SAMJ Vol 108, No 6 (2018) by HMPG

JUNE 2018

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CME Perioperative medicine and anaesthetics (part 2) EDITORIALS Climate change and listeriosis outbreaks IN PRACTICE Prolonged paralysis in organophosphate poisoning RESEARCH Handwashing and bacteria levels in theatre staff Medical studentsâ&#x20AC;&#x2122; perspectives on euthanasia and assisted dying Poor anticoagulation control in patients on warfarin in Cape Town Predictors of unplanned pregnancies among female students at TVET colleges

JUNE 2018 PRINT EDITION

FROM THE EDITOR 4

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

‘If exercise was a pill …’ B Farham

EDITORS EMERITUS Daniel J Ncayiyana, MD (Groningen), FACOG, MD (Hon), FCM (Hon) JP de V van Niekerk, MD, FRCR

EDITOR’S CHOICE CORRESPONDENCE

Under-5 mortality and the contribution of congenital disorders in South Africa H L Malherbe, A L Christianson, D Woods, C Aldous

IZINDABA

HMPG

30 days in medicine B Farham

CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za

OBITUARY Lionel Palmer Miles R Hendricks, C Naidoo, J Reddy, P Gordon

MANAGING EDITORS Claudia Naidu Naadia van der Bergh

EDITORIALS 14

ASSOCIATE EDITORS Q Abdool Karim, A Dhai, R C Pattinson, A Rothberg, A A Stulting, J Surka, B Taylor, M Blockman, J M Pettifor, W Edridge, R P Abratt, D L Clarke

Decentralised clinical training of health professionals will expand the training platform and enhance the competences of graduates B Gaede How climate change can fuel listeriosis outbreaks in South Africa M F Chersich, F Scorgie, H Rees, C Y Wright

CONTINUING MEDICAL EDUCATION 18

GUEST EDITORIAL Anaesthesia in South Africa N Ntusi

ARTICLES Anaesthesia for paediatric patients: Minimising the risk K Bester, H Meyer, M Crowther, R Gray

TECHNICAL EDITORS Emma Buchanan Kirsten Morreira Paula van der Bijl PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Clinton Griffin CHIEF OPERATING OFFICER Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za SALES MANAGER (CAPE TOWN) Azad Yusuf

Managing spinal hypotension during caesarean section: An update M W Gibbs, D van Dyk, R A Dyer

Myocardial injury after non-cardiac surgery: Time to shed the ignorance E Coetzee, B M Biccard

IN PRACTICE 31

CASE REPORT Prolonged paralysis in a child with organophosphate pesticide poisoning K Balme, M McCulloch, C Stephen

MEDICINE AND THE LAW Posthumous conception: Recent legal developments in South Africa D W Thaldar

RESEARCH 37

Staphylococcus aureus and Escherichia coli levels on the hands of theatre staff in three hospitals in Johannesburg, South Africa, before and after handwashing D O Matuka, B Binta, H A Carman, T Singh

Economic evaluation of safety-engineered devices and training in reducing needlestick injuries among healthcare workers in South Africa P de Jager, M Zungu, R E Dyers

Medical students’ perspectives on euthanasia and physician-assisted suicide and their views on legalising these practices in South Africa R K Jacobs, M Hendricks

June 2018, Print edition

JOURNAL ADVERTISING Reneé Hinze Ladine van Heerden Makhadzi Mulaudzi Charmalin Comalie ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Mrs H Kikaya, Dr M Mbokota, Dr G Wolvaardt ISSN 0256-9574 HMPG website: www.hmpg.co.za SAMA website: www.samedical.org Journal website: www.samj.org.za

Poor anticoagulation control in patients taking warfarin at a tertiary and district-level prothrombin clinic in Cape Town, South Africa I Ebrahim, A Bryer, K Cohen, J P Mouton, W Msemburi, M Blockman

Phenotypic and genotypic correlation of carbapenememase-producing Enterobacteriaceae and problems experienced in routine screening* A Singh-Moodley, O Perovic

Is adrenal suppression in asthmatic children reversible? A case series* E W Zöllner

Outcomes of outpatient ureteral stenting without fluoroscopy at Groote Schuur Hospital, Cape Town, South Africa* S Sinha, S Z Jaumdally, F Cassim, J Wicht, L Kaestner, A Panackal, C H Jehle, P Govender, S de Jager, E de Wet, M Dewar, M E Kolia, S Salukazana, C Moolman, A P van den Heever, B Kowlessur, G Pinto, J Lazarus

Predictors of unplanned pregnancies among female students at South African Technical and Vocational Education and Training colleges: Findings from the 2014 Higher Education and Training HIV and AIDS survey* N Mbelle, M Mabaso, G Setswe, S Sifunda High risk of suicide among high-school learners in uMgungundlovu District, KwaZulu-Natal Province, South Africa* N Khuzwayo, M Taylor, C Connolly *Abstract only, full article available online. CAREERS AND CLASSIFIEDS

