V 72 no 1 2002 by Joanne Paterson

TAY periodical NO LOAN Wl. UN9626B University of Western Ontario medical journal . UWOMJ .

OMJ Volume 72 Number 1

Contents EDITORIAL

Fingertips and Cuffs Jason Ashley

D EPARTME T ARTICLES

Profiles Dr. Benoit DeVarennes: The Montreal Experience with Surgical Heart Fai lure Treatment Maryanne Rockx History of Medicine The Socio-cultural roots of Anorexia nervosa Chetna Tailor

F EATURE ARTICLES

Advances and treatment of malignant hyperthermia A Review Christopher Brooks Off-pump computer-enhanced robot assisted endoscopic coronary artery bypass grafting: Caridac surgery in the new millennium Matth ew Danter, Darren Pay ne, WD. Boyd Considerations for surgical management of traumatic injury under conditions of war and di saster Brian Sullivan

Ethics and aesthetics: An inquiry into cosmetic surgery Sheilagh Maguin ess, Toni Zhong

Surgical Residencies: The impact of lifestyle on student recruitment, education and patient care Mark Reimer

Routine ultrasound in pregnancy Deepak Bhayana

The role of war in the development of plastic surgery Vickram Chahal

Cognitive Asymmetry in Alzheimer's Disease Yaniv Berliner

Current Practice of Radiation Therapy for Pituitary Adenomas Karm Guram

Faster, Higher, Stronger: the use of EPO to enhance athletic performance Hany Wu, Jam es Woo

A Cure for Non-Insu lin Dependent Diabetes found in Bariatric Surgery Heather Cox

It 's raining MEN Kieran Mclntyre

COMMENTS

John Dubois Martyn Judson MJ Rieder Marek Wystanski

A short history on the development of the suture Eric Wong

An assessment of Canada's health care system : Part I of2 David Mula

An assessment of Canada 's health care system : Part 2 of2 David Mula

H UM OR

"That's a Fine mess you've got yourself in" A Gut-wrenching Tale Alan J Cooper

ÂŠ2002 UWOMJ UWOMJ is published every 4 months.

Editorial Staff Upcoming Issues: EDITORIAL BOARD

Endocrinology and Metabolism and The Joint

COVER ART

The cover art was designed and constructed by Mr. Ian Seo. Mr. Seo is a graduate of programs in both journalism and graphic design . His illustrative work covers a variety of styles in both traditional and digitally-based mediums. Mr. Seo can be contacted at seo@globility.com

â&#x20AC;˘ .. Editor-in-Chief (middle) Senior Associate Editor (left) Junior Associate Editor (right)

Jason Ashley Shashar Sade Leanne Tran

Meds 2003 Meds 2004 Meds 2005

DEPARTMENTAL EDITORS Ethics Sr.: Boris So, Meds 2004 Jr. : Adnan Pirbhai, Meds 2005

Medicine and the Internet Sr. : Gabriel Chan, Meds 2004 Jr.: Deric Morrison, Meds 2005

Clinical Procedures Sr. : Elizabeth Au- Yeung, Meds 2004 Jr.: Ryan Punambo, Meds 2005

Profiles Sr.: Maryanne Rockx, Meds 2004 Jr.: Magdal ena Lipowska, Meds 2005

Diagnostic Review Sr.: Jessica Hopkins, Meds 2004 Jr. : Nina Ghosh, Meds 2005

Thinking on Your Feet Sr. : Chris Chu, Meds 2004 Jr. : Jay Banerj ee, Meds 2005

Health Promotion Sr.: Alan Kahn , Meds 2004 Jr. : Anna Labuda, Meds 2005

Zebra Files Sr: Chinedu Onochie, Med 2004 Jr: Suzanne Richter, Meds 2005

History of Medicine Sr.: Chetna Tail or, Meds 2004 Jr. : Marlis Sabo, Meds 2005

Senior Editors Azadeh Moaveni, Meds 2003 Mark Baumgartner, Meds 2003 John Lee, Meds 2003 Heather Cockwe ll , Meds 2002

Medicine and the Law Sr. : Birinder Singh, Meds 2004 Jr.: Leanne Tran, Meds 2005

Poster Designer Elizabeth Au-Yeung, Meds 2004

UWOMJ ADVISORY COUNCIL Dr. Co lby, Microbiology Dr. Wex ler, Anesthesiology Dr. Ri eder, Paediatrics

Dr. Silcox, Obstetri cs I Gynecology Dr. Nisker, Obstetrics I Gynecology

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UWOMJ 72(1) 2002

UWOMJ Room MS-175 Medical Sciences Building The University of Western Ontario London, Ontario N6A 5Cl Phone/Fax: (519) 661-4238 Email : journal@uwo.ca URL: www.med.uwo.ca/medjrnl For information about writing for the UWOMJ, please follow the guidelines outlined on the website. The UWOMJ is a peer-reviewed publication . All articles are reviewed by at least one external reader, in addition to the editorial staff. All editorial matter in the UWOMJ represents the opinions of the authors and not necessarily those of the editorial staff and advisory council. The editorial staff and advisory council assume no responsibility or liability for damages arising from any error or omission or from use of any information or advice contained in UWOMJ. Canada Post - Publication Mail Agreement Number I 720198 POSTMASTER: Undeliverable copies, please return to the address above.

Editorial

Fingertips and Cuffs

Jason Ashley, Editor-in-Chief

Dr. Joseph Bell, a name synonymous with medicine, has been ever so influential in the great mysteries of Sherlock Holmes. Dr. Bell was a preeminent surgeon and clinical teacher at the University of Edinburgh in Scotland. He served as the royal surgeon to Her Royal Majesty, Queen Victoria whenever she was in Scotland. He also published several textbooks and served as editor of the Edinburgh Journal of Medicine. Dr. Bell was described as "a sparse and lean man with the long and sensitive fingers of a musician, sharp grey eyes twinkling with shrewdness. He had an angular nose with a chin to match and a high-pitched voice." He was also noted to be a "widely read amateur poet, a competent raconteur, a keen sportsman, a naturalist and a bird-watcher" as well as "a good shot"' 路 Sir Arthur Conan Doyle clerked with Dr. Bell in 1878 at the Royal Infirmary's open clinic. Dr. Bell would boggle his students with deductions from virtually obscure information. He would take one look at the patient and be able to extrapolate their occupation as well as other personal and general information. For example, a lady with a child in one hand and a coat in the other, presented with a rash on her right hand . From Bell's keen eyes, nothing could be held back. He deduced that the lady had come down a certain road, and thus a certain part of town, by the dirt on her shoes. He also noted that the coat was too large for the child present, and hence she dropped a child off on the way to the Infirmary. Furthermore, armed with the knowledge of the road and its businesses, he realized that the lady was developing a rash on her hand from working with caustic chemicals at the nearby linoleum factory. This sort of presentation is not as uncommon in today's clinics and emergency departments as one might think. This story, or a form of it, was transmitted to us in our fledgling days of medicine. The thought that we might be able to be the " Great Detective", while perhaps fulfilling a youthful dream, serves a profound purpose. With the ever expanding scope of medicine, and the ever present lab test, the fine art of the general exam is becoming something of the past. Given that some of the physical exam markers have been proven not to be very effective, it is perhaps a natural evolution to lean a bit harder on various investigations rather to rely on the physical. There are vast amounts of knowledge that have to be consumed, digested,

and regurgitated by medical students and residents alike. With the information that must be known, sometimes the fine arts of medicine can be forgotten. As per usual teaching, the history starts, the physician and patient talk for a while, then a physical is done. That is the old adage isn't it? The first answer a medical student learns is ''I'd do a good history and physical." This may unfortunately suggest that the physical is separate from the history, and vice versa . The physical exam starts far from the laying on of hands . So often, the entire story and history of the patient will be laid out before you without the patient saying a word . When one walks in the room, one can tell immediately if the patient smokes, has a wound infection, as well as a gross toxicology screen (namely alcohol) . This can be done without even looking at the patient. While talking to the patient, take notice of company watches from retirement, shirt logos, and rings with logos or school rings. Look at their hands, are they calloused and thick or clean and thin? Is there dirt under their nails? Are there tobacco stains? Is the skin tanned from a recent trip? Is the skin jaundiced? It is the subtleties that can sometimes get overlooked. Fortune tellers can often tell your past and future , since these are the cues that they pick up on. While Dr. Bell's abilities are likely a combination of training and innate ability, we can all take a little lesson from the "Great Detective" . In the words of Doyle from A Study in Scarlet, "by a man's finger-nails , by his coat sleeve, by his boot, by his trouserknees, by his expression, by his shirt-cuffs-by each of these things a man's calling is plainly revealed."2 Elementary, my dear Doctor.

Jason Ashley, Editor-in-Chief REFERENCES: I . Booth, Martin. The Doctor and the Detective: A Biography of Sir Arthur Conan Doyle. New York: St. Martin s Press. 1997. 2. Doyle, AC. A Study in Scarlet. In Beeton's Christmas Annual. London : 1887.

UWOMJ 72(1 ) 2002

Comments

I have just finished reading your psychiatry issue of the UWOMJ (Volume 71 , number 3) and I am so impressed with the quality of the articles. Even yo ur Editori al "The soft stuff" was very refreshing. What impressed me is that I would have to go to several di fferent professional journals to f ind some of the topics covered in your single issue. Your three historical articles, that is , malarial therapy, prefrontal lobotomy and homosexua lity were particularly enlightening. The outstanding quality of all the artic les in this issue give me expansive optimism abo ut our new physicians comi ng into the system. My congratulations to all of the authors. I will save this issue for future reference . John R . Dubois, MD., FRCP(C) Professor Emeritus Department of Psychiatry University ofWestem Ontario

I recently read the issue Volume 71 ,(2), which, as you know, is the issue on surgery. I thoug ht it was quite interesting, and the articles inside were very we ll written. I am writi ng wi th respect to one article which is the review of Steven -John on Syndrome written by Ch inedu Onochie. Thi is an interesting article and presents the clini ca l spectrum of thi disease very well. With respect to the aetiology of the pathogenesis, I wo uld note that there has been considerabl e work done on this in the last several years, much of it at the Un iversity of Western O nta ri o . As an illustration , there are two recent articles in the Federation of American Societi es for Experimental Biology (FASEB) Jo urnal describing advances in the biochemi ca l and the aetio logy of the pathogenesi s of thi s reaction.' Michae l J. Reider, MD, PhD, FRCPC Drug All ergy C lini c University of We tern Ontario REFERENCES: 1. David A. Hess. Erin F O'LeGIJ'. Jam es T Lee, Wa sim Y. Alma wi. Joaquin Madrenas, and Michael J. Riede1: inhibition of cytokine produ ction and inte1jerence in JL-2 receptor-mediated Jak-Stat signaling by th e hy droxylamine metabolite of sulfamethoxa:ole. FASEB J. 200 I : 15(10) : 1855-7.

Michael Curry is to be congratu lated for his bri ef, succinct, yet comprehensive article entitl ed "Anxio us Alcoholics". As a physician practicing addictio n medi cine, I can concur that the clin ica l presentation of symptoms in alcoholi cs can be confus ing. Indi viduals may be sufferi ng from true a nx iety or 4

UWOMJ 72( I) 2002

alternative symptoms of the post-acute withdrawals syndrome which are similar. To compound matters , behavioural changes in themselves contribute to the confusion. Simply discontinuing the use of a chemical routinely taken is sufficient in some people to produce a sense of anxiety. The article alludes to the effectiveness of Alcoholics Anonymous not being well established. To the contrary, Project MATCH clearly indicated that recovering alcoholics participating in that Fellowship were every bit as successful in maintaining their abstinence as those engaged in cognitive-behavioural therapy.' The contentious issue of benzodiazepine use in the management of anxiety symptoms in recovering alcoholics is pervasive. From clinical experience, it appears that the g reat majority of patients are at less risk of relapsing into the use of alcohol if they avoid benzodiazepines. If all alternatives of pharmacotherapy have been exhausted, then delayed onset of action benzodiazepines may be app ro pri ate provided their use is closely monito red and the patients remain in contact w ith their psychosocial suppo rt network. A lternatively, buspirone may be effective if taken in high dose over a prolonged period of time but the use of SSRI 's may be more efficacious considering that they have Jess addi ctive pote nti al.2 Furthe rmore, it is also known that buspirone is less helpful in benzodiazepine abusers, many of whom have an alcoho l use di order.2 Martyn Jud on, MB, Ch .B, MRCGP, CCFP, ICADC ubstance buse Treatment and Addiction Medicine REFERENCES: 1. Project MAT H Research Group. Matching alcoholism treatment to client heterogeneity · Project MATCH post-treatment drinking ourcomes. Joumal of rudies in Alcohol. 1997: 58: 7-29. E1•ans. M. Gr(fflths RR. de Wir H. Preferences for dia:epam. bur not buspirone. in moderate drinkers. Psychopharmacology. 1996:123: 154163.

Yes, the difference between the theoretica l and e mpirical backgrounds, ba ed o n which psychiatrists and psychologists profess the ir respective vocations, are with no doubt at least as signifi ca nt as described by Dr. Larry Litman in hi s a rti cle publi hed by UWOMJ (Fa ll 200 I). Whether the presumed difference in prescribing practices reflect any reality- is another question. I beg to differ wi th the a uthor on everal issues. I am writing from a point of view of the prescribing phys ician. Dr. Litman - from that of a psychologist, assessing the problem theoretica lly (in Canada and, but for a few exceptions, the rest of the worl d psychologi ts do not pre cribe medications). But the probl e m is not merely theoretical. Despite the a utho r' ca utiou s co nclu sion that neither the psychologica l nor

the medical model of diagnosis, treatment and patient management, is superior to the other, we know that claims to superiori ty abound on both sides, and consociation freq uently gives way to more or less skillfully hidden di strust. I sense the presence of the latter in Dr. Litman 's article itse lf (and expose myse lf to the same suspicion ... ). I.

The psychologica l model of di agnosi ng is not "a system-oriented, holi sti c, integrat ive approach" in contrast to the medical one, as the author wri tes. For the last two decades, the medical model has been at least as system-oriented, holi stic and integrative, as the psychological one . If not more. For it deals, after all , not only with psychological and social factors , but also with biological aspects of health, illness and disease. Human biology does not constitute an area of a particular interest for the psychologica l model.

It is not convincing to refer to paternali sm of yore, when comparing the medica l model with the relatively recently developed psychologica l one. Neither the patients nor the society have ever expected the latter model to fulfill the enormous obligations they place on the form er. The contemporary medical model empowers the pati ents and invol ves them (or their substitutes, whenever required by law) in treatment, in the context of the patient's global functionin g; not only psychological but also biological, as well as soc ial in its broadest sense which includes accountabilities and responsibilities (also legal) carried by a phys ician. 3. Medicine, and medications, are not " likely to be combined with other interventions in the psychologica l model." Rather, it is the other way around: medications are combined with psychological interventions in the medical model. The medi ca l, bio-psycho-soc ial model, when employed by a physician, calls for the use of a psychological approach among others . Whether prescribing medicat ions without comprehensive biol ogica l education can be supported, is debatable. 4. Contrary to what Dr. Litman wri tes, it is not on ly in the psychological model that "symptom increa e does not on its own mean that the di sorder is worseni ng" (with the resulting in crease of "the likelihood that medi cation will be prescribed"). In the medi ca l model there is an agreement, based on experi ence, that some symptoms may increase with the all eviation of the di sorder (e.g. motor agitation in mel ancholi a, low mood in crisis resolution). In these situations medi cation could well be decreased or not prescribed altogether. 5. It is not only in the psychological model that "when symptoms are not interfering with treatment, medication may not be viewed as necessary or even appropriate." Actually, in the medi ca l model, many symptoms experienced by patients are viewed as not necessarily requiring medi cating. For a va ri ety of reason . Lack of the interference of symptom s with the psychologica l part of treatment is only one of the several facto rs miti gating prescribing of medi cations by a physician. In the

medical model , symptoms that do not result in patient's distress or an impairment in his or her functioning , frequentl y are not treated with medications. If, a Dr. Litman writes, "there are important [ . . . ] differences in the prescribing practice of doctors" (i.e. between psychiatrists and psychologists in the few jurisdicti ons that allow those latter to prescribe), we have not learned about them from hi s article. No data were given. Instead, conj ectures, deducted from the elements of the theoretical model s underlyi ng both professions, were presented. Marek Wystanski, MD, FRCP(C) Adjunct Professor Department of Psychiatry University ofWestern Ontario Staff Psychiatri t Regional Mental Health Care - St. Thomas REFERENCES 1. Litman LC. Differences in prescribing practice between board certified prescribing psychologists and psychiatrists. UWOMJ 2001; 71 (2) : 5960.

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UWOMJ 72( I) 2002

Profiles !

Dr. Benoit DeVarennes: The Montreal Experience with Surgical Heart Failure Treatment

Mmy anne Rockx, Medicine 2004

Heart transplantation is now a commonplace therapy for heart fa ilure and the London Hea lth Sciences Centre - University Campus in London , Ontario has been a leader in Canada with more than 450 transplants performed since the program 's inception in 198 1. Both London and Montreal have had extremely successfu l results fro m their transplant programs. Due to the shortage of donors and the side effects from the need for li fet ime immunosuppression, alternatives have been so ught. Several centres around th e world, including the Royal Victoria Hospital (part of the McGill University Hea lth Centre in Montreal) are emp loying vari ous surgica l techniques , such as implantati on of mechanical devices, as bridges to transpl antation and as destination therapy. Dr. Benoit DeVarenn e compl eted hi s medica l educati on at McGill , graduating with an MD degree in 1984, compl eting general surgery in 1989 and cardiac surgery in 199 1. He is currently the site director at the Royal Vic.

How did you choose to speciali ze in cardiac surgery? I must admit that throughout my Genera l Surgery residency, I very much enj oyed a ll aspects of surgery in general and it took me quite a long time to decide to go into Cardi ac Surgery. It was after a yea r of resea rch working on myocardi al preserva ti on with Dr A lbert Guerraty, Director of Cardi ac Transplantation that I eventua lly decided on Cardiac urgery. What probably attracted me the most to thi s f ield is th e dramatic interface between basic phys io logy and c lini ca l outcomes.

all the support that I needed . Right from the beginning, I was considered an equal citizen to all the other surgeons in the institution.

How did you become interested in heart failure I transplantation? I became interested in heart transplantation during my year of research with Dr Guerraty in 1986. From then on, I was actively invo lved w ith almost every single heart, heart-lung and lung transplantation that took pl ace at McGill until the end of my residency. My research background helped me greatly in the understandin g of the basic principles of cardiac transplantation. My knowledge of myocardi al preservation also allowed me to apply those principl es to complex cardiac surgeries . I became particul arly interested in mitral valve repair in 1991 when corrective valve surgery was starting in Canada. Reading the articles by Ca rl o Duran and Alain Carpentier convinced me that, especially in the etting of mitral regurgitation, aggressive mitral valve replacement would be much better for left ventricular. I then went on to study left ventricular remodeling after mitral va lve repair. I was one of the first individual s to ever report on the remode ling of the left ventricle after mitral valve repair.

Can yo u describe the impact of Right Ventricular Assist Devices (RVADs) on day-to-day surgery? RVADs do not have an impact on day-to-day surgery. They are very aggress ive h路eatment for end-stage right ventricu lar failure which wi ll often occur po t transplantation or after comp lex va lvul ar procedures , e pec ially in the setting of pulmonary hypertension. Th e indication s have to be very clear and the principles have to be c lea rly appli ed. The surgeon also has to be very attenti ve to th e deve lopm ent of left ventri cular failure . The technology hould be reserved for a very sma ll proportion of the patients on whom we operate.

What do you like best about cardiac surgery in Montreal?

Can yo u describe you Centre's experience with Left Ventricular Assist Devices (LVADs)?

Th e McGill in tituti on have always had the greatest respect and support for you ng cardiac surgeons starting in practice. Very early on in my career, I had the strongest support from my seni or partners wh ich a ll owed me to refine my surgica l techniques with

So fa r our Centre has utili zed a total of approxi mately 65 RVADs , LVADs or Bi-VADs usi ng centrifugal pumps and we now have upported 22 pati ents with other longer term systems such a th e Thoratec dev ice, the Novacor device, the Heart-Mate

UWOMJ 72( I) 2002

device as well as the Berlin Heart. Our mean duration of support with these latter devices has been close to 3 - 4 months. Our program was greatly enriched by the return of Dr Renzo Cecere who was supported by our group when he went to train in California in heart failure surgery. W hat do you see in the future for surgical heart failure therapy? I think that we are going to become more and more aggressive in treating failing hearts with various innovative methods which will tend to preserve the patients' own myocardium as much as possible. Whenever thi s wi ll not be possible, LVADs of a permanent nature will be utilized more and more. I am convinced that, as the costs decline over the next few years, this therapy will be applied to more and more people. I would not be surprised to see it completely replacing heart replacement therapy, such as transplantation, in the very near future. How has your practice changed in the past ten years?

Where do you see cardiac surgery in ten years from now? I think that beating heart surgery is going to plateau in the next year or so throughout North America as intermediate and long-term results demonstrate that the surgery is probably not any better than conventional extra-corporeal circulation surgery and I also think that the proportion of coronary artery disease patients is going to dramatically reduce as risk factor control is becoming more and more aggressive throughout the continent and that percutaneous coronary intervention s are becoming more and more successful. I also believe that valve surgery in failing ventricles will take place more and more in our day-to-day practice.

ACKNOWLEDGEMENT: I would like to thank Dr. DeVarennes, Dr. Ergina, Dr. Chedrawy, and Dr. Alsabti , and all the staff at the Royal Vic for making my elective there a most interesting experience.

I have become more and more aggressive in treating severe left ventricular dysfunction by virtue of the fact that we now have support of mechanical devices to support the failing heart in the interim before recovery.

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www.bocgases.ca UWOMJ 72( I) 2002

History of Medicine

The Socio-Cultural Roots of Anorexia Nervosa

Chetna Tailor. BSc (Hon ). Meds 2004

Self-starvation ha s a significant place in human history, however it was not untiJ the 19th century that the wo rld witnessed the birth of anorexia nervosa. A number of socio-cultural changes, induced by the agrarian, demographic, and industrial revolutions, empowered a new rising middle class. New ideologies regarding " the child" and "the family" arose. Beliefs regarding food , body image, and the female role also occurred during this time. The combination of these factors made it possible for the rise of anorexia nervosa.

Self-starvation , although a widely recogni zed current day phenomenon, existed long before the description of the modern day clirucal syndrome of anorexia nervosa in 1873 .I The reasons for its existence and incidence, however, have not remain ed constant. Se lf-starvation has not stood as an entity of its own but as a manifestation of the socia l infrastructure of particular time periods. Thus, it has its own hi story. The earl iest appearance of self-starvation was in magico-re ligious practices of widely divergent cultures and re li gions. These cu ltures shared the belief that food was susceptibl e to demonic forces that would exert their wi ll on their host after ingestion . The Egyptians wou ld fast during times of mourning as protection against evi l powers. As time progressed, self-starvation beca me a form ofpenance.2 The twe lfth century saw an increase in the participation offemales in spi ri tua l li fe which co incided in time with the rise in the number of fema le sai nts. Prolonged fasting, in order to puni sh the body fo r its vicious influences, was con idered a female mirac le and proof of sa intl ines .3 In the late medieva l period (fifteenth to seventeenth centuri es) and during the time of the Re form ati on (seventeenth and e ighteenth centuri es), prolonged absti nence from food bega n to be loo ked upon as the work of Satan and the fasters as victims of possess ion, some were even tried as witches.4 Self-starvat ion was not to di sappear from human hi story however, it was mere ly in slumber ready to be awoken in the modern day form of anorex ia nervosa during the nin eteenth century. The ferti le g ro und upon whi ch anorexia nervosa wa to fl ourish was the result of the many changes in Western Europe in the realm s of labor re lations, fami ly life, and politics th at had come to pass a century earli er. The agra ri an revo luti on resulted in an increase in agri cu ltura l product ion and the di sappearance of large famines . The demographic revolution , with an increase in sanitation , resulted in a popu lation ex plosion due to a great decrease in 8

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mortali ty. The Industria l Revo luti on gave birth to new means of production and thu the appearance of mass products. The socialpolitical revo lution of the time empowered a new rising classthe bourgeo isie . The emergence of two worldviews-the Enli ghtenment and Romanticism- and the rise ofthe new human sc iences in the 18th century also took their place alongside the many revolution in preparing the oiJ.2

THE CHILD Prior to the revo luti onary changes that brought about decreases in mortali ty, the re lationship between parent and child was quite different from that of the present day. Due to the instabili ty of hea lth and the re ultant large number of deaths within the family, there was minimal emotional investment made by the parent towards the child . This can be seen as a protective measure to preserve the sani ty of the parents as they could be expected to lose a signifi ca nt number of their chi ldren to the claws of death . The ignificant decrea e in mortality took away the need for such a defense mec hani m and broug ht about an increased emotional attachment of the parent towards the child - a child who was now much more c lose ly scrutin ized. As a result of this change, accompani ed by the ri se of the nli ghtenment, Romanti c i m and the sciences, chi ld development became a topi c of interest. Prior to this time the chi ld had been considered a " mini-adult" with no phys iolog ical or psycholog ica l change recogni zed as pa rt of their development. During the 17th and 18th centuri e there was a movement (strongly propaga ted by the French phil osoph er Jean-Jacques Rousseau) towards recogni zing childhood as a di stinct phase of development . In the econd half of the 18th century, adolescence was inc luded as yet another pha e in the continuwn from infancy to adu lthood . T he rea on for the delayed recognition of such as di stinct a

phase of development as adolescence may have been due to the fact that, prior to the 18th century, this phase wa not experienced in the same manner as it is now. The average age of menarche in the late eighteenth century was 16.6 years (an age by which, in earlier times, many children had traditionally moved out of the parental home). By the nineteenth century this age had decrea ed to 14.5 years. During this time there was also a height increase in the population, thus making the adolescent growth spurt more apparent. The rapid physical maturation that occurs during adolescence, which unmasked the existence of thi phase of development, has been attributed to the improved nutrition of the time.2

THE FAMILY The socio-cultural changes from the eventeenth century onwards manifested themselves through changes in family structure. The family model of the seventeenth century consisted of an extended family that included non-relatives, and was strongly connected to the rest of soc iety. By the nineteenth century, family structure had evolved into the partially secluded nuclear family. The family became separate from society and, in essence, became the means by which societal corruption could be fought . Morality, or the pursuit of morality, became the glue that held the nineteenth century family together. In order to serve that function, family roles became very rigidly defined. The husband held the dominant position and was responsible for the material aspects of domesticity. The wife served her domestic responsibilities as mother, spouse, and the moral fiber of the household. The child had a central place in the family as the "future torch bearer of culture and progress"2. The main focus of a child's upbringing was to provide them with moral training. There were strict rules of manners and systems of punishment aimed at "cultivating diligence, sense of duty and moderation" 2. The great emphasis placed on morality resulted in repression of women and children. The nineteenth century bourgeois home became a prison for both as neither was deemed morally strong enough to resist the corrupting influence of the outside world. The family meal had a central role in reinforcing the familial hierarchy and served as a vehicle through which affection and discipline were enforced. Punishment evo lved from brute force to subtle manipulation. Favorite methods of control were connected with food. A child was expected to eat everything that was given to them by their mother. Open detest to certain foods was rewarded with an additional portion. Violation of house rules resulted in having to go to bed without dinner. The constant expectation of the family to remain within their social stations made the ' ideal ' bourgeois family a structure of powerlessness.2

FOOD AND BODY IMAGE The growth of human sciences in the eighteenth century brought about a change in societal body size norms. Physicians began to propagate a moderate lifestyle for optimal health. Later in the century, numerical measurements became the key in assessing an individual's health and use of moderation. It was at this time that weighing became part of the physical exam. There was an increasing aversion to obesity that was experienced by males and females differently. Males were encouraged to attain and

maintain a moderate body we ight for health benefits. This was argued on the basis of Darwin 's idea of surviva l of the fittest. The healthiest individuals would live the longest and benefit ocially and materially from what their good health wo uld allow them to do . The propagation of a new idea l body fo rm for women , however, was minimally related to thi s medi ca l arg ument. The ideal of slenderness only gradua lly manifested itself on society. As newspapers and magazines began to show slender models and advertise means of achieving this ' ideal ' body weight, women began the now so commonly seen ritual of observation, comparison and correct ion . The ornamental mirrors of the earlier centuries now became household necessities by which women co uld assess themse lves. Photography was also emerging at this time and allowed greater precision in assessi ng one's own body. 2

THE CHANGING FEMALE ROLE The end of the nineteenth century saw the firs t wave of the female fight for ocial and political emancipation among the middle cia s. The role of the female - as a loya l wife and devoted mother responsible for protecting the middle class values - was thought to be undermined by this movement. The ultimate role of the female as the personification of motherhood and thus the middle c lass idea l of morality was now felt to be under attack. Conservative groups began to appeal to the "moral strength" of women to fulfill their roles. This conflict gave rise to mi sogyny directed towards the " new woman" . A young female growing up in these times would find it difficult to find the existence of a middle ground omewhere in between the old threatened ideologies and the movement towards a new ideology. She was faced with the emotional and intellectual dilemma of choosing between family and career. 2

THE EMERGENCE OF ANOREXIA NERVOSA The middle class female growing up in the late nineteenth century was faced with a number of stresses that were different from those experienced by her historical co unterparts. The changes in family structure placed greater confines on her actions and behaviour. As general nutrition improved, adolescence was experienced much earlier on while individuals were getting married at an older age. This increased the amount of time spent in the parental home and increased the intensity of parental love and consequently a feeling of claustrophobia within the family. Frustration grew as the sexually mature female confined by societal ideologies was forced to fill the role of an asexual being.2 The development of a new body image and the rise of the ' new woman ' movement increased the number of conflicting issues that females of the time had to face . In a quest for psychological "separation" and autonomy, the young female sought a new lever with which to fight the authoritarian influences in her life. 5 Self-starvation became an ideal choice. In a time when family affection and endearment were paramount, the threat of self-destruction by starvation elicited immediate action by the middl e class parents. Thus emerged the new disease of anorexia nervosa . The condition - l' anorexie hysterique ' - was first described by Lasegue in 1870. 4 There were three general phases. During the first phase the patient (between 15 and 20 years old), in response to a broad set of frustrations linked to adolescence,

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began to express a general uneasiness after eating - she would complain of a vague sensation of fullness or sudden pain that was unrelated to the type of food eaten. In the second phase the patient's "mental state" intensified and food became the sole object of preoccupation and conversation. She believed that her refusal to eat was a cure to her problems. In the third phase physical deterioration was explicit. Symptoms consisted of emancipation, debility, anemia, amenorrhea chronic thirst, dry/pale skin, unremitting constipation, atrophied stomach, vertigo, and fainting. 4 Treatment included removing the patient from the family and forceful feeding. 6 Self-starvation had entered a new phase of its history. The emergence of the "new woman" occurred concurrently with the climax of various other societal developments : the fight between the church and science, the ideals of the bourgeois family, forbidden sexuality, and evoking adolescence. It is interesting to note that the socio-cultural changes that resulted in increased affection and closeness within the family structure also resulted in the evolution of the modern day familia l characteristics that seem to predispose females to anorexia nervosa: enmeshment, over protectiveness , rigidity, and poor conflict resolution.

Although modern society is free from being on the verge of major changes in societal ideologies, anorexia still has a stronghold on the young. While the disease was confined to the middle class in the 19th century, anorexia nervosa now shows equal distribution among females of all social classes. One percent of young adolescent women have anorexia nervosa and, as its incidence and prevalence are increasing, this number can be expected to grow in the future. REFERENCES 1. Showalter E. Th e f emale malady : women, madness, and English culture, 183 0-1980. New York: Pantheon Books; 1985. 2. Vandereycken W. Van Deth R. From f asting saints to anorexic girls. New York: New York University Press; 1990. 3. Bell R. Holy anorexia. Chicago: University of Chicago Press; 1985. 4. Brumberg JJ Fasting girls: the emergence of anorexia nervosa as a modern disease. Cambridge, Mass: Harvard University Press; 1988. 5. Shorter E. Th e fi rst great increase in anorexia nervosa. Jo urnal of Social Hist01y 1987; 2(1): 69-96. 6. Bliss EL, Branch CH. Anorexia nervosa: its history, psychology, and biology. New York: Paul B. Ho ebe1; Inc; 1960.

