness of the value of tissue and organ donation. Only then will there be enough allograft skin in the bank to service the enormous number of burn patients requiring an allograft and for whom it will be potentially lifesaving, and the more than 60 other lives per deceased donor that can be enhanced through the application of allograft cornea, heart valves and bone. 1. Rode H, Berg A, Rogers A. Burn care in South Africa. Ann Burns Fire Disasters 2011;24(1):7-8. 2. Rogers AD, Price CE, Wallis L, Rode H. Towards a national burns disaster plan. S Afr J Surg 2012;49(4):174-177. 3. Allorto NL, Zoepke S, Clarke DL, Rode H. Burn surgeons in South Africa: A rare species. S Afr Med J 2016;106(2):186-188. DOI:10.7196/SAMJ.2016.v106i2.9954

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Fig. 3. Sheet autografting. 4. Rode H, Rogers AD, Numanoglu A, et al. A review of primary and secondary burn services in the Western Cape, South Africa. S Afr Med J 2015;105(10):853-857. DOI:10.7196/SAMJnew.8187 5. Rode H, Rogers A, Adams S, et al. The dilemma of treating major burns in South Africa. S Afr Med J 2013;103(9):608-609. DOI:10.7196/SAMJ.7361 6. Rogers AD, Allorto NL, Wallis LA, Rode H. The Emergency Management of Severe Burns course in South Africa. S Afr J Surg 2013;51(1):38. DOI:10.7196/SAJS.1309 7. Janžekovič Z. A new concept in the early excision and immediate grafting of wounds. J Trauma 1970;10(12):11031108. DOI:10.1097/00005373-197012000-00001 8. Kagan RJ, Winter R, Robb EC. The skin bank. In: Herndon DN, ed. Total Burn Care, 4th ed. Edinburgh: Saunders Elsevier, 2012:199-208. 9. Leon-Villapalos J, Eldariri M, Dziewulski P. The use of human deceased donor skin allograft in burn care. Cell Tissue Bank 2010;11(1):99-104. DOI:10.1007/s10561-009-9152-1 10. Chua A, Song C, Chai A, et al. The impact of skin banking and the use of cadaveric skin allografts for severe burn victims in Singapore. Burns 2004;30(7):696-700. DOI:10.1016/j.burns.2004.03.016 11. Rogers AD, Allorto NL, Rode H. Isn’t it time for a cadaver skin bank in South Africa? Ann Burns Fire Disasters 2013;26(3):142-146. 12. Alexander JW, MacMilan BG, Law E, et al. Treatment of severe burns with widely meshed skin autograft and meshed skin autograft overlay. J Trauma 1981;21(6):433-438. 13. Atiyeh BS, Hayek SN, Gunn SW. New technologies for burn wound closure and healing: Review of the literature. Burns 2005;31(8):944-956. DOI:10.1016/j.burns.2005.08.023 14. Etheredge HR, Turner RE, Kahn D. Attitudes to organ donation among some urban South African populations remain unchanged: A cross-sectional study (1993 - 2013). S Afr Med J 2014;104(2):133-137. DOI:10.7196/SAMJ.7519 15. McQuoid-Mason D. Human tissue and organ transplant provisions: Chapter 8 of the National Health Act and its Regulations, in effect from March 2012 – what doctors must know. S Afr Med J 2012;102(9):733-735. DOI:10.7196/SAMJ.6047

Accepted 11 April 2016.

IN PRACTICE

MEDICINE AND THE LAW

Improving the recording of clinical medicolegal findings in South Africa R Jina,1 MB ChB, MMed, PhD; J M KotzĂŠ,2 MB ChB, Dip For Med (SA) Clin 1 2

pidemiology and Surveillance Section, National Institute for Occupational Health, Johannesburg, South Africa E Department of Family Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

Corresponding author: R Jina (ruxana.jina@gmail.com)

Background. The accurate recording of findings in clinical medicolegal cases is important, yet the current J88 form used for this purpose in South Africa has been reported to have many flaws. In addition, there are reports of poor completion of the form, which could in part be due to its poor design and clarity. Objective. To describe the process that was undertaken to revise the current J88 form. Methods. A repetitive consultative process was used to revise the current J88 form and to obtain inputs from relevant government institutions. Results. A brief outline of the changes that have been made to the current J88 form and the reasons why these changes were proposed by national experts is provided. Conclusion. The revised J88 form will provide clearer guidance to healthcare providers on the completion of necessary information in an expedited fashion. It is hoped that the form will soon be approved by the necessary government institutions. S Afr Med J 2016;106(9):872-873. DOI:10.7196/SAMJ.2016.v106i9.11081

Accuracy of medical notes is important, particularly in forensic and clinical medicolegal cases. Any medical record can be presented in court, but many countries have developed special forms to facilitate the process. In South Africa the J88 form, which is owned by the Department of Justice and Constitutional Development (DOJ&CD), is used for this purpose. The latest J88 form has been in use for approximately 17 years, but over time healthcare providers and members of the criminal justice system have noted that it has flaws.[1] Research on rape cases has also shown that there is poor completion of the form, with multiple inaccuracies.[2] There are many potential reasons for this, including untrained or inexpert healthcare providers, the attitude of providers to clinical medicolegal cases, lack of time to complete the form properly, and poor design and language of the form. During the development of a national post-rape training programme for the Department of Health in 2007, the quality of documentation and its presentation in court was noted as a gap in current service delivery.[3] It was noted that parallel to the training programme, efforts had to be made to revise the J88 form so that it could enhance the documentation of clinical medicolegal evidence, even in the case of healthcare providers who had not received the national training. This would help them to complete the form more accurately and appropriately, recording information of relevance without missing any information of importance. At present, the form may be considered confusing with regard to what is important for adult v. child offences, and it raises unreasonable expectations relating to the significance of normal findings. Furthermore, the form requires healthcare providers to complete some additional information that may be considered irrelevant and may cloud understanding by the legal fraternity.

Objective

To describe the process that was undertaken to revise the current J88 form, the changes that have been made to the form, and the

process that has been followed so far to have the new form approved. Although the format of the form has been revised, taking both general and sexual offences into account, this article focuses on sexual offences as this area was considered to be most problematic.

Methods

A repetitive consultative process was used for the revision of the form during each stage when feedback was received. In 2007, at the 8th conference held by the South African Professional Society on the Abuse of Children, Dr Marianne KotzĂŠ, an experienced doctor from the Free State, and Adv. Retha Meintjes from the National Prosecuting Authority (NPA) began a process to have the current J88 form revised. In May 2007, the Gender and Health Unit of the South African Medical Research Council (MRC) became aware of this process and decided to support their work. With assistance from the MRC, a group of national experts comprising doctors and prosecutors met in November 2007 to discuss opinions on the current J88 form and approaches to how to improve it. This was followed by electronic communication whereby a new form was drafted and submitted to Adv. Meintjies in August 2008 for further action. Following this submission, feedback was received from the NPA in July 2009, followed by comments from the DOJ&CD. An individual meeting with an NPA representative was subsequently held in November 2011 to review both sets of comments and agree on an approach to address them. The revised form was extensively circulated to members of the original committee and to representatives in family medicine, emergency medicine and forensic services. Requests were also made for healthcare providers to pilot the form in their relevant working environments. A revised form was resubmitted to the NPA in May 2012, and after a year with no feedback, a motivation for the new form was submitted in October 2013. In March 2015, comments were received from the South African Police Service (SAPS), which were addressed in a submission made in March 2015. This was then followed by a second round of comments from the SAPS in

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IN PRACTICE

December 2015, with a revised form and details of how the comments were addressed being submitted back to the NPA in February 2016.

Results

A number of reasons to revise the form were considered pertinent. The current form does not reflect new research findings and opinions that had evolved extensively since the 1990s. The form also includes certain information that is only relevant to medical care and not the legal case and therefore impinges on patient confidentiality unnecessarily, e.g. age of menarche for female patients and contraceptive history. In other instances, information required could be misinterpreted by defence attorneys in favour of the suspect: for example, if the emotional state of a patient was recorded as normal or calm, could one argue that no offence had taken place? In addition, some of the information required, e.g. number of fingers admitted during the vaginal examination, is considered to be a violation of sexual rights by Human Rights Watch and the practice should be discouraged.[4] Finally, the current form does not adequately address the new definitions of rape.[5] Major changes were made to the design of the form to improve the flow and to replace as much of the form as possible with tick boxes. This was done to minimise the likelihood of healthcare providers leaving sections of the form blank, or writing in inappropriate or illegible information. The form was reorganised in the order of a medical examination, but also so that relevant questions for male and female sexual offences are clearer. At present, many healthcare providers miss pertinent questions that are relevant to male sexual offences/male rape, e.g. actions taken after the sexual offence occurred, as it is placed at the end of section D, which commences with information relevant to female patients only. Similarly, findings for the perineum are only placed with the gynaecological examination, and not included under the anal or male genitalia examination section. Areas that were considered to be poorly completed in previous studies were revised.[2] For example, a clear space is now provided for the history of the alleged offence, encouraging healthcare providers to complete the information on previous medical history more clearly. At present, healthcare providers tend to complete details of the offence in the section on medical history and medication while neglecting to give information on the latter, as no space is provided for reporting of the incident on the current form. Some examples of clinical signs of drug and alcohol intoxication are also provided on the revised form, and this is followed by questions on whether relevant blood and urine samples are collected. Normal, nonspecific or irrelevant findings have also been removed from the gynaecological, male genitalia and anal examination to limit confusion when these are recorded as being present. These include, among others, hymenal bumps, synechiae, smegma, sections for findings on the testes, vas deferens and epididymis, and reflex dilation on anal examination. Some areas have been revised to provide more pertinent information for the legal case. For example, in the current form information is required on the use of condoms in section D 12, but it

is unclear whether this relates to previous consensual encounters, as the question follows information on those encounters, or to the use of condoms during the sexual offence itself. This has now been replaced by a question on whether condoms were used during the offence, and whether any form of lubrication was used. Similarly, information on the menstrual cycle has been replaced by questions on whether the patient was menstruating at the time of the offence, after the offence or during the examination. Sections C 8, F 3, G 22 and H 16 have all been replaced with one conclusion section for the entire examination, inclusive of general assaults and sexual offences. This will allow healthcare providers to make one holistic conclusion pertaining to the patient as a whole. Although there was always a general feeling that the diagrams in the J88 form should be improved, this was not addressed during the revision as the team lacked the necessary drawing skills. However, revisions to the diagrams are still being encouraged, and it is hoped that the DOJ&CD will include this in the process when the form is redesigned and formatted for printing.

Conclusion

The revisions to the J88 form included opinions and input from national experts. However, it has been difficult to obtain consensus in all regards, especially in areas that lack clear scientific evidence, and where personal ideas or experiences sway opinions. This was especially difficult when deciding on the level of detail that is required on the patient’s previous sexual history. However, it is considered that the proposed form will dramatically improve the recording of clinical medicolegal evidence. Owing to the number of role-players involved, inputs have been required from the various parties and this has delayed the process, but healthcare providers who have been part of this process hope that the new form will be approved soon. Research ethics committee approval. As this was not a research study and did not involve any subjects of any kind, ethics approval was not obtained. Acknowledgements. The authors would like to acknowledge Rachel Jewkes, Neil McKerrow, Sagie Naidoo, and all other doctors and nurses who provided inputs on the revised form over the years. A special thanks to Bradley Smith and Retha Meintjes from the NPA, who co-ordinated the submissions and feedback from the various government departments. 1. Müller K, Saayman G. Clinical forensic medicine: Completing the Form J88 – what to do and what not to do. S Afr Fam Pract 2003;45(8):39-43. 2. Vetten L, Jewkes R, Sigsworth R, Christofides N, Loots L, Dunseith O. Tracking Justice: The Attrition of Rape Cases Through the Criminal Justice System in Gauteng. Johannesburg: Tshwaranang Legal Advocacy Centre, South African Medical Research Council and Centre for the Study of Violence and Reconciliation, 2008. 3. Jina R, Jewkes R, Christofides N, Loots L, eds. Caring for Survivors of Sexual Assault: A Training Programme for Health Care Providers in South Africa. Participant’s Manual. Pretoria: National Department of Health, 2008. 4. Kashyap A, Gerntholtz L. Dignity on Trial: India’s Need for Sound Standards for Conducting and Interpreting Forensic Examinations of Rape Survivors. New York: Human Rights Watch, 2010. 5. South Africa. The Criminal Law (Sexual Offences and Related Matters) Amendment Act 32 of 2007. 2007. https://www.issafrica.org/crimehub/uploads/sexual_offences_act32_2007_eng.pdf (accessed 24 July 2015).