ONLINE CONTENTS LISTED IN Index Medicus (Medline) Excerpta Medica (EMBASE) Biological Abstracts (BIOSIS) Science Citation Index (SciSearch) Directory of Open Access Journals (DOAJ) Current Contents/Clinical Medicine SAMJ SUBSCRIPTION RATES Local subscriptions ZAR1 632.00 p.a. Foreign subscriptions ZAR3 744.00 p.a. Single copies ZAR136.00 local, ZAR312.00 foreign Members of the South African Medical Association receive the SAMJ only on request, as part of their membership benefit. Subscriptions: Tel. 012 481 2071 Email: members@samedical.org The SAMJ is published monthly by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE Health and Medical Publishing Group (Pty) Ltd Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 Tel. 012 481 2069 Email: dianes@hmpg.co.za EDITORIAL OFFICE Suite 11, Lonsdale Building, Lonsdale Way, Pinelands, 7405 Tel. 021 532 1281 | Cell. 072 635 9825 Email: publishing@hmpg.co.za

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JUNE 2018

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CME Perioperative medicine and anaesthetics (part 2) EDITORIALS Climate change and listeriosis outbreaks

Background photo: Surgical instruments | Shaun Swingler

IN PRACTICE Prolonged paralysis in organophosphate poisoning RESEARCH Handwashing and bacteria levels in theatre staff

Box photos: General anaesthesia | Shutterstock; Handwashing | Shutterstock; Unplanned pregnancy | Shutterstock

June 2018, Print edition

Medical students’ perspectives on euthanasia and assisted dying Poor anticoagulation control in patients on warfarin in Cape Town Predictors of unplanned pregnancies among female students at TVET colleges

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FROM THE EDITOR

‘If exercise was a pill …’ Many years ago, when I was a GP in Labrador, Canada, I started lowimpact aerobics classes for the women in Forteau, the tiny settlement I was living in. The population on that part of the Labrador coast is an interesting one. Coming originally from the Channel Islands and South West England (incidentally where half my family also started out), they arrived in the 1800s, working for the fish barons in England. They were not supposed to overwinter, but inevitably people started to settle on the coast of Labrador and the island of Newfoundland, and this fascinating province of Canada was born. Forteau is a very small town and we arrived just after the cod moratorium in 1992, when cod stocks were so low that people were no longer allowed to fish, taking away their entire livelihood and way of life. It was a community in some degree of crisis, and their health problems reflected this. However, their underlying health was also badly affected by inactivity and one of the worst diets I have ever come across. The levels of obesity were way above the average for that time (more than 20 years ago now) and chronic diseases of lifestyle were rife. When I started the exercise classes, given by myself and the local public health nurse, the women were wary – ‘what about my arthritis, doctor?’ was a common concern. But they came along to see what this crazy South African had in mind – and they became hooked! When I stopped giving the regular classes, the same group of women started their own walking groups and I would see them striding past my house at the end of the village at least twice a week, in all weather (except blizzards!). And without exception they told me they felt generally better. I was an advocate of exercise as a form of treatment for just about anything long before evidence of the benefits of regular exercise started to emerge. I know that this is because I experienced such benefits myself, particularly with the form of autoimmune arthritis that I suffer from, but also because I discovered its benefits earlier in life, when my father dragged me onto the squash court as a teenager suffering from generalised angst! And I have advocated it all along – to patients when I was in practice, and to friends and general acquaintances ever since. Over the years, there has been

more and more evidence to show that my evangelical approach to exercise is correct, and now the Clinical Oncology Society of Australia has broken ground by actually prescribing exercise along with surgery, chemotherapy and radiation in cancer care. In a revolutionary position statement,[1] they state that exercise is an essential component of the treatment of cancer. Clinical evidence has established strong evidence that exercise attenuates cancer-related fatigue, alleviates pyschological distress and improves quality of life across multiple general health and cancer-specific domains. Emerging evidence suggests that regular exercise before, during and after cancer treatment decreases the severity of treatment side-effects and reduces the risk of developing new cancers. Some years ago, I used to run with a woman who was having chemotherapy for breast cancer. She said that the worst she ever felt during the chemo was sometimes not feeling like her evening beer – very different from my experience of other women who have gone through cancer chemotherapy. The lead author of the position statement, Prof. Prue Comrie from the Australian Catholic University, summed it up when speaking to the Guardian Online:[2] ‘If we had a pill called exercise it would be demanded by cancer patients, prescribed by every cancer specialist, and subsidised by government.’ Let’s give all our patients the chance to benefit from this ‘pill’. Bridget Farham Editor ugqirha@iafrica.com 1. Comrie P, Atkinson M, Bucci L, et al. Clinical Oncology Society of Australia position statement on exercise in cancer care. Med J Aust 2018 (epub 7 May 2018). https://doi.org/10.5694/mja18.00199 2. The Guardian. https://www.theguardian.com/society/2018/may/07/cancer-if-exercise-was-a-pill-itwould-be-prescribed-to-every-patient (accessed 8 May 2018).