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UWOMJ 72(1 ) 2002

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Feature Articles

Advances and treatment of malignant hyperthermia - A Review

Chris Brooks, Meds 2003

Malignant hyperthermia is an autosomal dominant condition which can present with exposure to volatile anaesthetics, and the non-depolarizing muscle relaxant succinylcholine. These two classes of drugs are known as triggers. Pig animal models suggest that malignant hyperthermia is the direct result of excess intracellular Ca2+ in skeletal muscle cells, which culminates in a state of hypermetabolism within these myocytes. During or shortly after administration of a triggering agent, the patient will typically present with two or more of the following signs: hypercarbia, lactic acidosis, muscle rigidity, tachycardia, hypertension. The immediate treatment of malignant hyperthermia involves the removal of triggering anaesthetics and the administration of dantrolene, which is known to inhibit the entry of Ca2+ within the muscle cell cytoplasm. Supportive care, oxygenation, and treatment of acidosis and electrolyte disturbances are vital. Family members at risk of carrying malignant hyperthermia gene(s) should be screened with an in-vitro muscle contracture test. All patients with malignant hyperthermia and those who are potentially susceptible are advised to alert their anesthesiologist of their condition prior to any surgical procedure. With appropriate management, individuals with malignant hyperthermia or those considered malignant hyperthermia susceptible can safely undergo anaesthesia.

INTRODUCTION

PATHOPHYSIOLOGY

Malignant hyperthermia (MH) is most accurately described as a syndrome of striated muscle hypermetabolism, resulting in the classic presentation of hyperpyrexia and rhabdomyolysis. The first documentation of MH appeared in The Lancet in 1960, after two Australian physicians noted a peculiar reaction to halothane, a general anaesthetic, in a 21 year old patient.! This case was intriguing given the fact that 10 of this patient's family members had died during or shortly after administration of an anaesthetic. Following this initial report, similar cases began to appear in other regions of the world. However it wasn 't untill966, at a symposium in Toronto, that the term "malignant hyperthermia" was coined. The term stemmed from the rapid rise in body temperature and the nearly complete (70%) fatality that accompanied all known cases at the time.2 Today, MH has come to embody a far more complex syndrome. MH is now known to affect 1 in 15,000 children and 1 in 50 000 adults with 50% of initial presentations occurring prior to ' age' 15.3 As was the case in 1960, most individuals with MH appear to be in good health, with no clinical findings on physical exam. However, they possess a subclinical myopathy, and with exposure to the appropriate anaesthetic triggers they can quickly be in a life threatening circumstance.

The MH swine animal model, discovered by Hall and colleagues in 1966,4 reveals that MH is caused by abnormal Ca2+ influx into the myoplasm of skeletal muscle cells. More specifically, the clinical manifestations of MH are directly correlated with an abnormally elevated level of intracellular Ca2+ within striated myoplasm. The resulting increased in muscle rigidity and destruction, as well as ATP hydrolysis, manifests clinically as tachycardia, hypercapnea, hypoxemia and hyperthermia.s Given the fact that the majority of the intracellular Ca2+ is stored within the sarcoplasmic reticulum (SR) within each myocyte, the preponderance of genetic research has been focused on mechanisms of Ca2+ regulation within the SR. Using the swine animal model, and human muscle biopsies, researchers have deduced that MH is caused by defects within a SR Ca2+ channel or its regulation. These defects lead to a lowered threshold of Ca2+ release under anaesthetic triggers. 6 The most common gene mutation, resulting in an autosomal dominant transmission, has been linked to the RYR gene ( 19q 13 .I) which encodes for a Ca2+ channel in the SR.7 Unfortunately RYR mutations account for less than 5% of the affected individuals, with the remainder demonstrating a polygenic, multifactorial mode of inhereitance. 8

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MHTRIGGERS Ironically, the majority of the triggers of MH are the most commonly used general anae thetic in the world today. Among the anaesthetic agents reported to have cau ed MH are halothane, enflurane, isoflurane, sevofl urane, desflurane, methoxyflurane, cyclopropane, ether, succi nylcholi ne and decamethonium. 9 Unfortunately, the onset of MH to uch agents is highly unpredictable; ranging from minute after anae thetic induction, to 26 hours post surgery. I o The situation i made even more complex when it is factored in that 50% of affected individuals had previously tolerated a triggering anaesthetic without an MH episode. 11 It i believed that there are several factors that may aid in attenuating an MH reaction, uch a premedication, brief duration of anaesthetic and metabolically depre sant induction agents .12

HOW TO RECOGNIZE A MH EPISODE Although the hallmark sign of MH is a hi gh core temperature, this is in fact a relatively late finding . Far before detecting an elevated temperature, an observant ane thesiologist will most likely notice increased muscle rigidity, tachycardia, hypertension, elevated end-tidal C02 tension (ETC02) and perhaps lactic acidosis .13 Of the early signs of MH , the earli est and most striking will likely be an elevated ETC02, with an accompanied breakthrough increa e in respiration . The patient is confirmed as being the ource of the C02 if increases in minute ventilation and a flow rate of I OL/minute does not correct the hypercarbia.14 Hypercarbia alone is not sufficient to confirm an MH episode. A diagnosis of MH w ill require the concomitant presentation of at least two of the early signs mentioned above, and will often include masseter muscle rigidity or trismus as one of them. Masseter muscle rigidity ha been reported in 50-70% of confirmed cases. IS Another highly sensitive finding in MH is an e levated serum creat inine kinase (CK) leve l, often greater than 20,000IU/L. Unfortunately this is a very non-specific finding, and is usually only elevated two to three days following an MH epi sode , and is therefore used to confirm any suspicions concerning the diagnosis .16 Despite the fairly limited signs, a diagnosis of MH is made much more difficult by the fact that each sign alone is very nonpecific and that MH can present hours following the discontinuation of all anaesthetic agent .

HOW TO TREAT A SUSPECTED MH CRISIS If an MH episode is suspected based on any combination of the above clinical signs, the inhalational anaesthetic should be di scontinued immediately and the surgery interrupted or postponed pending the results of formal MH tests. In many instances, this may be enough to arrest an MH episode.l7 In the event that surgery can not be postponed, discontinue known anaesthetic tri ggers, and institute safe agents such as nitrous oxide, non-depolarizing muscle relaxants, propofol, barbiturates, ketamine, droperidol , opioids or local anaesthetics.1 7 In cases of fulminant MH (PaC02 greater than 60nunHg and rising, base deficit less than -5mEq/L and falling, and temperature increase of 1.5째C every 15 minutes) the following treatment protocol is advised: 18 12

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Discontinue triggering anaesthetics and hyperventilate with 100% 02 at I OL/min. Change the circle system and C02 absorbent on the anaesthetic machine. Administer dantrolene sodium 2-3mg/kg bolus, with increments up to 1Omg/kg total. Continue dantrolene until signs of MH are controlled . Administer bicarbonate to correct the metabolic acidos is. Actively cool the hyperthermic patient. Correct any dysrhythmia using standard agents, w ith the exception of calcium channel blockers (they can cause hyperkalemia with dantrolene). Monitor ETC02, arterial and venous blood gases, serum K+, Ca2+ and urine output. After the acute episode has s ubsided, it is recommended that dantrolene be continued for 24-48 hours (1 mg/kg IV q 6hrs) and that the patient be monitored for at least 24 hours in ICU.1 8 Dantrolene wa first di covered to reverse MH crises in pigs in 1977 and has since become the drug of choice for the treatment and prevention of MH in humans .19 Dantrolene is a diphenylhydantoin analogue, which selectively binds skeletal muscle SR Ca2+ channels, thereby inhibiting the abnormally high levels of intracellular Ca2+ seen during an MH episode.2o The discovery of dantrolene has resulted in the sing le most beneficial effect on the prognosis ofMH, reducing the mortality rate ofMH from 70% in 1966 to 10% currently. 21

CONFIRMING THE DIAGNOSIS The most accurate diagno i of MH requires the successful urvival of an MH crise . The econd best diagnostic tool, and go ld standard for screening patients at risk of MH, is in-vitro muscle contracture test , which has a sensitivity of97 percent and specificity of 78 percent.22 Given the potential for hazardous events during future urgeries and the possibility of an autosomal dominant pattern of transmi ion, patients with equivocal presentations and family members of confirmed MH susceptible patients should be coun eled to undergo in-vitro muscle contracture testing. The te t involves a sessment of muscle strips obtained from the va tus laterali (usually), for their increased ability to contract under normally subthreshold stimuli . A positive re ult, using the North American protocol, is a contracture of at least 0.7g with 3% halothane (triggeri ng anaesthetic) or at least 0.3g with 2mmol/L caffeine. 22 A patient or family member with a positive in-vitro muscle contracture test should be counseled regarding the implications of being MH susceptible. This will include a simple explanation of the condition, its possible future mode of transmission, and possible co-existing condition such as heatstroke, rhabdomyolysis, muscle pains, central core di ease, neuroleptic malignant syndrome and sudden infant death yndrome or SIDS .23 Perhaps most importantly, all people with confirmed MH shou ld be instructed to alert their condition to their family physician and future anesthe iologists. This may also be achi eved by acquiring a Medic Alert bracelet indicating they are

MH susceptible and must avoid volatile halogenated anaesthetic agents and succinylcholine. Patients should also be encouraged to contact the Malignant Hyperthermia Association at Toronto General Hospital for more information regarding the disease. All people who test positive for MH through the in-vitro muscle biopsy screen or those who have had a treated episode of MH should be registered with the North American MH registry to ensure their safety in the event of future anesthetic exposures.

ANAESTHETIC USE IN KNOWN MH PATIENTS

Previous MH triggers and a family history of MH are part of all preoperative anesthesiology questionnaires and a vital part of the anesthetic preoperative history. For those with a positive family history of MH, it is important they be reassured that they can receive an anesthetic safely. In fact no patient with known MH of a family history of MH has died as a result of an anesthetic .24 To avoid exposure to commonly used triggering anaesthetics it is recommended that the tubing and C02 absorber be changed on the anaesthetic machine, as well as removing all vaporizers and flushing the system with 0 2 at lOL/minute for 20 minutes .24 Of course it goes without saying that only trigger free general anaesthetics should be used for induction and maintenance. It is recommended that adequate dantrolene and sodium bicarbonate be at hand in the event of an MH reaction.24 All hospitals that employ the use of triggering agents are required by certification law to keep a minimum of 36 vials of dantrolene on site in the event of an MH reaction. During the administration of the anaesthetics , the patient's ETC02 and core temperature should be monitored, and there should be a ready venous access for sampling.25 Despite the safety of non-triggering general anaesthetics, both patient and their anesthesiologist may prefer to employ regional anaesthetic. Both ester and amide local anaesthetics have been used without incident in MH susceptible humans .26

10.

CONCLUSION

21 .

Historically a devastating familial disease causing death during anesthesia and surgery, MH has become a genetic disease treatable with early recognition, prevention and screening. For that reason, the anesthiologist never keeps a diagnosis of MH far out of reach when an otherwise healthy patient takes a rapid turn for the worse. Fortunately, with the di scovery of an appropriate animal model , researchers have been able to delineate a great deal of the pathophysiology and treatment of MH. Perhaps with the completion of the human genome project it may one day be possible to screen for MH susceptibility; thereby minimizing the potential threat this disease poses to surgical patients.

11 .

12. 13.

14.

15. 16. 17. 18.

19.

20.

22.

23. 24.

25. 26.

Mickelson JR, Ross JA , Reed BK, Louis CF En hanced Ca2 +-induced calcium release by isolated sarcoplasmic reticulum vesicles from malignant hyperthermia susceptible pig muscle. Biochemical Biophysical Acta 1986; 862:318. McCarthy TV. Healy JMS, Heffron JJA , et a/. Ryanodine receptor is a candidate fo r predisposition to malignant hyperthermia. Nature 1990; 343:562-4. Deufel T, Golla A, lies D, et a/. Evidence fo r genetic heterogeneity of malignant hyperthermia susceptibility. American Journal of Human Genetics 1992; 50:1151-61. Gravenstein N, Kirby RR. Eds. Complications in Anesthesiology, 2nd ed. Philadelphia: Lipponco/1-Ra ven Publishers, /996: 141-162. Murphy AL, Conlay L, Ryan JF, Roberts JT. Ma lig nant hyperth ermia during a prolonged an esth etic fo r realla chment of a limb. Anesthesiology 1984; 60:149. Halsall PJ, Cain PA , Ellis FR. Retrospective analysis of anaesthetics received by patients before susceptibility to malignant hype1py rexia was recogni::ed. British Journal ofAnaesthesiology 1979; 51: 949. Gravenstein N, Kirby RR. Eds. Complications in Anesth esiology, 2nd ed. Philadelphia: Lipponco/1-Ra ven Publishers, 1996: 141-62. Layon AJ Anesthesia : physiology and pas/an esth esia problems. In JM Civella. RR Kirby, RWTaylor Eds. Critical Care, 2nd ed. Philadelphia : JB Lipponcott, 1992:581. Ryan JF Malignant hyperthermia. in CJ Cote, eta/ Eds. A Practice of Anesthesia for Infants and Children, 2nd ed. Philadelphia: WB. Saunders, 1993:626-9. Schwart:: L, Rockoff MA , Koka B V. Masseter spasm with anesth esia: incidence and implications. Ane th esiology 1984; 61 :772. Denborough M. Malignant hyperth ermia. Lancet 1998; 352:1131-6. Gravenstein N, Kirby RR. Eds. Complications in Anesthesiology, 2nd ed. Philadelphia: Lipponcott-Ra ven Publishers, 1996: 141-62. Em ergency th erapy for malig nant hyperth ermia . Westport, CT: Malignant Hyperthermia Association of the United States, 1993. (also fo und on W1Vlv.mhaus.org) Harrison GG. Th e prophy laxis of malignant hyperth ermia by oral dantrolene sodium in swine. British Journal of Anaesthesiology 1977; 49:1-4. Ben Abraham R, Cahana A, Krivosic-Horber RM, Perel A. Malignant hyperthermia susceptibility: Anaesthetic implications and risk stratification. QJM 1997; 90: 13-8. Harrison GG. Dantralene-dynamics and !.:1netics. British Journal of Anaesthesiology 1988; 60:274-86. Larach MG, Landis JR, Shirk SJ, Dia:: M. Th e North American Malignant Hyperthermia Regishy Prediction of malignant hyperth ermia susceptibility in humans: Improving sen itivity of th e caffeine halothane contracture test. Anesth esiology /992; 77:A 1052 Denborough M. Malignant hyperthermia. Lancet 1998; 352: I 131-6.25. Ryan JF. Ma lignant hyperthermia . In CJ Cote, eta/ Eds. A Practice of Anesth esia for Infants and Children, 2nd ed. Philadelphia: WB. Saunders. 1993:626-9. Gravenstein N, Kirby RR. Eels. Complications in Anesthesiology, 2nd ed. Philadelphia: Lipponcoii-Raven Publishers, 1996:141-62. Berkowit:: A, Rosenberg H. Femoral block with mepivacaine fo r muscle biopsy in malignant hyperth ermia patients. Anesth esiology /985; 6]:65 1.

REFERENCES 1. Denborough MA , Lovell RRH. Anaesthetic dea ths in a f amily. Lancet 1960; ii:45. 2. Gordon RA . Malignant hyperpy rexia during general anesthesia. Canadian Anaesthesiology Society Jouma/1966; 13:415. 3. Sh路a::is KP, Fox AW Malignant hyperth ermia: A review of published cases. Anaesth etics & Analgesia 1993; 77:297-304. 4. Hall LW. Woolf N, Bradley JWP. et a/. Unusual reaction to suxamethonium chloride. British Medical Journa/1 966; 2:1305. 5. Denborough M. Malig nant hyperth ermia. Lancet 1998; 352:1 131-6.

UWOMJ 72( 1) 2002 13

Off-pump computer-enhanced robot assisted endoscopic coronary artery bypass grafting: Cardiac surgery in the new millennium

M.R. Danter, Meds 2003 D.M. Pay ne, Meds 2003 WD. Boyd, MD, FRCS(C) Associate Professor, Department of Surgery, Th e University of Western Ontario Consultant Cardiac Surgeon & Director of Min imally Invasive Cardiac Surgery, London Health Sciences Cen tre- University Campus

Coronary artery bypass grafting (CABG) is a viable treatment for relief of coronary artery stenosis. This procedure has remained relatively unchanged since its conception, typically involving a large midline incision, cardioplegia and maintenance of systemic blood flow using cardio-pulmonary bypass (CPB). It can result in considerable incisional pain and lengthy hospital stays. CPB is also associated with neurological sequelae, renal failure and microemboli. Consequently, less invasive techniques utilizing smaller incisions and eliminating the use of CPB are being investigated. These techniques have recently been merged with robotic microsurgical systems and advanced imaging. Recent success in Europe using robotic techniques confirmed the feasibility of robotic assisted CABG in humans. Cardiac surgery came closer to a truly closed chest procedure without CPB or cardioplegia when surgeon s at London Health Sciences Centre (LHSC) performed the world 's first totally endoscopic coronary artery bypass on a beating heart. The Zeus system, used by surgeons at LHSC, consists of three main components: a surgical console providing surgical " tete-presence", a computer console for digital interpretation of the surgeon's movements, and robotic manipulators that translate the surgeon's motions to the endoscopic instruments. Patient eligibility is assessed pre-operatively and is currently limited to those with single vessel disease or patients with multi-vessel disease that are candidates for a staged robotic bypass/percutaneous angioplasty or stent " hybrid" procedure. Initial results are promising with decreased pain, perioperative morbidity, postoperative ICU and hospital stay. Surgeons at LHSC have proven the technical feasibility of robotic assisted endoscopic coronary artery bypass surgery on a beating heart. However, long-term evaluation of these revolutionary techniques is required before advocating their widespread appli ation .

INTRODUCTION Cardi ovascu lar di sea e claims more li ve ann ua lly than the next 8 leading causes of death comb ined' , and i c hemic heart di sease remain s the single leading ca use of morta li ty in North America . Coronary artery bypass graft (CABG) surgery is a viabl e trea tm ent for re li ev in g coronary artery stenos is. Thi s procedure has re mai ned re lative ly un changed s ince its conceptio n, typica lly invo lvi ng a large inci s ion to plit the breastbo ne and o pen the chest cavity. The hea rt is then arrested and systemic blood flow is maintained u ing ca rdio-pulmonary bypass (CPB). While th ese procedures provide th e surgeon with optima l visualiza tion and ex posure of th e hea rt, they have several drawback . Fir t, there is cons iderabl e incis ional pain and prolonged le ngth of post-operative hospital tay. In addition , C PB is associated wi th del eterious effects suc h as memory loss, stroke, coagu lopathy, 14

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renal fai lure, microemboli2 and increa ed intra-operative transfuion req uirementsJ. The e shortcomings prompted investigations o f less invasive bypass techniques that utili ze sm aller incisions and e liminate the use of CPB 4 . This s igni fica ntly reduces pain , morbidity, surgical costs and recovery times. These second-generation techniques u ually empl oy e ndoscopes, three-dimensional visuali zation system and coro nary artery stabi Iization systems that all ow the anastomos is to be performed via sm a ll er incision s between the ribs . There are, however, limitatio ns to these urgical approaches . Long instrument are required whi c h limit dexterity and can accentuate tre mor. In addition, minithoracotomy and minima l access incis ions make anastomo is to more late ral coronary vessels difficult due to buttress ing of insh路uments aga inst the chest wa ll6. The e conventiona l minima lly invas ive techniques, therefore, remain

cardiac surgery. Although they have different features, their basic design consists of three main components. A surgical console from which the surgeon manipulates instrument handles provides "tele-presence" of the surgeon within the che t cavity. This motion is digitized and interpreted by the second component of the ystem: a computer console. At this level, custom software eliminate tremor and sca les the motion of the su rgeon 's movements. The third component, the robotic manipulator receives this information from the com puter and translates the motion to endoscopic surgica l instruments , which are inserted The Zeus Robotic Computer-Assisted Microsurgical System. Shown in the foreFigure 1. into the che t cavity. ground is the surgeon's computer console from which the endoscopic microsurgical Surgeons at the London instruments are manipulated. In the background, the robotic arms are mounted on Health Sciences Centre utithe operating table providing surgical tele-presence. lized the Zeus robotic microsurgica l system to perform technically demanding for even the most skill ed su rgeon. the world 's first off-pump endoscopic coronary artery bypass on Recently, however, these techniques have been merged with robota beating heart (Figure 1). ic computer controlled endoscopic microsurgical systems and THE ZEUS ROBOTIC SURGICAL SYSTEM advanced imaging devices to enhance visualization and surgical The Zeus robotic microsurgical ystem is mounted on the precision. These modem computer enhanced instruments offer operating table and use three robotic arms that manipulate a increased mobility within the confined space of the chest cavity variety of endoscopic instruments. These anns are inserted into and allow for the dexterity needed to perfonn coronary artery the thoracic cavity through 5-mm inci sions. The first arm is an anastomosis. In addition, custom designed software can eliminate endo cope attached to a video camera and is inserted through the tremor and provides scaling of the surgeon's movements. The fifth intercostal space at the anterior axi ll ary line. The endoscope emergence of these robotic computer driven endoscopic dev ices is then attached to a voice controlled robotic camera holder such as the Zeus Robotic Surgical System (Computer Motion Inc., (AESOP, Computer Motion, Goletta, CA). The other two arms Goletta, California), voice activated digital visua li zation (AESOP, Computer Motion), and instrumentation wi th increased range of are inserted at the fourth and six th intercostal spaces at the midaxillary lin e. These arm manipu late the instrument invo lved motion have led a number of cardiac surgeons to re-investigate the in dissection and anastomosis of the bypa s graft. The modern utility of minimally invasive surgery. instruments provide the surgeon with 5 degrees of freedom corIn 1999, surgeons in Germany and France performed the responding to pan, roll , tilt, in/out and grasping motion world's first totally robotic assisted coronary artery bypass on humans7.8 Although these operations we re performed on an SURGICAL METHODS: arrested heart and used CPB, they confirmed the feasibi li ty of ENDOSCOPIC COMPUTER-ENHANCED CABG robotically assisted human CABG. This is an important step Patient eligibi lity is assessed pre-operatively. Initially, only towards the "Holy Grail" of minimally invasive surgery: a truly pati ents with single ves e l coronary artery di sease and good pulclosed chest procedure wit hout cardiop leg ia or CPB. In monary function test were elected. In addition, the presence of September 1999, thi s vision became a reality when surgeons at an intra-myocardial target coronary artery is a contraindication London Health Sciences Centre (LHSC) successfu lly performed for the microsurgical procedure. the world 's first totally endoscop ic coronary artery bypass on a Patients undergoing endoscopic coronary artery bypass beating heart. surgery are lightly anaesthetized, and receive minimal narcotics SURGICAL SET UP and benzodiazapines. Double lumen intubation is performed and the left lung is collap ed, in order to facilitate visualization and Presently there are two microsurgica l systems avai lable for

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working space. The intern al thoracic artery is then harvested endoscopically from the surgeon console usi ng a vo ice-controlled camera and robotic assistance. The pericardium is then opened endoscopically with the hannonic scal pel and the course of the anterior descending coronary artery is determined. In order to decrease motion of the beating heart, an articulating endoscopic cardiac stabilizer is placed between the ribs and guided to straddl e the target vesse l. Snare are then placed proximally and di stally to the proposed ite of coronary artetiotomy in order to control bl ood flow. Arteriotomy i then performed and an intraluminal coronary artery shunt is in erted to decrease bleeding and prevent ischemia. The internal thoracic artery is then anastomosed to the anterior descending coronary artery by remote tele-ma nipulation and vo ice activated robotic camera control. Intra-operative graft flow is verifi ed with a tran it-time ultrasound probe prior to closing the chest. Coronary angiography is performed in all patients prior to leaving the hospital to obj ectively assess the qua li ty of the anastomosis .

DISCUSSION The initi al success of the e endoscop ic cardiac procedures lends support for the research invested in advanced minimally invasive surgical techniques. Surgical interventions in cardiac surgery that avoi d median sterneotomy and cardi o-pulmonary bypa ignjfi cant ly decrea e pain and the associated risk of adverse cardi ova cu lar and neurological equelae . In addition, off-pump CABG is an attractive opti on for patients whose comorbiditi es put them at increased risk of surgica l mortali ty9. There are, however, a number of hurd le to be overcome in the evo luti on towards widespread appl ication of robotic ass isted endoscopic coronary artery bypass surge ry with out ca rdi opu lmonary bypass. The manipulation of the urgical handl e remains technically challenging and systems vary a to the tactil e (haptic) feed back available to the surgeon . Th erefore, accurate manipul ation during anastomosis, th e most crucial determ inant of a positive outcome, invo lves a learning curve. Training of surgeons in thi technique also po es a significant log i tical hurdl e. Port acce to the target ves e l may al o require alternative im ag ing technique in order to optimize in strum ent pl acement6. T hi is a signi ficant con ideration in that the robotic endoscop ic setup required to fac ilitate ana tomosis proved to be the most difficu lt part of the procedure10. This, combined with the overhead co t of the robotic sy terns, could potenti ally jeopardize the wide pread ava il ability of the technique and lim it it to a few academi c centre . Rega rdl es of these limitat ion the potenti al benefit including reduced pai n, morbidity and ultim ately cost and length of hospital stay are very encourag ing. Of cou rse, long term eva lu ati on of thi s revo luti onary surg ica l techniqu e is req uired be fore it wide sprea d appli cation . Undo ubted ly ca rdi ac s urgery will prove to be very exc iting in the new mill ennium .

ROBOTIC COMPUTER ASSISTE D SU RGERY IN THE FUTURE? The impli cation of robotic comp uter a isted urgery are exci ting and potentially far-reachi ng. The te le-presence ca pabi I ity of th e Zeus technology a ll ows for th e future application of remote s urgery. It co uld be pos ibl e in the future for a surgeon in 16

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North America to perform endoscopic surgery on a patient on another continent. In fact, NASA initially funded the development of the Zeus technology. They were interested in designing a system that could perform remote surgery on astronauts in orbit, or on prolonged journeys. The tele-presence applications of this technology could conceivably increase accessibility of tills exciting new procedure . Without question, robotic systems of the future will be smaller, cheaper and capable of sensing force-feedback. Computerenhanced mi crosurgica l instruments that incorporate " intelligent" robotics will assist new generations of surgeons. New optical systems that sense and digitize laser light will someday permit clear visualization in a moving blood fie ld allowing for intravascular cardiac repairs that are presently impossible. Despite the exc itement surrounding the future of cardiac surgery, we all must remember that the goal of this operation is long-term cardiac function , and not solely the enhancement of surgical technique. REFERENCES: I. Sweet CA . Today 's promising heartfrontier: minimally invasive surge/)'路 Today's Swgical urse. 1998; _0(1): 16-_/. 2. Scarlett MV. Minimally invasive cardiac surge1y: A new jrontie1: Critical Care ursing Quarterly /998; 21(1) :16-23. 3. Baumgarmer FJ, Yokoyama T. Gheissari A, Capouya ER, Panagiotides GP, Dec/us in RJ. Effect of off-pump corona1y arte1y bypass grafting on morbidity. Am J Cardiology 2000; 6:1021-1022. 4. Shennib H. Bastawisy A, McLoughlin J, Moll F. Robotic computerassisted telemanipulation enhances coronal)' artel)' bypass. J Th orac and Cardiol'asc Surg 1999; l/ 7(20):310-313. 5. Del Ri::::::o OF. Boyd IVD. Ol'ick RJ, McKen:::ie FN, De ai N. Menkis A H. Safety and coste-e.ffectil'eness of MIDCA BG in high-risk CA BG patients. Ann Thora Sw g 1998, 66:1002- 7. 6. Watanabe Go, Misaki T. Kotoh K, Kawakami K, Ya mashita A, Ueya ma K. Multiple minimalZl' invasive direct coronGIJ' arte1y bypass grafting fo r the complete rei'G culari:::ation of the left ventricle. Ann Thorac Surg /999; 68:131-6. 7. Reichenspumer H. Damiano RJ. Mack M, Boehm DH, Gulbins H, Detter . Meiser B. Ell ass R. Reichart B. Use of the l'Oice-controlled and computer-assisted surgical system :::eu for endoscopic coronal)' arte1:1' bypa s grafting. J Th orac and Cardiovasc Surg 1999; 11 8(1) : 1116. 8. Lou/met D. wpentierA . d 'Attelli N, BerrebiA, ardon C. Pon:io 0, Aupecle B. Reiland JYAI. Endo copi corona1:1' arteiJ' bypass grafting with th e aid of roboti a sisted instruments. J Thora c ardiova c urg 1999: II (1 }:4-1 0. 9. Tug tekin SAl. Gulielmos V. ichon R. Kapper! U. Marschke K. Knaut M, Schuler S. Off-pump surael)' for anterior l'essels in patient with sever dysfim ction of the left l'entricle. A nn Thora c Swg 2000: 70: I 034- 1036. 10. Boyd IVD. Rayman R. Desai NO. Menki s AH, Dabkowski JV. Ga napathy S. Kiaii B. Jablonsl.)' G. McKen:::ie FN. Novick RJ losed-chest coroncu:l' ariel)' bypass grafting on th e beating heart with the u e of a C0 /11 p uter-enhanced surg ical robotic systems. J Th orac and ardiovasc Surg 1000: 110(4):807-809.

Considerations for surgical management of traumatic injury under conditions of war and disaster

Brian Sullivan, Meds 2003

Medical personnel operating under conditions of war and disaster find themselves in situatio ns that demand their optimum knowledge, skill and ingenuity. Several areas of practice must be modified in or路der to meet these s.pecific challenges. Modifications must be made to include unsterile workin g conditions, inadequacies of eqmpment, and deluges of multiple, seriously wounded ca sualties. This article examin es anesth esia infection prevention, and blood and fluid management as they are performed under th e conditions of war a~d disaster. Total intravenous anesthesia is often used to overcome the logistical difficulties associated with inhaled ~nesthesia. T~e importance of adequate wound debridement and antibiotic prophylaxis of traumatic injur路ies IS str~ssed. F~nally, three creative albeit dramatic means of restoring fluid to volume depleted patients are descnbed to Illustrate the degree of unconventionality that is often dictated by au stere condition s.

INTRODUCTION The conditions of war and disaster present unique challenges to the effecti ve surgica l management of injuri es. Althoug h traumatic injury due to expl osion or gunshot is excepti onal under ordinary circum stances, such inj uries are co mmonly enco untered and obviously expected under conditi ons of war. In additi on, wa r and di saster further stress hea lth care prov iders with multiple cases of severe trauma simultaneously, demanding rapid and adept tri age.' M edi ca l personn el co nfronted w ith cri sis situati ons frequently fi nd them selves wi tho ut adequate manpower and equipment. Often the most bas ic expectations of th e operating theatre, such as steril e conditi on , adequate lighting, surgica l instruments and sufficient suppo rt staff are un ava il abl e.2 The establishment of modern, mobile faci lities during re li ef efforts or in ongoing conflicts by the military ca n enabl e personnel to achieve success in trauma management th at riva ls what is expected under non-disaster conditi ons. An example of parti cul arly effecti ve delivery of trauma management was achieved in 1995 during the war in Bosni aHerzegovina.3 The establ ishm ent of an excepti onally we ll equipped f ield hospital by the German military, inc luding ventilator units, radiology (including CT) and laboratory services offered victims of traumatic motor vehicle accidents and gunshot wounds advanced resuscitation and life sav ing surgery. In one case, a 14-year-old boy who sustained a gunshot wo und to the head was stabilized, ventilated and operated upon. His surgery included balanced tota l intravenous anesthesia, debridement and endoscopic removal of the bullet. Success in th is case was

achieved in a terile, we ll-lit operating th eatre eq uipped with mi cro-neuros urgica l instrum ents and access to a fu lly equipped intensive care unit. There are several areas of particular co n iderati on fo r medica l teams manag ing ca es of traumatic wa r inj ury. Specialized equipment, know ledge and techniques are often required to compensa te fo r logistical and material limitations. Expertise in these areas has deve loped thro ugh experience in treating traumati c injuri es in the wa rs of thi century with dramatic improvements in s urviva l being made in each subsequent ca mpaign . For example, abdomina l g unshot wo unds in World War I were fa tal in 70% of cases . In co mpariso n, similarly injured A merica n o ldiers in Korea and Vietnam experi enced a morta li ty ra te less than 20%.4 The advance mo t responsibl e for thi s improvement was the use of anti biotics, whi ch were fi rst employed in World War II by the A merican Army in Ita ly. Conco mitant advances in surgica l debridement and hemorrhagic shock management were nonetheless integra l to uch a dramatic improvement. Thi s article will investigate trauma management under austere cond itions with respect to three specific areas . Anesthesia under fie ld cond itions will be addressed with an empha is on the usefu lness and practica li ty of total in travenous anesthesia. A discuss ion of wound management wi ll ensue, particul arly considering infect ion prevention through effective de bridement and antibiot ic prophylaxis . Finally, blood volume management will be exp lored, a hemorrhagic shock is of paramount importance in maintaining life in the acutely, traumatica lly injured victim of war.