Accepted 30 May 2016.

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IN PRACTICE

CLINICAL ALERT

Invasive carbapenem-resistant Enterobacteriaceae infection at a paediatric hospital: A case series O O Malande,1 MB ChB, MMed (Paed), Cert ID (SA) Paed; A du Plessis,2 BPharm; D Rip,3,4 PhD (Biotechnol); C Bamford,3,4 MB ChB, DCH (SA), MPhil (Mat Child Health), FCPath (Microbiol), MMed (Med Microbiol); B Eley,1 MB ChB, FCPaed (SA), BSc Hons aediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital, Cape Town, and Department of Paediatrics and Child Health, P Faculty of Health Sciences, University of Cape Town, South Africa 2 Main Pharmacy, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 3 National Health Laboratory Service, Microbiology Laboratory, Groote Schuur Hospital, Cape Town, South Africa 4 Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: O O Malande (ombevaom@gmail.com)

Background. There are no paediatric reports of invasive infection caused by carbapenem-resistant Enterobacteriaceae (CRE) from Africa. Objectives. To document a series of cases of CRE infections at a tertiary children’s hospital in Cape Town, South Africa, describing the clinical and microbiological findings in these children. Methods. A retrospective, descriptive study was completed using data from a series of children with invasive CRE infection between 2010 and 2015, sourced from their clinical notes and microbiology results. Results. The first of 10 invasive CRE infections during the study period occurred in November 2012. Nine CRE infections were caused by Klebsiella pneumoniae, and one by both K. pneumoniae and Escherichia coli. The median age was 25 months (interquartile range (IQR) 5 - 60). All 10 CRE infections were hospital acquired. The median length of hospitalisation before CRE infection was 28.5 days (IQR 20 44). Eight of the children were exposed to carbapenems during the 12-month period prior to invasive CRE infection. Six were treated with colistin and carbapenem combination therapy, of whom 2 died, including 1 of a non-CRE event. The other 4 children received colistin monotherapy. All these children died, including 2 from non-CRE events. Conclusions. Children with invasive CRE infection and severe underlying disease must be treated with combination antibiotic therapy. Strict infection control practice and antibiotic stewardship are necessary to contain the spread of CRE and limit the number of new infections. S Afr Med J 2016;106(9):877-882. DOI:10.7196/SAMJ.2016.v106i9.11028

Invasive infection caused by carbapenem-resistant Enterobacteria ceae (CRE), first documented in the late 1990s, has become a serious global public health problem.[1] Resistance to carbapenems may result from several mechanisms, including alteration of outer membrane permeability due to loss of porins, upregulation of efflux systems together with extended-spectrum β-lactamases (ESBLs), or commonly the production of carbapenemases.[2] A large number of carbapenemases belonging to all four classes of β-lactamases have been described. However, clinically relevant carbapenemases belong to three of these classes, namely class A β-lactamases such as Klebsiella pneumoniae carbapenemase (KPC) and Guiana extended-spectrum carbapenemase (GES), class B metalloβ-lactamases such as Verona integron-mediated metallo-β-lactamase (VIM), imipenemase (IMP) and New Delhi metallo-β-lactamase (NDM), and class D β-lactamases including oxacillinase (OXA) subtypes such as OXA-48.[3,4] The first CRE invasive infections in South Africa (SA) were reported in adult patients from Gauteng Province in 2011, caused by NDM-1- and KPC-2-expressing K. pneumoniae isolates.[5] Since then, invasive infections caused by CRE-carrying resistance genes of these three classes of β-lactamases have been reported in SA.[6] Publications from the USA, Europe, Asia and the Middle East have begun to describe CRE infection in children.[7-15] Age at presentation ranged from 0 to 18 years, and ~40% (32/79) were <12 months of age. The main types of infection were bloodstream infection, urinary tract infection and soft-tissue infection.[7-15] The crude case fatality rate was 7.4% (5/68).[13-15] A wide spectrum of potential risk factors for CRE infection was identified, including previous admission to an intensive care unit (ICU), hospitalisation for >48 hours, the presence of an indwelling device, underlying medical conditions, necrotising enterocolitis and/or

short-bowel syndrome, solid organ or stem cell transplantation, exposure to immunosuppressants, previous exposure to antibiotics, including third-generation cephalosporins, fluoroquinolones or carbapenems, and previous infection by a multidrug-resistant organism.[13,15] None of these reports was from Africa.

Objectives

To describe a series of cases of CRE at a paediatric hospital and document the clinical and microbiological experience of children with invasive CRE infection in an SA context.

Methods

A retrospective study was completed at Red Cross War Memorial Children’s Hospital (RCWMCH), a tertiary referral hospital in Cape Town that cares for sick children. Microbiology specimens from children treated at RCWMCH are processed at the central National Health Laboratory Service (NHLS) laboratory at Groote Schuur Hospital (GSH), Cape Town. The NHLS microbiology database at GSH was searched for minimum inhibitory concentration (MIC) breakpoints confirming the presence of phenotypic carbapenem resistance of Enterobacteriaceae isolates in patients hospitalised at RCWMCH during the period January 2010 December 2015. The Clinical Laboratory Standards Institute (CLSI) MIC breakpoints used to establish carbapenem susceptibility or resistance in Enterobacteriaceae isolates are summarised in the next section.[16]

Microbiological evaluation

All testing was completed at the NHLS microbiology laboratory, GSH. Identification and susceptibility testing of Enterobacteriaceae

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was carried out primarily with the Vitek 2 system (bioMèrieux, France) using the GN and N133 cards, respectively, supplemented where necessary with E-test (bioMérieux) to confirm the MICs of ertapenem, imipenem and meropenem. The susceptibility of bacterial isolates was evaluated for the following antibiotics: ampicillin, amoxicillin plus clavulanic acid, piperacillintazobactam, cefuroxime, cefoxitin, ceftriaxone, ceftazidime, cefepime, ertapenem, meropenem, imipenem, ciprofloxacin, gentamicin, ami kacin, co-trimoxazole, tigecycline and colistin. Carbapenem susceptibility tests were conducted and interpreted according to the CLSI 2010 - 2015 criteria.[16] MIC breakpoints for Enterobacteriaceae were ≤1 µg/mL (imipenem and meropenem) and ≤0.5 µg/mL (ertapenem) for susceptible isolates, 2 µg/mL (imipenem and meropenem) and 1 µg/mL (ertapenem) for intermediately resistant isolates, and ≥4 µg/mL (imipenem and meropenem) and ≥2 µg/mL (ertapenem) for resistant isolates. Detection of specific carbapenemase genes was carried out by the Centre for Opportunistic, Tropical and Hospital Infections of the National Institute of Communicable Diseases, using in-house polymerase chain reaction assays. DNA was extracted from cultured isolates using the ZR-96 Fungal/Bacterial DNAkit (Zymo Research, Inqaba, SA). The following carbapenemase genes were targeted: blaNDM, blaVIM, blaIMP, blaKPC, blaGES and blaOXA-48-like.

Clinical features of CRE infections

Case definitions

Microbiological characterisation of CRE isolates

Invasive CRE infection was diagnosed when CRE was isolated from any given body site (other than rectal/faecal swab culture) that was associated with clinical manifestations of infection. Hospital-acquired infection was defined as CRE infection detected ≥48 hours after hospital admission and not incubating at the time of hospitalisation. Healthcare-associated infection was defined as CRE infection detected within 48 hours of hospitalisation in children who had contact with the healthcare service, including admission to an intermediate-care facility within the previous 12 months. Community-acquired infection was defined as CRE infection detected within 48 hours of hospital admission without previous contact with the healthcare service.[17]

Data collection

Clinical information was extracted from the hospital records of children with infection caused by CRE, including age, gender, clinical manifestations at the time of the CRE culture result, HIV status, and antibiotic use during the 12-month period preceding CRE infection, antibiotic treatment of the CRE infection and outcome of the CRE infection. Microbiological information on the CRE isolates cultured from children infected or colonised with CRE was extracted from the NHLS microbiology database and included genus and species, results of selective carbapenemase gene screening and the antibiotic sensitivity pattern. All data were entered on standardised datasheets.

Data analysis

Data were transferred anonymously to an Excel 2010 spreadsheet (Microsoft, USA) and analysed using descriptive statistical methods.

Ethical considerations

The study was approved by the Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town (reference number: HREC/REF 909/2014), and was conducted in accordance with the Declaration of Helsinki.

Results

The first invasive CRE infection at RCWMCH was recorded in November 2012. A further 9 children developed invasive infection caused by CRE during the study period, 1 in 2013, 3 in 2014 and 5 in 2015.

The 10 cases in this series are described in detail in Table 1. The median age was 25 months (interquartile range (IQR) 5 - 60). All 10 children were hospitalised for >48 hours before the onset of their CRE infection, implying that all 10 CRE infections were hospital acquired. The median length of hospitalisation before CRE infection was 28.5 days (IQR 20 - 44). Six of the children developed bloodstream infection, 2 manifested with intra-abdominal sepsis, 1 had sepsis and empyema and 1 had deep-seated burn wound infection (Table 1). Four of the 10 children developed CRE infection in the paediatric ICU. Table 2 summarises potential factors contributing to CRE infection. Five children with CRE infection were treated with parenteral colistin (colistimethate sodium, Sanofi), hereafter referred to as colistin) and imipenem combination therapy, and 1 child with colistin and meropenem combination therapy. Of these 6 patients, 1 died of a non-CRE event and one from CRE infection. The remaining 4 children were treated with colistin monotherapy. All died, 2 from CRE infection (patients 3 and 5) and 2 from non-CRE events after treatment with colistin monotherapy (patients 8 and 9) (Table 1). According to the susceptibility profiles of the pathogens causing invasive CRE infection in these patients (Table 3), 1 might have benefited from colistin-carbapenem combination therapy (patient 5), and 2 from colistin-amikacin combination therapy (patients 3 and 8).

Nine CRE infections were caused by K. pneumoniae, while the infection in patient 2 was caused by both K. pneumoniae and Escherichia coli (Table 3). Carbapenamase genes were identified in isolates from 4 of the 8 patients screened. Three and 5 of the 11 isolates were sensitive to meropenem and imipenem, respec tively. None of the isolates was sensitive to ertapenem. Furthermore, 6/11 (54.5%) and 7/11 (63.6%) of the isolates had MICs ≤4 μg/mL for meropenem and imipenem, respectively. All 11 isolates were susceptible to colistin and 5 were sensitive to amikacin.

CRE gastrointestinal colonisation

Between 18 May and 29 July 2013, 48 children who had been treated in the ward where patient 2 manifested with CRE were screened for CRE colonisation by rectal swab culture. Faecal colonisation with CRE isolates carrying the NDM gene was documented in 4/48 (8.3%). One was colonised by a K. oxytoca isolate, 1 by a K. pneumoniae isolate and 2 by E. coli isolates. Of the remaining 44 children, 1 was colonised by a carbapenem-resistant K. pneumoniae isolate carrying a GES gene, and another by a carbapenem-resistant E. coli isolate. This E. coli isolate was Hodge test-positive, suggesting that it produced a carbapenemase, but none of the six common carbapenemase genes was detected.

Discussion

This is one of the very first studies to report on the outcome of invasive CRE infection among children in an African setting. Since the first invasive CRE infection was diagnosed at our hospital in November 2012, there has been a steady increase in the annual number of cases. The emergence of CRE infection to some extent follows a change in the empirical antibiotic policy for hospital-acquired sepsis. At the beginning of 2012, because of escalating numbers of hospital-acquired infections caused by ESBL-producing Enterobacteriaceae, empirical antibiotic cover for hospital-acquired infections was changed from piperacillin-tazobactam plus amikacin to a carbapenem, usually ertapenem or, where appropriate, meropenem.[18,19] High carbapenem exposure during the 12-month period before the development of CRE infection in the 10 patients, together with a general increase in carbapenem use at our hospital over time (data not shown), probably

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4, female

15, female

93, female

6, male

60, female

Age (mo), gender

Patient

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This child was admitted to the ICU on 22/12/2014 with a hot-water burn involving 80% of her body surface area. Initial culture results were negative, and she was transferred to the burns ward on 28/12/2014. Eight days later she developed ESBL-producing K. pneumoniae BSI requiring ceftazidime and ciprofloxacin for 14 days. A repeat blood culture on 15/1/2015 was negative, indicating that the BSI had been effectively treated. CR K. pneumoniae colonisation was documented on a rectal swab on 13/1/2015.