S Afr Med J 2018;108(6):446. DOI:10.7196/SAMJ.2018.v108i6.13395

June 2018, Print edition

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EDITOR’S CHOICE

CME: Perioperative medicine and anaesthetics (part 2)

Anaesthesia facilitates performance of surgical and other interventional procedures by quickly, safely and pleasantly producing analgesia, absence of awareness and anxiety, and adequate muscle relaxation. An important aspect of perioperative anaesthetic care is maintenance of physiological homeostasis, including haemodynamic stability, ventilation, oxygenation and temperature. The anaesthetic team may also provide additional services, such as preoperative evaluation, postoperative management in the post-anaesthesia care unit or intensive care unit, and management of both acute and chronic perioperative pain. Before elective anaesthesia, all patients are evaluated by an anaesthesiologist to assess medical status and preparedness for the planned procedure, implement strategies to reduce risks and create an anaesthetic plan. Fasting guidelines to prevent pulmonary aspiration of gastric contents are applied in all patients undergoing elective surgery, including procedures performed under general anaesthesia (GA), regional anaesthesia, and monitored anaesthesia care. Prediction of the degree of difficulty of airway management and ventilation is an important part of the pre-anaesthetic evaluation. There are benefits and risks to any type of anaesthetic. When assessing whether avoidance of GA is appropriate, considerations include the patient’s ability to lie motionless in the position required for the procedure, and whether the patient can co-operate and communicate and is willing to undergo the procedure, given the possibility of awareness with recall. In many cases, a combined technique (i.e. GA plus epidural or peripheral nerve block for supplemental analgesia) provides both optimal intraoperative conditions and excellent multimodal management of postoperative pain. In this issue of CME, several topics are reviewed that hold great relevance for non-specialists and specialists alike; it is hoped that these will improve the practice of anaesthesia in South Africa (SA). First, advances in paediatric anaesthesia are considered. Second, the management of spinal hypotension and associated complications following caesarean section is reviewed. Third, the management of myocardial injury after non-cardiac surgery is reviewed. It is to be hoped that the series of articles included in the CME issues on perioperative medicine and anaesthesia will improve knowledge, enhance practice, and translate into improved care of SA patients.

Staphylococcus aureus and Escherichia coli levels on the hands of theatre staff in three hospitals in Johannesburg, SA, before and after handwashing

Hand hygiene is a fundamental component of infection control. Hand contamination with S. aureus and E. coli may contribute to infections. Matuka et al.[1] assessed the effectiveness of different handwashing methods in reducing the levels of bacterial flora, especially S. aureus and E. coli, on the hands of theatre staff. A cross-sectional study was conducted among 70 staff in surgical theatres of three randomly chosen hospitals in Johannesburg. Samples were taken before and after handwashing using the modified glove juice method and the fingernail press technique. Standard microbiological techniques were used to identify bacteria. Descriptive statistics and non-parametric analysis were used to compare the differences between hospitals and to determine the effects of handwashing on microbial flora and skin irritation. S. aureus organisms were isolated in the prewash samples of 29 workers (41%) and in the postwash samples of 20 (29%). Of the

29 with positive prewash cultures, 19 (65.5%) showed decreased postwash counts, while 10 (34.5%) showed no change or increased counts. Four workers with a negative prewash count had a positive postwash count. No statistical differences were found between postwash counts categorised by the type of cleansing formula used and the washing technique. E. coli organisms were identified in the prewash count of the fingertip press of one worker. Almost half of the theatre staff carried S. aureus isolates on their hands prior to handwashing and approximately one-third after handwashing. Closer monitoring of handwashing techniques should be introduced.

Is adrenal suppression in asthmatic children reversible?

Six hypocortisolaemic asthmatic children on steroids given at physiological doses were identified during a previous study. The objective was to establish whether hypothalamic-pituitary-adrenal axis suppression (HPAS) could be reversed in hypocortisolaemic asthmatic children treated with steroids without sacrificing asthma control. In this case series,[2] treatment of six hypocortisolaemic patients was modified by introducing steroid-sparing asthma medications. Serum cortisol and repeat overnight metyrapone tests (ONMTPTs) were done until HPAS was reversed in all patients. A retrospective folder review was performed and the following data were extracted: body mass index standard deviation score (BMI SDS), adherence, daily steroid type and dose, treatment modification, serum cortisol, final ONMTPT result and time taken to achieve normalisation. The median serum cortisol level recovered to 311 nmol/L after 0.9 years (median). The ONMTPT normalised within 3.3 years (median). Steroid load decreased from 9.2 to 5.0 hydrocortisone equivalent mg/m2/d (medians), while asthma score improved from 1.42 to 0.85 (medians). Poor adherence was noted in two children before and four after treatment modification. BMI SDS decreased from –0.08 to –0.16 (medians). Hypocortisolaemia and HPAS could be reversed in asthmatic children treated with physiological doses of steroids by reducing steroid load by 40% and supplementing therapy with steroid-sparing medication. Poor adherence may have either contributed to or retarded HPA recovery. Simultaneously, asthma control improved. Confirmation by a prospective study would be ideal, but may not be feasible.