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ANESTHESIA While the basic anesthesiologic principles of airway management, vital sign monitoring and peri- and post-operative analgesia remain of utmost importance under conditions of disaster and war, achieving these objectives requires a specialized approach. The austere working conditions associated with disasters render the availability of standard anesthetic delivery and monitoring equipment uncertain. In particular, anesthesia ventilators and vaporizers are often unavailable and medical gas difficult to obtain and transport. I Therefore, total intravenous anesthesia (TIVA) is often employed to overcome logistic and resource challenges. Under extreme conditions, the rapid induction, ease of maintenance, and rapid awakening provide TIVA an advantage over standard anesthesia methods. Furthermore, the same agent used for anesthetization can be used as post-operative pain controLS Historically, ketamine has been a popular choice for anesthesia in field hospitals . It is useful for many indications, can be effectively administered through several routes (IY, IM, rectally, orally, intranasally, epidurally and intrathecally) and offers a range of anesthetic properties including amnesia, sedation and analgesia.s Moreover, it is stimulatory to the circulation (important in patients suffering hemorrhagic shock) and relieves bronchospasm which may be induced by concomitantly administered narcotics, such as oxycodone. In addition, it is the preferred drug fo r provi ding analgesia in entrapments, which are common in war trauma. 6 The principal drawback of ketamine, which is chemically related to phencyclidine (PCP), is its tendency to induce psychotic symptoms in as many as 60% of patients 5.7 Considering the amnestic effects of ketamine, though, the transient psychosis should not be prohibitive, particularly when alternative anesthetic options are not avai lable. A second drawback of ketamine has been elicited by Sawyer et al. in swine studies.& It has been shown that the chemical warfare agent sulfur mustard, used for its cytotoxic, mutagenic and vesicant properties, can have a disastrous interaction with ketamine. Pigs exposed to sulfur mustard who were then induced with 100 mg IV ketamine experienced inunediate apnea lasting 23 minutes. Thus, ketamine may be lethal if administered to a patient who has suffered chemical warfare attack and shou ld therefore be avoided whenever chemical warfare is occurring in conjunction with conventional ballistic warfare. An alternative TIVA protocol to ketamine has been described by Saissy et al. By combining the sedative propofol and the analgesic alfentani l in a simplified infusion, an adequate course of anesthesia was obtained .9 Although this mixture is no longer used for anesthesia under non-battlefield cond itions, it is practical and effective in remote locations.

WOUND MANAGEMENT AND INFECTION PREVENTION Traumatic injuries sustained in wars and disasters possess several characteristics, such as devitalized tissue, the presence of debris, and contamination by bacteria, that make wound management of paramount importance. A striking example of the dramatic circumstances of war that increased the risk of wound infection was encountered in Vietnam, in which Vietcong forces 18

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deliberately contam inated bullets with excreta before fi ring them. 10 In a survey of surgical cases during the Lebanese War (between 197 5 and 1986), wound infection was the primary complication, affecting 11.5% of all surgical patients and accounting for 37% of all surgical complications. II In addition, the comb ination of vitamin deficiency, malnutrition and inadequate access to sanitation puts victims of genocide and civil conflict in impoverished nations at higher risk of protracted wound healing and infection. The two broad categories of wound management are surgical debridement and antibiotic prophylaxis and treatment. An antibiotic regimen offering broad spectrum activity and a long half-life, such as piperacillin and tazobactam or ceftriaxone, should be administered before reaching hospital, especially if evacuation is delayed. 12 Ceftriaxone is particularly useful because of its high index of tissue penetration and broad spectrum . A broad spectrum is critical because injuries sustained under conditions of disaster and war must be expected to be contaminated by both Gram classes as well as aerobic and anaerobic organisms. Examples of organisms that commonly contaminate war wounds and cause a mixed infection are Pseudomonas aerug-

in osa, Streptococcus viridans, Bacteroides fragi lis, Escherichia coli and others of the Enterobacteriaceae family. Penetrating abdominal trauma poses significant infection risk, considering that the latter three are normal components of intestinal flora .l3 Other important practical considerations are availability, cost effectiveness and patient tolerance. Perhaps the most important practical issue relates to delivery; ceftriaxone can be administered in a single IV dose that will maintain potency for 24 hours, until surgical debridement can be completed. This alleviates the need for personnel to devote time to multiple administrations, which may be critical under disaster conditions of multiple casualties. Upon reaching the treatment faci lity, surgical debridement should be undertaken. Thi should be extended to excising all devitalized tissue and thereby eliminating a prime site for bacterial colonization. Upon completing debridement the application of a topical antibiotic, such as polybactrin, neosporin or sulfamylon, is an appropriate adjunct.l4 In addition, increased subfascial pressure and concomitant impairment of circulation should be a ses eel, considering the potential for compartment syndrome to occur. Relieving the subfascial edema by fasciotomy is tantamount to preventing compartment syndrome and avoiding its potential complications of limb loss and renal insufficiency secondary to myoglobin released fro m devitalized muscle. I . With a.dvanc~d .knowledge in wound care garnered through f1eld expenence, It 1s possible to achieve wound morbidity rates that are comparable to those seen in traditional hospitals. Lucha et al. reported an overall infection rate of 3.7% which is well wit~in the range expected fo r standard operating conditions.2 The1r use of a wound classif ication system which dictated whether anti?iotics would be used prophylactically (clean cases) or therape~tl cally as required (contaminated or frankly dirty cases) was mtegral to their success. BLOOD AND FLUID MANAGEMENT War wounds are typically penetrating explosive or missile trauma, making hemorrhage a principal concern in the majority

of casualties of war. Is The treatment of shock is complicated by the reality that blood sources may be absent or limited, depending on the circumstance in which the casualty is being treated. Moreover, complications such as coagulopathies are of particular concern during fluid replacement in the field because platelets are generally not available due to their short half-life.I6 In addition, septic trauma raises the risk for disseminated intravascular coagulation particularly when damage to the liver or pancreas has been sustained. I?, 18 A novel solution to these challenges is illustrated by a case in which an Albanian Kosovar man suffered multiple gunshot wounds to the chest, abdomen, ear and hand. Due to his admission with a hematocrit of 21 .6% and poor clotting, he received 6 units of PRBCs and four litres of crystalloid peri operatively. This large transfusion increased his blood volume without adding platelets, leading to thrombocytopenia and coagulation factor dilution coagulopathy. Platelets were unavailable and coagulation and platelet function tests (required to enable safe autotransfusion) could not be conducted. In response, healthy military personnel were solicited to provide fresh, cross-matched, whole blood. This rescued the patient from both his hemorrhage and coagulopathy, presumably saving his life.I6 It is interesting to consider that whole blood transfusions have their origins in World War I combat and they remain effective today under similar circumstances. While autotransfusion was not performed in the previous case, if lethal exsanguination is imminent and blood collection supplies are not available, primitive autotransfusion may be attempted as a last resort. This can be accomplished with resources as limited as an infusion set, a sterile funnel, open weave gauze as a filter and a scoop. Blood is collected from the thoracic or abdominal cavity and poured into a funnel connected to the infusion set which immediately returns the blood to the patient's circulation. I A final example of a means of expanding blood volumes in desperate situations involves the use of a fresh green coconut as a source of IV fluid. In impoverished, tropical countries where sterile IV solutions are not available, coconuts can be connected to an infusion set and infused directly in to the patient. The sterile nut milk contains electrolytes, water, carbohydrates, fatty acids, amino acids and indispensible trace elements in proportions that are tolerated well by the patient. The only adverse consideration is that the fluid is high in potassium. Nevertheless, in emergency cases, this method can rescue patients from severe shock and can also be useful to treat dysentery, cholera and malnutrition. I The previous three examples are intended to illustrate the degrees of creativity that were employed under increasingly limited conditions. This principal is integral to the treatment of war and disaster trauma patients where resources are limited. Prudent medical staff must be aware of its resources, able to manage them efficiently and be able to implement appropriate, albeit unconventional, approaches when necessity demands. Such approaches, although developed under tragic conditions, have advanced strategies of trauma management and proven useful in subsequent wars, disasters and even non-crisis trauma.

ACKNOWLEDGEMENT The author would like to thank Dr. G. Brock and Dr. G. E . Meads from the St Joseph 's Health Care Centre for kindly reviewing this article. REFERENCES 1. De Boer J, Dubouloz M, eds. Handbook of Disaster Medicine. Nieuwegein, Th e Neth erlands: Nentenaar hoek, 2000: 41-43. 2. Lucha Jr. PA , Wallace D, Pasque C, Brickhouse N. Olsen D, Styk S, Dortch M, Beckman Jr. WA . Surgical Wo und Morbidity in an Austere Surgical Environment. Militmy Medicine 2000; 165(1) : 13-16. 3. Madei WF, Klieser HP. In tensive Care Medicine in the German Field Hospital during th e Implementation Force Mission in Trogi1; Croatia. Milita ry Medicine 2000; 165(6) : 445-44 7. 4. Hell K. Characteristics of th e ideal Antibiotic for Prevention of Wound Sepsis Among Militmy Forces in the Field. Review of Infectious Diseases 1991; 13(Suppl 2) : S164-169. 5. Levanen J Ketamine and Oxy codone in th e Management of Postoperative Pain. Militmy Medicine 1999; 165(6) : 450-455. 6. Co ttingham R, Thomson K. Use of Ketamine in Prolonged Entrapment. Journal ofAccident and Em ergency Medicine 1994; 11 : 189-191 . 7. Kaplan HI, Saddock BJ Synopsis of Psychiatry. Williams and Wilkins; 1998. 8. Sawyer TW, Conley J, Hunter K, Lundy P. Hamilton M. Domestic Swin e Model fo r th e Assessment of Chemical Wm f are Agent-Anesthetic Interactions: Some Effec ts of Sulfur Mustard. Military Medicine 2000; 165(8) : 573-5 79 9. Saissy J, Bargues L, Servin F, Ducourau J Simplified Use of Mixed Propofol and Alfentanil f or Anesth esia in Remote Locations. Milita ry Medicine 2000; 165(3): 195-199. 10. Ja cobE, Setterstrom JA . Infection in War Wounds: Experience in Recent Milita ry Conflicts and Future Considerations. Milita ry Medicin e 1989; 154(6) : 311-314. 11 . Nassoura Z, Hajj H, Dajani 0 , Jabbour N. Ismail M, Tarazi T, Knoury G, Najjar F Trauma Management in a War Zone: The Labanese War Exp erience. The Journal of Trauma 1991 ; 31 : 1596-1599. 12. Czymek R, Lenz S, Dusel W. Prevention of Infection in War Wounds. Chirurgerie 1999; 70(10) : ll56-JJ62. 13. Kirton OC, 0 'Neill PA , Kestner M, Tort ella BJ Perioperative Antibiotic Use in High Risk Penetrating Hollow Viscus Injury: A Prospective Randomized, Double-Blind, Placebo-Control Trial of24 Hours versus 5 Days. The Journal of Trauma 2000; 49: 822-832. 14. Nichols RL. Surgical Wound Infection . American Journal of Medicine 1991 ; 91 : 54S-64S. 15. !lie N. Petricevic A, Radonic V. Biocic M, Petricevic M. Penetrating Thoraco-abdominal War Injuries. Int Surge1y 199 7; 82: 316-318. 16. Grosso SM, Keenan JO. Wh ole Blood Transfusion for Exsanguinating Coagulopathy in a U. S. Field Surgical Hospital in Postwar Kosovo. The Journal ofTrauma 2000; 49:145-148. 17. Mimica Z, Biocic M, Bacic A, Banovic I, maskovic J, Druzeijanic N, Frankovic E, Petricevic A. Th e Problems and Characteristics of Hepatic War Trauma Management in Central Dalmatia during the 1991-1995 War in Croatia. Milita1y Medicine 2000; 165(3) : 173-1 77. 18. May ben y JC, Sharma S, Delough ery TG, Mullins RJ Fatal Cerebroembo/ism fro m Nonbacterial Th rombotic Endocarditis in a Trauma Patient: Case Report and Review. Militmy Medicine 2000; 165(1) : 83-86.

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An assessment of Canada's health care system: Part 1 of 2

David E. Mula, ESc. MBA, Meds 2004

Health care is an iss ue at our very hearts as Canadians. It is based on need, rather than one's own ability to pay is what distinguishes our system from most others in the world. The problem is finding the funding for the system while maintaining other programs, keeping taxes reasonable, and controlling the deficit. Policy changes intended to achieve cost control in developed countries run the risk of introducing financial barriers to health care. Although problems faced are similar, different countries are dealing with the situation in different ways. Many nations have undergone changes in health care financing and services in the last decade to deal with the rising costs. Differences in methods to deal with these costs have led to problems in the access, financial burden, or quality of health care in the country. As governmental spending is tightened, there is growing desire for supplemental insurance by the middle class to assure high-quality care. Even the Canadian system, which has rejected the transformation to American-style medicine, is slowly edging that way, by cutting health services that are taken over by the private industry. Canada's population is aging, which increases the demands on health care. Therefore, the Canadian health care system will be experiencing severe shortcomings in the future if modifications are not made soon. It must develop new strategies in order to maintain the quality of life that we are accustomed to. A balance must be truck between quality of care and cost effectiveness to meet the needs of all Canadians in the next century.

Health care is an issue at our very hearts as Canadians. We take great pride i.n our system, ba ed on the five principl es of the Canada Health Act of 1984 : univer ali ty, access ibility, comprehensiveness, portability between provinces, and public adm ini stration .l The fact that the provi sion of health care is ba sed on need, rather than one 's own abi li ty to pay is what distinguishes our system from most others in the world . It is a lso one of the factors that has led to Canada's high ranking (first in the world) in th United Nation's Human Deve lopment Index, which inc lude iss ues such as infant mortality and life span .2 However, such a universa l y tern is not without its economic costs. Health care funding has , and will continue to be, one of th e major issues in Canadian politics. The problem is findi ng the funding for the system while maintaining other programs, keepi.ng taxes reasonable, and contro lling the deficit. Thi s is a difficult task, considering just how much is spent on health care: $76.6 billion in 1997 (up from $75 .5 billion in 1996).3 The system has not become tarved of fund s (as the politica l impression may eem), however, fisca l control have become much tighter. There is a revolution in Canadian health care taking place. The annua l flood of new money to the system, as was the ca e i.n the past, ha been reduced to a trickle. Health care is costly in any industrialized nation . In the 20

UWOMJ 72( 1) 2002

1980s and early 1990 , lowing the growth of total health care spending wa an important concern. Health poli cy was driven in mo t counh路ies by governmental budgetary pres ures , a well as a de ire to co ntrol ri ing taxes ..J Canada was no exception. The ea rly 1990s began with economi ts wondering how the country could maintain a ystem that wa consumi.ng an ever-larger hare of national resource . By 1992, health spending reached 10.2 percent of Canada' gro dome tic product (GDP), second only to the Americans. Through health care reforms via lowing the annual flow of new money, Canada 's health care spendi ng had decreased to 9.6 percent of the GDP by 1995. This placed Canada behind not only the Ameri can but also the German and French3, and this trend has continued. Policy changes intended to achieve cost control in developed co untri es run the risk of introducing financial barriers to health care. Although problem faced are imilar, different countri es are dea ling with the ituation in different ways . All have experienced rapid increases in the co t of medical and hospital serv ices, and many regard cost control their main aim . l Different types of cost control mechanisms have different implications for acce s. Canada and Au tralia , who share many simil aritie , have taken very different paths in the last decade. While Canada has preserved its universa l acce s, A ustralian policy has been pro-

moting a two-tier system through the provision of subsidies for private insurance. This policy of having a parallel private sector has been argued to be of great benefit to the community and government. People who use private insurance pay taxes as well as private health insurance charges. It th erefore relieves pressure on government financing . I However, thi s system only gives the best health service and choice to those who can afford it, neglecting those using the publ ic system . A lso, the private sector is partially subsidized, which takes funds away from the publi c system. I Recently, countries such as Portugal, Japan, and Iceland have resorted to the implementation of user charges to control costs . Several other countries have either implemented user charges or moderately increased fees in the 1990s. (Presently, the health care systems of Canada and the United Kingdom (UK) remain the only ones without direct user fees .) These measures have resulted in a marked slowdown in the growth of health expenditures in the 1980s and early 1990s. 1 Despite the popularity of user charges, most governments are unable to achieve all their goals. Cost control has improved but access to health care has decreased since user fees increasingly shift the financial responsibility onto consumers to relieve some of the pressures of rising costs.! Many nations have undergone changes in health care financing and services in the last decade to deal with the rising costs. Differences in methods to deal with these costs have Jed to problems in the access, financial burden, or quality of hea lth care in the country. The United States (US) is the only major industrialized nation that does not provide some kind of universal health insurance coverage.4 The result is that one in four people have reported at least some diffi culty in getting medica l care for themselves or family members . This is significantly higher than the average of 15% of populations reporting difficul ty with access in other industria lized nations such as Australia, New Zealand, the UK, and Canada.s Access problems in the US are mostly financial , with individuals having insufficient money or insurance to pay for care. In the other nations mentioned, waiting times for care comprise the major obstacle in gett ing medical care. Wai ting times are the longest in the UK, where 33 % waited at least four months for non-emergency surgery versus 1% in the US, and Ca nada being in the middle w ith 12%. [5] As indicated, wa iting times for medical services are sign ificantly longer in Canada (e.g. 150 days for an MRI vs. 3 in the US). However, despite the introduction of managed care in the US health care cost sti ll tend to be hi gher. This is illustrated by the ' median charge for total knee replacement urgery in the US being $26,805 vs. $ 10,651 in Canada. Data on aggregate expenditures shows that there is a one-third higher cost per person in the US 's privatized system than in Canada 's universal system (the equivalent to $3 00 billion extra per year). In addition , life expectancy at birth and at age 60 are both higher in Ca nada , indicating that the extra cost is not necessarily associated with superior health outcomes.6 Competition in the American private health care industry h ~s not resulted in decreased costs. The predom111antly publi c National Health Service in the UK produces services most cheaply, the US 's private system is the most costly, and Canada's is in between. I A government "monopoly" has the capacity to control

health expenditures. When a system has multiple private in surers, no one player has the capacity and/or incentive to attempt to control costs, which are shifted over to patients. Another reason for the high expenses of a private insurance system is administrative costs. It is estimated that 20% of the US ' spending is devoted to administration, marketing, advertising, and promotion, while administrative costs in Canada are a mere 1. 7% .1 With all this data, it is striking that other countries are beginning experience a breakdown in universal governmenta l hea lth care coverage. As governmental spending is tightened, there is growing desire for supplementa l insurance by the middle class to assure high-quality care.4 Much of Latin America is moving towards system s simil ar to that of the United States.7 Even the Canadian system, whi ch has rejected the transformation to American-style medi ci ne is slowly edgi ng that way, by cutting hea lth services that are taken over by the private industry. An interesting development in Canada has been that health decision-maki ng has become more decentralized in the last decade. The federal government is abl e to influence policy through the five national standards of the Canada Health Act, as well as through its financial transfers. However, its influence is limited. The federal government cannot regulate the prov inces, but can only co llaborate with them to develop national strategies for hea lth services and f inances. 1 While there are common objectives among the provinces: increased efficiency, fl ex ibility, integ ration, cost control, and communi ty pa1iicipation, the reforms being undertaken are very different. Some provi nces are eroding away authority from loca l bodi es, some are delegating managerial authority to lower leve ls, and authority is being centrali zed in others.! It is usually easier to cut costs or shift them to consumers in more decentralized systems. Governments wishing to cut costs attempt to pass responsibility to other levels of government or institutions. In a centrali zed system, such as that in Australi a, cost cutting/shifting is highly vis ible, and can eas ily arouse political controversy.! We would therefore expect to see the erosion of access in Canada to be greater than in Australi a, but the opposite is true . Despite cost cutting measures, Canada has maintained its principle of universa lity due to the political and public rejection of the privatization of hea lth ca re in thi s country. The lack of a strong federal governm ent influence on health care may impede Canada 's ability to deve lop a national strategy. Any strategy must be agreed upon by both the federal and the provincia l levels of government. This may be difficult, due to strong regional differences within Ca nada, as we ll as the issue of hea lth care being ex tremely sensitive to all Canadian s. Canada' health care system appears to be doing relatively we ll in the world at the moment. However, the medical needs of the population are not stagnant, and wi ll continue to change. Hon g Kong's govenunent, which has universal health care, is aggressively looking at ways to sustai n their system in order to meet the demands of an aging popu lation 2 Canada 's population is not immune to these effects that are being faced by the industriali zed countries. By 2020, 20% of Canadians wi ll be over 65 (more than double what it is now) . The Canadian elderl y is also living longer. The average health care cost of an e lderly individual is severa l times that of a yo ung Canadian. Therefore, the

UWOMJ 72(1) 2002 21

REFERENCES 1. Gray, Gwen. Access to medical care under strain : New pressures in Canada and Australia. Journal of Health Politics, Policy and Law

Canadian health care system will be experiencing severe shortcomings in the future if modifications are not made promptly. An optimal health care system would be one that provides universal quality care, while controlling costs. Recent trends in the Canadian system (reducing health care spending compared to GDP) have recently increased efficiencies and reduced costs to the system. However, the quality and access of service has been in question: long waiting lists, overcrowded emergency rooms. This has reduced Canadians ' confidence in the system , and has brought about public outcry. Health care costs will continue to increase due to inflation, increasing population, new technology and medications, an aging population, etc. Canada 's health care system must develop new strategies in order to maintain the quality of life that we are used to. A balance must be struck between quality of care and cost effectiveness to meet the needs of all Canadians in the next century.

Our journey toward renewal of the London hospitals continues.

1 998;23(6) :905-947. 2.

3. 4. 5. 6. 7.

Mille1; G. Ijller J1: Living in the Environment (ninth edition). 1996, Wadsworth Publishing Company. The High Cost of Healing: It s not how much, but where it s spent that counts most. Mac/eans 1998;111 (24): 16(1) . Davis, K. International health policy: Common problems, alternative strategies. Health Affairs 1999;18(3) :135-143. Donelan, K. , eta/. T11e cost of health system change: Public discontent in jive nations. Health Affairs (May/June 1 999):206-2 16. Bell, C., eta/. Shopping around for hospital services: a comparison of the United States and Canada . JAMA 1998;279(13):101-5 The Americas shift toward private health care. (Canada, Mexico, and South America). The Economist (US) 1999;351 (8 11 8).

London Hospitals

Building Together QONDON Jhâ&#x20AC;˘ l!h

IIâ&#x20AC;˘ t'S l

~SIJOSEPH'

www .londonhospitals.ca Building a future ... The vision for London Hospitals is not about new buildings; it's about providing our physicians and staff with the tools they need to give patients the best care possible . Toward that end much is changing . Emergency services will consolidate in expanded facilities at Victoria and University Campuses . A new tower will rise at the corner of Commissioners and Wellington roads and the facilities at South Street will begin to close . St. Joseph 's Hospital will become the focal point for ambulatory care and day surgery in the city. Through the efforts of our physicians , staff and leadership, we are able to sustain excellence in patient care , research , and teaching , while we work through this complex , yet exciting , transformation of London's hospital system . At the end of this journey, we will set a standard of health care excellence that will endure for generations to come .

Committed to providing the best health care system possible

UWOMJ 72( 1) 2002

An assessment of Canada's health care system: Part 2 of 2

David E. Mula, BSc, MBA, Meds 2004

If Canadians are to expect high quality health care, while controlling costs, major changes will be needed. Our

fee-for-service system may lead to over-treatment of fewer patients, however a salaried service may lead to the under-treatment of many. One method of improving the overall efficiency of the Canadian health care system (reducing wasted spending) is to restructure the fee-for-service system to contain incentives towards efficiency. Information technology has the potential to improve the efficient distribution of health resources. Since hospital care and emergency room treatment represent the most costly segment of the health sector, shifting care out of the hospital is essential. However, to be truly effective, alternatives must be established. Advances in surgical, drug and medical technology improve the speed, convenience and quality of patient care. By investing in disease prevention and health promotion now, rather than dealing with the symptoms later, there will be substantial savings. Privatisation and a two-tiered system are avenues that Canada may have to consider in the future. However, other less controversial methods of changing the concept of health care to make it not such a " free commodity" should be looked at as well. Health care is a very sensitive issue in Canada. What is certain is that health care costs will continue to rise. Reducing waste of health care dollars is the first and most important step in maintaining our system.

As Canada enters the next millenniwn , a key concern wi II continue to be the country's health care system. Our system, which guarantees access through the Canada Health Act of 1984, is one of the contributing factors to Canada's top rankings in the United Nation's Human Development Index. 1 However, Canada, like all other industri alised nations, is fac ing a f inancing cri sis with rising costs of health care. Thi s generates a common concern of how best to control the rate of growth in hea lth care expenditures, while maintaining good health care delivery. If Canadians are to expect high quality care, whil e controlling costs , major changes will be needed. The medi cal needs of the next century will be di ffe rent than that of the last: waiting lists are longer, emergency rooms are more overcrowded, and the population is getting older. If something is not done now to improve the situation and prepare for the fu ture, the health care services that we 've come to enj oy and expect wi ll soon no longer exist. One specif ic problem with Canada 's system is that the feefor- service structure incorporates a fi nancial ince nti ve to treat. Hence, the argument is that a physician may order more services per patient, and offer more spec iali st care than in a country such as the United Kingdom (UK), where doctors are compensated on a capitation basis (p er patient). 2 Also, it is much eas ier fo r patients in thi s country to seek second, third, and fo urth phys ician opinions. Therefo re, our fee-for-service system may lead to

over-treatment of fewer pati ents. However, a sal ari ed service, like that in UK, may lead to the under-treatment of many.2 Therefore, one meth od of improving the overall efficiency of the Canadi an health care system is to restructure the fee-forservice system to contain incentives towards efficiency. This system would eliminate the f inancial benefit of ordering wasteful and unnecessary treatments, but would have to also not encourage the undertreatment of more pati ents. Al so, guidelines specify ing situati ons whereby a pati ent would be all owed to seek second opinions would have to be establi shed. Informati on technology has the potential to support and improve health, through the development and implementation of a hea lth network system. The implementation of such a network may be coupl ed with the use of so called " smart cards". Such cards, which are relatively inexpensive and may replace ex isting hea lth cards, are able to store a great deal of patient info rmation, and may be updated periodi ca lly.-! Such a system will be able to improve the efficient di stribution of health reso urces, through the eli mination of much of the waste. If results of lab tests, and examinations of patients are entered onto this system, a phys ician will have easy access to thi s info rmation. Thi will enable health care workers to use this informat ion in a more efficient manner eliminating the need for repeating tests , calls from pharm acists' regarding treatment compl ications or incorrect prescriptions, and UWOMJ 72(1 ) 2002 23

reduce fraudulent use of the health care system . This w ill also allow phys icians to recognize if a patient has already seen a doctor for the same illness, potentially reducing the occurrence of patients seeking multiple opinions for the same symptom s. Perhaps a fundam ental change in how the health care system operates is in order. A change in the delivery systems to provide care at lower cost has been reviewed by numerous industria lised nations. Since hospital care is the most costly segment of the health sector9, countries such as Canada are seeking ways to shift care out of the hospital. Canada has already started such a movement, but has resulted in numerous hospital closures and bed reductions in some provinces .9 Consequently, alternate ways of reducing hospital care is needed . Advances in surgical , drug and medical technology improve the speed, convenience and quality of patient care. For example, laproscopic surgery reduces th e trauma and pain after an operation , and thus speeds up recovery.3 Canada has aggressively been pushing outpatient or day surgery, but at rates that are sti ll considerably lower than that of the United Kingdom.9 Such techniques can reduce hospital stay , and are therefore much more economically beneficial to the sy tern . Another method of reducing patient visits to hospitals is to make sure that there is incentive to go to emergency departments only when necessary. Canad ians must not be denied access to emergency care if needed, however, if the same care can be given in a clini c, that's where it should be done. A large proportion of emergency room (ER) visits are from peopl e who could be treated outside th e hospital. Since the cost to treat a person in the ER is more than twice that of treatment in a clinic, a shift must be made in both people's perception of what the hospital is for, and avai lability of care outside the hospital. Clinics wi th various hea lth care workers and a phys ician avai lable 24 hours is one way of avo iding hospital visits. Thi will give patients w ith relatively le s severe problems an option other than visits to emergency rooms . Most care wi ll then occur out of hospitals, with a great deal of em phas is placed on home-care systems . I I Thi s wi ll reduce usage of th e hospital for only operations, recovery, and life-threatening illn ess/injuries. A cost-cutting meas ure, whi ch indirectly affects health care expenditure is di sease preventi on and hea lth promotion . Some areas to emp hasise are immuni ation, hea rt disease and cancer prevention, early detecti on progra ms, alcohol and dru g abu e avoida nce, injury preve ntion , and anti -tobacco strateg ies. Programs specifi ca lly for children's hea lth should be a priority (prenatal care, postnatal in struction for parents, proper nutrition , protection from abuse or neg lect, etc.)3 ince hea lthy babi es make for hea lthi er adu lts. Also , recogni sin g th at some pati ents hou ld not be made to wa it for procedures is a necess ity. For exa mple, making an elderl y perso n wa it month before cataract surgery is illogica l, when we know that peopl e with ca taract have a much g reater chance of injury from falls whi ch ultimately costs th e y tern a g reat dea l more. 10 By investing in prevention now, rather than dea lin g with the symptom later, th ere will be substantial savings in the future, both financially and in quality of life. For th e future of th e anadi an hea lth care system, changes may have to be made on a fundamenta l leve l to adjust the system to meet the new chall enges of a chang in g environment (popu la24

UWOMJ 72( l ) 2002

tion demographics, technology, innovation, politics, etc.). Unfortunately, it is almost impossible for Canada to develop a national strategy on health care since there are so many differences throughout the country. There is also conflict between federal and provincial governments over this matter. The federal government has cut transfer payments to provinces over the past few years, covering 21.5% of health expenditures in 1997, compared to 30.6% in 1980.5 Health Minister Allan Rock has proposed to inject new money to the provinces, as long as Ottawa has some say over how the money is spent. Provincial governments call this an infringement on their jurisdiction.6 The two levels of government must resolve these differences if Canada is to develop separate regional strategies to resolve the potential health care crisis that may be developing. Provinces must develop programs to ensure the long-term viability of health care for their inhabitants. Programs such as Educating Future Physicians for Ontario (EFPO) make medical education more responsive to the evolving health care needs of Ontario society. 7 Provincial strategies must also be able to deal with physician over/under supply, geographic distribution, and specialty mix of phys icians . Policies can affect the number of new physicians entering medical school, treatment of immigrants with medical degrees, incentives to practice in rural areas, and the number and type of internships offered to physicians.s Such a strategic plan maybe to increase the number of family practitioners, or the number of physicians speciali sing in geriatrics, as these two areas will need to expand to meet the needs of an ageing population. Many countries are now leaning towards privatisation as part of their health care model in order to control costs and maintai n/improve the quality of care. " When health care becomes a free commodity . . . it is treated less seriously. It is abused in major or minor ways. People see doctors for colds . .. costs soar as they do in any state enterprise.' 12 Privatisation is one avenue that Canada may have to con ider. However, health care costs in the US are much higher than in countries with universal coverage, and the concept of such a system here would be absurd to most Canadians. An alternative would be a two-tiered system - supp lementation of the current public system with a parallel privatized ystem . Proponent of a two-tiered ystem would say that it lessens the pressure on the public system , and gives patients a choice to ga in access to care by paying for it themselves. However, opponents argue private access does not necessarily shorten waiting times, nor does it lessen the pre sure on public system. 13 In addition , such a system may go against the Canada Health Act, which guarantees universa lity. A two-tiered system would encounter a great deal of opposition in thi s country, thus other methods of chang ing the concept of health care to make it not such a "free commodity" should be looked at. One way is to charge a nominal fee (5 or 10 dollar) to ee a physician. Another one is to implement a hea lth care debit ca rd, which would give a tax rebate for using less hea lth care resotLrces than a set amount but yet not interfering w ith goi ng over that amount. 14 Both the e strategies do not interfere with the univer ality principle, and have the potential for eliminating wasteful health care spending. Health ca re is a very sensitive issue in Canada. People fear change; not understanding why it is necessary or that it is in their

own self-interest. What is certain is that health care costs will continue to rise. Reducing waste of health care dollars is the first and most important step in maintaining our system. Using technology, changing our concept of hospitals, disease prevention and health promotion, and perhaps looking into concepts of privatisation are just some options. There are numerous alternatives and the choice of which to embark on is not an easy decision, but action must be taken now in order to preserve both the quality and universality of care in this country. REFERENCES 1. Gray, Gwen. Access to medical care under strain : New pressures in Canada and Australia. Journal of Health Politics, Policy and Law 1998;23 (6): 905-94 7. 2. Eden, Ron, et a/. Benchmarking on costs in health care. Management Accounting. 1998; 76(3): 28-30. 3. Ontario Minis fly of Health Business Plan Jun e 1997. Available: www.gov.on.ca/MOH/english/pub/ministrylbplan97.hflnl#message 4. Neame, Roderick. Smart cards - th e key to trustworthy health information systems. British Medical Journa/199 7;3 14(7080):573(5).