This child with Crigler-Najjar syndrome type 1 was hospitalised on 16/7/2014. After a liver transplantation on 16/7/2014 she was admitted to the ICU and treatment with tacrolimus and methylprednisolone was commenced. She was transferred to a general ward 6 days later in a stable condition. Four days later she experienced fever and deranged liver enzymes, and was commenced on meropenem for presumed sepsis. A blood culture done before meropenem was started was negative.

This child was admitted to a general paediatric ward on 16/7/2014 with pneumonia complicated by a right-sided empyema. She had had a successful liver transplantation at 1 month of age and was receiving tacrolimus and methylprednisolone. Treatment with cefotaxime and ampicillin was commenced. There was no growth on the admission blood culture.

This child with dilated cardiomyopathy, known to the cardiology service, was admitted from home on 29/1/2014 into the ICU with congestive cardiac failure.

This child was admitted directly to the ICU on 27/2/2013 with bowel perfora tion due to NEC. She had been discharged from the GSH-NICU 5 days earlier, having been managed for prematurity and HIV exposure. Partial colectomy and ileostomy were done on 27/2/2013, and meropenem was administered for 21 days for presumed bacterial sepsis. After 3 days in the ICU, she was trans ferred to a general ward for ongoing care. On 21/4/2013 she was readmitted to the ICU with fever and wound infection; meropenem was re-started and continued for 9 days until 29/4/2013, when she was transferred back to the general ward. On day 84 of admission, culture of the laparotomy wound site documented colonisation by CR K. oxytoca and CR Escherichia coli.

This child was hospitalised on 28/10/2012 with multiple liver abscesses due to Entamoeba histolytica, requiring laparotomy and ICU admission. On day 5, ESBL-producing Klebsiella pneumoniae BSI was diagnosed, requiring ertapenem for 12 days. Poor wound healing and dehiscence necessitated 12 additional laparotomies.

Clinical course

Table 1. Description of the case series of CRE infections

On day 29 of admission, while in the paediatric burns ward, the child developed CR-K. pneumoniae BSI.

On day 23 of admission, while still on meropenem, the child developed fever and raised septic markers. A repeat blood culture cultured CRE. This infection was complicated by neutropenia, coagulopathy and deranged renal and liver function.

On day 6 of admission, repeat blood culture for persistent fever and elevated septic markers cultured CRE. This infection was complicated by deranged liver function.

On day 20 of admission, while in the ICU, the child developed septic shock. CRE was documented on blood culture. The infection was complicated by renal failure and coagulopathy.

On day 90 of admission fever and wound infection recurred, accompanied by elevated septic markers and a purulent discharge from the incision site, necessitating a laparotomy. A pus swab from the peritoneal cavity cultured CRE. This infection was complicated by coagulopathy and deranged liver function.

On day 28 of admission while still in the ICU, intraabdominal infection developed. A peritoneal swab obtained at laparotomy cultured CRE. This infection was complicated by septic shock, coagulopathy and deranged liver function.

CRE infection

Continued ...

This infection was successfully treated with colistin and imipenem for 10 days. A repeat blood culture on 31/1/2015 was negative. Three days after completing antibiotics the child developed wound sepsis caused by a drug resistant Pseudomonas aeruginosa isolate. Despite appropriate antibiotic therapy, she died of this new infection on 13/2/2015, 53 days after hospitalisation and 24 days after CRE diagnosis.

Colistin was commenced for the CRE infection. Meropenem was discontinued. However, the child’s condition deteriorated and she died 4 days after diagnosis of CRE infection and 26 days after hospital admission. The cause of death was liver failure with coagulopathy.

The CRE infection was treated successfully with colistin and imipenem for 14 days. The child was discharged 16 days after CRE diagnosis. The total duration of hospitalisation was 24 days.

The CRE infection was treated with 14 days of colistin monotherapy. The clinical condition worsened, and the child died 15 days after CRE diagnosis, and 35 days after admission, from progressive sepsis.

The CRE infection was treated successfully with colistin and imipenem for 10 days. The child was discharged 10 days after CRE diagnosis and 100 days after hospitalisation.

The CRE infection was successfully treated with colistin for 16 days plus imipenem for 14 days. The child was discharged 48 days after CRE diagnosis and 78 days after hospitalisation.

Treatment and outcome

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This child was referred to a general ward from a secondary hospital on 16/8/2015 with newly diagnosed HIV infection and worsening respiratory infection. Two days later he was transferred to the ICU for IPPV. On 29/8/2015 he was started on a 10-day course of ertapenem for a K. pneumoniae BSI. On 9/9/2015 while still in the ICU meropenem and vancomycin was commenced for presumed line sepsis. Despite negative blood cultures, these antibiotics were continued. On routine tracheal aspirate on 7/9/2015, CR K. pneumoniae was cultured.

This child was admitted to the ICU on 7/4/2015 after a hot-water burn involving 40% of her body surface area. She was transferred to the burns ward 5 on 12/4/2015. Two days later she developed a BSI caused by a sensitive K. pneumoniae isolate that was effectively treated. On 2/5/2015, she developed another BSI caused by an ESBL-producing K. pneumoniae isolate, successfully treated with meropenem for 10 days. On 26/5/2015 she developed ESBLproducing Enterobacter cloacae BSI that was successfully treated with colistin and imipenem for 7 days.

This child, on tacrolimus and methylprednisolone following liver transplantation in 2000, was hospitalised on 26/1/2015 with presumed sepsis and started empirically on ampicillin and cefotaxime. She developed pneumonia 4 days later, complicated by left-sided empyema. Antibiotic therapy was changed to ertapenem, and a percutaneous chest drain inserted. Analysis of the pleural fluid showed the presence of acid-fast bacilli; four-drug antituberculosis therapy was commenced and ertapenem changed to meropenem, which was continued for 10 days. Drug-susceptible tuberculosis was confirmed on pleural fluid culture. On 19/2/2015 she received another 8-day course of meropenem for recurrent sepsis.

This child was hospitalised on 29/1/2015 with a hot-water burn involving 75% of her body surface area. On day 8 she was transferred to the ICU after surgical grafting. Two days later while in ICU she developed P. aeruginosa septicaemia that was treated with piperacillin-tazobactum and amikacin.

Clinical course

This infection was successfully treated with colistin for 14 days. On 16/9/2015, the child developed a left-sided corneal abscess caused by P. aeruginosa and treated with gentamicin. However, her general condition deteriorated, resulting in death on 19/9/2015, 165 days after hospitalisation and 30 days after CRE was diagnosed.

On day 135 of admission while in the burns ward, the child developed deep burn wound infection caused by CRE.

The child was commenced on colistin on 18/9/2015 and meropenem was continued. However, his condition deteriorated and he died on the same day that CRE infection was diagnosed and 33 days after hospitalisation.

CRE infection was treated with colistin for 8 days. The child improved in response to antibiotic therapy. However, 14 days after CRE was diagnosed she deteriorated with worsening liver function, coagulopathy and renal failure. She died of liver and renal failure on 14/4/2015, 39 days after CRE diagnosis and 78 days after hospitalisation.

On day 44 of admission the child developed septic shock necessitating ICU admission. Blood cultures were negative, but pleural empyema fluid cultured CRE. This infection was complicated by coagulopathy and deranged liver function.

On 18/9/2015 the child developed septic shock. The blood culture grew CRE. This infection was complicated by coagulopathy, renal failure and liver failure.

The CRE infection was treated successfully with colistin and imipenem for 14 days. The child was discharged 48 days after CRE infection and 63 days after hospitalisation.

Treatment and outcome

On day 18 of hospitalisation and day 6 of ICU admission, she experienced persistent fever while still on antibiotic therapy. Repeat blood culture cultured CR K. pneumoniae.

CRE infection

BSI = bloodstream infection; NEC = necrotising enterocolitis; GSH-NICU = Groote Schuur Hospital neonatal intensive care unit; CR = carbapenem-resistant; IPPV = intermittent positive-pressure ventilation.

5, male

198, female

35, female

44, female

Age (mo), gender

Patient

Table 1. (continued) Description of the case series of CRE infections

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Table 2. Potential factors contributing to CRE infection (N=10) Factor

n (%)

Corresponding cases as shown in Table 1

Transfer in from another hospital

2 (20)

1, 10

Colonisation with CRE within 6 months of invasive CRE infection

3 (30)

2, 6, 10

HIV infection

1 (10)

Parenteral nutrition at the time of CRE infection

2 (20)

1, 2

Exposure to carbapenems during the preceding 12 months

8 (80)

1, 2, 3, 4, 5, 8, 9, 10

Exposure to cephalosporins during the preceding 12 months

5 (50)

2, 3, 4, 5, 6

Exposure to fluoroquinolones during the preceding 12 months

5 (50)

3, 4, 5, 6, 9

Age <1 year

4 (40)

2, 3, 4, 10

ICU admission within the month preceding CRE infection

8 (80)

1, 2, 3, 5, 6, 7, 9, 10

Surgical procedures/operations within the month preceding CRE infection

6 (60)

1, 2, 4, 6, 7, 8

Central intravenous catheterisation within the month preceding CRE infection

4 (40)

2, 3, 5, 6

Hospitalisation for a period of >14 days within the 6 months preceding CRE infection

8 (80)

1, 2, 3, 5, 7, 8, 9, 10

Two or more hospital admissions within the 12 months preceding CRE infection

3 (30)

3, 5, 8

Immunosuppressive therapy, including glucocorticosteroid therapy, for ≥3 months at the time of CRE infection

3 (30)