Medical students’ perspectives on euthanasia and physician-assisted suicide (PAS) and their views on legalising these practices in SA

Euthanasia/physician-assisted suicide have been a controversial and sometimes taboo topic for a long time, not only in SA but internationally. A recent (SA) judicial case has seen the topic debated again. Consensus on accepting or abolishing these practices in SA has yet to be reached. All relevant role players need to be adequately engaged before policy can be informed. The objective of this study by Jacobs and Hendricks[3] was to determine the views of future doctors (medical students) regarding euthanasia and PAS and to ascertain their stance on its legalisation in SA. A paper-based, semi-quantitative descriptive study design consisting of 16 questions, using convenience sampling of third- to fifth-year medical students at Stellenbosch University, was used. The overall response rate was 69.3% (N=277). In total, 52.7% of participants (n=146) felt that the practices of euthanasia/PAS should be legalised in SA. Results varied depending on patient morbidities.

June 2018, Print edition

*P 1 c C e a P

EDITOR’S CHOICE

If a patient had terminal disease with intractable suffering, 41.9% of participants would terminate the patient’s life upon request. A further 36.1% of participants stated that they would have no part in ending a patient’s life, while 35.0% said that they would be comfortable with providing the patient with the correct means to end their life (PAS). The majority of participants (80.1%) indicated that they would prefer a dedicated ethics committee to decide who receives euthanasia/ PAS. Many factors influenced participants’ responses, but differences in opinion between and within the various religious groups were particularly evident in the responses received. More than half the respondents in this study were open to legalising euthanasia/PAS, substantially more than in previous

studies. However, only 41.9% of respondents would consider actually performing euthanasia/PAS, for certain patients. Views of other healthcare workers as well as the public are required before policy can be informed. BF 1. Matuka DO, B Binta B, H A Carman HA, T Singh T. Staphylococcus aureus and Escherichia coli levels on the hands of theatre staff in three hospitals in Johannesburg, South Africa, before and after handwashing. S Afr Med J 2018;108(6):474-476. https://doi.org/10.7196/SAMJ.2018.v108i6.12485 2. Zöllner EW. Is adrenal suppression in asthmatic children reversible? A case series. S Afr Med J 2018;108(6):502-505. https://doi.org/10.7196/SAMJ.2018.v108i6.13031 3. Jacobs RK, M Hendricks M. Medical students’ perspectives on euthanasia and physician-assisted suicide and their views on legalising these practices in South Africa. S Afr Med J 2018;108(6):484-489. https://doi.org/10.7196/SAMJ.2018.v108i6.13089

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June 2018, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

CORRESPONDENCE

Under-5 mortality and the contribution of congenital disorders in South Africa

To the Editor: The article ‘Child mortality in South Africa: Fewer deaths but better data are needed’,[1] which appeared in the March 2018 SAMJ Maternal and Child Health Supplement, reviews nationally representative mortality data and the causes of death in children under 5 years of age in South Africa (SA). Two different terms are used synonymously without definition in this article – ‘congenital disorders’ and ‘congenital abnormalities’. By definition, congenital disorders (CDs) are abnormalities in structure or function present from birth, including inborn errors of metabolism.[2] Congenital abnormalities (often used interchangeably with ‘congenital anomalies’) are a subset of CDs, previously defined in the literature as obvious structural abnormalities as categorised in Chapter XVII: ‘Congenital malformations, deformations and chromosomal abnormalities’ in the International Statistical Classification of Diseases and Related Health Problems (ICD-10) – which excludes a third of CDs included elsewhere in the ICD-10.[3-6] Congenital abnormalities are also referred to by Bamford et al.[1] as a separate entity from non-communicable diseases (NCDs), contrary to the World Health Organization (WHO) definition of CDs as an NCD and the concept of CDs as being the first NCD experienced in life.[7-10] Excluding CDs from this disease category has implications for achieving the Sustainable Development Goal (SDG) 3 target of reducing premature mortality from NCDs by one-third.[11] While the abovementioned article highlights potential underestimates in the vital registration data of deaths due to HIV infection and malnutrition, this consideration is not given for CD diagnoses omitted from death certificates.[1] This is despite the parallel between these diagnoses in being omitted as the correct recorded cause of death (contributory or otherwise) due to reluctance with regard to HIV cases and non-/misdiagnosis of CDs. The Child Problem Identification Programme (Child PIP), in particular, has cited a lack of clinicians necessary to make accurate diagnoses as a limitation in the cause of death categorisation.[12,13] The recommendation by Bamford et al.[1] to scale up interventions to reduce deaths from emerging causes of under-5 child death includes congenital abnormalities, which have risen from 3.9% in 2011 as a proportional cause of death to 5.9% in 2015. Combined with the simultaneous reduction in infectious diseases, e.g. diarrhoea and pneumonia, this is indicative of the ongoing positive epidemiological transition in SA.[9,14] Following the trend of high-income countries where CDs account for up to 28% of under-5 deaths,[15] it is imperative that these interventions include relevant medical genetic services for the care and prevention of those affected by and at risk of CDs. With up to 70% of CDs potentially prevented or cured and subsequent disability ameliorated, the potential impact of addressing CDs cannot be ignored owing to the sizeable proportion of preventable child deaths.[16-19] This makes the prioritisation of CDs key to reducing preventable child and neonatal deaths and to attaining the SDG targets.[11] For the quality of data in death notification forms to improve, capacity must be increased to ensure the accurate diagnosis of CDs as the cause of death for both neonatal and child deaths. With tertiary-level genetic services available in only 3 of the 9 provinces and national surveillance grossly underreporting CDs, there is much room for improvement.[20,21] It is anticipated that the restructuring of disease surveillance, including CDs, under the National Public Health Institute of South Africa (NAPHISA) will rectify some of these issues, but more targeted action is required.[22]