5. 6. 7. 8.

9. 10. 11 . 12. 13. 14.

The high cost of healing: it s nor holl' much, but \\'here irs spent that counts most. Maclean 's 1998; lll (24): 16( 1). Lewis, Robert. Year of the report card. Maclean's (Ja n. 18, 1999):4(1). EFPO - Educating Future Physicwns for Ontario Project. Available: www. efpo. 01gluwo Sullivan, Robert B. , er. a/. The el•olut1on of divergences in physician supply policy in Canada and the United States. JAMA 1996;276(9): 704(6). Davis, Karen . Pagination 1999; 18(3): 135-43. Missing th e real issue in the medicare debate. Maclean's 1998, ill (24):61(1) . Came, Bany. A healthy debate: the forum explores visions for th e future. Maclean 's 1996; 109(49): 78(3). Amiel, Barbara. Ho w to preserve rhe health care safety net. Maclean's 1996; 109(49) .· 13(1). DeCoste1; Carolyn A. , et. al. Private health care in Ca nada: savior or siren? Public Health Reports 1997; 11 2(4):298(8). Gillies, James . The case for a health care debit card. Maclean s (Feb. 27, 1999)

GREY BRUCE

Health SERVICES Grey Bruce Health Services is one organization operating on seven sites in Grey and Bruce Counties. Our family physicians and specialists practice in the six hospitals and two clinics, ranging from Meaf?rd, Ma~kdale and Southampton in the south, Owen Sound m the rruddle and Wiarton, Lion's Head and Tobermory in the north, with a total of 360 beds. The Owen Sound site is a Level C referral centre with 238 beds and a full complement of consultants. Located two hours from Toronto on beautiful Georgian Bay and Lake Huron; enjoy swimming, diving, sailing, fishing, skiing (both downhill and cross country), hiking, golf, cycling, snowmobiling, Jr."A" Hockey, theatre, and Folk Fe.stlval are just some of the activities available in these recreatiOnal communities. We are looking for: • Family Physicians . • Internists (General, Rheumatology, Cardiology) • Obstetricians • Physiatrist • Psychiatrists • Pediatricians Interested parties are requested to contact: Sharon Winegarden, P.O. Box 1800, Owen Sound, Ont. N4K 6M9 519-793-4409 Fax 519-376-9760 Email: Blackdogpottery@BMTS .com

Learn more about exciting practice opportunities at River Valley Health in western New Brunswick, Canada by calling 1-877-538-5500 or visiting

www.rivervalleyhealth.nb.ca

~ rIll ~

RJver

Vall~ Health

Regie Santet Vallee

UWOMJ 72(1) 2002 25

A short history on the development of the suture

Eric Wong, Meds :!001

A suture is a strand of natural or synthetic material that is used to ligate blood vessels and to approximate tissue. Indirect evidence for the use of sutures dates back to 1600 BC. Direct references made to the usage of sutures to close wounds were first found in ancient Indian medical texts. Subsequently, the Greeks, Romans, and Arabs made valuable contributions to the development of the surgical suture. The Renaissance marked a return of the suture as a tool to achieve hemostasis. Major advances in the 19th and 20th centuries laid the foundation for the development of the plethora of surgical sutures available today. New horizons for the suture industry include research and development in antiseptic sutures and sutures with wound healing accelerating properties.

INTRODUCTION "Suture! " "I need more Vi cry!速" "More suture please! " These statements are heard so often throughout any urgica l operation that everyone in the operating theatre should have a basic knowledge about sutures. However, in the eyes of medical students, the "suture" is simply an anci ll ary part to a surgica l operation and there are usually grander topics for learning and di scussion. It is, therefore, the purpose of thi s artic le to provide some background understanding about sutures by rev iew ing major historical events in the ir development. A suture is defined as a strand of natural or synthetic materia l that is used to li gate blood vesse ls and to approximate ti ss ue. I

CHRONOLOGICAL DEVELOPME NTS OFTHE SUTURE It is estimated that eyed needl es were invented sometime between 50,000 and 30,000 BC, and there is speculation that these needles may have been used for sew ing.2 It wa not until 26

UWOMJ 72( J) 2002

approximately 1600 BC that hi torica l texts made reference to the act of stitching or clamping. These texts contained the oldest surgica l hi story known and were the Egyptian papyri that Edwin Smith , an Egyptologist, had boug ht aro und 1862. They were not published and translated until the 1900 's.2-4 Direct reference to the suturing of wounds was not found until the di scovery ofCharaka's Samhita, an Indian medical treati se that was written around 1000 BC. Another Indian surgical treatise, Susruta 's Samhita, was written about 400 years later. It li sts detail ed accounts of various surgical operations that incorporated the use of sutures. In particular, it described intestinal operations whereby wound closures were achieved by a particular spec ies of ants. 4 Such a closure procedure was achieved by allowing these ants to bite and clamp both sides of the wow1d, and then twisting off the their bodi es. 2 Ancient Greek manuscripts also made reference to the suturing of wounds . They described the cleansing of wound with wine and stitching with bronze needles .3 It was not until after the birth of the Roman Empire that another hi storical text about sutures was found . De Re Medicine was written by a Roman medical journalist by the name of Aurelius Cornelius Celsus around 30 AD. In his work, Celsus gave the f irst account of intestinal suturing and the clea nsing of

wounds with vinegar and wi ne before suturing. 2-5 About 100 years later, Caludius Galen of Pergamon , a Roman surgeon and physician for gladiator , wrote an extensive co ll ection of over 400 medical treatises. In his treati ses, Galen recommended the use of ligature to stop bleeding and reported the suturing of musc les and tendons .3·4 In De Methodo Medendi, he described "catgut" as a suture that has been used since ancient times and was made from intestines of herbivores) According to Galen, catgut was used because it was sh-ong and was ava ilabl e from musicians. It is believed that catgut came from the word " kitgut", where " kit" referred to a musical in trument.2.4 Arabic physicians continued to develop the suture after the collapse of the Roman Empire.s Rhazes (in latinized form), was born in 852 AD and introduced abdominal suturing with catgut.4.5 The "Prince of Physicians", Avicenna of Eastern Ca liphate, was originally a religious scholar who only later studied medic ine . He was the " Prince of Physicians" because of hi s exten ive, recognized writings on philosophy, natural hi story, mathemati c , law and medicine. His contribution to the development of the suture was the construction of the first monofilament suture using pi g bristles after he reali zed that traditional sutures such as linen broke easily in the face of gross infection 2 Then there was the " Prince of Surgeons", Albucasis, who was born in 936 AD. He wrote AI- Tasrif, a collection of thirty volumes of writing pet1aining to medicine. And within it, there were three surgical volumes that had detailed descriptions of hi s surgical operations and illustrations of the surgical instruments that he used . He also described the use of ants for wound closure.s Infection, hemorrhage, and pa in prevented further advancement in utures until the Renaissance) Prominent individuals who contributed to the development of the suture included Ambroise Pare, a French military surgeon . He reintroduced the use of sutures as an alternative to cautery by hot irons and boiling for achieving hemostasi s in 1555 .2 Following Pare, Andreas Vesalius, a Belgian, published anatomical drawings of the human body and advocated the suturing of all wounds and severed tendons .2.4 William Harvey further contributed to the popularity of ligature usage by publishing a book on the human circulatory system. The 19th and 20th centuries marked a time when important advancements in sutures were made. These developments were led off by Joseph Lister, who, after accepting Loui s Pasteur's ( 1822-1895) attribution of infection to microorganisms, began to use carbolic acid to destroy bacteria during surgical operations in 1867.3 Later, Lister recognized the need for sterile sutures and developed the antiseptic suture. It was made by soaking sutures through carbolic acid before usage and became very popular within the surgical community. 2.3 In addition, he pioneered a way to prolong absorption of catgut to allow for longer healing times for wound and vessels by coating catgut with chromic acid. Lister borrowed this technique from leather industry 's method of using chromic acid to tan leather. 2 By the 1900 's, the catgut industry was fully established in Germany where catgut was made from sheep intestines. In 1902, sterilization of sutures with iodine was introduced by Claudius, which became the preferred method of suture sterilization in the next fifty years.2 Later, George Merson, a pharmacist from

Ed inburgh , developed eyel e s needled utures called " Mer uture" in the 1920 's that reduced ti ssue damage during suturing .2.3 During and after World War II , synthetic non-absorbable suture , such as nylon and polyester, were introduced . In 1960, the use of Cobalt 60 isotope to terili ze sutures allowed packaging to be done before sterilization, which further enhanced the sterili ty of sutures.2 And in the 1970s, Dexon and Vicry l , two absorbabl e synthetic absorbable suture were introduced. The advantage of syntheti c absorbable sutures is their reproducible deg radability inside the body, which minimize ti sue reactions after the sutures have lost their function. I

THE PRESENT AND FUTURE OF SUTURES Although suture ' dominance continue to pers ists in wound closure and vesse l ligation , the search for greater efficiency led to the development of other alternati ve devices. These include surgica l clips that were first u ed in early 19001 , surgica l staples that were introduced in the 1970s6, and tissue adhesive for wound closure7 These devices currentl y represent adjuncts to sutures in many surg ical operations. One of the ongoing research themes for utures is the developm ent of suture that have anti-microbial propet1i es .s REFERENCES I. Chu CC. Int roduction. In : Chu CC, Von Fra unhof er JA , Greisler HP, editors. Classification and general characteristics of suture materials. Florida : CR Press Inc; 1997. p.l-5. 2. Ma cken:.ie D. Th e histOI)' of sutures. Medical His tO/ )'. 1973: 17(2) : 158168. 3. Black JJ A stitch in tim e-1 Th e his tO/ )' of sutures. Nursing Tim es. 1982: 78(15)61 9-623. 4. Snyder C. On th e history of the suture. Plastic & Reconstructive Surge1y . 1976: 58(4) :401-406. 5. Ahmad A, 0 'Lew y J Ob ervations on early suture materials: Th e firs t stitch in tim e. American Surgeon. 1997; 63(1 1): 1027- 10:!8. 6. Von Fraunhofe r JA . Ligating clips and staples. In : Chu CC, Von Fraunhofer JA. Greisler HP. editors. Cia sification and general characteristics of suture materials. Florida: CRC Pres Inc: 1997. p.307-3 16. 7. Jkada Y Tissue adhesi1•es. In : Chu CC, Von Fraunhofer JA , Greisler HP, editors. Classification and general characteristics of suture materials. Florida: CRC Press Inc: 1997. p.31 7-346. 8. C/111 CC. New eme1g ing materials for wound closure. In : Chu CC, Von Fraunhofer JA , Greisler HP. editors. Classification and general characteristics of suture materials. Florida : CRC Press Inc: 1997. p.34 7-384.

UWOMJ 72(1) 2002 27

Ethics and aesthetics: An inquiry into cosmetic surgery

Sh eilagh Maguiness, Meds 2002 Toni Zhong, Meds 2002

In today's media-crazed, appearance obsessed society, it seems that aesthetic surgery has upped the ante on the ability to attain the ' perfect' body. Much to our surprise, we recently discovered that the achievement of this ' perceived' perfection is more accessible than one may think. It's very accessibility and the nature of solicitation of procedures that some physicians practice has brought forth many concerns regarding the ethics surrounding the profession. However, this topic is multidimensional, and reaches far beyond the scope of this short editorial. The purpose of our discussion is not to dismiss the benefits that cosmetic surgery may have, rather, we hope to raise some questions regarding the ethics and the purpose of aesthetic surgery from our unique perspective, as both women and future physicians. The following is our reflection on a personal experience fraught with unsettling issues about women, ageing, body image and ultimately, self-esteem.

In July 2000, an interesting announcement at an upscale Toronto fitness center caught our undivided attention. On the bulletin board that posts tips on healthy living and dates of upcoming fitness seminars, we found a scheduled talk on ' Cosmetic Surgery and Its Benefits '. After inquiring, we were informed that at the request of the gym, a well-respected female Plastic Surgeon would be giving the presentation. Considering the setting and the target audience, we felt compelled to investigate the moral and ethical background of this talk. We signed up for the seminar, and we went. When we walked into the gym on the evening of the seminar we saw a sea of middle-aged female faces. The audience was 99% female , (two husbands were present) and they were all waiting in anticipation for the young plastic surgeon to begin her talk. The presentation began with a slide show depicting before and after images of various procedures. The results were often dramatic. Patients looked younger, thinner, perkier, prettier. So why didn 't we fee l good about what they had done to their bodies? Ironically, we were told that the ideal candidate for any cosmetic surgery is a 20-year old aerobics instructor. We were bewildered. Is the perfect candidate not already perfect in herself? Who is defining this perfection, this ' ideal body' , and why does it make us hate our own? The commentary accompanying the slides made us feel defeated and inadequate about our own bodies, even though that was not the intention. We watched in horror as one set of breasts was touted as more ' feminine ' than the pre-augmentation pair. We

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looked down at our own chests and suddenly felt embarrassed and unwomanly. We could not imagine how the other women in the audience felt , or how we will feel about our breasts 15 years from now when gravity finally defeats the elasticity of our skin. '>As we sat in the audience listening to the Plastic Surgeon extol the virtues of youth, beauty and breast augmentation, we were deeply saddened to see an entire group of women who believed that surgery could give them a beauty that should come from within. In evaluating the entire experience of the seminar, even more troubling than the content was the role of the fitness center in perpetuating such ' beauty myths ' in a volatile population. Although not the case for everyone, many patrons of health clubs are young people who are concerned with improving their appearance. This population is very vulnerable to internal and external pressures about how their bodies should look. Many patrons of the gym are in search of the ideal body as falsely represented on the covers of the glossy magazines that taunt them. They feel compelled to work out at the gym in order to look 'better' and subsequently feel good about themselves. What is the purpose of the gym then? Is it not to promote healthy living? If so, it is certainly misrepresenting its mandate by giving seminars on Cosmetic Surgery as a way to achieve the unattainable. Also unattainable is eternal youth. Most of the women who attended the seminar were middle aged and interested in skin rejuvenation procedures such as laser surgery, chemical peels and face-lifts. We wondered if the motivation which drove them to seek cosmetic surgery reflected our societal stereotype of the

elderly as sick and burdensome. Solar elastoses (sun-spots) are not unsightly and wrinkles are not deformities. With this in mind, cosmetic surgery for the ageing face removes anatomica lly normal features. It carves out years of experience and individuality and recreates a more youthful fa<;ade . It alarms us that surgical procedures to ' correct' aging are likely contributing to the erosion of respect for the elderly that was once fundamental in our society. In a recent article published in the CMAJ, Walter Peters from the University of Toronto gives a book review on Sander L. Gilman's book "Making the Body Beautiful: a cultural history of aesthetic surgery". In the 1999 book, Gilman writes that " in a world in which we are judged by how we appear, the belief that we can change our appearance is liberating". Although this school of thought is becoming widely accepted, we feel that changing your appearance to conform to societal norms is quite the opposite of ' liberating'. Women are victims of the media. We live in the paradoxical world of excess and vanity. So much is expected of us that a fulfilling career is not enough. The media tells us we must achieve perfection. We have to be nurturing mothers, loving wives, waif thin, and beautiful, too. Common sense tells us that this is an impossibility, but cosmetic surgery affords women the ability to choose at least part of this ideal and make it a reality. In essence, this choice removes freedom . When the tools are available, there is no choice, there is only the pressure to use them. Our final thought regarding the ethics surrounding cosmetic

surgery is to question the very nature and validity of the discipline itself. The intent of any medical procedure, particularly one as invasive as surgery, is to correct the underlying pathological condition. Cosmetic augmentation serves a different purpose. The question becomes, what is this purpose and is it achieved? Women with negative body image issues seek to alter their bodies to improve their self-esteem. However, does this physical alteration address the fear and insecurities that are at the root of the problem? We wonder how the women felt after the procedure. Did they feel more confident about themselves, more desirable to their partners, and most importantly were they happier? There is no doubt that the ethics behind cosmetic alteration are complex. The only thing that we know for certain is how we felt about what we have seen. We have seen the insecurities of other women and we have felt our own. We live with the constant pressure from society to achieve perfection and it is compounded by our own desire to be our best. However, the realm of perfection has been pushed to supernatural limits achievable only through artificial measures, namely cosmetic surgery. We used to want what we could not have, the most frightening thing now is that we can have it, but at what price?

ACKNOWLEDGEMENT The authors would like to thank Dr. J. Nisker for consenting to allow this submitted bioethics project to be published as an article. Leamington District Memorial Hospital, situated on the beautiful shores of Lake Erie, a short dri ve south of Windsor and Detroit has immediate openings for:

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With an Underserviced Area designation, number of Family Physicians are urgently needed. We have openings also for Family Doctors with an interest in Emergency Medicine. Through the generosity of the community, the construction of a suite of hospital-based offices has been recently completed and is available for Family Physicians who wish to open a new Family Practice. The Town of Leamington, located in the southernmost part of the mainland of Canada, enjoys numerous recreational facilities, easy access to natural area such as Point Pelee National Park and Pelee Island, abundant fresh produce, and excellent schools and churches. A balanced Lifestyle in excellent working conditions make this a wonderful area to practice in. Please visit our website at: www.leamingtonhospital.com

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UWOMJ 72(1) 2002 29

Surgical Residencies: The impact of lifestyle on student recruitment, education and patient care

Mark Reimer. Meds 2002

Surgical residencies have the reputation of being the boot camps of medicine. Long hours, sleep deprivation, little time off and the chance to save and lose lives attract, and yet, repel many to surgery. This article exa mines the time commitment required from surgical trainees and the reasons medical students cite for choosing surgical careers. After reviewing the effect of sleep deprivation on resident performance, I conclude that the relationship between resident lifestyle, educational quality a nd patient care is not yet known conclusively, but that residents ' long hours of work probably do not impact negatively on patient care.

Call is a major determinant of resident lifestyle. Recent changes to the co llective agreement of Ontari o res idents have reduced on ca ll requi rements for in hospital call to one ni ght in four, from one in three, and for home ca ll to one in three, down fro m one in two . I In the U.S ., gu idelines that limit resident work hours from the Accreditation Council for G raduate Medi cal Educati on (ACGME) state that internal medi cine residents should work no more th an 80 hours per week, take ca ll a max imum of one in three and have at least one day in seven free from pati ent care duties.2 These requirements still exist in surgery, but they become opti onal when the continui ty of pati ent care requires the res ident to work longer. The guidelines state that stres and fatigue are not to be avo ided, unl ess they are undue, and that excessively di fficult and prolonged duti es ca n be perfo rmed, but not regu larly.2 In spite of the fl ex ibili ty built into these work-hour requirements, 36% of U.S. gene ral surgery programs vio lated them in 1999.2.3 Thi s paper w ill review the literature on the e ffect of call on resident performance. What is lost when tired and stressed residents continue to work? The answer lies in knowing the purpose of post-g radu ate medi ca l educati on. On one hand, res idents primaril y wa nt to learn . On the other, they provide an almost limitless source of budget- fri endly labour. In the middl e li es the patient, whose best interest should come f irst. To properly m eet patients' needs, residents must work synerg isti ca lly with their consultants instead of in parall el to them .4 Wh en residents work without adequ ate backup, odds that pati ent care w ill be compromised increase, and opportunities for educational interaction between consultant and res ide nt decrease. Id eally, a res ident 's respons ibiliti es will depend on hi s/her competency and on the a mount of supe rv ision 30

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avai lable. In rea lity, however, the ACGME has fotmd that while res ident supervision is generally not optimal, it is at least adequate.4 In spite of this fun cti oning compromise between the reside nt as student and as labourer, pati ents cannot help but regard with suspicion the ability of a res ident who has not slept in the last 36 hours. Patients know how hard it is to be full y alert after a night without rest. Ju st as the working hours of truck drivers and airline pil ots are regul ated, it has been suggested that the work hours o f doctors also be limited to safeguard both the pati ent and the doctor.s Even though the most important fac tor in choosing a special ty was controllabl e lifesty le a mong medical students6, this was not the primary cons ideration of students wanting to become surgeons. Medica l students select surgical careers with different c rite ri a than do student entering internal medicine. The Ohio U ni versiti es Co llege of Medicine recently surveyed 205 medical tudents at the start of their third and fourth year of a six-year combined BS-MD prog ram .7 O f the 76 surveys returned, 43 pl a1med careers in surgery a nd 33 in medicine. Compared to those students preferring internal medicine, those choosing surgery were more likely to be influenced by role models (P < 0 .006), career opportunities (P < 0 .006), and by acade mic opportuniti es (P < 0.0 13). Surgical enthusiasts were less likely to be discouraged by lifestyle (P < 0 .00 1), time commitment (P < 0 .001 ), call schedule (P < 0 .001 ) and by the length of residency (P < 0 .028). No s ignifi cant differences were fow1d among financial rewards, prestige, or technical and inte llectual challenges. In both groups, about 20% of famili es or significant othe rs di scouraged the stude nt from entering a surgical career. A lthough lifestyle factors are not the primary conside ration

of students wanting to become surgeons, just how do residents spend the many nights on call that have labeled surgical res idencies as synonymous with poor lifestyle? Time is arguab ly the resident 's most valuable asset. Surprisingly, not much is known about how urgical re idents pend their nights on call. A recent study observed how second and third year residents in pediatrics and genera l medicine in an urban U.S . 700 bed hospital spent their on-call time between 7 PM and 7 AM. 8 Results showed that 5.3 and 5.7 hours nightly for the internal and pediatrics residents respectively were spent on basic personal activities such as sleeping, eating, socializing and reading in the call room . Time spent on chart review and documentation was 2.6 and 2.2 hours, respectively. Discussing cases with team members amounted to about 1.5 hours for both groups and time spent with patients was 1.5 and 1.3 hours , respectively. The average time spent with each new patient ranged between 16 and 20 minutes .8 Residents spent more time with documentation than with patients . The educational and patient-care importance of preparing documentation may be questionable if it causes the resident to function less efficiently the following day. Further inve tigation is required to determine if reducing the amount of time on-call surgical residents devote to administrative functions improves their learning and patient care. The conc lusions about the effect of long hours of call depend on the markers of performance that one chooses to cite. The relationship between sleep deprivation and clinical performance seems obvious, and has resulted in limits on maximum resident duty-time being established following the Libby Zion court case in New York over a decade ago .9 A 13 year-o ld study by Deaconson et al. showed that sleep deprivation has no negative impact on resident performance.' o A more recent study looked at whether post-call status affected the ABSITE standardized exam scores of 424 New England general surgery residents. II Residents take this exam annually. The average score increases linearly with the resident's post-graduate year of training. Again , post-call status was found to be insignificant in affecting the surgical resident 's exam score at each post-graduate year level (P < 0.03), except for PGY-2. Contrary to these results, a similar study examining the standardized test scores of family medicine residents did show a significant correlation between post-call status and decreased exam performance at all PGY levels. 1' The following three assertions may help to understand these differences : l) chronic sleep deprivation as experienced by surgical residents cannot be reversed with one night of rest; 2) adaptation to chronic sleep deprivation may occur; and 3) family medicine residents are sleep-deprived less often, and so sleep deprivation the night prior to an exam may have a greater impact on them . 1' Consequently, it is likely that chronic sleep deprivation in surgical residents does not affect their daily functioning. It would be methodologically difficult to conduct a rigorous comparison of surgical resident performance in chronically sleep deprived versus well-rested groups, but such information would improve our understanding of how sleep deprivation affects patient care and the quality of residency education. Surgical residency exists to train competent and empathetic surgeons. Learning is a life-long process that continues well beyond graduation. For example, 10% of American neurosurgery graduates questioned their competency to perform all the required

procedures at the end of their training.1 2 Looking at patient care after graduation, anoth er study reports that hospitals perfo rming more th an 30 craniotomi e per year had a 43% reduction in mortali ty rates co mpared to those performing less than 30 per year (8 .8% versus 15 .5% mortali ty respectively, P < 0.0001 ). 13 Indeed, little evidence ex ists to show that ri gorous residency training negatively impacts on patient care, but it is clear that the maintenance of surgical skill and medi ca l knowledge requires lifelong practice and continual learning . Patients deserve nothing less. REFERENCES 1. New Ca ll Provisions Enforcable JamtaiJ' 1. PA1RO News. Available at: <h ttp ://www.pa ira.orglabout/c allschedul i ngrules. h tml>. Accessed February 3, 2001 . 2. Leach, DC. Residents ' work hours: the achilles heel of th e profession? Academic Medicine 2000; 75:11 56-5 7. 3. Stone MD, Doyle J, Bosch RJ, Bothe A, Steele G. Effect of resident call status on ABS!TE pe1jormance. Surge1y 2000; 128:465- 7f . 4. Leach, DC. Residents ' work hours: the achilles heel of th e profession? Academic Medicine 2000; 75:11 56-5 7. 5. Kin~ 路an MC. A tim ely question about physicians' work hours. CMAJ 1998; 158: 170. 6. Er::.urwn VZ, Obermeyer RJ, Fecher A, Thyagarajan P, Tan P, Kaler AK, Hirko MK, Rubin JR . What influences medical students' choice of surgical careers? Sw路geiJ' 2000; 128:253-6. 7. Griffen WO, Schwart::. RW. Controllable lifestyle as a f actor in choosing a medical CQI'ee/~ Am J Swg 1990: 159:189- 90. 8. Moore SS, Nenleman MD, BeyerS, Clwlasani K, Fairbanks RJ, Goyal M, Carter M. How residents spend their nights on call. Academic Medicine 2000;75: 1021-24. 9. Stone MD, Doy le J, Bosch RJ, Bothe A, Steele G. Effect of resident call status on ABS1TE pe1jormance. Surge1y 2000; 128:465- 71. 10. Deaconson TF, O'Hair DP, Levy M, Lee MB-F, Schuenemann AL, Condon RE. Sleep deprivation and resident petforman ce. JAMA 1988;260:1721- 7. 11 . Stone MD, Doyle J, Bosch RJ, Bothe A, Steele G. Effec t of resident call status on ABS1TE perfo rmance. Sw ge1y 2000;128:465- 71. 12. Long DM. Co mpetency -based residency training : the next advance in g raduate medical education. Academic Medicine 2000;75: 11 78-83. 13. Solomon RA , Mayer SA. Tanney JJ Relationship between the volume of craniotomies fo r cerebral an ewy sm pe1jorm ed at New York state hospitals and in-hospital mortality. Sh路oke 1996;27:13- 7.

UWOMJ 72(1) 2002 31

Routine ultrasound in pregnancy

Deepak Bhayana, Meds 2002

The development of ultrasound over the last three decades has arguably been the most important advancement in the management of pregnancy. However, there is still much controversy over the use of ultrasound in the management of a low-risk, routine pregnancy. The benefits to the routine ultrasound include confirmation of dates, detection of multiple pregnancies, missed abortions, intrauterine growth retardation (IUGR) and some congenital malformations. Nevertheless, one must consider the risks associated with prenatal ultrasound and its capability as a screening tool to positively affect perinatal mortality and morbidity. Results from most studies indicate that routine ultrasound during pregnancy is safe, but has little effect on perinatal outcomes. Nonetheless, the Canadian Task Force on the Periodic Health Examination in 1992 has recommended one routine antenatal ultrasound despite recognizing the lack of evidence for ultrasound to positively affect perinatal morbidity and mortality. The controversy over the use of routine antenatal ultrasound will remain an ongoing controversy that may only be resolved with further quality research.