4, 5, 8

Table 3. Microbiological characteristics of CRE isolates Patient

Specimen type

Carbapenem-resistant pathogens

Carbapenemase gene

MICs

Antibiotic susceptibility profile

Peritoneal swab

K. pneumoniae

Negative

Meropenem: 1 µg/mL Imipenem: 1 µg/mL Ertapenem: >8 µg/mL

Meropenem, imipenem, colistin

Peritoneal swab

E. coli

blaNDM

Meropenem: 2 µg/mL Imipenem: 4 µg/mL Ertapenem: >8 µg/mL

Tigecycline, colistin

Peritoneal swab

K. pneumoniae

blaNDM

Meropenem: <1 µg/mL Imipenem: <1 µg/mL Ertapenem: 1 µg/mL

Amikacin, imipenem, meropenem, tigecycline, colistin

Blood culture

K. pneumoniae

blaGES

Meropenem: >32 µg/mL Imipenem: >32 µg/mL Ertapenem: >8 µg/mL

Amikacin, colistin

Blood culture

K. pneumoniae

Negative

Meropenem: 8 µg/mL Imipenem: 2 µg/mL Ertapenem: >8 µg/mL

Ciprofloxacin, tigecycline, colistin

Blood culture

K. pneumoniae

Negative

Meropenem: 4 µg/mL Imipenem: 1 µg/mL Ertapenem: >8 µg/mL

Imipenem, tigecycline, colistin

Blood culture

K. pneumoniae

blaNDM

Meropenem: >16 µg/mL Imipenem: >16 µg/mL Ertapenem: >8 µg/mL

Colistin

Blood culture

K. pneumoniae

Negative

Meropenem: 2 µg/mL Imipenem: 0.5 µg/mL Ertapenem: >8 µg/mL

Amikacin, imipenem, colistin

Pleural fluid

K. pneumoniae

blaNDM

Meropenem: > 32 µg/mL Imipenem: >32 µg/mL Ertapenem: >8 µg/mL

Amikacin, colistin

Burn tissue swab

K. pneumoniae

Not done

Meropenem: >16 µg/mL Imipenem: >32 µg/mL Ertapenem: >8 µg/mL

Colistin

Blood culture

K. pneumoniae

Not done

Meropenem: 0.5 µg/mL Imipenem: 0.5 µg/mL Ertapenem: >8 µg/mL

Ciprofloxacin, amikacin, imipenem, meropenem, gentamicin, colistin

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contributed to the emergence of carbapenem-resistant isolates in the local microflora. Other contributory factors include exposure to other antibiotic classes, particularly cephalosporins and fluoroquinolones, prolonged hospitalisation (for ≥4 weeks) before the development of CRE infection in 6 of the 10 children, prior faecal colonisation with CRE in 3 patients, and suboptimal infection control practice.[20] Inadequate infection control practice was demonstrated during the investigation of contacts of patient 2. Of 48 children who were in contact with this patient, 4 were asymptomatically colonised with Enterobacteriaceae carrying the same carbapenemase gene as patient 2. We cannot be certain that colonisation occurred as a result of direct transfer from patient 2. However, it is likely that some were colonised through direct transfer, given that CRE is easily transmitted between humans if adequate containment measures are not implemented, and because these children were managed in close proximity to patient 2. [21] Colonisation of multidrug-resistant pathogens, including CRE, may persist for lengthy periods. In one study of 51 infants colonised with ESBL-producing K. pneumoniae, the median faecal carriage time was 12.5 months and carriage persisted for up to 24 months.[22] In another study, of adults in post-acute facilities, faecal carriage of carbapenemresistant K. pneumoniae persisted for >10 months in 30% of colonised patients. [23] Persistent carriage is therefore an important reservoir for the spread of these organisms. Screening also identified 2 patients in contact with patient 2 who were colonised by CRE isolates unrelated to that of patient 2, indicating that asymptomatic faecal carriage among hospit alised children may be widespread, and may have contributed to the emergence of CRE infections at our hospital. Prolonged hospitalisation and previous admission to an ICU in most of our patients provided the opportunity for acquiring CRE from asymptomatic carriers. In vitro studies have shown enhanced activity against CRE isolates with antibiotic combination therapy.[4] Observational studies have documented inconsistent outcomes following mono- or combined therapy. In one review of case reports and case series, polymyxin monotherapy was associated with higher treatment failure rates than combination therapy.[24] However, a systematic review of 20 nonrandomised studies showed a mortality rate of up to 67% among patients who received colistin-carbapenem combination therapy; among patients treated with monotherapy, the mortality rate was up to 57% for colistin and up to 80% for tigecycline.[25] Observational studies suggest that combination therapy is superior in patients with severe infections caused by CRE.[4,26] Despite these inconsistencies, there is strong support for using combination therapy when treating invasive CRE infection. Various combinations have been used, including colistin plus a carbapenem, colistin plus tigecycline, colistin plus an aminoglycoside, or colistin plus a carbapenem plus tigecycline. When combining colistin with a carbapenem, an additive effect may be achieved if the carbapenem MIC is ≤4 μg/mL and possibly if it is ≤8 μg/mL.[4] Six of the children in the current case series were treated with combination therapy comprising colistin plus a carbapenem. In 5 of these, the MICs of the carbapenem-resistant isolates for imipenem and/or meropenem were ≤4 μg/mL. The isolate of the remaining child (patient 6) had very high meropenem and imipenem MICs. This child’s CRE infection was treated successfully, but she died of a subsequent Pseudomonas aeruginosa infection (Table 1). All 4 children who were treated with colistin monotherapy died. The antibiotic sensitivity profiles of their isolates (Table 3) showed that combination antibiotic options existed for 3 of these children. Why combination therapy was not prescribed is not clear from their clinical notes. Six of the 10 children died, 3 from non-CRE-related events after the treatment of their CRE infections. The CRE-related mortality rate of 30% was higher than the crude mortality reported in recent paediatric studies, but lower than the mortality recorded in many

adult studies.[4,13-15,25] Higher mortality in the present case series may be due to the small sample size, severe underlying illness, and the administration of colistin monotherapy to 40% of the children.

Conclusions

This study has provided useful insights about the patients who acquire CRE infection at our hospital and their response to treatment. Until randomised controlled trials define optimal treatment strategies, CRE infection manifesting in children with severe underlying disease such as those described in our case series must be treated with combination antibiotic therapy to optimise outcomes. Attention should be focused on improving infection control practice to contain the spread of CRE isolates, and intensifying antibiotic stewardship to reduce unnecessary antibiotic selection pressure and in so doing restrict the number of CRE infections. Acknowledgements. The authors thank all the children in this study, their caregivers and the medical personnel who attended to them. 1. Yigit H, Queenan AM, Anderson GJ, et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 2001;45(4):1151-1161. DOI:10.1128/AAC.45.4.1151-1161.2001 2. Chen L, Mathema B, Chavda KD, et al. Carbapenemase-producing Klebsiella pneumoniae: Molecular and genetic decoding. Trends Microbiol 2014;22(12):686-696. DOI:10.1016/j.tim.2014.09.003 3. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 2011;17(10):1791-1798. DOI:10.3201/eid1710.110655 4. Tängdén T, Giske CG. Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: Clinical perspectives on detection, treatment and infection control. J Intern Med 2015;277(5):501-512. DOI:10.1111/joim.12342 5. Brink AJ, Coetzee J, Clay C, et al. Emergence of New Delhi metallo-beta-lactamase (NDM-1) and Klebsiella pneumoniae carbapenemase (KPC-2) in South Africa. J Clin Microbiol 2012;50(2):525-527. DOI:10.1128/JCM.05956-11 6. Brink AJ, Coetzee J, Clay C, et al. The spread of carbapenem-resistant Enterobacteriaceae in South Africa: Risk factors for acquisition and prevention. S Afr Med J 2012;102(5):599-601. 7. Marchaim D, Navon-Venezia S, Schwaber MJ, et al. Isolation of imipenem-resistant Enterobacter species: Emergence of KPC-2 carbapenemase, molecular characterization, epidemiology, and outcomes. Antimicrob Agents Chemother 2008;52(4):1413-1418. DOI:10.1128/AAC.01103-07 8. Cendejas E, Gómez-Gil R, Gómez-Sánchez P, et al. Detection and characterization of Enterobacteriaceae producing metallo-beta-lactamases in a tertiary-care hospital in Spain. Clin Microbiol Infect 2010;16(2):181-183. DOI:10.1111/j.1469-0691.2009.02888.x 9. Oteo J, Hernández-Almaraz JL, Gil-Antón J, et al. Outbreak of vim-1-carbapenemase-producing Enterobacter cloacae in a pediatric intensive care unit. Pediatr Infect Dis J 2010;29(12):1144-1146. DOI:10.1097/INF.0b013e3181efaa2d 10. Seema K, Ranjan Sen M, Upadhyay S, et al. Dissemination of the New Delhi metallo-β-lactamase-1 (NDM-1) among Enterobacteriaceae in a tertiary referral hospital in north India. J Antimicrob Chemother 2011;66(7):1646-1647. DOI:10.1093/jac/dkr180 11. Marchaim D, Chopra T, Perez F, et al. Outcomes and genetic relatedness of carbapenem-resistant entero bacteriaceae at Detroit medical center. Infect Control Hosp Epidemiol 2011;32(9):861-871. DOI:10.1086/661597 12. Little ML, Qin X, Zerr DM, et al. Molecular diversity in mechanisms of carbapenem resistance in paediatric Enterobacteriaceae. Int J Antimicrob Agents 2012;39(1):52-57. DOI:10.1016/j. ijantimicag.2011.09.014 13. Logan LK. Carbapenem-resistant Enterobacteriaceae: An emerging problem in children. Clin Infect Dis 2012;55(6):852-859. DOI:10.1093/cid/cis543 14. Limbago BM, Rasheed JK, Anderson KF, et al. IMP-producing carbapenem-resistant Klebsiella pneumoniae in the United States. J Clin Microbiol 2011;49(12):4239-4245. DOI:10.1128/JCM.05297-11 15. Dirajlal-Fargo S, DeBiasi R, Campos J, et al. Carbapenem-resistant Enterobacteriaceae in pediatric patients: Epidemiology and risk factors. Infect Control Hosp Epidemiol 2014;35(4):447-449. DOI:10.1086/675593 16. Clinical Laboratory Standards Institute. Performance Standard for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. CLSI document MI00-S22. Wayne, PA: CLSI, 2012. 17. Cardoso T, Almeida M, Friedman ND, et al. Classification of healthcare-associated infection: A systematic review 10 years after the first proposal. BMC Med 2014;12:40. DOI:10.1186/1741-701512-40 18. Lochan H, Bamford C, Eley B. Blood cultures in sick children. S Afr Med J 2013;103(12):918-920. DOI:10.7196/SAMJ.6979 19. Nuttall J, Whitelaw A. Red Cross War Memorial Children’s Hospital (RCWMCH) antimicrobial recommendations. 2012. http://www.paediatrics.uct.ac.za/sites/default/files/image_tool/images/38/ Antimicrobial_Recommendations_2012.pdf (accessed 12 December 2015). 20. Guh AY, Limbago BM, Kallen AJ. Epidemiology and prevention of carbapenem-resistant Enterobacteriaceae in the United States. Expert Rev Anti Infect Ther 2014;12(5):565-580. DOI:10.1 586/14787210.2014.902306 21. Centers for Disease Control and Prevention. Facility Guidance for control of carbapenem-resistant Enterobacteriaceae (CRE). November 2015. http://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf (accessed 10 December 2015). 22. Löhr IH, Rettedal S, Natås OB, et al. Long-term faecal carriage in infants and intra-household transmission of CTX-M-15-producing Klebsiella pneumoniae following a nosocomial outbreak. J Antimicrob Chemother 2013;68(5):1043-1048. DOI:10.1093/jac/dks502 23. Ben-David D, Masarwa S, Navon-Venezia S, et al. Carbapenem-resistant Klebsiella pneumoniae in postacute-care facilities in Israel. Infect Control Hosp Epidemiol 2011;32(9):845-853. DOI:10.1086/661279 24. Lee GC, Burgess DS. Treatment of Klebsiella pneumoniae carbapenemase (KPC) infections: A review of published case series and case reports. Ann Clin Microbiol Antimicrob 2012;11:32. DOI:10.1186/1476-0711-11-32 25. Falagas ME, Lourida P, Poulikakos P, et al. Antibiotic treatment of infections due to carbapenemresistant Enterobacteriaceae: Systematic evaluation of the available evidence. Antimicrob Agents Chemother 2014;58(2):654-663. DOI:10.1128/AAC.01222-13 26. Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: Superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012;56(4):2108-2113. DOI:10.1128/AAC.06268-11

Accepted 11 May 2016.

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CLINICAL ALERT

Human brucellosis in South Africa: Public health and diagnostic pitfalls J M Wojno,1,2 MB BCh, FCPath (SA), MMed Path (Microbiol); C Moodley,1,2 BSc Hons, PhD (Mol Cell Biol); J Pienaar,3 BVSc; N Beylis,1,2 MB BCh, FCPath (Microbiol); L Jacobsz,4 MB ChB, MMed (Clin Path); M P Nicol,1,2 MB BCh, MMed Path (Microbiol), DTM&H, FCPath (Microbiol), PhD; J Rossouw,5 BSc Hons, MSc, PhD (Microbiol Plant Pathol); C Bamford,1,2 MB ChB, FCPath (Microbiol), MMed Path (Microbiol) ational Health Laboratory Service, Microbiology Laboratory, Groote Schuur Hospital, Cape Town, South Africa N Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa 3 Department of Agriculture, Forestry and Fisheries (Animal Health: Beaufort West), Western Cape, South Africa 4 National Health Laboratory Service, George Hospital, Western Cape, South Africa 5 Special Bacterial Pathogens Reference Laboratory, Centre for Emerging and Zoonotic Diseases, National Institute for Communicable Diseases, Sandringham, Johannesburg, South Africa 1 2

Corresponding author: J M Wojno (tina.wojno@gmail.com)

Human brucellosis in South Africa (SA) is under-diagnosed and under-reported. This is because many clinicians have little or no experience in managing affected patients, and in part because of the nonspecific and insidious nature of the disease. A case of human brucellosis caused by Brucella melitensis in a patient from the Western Cape Province of SA is described, and the resulting exposure of staff members at two medical microbiology laboratories, as well as the public health investigation that was conducted, are discussed. The objective of this article is to highlight the need for strengthening integration between public health, medical and veterinary services and exposing deficiencies in public health, veterinary and laboratory practices. S Afr Med J 2016;106(9):883-885. DOI:10.7196/SAMJ.2016.v106i9.11020