To achieve the SDG 3 target to reduce the SA under-5 mortality rate from 37 - 40 deaths per 1 000 live births to the required target of ˂25 per 1 000, a 37% reduction is required.[1,11] Previously unprioritised health issues, including CDs, must now be addressed for this target to be reached. The literature is clear on the role of comprehensive medical genetic services in significantly reducing child mortality. With an infant mortality rate of 27 - 33 deaths per 1 000 live births, SA is long past the point of 40 infant deaths per 1 000 live births, when countries should implement these services.[1,8,10,16,23] To meet SDG 3 by 2030, the role of CDs in neonatal, infant and child mortality must be comprehensively addressed as a priority in SA. Author contributions. All authors were involved in the conceptualisation of this letter and provided input and technical contributions to the draft produced by the principal author (HLM). All authors signed off on the final version before submission. Funding. Thanks to the School of Clinical Medicine, University of KwaZulu-Natal, Durban, SA, for their ongoing support of this research via a post-doctoral research scholarship.

Helen L Malherbe School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa helen@hmconsult.co.za

Arnold L Christianson Wits Centre for Ethics (WiCE), Department of Philosophy, Faculty of Humanities, University of the Witwatersrand, Johannesburg, South Africa

David Woods Newborn Care, School of Child and Adolescent Health, Faculty of Health Sciences, University of Cape Town, South Africa

Colleen Aldous Emerging Academics Research Support, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

1. Bamford L, McKerrow N, Barron P, Aung Y. Child mortality in South Africa: Fewer deaths, but better data are needed. S Afr Med J 2018;108(Suppl 1):S25-S32. https://doi.org/10.7196/samj.2017. v108i3b.12779 2. World Health Organization. Management of Birth Defects and Haemoglobin Disorders. Report of a Joint WHO-March of Dimes Meeting. Geneva, Switzerland, 17 - 19 May 2006. Geneva: WHO, 2006:27. 3. Reid AE, Hendricks MK, Groenewald P, Bradshaw D. Where do children die and what are the causes? Under-5 deaths in the Metro West geographical service area of the Western Cape, South Africa, 2011. S Afr Med J 2016;106(4):359-364. https://doi.org/10.7196/samj.2016.v106i4.10521 4. Pillay-van Wyk V, Msemburi W, Laubscher R, et al. Mortality trends and differentials in South Africa from 1997 to 2012: Second National Burden of Disease Study. Lancet Glob Health 2016;4(9):e642-e653. https://doi.org/10.1016/s2214-109x(16)30113-9 5. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th revision. Geneva: WHO, 1992. 6. Bradshaw D, Groenewald P, Laubscher R, et al. Initial Burden of Disease Estimates for South Africa, 2000. Cape Town: Medical Research Council, 2003:84. 7. World Health Organization. Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013 - 2020. Geneva: WHO, 2013:55. 8. World Health Organization. Guidelines for the Development of National Programmes for Monitoring Birth Defects. Geneva: WHO, 1993:33. 9. Malherbe H, Christianson A, Aldous C. Need for services for the care and prevention of congenital disorders in South Africa as the country’s epidemiological transition evolves. S Afr Med J 2015;105(3):186-188. https://doi.org/10.7196/samj.9136 10. Christianson A, Modell B. Medical genetics in developing countries. Ann Rev Genomics Hum Genet 2004;5:219-265. https://doi.org/10.1146/annurev.genom.5.061903.175935 11. United Nations. Sustainable Development Goal 3: Ensure Healthy Lives and Promote Well-being for All and at All Ages. Geneva: UN, 2015. 12. Patrick M, Stephen C. Saving children: 2005. A survey of child healthcare in South Africa. Child PIP and MRC Unit for Maternal and Infant Health Care Strategies, 2005. http://www.childpip.org.za/ documents/report_saving_children_2005.pdf (accessed 12 May 2018). 13. Patrick M, Malherbe H, Stephen C, Woods D, Aldous C. Congenital disorders in South Africa: A review of Child PIP mortality data 2005 - 2017. S Afr Med J 2018 (in press). 14. Omran AR. The epidemiologic transition: A theory of the epidemiology of population change. Milbank Memorial Fund Quarterly 1971;49(4):509-538. https://doi.org/10.2307/3349375