The development of ultrasound over the last three decades has arguably been the most important advancement in the management of pregnancy. The refinement of the technology over time, combined with the widespread development of skills in performing and interpreting scans, have increased its use for prenatal diagnosis and treatment.! The antenatal identification of an abnormal fetus allows the opportunity for prenatal counseling and discussion of pregnancy optit>ns. Furthermore, prenatal diagnosis can influence antepartum and intrapartum management and permit planning of the mode and site of delivery, which will ensure optimal care for the fetus and newborn. There are various indications for ultrasonography during pregnancy (see Table 1). As the list is quite extensive, many pregnant patients will have clinical indications for ultrasound as part of their prenatal management. However, many physicians also order prenatal ultrasounds as a routine part of the management. This has led to much controversy in light of the recent efforts to increase the cost-effectiveness of medical care. Routine ultrasound examination is defined as a screening procedure performed on low-risk patients (i.e. those without a clinical indication for ultrasound) . It is intuitive that there are benefits to the routine ultrasound; for example, confirmation of dates, detection of multiple pregnancies, missed abortions , intrauterine growth retardation (IUGR) and some congenital malformations. Another important factor favoring routine ultrasound comes from parents. As a result, physicians are faced with the difficult task of deciding whether to use prenatal ultrasonog32

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raphy routinely when there is no clinical suspicion of a potential problem. Before considering the validity of routine ultrasound as a method of screening in pregnancy, one must determine the qualities of a good screening test. First, it must be able to detect disease in an early, asymptomatic period. Secondly, treatment of the condition in this early stage should make a difference in health outcome. With this in mind, routine ultrasound would be beneficfal if correction of dates meant appropriate use of steroids for fetal lung development, or for the avoidance of post-term status, which would in turn improve maternal and fetal health outcomes. Screening would not prove useful in cases of equally poor prognosis regardless of imaging, such as irreparable anomalies, or in cases of equally good outcomes, such as cleft lip. Another important requirement for a good screening program is that the ascertained condition be prevalent enough to yield sufficient cases and be severe enough to incur substantial morbidity and mortality. For example, it would be necessary to demonstrate a health disadvantage to pregnancies with incorrect dates , such as excess neonatal morbidity. Finally, one must discern between health intermediates and health outcomes. Detection of anomalies, correction of gestational age and suspected intrauterine growth restriction (IUGR) are health intermediates, whereas perinatal mortality, morbidity and Cesarean section rates are health outcomes. Health outcomes are measurable benefits for a screening program, whereas health intermediates are only useful if detection allows for treatment or

Estimation of gestational age for patients with uncertain dates or verification of dates for patients scheduled for termination of pregnancy. 2. Evaluation of fetal growth (especially when patient has suspected cause for uteroplacental insufficiency, or for other conditions where fetal malnutrition is suspected. 3. Vaginal bleeding of unknown etiology 4. Determination of fetal presentation, esp. near time of labour 5. Suspected multiple pregnancy 6. Adjunct to amniocentesis 7. Significant discrepancy in uterine size to dates 8. Pelvic mass on clinical exam 9. Suspected hydatidiform mole based on clinical signs of hypertension, proteinuria, ovarian cyst, absence of feta l heart 10. Suspected ectopic pregnancy 11. Serial evaluation of fetal growth in multiple Gestation

12. Fol low up for suspected placenta previa 13. Adjunct to special procedure, such as fetoscopy, intrauterine transfusion, embryo transfer, etc. 14. Suspected fetal death 15 . Suspected uterine pathology 16. IUD localization 17. Ovarian follicle surveillance 18. Biophysical evaluation for fetal well-being after 28 weeks 19. Suspected polyhydramnios or oligohydramnios 20 . Suspected abruptio placenta 21. Adjunct tot external version 22. Estimation of fetal weight and presentation in premature rupture of membranes or pre-term labour 23. Abnormal AFP value for gestational age 24. Follow up of identified abnormality 25. History of previous congenital abnormality

Table 1. Indications for ultrasound

management that will positively impact on health outcomes. Even though there is a theoretical risk of tissue damage caused by ultrasound, there is no consistent evidence of fetal risk caused by exposure during diagnostic ultrasound. Randomized clinical trials showed no difference in developmental, neurological, or psychological outcome, with as much as 12 year offollowup. 2 There has been suggestions that the rate of dyslexia is higher in children exposed to ultrasound in-utero. However a study conducted by Salvesen et al. demonstrated that this is not the case.3 Finally, there is no correlation between low birth weight and limited ultrasound exposure.4 Although the safety issue is still unresolved, the overwhelming evidence at this time would indicate that no untoward fetal effects can be anticipated with diagnostic levels of ultrasound. The most important health outcomes considered in trials attempting to test the safety of routine pregnancy ultrasound are overall perinatal mortality and morbidity. Almost all trials have demonstrated no difference in perinatal morbidity between control groups and the subject group undergoing routine pregnancy ultrasonography. 5- II Only one study 12 showed a significant decrease in perinatal deaths in the ultrasound arm, which can be attributed to the greater frequency of induced abortions. Only one study5 examined the specific morbidities (retinopathy, bronchopulmonary dysplasia, mechanical ventilation >48 h, necrotizing enterocolitis, intraventricular hemorrhage seizures and sepsis) and reported no difference between the routine ultrasound and usual care groups. No studies were found to have compared the difference in admission to a special care ward. One of the most common indications for ultrasound is confirmation of gestational age, especially in women who have irregular cycles or who are unsure of their last menstrual period. Studies examining the effect of ultrasound on health intermediates have shown greater accuracy of ultrasound in feta l dating

than dating generated via patient historyi 3, a reduction in induction of labour for post-term pregnancy5-8, and reduced rate of tocolysis in routine ultrasound groups versus control groups5 that was attributable to the increased accuracy of dating. However, as alluded to before, an improvement in health intermediates does not necessarily equal better health outcomes. In fact, there is great controversy over whether routine pregnancy ultrasound can positively affect perinatal morbidity and mortality. The RADIUS study5 and other studies8,9, I2 found that there is no difference in perinatal outcomes between the routine ultrasound group and the usual care control group. The capacity to be extremely accurate in the diagnosis of multiple pregnancy, especially early in the pregnancy, is another compelling reason for routine ultrasound scanning, as Madearis et al. had previously shown that twin pregnancies accounted for a disproportionate number of perinatal deaths.I4 However, does early diagnosis of multiple pregnancy reduce the associated perinatal mortality and morbidity? Waldenstrom et aJ. 8 showed that even though routine ultrasound would detect multiple gestations earlier, there was no benefits in perinatal mortality, prematurity, Apgar score or length of hospital stay. Maternal hospitalization, although not a health outcome, is costly and therefore an appropriate measure of the use of resources. Comparison of this end point between routine ultrasound and control groups had conflicting results. One trial showed a decreased rate of maternal hospitalization6 while another showed an increased ratei O, and some showed no difference.5,6,8,I2 The utility of ultrasound screening for anomalies is determined by sensitivity. Ultrasound is a test requiring skill in both interpretation and performance, which will vary according to the environment in which the test is performed. In low-risk populations , sensitivity of anomaly detection range from 14% to 85% and specificity range from 93 % to 99%. False-positive rates UWOMJ 72( I) 2002 33

range between 2-3 %. In high-risk populations, sensitivity range from 27% to 99% and specificity range from 91% to 100%. 15 The most important question is whether there is a benefit in health outcomes. For hopeless anomalies , early detection allows women the opportunity to terminate the pregnancy and avoid perinatal loss. Another situation where ascertainment of an anomaly would be benefici al is one in which there could be intrapartum treatment to help reduce perinatal morbidity and mortal ity. Emotional benefit is a lesser-emphas ized facet of the controversy on routine ultrasound . Most parents are undoubtedly anxious during the first two trimesters and the relief from anxiety they derive from a normal scan is immeasurable . Furthermore, the bonding between the prospective parents and the fetus is often overlooked. Finally, greater ease of obtaining patient compli ance, irrespective of an abnormal or normal scan, for the remainder of the pregnancy is a great benefit to both the caring physician and the health care system. In 1992, the Canadian Task Force on the Periodic Health Examinationt 6 recommendation summarized that the effectiveness of an early, routine ultrasound examination has not clearly demonstrated a benefit in increas ing fetal survival through the detection of treatable prenatal probl em. In addition, the positive and negative psychological effects of screening on the parents have not been clearly assessed . However, they would recommend a routine single examination in the management of women with no clinical indication for prenatal ultrasonography. The controversy over routine ultraso und is far from decided and may on ly be resolved with further quality resea rch studies . REFERENCES I. American College of Obstetricians and Gy necologist . Routine ultrasound in low risk pregnancy. ACOG practice pallerns 5. Washington DC; American College of Obstetricians and Gynecologists, 1997. 2. Stark CR. Orleans M, Ha verkamp AD, eta/. Short and long term risk after exposure to diagnostic ultrasound in utero. Obstet Gy necol, 1984; 63 :194-200. 3. Salvesen KA , Bakketeig LS, Eik-Nes SH, eta/. Routine ultrasonography in-utero and school perf ormance at ages 8-9 years. Lancet. 1992: 339: 85-89. 4. Lyons EA, Dyke C, Toms M, eta/. In utero exposure to diagnostic ultrasound: A 6-year f ollow-up. Radiology, 1988; 166: 687-90. 5. LeFevre ML, Bain MP, Ewigman BC, eta/. A randomi::ed trial of prenatal ultrasonic screening: Impact on maternal management and outcome. Am J Obstet Cy neco/, 1993; 169: 483-89. 6. Eik-Nes Sf-1, Okland 0. Aure J . et a/. Ultra ound screening in pregnancy: A randomized controlled trial. Lancet. 1984; 9: 1347. 7. Geerts LT, Brand EJ. Thron CB. Routine ob tetric ultrasound examinations in So uth Africa: Cost and effect on perinatal outcome- a prospective randomized controlled trial. Br J Obstet Cyneco/, 1996; I 03 :50 107. 8. Wa /denstrom U. Axelsson 0 , Nilsson S. et a!. Effects of routine onestage screening in pregnancy. A randomi::ed control trial. Lancet. 1988: 2: 585-88. 9. Ewigman BC, Crane JP, Firgofello FD. eta/. Effects of perina tal ultrasound creening and perinatal outcome. N Engl. J Med. /993: 329: 82 1-27. 10. Bakkateig LS, Eik-Nes Sf-1. Jacobsen C. eta/. Randomi::ed control of ultrasonic screening in pregnancy. Lancet, 1984: 2: 207-1 1. II . Tha cker SB. Quality of con/rolled trials. The case of imaging ultrasound in obstetrics; a review. BrJ Obstet Cy necol, 1985; 92: 43 7-44 .

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12.

13. 14. 15. 16.

Saari-Kempainen A, Karja/ainen 0 , Ylostalo P, et a/. Ultraso und screening and perinatal mortality: Controlled trial of systemic onestage screening in pregnancy. Lancet, 1990; 336: 38 7-91 . Youngblood JP, Franklin DW Obsteh·ical sonography. Some significant implications in antepartum management. Mo Med, 1986; 83(2): 93-98. Made(//·is AL, Jonas HS, Stockbauer JW, eta/. Perinatal death in twin pregnancy. Am J Obstet Cynecol, 1979; 134: 413-21 . Cromel SH, D 'Aiton ME. Diagnostic Ulh·asound in Pregnancy : An overview. Seminars in Perinatology, 1994; 18: 11 7-32. Canadian Task Force on the Periodic Health Examination. Periodic health examination, 1992 update: 2. Routine prenatal ultrasound screening. Can Med Assoc J, 1992; 147(5):627-33.

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The role of war in the development of plastic surgery

Vic/a-am Chahal, M eds 2002

This paper illustrates the profound influence of war in the evolution of plastic surgery. Plastic surgery is intertwined with the history of war and numerous examples throughout history illustrate how the brutal nature of armed conflict has cultivated the art of plastic surgery. Mutilation through war, revenge, or punishment has stimulated reconstructive techniques. Individuals who escaped death but sustained injury became patients whose needs carved out plastic surgery as a surgical specialty and gave it legitimacy in its own right.

Plastic surgery, like the phoenix, has arisen from the ashes of war. I The destructive element of human nature has served as a catalyst for its development. This paper illustrates the profound influence of war in the evolution of the field of plastic surgery. The chronology of plastic surgery stands throughout history on the pillars of war. The earliest origins of plastic surgery can be traced to ancient India in 800 BC where Sushruta developed the basic concepts of plastic surgery including the attached flap, skin grafting, and nasal reconstruction .2 It has been said that necessity is the mother of invention. In ancient India, the mutilation of appendages including the ears, nose, and genitals as a punishment for prisoners of war, thieves, and adulterers was common. I This spurred creative surgeons to try to make these individuals whole again. Plastic surgery is first mentioned in the West in the writings of Aulus Cornelius Celsus (25 BC-50 AD), who was a Roman nobleman. Based on his observations of injured soldiers of the Roman Empire, Celsus described the advancement of skin flaps from adjacent tissue to fill skin defects .3 He also considered the correction of ectropion, syndactyly, and partial reconstruction of the penis, lip, and nose .3 The great Byzantine Emperor Justinian II (677-711 AD) had his nose involuntarily amputated during a rebellion in 695. 4 To reign as emperor one invoked divine accession to the throne and consequently had to be free of any physical deformities. By cutting off the nose of Justinian II, the rebe ls thought he would never rule again. However, their plan was thwarted by clever surgeons who reconstructed the emperor's nose. A bust of the emperor shows a scar on hi s forehead likely from a skin flap used to reconstruct his nose.4 In the fifteenth century, two notable army surgeons recorded their surgical techniques. In 1460, Heinrich von Pfolspreundt, a Bavarian army surgeon, described plastic surgery techniques such

as rhinoplasty and cleft lip repair. S Hieronymus Brunschwig ( 1450-1533), an Alsatian army surgeon, outlined the treatment of gunshot wounds.6 Whether the result of a combat on the battlefield or a duel in the streets, the end result was the same - mutilation. Jobus van Meek 'ren described an account of a Russian nobleman whose head was cleft by a Tartar's sword.? The Russian 's head was repaired using a bone from a dog that was incorporated into the defect. 7 The American Revolutionary War saw John Jones recommend the primary repair of lacerated wounds of the face and the preservation of as much skin as possible.s The first account of the Indian method of nasal reconstruction in Europe was in an artic le in the Gentleman 's Magazine in October 1794. The case centred around a bullock driver in the British Army, Cowasjee. He had been taken prisoner along with four soldiers in 1792 . As a punishment and a warning to traitors, Sultan Tippoo had cut off their noses and hands. After arriving at the home of a senior British official, a man, who would later be immortalized as the Artist of Poona, said to be the on ly restorer of noses in India was sent for. The nasal reconstruction, seen for the first time by Europeans, was witnessed by two surgeons from Bombay: Thomas Cruso and James Findlay. The technique was introduced to Europe by Joseph C. Carpue in 1814, often touted as the first military plastic surgeon, who attempted it on the war injuries of two army officers.9 By the time of the American Civil War, pl astic surgery had started to take its modern day form. The American Civi l War allowed many surgeons to attempt and perfect several techniques. Reconstructions of the nose, cheek, chin, lip, palate, and eyelid were performed.I0- 14 Gurdon Buck performed the first total facial reconstruction for extensive destruction . IS In 1863, a Confederate army surgeon, CB Gibson, repaired a chin lost due to a gunshot UWOMJ 72(1) 2002 35

wound.I6 The Union army had its innovators as well. In 1864, Culberston used a nasolabial flap to cover a defect of the nose . 10 As war technology developed, so did that of plastic surgery. While a greater number of casualties existed, advancements in medicine allowed a larger number of injured soldiers to survive. Plastic surgery matured into adulthood in World War II when plastic surgeons began constructing jaw bones out of ribs, eyelids out of neck skin, lips from the ora l mucous membrane, and nostrils from earlobes. I The story of plastic surgery is intertwined with the history of war. Mutilation through war, revenge, or punishment has stimulated reconstructive techniques. The bodily disfigurement borne by the survivors of physical trauma in conjunction with the human longing for aesthetic normalcy laid a foundation for the development of plastic surgery. Individuals who escaped death but ustained injury became patients whose needs carved out plastic surgery as a surgical specialty and gave it legitimacy in its own right. REFRENCES I. Hauben DJ, Sonneveld GJ Th e Influence of War on the Development of Plastic Surge/)'· Annals of Plastic Surgery• 1983; I 0(1) :65-69. 2. Bhishagranw KKL. Th e Sushruta Samhita. English translation based on original Sans/.:r it series. Varanasi. India , Chowkhamba 1963.

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UWOMJ 72( I) 2002

3. 4.

5. 6.

9. 10. I 1. 12. 13. 14. 15. 16.

Celsus AC: De Re Medicinae (Book VI!, chap 9) . Loeb Classical Libral)'. London. W.Hein emann 1961 . Remensy nder JP, B igelow ME, Go ldwyn RM: Justinian 11 and Carmaagnola : a By=a ntin e rhin oplasty? Plast Reconstr Surg 1979;63 :19. Pfo lspreundt H. Buch der Bundth Ertznei. H. Haeser and Middeldorf Berlin G.Reim er 1868. Brunschwig H. Die i I das Buch der Chirurgia. Hautwirckung der Wund Art=. Augsbwg. H. Schonsp erger 1497. M ee 'ren J. Observatio nes Medico -Chirurg icae ex Belgico ab Amsterdam. A. Blasio 1682. Rogers 8 0. Swge1)' in the RevolutionGI )' WGI: Conn·ibutions of John Jones MD (1 729-179 1). Plast Reconstr Surg 1972; 49: 1. Freshwater MF, Su CT. Hoopes JE. Joseph Constantin e C01pue-jirst militOI)' plastic surgeon. Milital)' Medicine 1977; 142:603. Stark RB. Plastic surge1)' during the Civil War. Plast Reconstr Surg 1955;16:103. Stark RB. Swgeon and surgical care of Confedera te States Army. Virginia Medical Journal 1960;87:230. Stark RB. Plastic Sw·ge1y. New York, Hoeber 1962. Stark RB. Th e histO I)' of p lastic urgel}' in war tim e. Clin ?last Surg 1975;2:509. Stark RB. Friendship of three giants. Plast Reconsn· Surg 1962;40:599. Conll'ay H, Stark RB. Plastic Surge I)' at the New York Hospital One Hundred Years Ago. ell' York, Hoeve1; 1953. Gibson CB. Operations in reparatil'e surge')'· Confedera te States Medical Journal 1 64;1:104.

Cognitive Asymmetry in Alzheimer's Disease

Yan iv Berlin e1~ BSc (Hon s), Meds 2004

Alzh~i.mer's diseas~

(AD) is a degenerative neurologic disorder that affects memory, language, and other and. functional abilities. Previous research suggests that some AD patients display cognitive asym 7 metry, 10 whi~h one cerebral hemisphere is affected more than the other. Specifically, studies have found that .early on 10 the course of AD, patients with left-sided asymmetry (i.e., greater impairment of the left h.emis~here) tend to show greater deficits in language than in visuospatial abilities, whereas patients with r~ght-si~ed asy mme~ry show the reverse pattern of impairments. The purpose of the present paper is to proVIde a literature review of cognitive asymmetry in AD. cogmti~e

LITERATURE REVIEW Alzheimer's disease (AD) is a neurodegenerative disease resulting in defi cits in attention, memory, language, and other cognitive functions ' . AD is the most widespread of the dementing diseases, and accounts for one-half of all dementia2. AD progresses gradually, and in its early stages does not affect simple functions. For some time after acquiring the disease, people ca n walk about and make conversation in a normal fas hion. Thus, it does not appear that they are demented until more pronounced memory impairments emerge making it impossible for the patient to either work or dea l with new situations. In AD the brain ti ssue irrevers ibly deteri orates, and death occurs approximately 10- 12 years after the onset of the di sease. The main physiological change is atrophy of the cerebral cortex, hippocampus, and other brain areas as neurons are lost2 Neuronal loss results in memory impairments, as the temporal lobe structures are separated from the cerebral cortex. Furthermore, the pattern of neuronal degradation results in attention deficits, as the prefrontal structures are di sconnected fro m parietal structures. Because the cerebellum, spinal cord, and sensory areas of the cortex are generally less affected, AD pati ents appear relatively normal until the later stages of the disease2. In the normal aging process, physical changes occur to the frontal and temporal lobes3, resulting in neuropsychological deficits specifically in memory and executive functions. These deficits can be seen in tests of recent memory, which invol ve a delay of minutes to hours. However, memory deficits are less prominent in tests with no delay such as immediate recall. Deficits related to normal aging are different from impairments caused by AD. In the latter case, memory loss is much more significant, and the patient continually degrades, performing at a

decreasing leve l in subsequent years. The di agnos is of AD requires deficits in several areas of cogni tion4, yet the pattern of such impairment varies greatly among patients5. The rate of decline can be highl y variable, as demonstrated in several longitudinal studies of neuropsychological perfo rmance in AD patients6 Addi tionally, although the majority of patients display a symmetric progress ion of AD, a significant minority ex ists in whi ch the disease progression is a ymmetric (i.e., di ffe rently affecting the left and right cerebral hemi spheres). The result is that early on in the course of the disease, those patients with left-sided asymmetry (i.e., greater impairment of the left hemi sphere) tend to experience increased language defi cits , whereas patients with ri ght-sided asymmetry tend to exhibit disproporti onate visuospatial deficits. These patterns are referred to as cogni tive asymmetry, and have been demonstrated by neuropsychological performance, functi onal imaging, and motor te ting. Cognitive asymmetry in AD has been demonstrated through the use of neuropsychological tests. In such cases, researchers examine the asymmetry by administering a variety of tests that distinctly tap the function of the right and left hemispheres. For mstance, to test the function of the right hemisphere, Celsis et al.7 admini stered a test battery consisting of letter recognition Benton facia l recog~ition, WAIS Block Des ign, and WAIS Objec; Assembly. Tests believed to re ly on the left hemisphere for successful performance included letter search, Benton verbal fluency, and WAIS Digit Span. Lateral asymmetries were observed among a significant number of AD patients. Other researchers using _di~erent neuropsychological batteries but still using test~ that d1stmctly tap the right and left hemispheres, have obtained similar resuJts8,9,IO. The proportion of patients with cognitive UWOMJ 72(1) 2002 37

asymmetry has been found to vary between 20% and 40%8, II . Studies involving both functional imaging and performance on neuropsychological tests have suggested some relationship between cerebral blood flow and cognitive asymmetry in AD patients. Martin et aJ.II classified 42 patients into groups based on their cognitive abilities , including one group with relatively greater visuoconstructional deficits and one with relatively greater word-finding impairments. The researchers then carried out PET scans on both of these groups . They found that patients with greater word-finding deficits displayed reduced cerebral blood flow in the left hemisphere, whereas patients with greater visuoconstructional deficits displayed reduced right hemisphere blood flow. In a similar study, researchers obtained an index of cognitive asymmetry from the difference in patients ' scores on tests of syntax and drawing . Significant correlations were found between cognitive asymmetry and glucose metabolism of frontal , temporal, and parietal lobes. Such that left-sided asymmetry patients exhibited reduced glucose metabolism in the left hemisphere, and right-sided asymmetry patients exhibited reduced glucose metabolism in the right hemispherel 2. The same researchers subsequently reported that metabolic asymmetries were stable in direction, became more pronounced, and correlated even more highly with performance on neuropsychological tests when patients were retested 15 to 48 months laterl 3. These finding support the hypothesis that different scores on tests that rely on the right and left hemispheres represent a differential degradation of the brain. The asymmetric progression of AD has also been observed in motor functioning. Haxby et aJ. S using longitudinal PET imaging, reported that mild, moderate and severe AD patients exhibited greater metabolic asymmetry in premotor areas than did the controls, and that the degree of heterogeneity in this premotor area was comparable to that found in the parietal and temporal lobes. Further studies l4 found that finger tapping asymmetry in AD patients was significantly associated with cognitive asymmetries. The finding that motor asymmetry exists in AD is important as the cerebral localization of finger tapping is more robust than is localization of cognitive abilities. That is, the relationship between left-handed tapping and the right hemisphere is more reliable than the relationship between visual memory and the right hemisphere. Although the above-mentioned methods have shown that a cognitive asymmetry exists, a disagreement exists among researchers as to the directionality of this asymmetry. Some researchers have found no directional preference in the cognitive asymmetry exhibited by their patients1 5. That is, although asymmetric patterns were found, the number of patients with greater left hemisphere impairments was similar to the number of patients with greater right hemisphere impairments. However, other researchers have found a left hemisphere preference, where more patients display left than right hemisphere deficits9. Researchers who propose a left hemisphere preference hypothesize that the left hemisphere may be generally more vulnerable to disease then the right. Loewenstein et aJ.9 found predominant left hemisphere impairment among both patients diagnosed with AD and those with multi-infarct dementia. Similarly, greater left hemisphere vulnerability to dysfunction is suggested 38

UWOMJ 72(1 ) 2002

by other researchers who cite cerebral blood flow studies showing greater left hemisphere involvement among both normal individuals and AD patientsio. Amaducci et al.l6 found that in normal patients, the left temporal lobe has greater choline acetyltransferase activity than the right. Thus, it is possible that the greater complexity of left hemisphere function leads to greater impairment when the left hemisphere is damaged. This theory is supported by the finding that " silent" tumors or lesions are more often located in the left hemisphere9. Identifying patients as suffering from an asymmetrical progression of AD is important insofar as this knowledge aids patients and their caregivers to cope with the disease. Additionally, it has been found that patients with a severe language impairment, a left hemisphere function, experience a more rapid deterioration than patients whose language skills are less affected! . An important factor related to the cognitive asymmetry seen in AD is the age at onset of the disease. Seltzer and Sherwinlo found a significantly greater amount of language impairment in early-onset versus late-onset patients (less than or greater than 65 years old, respectively), although the duration of illness was similar for both groups. Similarly, other researchers, using the same criteria for age at onset as Seltzer and Sherwin, found that the late-onset patients were more impaired on nonverbal tests, such as drawing tasks from the Aphasia Screening Test and the Block Design subtest of the WAIS-R, than was the early-onset group. Conversely, the early-onset group made more errors on the Verbal scale of the WAIS-R and on the verbal components of the Aphasia Screening Test 17. In contrast, several studies have found that patients with visuoconstructional impairment tended to have an early onset of the disease, whereas patients with language impairments tended to have a late onset8,18,I9. Moreover, other studies have reported no relationship between age at onset and cognitive asymmetry II . An additional variable that could have important implications for cognitive asymmetry is level of education. Recent research has shown that low education increases the risk of developing AD.I4,20 Education is thought to increase synaptic density, which in turn, may prolong the time it takes to reach the critical threshold necessary to develop dementia. This theory posits that a highly educated patient with AD will take longer to exhibit the memory and attention problems associated with the disease than will an individual with less education. However, the relationship between cognitive asymmetry and level of education remains unclear, as relatively little research has been done on this topic. A recent study 14 found that AD patients with high levels of education had significantly higher levels of verbal ability but similar levels of spatial ability relative to AD patients with low levels of education. Theoretically, the left hemisphere of those patients with high levels of education was protected by a cognitive reserve and patients were more likely to exhibit finger-tapping asymmetry in favour of the right hand. Patients with low levels of education did not have this cognitive reserve and were more likely to exhibit finger-tapping asymmetry in favour of the left hand

CONCLUSION: Although the majority of AD patients exhibit a symmetric

progression of the disease, a significant subset of patients experience cognitive asymmetry, where one cerebral hemisphere is more affected than another. Investigations dedicated to determine the asymmetry of AD progression are important, as patients with left hemisphere impairment may experience a more rapid disease course than patients whose left hemisphere is intact. Although education level and age at onset of AD appear to be important factors in cognitive asymmetry, the exact relationship between the above factors is not yet understood. ACKNOWLEDGEMENTS:

The author would like to thank Dr. Jill Rich of the Psychology Department ofYork University, for her input and her help in editing the paper. REFERENCES 1. Haxby, J V. Raffaele, K. , Gillette, J , Schapiro, M B., & Rapoport, S. 1. individual trajectories of cognitive decline in patients with dementia of the Alzhemeir type. Journal of Clinical and Experimental Psychology 1992; 14, 575-592. 2. Lezak, MD. Neuropsychological assessment 1995. New York: Oxford University Press. 3. Troye1; A. K. , Graves, R. E., & Cullum, C.M. Executive functioning as a mediator of the relationship between age and episodic memory in healthy aging. Aging and Cognition 1994; 1:45-53. 4. McKhann, G., Drachman, D. , Fa /stein, M. , Katzman , R., Price, D., & Emanuel, S.M. Clinical diagnosis ofAlzheimer s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimers Disease. Neurology 1984; 34:939-944. 5. Rasmusson, D. X, & Brandt, J Instability of cognitive asymmetry in Alzheimer s Disease. Journal of Clinical and Exp erimental Neuropsychology 1995; 17:449-458. 6. Katzman, R., Brown, T., Thai, L.J , Fuld, P A., Aronson, M, Butters, N, Klauber, M.R., Wiederhold, W, Pay, M. , Renbing, X, Ooi, W L. , Hofstetter, R., & Terry, R. D. Comparison of rate of annual change of mental status score in four independant studies of patients with Alzheimer s disease. Annals of Neurology 1988; 24:384-389. 7. Celsis, P, Alain, A., Michele, P, Le Tinnie1; A. , Viallard, G., Demonet, J -F., Rasco!, A., & Vergnes, J Lateral asymmetries in primary degenerative dem entia of the Alzheimer typ e. A correlative study of cognitive, haemody namic and EEG data, in relation with severity, age of onset, and sex. Cortex 1990; 26:585-596. 8. Becker, J T., Huff, J , Nebes, R. D., Holland, A., & Bolle1; F. Ne uropsychological function in Alzheimers disease. Archives of Neurology 1988; 45:263-268. 9. Loewenstein, D. A., Barker, W W, Chang, J Y. , Apicella, A., Yoshii, F., Kothari, P, Levin, B., & Duara, R. Predominant left hemisphere metabolic dysfunction in dem entia. Archives of Neurology 1989; 46:146152. 10. Seltzer, B., & Sherwin, I. A comparison of clinical features in early and late onset primary degenerative dementia. Archives of Neurology 1983; 40:143-147. 11. Martin, A., Brouwers, P, Lalonde, F., Cox, C., Teleska, P, Fedio, P, Foster, N L. , & Chase, T. N To wards a behavioural typology of Alzheimer's patients. Journal of Clinical and Experimental Neuropsychology 1986; 8:594-610. 12. Grady, C. L. , Haxby, J V, Schlageter, N L. , Berg, G., & Rapoport, S. I. Stability of metabolic and neuropsychological asy mmetries in dementia of the Alzheimer type. Neurology 1986; 36:1390-1392.

13.

14.

15.

16.

17.

18.

19.

20.

Haxby, J V, Grady, C.L. , Koss, E., Ho rwitz, B., Heston, L. , Shapiro, M. , Friedland, R. P, & Rapoport, S. I. Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type. Archives of Neurology 1990; 74:753760. Massman, P J , & Doody, R. S. Hemispheric asymmetry in Alzheimers disease is apparent in motor fun ctioning. Journal of Clinical and Experimental Neuropsychology 1996; 18:11 0-1 21 Haxby, J V, Grady, C.L. , Duara, R., Schlageter, N L. , Berg, G. , & Rapop ort, S. I. Neocortical metabolic abnormalities precede nonmemory cognitive defects in early Alzheimers-type dem entia. Archives of Neurology 1986; 43 :882-885. Amaducci, L. , Sorbi, S., Albanese, A., Gianotti, G. Choline acetyltransferase (ChAT) activity differs in right and left human temporal lobes. Neu rology 1981; 31 (7) :799-805. Filley, C. M. , Kelly, J , & Heaton, R. K. Neuropsychologic fea tures of early - and late-onset Alzheimers disease. Archives of Neu rology (1986) ; 43:5 74-576. Koss, E., Friedland, R., Obe1; B., & Jagust, W J (1985). Differences in lateral hemispheric asymmetries of glucose utilization between early and late-onset Alzheimers type dementia. American Journal of Psychiatry (1985) ; 142:638-640. Albert, M S. , Duffy , F. H. , & McAnulty, G. B. (1990). Electrophysiological comparison between two groups of patients with Alzheimers disease. Archives of Neurology, 47, 857-863. Katzman, R. (1993) . Education and the prevalence of dem entia and Alzheimers disease. Neu rology, 43, 13-20.

UWOMJ 72(1) 2002 39

Current Practice of Radiation Therapy for Pituitary Adenomas

Karm Guram. Meds 2003

Pituitary adenomas are the most common primary intracranial neoplasms, with an estimated prevalence of 5 to 20% . Radiation therapy has played a major role in the treatment of these tumours, either as primary treatment, adjunctive to surgical resection, or for retreatment of recurring adenomas. For decades now, fractionated radiation therapy has stood as the benchmark for treatment of pituitary adenomas because of its excellent tumour control rates and low morbidity. However, radiosurgery, the delivery of highly focussed , stereotactically targeted radiation, has emerged as a potential technology for treatment. This paper will discuss the successes and downfalls of radiosurgery and evaluate its role in the treatment of pituitary adenomas. Radiosurgery holds the proposed benefits of focal irradiation, without injury to nearby tissues, along with the advantage of quicker treatment results. Also, it could potentially serve as first line treatment for nonresectable pituitary adenomas. However, long-term data is not available du e to short follow-up periods. For radiosurgery to come to the forefront of treatment for pituitary adenomas, more peer-reviewed, long term data on tumour control rates and side-effect profiles are needed.

INTRODUCTION/BACKGROUND Pituitary adenomas are the most common primary intracranial endocrine neoplasms. Preva lence has been approx imated at 5 to 20% from autopsy and magneti c resona nce studi es. 1.2.3 Approx im ately 79% of pati ents with pituitary ade nom as , mo tly mi croadenomas , prese nt as endocrine-active.4 Symptoms depend on the type of pituitary hormone(s) be in g secreted. Microadenomas have diameters less than 1Omm, usually located w ithin the sella. Macroadenomas, however, can mi grate outside the se ll a, manifesting as headaches, visual defects and crani al nerve pal sies.s Macroadenomas have an increased risk for optic chiasm compression through mas effects. Impaired normal pituitary function may also occ ur, but is almost exc lusively a sequella of macroadenomas. 6 The mainstays of di agnosis include imag ing, through CT or MRl . Labwork includes blood chemi try and co unt , and asse ment of pituitary fun ction .? Management for all pati ent includes minimizing tumour growth and press ure effects on surrounding tissue, contro lling hormonal hypersecretion , and treating pituitary dysfu nction . Surg ica l management, through transsphenoida l adenomectomy, is u ed to treat optic chi asm compression, with improvements in vis ua l field in ap prox imately 70-80% of patients.s Surgery is also used to confirm hi stology and as a potential cure for microadenomas . Medical management includes

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agents that suppress hyperfunction, such as bromocriptine, and mitotane, used during the interim, until a permanent response to radiation treatm nt i attained.