Brucellosis is a zoonotic infection mainly affecting farm animals such as cattle, sheep and goats. Brucella species primarily infect the reproductive tract, causing spontaneous abortions and infertility in livestock. Brucellosis has a worldwide distribution, but is most prevalent in areas with poorly established domestic animal and public health programmes.[1,2] According to the US Centers for Disease Control and Prevention, Africa is among the areas most commonly affected. Human brucellosis is thought to be considerably under-diagnosed, and although it is a notifiable disease in South Africa (SA), as in many parts of the world, it is probably under-reported.[1] Fig. 1 indicates the estimated seroprevalence of B. abortus in animals in SA. No formal B. melitensis surveillance occurs in SA. Humans are infected with Brucella by contact with sick animals or infected animal products. Organisms can be inoculated via cuts and/ or abrasions when handling infected animal carcasses or products of conception, or inhaled as aerosols during these and other procedures. Ingestion of unpasteurised milk/dairy products or undercooked meat can also lead to infection. High-risk individuals include farmers, veterinarians, abattoir workers and meat handlers.[2] Laboratory workers are also at risk if inadvertently exposed to live cultures of Brucella. Most cases of human brucellosis are caused by B. melitensis, which is the species associated with more severe disease. The usual animal reservoirs for Brucella are sheep and goats (B. melitensis), cattle (B. abortus), and pigs (B. suis). Disease in humans may have an acute or subacute onset, with the illness having a propensity to become chronic and relapsing. Brucellosis is a systemic disease, usually presenting as a febrile illness with constitutional symptoms such as anorexia, malaise, headaches and chills. The patient may complain of arthralgia and back pain, as well as abdominal pain. Clinical findings include lymphadenopathy and hepatosplenomegaly. Up to 40% of

patients with brucellosis have osteoarticular complications. [2] Chronic brucellosis is difficult to treat, requiring prolonged antibiotics and in some cases surgery. A definitive diagnosis of Brucella infection is established by isolating the organism from blood, bone marrow, cerebrospinal fluid, tissue, pus or other relevant samples.[2] A presumptive identification of the cultured isolate can be made using basic biochemical tests and colonial morphology. Cultured isolates should be referred to a specialised facility for further confirmatory testing and speciation, which can be done using molecular methods such as the Brucellaspecific, Bruce-ladder multiplex polymerase chain reaction (PCR) and biotyping.[1,3,4]

Case report

A 27-year-old man from a town in the Great Karoo, Western Cape Province, SA, initially presented to a local district hospital in November 2014 with a history of lower back pain and fever with new onset of vomiting and diarrhoea. On examination he appeared chronically unwell and had abdominal tenderness. Initial blood results showed pancytopenia, a normocytic, normochromic anaemia, and mildly elevated transaminases and canalicular enzymes. An abdominal ultrasound scan revealed diffuse hepatosplenomegaly with no granulomas or other focal lesions. One of two blood cultures sent by the regional hospital was positive for Gram-negative bacilli after 3 days of incubation. This provisional result was communicated to the treating clinician, who commenced ceftriaxone empirically. The bone marrow report showed prominent serous atrophy and listed common causes for this, which included chronic illnesses such as carcinoma, tuberculosis and other chronic infections. No granulomas were observed. On provisional testing of the cultured isolate, Brucella was suspected and the national and provincial departments of health were notified,

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prompting a veterinary investigation. An in-depth history revealed that the patient had regularly fed his dog with cattle, sheep and goat abattoir waste that was disposed of at an open-access municipal waste site in the local town. There was no history of consumption of unpasteurised milk. The cultured isolate was subsequently confirmed to be B. melitensis by the Department of Veterinary Tropical Disease at the Uni versity of Pretoria, using Bruce-ladder multiplex PCR.[3] Biotyping performed by the Agricultural Research Council-Onder stepoort Veterinary Institute identified the isolate as B. melitensis biovar 1.[4]

Laboratory exposure

By the time Brucella was suspected as the infecting agent, staff at two medical micro biology laboratories involved had potentially been exposed. Management of staff, which included post-exposure prophylaxis, varied depending on the risk category.[5] The exposed laboratory workers were followed up by occupational health and safety staff for 24 weeks. A total of 75 laboratory staff/visitors were identified as having been exposed to the organism. To make a serological diagnosis of Brucella, paired sera are collected at least 2 - 4 weeks apart looking for a four-fold or greater rise in antibody titre.[6] There are numerous commercial kits and serological methods commonly used and recommended, including the Rose Bengal test, serum tube agglutination and enzyme-linked immunosorbent assay (ELISA). [2] Serological testing using an ELISA, MASTAZYME BRUCELLA (MAST Diagnostics, UK), was performed for all exposed staff members at baseline and then at 6 and 24 weeks.[6] Five staff members had borderline or lowlevel positive IgG or IgM levels detected on serological testing at baseline. Repeat testing of the same samples as well as repeat samples sent 3 - 4 weeks later revealed considerable variability, particularly in IgM results. In the absence of local studies to determine appropriate cut-off values in SA, and in view of the known intrinsic variability of IgM assays as well as known cross-reactivity with Enterobacteriaceae, borderline results can be difficult to interpret. Failure to demonstrate a (four-fold or greater) rise in the titre for specific antibody in paired sera usually excludes recent infection.[6] None of the staff members tested had significant increases in titre (four-fold or greater rise in immunoglobulins) over the 24-week period. All exposed staff members remained asymptomatic throughout the 6-month follow-up period. Informed consent was obtained from the patient, and the study was approved by

the Human Research Ethics Committee, University of Cape Town, SA (HREC REF: 220/2015).

Veterinary investigation

The state veterinarian’s investigation revealed that two other people who had lambed goats on a nearby farm in 2014 had become ill and were subsequently diagnosed with brucellosis, based on serological testing. The state veterinarian placed the farm under quarantine and initiated sampling of the cattle, sheep and goats. Animals on surrounding farms were also sampled. Serological testing using either the Rose Bengal test or the complement fixation test was performed. These methods detect nonspecific antibodies to both B. melitensis and B. abortus. Of the 100 goats sampled on the farm in question, 44 tested positive for Brucella on serological testing. All animals on the farm were quarantined, but none had been sacrificed at the time of writing and no samples were available for culture and confirmation of the Brucella species. As goats do not contract B. abortus, it was concluded that the most likely strain causing the outbreak was B. melitensis. No animals on other surrounding farms had tested positive for Brucella at the time of writing.

Discussion

The Department of Agriculture, Forestry and Fisheries relies on notifications of diseases and important epidemiological incidents from veterinarians. The first documented cases of veterinary B. melitensis in SA were in sheep in 1965 in the Transvaal Province.[7]

Vaccination is the foundation of a functional Brucella control programme in livestock. This involves the B. abortus strain 19 (S19) and B. abortus RB51 vaccines for cattle and B. melitensis Rev. 1 vaccine for sheep and goats. These are both live attenuated vaccines with the potential of being pathogenic to humans if not administered appropriately. [1,8] Vaccination regulations in SA as stipulated by the Animal Diseases Act 35 of 1984 have specific guidelines on vaccination of animals against Brucella. There are currently no safe, efficacious vaccines recommended for routine use in prevention of brucellosis in at-risk humans. Prevention strategies therefore require robust animal programmes and adherence to prevention/eradication and control protocols.[1] From a public health perspective, the key targets would be the prevention of infection due to direct/indirect contact with infected livestock or live vaccines and prevention of food-borne illness, as well as strengthening the diagnosis and management of human cases with increased awareness and safe laboratory practices when Brucella species are suspected. From a veterinary perspective, occupational hygiene involves safe injection practices for animals, monitoring and surveillance of disease in livestock, and having adequate protocols in place to manage an outbreak effectively. The prevention of food-borne illness includes community education campaigns around the consumption of unpasteurised dairy products or undercooked meat. Patients with brucellosis often present with nonspecific signs and symptoms. Symptoms may persist for weeks to months. In the context of a country with a high

Fig. 1. Map of SA indicating outbreaks of Brucella abortus in animals, 2010 - 2014 (courtesy of the Department of Agriculture, Forestry and Fisheries, SA).

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prevalence of tuberculosis and HIV infection, patients presenting with features of chronic brucellosis may be misdiagnosed and mistreated. As outbreaks of B. melitensis in animals in SA are generally infrequent[9] and human cases are even less common, there is a lack of awareness among clinicians and laboratory staff, who have limited experience in diagnosing and handling this organism, with subsequent delay in diagnosis. A high index of suspicion and a proper social and exposure history are therefore essential in making a timely diagnosis. Effective communication between the clinician and the laboratory regarding suspected infections is imperative to ensure that all biological samples are handled appropriately. The testing laboratory should have protocols in place to ensure staff safety and maintain good safety practices. When working with a World Health Organization biosafety risk level 3 organism such as Brucella, all work should also be performed in an appropriate biosafety cabinet, in a biosafety level 3 facility, by individuals trained for this work.[10]

Conclusion

A multidisciplinary Brucella control programme can be effective in preventing human infections with an approach that integrates three key elements: veterinary service, public health, and the medical healthcare system.

Acknowledgements. We thank Antuan van Rooyen, Braam Muller, Chad Centner, John Simpson, Noluthando Masiza, Odette Abrahams, Henriette van Heerden, staff at the National Health Laboratory Service, Microbiology, Groote Schuur Hospital and Immunology, Tygerberg Hospital, staff at the National Institute for Communicable Diseases, Noel Nel, Monika Esser, Charlene Jacobs, Sunelle Strydom, and the Department of Agriculture, Forestry and Fisheries. 1. Godfroid J, Scholz HC, Barbier T, et al. Brucellosis at the animal/ecosystem/human interface at the beginning of the 21st century. Prev Vet Med 2011;102(2):118-131. DOI:10.1016/j. pretvetmed.2011.04.007 2. Corbel MJ. Brucellosis in Animals. Geneva: World Health Organization, 2006:13-41. 3. Garcia-Yoldi D, Marin CM, de Miguel MJ, et al. Multiplex PCR assay for the identification and differentiation of all Brucella species and the vaccine strains Brucella abortus S19 and RB51 and Brucella melitensis Rev1. Clin Chem 2006;52(4):779-781. DOI:10.1372/clinchem.2005.062596 4. Whatmore AM. Current understanding of the genetic diversity of Brucella, an expanding genus of zoonotic pathogens. Infect Genet Evol 2009;9(6):1168-1184. DOI:10.106/j.meegid.2009.07.001 5. Centers for Disease Control and Prevention. Assessing laboratory level risk level and PEP. http://www. cdc.gov/brucellosis/laboratories/risk-level.html (accessed 12 March 2015). 6. Centers for Disease Control and Prevention. Serology. http://www.cdc.gov/brucellosis/clinicians/ serology.html (accessed 12 March 2015). 7. Emslie FR, Nel JR. An overview of the eradication of Brucella melitensis from KwaZulu-Natal. Onderstepoort J Vet Res 2002;69(2):123-127. 8. Avila-Calderon, Lopez-Merino A, Sriranganathan N, et al. A history of the development of Brucella vaccines. Biomed Int 2013;2013(743509):1-8. DOI:10.1155/2013/743509 9. National Institute for Communicable Diseases-National Health Laboratory Service. Brucellosis. Communicable Diseases Communique 2011;10(1):1-2. 10. Martin-Mazuelos E, Nogales MC, Florez C, et al. Outbreak of Brucella melitensis among microbiology laboratory workers. J Clin Microbiol 1994;32(8):2035-2036.

Accepted 23 May 2016.

CASE REPORT

Sirolimus-induced lymphoedema K G Motse, MB ChB, Dip HIV Man (SA), FCP (SA); M J Mashabane, MB BCh, FCP (SA), Cert Nephrol (SA) School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; and Division of Nephrology, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa Corresponding author: K G Motse (kagiso.motse@gmail.com)

Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), used as an immunosuppressant for solid-organ transplant recipients and patients with autoimmune disorders. We report a case of lymphoedema, a rare complication of sirolimus, and discuss the mechanism of drug action, the adverse effects and the challenges of treating a kidney transplant recipient with this complication in a resource-limited environment. Lymphoedema is a rare complication of sirolimus, and the mechanisms are not completely understood; however, early recognition can prevent permanent disfiguration. This case highlights the need for early recognition of adverse drug effects and further research into their pathophysiology and management. S Afr Med J 2016;106(9):886-887. DOI:10.7196/SAMJ.2016.v106i9.11061

Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is used as an immunosuppressant for solid-organ transplant recipients and patients with autoimmune disorders. We report a case of lymphoedema, a rare complication of sirolimus, and discuss the mechanism of drug action, the adverse effects and the challenges of treating a kidney transplant recipient with this complication in a resource-limited environment.

Case report

A 42-year-old black South African (SA) man received a cadaveric kidney transplant for end-stage renal disease secondary to type 1 diabetes mellitus. Before the transplant, he had been receiving haemo dialysis via a left brachiocephalic arteriovenous fistula for 3 years and peritoneal dialysis for 2 years before that.