June 2018, Print edition

P (a Tr re

CORRESPONDENCE

15. World Health Organization. World Health Statistics 2015. Geneva: WHO, 2015:164. 16. Alwan A, Modell B. Recommendations for introducing genetics services in developing countries. Nat Rev Genet 2003;4(1):61-68. https://doi.org/10.1038/nrg978 17. World Health Organization. Control of Hereditary Diseases: Report of a WHO Scientific Group 1993. Geneva: WHO, 1996:92. 18. Czeizel A, Intôdy Z, Modell B. What proportion of congenital abnormalities can be prevented? BMJ 1993;306:499-503. https://doi.org/10.1136/bmj.306.6876.499 19. Whitt KJ, Hughes M, Hopkins EBS, Maradiegue A. The gene pool: The ethics of genetics in primary care. Annu Rev Nurs Res 2016;34(1):119-154. https://doi.org/10.1891/0739-6686.34.119 20. Lebese L, Aldous C, Malherbe H. South African congenital disorders data, 2006 - 2014. S Afr Med J 2016;106(10):992-995. https://doi.org/10.7196/samj.2016.v106i10.11314

21. Malherbe H, Aldous C, Woods D, Christianson A. The contribution of congenital disorders to child mortality in South Africa. In: Padarath A, King J, Mackie E, Casciola J, eds. South African Health Review 2016. 19th ed. Durban: Health Systems Trust, 2016:137-152. 22. South Africa. National Public Health Insitute of South Africa Bill, No. B16-2017, 2017. 23. Modell B, Kuliev A. The history of community genetics: The contribution of the haemoglobin disorders. Commun Genet 1998;1:3-11. https://doi.org/10.1159/000016129

S Afr Med J 2018;108(6):447-448. DOI:10.7196/SAMJ.2018.v108i6.13331

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30 days in medicine Australian body promotes exercise as part of cancer treatment

In a position statement published in the Medical Journal of Australia, the Clinical Oncology Society of Australia has said that exercise is an essential component in the treatment of cancer. This statement, endorsed by a group of 25 influential health and cancer organisations, including the Cancer Council Australia, is the first evidence-based approach to making exercise a mandatory part of cancer treatment. The main recommendations are that exercise is part of standard practice in cancer care and is viewed as adjunct therapy, that all members of the multidisciplinary team promote physical activity and recommend that those with cancer stick to exercise guidelines, and that best practice care includes referral to an accredited exercise physiologist or physiotherapist with experience of cancer care. The body states that clinical research has established strong evidence that the improvements in physical function as a result of exercise attenuate cancer-related fatigue, alleviate psychological distress and improve quality of life across multiple general health and cancer-specific domains. Emerging evidence suggests that regular exercise before, during and after cancer treatment decreases the severity of treatment side-effects and reduces the risk of developing new cancers and comorbid conditions such as cardiovascular disease, diabetes and osteoporosis. Comrie P, Atkinson M, Bucci L, et al. Clinical Oncology Society of Australia position statement on exercise in cancer care. Med J Aust 2018 (epub 7 May 2018). https://doi.org/10.5694/mja18.00199

Physical activity reduces the risk of developing depression – at any age

An article published in the American Journal of Psychiatry showed that people with higher levels of physical activity had a 17% lower risk of depression than those with lower physical activity. These protective effects of physical activity were seen in people of all ages. A higher level of physical activity was associated with a 10% reduction in depression in children and adolescents, adults and the elderly. The large meta-analysis pooled data from 40 prospective cohort studies, including a total of 266 939 people who were free of mental illness at baseline, with an average follow up of 7.4 years. Researchers were not able to specify an ‘optimal dosage’ of physical activity because the studies assessed physical activity in different ways. However, a sub-group analysis of the four studies that evaluated the effect of 150 minutes of exercise a week or moderate to vigorous activity showed that this was effective in reducing the risk of newonset depression. Schuch FB, Vancampfort D, Firth J, et al. Physical activity and incident depression: A meta-analysis of prospective cohort studies. Am J Psychiatry 2018 (epub 25 April 2018). https://doi.org/10.1176/appi. ajp.2018.17111194