FRACTIONATED RADIOTHERAPY The benefit of dose frac tionation (splitting of total radiation dose into ma il er frac ti ons) wa first demonstrated by French radiobiologist, laude Rega ud ea rli er this centwy9 Dose frac tionation is now central to the utilization of radiation for cancer treatment . Radi ati on dose, along with non-phys ical factors , such as repa ir of sub-lethal injury, reas ortment into more radiosensitive phases of the ce ll cyc le, repopu lation of ce ll s, and the reox ygenati on of ce ll s, affects ce ll responses to radiation-induced injury.7 Fractionated radiotherapy takes advantage of the differences between tumour and normal ce ll s with respect to these "4 R's of radiobiology" to ensure the destruction of twnom cell s, whil e preserving the surviva l of normal tissue. Modern fractionated radiotherapy for patients w ith pituitary adenoma re li es on stereotactic (inunobili zation) and conformal in ten ity-modulated (precise shaping of beam to tumour volume) delivery of dose to the neoplasm. Radiation is delivered using high energy photons or x-rays , u ually of 4 MV or greater, generated by linear acce lerators .? Patient are immobilized on a flat couch, and wi th the u e of head moulds or frames, a linear accelerator mounted on a rotating gantry delivers high energy x-ray to

the tumour volume from several portals or angles.l o Treatments are usually given five days a week, for approximately five weeks. Follow-up is provided for many years, depending on post-treatment imaging results, hormone profile and clinical sequelae.? Radiation treatment for pituitary adenoma is indicated in hormone hypersecretion, to control tumour volume and preserve any normal gland function remaining. Treatment is also given adjunctive to sub-total surgical resection, recurrence of tumour growth refractory to surgical or medical treatment, and for patients who are high surgical risks. I Modern doses prescribed for pituitary range from 45-54 Gy, given at a median dose of 1.8 Gy daily, for 25 fractions. 11 This protocol has shown to control tumour growth in approximately 90% of patients at 10-yrs post treatment.1 2, 13 Breen eta! found that irradiation of non-functioning adenomas had a control rate of 87 .5% at 10 years, 77.6% at 20 years and 64.7% at 30 years post-treatment. Sheline et al demonstrated through the recurrence of visual field deficits of null adenomas and prolactinomas, that only 7% and 4% of patents had tumour regrowth with solely radiotherapy or post-surgical radiotherapy, respectively.14 Fractionated radiotherapy however, is less successful in controlling endocrine active adenomas . Although control is achieved in 80% of acromegalies, 50% to 80% of Cushing's Disease, and approximately one third of prolactin hypersecretion, normalization is gradual , ranging from a several years for GH elevation, to a few months to a year in Cushing's disease. I Although fractionated radiotherapy is effective and relatively free of major side effects, time to normalization, appears to be a drawback. However, new technologies of radiation therapy are emerging. One of these methods, radiosurgery, may prove to be a more appropriate method of treating pituitary adenomas.

RADIOSURGERY Radiosurgery is highly focussed radiotherapy using stereotactic localization and single fraction radiation ranging from 12 to 20 Gy. Radiosurgery for pituitary adenomas requires treatment to a localized target, while sparing normal structures like the hypothalamus or optic chiasm. This is achieved by mapping tumour volume with CT or MR1 , conformal delivery of radiation, and sharp fall-off of dose at volume edges, with minimal dose scatter. IS There are two main technologies currently in common use . Both utilize high energy photons. The first , named Gamma-knife, is basically a source composed of 20 I fixed cobalt-60 rods, I mm in diameter, all targeting one isocentre, simultaneously.1 6 The second method is termed LINAC radiosurgery. It utilizes x-rays to target an isocentre similarly to the Gamma-knife. However, only a single beam of radiation is emitted in the latter technique, which arcs around the pituitary tumour, using a movable gantry system. 16 Both methods have similar radiation delivery profiles, however, the Gamma-knife may offer a more favourable internal dose gradient, fall-off, and centre dose to target. 15 Potential advantages of radiosurgery include higher tumourcidal dose of radiation to overcome the pituitary adenoma, while at the same time, sparing nearby important structures . Furthermore, with the need for only one administration of radiation the treatment schedule for patients is shorter as compared with fractionated radiotherapy. However, this prohibits the

exploitation of radiobiological properties that fractionation relies on (the "4 R 's"). Radiosurgery has also been considered as a potential method of primary treatment for unresectable pituitary adenomas . Using high energy stereotactic methods, radiosurgery could administer treatment focally to adenomas localized to the cavernous sinus, a site inaccessible to surgeons.? Although radiosurgery seems to have many benefits for the treatment of pituitary adenomas , it has not gained widespread popularity. In order for it to accepted by today 's radiation oncologist, radiosurgery must prove to be as efficacious as fractionated radiotherapy, while demonstrating a similar safety profile.

COMPARISON OF FRACTIONATED RADIOTHERAPY AND RADIOSURGERY The newer technique of radiosurgery has shown potential superiority to fractionated radiotherapy for pituitary adenomas in several aspects of tumour control. However, it is a relatively new technology and user inexperience must be taken into account for current failures . Unlike the favourable control of tumour size with fractionated radiotherapy, there are relatively few studies related to tumour size control with radiosurgery, because mainly microadenomas, and not macroadenomas have been investigated by radiosurgery. However, studies related to the normalization of hormone secretion in endocrine active tumours are available and may be taken as indirect predictors of tumour size control. Early results found that radiosurgery was able to attain a 48% (14/29) rate of remission of in pituitary adenoma-related Cushing 's Disease and 10-20% for GH oversecretion.17, 18 More recent studies however, like Landolt et al , demonstrated radiosurgery, using the gamma knife technology, comparable for normalization of GH levels to conventional fractionated radiotherapy. More importantly, 70% of the 16 patients treated radiosurgically showed normalization within a mean of 18 months, whereas the same percentage of patients treated with fractionated radiotherapy took 7.5 years to achieve these normal hormone levels.19 A Virginia study found that 58% of 39 Cushing 's Disease patients normalized their urinary free cortisol levels in a mean of 13 months. However, results were poor for prolactinomas and Nelson's syndrome.20 Although it seems that radiosurgery may allow for quicker normalization of endocrine active pituitary adenomas, long term data on control is sparse. Mean follow-up for patients treated with radiosurgery as compared to fractionated radiotherapy is on average 1.4 years and 7.5 years respectively.1 6 Nonetheless, there seems to be promise in this new technique, as there may be a potential for quicker tumour control. One obstacle facing radiosurgery is that no long term peer reviewed publications are available. This takes away from the weight of evidence from data for radiosurgery studies thus gathered . It is well recognized that fractionated radiotherapy is relatively safe with regard to radiation side effects. It holds a less than I% risk of secondary carcinogenesis, and a 1-2% risk of brain or optic nerve injury. I Many patients treated with fractionated techniques develop pituitary failure over time . I Side effects of radiosurgery are expected to be similar, however, long term studies using modern radiosurgery techniques are not available.

UWOMJ 72(1) 2002 41

CONCLUSIONS

12.

A mainstay of treatment for pituitary adenomas includes radiotherapy, either primary or adjunctive to surgical resection . For years now, fractionated radiotherapy has been the benchmark of radiation, based on success of treatment, and low morbidity. Radiosurgery has now emerged as a potential alternative, especially for pituitary microadenomas. Advantages include shorter radiation schedules for patients and decreased time to normalization of excess hormone secretion. However, more peer reviewed studies and long-term follow-up of patients are needed, both to delineate efficacy of this new technology, and gain evidence of a side effect profile. Perhaps radiosurgery will find a specific niche in the treatment of pituitary adenomas. With time new technologies will arise, and so will experience in treating these tumours. One such technology is tomotherapy, aCT scanner equipped with a linear accelerator source, which would allow conformal treatment combined with accurate patient positioning through daily CT imaging.2 I Perhaps this technology too, will have a role in the future for treatment of pituitary adenomas.

13.

ACKNOWLEDGEMENT The author would like to sincerely thank Dr. Fisher and Dr. Bauman for reviewing the manuscript. Dr. Fisher and Dr. Bauman are both radiation oncologists at the London Regional Cancer Centre, specialized in treating CNS cancers.

REFERENCES 1. Arafah, BM. Nasrallah MP. Pituita1y tumours: Pathophysiology. clinical manifestations and management. Endocrin e-Related Cancer 2001 ; 8: 287-305. 2. Burrows GN, Wortzman G. Rewcastle NB. Holgate RC, Kovacs K. Microadenomas of the Pituital)' and abnormal sella tomograms in tillSelected autopsy series. New England Journal of Medicine 198 1; 304:156-58. 3. Hall WA , Luciano MG. Doppman JL , et a!. Pituitwy magnetic resonance imaging in normal human volunteers: occult pituita1y adenoma in the general population. Ann intern Med 1994; 120: 8 17-20. 4. Wilson CB. Surgical management of endocrin e-active pituita1y adenomas. in : Walker MD. ed. Oncology of the nervous system. Boston: Martinus-Nijhoff 1983: 11 7. 5. Poon A, McNiel/ P. Harper A, et a!. Patterns of visual loss associated with pituitwy microadenomas. Aust N Z J Med 1995; 23:107- 15. 6. Hardy J. Ve::ina JL. Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neural 1976; 15: 261 - 273. 7. Grimsby PW Pituitwy. in: Pere:: 'A . Brady U V, eds. Principles and practice of radiation oncology. 3rd ed. Philadelphia: Lippincott-RCII•en; 1998: 829-848. Young WF. Sciethauer BF. Kovacs KT. Horvath E. Da vis DJ-1, Randall 8. RV. Gonadotroph adenoma of the pituita!)' gland: a clinicopathologic analysis of 100 cases. Mayo Clinic Proceedings 1996; 71: 649-56. 9. Mould RF. A CeniUI)' of X-rays and Radioactivity in Medicine. institute of Physics Publishing. Philadelphia, 1993. 10. Mitsumori M, Schrieve DC. Alexander E 3rd. e/ a!. initial clinical results of LJNAC-based stereotactic radiosurgery• and ·tereotactic radiotherapy fo r pituita1y adenomas. lnt J Radial Oneal Bioi Phys 1998;42:573. 11 . Tsang RW Brierley JD. Pan::arella T. Gospodarowic:: M. Sutcliffe SB, Simpson WJ Radiation th erapy for pituitary adenoma : Treatment outcome and prognostic fa ctors. lnt J Radial Oneal Bioi Phys. 1994; 30(3): 557-65.

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14. 15. 16. 17.

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Zierhut D, Flentje M, Adolph J, eta!. External radiotherapy ofpituitary adenomas. lnt J Radial Oneal Bioi Phys 1995;33:307 Tsang RW, Brierley JD, Pan::arella T. et a!. Role of radiation therapy in clinical hormonally-active pituitary adenomas. Radiother Oneal 1996;41 :45 Sheline GE TJ Pituitwy tumours. In : Perez CA BL, ed. Principles and practice of radiation oncology. Philadelphia: Lippincott, 1987:1108. Marcou Y. Plowman PN. Stereotactic radiosurgery for pituita')' adenomas. TEM 2000; 11 (4) : 132-3 7. Plowman PN. Pituita1y adenoma radiotherapy- when, who, and how? C/in Endocrinol (Oxj) 1999; 51 :265- 71. Thoren M, et. a/. Stereotactic radiosurgel)l with coba/t-60 gamma unit in the treatment of growth hormone producing pituitwy tumours. Neurosurge1y 1991; 29: 663-668. Degerblad M, Rahn T. Bergstrand G, Thoren M. Long-term results of stereotactic radiosurge1y to the pituitwy gland in Cushing's Disease. Acta Endocrino/ogica 1986; 112: 310-14. Landolt AM, Haller D, Lomax N. Scheib S, Schubiger 0 , Siegfried J, We/lis G. Stereotactic radiosurge1y for recurrent surgically n·eated acromegaly: A comparison with fra ctionated radiotherapy. Journal of Neurosurge1y 1998; 88: 1002-1008. Laws ER, Thapur K. Surgical management of pituitwy adenomas. In Pituitwy tumours. Bailliere 's Clinical Endocrinology and Metabolism (Fagin , J, ed.) 1995; 391-40 . Bauman G, Battista J, VanDy k J A centwy of radiation oncology. UWOMJ 2001; 71(1): 46-51 .

Faster, Higher, Stronger: the use of EPO to enhance athletic performance. A review of the physiological effects of erythopoietin, the state of detection methods and the implications for international sports.

Hany Wu, Meds 2005 and James Woo, Meds 2005

Erythropoietin (EPO) has long been recognized by athletes for having performance enhancing effects. Its appearance at the Salt Lake City 2002 Olympic Winter Games highlights the need for governing sports bodies to fund more random testing and research into the detection of EPO as well as other performance enhancing drugs. This article reviews the physiological effects of recombinant human erythropoietin (rhEPO) and the current methods of detection and their limitations. Regular low dosage injections of rhEPO increase hemoglobin concentration and hematocrit. Therefore, the total oxygen carrying capacity of the blood is increased and the result is a small but significant increase in performance. Currently, athletes undergo an indirect test that detects the effects of rhEPO and direct testing for the presence of rhEPO in blood or urine. In order for these anti-doping measures to be successful, adequate funding and organization is of paramount importance.

The 2002 Winter Olympics in Salt Lake City were tainted with athletes suspected of using performance-enhancing drugs . Russian cross-country skiers Natalia Baranova, Larissa Lazutin and Olga Dani lova were disqualified from their races and stripped of medals after they tested positive for darbepoetin, a substance related to erythropoi eti n (EPO). However, these were not isolated cases; at least 3 to 7% of elite endurance sport ath letes use recombinant human erythropoei tin (rhEPO), a syntheti c EP0. 1. Pharmaceutical manufacturers produce rhEPO in Chin ese ovarian hamster cells for medical conditions such as anem ia. However, many endurance athl etes have recognized that regular subcutaneous inj ections of rhEPO can increase their performance and thus their chances of winn ing a medal. Unfortunately, using rhEPO has a price - it can cause adverse effects such as hyperviscosity, arterial hypertension, cerebra l convul sion and thromboembolism I. EPO is a glycoprotein made by ce ll s adj acent to the proxi mal renal tubules in response to hypoxia. It acts on erythoid precursors in the bone marrow and stimulates proli feratio n and differentiation of erythrocytes. rhEPO is a lmost identical to EPO in terms of structure and physiological action. Si nce rhEPO increases hematocrit and one-third of the erythrocyte' vo lume consists of hemog lobin, an increased amount of hemoglobin is carried in the bl ood2. Casoni eta/. showed that low dosage administration of rhEPO increased hemoglobin concentration from 142 giL to 151 giL and hematocrit from 41.7% to 46 .3%3. Hemoglobin acts to deliver oxygen to the tissues and consequently, the total amount of

oxygen delivered per unit time is increased with rhEPO use. Bulbulian et a /. discovered that maximal oxygen consumption (V02max) in athletes such as cyclists and runners was a major predi ctor of performance in endurance races . The researchers determined that oxygen supply was the limiting factor rather than th e cell's metaboli c capacity4. Since rhEPO usage results in a phys iologica l outcome of increased oxygen delivery to the tissues, it is important to establish how rhEPO can affect performance. Russell eta /. found that regular low dose rhEPO injections (20 IUkg- 1 body mass 3x/week for 5 weeks) were successful in maintaining hematocrit at elevated levels and consequently, an increased V02max of 6%-8%. Th.i s elevation in V02max can translate into race time improvements of 2%-6% for races lasting between 4 and 45 minutes. In additi on, a 3%-5% increase of V02max was susta ined for 4 weeks following inj ection cessations. For internationally competitive athletes, a sma ll decrease in race time can translate into a go ld medal. The firs t suspected use of rhEPO to enhance athleti c performance in endurance sports occurred between 1987 and 1990 when nineteen European cyc li sts died6. However, it wasn 't until the 2000 Sydney Olympics that an official protocol was establi shed for testing the illicit use of rhEPO in athletes. The major reason for this delay is that rhEPO shares many of the same biochemica l and immunological markers that exist in endogenous EPO. In addition , many of the effects of rhEPO occur with legal hi gh altitude training. As such, although scientists could suspect rhEPO usage, it was not until recently that they could prove it. UWOMJ 72( I) 2002 43

Strategies for testing for the presence of rhEPO can be divided into two broad categories: indirect and direct testing. Indirect testing involves testi ng for other biological markers that occur with rhEPO use whi le direct testing looks for the presence of rhEPO. Three methods of indirect testing have been proposed and one has been approved for use in international competition . The first proposed indirect method was discovered while looking at the effects of rhEPO on humans. Casoni eta/. noticed that increases in haematocrit from rhEPO injections resulted in an unusually high proportion of macrocytic hypochromatic erythrocytes. These RBCs had a dramatic increase in mean corpuscular volume (> 128fL) but a decrease in mean corpuscular hemoglobin (<28pg). In addition, these changes were not related to defi ciencies in vitamin B 12, folic acid or iron . Unfortunately, when the specificity of the test was set at 100% (no false positives) , the test could only detect 50% of subjects who had taken EPOJ. Therefore a more sensitive test was needed. Since serum soluble transferrin receptor (sTfr) is released from erythropoietic progenitors, it is possibl e to use this as an indirect marker for rhEPO. However, endogenous EPO would also affect this marker so clinical trial s were needed to see if thi s method would work. Studies have shown that up to 90 minutes of strenuous exercise does not affect sTfr levels7. When studies were done to examine the confirmatory value of a sTfr test with I 00% specificity, 80% of subjects who received EPO where detected . Unfortunately, these results were only valid for one week after the subj ect's last rhEPO inj ections. Considering that the physiological effects of rhEPO may last up to three weeks athletes can time their last injection and avoid detection . Although this test is markedly better than the previous one, sensitivity could be further improved. The final testing method that was approved incorporates the two previous tests plus three additional facto rs (haematocrit, reticulocyte haematocrit and serum EPO) in a mathemati ca l equation. Research conducted by the Australian Institute of Sport measured these hematological vari abl es from subj ects who were usi ng rhEPO and control s. Using a mathemati ca l equation , a value called an ON model score was generated. Thi s score di scriminated rhEPO users from control s 95% of the time9. Thi s approach makes sense because artifi ciall y raising one's oxygen carrying capacity must result in abnormal changes in hemato logy. This highly sensitive and spec ifi c test was approved for th e Sydney Olympics. As previously mention ed, direct testing for rhEPO is very difficult beca use rhEPO and EPO share the sa me immun olog ica l and biochemi ca l properties. The first direct te ting method take advantage of the fact th at rhEPO is less anioni c than endogenous EPO. In order to detect this difference, an electrophoretic mobility assay may be used. Since rhE PO has such a short half life, this test is only effective if conducted within 24 hours of the inj ection. Both blood and urine sampl es can be used iO. The econd direct testing method takes advantage of th e fact that rhEPO has sli ghtly different sugar properti es than endogenous EPO. These differences can be di stingui shed using isoe lectri c patterning. An advantage of thi s method is that it may be admini stered up to 72 hours after the last rhEPO inj ecti on II . However, a major drawback is

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that both direct methods must be administered long before their physiological effects have expired. After reviewing the scientific literature on the detection of EPO the IOC decided to use the ON model score test along with ' a confirmatory isoelectric patterning of both blood and urine samples at the 2002 Salt Lake City Olympics. In order to meet the requirement that the test be given almost immediately after the rhEPO injection, tests were performed weeks in advance of the competition. Since rhEPO needs to be injected every few days to have maximal effect, by randomly testing the athletes weeks before the competition, an athlete could not time their injections to avoid detection. Despite significant risks of mortality and morbidity, many athletes continue to use performance enhancing substances because the stakes are incredibly high. An Olympic medal or world championship can bring immense wealth from sponsors and governments. As a result, athletes will continue to cheat unless international federations can provide enough deterrence so that the ri sk and consequences of being caught far outweigh the gains fro m winning. EPO illustrates the victori es and failures of trying to protect athletes and the questionable integrity of some athletes in competitive sports. Previous lack of anti-doping funding has hindered development of detection tests for drugs such as EPO and human growth hormone. However, the formation of an independent World Anti-Doping Agency (WADA) and a new commitment to funding have resulted in so lutions to combat cheating. Their ucces was highlighted with the disqualification of cross-country skiers who used EPO. In addition, WADA was abl e to ban athl etes who tried to fool EPO tests by taking HES (a drug that manipul ates plasma vo lume). This was the first time the organization was one step ahea d of the cheaters. In order for WADA to remain successfu l, the ir funding must continue to parallel that u ed to design performa nce enhancing drugs and cover the cost of testing athletes (currently over $ 130 US each)1 2. Hefty financial penalties for testing positive or an across the board fee for drug test ing could be addition a l source s of revenue. Furthermore, athl etic federations also have a responsibility to their athl etes by en uring fair competition. A portion of their member hip revenue should also be used. With these additional poli cie , the strength of WADA will continue to eliminate cheating from sports. References I.

2. 3.

Randall W Detection of DNA-recombinant human epoetin -alfa as a pharmacological ergogenic aid. Sport Med 2002: 32(2) : 125-142. McKen:::ie, SB. Th e e1ythrocyte. in: Textbook of hematology Baltimore: Williams and Wilkins; 1996. p. 41 . Casoni I. Ricci G. Ballarin E, Borsetto C. Gra::::::i G et a/. Hematological indices of eiJ'thropoietin admini !ration in athletes. /nt J ports Med 1993 Aug; l 4(6) :307-3 1/ . Bulbulian R, Wilcox A R. Darabos BL. 1986. Anaerobic contribution to distan ce running pe1jormance of tra ined cross-countn• athletes. Med Sci ports Exerc l 8: 107- 11 3. Russell G. Gore C. Ashenden M, Parisotto R, Hahn A . £./fe et of prolonged low doses of recombinant human etJ•!hropoietin during submaxun a/ and max imal exercise. Eur J Appl Physiol 2002:86:442-449. Shaskey D, Green G. Sports Ha emato logy. Sports M ed Jan : 29(1):27-38.

Gareau R, Gagnon MG, Theilend C, Chenard C, Audran M, Chana/ JL, eta/. Transferrin soluble receptor: a possible probe for detection of e/) 1thropoietin abuse by athletes. Horm Metab Res 1994 Jun ;26(6):3 11 -2. 8. Birkeland KJ, Stray- Gundersen J, Hemmersbach P, Hallen J, HaugE, Bahr R. Effect of rhEPO administration on serum levels of s TjR and cycling pe1jormance. Med Sci Sports Exerc 2000 Ju/;32(7): 1238-43. 9. Parisotto R, Wu M. Ashenden MJ, Emslie KR, Gore CJ, Howe C. et a/. Detection of recombinant human e1y thropoietin abuse in athletes utilizing markers of altered ery thropoiesis. Ha ematologica 2001 Feb;86(2): 128-3 7. Wide L, Bengtsson C, Berglund B. Ekblom B. Detection in blood and urine of recombinant e1y thropoietin administered to healthy men. Med Sci Sports Exerc 1995 Nov;27(JJ):1569-76. 10. Lasne F, de Ceaurriz J Recombinant erythropoietin in urine. Nature 2000 Jun 8;405(6787):635. 11 . Abbott A. What price the Oly mpian ideal? Nature 2000 Sept 14; 407: 124-127.

U.S.A. Immigration Law William Newell Siebert Attorney at Law 307 North Michigan Avenue Suite 924 Chicago, Illinois 60601 Voice: (312) 329-0646 Fax: (312) 553-4419 E-Mail: wsiebert@siebert-immigrationlaw.com

PRACTICE CONCENTRATED IN U.S. IMMIGRATION LAW SINCE 1969 UWOMJ 72(1) 2002 45

A Cure for Non-Insulin Dependent Diabetes found in Bariatric Surgery

Heather Cox, Meds 2003

Classically, obesity has been strongly associated with a number of health risks, most commonly, non-insulin dependent diabetes (NIDDM). Studies have shown that a reduction in central obesity often provides patients with better glycemic control and less need for medication. Much time, effort and finances are spent on encouraging the diabetic patient to lose weight, however, this is difficult to achieve and certainly it is difficult to maintain weight loss. As such, the disease and its complications ensue. Recent studies of severely obese (BMI >35) diabetic patients undergoing gastric bypass have shown quick remission of NIDDM far earlier than weight loss is appreciated. In addition, euglycemia is maintained even if weight is regained. This research thereby challenges the notion that fat alone is exacerbating insulin resistance and that more importantly we should explore the role of the foregut in NIDDM.

The Centre for Disease Control and Prevention have warned the North American public that obesity is considered an epidemic and that this epidemic is likely to become a significant public health issue in the upcoming years'. The prevalence of obesity in the US was 19.6%, a 61% increase from the last 10 years , and 40% of Australians are considered overweight today'. This epidemiology is of concern as obesity and to a lesser extent, being overweight, has been associated with a number of significant medical disorders that cause morbidity and mortality and have enormous health care costs2. Obesity has been associated with coronary artery disease3-6, hypertension, diabetes mellitus, degenerative joint diseases, chronic back pain, hepatobiliary diseases, depression and gallstones?. In 1998 it was felt that approximately 56 billion dollars was spent on the treatment of obesityrelated health disorders3. Obesity also plays a role within endocrine disorders, as conditions such as non-insulin dependent diabetes (NIDDM), polycystic ovarian syndrome, hypo and hyperthyroidism, ovarian and

NIDDM Polycystic Ovarian Syndrome Hypo and Hyperthyroidism Ovarian and Prostate malignancies

Table 1. Obesity Associated Endocrine Conditions

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prostate malignancies, are more common in the obeses,9. Some researchers feel that presence of obesity signals the presence of an altered metabolism iO. Syndrome X, a metabolic disorder which clusters obesity, hypertension, dyslipidemia and NIDDM is most strikingly correlated with insulin resistance" . In an effort to compensate for reduced insulin effects on target organs, hyperinsulinemia ensues in order to achieve glucose homoestasist 2. It is well accepted that NIDDM is associated and exacerbated by obesity, in particular central obesity 13 . In fact, even those with a BMI of 25-30 kg/m2 have a higher risk of developing NIDDM than those of normal weight. Of all the conditions associated with obesity, NIDDM has the highest proportion of obese patients 13.

WEIGHT LOSS IN THE DIABETIC PATIENT A reduction of body weight by 5-10% can reduce the risk of NIDDM by as much as 50% 13. That same weight loss in an obese patient that already has NIDDM begins to show improvement in

21 % reduction risk in all diabetes-related complications 25% reduction in diabetes mortality 17% reduction in total mortality

Table 2. Benefits of a 1% reduction in HBAtc levels from the UK Prospective Diabetes Study (Van Gaan)

glycemic control, insulin sensitivity and lipid abnormalities via a reduction in glycated hemoglobin !evels13. Despite these promising advances, such changes are rarely noticed in the diabetic patient. Most patients but in particular diabetic patients, have difficulty loosing weight and maintaining that weight loss1 3. Medications such as orlistat and sibutramine have been shown to induce weight loss and improve diabetic control but that state is only maintained if the patient maintains taking the medication 13. So how can we aid obese diabetic patients to minimize the morbidity and mortality of their condition in a lasting way? Recent studies in the realm of bariatric surgery suggest that the medical community may require an entirely new approach to obesity and diabetes. That in fact, perhaps weight reduction alone is not responsible for improved glycemic control and that there may be a way to cure the obese NIDDM patient of their diabetes. Bariatric surgery is a collection of surgical procedures offered to the severely obese (body mass index (BMI) > 35 kg/m2) that meet a NIH criteria14 in an effort to normalize the BMI and improve some of the metabolic and physiologic abnormalities related to obesity 15. The basic principles of bariatric procedures are the use of intestinal malabsorption and/or gastric restriction1 4. In malabsorptive procedures (Table 3), the small intestine is rearranged to decrease the efficiency of nutrient absorption by the intestinal mucosa14. Whereas in restrictive procedures (Table 3), a small neogastric pouch and/or outlet limits food intake14. Many procedures combine these two principles and some procedures have been met with disappointing complications and/or unacceptable mortality rates1 6. However, the Roux-en-Y gastric bypass (GBP) and vertical banded gastroplasty (VBG) have met with success for weight management. To date only surgery offers major sustained weight loss in the obese NIDDM patient1 7. Malabsorptive procedures Restrictive procedures Jejunoileal bypass Vertical Banded Gastroplasty Biliopancreatic diversion Adjustable Gastric Banding Duodenal switch Gastric Bypass

ed patients. Major complications of this procedure are stomach and duodenal ulcers, gastrointestinal bleeding, torsion of the Roux limb, gallstone formation and stomal stenosis1 6. Together these represent a complication rate of approximately I 0% 16. In VBG the gastric stapling line extends upward from the angle of His with a reinforced stoma at the lesser curvature1 6. This restrictive procedure did deter the ingestion of large solid meals but was not able to deter patients from ingesting calorierich drinks such as milkshakes. As such studies of the long-term weight loss after this procedure found that only 38% of patients were able to maintain at least 50% excess weigh loss at 3 years14. The latest approach being applied, especially in the younger patient, is the VBG-GBP in which the stomach is transected and a limb of the jejunum is placed between the pouch and the excluded stomach1 8. A number of recent studies of severely obese diabetic patients have shown that most diabetic patients quickly (i.e less than 14 days postoperatively) enter remission from their NIDDM after gastric bypass and other bariatric procedures (i.e. biliopancreatic diversion) 11 ,19,20. Rigorous follow up to 14 years found that 82.9% of diabetic patients maintained euglycemic states as marked by serum glucose levels, insulin requirements and HbA1 c2o. In addition, post GBP patients were also found to have improvements in HDL, LDL cholesterol and triglyceride leve!s16. Consequently surgical patients were also found to have a lower mortality rate (mostly due to decrease in cardiovascular deaths) when compared to matched control groups2o. CHALLENGES TO THE CURRENT SCHOOL OF THOUGHT Given that the improvement in glycemic control occurred far earlier than weight loss11 and that the glycemic control was more complete than the weight loss20, this research greatly questions the mechanisms by which obesity manipulates insulin resistance. In a study comparing two groups of matched obese diabetic

Malabsorptive procedures

Restrictive procedures

Jejunoileal bypass Biliopancreatic diversion Duodenal switch

Vertical Banded Gastroplasty Adjustable Gastric Banding Gastric Bypass

Table 3. Bariatric proceduresl4 The Roux-en-Y GBP procedure combines the restnchve technique of partitioning the stomach into a small proximal portion and a larger distal bypassed portion with the malabsorptive technique of a loop gastrojejunostomy to drain the proximal portion14. In addition, the dumping physiology characterized by lightheadedness, nausea, palpitations, diaphoresis and diarrhea, negatively reinforces the consumption of calorie-rich liquids 14 . GBP has been shown to be the superior technique for weight loss in a number of trials; the most recent finding that a 62% loss of excessive weight was maintained at 10 years follow up 14 . Weight loss was approximately 33% of total body weight and only 2025% of patients were found to have inadequate weight loss1 6. Another advantage is that this procedure may be performed !aparoscopically by experienced surgeons and in carefully select-

women who differed only in the way in which their food was routed, it was shown that when food was excluded from the distal stomach, antrum, duodenum and proximal jejunum (GBP), the bypassed group had significantly lower levels of plasma insulin and fasting plasma glucose. This suggests that fat mass is not an adequate determining factor for the maintenance ofNIDDM 20. So does the foregut have a role in the insulin resistance of NIDDM? It is known that dumping symptoms in GBP patients in response to oral glucose intake is associated with an elevated enteroglucagon leveJ1 4, however is this sufficient to explain the above phenomenon? Is there overstimulation of some intestinal hormone? of islet cells? Clearly these questions are not easily answered. At the very least though, we have evidence that NIDDM can be improved in the obese patient, and presumably UWOMJ 72(1) 2002 47

further research into this phenomenon cou ld lead to a cure for NIDDM and a reduction in associated complications in patients of all sizes.

Neal, Pallett & Townsend

LLP

CH ARTERED A CCOUNTANTS

REFERENCES 633 Colborne Street, Suite 300, London, Ontario N6B 2V3

1. 2.

3. 4.

9. 10. 11 .

12. 13.

14.

15. 16. 17. 18.

19. 20.