After the transplant, the patient received basiliximab, methyl prednisolone and byclosporine for induction immune suppression and then triple therapy with cyclosporine, prednisone and myclophenolate mofetil (MMF) for maintenance immune suppression. In August 2009, he developed biopsy-proven mild calcineurin renal toxicity, and the cyclosporine was replaced with sirolimus. The mean sirolimus dose was 2 mg daily, with blood trough levels ranging between 3.8 and 11.3 ng/mL (mean 4.5, therapeutic range 4 - 11). The patient first complained of progressive painful bilateral lower limb swelling, the left leg being more affected than the right, in September 2010, 13 months after the initiation of sirolimus. Despite the graft being in the right iliac fossa and multiple previous central venous catheterisations of both femoral veins, Doppler ultrasound

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assessments excluded a venous cause for the leg swelling. Graft function remained stable, with a mean creatinine level of 125 µg/ mL. Lymphangiography showed almost complete obstruction of the deep lymphatic system of the lower limbs with back-diffusion into the peripheral superficial lymphatic system, the left leg more affected than the right. In the absence of a significant family history and other causes for lymphatic obstruction, the patient was diagnosed with sirolimusinduced lymphoedema. Initially the treatment was continued because he had excellent graft function despite the physical disfigurement. Low-dose loop diuretics did not result in any notable improvement. The lymphoedema worsened, and sirolimus treatment was stopped in April 2015 when the patient was unable to cope with the pain and the disfigurement impacted on his quality of life. He is currently receiving tacrolimus, MMF and prednisone for immune suppression, and his graph function has remained stable. There has been slight improvement in the lymphoedema with physiotherapy and cone compression bandaging.

Discussion

The prevalence of chronic kidney disease (CKD) has increased significantly over recent decades. It is currently estimated to be 6 - 18% worldwide.[1] The burden of disease is highest in low-income settings such as sub-Saharan Africa, where the incidence is estimated to be three to four times higher than in developed countries.[2] In SA, there was a 67% increase in deaths due to CKD from 1999 to 2006.[3] In the black African population, malignant hypertension is the most common cause, followed by diabetes mellitus and glomerulonephropathies. [4] Part of the challenge in managing CKD is late presentation of patients, a lack of adequate screening programmes and risk factor control, and the high cost of renal replacement therapy. Organ transplantation is the treatment of choice for end-stage renal failure, but it carries a high burden of cost to both the patient and the healthcare system because patients require lifelong immune suppression to prevent acute and chronic rejection. Sirolimus (also known as rapamycin) is a macrocylic lactone immunosuppressive agent produced by Streptomyces hygroscopicus. It inhibits T-lymphocyte activation and proliferation due to antigen and cytokine stimulation, and reduces antibody production. It binds to the immunophilin FK binding protein-12 (FKBP-12) and forms an immunosuppressive complex within the cell. The sirolimus/FKBP-12 complex binds to and inhibits activation of the regulatory kinase, the mammalian target of rapamycin (mTOR), thus inhibiting the progression from G1 to the S phase of the cell cycle. Sirolimus is currently used in patients with organ transplants and some autoimmune diseases. As with other immunosuppressive agents, adverse effects such as a predisposition to infections, cyto penias and poor wound healing may limit its use. However, compared with calcineurin inhibitors, it is associated with lower rates of nephrotoxicity, hypertension and malignancy, all of which have an impact on long-term graft function. The most common side-effects of sirolimus are dyslipidaemia, anaemia, arthralgia, gastrointestinal disturbances, skin abnormalities, stomatitis, electrolyte abnormalities, pneumonitis and peripheral oedema.[5] Patients with lymphatic obstruction can present with lymphoceles (12 - 13%), eyelid oedema, angio-oedema, pleural/pericardial effu sions and lymphoedema.[6] Bilateral limb oedema is commonly

associated with mTOR inhibitors, more commonly in patients on sirolimus than in those on evarolimus,[7] but the recent literature has indicated an increase in lymphoedema related to the drug, which is often permanently disfiguring.[8-10] According to previous case reports, it occurs between 7 months and 2 years on treatment and does not have a gender predisposition.[9] Various mechanisms for the development of lymphatic obstruction in patients on sirolimus have been proposed. Most theories arise from the fact that mTOR is a downstream signal in the vascular endothelial growth factor pathway that mediates lymphatic survival, proliferation and passage. As a result, inhibition of the kinase disrupts lymphangiogenesis.[11] Making the decision to stop treatment with sirolimus in our patient was challenging. Owing to the cost of drugs and problems with reliable supply, the treating facility did not have many options, and the patient also had good, stable graft function on sirolimus. However, his painful and disfiguring lymphoedema was affecting his quality of life. In view of his past history of calcineurin toxicity, the decision to change immunosuppressants could not be made lightly because of the possibility that his graft function would be compromised. Nonetheless, we needed to consider the psychological effect of his deformity and the effect it might have on compliance with treatment. Non-adherence would ultimately also have resulted in graft failure. The patient’s lymphoedema partially subsided after sirolimus was discontinued. His graft function remains stable on tacrolimus, MMF and prednisone. This case highlights the importance of early recognition of drug complications, which may prevent permanent disfiguration and discomfort. However, in a resource-limited environment where treatment options are few, drugs are expensive and drug supply is sometimes unreliable, clinicians may be faced with the difficult task of deciding between the lesser of two evils – cessation of life-saving treatment, and irreversible deformities.

Conclusion

Lymphoedema is a rare complication of sirolimus, and the mechan isms are not completely understood. However, early recognition can prevent permanent disfiguration. This case highlights the need for early recognition of adverse drug effects and further research into their pathophysiology and management. 1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: Global dimension and perspectives. Lancet 2013;382(9888):260-272. DOI: 10.1016/ S0140-6736(13)60687-X 2. Naicker S. End stage renal disease in Sub Saharan Africa. Ethn Dis 2009;19(Suppl 1):S1-13-5. 3. Moosa MR, van der Walt I, Naicker S, Meyers AM. Important causes of chronic kidney disease in South Africa. S Afr Med J 2015;105(4):320. DOI:10.7196/SAMJ.9535 4. Gold CH, Isaacson C, Levin J. The pathological basis of end stage renal disease in blacks. S Afr Med J 1982;61(8):263-265. 5. Merkel S, Mogilevskaja N, Mengel M, et al. Side effects of sirolimus. Transplant Proc 2006;38(3):714715. DOI:10.1016/j.transproceed.206.01.044 6. Gharbi C, Gueutin V, Izzedine H. Oedema, solid organ transplantation and mammalian target of rapamycin inhibitor/proliferation signal inhibitors (mTOR-I/PSIs). Clin Kidney J 2014;7(2):115-120. DOI:10.1093/ckj/sfu001 7. Moro JA, Almenar L, Martínez-Dolz L, et al. mTOR inhibitors and unilateral edema. Rev Esp Cardiol 2008;61(7):987-988. DOI:10.1016/S1885-5857(08)60264-9 8. Desai N, Heenan S, Mortimer P. Sirolimus-associated lymphoedema: Eight new cases and a proposed mechanism. Br J Dermatol 2009;160(6):1322-1326. DOI:10.1111/j.1365-2133.2009.09098.x 9. Al-Otaibi T, Ahamed MRN, Al-Kandari N, et al. Lymphoedema: An unusual complication of sirolimus therapy. Transplant Proc 2007;39:1207-1210. DOI:10.1016/j.transproceed.2007.03.058 10. Romagnoli J, Citterio F, Nanni G, et al. Severe limb lymphedema in sirolimus-treated patients. Transplant Proc 2005;37:834-836. DOI:10.1016/j.transproceed.2004.12.180 11. Kerjaschki D. How to control lymphangiogenesis: A novel role for rapamycin. Kidney Int 2007;71:717719. DOI:10.1038/sj.ki.5002184

Accepted 25 February 2016.

September 2016, Print edition

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CASE REPORT

Neonatal tetanus associated with skin infection M Maharaj, MB ChB; N Dungwa, MB ChB, DCH, FC Paed (SA), FAAFP, FCFP, Dip HIV Man Department of Paediatrics and Child Health, Witbank Hospital and School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa Corresponding author: N Dungwa (nomdungwa@yahoo.com)

A 1-week-old infant was brought to a regional hospital with a history of recurrent seizures following lower abdominal septic skin infection. She was found to have neonatal tetanus, and a spatula test was positive. The tetanus infection was associated with a superficial skin infection, common in neonates. Treatment included sedatives (diazepam, chlorpromazine, phenobarbitone and morphine), muscle relaxants, antibiotics and ventilation in the neonatal intensive care unit. Intrathecal and intramuscular immunoglobulin were given, and the wound was treated. The infant recovered, with no seizures by the 16th day from admission, and was off the ventilator by the 18th day. This was shorter than the usual 3 - 4 weeks for neonates with tetanus at the hospital. The question arises whether tetanus immunisation should be considered in infants with skin infections, which frequently occur in the neonatal period. S Afr Med J 2016;106(9):888-890. DOI:10.7196/SAMJ.2016.v106i9.11139

The World Health Organization (WHO) defines South Africa (SA) as having eliminated neonatal tetanus. The National Department of Health (NDoH) treatment guidelines no longer cover the treatment of severe neonatal tetanus.[1] However, clinicians need to be alert, as cases do arise even in countries considered to have eliminated the disease. We have encountered three clinical cases, including the one presented here, over a period of 8 months. Inadequate antenatal immunisation was a factor in the case presented. We present a protocol for doctors encountering this rare but life-threatening condition.[2]

Case report

Initial presentation

An 8-day-old infant was brought to the emergency department of a regional hospital in the morning with a history of 14 hours of recurrent seizures. The child’s mother had consulted a general practitioner the previous day to look at sores on the child’s abdomen. A course of antibiotics, a topical antibiotic and paracetamol were prescribed. Later in the evening, the child suffered seizures. Local traditional practitioners were consulted, to no avail. On arrival at the hospital, the infant was found to have scalding infection of the perineum together with generalised seizures. The following parameters were also recorded: weight 3 700 g, temperature 37oC, length 43 cm, head circumference 35 cm, mid-upper arm circumference 12 cm and oxygen saturation 98% in room air. The blood glucose level was normal. Two doses of intravenous (IV) diazepam as well as two doses of IV midazolam were administered but failed to stop the seizures. Appropriate loading doses of valproic acid and phenytoin were given. Eventually a midazolam infusion was started, and after a while no further seizure activity was observed. A lumbar puncture was performed and blood was drawn for various tests (Table 1).

Family background

The child’s 23-year-old mother was married and unemployed. The delivery had been vaginal, the infant weighing 3 440 g and with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. This was the mother’s third pregnancy. The first pregnancy was uneventful, although she had booked late at 6 months. That child is well. She miscarried in the second trimester of the second pregnancy, and a

Table 1. Results of laboratory tests done at admission FBC

Normal

Bilirubin (day 5)

Below phototherapy range (remained low)

U&E

Normal

CMP (mmol/L)

Normal

CSF

Normal

CRP

6 mg/L on admission, higher later

Pus swab of abdomen

No growth

Serum glucose

Normal

FBC = full blood count; U&E = urea and electrolytes; CMP = calcium, magnesium and phosphate; CSF = cerebrospinal fluid; CRP = C-reactive protein.

macerated fetus was delivered. During her third pregnancy the mother had booked at the local clinic at 5 months. Two doses of tetanus toxoid were administered. Blood tests were negative for HIV and syphilis. Her blood group was listed as RH-negative, and she was given anti-D immunoglobulin after the baby’s birth to prevent rhesus sensitisation. The husband is 32 years old and works in a coalmine. They live in a shack in an informal settlement in Witbank, Mpumalanga Province. Soon after delivery, the mother went to live with the mother-in-law in a four-roomed house in KwaGuqa township, Witbank. They denied performing any traditional rites on the baby. Surgical spirit was being applied to the umbilical cord stump to prevent infection. The infant was admitted with the diagnoses of status epilepticus, suspected meningitis and suspected staphylococcal scalded skin syndrome (Fig. 1).

Hospital course

In the neonatal intensive care unit (NICU), the infant was started on treatment with cefotaxime IV, cloxacillin IV and Bactroban topical antibiotic ointment for the abdomen. After the midazolam infusion was reduced, it was noticed that she responded with spasms to touch, procedures and noise. There were clinical signs suggestive of mild pneumonia. She was observed to be surprisingly mentally alert after prolonged seizures. Besides the spasms she also had a scalded skin infection and a chest infection, but the other systems were normal.

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Fig. 1. The distribution of the scalded skin sepsis.