B Farham Editor ugqirha@iafrica.com

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OBITUARY Lionel Palmer Miles

When the history of dental postgraduate studies at the University of the Western Cape (UWC), once fondly known as the Intellectual Home of the Left, is written, the name of Lionel Palmer Miles will be mentioned with great pride. Lionel Miles was born in Molteno in the Eastern Cape on 5 February 1928. Having matriculated from Queen’s College in Queenstown, he completed his dental degree at the University of the Witwatersrand in 1951, after which he opened a dental practice in Worcester. In 1960 he travelled to England, where he specialised in maxillofacial surgery at the East Grinstead Hospital and Queen

Mary’s Hospital, Roehampton, under the tutelage of Sir Robert Bradlow, Sir Terence Ward and Mr Norman Rowe. In London he met his future wife Marion, a Canadian-born nurse, and they married in 1963. They returned to South Africa in 1965, when Lionel was appointed as a full-time specialist in maxillofacial surgery at Groote Schuur Hospital (GSH), thereby becoming the first maxillofacial and oral surgeon south of the Vaal River. In 1968 he joined Prof. Manie Breytenbach in the first specialist maxillofacial and oral surgery practice in Cape Town, while continuing as a part-timer at GSH. Recognising the need for the postgraduate training of historically disadvantaged dentists, Lionel joined the Faculty of Dentistry at UWC in 1983, serving at the same time as Chair and Head of Maxillofacial Surgery at GSH. In 1987, he reluctantly accepted the post of Dean of Dentistry at UWC, a post he served with great distinction. A deeply religious person, Lionel believed in fairness, justice and equality for all, and showed a deep compassion for humanity. When the divisions wreaked by the horrors of the apartheid system became visible in his professional life, Lionel, in his inimitable way, worked his quiet diplomacy and was able to transcend the many political, cultural

June 2018, Print edition

and social barriers that were suffocating the university and teaching hospitals at that time. A talented musician, Lionel was an accomplished pianist and organist and was choir master at the Church of the Good Shepherd – Protea. He was also a member of the Cape Town Male Choir. His legacy is not simply in the pioneering of maxillofacial and oral surgery in Cape Town and at UWC, but can be found in the patients, students, academics, colleagues, worshippers, friends and family whose lives he touched. Lionel passed away in Cape Town on 24 December at the age of 89. He is survived by his wife Marion, children Jane and Gordon, and three grandchildren. Rushdi Hendricks University of Cape Town, South Africa Chris Naidoo South African National Defence Force Jairam Reddy University of the Western Cape, Cape Town, South Africa Peter Gordon University of Cape Town, South Africa peter.gordon@uct.ac.za

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

EDITORIAL

Decentralised clinical training of health professionals will expand the training platform and enhance the competencies of graduates The South African Association of Health Educationalists (SAAHE), at its 2017 National Conference in Potchefstroom, deliberated on the critical issue of the appropriate training of healthcare professionals in South Africa (SA) and resolved to continue and intensify its advocacy for distributed clinical training of healthcare professionals in the country. In its Consensus Statement,[1] SAAHE defines distributed training as the ‘training of students outside the central academic hospitals’ in district and other appropriate healthcare facilities embedded in the community, in which the students are immersed ‘in the experience of social determinants of health, in understanding the continuum of comprehensive care and the role of context in health and illness, and in addressing the maldistribution of human resources for health’. The development of decentralised training platforms as part of the education of health professionals in SA is being discussed in many forums, and the Consensus Statement has attracted wide interest from professional, academic and statutory bodies. Decentralised training has received the support of leaders of many universities around the world that offer medical and health professional training, who regard decentralised training as an essential component of the endeavour to increase graduate output and to improve outcome competencies for health professionals.[2] In respect of undergraduate medical training in particular, decentralisation has become more urgent in the SA context owing to the growing numbers of senior medical students needing clinical training in the face of limited capacity at academic hospitals. The increase is due in part to the Nelson Mandela-Fidel Castro Collaboration students returning from Cuba, whose programme includes a period of training at SA medical schools, and in part to the increasing intake of students by SA medical schools at the instance of the Minister of Health. The large numbers of students involved have made medical schools uneasy, fearing that quality will be compromised for quantity, thus reflecting the dilemmas that have accompanied massification of higher education more generally.[3] However, capacity and other logistics are not the only justification for distributed professional training. Experience from elsewhere in the world has shown that health professional training in non-academic hospital settings produces graduates who are better fit for purpose[2,4,5] and who are competent and confident to work in generalist settings in many healthcare systems throughout the world.[6,7] This is echoed in the report of the Lancet Commission on Health Professional Education for the 21st Century[8] and the World Health Organization guidelines on transforming health professional education.[2] Various initiatives of decentralised training have been around in SA for some years, albeit on an ad hoc basis and driven by individual institutions with little national co-ordination. The Walter Sisulu medical school was founded on – and remains – a distributed training model. A number of other medical schools (including the University of the Witwatersrand, Pretoria University, the University of KwaZulu-Natal and Stellenbosch University) have for a long time undertaken a variety of initiatives to extend training into rural health facilities, and the envisaged new medical school at the Nelson Mandela Metropolitan University is intended to be wholly based on distributed training. Currently, the Stellenbosch University Collaborative Capacity Development through Engagement with