Frankish, Helen. Obesity and diabetes epidemics show no sign of abating. Th e Lancet, 2001 Sept (358) : 896. Shikora , Scott A. Approaches to the Medically Complicated Patient Surge1y. Proceedings from the Na tional Conference of Obesity 2001 Jun e: 1- 7. Wolf, AM., Coldit: GA ., Current estimates of the economic cost of obesity in the United States. Obesity Research.1998(6): 97- 106 Fleming RM. Th e effect of high-. moderate-, and low-fat diets on weight loss and cardiovascular disease risk fac tors. 2002 Preventive Cardiology. 5(3): 11 0-8 Summe1: Wofford MR. Da vis MM. Harkins KG. King DS. Wyalf SB. Jones DW Th erapeutic considera tions in th e treatm ent of obesity hypertension. Journal of Clinical Hypertension. 2002: 4(3): 189-96, May -Jun. De Pergola G. Pannacciulli N. Zamboni M. Minenna A. Brocco G. Sciaraffia M. Bosel/o. Giorgino R. Homocysteine plasma levels are independently associated with insulin resistance in normal weight, overweight and obese pre-menopausal women. [Journal Article} Diabetes. Nutrition & Metabolism - Clinical & Experim ental. 2001 ;14(5) :253-8. Oct. Jung, RT , Obesity as a disease. British Medical Bulletin. 1997: 53:30732 1. Chang RJ. Kat: SE. Diagnosis of p olycystic ovary syndrome. Endocrin ology & Metabo lism Clinics of No rth America. 1999; 28(2):397-408, vii, Jun . Marin P A rver S. Androgens and abdominal obesity. Baillieres Clinical Endocrinology & Metabolism. 1998: 12(3):441-51, Oct. Tremblay A. Doucet E. Obesity: a disease or a biological adaptation? Obesity Reviews 2000; 1(1) :27-35, May. Stubbs, Richard, Wic/.;remesekera, S. Kusal. insulin Resistan ce in the Severely Obese and Links with Metabolic Co-morbidities. Obesity Surge1y 200 1;12:343-348. Reaven GM., Role of insulin resistance in human disease (syndrome X): an expanded definition. Ann Rev Med 1993:44:121-1 31. Van Gaal, LF, Peiffer, FW Th e importance of obesity in diabetes and its treatm ent with sibutramin e. i nternational Journal of Obesity 2001;2 5(suppi):S24-S28. Mun , Edward, Blackburn. George. Matth ews. Jeffrey B., Current Status of Medical and Surgical Th erapy for Obesity. Gastroenterology 2001:120(3): 696-68 1. Alva rez-Cordero, R., Final Reflections: Wei/ness after Obesity Surge1y . World Journal ofSurge1y . 1998;22:1018- 102 1. Greenway, FL .. Sw-gel)' fo r Obesity. Endocrinology and Metabolism Clinics of No rth America 1996;25(4) : 1005- 102 1. Campbell, L. , Rossner, S., Man agement of obesity in patients with Type 2 Diabetes. Diabetic Medicine 2001;18: 345-354. Capella, JF., Capella R. An assessment of vertical banded gastroplastyRoux -en- Y gastric bypass for the treatment of morbid obesity. American Journal ofSurge1y 2001;183:11 7- 123 Rubino, F., Gagne1; M .. Marescaux, J , Surgical treatment of type 2 diabetes mellitus. Th e Lancet 2001:A ug 358: 668-669. Poires, WJ , Albrecht. RJ , Etiology of7jipe If Diabetes Mellitus: Role of the Foregut. World Journal of Surgery 2001;25:527-53 1.

UWOMJ 72( I) 2002

(519) 432-5534

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P ARTNERS

Barrie Nea l Glenn Hardman

David Palleu John Prueter

Jonathan Townsend L. J. Sandy Wetstein

It's Raining MEN

Kieran Mcintyre, MEDS 2003

The advent of genetic testing has p~ovided insights into the pathogenesis of inherited familial cancer syndromes. and now ?ffers bot~ screenmg .and treatment for patients and members of their family. Multiple endocnne neoplasia (MEN) IS one such mherited form of cancer that has recently had both identification of the genes and cellular signalling pathways involved in tumourgenesis. Patients with MEN and their family members can now be screened and undergo treatments shown to improve quality of life and survival due in large part to this research. The following is a case presentation of an individual that unfortunately inherited two independent forms of cancer. The case demonstrates the devastating impact of an inherited illness not only on a patient and their family but on generations of their descendents as well.

CASE REPORT A pleasant 53 year-old gentleman comes to his family doctor's office in a very small northern Ontario town for routine follow up of test results and to receive his monthly testosterone injection. He had recently returned from a routine appointment with a tertiary care centre endocrinologist involved in his case and had also seen a dermatologist regarding numerous multiple flesh coloured skin papules. The patient has three older brothers, one of which died in his fifties from a myocardial infarction whi le his other two both have similar skin lesions and histories of parathyroid adenomas and thyroid cancers. The patient's condition was first diagnosed during his thirties when he presented to his family doctor with a three-month history of fatigue , abdominal pains, anorexia and constipation . X-rays of the patient's abdomen were taken for suspicion of a bowel obstruction which serendipitously revealed multiple small radioopaque kidney stones; blood tests showed a corrected serum calcium of >2.9mmol/L, an elevated intact serum PTH level and a serum phosphate well below the laboratory range. The diagnosis of hyperparathyroidism secondary to parathyroid adenoma was suspected and confirmed by ultrasound. The patient had 3 and one-half of his parathyroid glands removed and began periodic evaluations of his serum calcitonin levels. After the surgery, the patient reported still feeling fatigued and began complaining of significant muscle weakness and gaining weight in an unusual manner; demonstrated by significant

truncal obesity and edema. Clinical and laboratory investigations showed the patient was hypertensive with an elevated urine cortisol level appropriately suppressed by I mg of dexamethasone. The patient started taking oral ketoconazole to suppress and underwent an MRl that demonstrated a pituitary mass , which effectively confirmed the diagnosis of Cushing's disease. The patient underwent trans-sphenoidal resection of his pituitary tumour and had complete resolution of his muscle weakness and other symptoms. Unfortunately, on ly a few years following his second surgery, the pattent began to have some difficulty swallowing and noticed a painless, palpable mass just below the level of his cricoid carti~ age. Fine needle ~spiration of the nodule demonstrated pathologIcal changes conststent with medullary cancer of the thyroid so th~ patient subsequ_ently had a total thyroidectomy and post-operative radtattOn ofhts neck. The patient 's underlying diagnosis was confirmed by genetic testing after the he was referred to an endocrinologist following the diagnosis of thyroid cancer. Soon after being diagnosed with hyperparathyroidism Cushing's syndrome and medullary thyroid cancer, the patien~ was notified that the most recent of his periodic CT exams showed a unilateral abdominal mass over his left kidney and that the urine samples that he provided to his family doctor every three months showed an elevated level of VMA (vanillylmandelic acid). These findings were consistent with the development of an adrenal adenoma or pheochromocytoma and the patient admitted that he ha~ been experiencing episodes of uncontrolled shaking and poundmg headaches associated with unexplained sweating UWOMJ 72( I) 2002 49

for the past few months. The patient found himself yet again referred for surgical evaluation and underwent bilateral adrenalectomy with subsequent testosterone and glucocorticoid replacement. After this brief respite, the patient continued to undergo CT examination which revealed a mass in the superior pole of his right kidney that could not be adequately di stingui shed from his kidney and represented either a recurrence of adrenal adenoma tissue from residual chromaffi n cell s or a developing renal cell carcinoma. The patient had been referred for surgical removal of the mass and was willing to undergo complete right nephrectomy if indicated but was last seen heading off on a much needed and well deserved vacation.

DISCUSSION The patient and hi s family were invited by the National Institute of Health (NIH) in Bethesda Md. for genetic testing which demonstrated the patient had point mutations in the RET proto-oncogene on chromosome 10, thereby confirming the di agnosis of Multiple Endocrine Neoplasia (MEN). Unfortunately, three of the pati ent's grandchildren and one of hi s children also inherited the same mutati on; the grandchildren were the offspring of the patient 's only affected child. They have all undergone prophylactic thryoidectomies and are being followed for development of pheochromocytomas. Multiple endocrine neopl asia (MEN) is inherited in a classic Mendellian autosomal dominant pattern and is subdivided into MEN-I and MEN-2 based on genetic abnormalities and specific tumours that deve lop in patients with each syndrome I , 2. MEN-I , or Wermer 's syndrome is characterized by the occurrence of neuroendocrin e parathyro id, pancreas, duodenum and pituitary tumours3, 4. The MEN-2 syndrom e is divided into three clinical vari ants referred to as MEN-2A (Sippl e 's syndrom e), MEN-2B and familial medullary thyroid carcinoma (FMTC) which share medullary thyroid carcinomas as part of the di sease phenotypeS, 6. MEN-2A is distinguished from MEN-2B by the occurrence of pheochromocytomas in the former and the deve lopment of a Marfanoid habitus in the latter7 8 9. (Refer to tabl e I) The genetic abnormalities underlying MEN have recently been sequenced and are an elegant demonstration of the importan t role pl ayed by tumour suppressor and proto-oncogenes in maintai ning the equilibrium of ce llul ar di vision. In MEN-I , the gene abnormality has been mapped to chromoso me JJI O and involves the inactivation of menin, a tumour suppressor protein that when inacti vated cannot suppress lunD-med iated transcription .ll ,l2, 13 MEN-2 has been attributed to the RET oncogene located on chromosome l 0 that encodes a tyrosine kinase receptor involved in initiating a signalling network crucial for neura l and kidney development.l4,15, 16 A mutated RET gene product leads to uncontroll ed signalling and subsequent tumour deve lopment in the ti ssue derived from neural crest ce ll s: C-cell s of the thyroid, chromaffin cell s of the adrenal medull a and parathyroid cells. There are now multipl e documented mutations of the RET gene all leading to the f in al common pathway of an altered RET gene product that in turn leads to the clini ca l manifestations of MEN-2a , MEN-2b and FMTC.17, 18 The inactivation of th e RET oncogene through mutation of a specif ic gene ex on is also seen in approximate ly 25% of patients with the inherited form of 50

UWOMJ 72( I) 2002

Hirschsprung's disease, a congenital absence of enteric innervation that occurs in approximately I in 5000 live births. 19路 20 路 21 However, since only a minority of patients with Hirschsprung 's disease have the specific gene mutation and not all patients with the necessary mutation in MEN-2 develop Hirschsprung 's disease, there are more factors as yet unidentified in the development of this intestinal motility disorder. The pati ent in the case above was a somewhat unusual presentation of MEN-2a in that he had two independently inherited forms of cancer as well as developing Cushing's disease which is presumed to be unrelated to the underlying genetic abnormality with which he was diagnosed. Corticosteroid excess in association with pheochromocytomas or medullary cancer of the thyroid have been described only through case reports in the literature and are rarely assoc iated with MEN-2a since these cases involved ectopic ACTH production22. The presence of skin lesions in this patient are not related to the MEN syndrome, and are due to a second autosomally dominant trait that the patient has been unfortunate enough to inherit call ed Birt-Hogg-Dube (BHD) syndrome which has been mapped to an abnormal gene on chromosome 1723. The benign skin lesions ofBHD, first described in 1977 compose a triad of hamartomas with folliculo-sebaceous differentiation or fibrofolliculomas, trichodiscomas, and acrochordons (skin tags) 24. There are reports that the BHD syndrome is one and the same as another skin condition known as Hornstein and K.nickenberg (HKS) syndrome associated with intestinal polyposis; the confusion is thought to arise from procedures related to ti ssue sectioning25. The patient in this case has had multiple screening colonoscopies starti ng in nis early forties and not had any polyps reported to date. BHD syndrome has also been shown to segregate with renal cell cancers26,27, making the developing les ion in thi s patient suspi cious of yet another neopl asm. The pi cture is somewhat obscured however, in that the RET gene is known to be involved in the development of the kidney and pati ents with MEN2A have been shown to have kidney neoplasms in the absence of BHD syndrome; orne investigators therefore argue for routine abdominal exami nations to screen for kidney abnormalities in these patients. 28 The most important aspect in the care of patients with either documented or suspected MEN is to obtain a diagnosis by genetic testing. Gene testing is now avai labl e for both patients and offspring of MEN-I and MEN-2 who have a 50% chance of inheriting the mutation fro m their parent. A list of available laboratories for geneti c te ting is ava il abl e at http://endrcr06.mda.uth.tmc.edu. Multiple studi es have demonstrated that prophylactic thyroidectomy at an early age and monitorin g of serum calcitonin is effective in preventing the thyroid cancer responsibl e for most deaths in the group of patients with MEN29,30,31. For patients with documented hyperparathyroidi sm, the current reconunendations are a total parathyroidectomy wi th heterotopic autologous transplantation of parathyroid ti ssue32 and routin g screening of urine epinephrine and VMA for ph eochromocytoma screening33. The treatment of B~D is based on patient preference of biopsy proven benign les1ons; current recommendations do not invo lve removal but laser therapy has been shown to be quite effective wi th minimal scarring,34,35

Table 1: Disease Associations in the Multiple Endocrine Neoplasia (MEN) Syndromes

MENl

MEN2

Parathyroid hyperp lasia or adenoma Islet cell hyperplasia adenoma, or carcinoma Pituitary hyperplasia or adenoma Other less common manifestations: foregut carcinoid, pheochromocytoma, subcutaneous or visceral lipomas, dermal angiofibromas or collagenomas

REFERENCES 1. 2. 3. 4.

8. 9.

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16. 17.

Thakker, R. V. Multiple Endocrine Neoplasia, Harm Res 2001;56 Suppl 1:67-72 Brandi ML et a/. Guidelines fo r diagnosis and therapy of MEN type I and type 2. J Clin Endocrino/ Metab 2001 Dec;86(12):5658-71 Marx, S. et a/ Multiple Endocrine Neoplasia I : Clinical and Genetic topics Ann Intern Med 1998 Sep 15; 129(6):484-94 Komminoth , P. Pathology of MEN-1 : morphology, clinicopathologic correlations and tumour development J Intern Med 1998 Jun ;243(6):455-64 Komminoth , P. Multiple endocrine neoplasia type I and 2: fro m morphology to molecular pathology 199 7 Verh Dtsch Ges Patho/ 1997;81:125-38 Altanerova V. Cancers connected with mutations in RET proto-oncogene Neoplasma 2001;48(5):325-31 Fassbender WJ et a/. Multiple endocrine neoplasia (MEN)-an overview and case report- patient with sporadic bilateral pheochromocytoma, hyperparathy roidism and mmfanoid habitus. Anticancer Res 2000 Nov-Dec;20(6C):4877-87 Calendw; A. Genetic testing in multiple endocrine neoplasia and related syndromes. Forum (Genova) 1998 Apr-Jun;8(2): 146-59 Stratakis CA A concise genetic and clinical guide to multiple endocrine neoplasias and related syndromes J Pedian' Endocrinol Metab 2000 May; 13(5):457-65 Chakrabarti R et a/. Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11 q 13. Genes Chromosomes Cancer 1998 Jun ;22(2):130-7 Marx, SJ. eta /. Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MENI ) J Intern Med 1998 Jun ;243(6):44753 Pannett AA, Thakker RV. Multiple endocrine neoplasia type 1 Endocr Relat Cancer 1999 Dec;6(4) :449-73 Gob/, A.E. eta/, Men in represses lunD-activated transcription by a histone deacety/ase-dependent mechanism Biochim Biophys Acta 1999 Oct 6; 1447(1):51-6 Manie, S. eta/., Th e RET receptor: function in development and dysfunction in congen ital malformation Trends Genet 2001 Oct; 1 7(10):580-9 Hansford, J.R and Mulligan, L.M Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet 2000 Nov;37(1 1):81 7-27 Eng, C., RET proto-oncogene in the development of human cancer J Clin Oneal 1999 Jan ; 1 7(1):380-93 Martinez Diaz-Guerra Get a/. Cushing's syndrome associated with a metastatic medullary carcinoma of th e thyroid. A report of 2 cases and a review oft he literature Rev Clin Esp 1995 Dec; 195(12):849-52

18.

19.

20. 21.

22.

23.

24.

25.

26. 27.

28.

29. 30.

31 .

32.

33. 34.

MEN2A

MEN2B

MTC Pheochromocytoma Parathyroid hyperplasia or adenoma Cutaneous lichen amyloidosis Hirschsprung disease FMTC

MTC Pheochromocytoma Mucosal and gastrointestinal neuromas Marfanoid features

Nakao, A., et a/. A family of multiple endocrine neoplasia type 2A with th e RET proto-oncogene mutation in codon 618 (Cys->Arg). Jpn J Clin Onco/2001 Apr;31(4):157-61 Eng, C. Seminars in Medicine of the Beth Israel Hospital, Boston: Th e RET Proto-Oncogene in Multiple Endocrine Neop/asis Type 2 and Hirschsprung's Disease N Eng/ J Med 1996; 335:943-951 Ibid, Eng. C. Mutations of th e RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease Hum Mutat 1997;9(2) :97-109 1noue, K. eta!., Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease J Pee/ian路 Surg 1999 Oct;34(10) : 1552-4 Khoo, S.K. eta/, Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 1 7p12-q1 1. 2. Oncogene 2001 Aug 23;20(37) :5239-42 Birt AR, Hogg GR, Dube WJ Hereditwy multipleflbrofol/iculomas with trichodiscomas and acrochordons Arch Dermatol 19 77 Dec; l 13(12):1674-7 Schulz, T. Birt-Hogg-Dube syndrome and Hornstein-Knickenberg syndrome are the sam e. Different sectioning technique as the cause of different histology. J Cutan Patho/1999 Jan ;26(1):55-61 Taro, J.R. Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia Arch Dermato/1999 Oct; 135(10): l195-202 Scmidt, L.S. eta/, Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2 Am J Hum Genet 2001 Oct;69(4):876-82 Lore, F., et a/. Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations. J Intern Med 2001 Ju/;250(1):3742 1/eJ; M.A. eta/, Multiple endocrin e neoplasia type 2A : a 25-year review J Pediatr Surg. 1999 Jan ;34(1):92-6 Lallie1; M. et a/. Prophy lactic thyroidectomy fo r medullwy thyroid carcinoma in gene carriers of MEN2 syndrome J Pediatr Surg. 1998 Jun ;33(6) :846-8. He1jarth K.K et al. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A Surgery 1996 Dec; 120(6):966-73 Eisenhofer G. et a/., Plasma Normetanephrine and Metan ephrine for Detecting Ph eochromocy toma in von Hippei- Lindau Disease and multiple endocrin e neoplasia T)'pe 2 N Eng/ J Med 1999; 340:1872-1879 Gambichler T et a/. Treatm ent of Birt-Hogg-Dube syndrome with erbium: YAG lase1: JAm Acad Derma to/ 2000 Nov;43(5 Pt 1):856-8. Ja cob C.! and Dover J. S. Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin res~ofacing Arch Dermatol 2001 Jan ; 137(1) . 98-9

UWOMJ 72(1) 2002 51

Humour

"That's a Fine mess you've got yourself in" A Gut-wrenching Tale

Alan J Cooper, MD FRC Psych., DPM. , Dip. Pharm. Med. Director of Re earch and Education St. Thomas Psychiatric Hospital Professor of Psychiat1y University of Western Ontario Consultant Psychiatrist

October 2000, I turned 65 . I had not undertaken a medical examination since 1976 (a requirement of Immigration Canada before I was allowed into the land of the maple leaf) . Furthermore, I had recently been experiencing intermittent abdominal pain and diarrhoeae. My mother had succumbed to colon cancer at the age of 70, and since I was more like her than my father, I decided it was time to consult a physician. So, before my courage ebbed, I made an appointment to see Dr. D. a highly rated local internist whom I'd met socially a couple of times. Dr. D 's examinat ion was comprehensive. After its comp letion, he censoriously commented that I should cut down on my drinking. He continued that I was hypertensive with probable left ventricular hypertrophy, and more cautious ly intimated that I could have an aortic aneurysm. Dr. D wrote me up for the usual zillion lab tests; an EKG and routine chest x-ray. Additionally, he recommended an abdominal ultra sound and, given my bowel symptoms and mother's history, advised that I had either a barium enema or a colonoscopy. After debating the pros and cons of both procedures, he suggested the former as " being less traumatic to an individual of my vintage". I was given an appointment to return in some two months, when the tests had been completed and the results were to hand. I duly cal led the x-ray department of the loca l hospita l and a date was set two weeks hence, for the examinations. The ultra sound was scheduled for 9:00 - 9:30 a.m.; the barium enema to fo ll ow immediately after. The receptionist, on learning that I had not previously been "subjected" to a barium enema, promised to send me an "information leaflet" which would give me details of the procedure. She emphasized the requirement to fast for at least 36 hours before, as well as cleaning out the bowels with a Fleet enema, thereby to ensure top-quality pictures. I must confe s that I didn't li ke one littl e bit of what she had told me. The unknown always fi ll s me with anxiety. Sure enough, the leaflet arrived severa l days before the scheduled tests, and I read it carefully. The 36-hours fasting was 52

UWOMJ 72( 1) 2002

no big deal , although my stomach did grumble somewhat in anticipation . The oral laxative was something else. I had reviewed the x-ray department instructions pertaining to the Fleet enema, several times because I found them hard to believe: I was required to drink two 45-ml bottles of Fleet, 18 hours and 15 hours before the barium examination, together with at least four-to-five pints of water. Since the manufacturer's insert-leaflet that came with the bottle, cautioned a maximum dose of not more than five milliliters for an adult, I was naturally somewhat taken aback; so I called the x-ray personnel for clarification. The receptionist adamantly confirmed that, yes I was to drink the two bottles as instructed. She stressed, somewhat testily it seemed to me, the abso lute necessity for my large bowel to be as "clean as a whistle". Her tone implied that anything less simply would not do, and I would be wasting my own and everybody e lse 's time. As I swa llowed the first 45 ml , which incidentally had the most disgusting taste, I pondered why it was named "Fleet" - I was to find out pretty soon! I had been warned by the x-ray receptionist not to stray too far from a washroom. Otherwise, she hinted darkly, I cou ld be in "quite a mess". Always obedient, I sat on the patio and awaited developments. Some six hours later and five pounds lighter, my vio lent diarrhea had almost stopped. And I swear that my gastrointestinal tract, all 26 feet of it, had never been emptier nor cleaner - but what a price to pay! Waves of nausea, excruciatingly painful perista lsis; irresistible vo iding of first semi-fluid, bile-stained feces, which became paler and more liquidy; finally, torrents of what looked like "almost-pure water", which could not be stopped despite by best efforts to keep my ana l sphincter tightly closed. Then I knew why: "Fleet" by name, " Fleet" by nature. "Ah , well ," I thought, "the worst is over." If only I knew! The abdomina l ultrasound investigation started promptly as arranged at 9 :00 a.m. The technician was a friend ly talkative middle-aged woman; an exce ll ent mother, no doubt., Once sh; reali zed that I was a physician, she cordially invited me to watch the sc reen , as each assayable abdominal organ was grossly eva !-

uated. I was both fascinated and apprehensive. I was amazed at the technology but fearful of what might be revealed. She skillfully moved the ultrasound probe across my "greased stomach" and spun dials and pushed buttons; ghostly silhouettes of various structures phantasmagorically materia lized on the computer screen. She moved me this way; that way; zoomed in and out, made numerous measurements in several planes and throughout, conversationally conveyed her impressions to me. "Look," she said, pointing to a bean-shaped structure , "there 's a stone in your left kidney. It's approximately one centimeter across and it doesn 't appear to be obstructing anything." She smiled comfortingly. "That's your descending aorta," she murmured, gesticulating. "It does seem to be somewhat dilated." She frowned. "It 's a tad more than 2.5 centimetres in diameter but I will leave it to the radiologist to decide whether it 's aneurysm and what that might mean." I must say I was somewhat startled at this finding. I'd considered myself pretty healthy. It just goes to show that you never know what is going on in the inner-most recesses of your body. The operator moved the probe again and murmured appreciatively, "What a dainty spleen - it 's a real cutie." I smiled smugly. "But," she continued wrinkling her nose , "your pancreas is no more than ho-hum ." I felt somewhat slighted and responded defensively, "What do you mean my pancreas is ' ho-hum '?" She weighed her words carefully and continued, "Well , it's kind of mediocre," and more provocatively she added, "with uch a little tail." I paused: "Perhaps she knows something about my other little tail ," I mused darkly. However, I bit by tongue and kept my suspicions to myself, although she must have wondered why I gave her such a baleful look and lapsed into sulky introspection. No doubt unnerved by what she perceived to be hostility, the technician completed the remainder of the examination in nearsilence. She coolly dismissed me, advising that in due course, the radiologist would report and the final results dispatched to my physician, Dr. D. I walked down the corridor to the x-ray suite - the enema was next. The technician was altogether different from the slight and motherly ultrasound operative who had probed by abdomen with delicate finesse . This woman was big, bull-necked, with powerful shoulders and muscular forearms . She was built like King Kong. "Oh, my god," I thought in near panic, "I hope she 's gentle." Matter-of-factly, she described the procedure. Then she ordered me to lie on my stomach, legs apart so the "small tube", through which the barium contrast medium and air would be introduced into my rectum, could be inserted. To the unasked question she elaborated jauntily, that the air would inflate my colon and allow the barium to adhere evenly to mucosal lining, "Absolutely essential for good-quality pictures," she said jauntily. She allowed that I might feel a "slight pressure" as the materials were infused, but tut-tutted that it was "no big deal". And, her facial expression added that she hoped I was not a cry-baby. Then, without ceremony she thrust what felt like a largediameter garden hose into my nether parts and taped it securely to

my buttocks, "To make ure it stays in," she explained unnecessarily. Now, lying on my back, she had turned me over with those irresistibly powerful arms , like a baby. I felt humiliated and violated - I was helpless in her vice-like grip. She pressed some sort of button and the ordeal began! "A little pressure," she had said. "Oh my god! " What an understatement. And it was all so quick. One moment I wa simply in anticipatory discomfort (with a hose up my bum!) and the next, in extremi . I felt that I was about to burst and my guts, which had been relatively quiet until now, began to writhe and gurgle violently in a reflex attempt to expel their contents. "That 's good," declared King Kong approvingly. "You 're nicely distended. The pictures will be first-class." She continued, "Oh, by the way, you will probably have an overwhe lming urge to evacuate your bowels- if that happens, let rip - we're used to it. Don't be embarrassed, we'll clean you up ." Waves of humiliation swept over me a the pressure in my intestines continued to build relentlessly. I feared the worst! If you've ever suffered from severe diarrhea , when miles away from a washroom, you '11 get a fair idea as to what I was going through. On the one hand, I desperately wanted to " let go" and allow the gallons of co lonic contents to flush ; on the other hand, being an inhibited (ana lly-retentive) , we ll-brought-upEnglish man, highly toilet-trained at an early age by a fastidious mother, I was equally determined to "hold it in". I was laying no bets. My tormenter, apparently concerned, asked, "Are you okay?" I stifled a scream and in a weak voice game ly lied. "Oh yes, doing fine . Just a slight feeling of fullness in my stomach." The next 30 minutes was a sweaty nightmare. The table was elevated, rotated; angled, etc. King Kong heaved my helpless body through 360 degree ; prone, sup ine; left side, right side; upright. "To get a full profile," she elaborated. And throughout, the (x-ray) machine "whirred and burped" busily as what seemed to be zillions of photographs were taken. From time-to-time, the disembodied voice of the radiologist, who , for all I knew, could have been on another planet (I never did see her) intoned instruction : "Breathe in , hold it, breath out. Relax, don 't strain; don 't move," etc. And every so often unconvincing platitudes which were , I think , meant to be encouragements. "Aren 't we doing we ll ?" or, " Not much longer", etc. Finally, it wa over. The technician enthused, "Terrific pictures - clear as daylight. Dr. S (the radiologist) , is very pleased. Indeed, she won ders whether you might allow her to use your xrays when she gives her next se minar to the residents on ' how to do the perfect barium enema '." I smiled weakly and pointed to the garden hose sti ll insitu. "Oh," she said, "I better deflate you." Deftly she released a va lve and I was in instant bliss. The sort of "bitter-sweet" experience I imagine might be associated with a supra-pubic stab through the unanaesthetized abdomina l wall with a sca lpel into the bladder to relieve the agony of acute urinary retention . I could have kissed her. "You are a brave little so ldier," she said adnuringly, "Hardly UWOMJ 72( I) 2002 53

a peep out of you during the entire procedure." I thought, "If only she knew." "You'd better go to the washroom and get rid of the rest of the barium," she instructed. "Take your time - there 's a lot in there you know." Three minutes later I was back. "Finished already?" she inquired with some surprise. "Yes," I replied. "There didn 't seem to be as much left as you thought." She cautioned: " Sometimes it doesn 't all come out right away," she added. "If! was you, I'd try again. You don't want to mess your pants do you?" Stubbornly I retorted, "I'm alright - there's nothing up there." "Okay," she added, "but don 't say I didn 't warn you." I was half-way to St. Thomas driving on the 402 (not a washroom within 35 miles), when ominously my guts started to rumble and roil. Despite teeth-clenching efforts the burgeoning cramps could not be denied. By the time I reached my destination I was sitting miserably in a slurry of barium. As I gingerly eased myself upright and out of the car, gravity added insult to injury and the loathsome stuff seeped from my boxers and slowly trickled down my legs. Six weeks later, in Dr. D's office, we reviewed the results of my tests. He confirmed my left ventricular hypertrophy, the kidney stone and my non-clinically significant aortic aneurysm (of 2.6 em diameter). He said nothing about by dainty spleen, nor my ho-hum pancreas. He waxed lyrically about the quality of the barium enema pictures - "the best he 'd seen in years" - which showed extensive diverticulosis but nothing sinister. However, he concluded, because of my family history, routine annual barium enemas were mandatory. Dr. D picked up my look of anguish immediately. But he paused, then with a broadening, wolfish grin, responded, "Well, maybe every other year," or, he continued, "perhaps you'd prefer to go for the colonscopy." My guts began to heave!