Blood pressure was within normal limits. Occasional sweating was observed. A spatula test was positive.[3] A diagnosis of tetanus was made, and the North West Province Health Department Bana Pele Child Health Handbook[2] protocol was instituted. After reviewing the above results and making the diagnosis of tetanus, the following treatment was followed: Wound management. The scalded skin infection areas on the perineum and lower abdomen were debrided, sloughectomy was performed, and the areas were irrigated and dressed with Betadine. Antibiotics. Metronidazole was admini stered for 10 days. Penicillin G and IV genta micin were initiated, but later discontinued in favour of IV cloxacillin. Supportive management. The infant was ventilated and a maintenance drip was started at 150 mL/kg/d. As there were no isolation rooms, screens were used to create a dark, secluded area. Everybody was told to avoid making a noise. Procedures, including gentle suction, were kept to a bare minimum, and sedation was given before these activities. Feeding was started after 2 days. This was well tolerated and increased gradually. The dietician prepared a special diet with extra calories and protein, because tetanus increases daily nutritional requirements. The case was notified. Sedation. IV phenobarbitone loading was followed by daily oral maintenance. IV chlorpromazine was given (6-hourly) and stopped only when the infant was recovering and experiencing fewer spasms. IV diazepam was used before procedures, as required and when she was paralysed. Paralysis. IV pancuronium was used, 6-hourly for 2 days, then as required when spasms occurred. Immunological treatment. The infant was given tetanus immunoglobulin, 250 IU intrathecally and the remaining 250 IU intramuscularly. A second dose of 500 IU was administered intramuscularly. Vaccination. Tetanus toxoid immunisation was given to both mother and child.

The mother had booked late, so had received only two doses instead of three. Her immunisation history in her previous pregnancies and in childhood is unknown. Antitetanus immunoglobulin levels were not checked before maternal immunisation, in line with accepted cost-control practices. A home visit was done to assess the household and to educate and counsel the family. A very cordial and fruitful meeting was conducted with the grandparents. After 3 days on IV cloxacillin, the scalded skin showed little improvement. A change was made to IV clindamycin, with good clinical results. The infant was ventilated for 18 days, observed for a further 4 days, and then discharged. She had been free of seizures by day 16 on the ventilator in the NICU. Standard doses of the above drugs were used. No significant autonomic crises were encountered. The blood pressure remained stable most of the time. The patient developed a Klebsiella nosocomial infection with pneu monia and a C-reactive protein level of 83 mg/L after 10 days in the NICU. This was sensitive to ciprofloxacin, and she responded well to treatment. There were no significant changes in other blood results during the NICU stay. It is worth noting that our patient, who had significant disease and was treated with intrathecal immunoglobulin, recovered relatively quickly, in 16 days. Intrathecal immunoglobulin has been shown to lead to faster resolution of symptoms compared with intramuscular administration.[4]

Discussion

Contextual issues

The context in this case of neonatal tetanus involved the extended family, traditional healers and cultural beliefs. A delay in presentation occurred because the family

consulted a healer before bringing the infant to the hospital. The health system, locally and internationally, must continually update its guidelines and practices to try to eliminate this potentially very harmful practice. The extended family mainly involved the grandparents, who are often the custodians of culture and traditions. A home visit with them was scheduled and honoured. The main focus was to educate and demystify the illness, which often starts abruptly and can lead to suspicions of witchcraft. Practices such as applying faecal matter to the cord were discouraged. The family unit was educated about tetanus. (Incidentally, tetanus does not have a universally accepted name in the Sotho and Nguni languages. The Zulu term ngqi, used for tetanus in dictionaries, is not generally known.) The importance of an early visit to the clinic when a neonate is ill was emphasised. Our patient presented only after almost 4 days of a necrotising skin infection, which predisposed her to the tetanus. The traditional healers involved in the infant’s treatment refused to be interviewed, yet such healers are an integral part of the primary care network in SA. It would be of great benefit to the community if these practitioners were to complete the WHOrecommended village health worker’s course. It is essential that the NDoH maintains the cold chain for vaccines. In our case, investigations are underway to see whether the cold chain had been affected by the recurrent load shedding on the electrical grid. Generators should be available at all sites where vaccines are stored, which is not the case at present. We have seen three cases of neonatal tetanus in our area recently. The 2013 NDoH hospital paediatric tetanus immunisation and treatment guidelines[1] do not cover management of severe cases. The

Table 2. Wound management, tetanus prevention and passive immunity administration Clean, minor wounds including infection-related ones

All other wounds including infection-related ones

Unknown or <3 doses of TT-containing vaccine

TT and recommend catch-up vaccination

TT and recommend catch-up vaccination: TIG <5 years 75 IU, 5 - 10 years 125 IU, >10 years 250 IU

≥3 doses of TT-containing vaccine and <5 years since last dose

No indication

≥3 doses of TTcontaining vaccine and >5 years since last dose

TT recommended

Vaccination status

TT = tetanus toxoid; TIG = tetanus immunoglobulin.

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fact that higher-than-usual diazepam doses are often needed, and are well tolerated, is not stated. This inadequacy should be addressed as a matter of urgency. The WHO should aim for eradication of tetanus. A country is certified as having eliminated the disease if there is <1 case per 1 000 live births for at least 2 years. A comprehensive immunisation programme can eradicate neonatal tetanus (zero cases target). This is possible if all pregnant women are fully immunised. Treatment of this condition is expensive, while immunisation is far cheaper. It is time to aim for the eradication target.

Prevention of tetanus in children

KNOWLEDGE • KNOWLEDGE

Serum immunoglobulin levels of >0.01 IU/mL are protective. Infants should be immunised, as advised by the WHO. In SA, this guideline is offered in the national ‘Road To Health’ booklet. It is important to administer a booster after every 5 years and to follow antenatal tetanus immunisation protocols. Neonates who have had tetanus should be immunised at discharge, as per the guidelines. However,

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it is safe to immunise patients at diagnosis. This also avoids the possibility of its being forgotten on the day of discharge. Table 2 summarises wound management, prevention and passive immunity administration. Our patient contracted tetanus as a result of a complication related to the neonatal scalded skin syndrome. Tetanus immunisation should be considered in neonates with skin infections. Significant skin disruptions, such as epidermolysis bullosa and other severe infectious or vesicular eruptions, must also be considered indications for immunisation (Table 2). 1. National Department of Health, South Africa. Infective and infectious disease. In: Hospital Level Paediatrics. Standard Treatment Guidelines and Essential Medicines List. Chapter 8, section 36. Pretoria: NDoH, 2013. 2. National Department of Health, South Africa. The newborn. In: Bana Pele Child Health Handbook, North West Province. Chapter 3.16. Pretoria: NDoH, 2014:145. 3. Apte NM, Karnad DR. The spatula test: A simple bedside test to diagnose tetanus. Am J Trop Med Hyg 1995;53(4):386-387. 4. Ahmad A, Qaisar I, Naeem M, Mazhar AU, Ashfaq M. Intrathecal anti-tetanus human immunoglobulin in the treatment of neonatal tetanus. J Coll Physicians Surg Pak 2011;21(9):539-541.

Accepted 6 June 2016.

2017 Masters of Philosophy (MPhil) Programme in Applied Ethics This programme, which is offered by the Philosophy Department and the Centre for Applied Ethics (CAE), aims to engage in the challenges of a developing nation by equipping professionals in the medical, business, government, NGO, environmental, development and educational sectors with the knowledge and skills needed to address moral issues in their fields of expertise. In 2017, the MPhil Programme will be offered again. It is a one-year programme, and students choose a specialisation in either Biomedical, Business or Environmental Ethics. Structure: On-campus tuition (in English) for two week sessions (one in the first and one in the second semester) combined with structured self-study. Participants in the programme will have to write a thesis, which contributes 50% of the final mark. Requirements: Normally four years’ university training, which includes a Bachelors degree plus an Honours degree or a postgraduate Diploma in Philosophy or Applied Ethics. Doctors and all healthcare workers are strongly encouraged to apply. Applicants must state their background in philosophy and/or applied ethics clearly. Closing date for applications: 30 November 2016 Application forms and further information: Ms J. Engelbrecht, Department of Philosophy, Stellenbosch University, Private Bag X1, Matieland 7602. Tel: 021 808 2418, fax: 021 808 3556, e-mail: jengelb@sun.ac.za www.ayandambanga.co.za

September 2016, Print edition

RESEARCH

The South African child death review pilot: A multiagency approach to strengthen healthcare and protection for children S Mathews,1 MPH, PhD; L J Martin,2 MB BCh, Dip For Med (SA), MMed Path (Forens); D Coetzee,3 BA, MB BCh, DTM&H, FCPHM (SA), MS (Epi); C Scott,4 MB ChB, FC Paed (SA); T Naidoo,5,6 MB ChB, Dip For Med (SA), LLM MDL, FC For Path (SA); Y Brijmohun,5,6 MB ChB, FC For Path (SA); K Quarrie,5 MB ChB, Dip For Path (SA), FC For Path (SA), MMed hildrenâ&#x20AC;&#x2122;s Institute, Faculty of Health Sciences, University of Cape Town, South Africa C Division of Forensic Medicine and Toxicology, Faculty of Health Sciences, University of Cape Town, South Africa 3 Health Impact Assessment, Western Cape Department of Health, Cape Town; and School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 4 Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa 5 Forensic Pathology Services, KwaZulu-Natal Department of Health, Durban, South Africa 6 Department of Forensic Medicine, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa 1 2

Corresponding author: S Mathews (shanaaz.mathews@uct.ac.za)

Background. Child mortality trends in South Africa (SA) show a decrease, but remain high and appear to have plateaued. To attain the new sustainable development goals, we need a better understanding of causes of death and the associated factors. Objectives. To describe the SA child death review (CDR) pilot, the pattern of child deaths reviewed and the factors associated with these deaths. Methods. CDR teams were established at two pilot sites, Salt River mortuary (Western Cape Province) and Phoenix mortuary (KwaZuluNatal Province). All child deaths were reviewed by a multidisciplinary team at the pilot sites for the period 1 January 2014 - 31 December 2014. Results. The CDR pilot reviewed 711 cases. Over half (53.3%) were natural deaths, as opposed to 42.6% non-natural deaths. Most infant deaths (83.9%) were due to natural causes, while 91.7% of deaths in the 15 - 17-year-old age group were due to injuries. The leading cause of deaths reviewed (30.8%) was respiratory tract infection (RTI), mainly among infants (51.6%). Homicide was the second most common cause of death and affected children of all ages, with the highest burden (52.8%) in the 15 - 17-year age group. Child abuse and neglect accounted for 11.3% of deaths. RTI was shown to be more likely after the neonatal period (odds ratio (OR) 2.92; p<0.000) and in preterm infants (OR 1.98; p=0.005). Conclusions. CDR teams have been effective in improving identification of the causes of out-of-hospital deaths, as well as by identifying remediable factors critical to reducing child deaths further. S Afr Med J 2016;106(9):895-899. DOI:10.7196/SAMJ.2016.v106i9.11234

Full article available online at http://dx.doi.org/10.7196/SAMJ.2016.v106i9.11234

A cross-sectional study of socioeconomic status and cardiovascular disease risk among participants in the Prospective Urban Rural Epidemiological (PURE) Study B A Egbujie, MBBS, MPH; E U Igumbor, MPH, PhD; T Puoane, MPH, DrPH School of Public Health, University of the Western Cape, Bellville, Cape Town, South Africa Corresponding author: B A Egbujie (greatdabon@yahoo.com)

Background. Cardiovascular diseases (CVDs) are a challenge to populations and health systems worldwide. It is projected that by 2020 about a third of all deaths globally will be caused by CVDs, and that they will become the single leading cause of death by 2030. Empirical

September 2016, Print edition

RESEARCH

evidence suggests that there is socioeconomic patterning in the distribution and prevalence of risk factors for CVD, but the exact nature of this relationship in South Africa remains unclear. Objective. To examine the association between socioeconomic status (SES) and risk factors for CVD in a cohort of adult South Africans living in rural and urban communities. Method. This was a cross-sectional analytical study of baseline data on a population-based cohort of 1 976 SA men and women aged 35 - 70 years who were part of the Cape Town arm of the Prospective Urban and Rural Epidemiology (PURE) Study. Results. We found a complex association between SES and CVD risk factors, its pattern differing between urban and rural participants. Marital status showed the most consistent association with CVD risk in both groups: widowed participants living in urban communities were more likely to be hypertensive as well as diabetic, while single participants in both locations were more likely to use alcohol and tobacco products. Level of education was the only SES variable that had no significant association with any CVD risk factor in either study group. All measured SES variables were significantly different between urban and rural participants (p<0.05), with diabetes, obesity and alcohol use significantly more prevalent in urban than in rural participants (p<0.05) while hypertension and tobacco use were not (p≥0.05). Conclusions. In this cohort of South Africans, there were significant associations between SES and CVD risk, with marked differences in these associations between rural and urban locations. These findings highlight the need to consider SES and area of residence when designing interventions for CVD prevention and control. S Afr Med J 2016;106(9):900-906. DOI:10.7196/SAMJ.2016.v106i9.10456