UWOMJ 72( I) 2002

Z•~»•-r~~ ·

atorvastatin calcium

tablets

EFFICACY TO REACH TARGETS ••LIPITOR• (atorvastatin calcium) 10 mg, 20 mg, 40 mg and 80 mg tablets THERAPEUTIC Cl.AS$1FICATION: Upld Metabclism Regulator ACTIONS AND CLINICAL PHARMACOLOGY UPITOA (atorvastatin calcium) is a synthetic lipid-lowering agent. ~ Is a selective, competitive Inhibitor of 3-hydroxy-3-methyfglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate which is an early and rate-limiting step in the biosynthesis of cholester~ . ' LIPITOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic Low Density Lipoprotein (LDL) receptors on the cell-surtace for enhanced uptake and catabclism of Low Density Lipoprotein (LDL). LIPfTOR reduces LDL-Cholesterol (LDL -C) and the number of LDL particles. Up itor also reduces Very Low Dens1ty Upoproteln-Ch~esterol (VLDL-C), serum triglycerides (TG) and Intermediate Dens~ Lipoproteins QDL), as well as the number of a~ipoprotein B (apo B) containing particles, but increases High Dens~ Upoprote1n-Cholester~ (HDL-C) Elevated serum c~ester~ due to elevated LDL-C Is a major risk factor for the development of cardiovascular d1sease. Low serum concentration of HDL-C is also an independent risk factor. Elevated plasma TG is also a risk factor for cardiovascular d1sease, particularly if due to increased IDL, or associated w1th decreased HDL-C or increased LDL-C Atorvasta!ln IS rapidly absorbed after oral admimstration, max1mum plasma concentrations occur w1thln 1 to 2 hours Atorvasta!ln tablets are 95% to 99% b1oava1lable compared to solutions Mean distnbution of atorvastatin is approXJmately 381 litres. Atorvastatin is ~98% bound to plasma proteins Atorvastatin is extensr;ely metabclized by cytochrome P-450 3A4 to orlho- and para-hydroxytated denvat1ves and to various beta-oXJdatlon products Approximately 70% of circulabng 1nh1brtory activity for HMG-CoA reductase is attributed to active meta~1tes Atorvastabn and ~s metabolrres are eliminated by biliary excretion. Less than 2% of a dose of atorvastatin is recovered In unne following oral administration. Mean plasma elimination half-life of atorvastatin in humans Is approximately 14 hours, but the half-lffe of inhibiTory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of longer-lived active metabolites INDICATIONS AND CLINICAL USE UPITOR (atorvastatin calcium) is ind1cated as an adjunct to lrtestyle changes, including diet, [at least equ1valent to the Adult Treatment Panel Ill (ATP IIQ TLC d1et], for the reduction of elevated total ch~ester~. (total-C), LDL-C, TG and a~ipoprote1n B (apo B) in hyperlipidemic and dyslip1dem1c cond1!1ons, when response to d1et and other nonpharmacolog1cal measures alone has been inadequate, 1nclud1ng: • Pnmary hyperc~esterolemia (Type lla), • Combined (m1xed) hyperl1p1dem1a (Type lib), 1nclud1ng fam11ial comb1ned hyperlipidemia, regardless of whether cholester~ or tnglycendes are the lipid abnonmality of concern: • Dysbetalipoproteinemia (Type IIQ; • Hypertriglycendem1a (Type IV): • Familial hyperchoester~emia (l'omozygous and heterozygous). For homozygous familial hyperchoester~m1a , UPfTOR should be used as an adjunct to treatments such as LDL aphere~s. or as monotherapy ff such treatments are not avallaible. UPfTOR also raises HDL-cholesterol and therefore lowers the LDL-CIHDL-C and totai-CIHDL-C ratios in patients w1th primary hypercholesterolemia and comb1ned (mixed) hyperlipidemia (Frednckson Type lla and lib dyslip1dem1a). In pooed data from 24 controlled clinical trials, UPfTOR raised HDL-C levels 5%-7% 1n pnmary hypercholesterolemiC (type lla) paMnts and 10%-15% in mixed (type lib) dyslipidemic patients. These changes in HDL -C with HMG-CoA reductase inhibitors should be considered as modest when compared to those observed in LDL-C and do not play a primary role 1n the lowering of LDL-CIHDL-C and totai-CIHDL-C rabos In climcal trials, UPITOR (1 0 to 80 mg/day) significantly 1mproved lipid profiles in patients with a w1de variety of hyperlip1dem1c and dyslip1demic conditions In 2 dose-response stud1es in mildly to moderately hyperlipidemiC patients (Frednckson Types lla and lib), UPfTOR reduced the levels of total c~ester~ (29-45%), LDL-C (39-60%), apo B(32-50%), TG (19-37%), and 1ncreased high density lipoprotein c~ester~ (HDL-C) levels {5-9%). Comparable responses were ach1eved 1n pat1ents with heterozygous familial hypercholesterolemia, non-familial fonms of hypercholesterolemia, comb1ned hyperlipidemia, includ1ng familial combined hyperlipidemia and pabents With non-insulin dependent diabetes mellitus. In patients with hypertriglycendemia (Type IV), UPITOR (1 0 to 80 mg dally) reduced TG (25-56%) and LDL -C levels (23-40%). UPITOR has not been studied 1n conditions where the major abnonmalrty IS elevation of chyfomicrons (TG levels > 11 mmolll), i e types I and V In an open-label study in patients with dysbetalipoproteinemia (Type IIQ, UPfTOR (1 0 to 80 mg daily) reduced totai-C (40-57%), TG (40-56%) and IDL-C + VLDL-C levels (34-58%) In an open label study 1n patients w1th homozygous fam11ial hyperc~esterolem1a (FH) UPITOR (1 0 to 80 mg druly) reduced mean LDL-C levels (22%). In a p1lot study, UPfTOR 80 mg/day showed a mean LDL-C lowering of 30% for pabents not on plasmapheresis and of 31 % for patients who continued plasmapheresis A mean LDL-C lowering of 35% was observed in receptor defecWe patients and of 19% in receptor negative patients (see PHARMACOLOGY, Clinical Stud1es) For more details on efficacy resu~ by pre-defined d~oon and~ data by Fre<ilckson types,see PHARMACOLOGY, Clinical Stucies Prior to initiating therapy with UPfTOR, secondary causes should be excluded for elevabons in plasma lipid levels (e g. poorly controlled diabetes mellitus, hypothyroidism. nephrobc syndrome, dysproteinemias, obstructive liver disease, and alcoh~ism), and a lipid profile pertormed to measure total c~esterol, LDL-C, HDL-C, and TG For patients w1th TG <4.52 mmoi/L (<400 mg/dL), LDL-C can be estimated us1ng the following equabon· LDL-C (mmoi/L) = totai-C - [(0.37 x (TG) + HDL-C)) LDL-C (mg/dl) = totai-C- {(0 2 x (TG) + HDL-C))' For patients With TG levels >4.52 mm~ (>400 mg/dL), th1s equabon IS less accurate and LDL-C concentrabons should be measured directly or by ultracentnfugabon Pabents wllh h1gh or vary high tnglycende levels, i e >2 2 mm~ (200 mg/dL) or >5 6 mm~ (500 mg/dl.), respectively, may require tnglycende-k1Nenng therapy ~enofibrate, bezafibfate or niCObniC ac1d) alone or 1n comb1nabon w1th UPfTOR In general, combination therapy with fibrates must be undertaken cautiously and only after risk-benefit analysis (see WARNINGS, Muscle Effects, PRECAUTONS, Pharmacokine1ic Interaction Stud1es and Potential Drug Interactions) Elevated serum triglycendes are most often observed 1n patients w1th the meta~1c syndrome (abdormnal obes1ty, atherogen1c dysliptdemm (elevated tnglycerides, small dense LDL particles and low HDL-cholesteroQ, 1nsulin resistance w1th or without glucose intolerance, raised blood pressure and prothromb1c and proinflammatory states). (For the treatment of specrtic dyslipidemias refer to the Report of the Canadian Wori<Jng Group on Hypercholesterolemia and Other Dyslipidemias or to the US NCEP Expert Panel on Detection, Evaluation. and Treatment of High Blood Cholesterol In Adults [Adult Treatment Panel Ill), under SEUECTED BIBLIOGRAPHY in product monograph) When drugs are prescribed attention to therapeutic lrlestyle changes (reduced 1ntake of saturated fats and cholesterol, weight reduction, 1ncreased phys1cal actiVIty, 1ngesbon of s~uble fibres) should always be ma1ntamed and retnforced The Atorvasta!ln Versus Revasculanzation Treatments (AVERT) study exam1ned the effect of IntensiVe l1p1d-lowenng 1n pabents w1th stable coronary artery disease and LDL-C at least 3 0 mmolll 1n patients referred for percutaneous translum1nal coronary angioplasty (PTCA). Patients were randomized for 18 months to UPfTOR 80 mg da1ly or to PTCA W1th usual med1cal care which could 1nclude lipid meta~1sm regulators The results of the AVERT study should be conSidered as exploratory s1nce several lim1tat1ons may affect 1ts des1gn and conduct In the med1cal-treated group w1th LIPITOR there was a trend for a reduced inc1dence of 1schem1c events and a delayed t1me to first 1schem1c event The results also suggest that 1ntensive treatment to target LDL -C levels w1th LIPfTOR 1s additive and complementary to angiOplasty and would benef1t patients referred for th1s procedure (see SEUECTED BIBLIOGRAPHY 1n product monograph) CONTRAINO!CATIONS HypersenSitiVIty to any component of th1s med1cat1on ActiVe lr;er cisease or l.fleXIJillned persistent eleva!JonS of serum lnYlsa>n1nases excee<lng 3 bmes the 4JPff 11m~ of normal (see WARNINGS) Pregnancy and lactation (see PRECAUTIONS). WARNINGS Phanmacokinetic Interactions The use of HMG-CoA reductase 1nhibitors has been assoc1ated with severe myopathy, includ1ng rhabdomyolysis, wh1ch may be more frequent when they are co-administered with drugs that inhibit the cytochrome P-450 enzyme system Atorvastalln 1s metabolized by cytochrome P-450 1soform 3A4 and as such may interact W1th agents that 1nh1b1! thiS enzyme (See WARNINGS, Muscle Effects and PAECAUTONS, Drug Interactions and Cytochrome P-450-medlated Interactions) 1 FnedewaldWTetat C/tnCilem1972.18(6)489·502

Hepatic Effects In e1oca1 trl3s,persistent meases 1n serum transamll1aSes greater than !!Tee nmes the 4JPff ~mrt of normal ocrured 1n <1% of pabents who receM!d UPfTOR When the dosage of UPfTOR was reduced, or when drug treatment was Interrupted or discontinued, serum transamii13Se levels returned to pretreatment levels The meases were generally not associated With taiJ1Cice or other dllical signs or symptoms Most pabents continued treatment With a redUCed dose of UPfTOR wrthout d1n1Cai seq.Jelae Liver funct1on tests should be pertormed before the 1n1tlat1on of treatment and penod1caltv ttJereatter Special anent1on should be paid to patients who develop elevated serum transaminase levels, and In these patients measurements should be repeated promptly and then pertormed more frequently !! Increases In alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, partlcula~y if they rise to greater than 3 times the upper limit of nonmal and are perslsten~ the dosage should be reduced or the drug discontinued. UPITOR should be used wllh cauton in patients who consume substanbal quanbties of alcohol and/or have a past h1story of liver disease Active liVer disease or unexpla1ned transam1nase elevattons are contraind1cabons to the use of UPfTOA, rt such a condition should develop dunng therapy, the drug should be d1sconbnued Muscle Effects Myopathy, defined as muscle ach1ng or muscle weakness 1n contuncbon W1th 1ncreases In creabn1ne phosphokJnase (CPK) values to greater than ten t1mes the upper limit of normal, should be cons1dered 1n any patient wrth d1ffuse myalgia, muscle tenderness or weakness, and/or marked elevatton of CPK Patents should be advsed to report promptly unexplruned muscle prun, tenderness ()( weakness, particularly 1f accompanied by malruse or fever UPfTOR therapy should be d1sconbnued rt markedly elevated CPK levels occur or myopathy IS d1agnosed or suspected The risk of myopathy and rhabdomyolys1s dunng treatment With HMG-CoA reductase 1nh1bitors IS 1ncreased w1th concurrent admmtrabOn of cyclosponn, f1bnc acid denvawes, erythromycin, clanthromyc1n, n1ac1n (nicotiniC acid), azole anbfungals or nefazodone As there Is no expenence to date w1th the use of UPITOR g1ven concurrently w1th these drugs, w1th the exception of pharmacokinetic studies conducted in healthy sub1ects with erythromycin and clanthromycin, the benefrts and risks of such combined therapy should be carefully considered (see PRECAUTIONS, Pharmacokinetic Interaction Studies and Potenbal Drug Interactions) Rhabdomyolys1s has been reported 1n very rare cases W1th UPfTOR (see PRECAUTONS, Drug Interactions) Ahabdomyolysis with renal dysfunction secondary to myoglobln!J(Ia has also been reported w~ HMG-CoA reductase inhibrtors. UPfTOR therapy should be temporanly Withheld or d1sconnnued 1n any pabent W1th an acute senous condmon suggestive of a myopathy or havmg a nsk factor pred1sposmg to the development of renal fi!IIU(e secondary to rhabdomyolysis (such as severe acute 1nfecbon, hypotension, major surgery, trauma. severe meta~ic, endoame and electrolyte disorders, and uncontr~led se1zures) PRECAUTIONS General The effects of atorvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol on cardiovascular morbidity or mortality or total mortality have not been established. Before 1nstitubng therapy W1th LIPfTOR (atorvastatin calc1um), an anempt should be made to contr~ elevated serum lipoprotein levels w1th appropriate d1et, exerose, and we1ght reduction 1n overwe1ght pabents, and to treat other under1ymg med1cal problems (see INDICATIONS AND CLINICAL USE) Patients should be advsed to 1nfonm subsequent phys1c1ans of the pnor use of LIPITOR or any other lipld-lowenng agents Elf ct on the Lens Current long-term data from clinical tnals do not 1nd1cate an adverse effect of atorvastabn on the human lens Effect on Ubiquinone !CoO" l Levels Slgn1f1cant decreases 1n c~rculabng ub1qwnone levels 1n pabents treated With atorvastat1n and other stat1ns have been observed The clin1cal s1gn1f1cance of a potential long-term statin-lnduced def1c1ency of ubiQUinone has not been established ~has been reported that a decrease 1n myocardial ub1qwnone levels could lead to Impaired card1ac function 1n patents with bcrderl1ne congestive heart fa11ure (see SEUECTED BIBLIOGRAPHY 1n product monograph) Effect on lipoprotein lal In some patients, the beneficial effect of lowered total cholester~ and LDL-C levels may be partly blunted by a concormtant increase 1n 4J(a) lipoprotein concentrations Present knowledge suggests the Importance of h1gh 4J(a) levels as an emerg1ng nsk factor for coronary heart disease tt 1s thus deSiraible to mruntam and retnforce lrlestyfe dhanges 1r1 h1gh nsk pabents placed on atorvastabn therapy (see SEUECTED BIBLIOGRAPHY 1n product monograph) Hypersensitivity An apparent hypersens~ syndrome has been reported w1th other HMG-CoA reductase 1nhibrtors wh1ch has 1ncluded 1 or more of the follow1ng features anaphylaxiS, angioedema. lupus erythematous-like syndrome. polyrnyalgia rheumat1ca, vasculrt1s, purpura, thrombocytopenia, leukopenia, hemolybc anemia, posit1ve ANA, ESR Increase, eos1noph11ia, arthritiS, arthralgia, urticaria, asthenia, photosens1tiV1ty, fever, chills, flush1ng, malaise. dyspnea, toxic epidermal necrolys1s, erythema mu~rtorme , Including Stevens-Johnson syndrome Although to date hypersensitivity syndrome has not been descnbed as such, LIPfTOR should be d1scont1nued ~ hypersensitivity IS suspected Use jn Pregnancy LIPITOR is contraindicated during pregnancy (see CONTRA!NO!CATIONS). AtherosclerosiS IS a chron1c process and d1sconnnuabon of lipld-lowenng drugs dunng pregnancy should have little impact on the outcome of long-term therapy of pnmary hypercholesterolemia Cholesterol and other products of cholesterol biosynthes1s are essential components for fetal development Qnclud1ng syntheSIS of steroids and cell membranes). Since HMG-CoA reductase 1nh1bl!ors decrease c~ester~ syntheSis and possbly the syntheSis of other biologically actiVe substances denved from cholester~. they may cause harm to the fetus when adm1n~stered to pregnant women. There are no data on the use of LIPfTOR during pregnancy UPITOR should be adminiStered to women of chlldbeanng age only when such patients are h1ghly unlikely to conce1ve and have been 1nfonmed of the potential hazards If the pabent becomes pregnant while taking UPITOR. the drug should be diSContinued and the patient appnsed of the potential nsk to the fetus Nursing Mothers In rats, milk concentrabons of atorvasta!ln are Similar to those 1n plasma It IS not known whether th1s drug IS excreted 1n human milk Because of the potential for adverse reacbons 1n nurSing Infants, women taking LIPfTOA should not breast-feed (see CONTRANDICATIONS) Pediatric Use Treatment expenence 1n a pediatric population is lim1ted to doses of LIPITOR up to 80 mg/day for 1 year 1n 8 patients w1th homozygous fam11ial hypercholesterolemia No clin1cal or biochemical abnormalines were reported 1n these patients Geriatric Use Treatment expenence 1n adults 70 years or ~der (N=221) w1th doses of UPITOR up to 80 mg/day has demonstrated that the safety and effectiVeness of atorvastalln 1n th1s population was Similar to that of patients <70 years of age PhanmacokJnenc evaluation of atorvasta!ln 1n subJects over the age of 65 years 1nd1cates an Increased AUG As a precautionary measure, the lowest dose should be adminiStered 1n1t1ally (see PHARMACOLOGY, Human Pharmaco~net1cs, SEUECTED BIBLIOGRAPHY 1n product monograph) Renal tnsufficienc Plasma concentrations and LDL-C lowenng eff1cacy of LIPITOR was shown to be Similar 1n patients w1th moderate renal 1nsuff1Ciency compared w1th pat1ents w1th normal renal funcbon However. Since several cases of rhabdom~1s have been reported 1n patients w1th a h1story of renal 1nsuff1C1ency of unknown sever1ty, as a precautonary measure and pend1ng further expenence 1n renal d1sease, the lowest dose (10 mg/day) of LIPfTOR should be used 1n these pabents S1m1lar precautons apply 1n patients w1th severe renal insuff1c1ency [creatinine clearance <30 mUmin (<0 5 mUsec)). the lowest dosage should be used and Implemented cautously (see WARNINGS. Muscle Effects. PRECAUTONS, Drug lnteracbons) Refer also to DOSAGEAND ADMINISTRATION. En crine Function HMG-CoA reductase 1nh1brtors 1ntertere With choester~ syntheSIS and as such m1ght theorebcally blunt adrenal and/or gonadal sterOid production Clinical studies With atorvastann and other HMG-CoA reductase 1nh1brtors have suggested that these agents do not reduce plasma cortiro concentrabon or 1mpair adrenal reserve and do not reduce basal plasma testosterone concentrabon. However, the effects of HMG-CoA reductase Inhibitors on male fertJiity have not been studied 1n adequate numbers of pabents The effects, rt any. on the prtwtary-gonadal aXJS 1n premenopausal women are unknown. Pabents treated With atorvastabn who develop cliniCal evdence ol endocnne dysfunction should be evaluated appropnately Cauton

should be exerased d an HMG-CoA reductase rnhib<tor or other agent used to lower cllolesterollevels is admrmstered to patients receiVing other drugs (e g ketocooazole, spironolactone or dmetxlrne) that may decrease the levels of endogenous steroid hormones Phaanacoklnetlc Interaction Studies and Potential Drug Interactions Pharmaeol<inetic rnteracnon studies conducted 1-Ath drugs rn healthy sub;ects may not detect the pcssrbilrty of a potential drug rnteraction rn some paMnts due to d1fferences rn underlying drseases and use of coocom1nart med1ca ons (see also Genatnc Use, Renal insufficiency, Patients With Severe Hypereholesterolem,a! Concomitant Therapy wijh Other Lipid Metabolism Regul ators: Combrned drug therapy should be approached wrth caution as informabon from controlled studies is limrted Bile Acid Sequestrants: Patie!!lS wnh mild to moderate hypercholesterolemia lDL-C reduellon was greater when UPITOR 10 mg and colesnpol 20 g were coadmrnistered (-45%) than when el!her drug was admrnistered alone (-35% for UPITOR and -22% for colestipcQ. Patients wi!h severe hypercholesterolemia· LDL-C reducnon was srm1tar (-53%) when UPITOR 40 mg and colestipcl 20 g were coadm1n1Stered when compared to that with UPITOR 80 mg alone Plasma concentration of atorvastatin was lower (approximately 26%) when UPITOR 40 mg plus colestipol20 g were coadmrnistered compared With UPITOR 40 mg alone However, the combrnanon drug therapy was less effectrve rn lowenng the tnglycendes than UPITOR monotherapy m both types of hypercholesterolemic patients (see PHARMACOLOGY, Clinical Studres) When UPITOR is used concurrently With colestipcl or any other res1n, an rnterval of at least 2 hours should be maintamed between the two drugs, Since the absorption of UP OR may be rmpa~red by the res1n Fibric Acid Derivatives (Gemfibrozil, Fenofibrate, Bezafibrate) and Niacin (Nicotinic Acid): Although there is l1mrted experience with the use of UPITOR gNen concurrently With fibnc acid derivatives and nracln, the benefits and nsks of suCh comb1ned therapy should be carefully conSidered The nsk of myopathy dunng treatment w1th other drugs rn th1s class. indud1ng atorvastatln, rs rncreased With concurrent adm1nistra on (see WARNINGS. Musde Effects and SELECTED BIBLIOGRAPHY 111 product monograph) Coumarin Anticoagulants: UPITOR had no climcally s'gn,ficant effect on prothrombin t1me when adm,nlstered to patients receiVing chrome wa!fann therapy (see SELECTED BIBLIOGRAPHY rn product monograph). Digoxin: In healthy subjects, drgoxm phanmacokmetrcs at steady-state were not signrfrcantly altered by coadmrnlstraMn of drgoxm 0 25 mg and UPITOR 10 mg da•ly However, d1gOx1n steady-state concentratrons rncreased appro~mately 20% followmg coadmrmstrauon of d1gox'n 0 25 mg and LIPITOR 80 mg darry fsee Human Pharmacokmetics) Patients taklng d1goxrn should be monnored appropnately Antihypertensive agents (amlodipine): In Cl1n1cal stud1es. UPITOR was used concomrtantly With antihypertensNe agents Without e<Adence to date of clinically slgmficant adverse rnteractions In healthy subjects, atorvastabn pharmacokinetics were not attered by the coadmrnlstration of UPITOR 80 mg and amlod'p'ne 10 mg a steady state (see Human PharmacokJnetics) (quinapril): In a random~ed, open-label study rn healthy subje s. steady-state qumapril doSing (80 mg OD) drd not significantly affect the pharmacokmenc profile of atorvastatln tablets (1 0 mg DDt (see Human Pharmacolkinetics) Oral Corrtraceptives and Honnone Replacement Therapy: Coadministration of UPITOR wrth an oral contraceptive, contaJning 1mg norethindrone and 35 ug eth,nyt estrad,ol, increased plasma concentraMns (AUG levels) of norethrndrone and eth1nyt estrad1ol by approximately 30% and 20%, respectrvely These 1ncreases should be considered when setect1ng an oral contraceptrve In climcal stud1es. UPITOR was used concomrtantly With estrogen replacement therapy wrthout ev1dence to date of clrnrcally Significant adverse rnteracnons Antacids: Adminrstration of alumrnum and magnesium based antacrds, such as Maalol<"'· TC Suspension, wrth UPITOR decreased plasma concentratrons of UPITOR by approxrmately 35% UOL -C reductron was not altered but the tnglycendelowenng effect of UPITOR may be a ected Cimetidine: Admmtration of crme d1ne 1vl!h UPITOR d1d nor alter plasma concentratrons or LDL-C lowenng efficacy of UPITOR, however, the trrglycende-lowering effect of UPITOR was reduced from 34% to 26% Cytochrome P-450-mediated Interactions: Atorvastatin rs metabolized by the cytochrome P-450 rsoenzyme, GYP 3A4 ErythromyCin, a GYP 3A4 111h1Mor. weased atorvastatin plasma levels by 40% Coadm1mstration of GYP 3A4 rnhrb<tors, suCh as grapefrul! JUICe, some macrolide an broncs (I e e<ythromyc,n, ctanthromyc,n), Immunosuppressants (cydospcnne), azote ant,fungal agents (I e rtraconazole, ketocooazole), protease rnh,brtors, or the antidepressant, nefazodone, may have the pctennal to rncrease plasma concentrations of HMG-CoA reductase inhrbrtors. rncludrng UPITOR (see SELECTED BIBLIOGRAPHY rn product monograph). Cautioo should thus be exercrsed With concomrtant use of these agents (see WARNINGS, Pharmacokinetic Interactions, Muscle Effects, PRECAUTIONS, Renal Insufficiency and Endocnne FunctJon, DOSAGE AND ADMINISTRATION SELECTED BIBLIOGRAPHY rn product monograph) In healthy subjects, coadmrnistration of maximum doses of both atorvastann (80 mg) and tertenadrne (120 mg), a GYP 3A4 substrate, was shown to produce a modest increase in tertenad,ne AUG The QTc rnterval remained unchanged However, srnce an interacnon between these two drugs cannot be e'duded 1n patients With pred1spcsing factors for arrhythmra. (e.g preexrsting prolonged QT rnterval, severe coronary artefy ~sease. hypckalem,a), cautioo should be exerdsed when these agents are coadm1nrstered (see WARNINGS. PhanmacokJnetx: lnteracnons, DOSAGE AND ADMIMSTRATION) Antipyrine: Antipynne was used as a non-specrfrc model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P-450 system). UPfTOR had no effect on the phanmacolkinetics of antrpynne, thus rnteractrons wrth other drugs metabolrzed VIa the same cytochrome 1sozymes are not expected Macrolide Antibiotics (azilhromycin, darilllromycin, erythromycin): In heatthy a~iJtts, coadmnrstration ci UPITOR (10 mg 00) and azJthrom)'Cin (500 mg OD) did not Slgndicantly aner the plasma coocentranons of atorvastann. Hcl.vevef. coadminiStration of atorvastatrn (10 mg OD) With e<ythrornyclfl (500 mg OIDJ or clanthrornycrn (500 mg BO). whdl are both GYP 3A4 rnh1bl!ors, roeased plasna concennanons of amastaDn approxrmately 40% and 80%, respectJvely (see Wi\Rfii<JGS, Musde Effects, Human Ph<rmacoklnetK:s) Protease Inhibitors (nelfinavir mesylate): In healthy adulls. coadmmtratlon of netfinaVIr mesytate (1250 mg BIOI. a known GYP 3A4 rnh1bitor, and atorvastann (1 0 mg 00) resulted rn 1ncreasP.d plasma concentratrons of atorvastatln AUG and Cmax of atorvastann were rncreased by 74% and 122% respectiVely Patients with Severe Hyoercholesterolemia: Hrgher drug dosages (80 mglday) requrred for some patrents wrth severe hyperCholesterolemia (rncludrng familial hyperCholesterolemia) are associated wrth increased plasma levels of atorvastatrn Caution should be exercised in such patients who ar also severely renally Impaired, elderly, or are concomitantly being administered digoxin or CYP 3A4 fnhibijors (see WARNINGS, Phannacokfnetlc Interactions, Muscle Effects; PRECAUTIONS, Drug Interactions; DOSAGE ANO ADMINISTRATION), Drug/laboratory Test Interactions UPITOR may elevate serum transamrnase and creatinine phospholkinase levels (from skeletal musde) In the drfferential dragnOSis of chest pan rn a pabent on therapy w1th UPITOR. card1ac and noncard1ac fracnons of these enzymes should be determrned ADVERSE REACTIONS UPITOR rs generally well-tolerated Adverse reactions have usually been m1ld and transient In controlled clrnrcat studres (placebo-controlled and acnve-controlled comparative studres w1th other lrprd lowenng agents) 1n1101Ving 2502 patrents. <2% of patients were drscontrnued due to adverse expenences attrrbutable to LIPITOR Of these 2502 patrents, 1721 were treated for at least 6 months and 1253 for 1 year or more Adverse experiences occurnng at an 1ncrdence <: 1% rn patrents partrcrpaling rn placebo-controlled clinical studres of LIPITOR and repcrted to be pcssrbly, probably or definrtely drug related are shown 1n Table 1 below TABLE 1. Associated Adverse Events Reported in >1% of Patients fn Placebo-Controlled Clinical Trials Placebo % (n 270) LIPITOA % (n- 1122) GASTROINTESTINAL Constipation Diarrhea 1 Dyspepsra 2 Flatulence 2 Nausea 0 NERVOUS SYSTEM Headache MISCELLANEOUS Parn <1 1 Myalgra Asthenra <1 The followrng addrtional adverse events were reported 1n clrnrcal tnals, not all events listed below have been associated with a causal relationship to LIPITOR therapy Muscle cramps, myositis, myopathy, paresthesra, penpheral neuropalhy, pancreatitis, hepatitis, choiestatrc Jaundice, anorexra, vomit1ng, alopecra, pruntus. rash. rmpotence, hyperglycemia, and hypoglycemia Posl-marl<eting exoedence· Very rare reports severe myopathy With or Wlihoul rhabdomyolysrs (see WARNINGS, Muscle Effects; PRECAUTIONS, Renal InsuffiCiency and Drug tnteractrons) lso!aled repcrts thrombocytopenra, arthralgia and allergic reactions lflCiud,ng urtx:ana, angroneuroliC edema. anaphytaxrs and bullous rashes (rnclud1ng e<ytheme muHdorme. Stev1ens-Jolvlson syndrome and toxrc epidennal necrollysrs) These may ve no causal relatronsh'P to alorvastatrn

Ophthalmologic observations: see PRECAUTIONS. Laboratory Tests Increases in serum transaminase levels have been noted in clinical trials (see WARNINGS). SYMPTOMS ANO TREATMENT OF OVERDOSAGE . There is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient should be. treated symptomatically and supportive meaSIJ'es instituted as required Due to extensive drug binding to plasma proteins, hemodralysrs rs not expected to srgnificantly enhance atorvastatin clearance DOSAGE AND ADMINISTRATION Patients should be placed on a standard cholesterol -lowering diet [at least equivalent to the Adu~ Treatment Panel ill (ATP IIQ TLC diet] before receiVing UPITOR, and should continue on this diet during treatment with UPfTOR. If appropriate, a program of werght control and physical exercise should be implemented Prrmarv Hypercholesterolemia and Combined IMixedl Hyperlipidemia Including Familial Combined Hyperlipidemia. The recommended dose of UPITOR is 10 mg once a day. The majority of patients achieve and maintain target cholesterol levels With UPITOR 10 mglday A significant therapeutic respcnse is evident within 2 weeks, and the maximum response rs usually achreved within 2-4 weeks The respcnse is maintained during chronic therapy. Doses can be grven at any time of the day, with or wrthout focd, and should preferably be given in the evening. Doses should be individualized according to baseline UOL-CandlorTG levels, the desired LDL-C and/or TG target (see the Detection and Management of Hypercholesterolemra, Working Group on HyperCholesterolemia and other Dyslipidemias [Canada] and/or the US National Cholesterol Education Program [NCEP ,A du~ Treatment Panelllij), the goal of therapy and the patient's respcnse . Adjustments of dosage, ff necessary: should be ~ade at rntervals of 4 weeks or more The recommended dose range for most patients is 10 to 40 mg/day The maxrmum dose rs 80 mg/day, whiCh may be requrred rn a mrnonrty of patients (see section below) lipid levels should be monitored periodically and, if necessary, the dose of LIPfTOR adjusted based on target lipid levels recommended by guidelines. The followmg reductions rn total Cholesterol and UOL -C levels have been observed in 2 dose-respcnse studies, and may serve as a gurde to treatment of patients With mild to moderate hyperCholesterolemia TABLE 2. Dose-Response in Patients With Mild to Moderate Hypercholesterolemia (Mean Percent Change from Baselinee UPITOR Dose (mg/day) Lipid Parameter 80 20 40 10 (N-23) (N-20) (N-22) (N-21) -29

-33

-37

-45

-39

-43

-50

-60

a Results are pooled from 2 dose-respcnse studies. b Mean baseline values. In patrents wrth severe dysliprdemras, rnctud1ng homozygous and heterozygous familial hypercholesterolemia and dysbetalrpoproternemra (Type IIQ, higher dosages (up to 80 mg/day) may be required (see WARNINGS, Pharmacoklnetic lnteracnons, Muscle Effects, PRECAUTIONS, Drug lnteracnons) Concomitant Therapy See PRECAUTIONS, Drug Interactions Dosage in Patients With Renal Insufficiency See PRECAUTIONS PHARMACEUTICAL INFORMATION Drug Substance Proper Name· Atorvastatin calcium Chemical Name [R-(R· ,A")]-2-(4-fluorophenyt)-B, o-drhydroxy-5-(1-methylethyt)-3-phenyi-4-[(phenylamino) carbonyi] 1tJ-pyrrole-1-heptanorc acrd, calcrum salt (2.1) tnhydrate Emprncal Formula (C,H,.FN,OJ,Ca• 3H,O Molecular We1ght 1209 42 Structural Formula

n!"' }-.

0~1

fr ta

• UI_O H , _..,0

Descnptron Atorvastann calcrum rs a white to off-wh;te crystalline pcwder that rs pracncally rnsoluble 1n aqueous solutions of pH 4 and below Atorvastat1n catcrum rs very slightly soluble 1n drstrlled water, pH 7 4 phosphate buffer and acetonitnle, slightly soluble rn ethanol, and freely soluble rn methanol Tabf t om osltl · Each tablet contains either 10 mg, 20 mg, 40 mg or 80 mg atorvastatin as the actNe ingredrent Each tablet also contains the followrng non-medrcrnatrngred1ents calcium carbonate, candelllla wax. croscarmellose sodrum. hydroxypropyt cellulose, lactose monohydrate. magnesium stearate, mrcrocrystallrne cellulose, hydroxypropyl methylcellulose. polyethylene glycol, talc, titanrum d1oxrde, pclysorbate 80 and stmethrcone emulsron Stabjlitv and Storage Recommendations; Store at controlled room temperature 15 to 3QOC AVAILABILITY OF DOSAGE FORMS LIPITOR (arorvastalrn calcium) rs available rn dosage strengths of 10 mg, 20 mg. 40 mg and 80 mg atorvastatin per tablet 10 mg: Whrte, ellrptical, frlm-coated tablet, coded "10" on one Side and "PO 155" on the other Avarlable rn bottles of 90 tablets 20 mg: Whrte. elhptrcal. film-coated tablet, coded "20" on one side and "PO 156" on the other Avarlable rn bottles of 90 tablets 40 mg: White, elliptical, film-coated tablet, coded "40" on one side and "PD 157" on the other Available in bottles of 90 tablets 80 mg: Wh1te, ellrptical. film-coated tablet, coded "80" on one Side and "PD 158" on the other Blisters of 30 tablets (3 StripS X 10) References: 1. LIPITOR (atorvastatin .calcrum) Product Monograph, Plrzer Canada Inc , Feblruary 2002. 2. IMS Health MIDAS, Quarter 3 1997 -Quarter 3 2002 3. Prtt B, Waters D, Brown 'IN et at Aggressive hpid-lowenng therapy compared wrth angioplasty in stable coronary artery drsease N EngtJ Med 1999,34170-76 4. Data oo File, Pfizer Canada Inc. 5. Simon Day Drctronary for Clinical Tnals. 1999, John Wrley & Sons Ltd Pages 137-138

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