Full article available online at http://dx.doi.org/10.7196/SAMJ.2016.v106i9.10456

The histological significance of atypical glandular cells on cervical cytology: Experience at Groote Schuur Hospital, Cape Town, South Africa L D Hoffman,1 MSc; H-T Wu,2 MB BCh, MMed, FCPath, FRCPath 1 2

B ChB III candidate, Faculty of Health Sciences, University of Cape Town, South Africa M Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town; South African Medical Research Council Gynaecological Cancer Research Centre, Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Cape Town; and D7 Anatomical Pathology Laboratory, Groote Schuur Hospital/National Health Laboratory Service, Cape Town, South Africa

Corresponding author: L D Hoffman (hoffmanld@yahoo.com)

Background. Atypical glandular cells (AGC) identified on Pap tests may be markers for potentially significant pathology. Objectives. Primarily, to correlate AGC findings at Groote Schuur Hospital (GSH), Cape Town, South Africa, with subsequent histological investigations and attempt to identify predictors of pathology relevant to the clinical management of women with a cytological diagnosis of AGC. Secondly, to compare the GSH data with data from similar international studies. Methods. Records of AGC Pap tests were retrieved from the laboratory database in the anatomical pathology laboratory at GSH and clinically relevant information was summarised based on the available information. Standard descriptive statistics were used to summarise the study data, and Fisher’s exact test was used to compare categorical outcomes, where possible. Results. Of the 237 women with a cytological diagnosis of AGC and who had subsequent histological diagnoses, 120 (50.6%) had significant pathology (cervical intraepithelial neoplasia (CIN) 2 or worse). Significant cervical pathology was most common in women aged <50 years, while significant endometrial pathology predominated in women aged ≥50 years. The results of the GSH study were largely consistent with international findings, but the risk of malignancy was six times higher in the GSH population than in a comparable international group. Conclusion. AGC identified on Pap tests may be markers for potentially significant pathology. Human papillomavirus DNA testing is recommended for younger women diagnosed with AGC to reduce invasive investigations and minimise expenses in a resource-poor setting. S Afr Med J 2016;106(9):907-911. DOI:10.7196/SAMJ.2016.v106i9.10472

Full article available online at http://dx.doi.org/10.7196/SAMJ.2016.v106i9.10472

September 2016, Print edition

RESEARCH

Missed appointments among rifampicin-resistant tuberculosis (RR-TB) patients at a decentralised RRTB outpatient clinic in Johannesburg, South Africa R Gajee,1 MB ChB, MBA, MPH; K Schnippel,1,2 MPA; N Mthupha,1 BSc, MB ChB, Dip HIV Man; B Muzah,1 MB ChB, MSc, Dip HIV Man; R H Berhanu,1,3 MD, DTM&H, Dip HIV Man ight to Care, Johannesburg, South Africa R Clinical HIV Research Unit, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 School of Medicine, University of North Carolina, Chapel Hill, NC, USA 1 2

Corresponding author: K Schnippel (kschnipp@gmail.com)

Background. With the implementation of outpatient (ambulatory) decentralised rifampicin-resistant tuberculosis (RR-TB) treatment in South Africa (SA) since late 2011, the high rates of loss from treatment are a significant concern. Missed appointments lead to treatment interruptions and may contribute to amplification of resistance, ongoing transmission of RR-TB and an increased risk of morbidity and mortality to the patient. Objective. To describe characteristics of patients who missed scheduled appointments during ambulatory RR-TB treatment. Methods. The study was a retrospective, deidentified electronic medical record review of RR-TB patients at an outpatient clinic in Johannesburg, SA, from March 2013 to December 2014. Associations between missed appointments and clinical and demographic characteristics were analysed using time-to-event Cox proportional hazards regression. Results. Of 172 patients who met the eligibility criteria, 53.5% missed at least one appointment and 39.5% missed three or more. More than half (59.8%) of first missed appointments occurred within the first 3 months after treatment initiation. The median number of days from initiation until the first missed appointment was 82 (interquartile range 52 - 260.5). HIV-infected patients with a CD4 count of â&#x2030;¤100 cells/ ÂľL (adjusted hazard ratio (aHR) 4.25, 95% confidence interval (CI) 1.49 - 12.18), patients referred from an inpatient facility (aHR 1.96, 95% CI 1.18 - 3.25) and patients aged 18 - 24 years as opposed to those aged 35 - 44 years (aHR 3.26, 95% CI 1.20 - 8.84) were all more likely to miss one or more appointments. Conclusion. HIV-infected patients with a low CD4 count, patients referred from inpatient care and young patients are at high risk of missing appointments and should receive interventions targeted at improving retention. S Afr Med J 2016;106(9):912-917. DOI:10.7196/SAMJ.2016.v106i9.10570

Full article available online at http://dx.doi.org/10.7196/SAMJ.2016.v106i9.10570

Effects of diabetes mellitus on health-related quality of life at a tertiary hospital in South Africa: A cross-sectional study R Daya,1 MB BCh, FCP (SA), MMed; Z Bayat,2 MB BCh, FCP (SA); F J Raal,3 FRCP, FRCPC, FCP (SA), Cert Endo, MMed, PhD epartment of Endocrinology, Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa D Department of Endocrinology, Internal Medicine, Helen Joseph Hospital, Johannesburg, South Africa 3 Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: R Daya (reyna.daya13@gmail.com)

Background. Diabetes mellitus (DM) is a chronic metabolic disease that potentially causes debilitating and life-threatening complications, demands a lifestyle change, and has important implications with regard to wellbeing and health-related quality of life (HRQOL). Objectives. To: (i) determine the HRQOL of a sample of patients with type 2 diabetes; (ii) describe the demographics (age, gender, and smoking and alcohol use) of the population studied; (iii) document the following parameters, which are important in determining the

September 2016, Print edition

RESEARCH

control and severity of type 2 diabetes: (a) glycosylated haemoglobin (HbA1C), (b) total amount of insulin required per day (if on insulin therapy), (c) body mass index (BMI), and (d) exercise compliance; (iv) determine whether there was an association between any or all of the above parameters and the HRQOL of these patients; and (v) determine whether coexisting diseases (hypertension (HT) and dyslipidaemia) were present, and compare HRQOL between diabetic patients with and without these diseases. Methods. This was a cross-sectional and descriptive study of 200 patients attending the diabetes clinic at Helen Joseph Hospital, Johannesburg, South Africa. HRQOL assessments were made using the Diabetes 39 (D-39) questionnaire, which patients filled in once consent had been obtained and if they fulfilled the inclusion criteria. Patientsâ&#x20AC;&#x2122; questionnaire forms were then analysed with regard to their demographics (age and gender), exercise regimen, smoking and alcohol history, employment status, living arrangements, age of diagnosis of DM, and concurrent use of antihypertensive and cholesterol-lowering drugs. The patientsâ&#x20AC;&#x2122; files were analysed and various clinical parameters were noted (HbA1C, lipogram, BMI, number of insulin units used per day, and whether any antihypertensive and/or lipidlowering drugs were used). Results. There was an association between HRQOL and HbA1C, and between HRQOL and HT and dyslipidaemia. Conclusions. No association was found between HRQOL and other clinical parameters, namely number of insulin units used per day, exercise, BMI, lipogram and the use of oral hypoglycaemic agents. Demographic parameters (age, gender, age at diagnosis, employment status and living arrangements) were also shown to have no impact on HRQOL. We found no association between HRQOL in patients who consumed alcohol and smoked cigarettes and in those who did not. S Afr Med J 2016;106(9):918-928. DOI:10.7196/SAMJ.2016.v106i9.9899

Full article available online at http://dx.doi.org/10.7196/SAMJ.2016.v106i9.9899

A follow-up study of a large group of children struck by lightning L M A Silva,1 PhD; M A Cooper,2,3 MD; R Blumenthal,4 MD; N Pliskin,5 PhD epartment of Psychiatry, University of Texas-Southwestern, Dallas, Texas, USA D Department of Emergency Medicine, College of Medicine, University of Illinois, Chicago, Ill., USA 3 African Centres for Lightning and Electromagnetics Network, Makerere University School of Business, Kampala, Uganda 4 Department of Forensic Sciences, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa 5 Department of Psychiatry, College of Medicine, University of Illinois, Chicago, Ill., USA 1 2

Corresponding author: M A Cooper (macooper@uic.edu)

Background. On 11 November 1994, 26 preadolescent girls, 2 adult supervisors and 7 dogs were sleeping in a tent in rural South Africa when the tent was struck by lightning. Four of the girls and 4 of the dogs were killed. The 2 adults were unharmed, but all but 3 of the children suffered significant injuries. An article in 2002 detailed the event and examined the medical and psychological changes in the surviving girls. Objective. To understand the medical and psychological changes secondary to lightning strike years after injury. Methods. An online questionnaire was prepared that included a checklist of physical and psychological symptoms. Participants were asked to report on both initial and current symptoms. Eleven of the 22 survivors were contacted, and 10 completed the survey. Results. Participants reported that initial physical symptoms generally resolved over time, with ~10 - 20% continuing to experience physical symptoms. Vision problems persisted in 50% of respondents. Psychological symptoms, overall, had a later onset and were more likely to be chronic or currently experienced. Depression and anxiety, specifically, were higher among the survivors than the reported incidence in South Africa. Conclusions. Initial and current/chronic physical and psychological symptoms following lightning strike are reported, adding to the body of literature on the long-term after-effects of lightning strike on survivors. A brief discussion on post-traumatic stress disorder symptomatology and post-lightning shock syndrome is provided. S Afr Med J 2016;106(9):929-932. DOI:10.7196/SAMJ.2016.v106i9.10564

Full article available online at http://dx.doi.org/10.7196/SAMJ.2016.v106i9.10564

September 2016, Print edition

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The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it The convenient pocket-sized design enables you to fit it comfortably into your hospital bag or coat pocket, so it can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the can always be at hand for ready reference. South African Medicines Formulary (SAMF), a joint initiative of the University of Cape Town’s Division of Clinical Pharmacologyyand the Health and Medical Publishing Group, University of Cape Town’s Division of Clinical Pharmacolog and the Health and Medical Publishing Group, publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate publishers for the South African Medical Association, provides easy access to the latest, scientifically accurate information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated information, including full drug profiles, clinical notes and special prescriber’s points. The thoroughly updated 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines. 12th edition of SAMF is your essential reference to the rational, cost-effective and safe use of medicines.

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True (A) or false (B): SAMJ Invasive carbapenem-resistant Enterobacteriaceae (CRE) infection at a paediatric hospital 1. Resistance to carbapenems may result from several mechanisms, but uncommonly through the production of carbapenemases. Neonatal tetanus associated with skin infection 2. South Africa (SA) is defined by the World Health Organization as having eliminated neonatal tetanus. 3. Neonates who have had tetanus do not need to be immunised. The South African child death review pilot: A multiagency approach to strengthen healthcare and protection for children 4. Even though under-5 mortality in SA has declined, the country has not met the Millennium Development Goal to reduce under-5 mortality by two-thirds. 5. More than half (53.3%) of the child deaths reviewed were due to natural causes. A cross-sectional study of socioeconomic status and cardio vascular disease risk among participants in the Prospective Urban Rural Epidemiological (PURE) Study 6. SA’s Gini coefficient of 0.63 makes it one of the most unequal countries in the world. 7. The prevalence of hypertension in study participants was higher in rural than in urban areas. 8. All risk factors with the exception of tobacco use were more prevalent among urban participants.

CME Surgical management of movement disorders 11. Surgery for movement disorders does not offer a cure, but longterm control. 12 The non-motor symptoms associated with Parkinson’s disease are not amenable to surgical intervention. 13. The mainstay of focal dystonia management is local intramuscular injections of botulinum toxin. 14. Patients may be awake during neurosurgical procedures for musician’s cramp. 15. Essential tremor is absent at rest. Surgical management of pain 16. Neuropathic pain is described as ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’. 17. Hypersensitivity to noradrenaline contributes to the complex regional pain syndrome. 18. Malocclusion causing facial pain may be incorrectly labelled trigeminal neuralgia. 19. Music therapy is an adjunct to medical therapy in the management of chronic pain. 20. Ongoing mechanical instability may be a cause of pain in spinal cord injury.

A follow-up study of a large group of children struck by lightning 9. Upward streamers that result from lightning strikes may carry several hundreds of amperes of current that are transmitted through or around the victim. 10. There are up to 100 lightning-related fatalities annually in SA.

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September 2016, Print edition

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