Districts (SUCCEED) project is supporting a national process in developing models to shift clinical training from the metropolitan academic hospital centres to district hospital and community settings.[9] This editorial seeks to add to the advocacy for a national consensus-based commitment to the adoption of a comprehensive, across-the-board policy on distributed clinical training for SA as envisaged in the SAAHE Consensus Statement. This will require the co-operation of all the principal stakeholders, among others the health sciences faculties, the professional accreditation agencies, and the departments of Health and of Higher Education. There will be a need for agreement on an appropriate core curriculum among medical schools and the Health Professions Council of South Africa, and a commitment on the part of the state to fund and equip rural training centres suitably. Such a national consensus will require three paradigm shifts. The first is acceptance of the relocation of much of the training from the metropolitan academic hospitals to the district hospitals, primary care clinics and community settings. This shift is both a geographical one and a shift within the healthcare system, and needs to be paired with innovative modalities of knowledge transfer and greater use of information technology. This shift reflects trends in many a medical school throughout the world[10] in both developed countries and lowand middle-income countries. The second is the reimagination of the healthcare system in terms of infrastructure and logistics upgrade to benefit training and facilitate the implementation of the National Health Insurance system. Community-embedded training invariably benefits local services. It enhances the quality of care for the affected communities and emphasises the inter-dependence of and mutual benefit to the healthcare system, universities and communities to develop appropriately trained graduates.[11] The third shift is a change in educational philosophy towards generalism. Deeply embedded in the traditional curriculum common to most medical schools is the domination of specialism. The rotations are based on specialist disciplines that teach disciplinespecific content in sequential ‘blocks’. Medical training at central academic hospitals tends to be unduly specialty-biased, whereas the graduating doctor should rather be equipped and orientated to work with an undifferentiated patient population. Decentralisation calls for a rebalancing of curricular content and processes to reflect this reality and examine how the crucial contribution of the specialist can be meaningfully integrated. Developing and sustaining decentralised training platforms offers major opportunities to make changes in health professional education that effectively not only respond to policy imperatives but develop high-quality, fit-for-purpose health professionals for the 21st century. Bernhard Gaede Head, Department of Family Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; and Convenor, Decentralised Education Special Interest Group Nationally (DESIGN), a special interest group of the South African Association of Health Educationalists gaedeb@ukzn.ac.za

June 2018, Print edition

EDITORIAL

1. South African Association of Health Educationalists. Consensus Statement on Decentralized Training in the Health Professions. 2017. http://saahe.org.za/2017/07/consensus-statement-on-decentralisedtraining-in-the-health-professions/ (accessed 1 August 2017). 2. World Health Organization. Transformative Scale Up of Health Professional Education – an Effort to Increase the Numbers of Health Professionals and to Strengthen their Impact on Population Health. Geneva: WHO, 2011. 3. Guri-Rosenbilt S, Sebkova H, Teichler U. Massification and diversity of higher education systems: Interplay of complex dimensions. High Educ Policy 2007;20(4):373-389. https://doi.org/10.1057/ palgrave.hep.8300158 4. Couper ID, Worley PS. Meeting the challenges of training more medical students: Lessons from Flinders University’s distributed medical education program. Med J Aust 2010;193(1):34-36. 5. Reid SJ, Worley P, Strasser R, Couper I, Rourke J. ‘What brings us together’: The values and principles of rural medical education. In: Chater AB, ed. WONCA Rural Medical Education Guidebook. Bangkok: World Organization of Family Doctors (WONCA), 2014. http://www.globalfamilydoctor.com/site/ DefaultSite/filesystem/documents/ruralGuidebook/RMEG.pdf (accessed 3 August 2017) 6. World Health Organization. The World Health Report 2008 – Primary Health Care: Now More Than Ever. Geneva: WHO, 2008.

This open-access article is distributed under CC-BY-NC 4.0.

7. Pillay Y, Barron P. The Implementation of PHC Re-engineering in South Africa. Pretoria: National Department of Health, 2012. 8. Frenk J, Chen L, Bhutta ZA, et al. Health professionals for a new century: Transforming education to strengthen health system in an interdependent world. Lancet 2010;6736(10):6184-6185. https://dio. org/10.1016/S0140-6736(10)61854-5 9. De Villiers MR, Blitz J, Couper I, et al. Decentralized training for medical students: Toward a South African consensus. Afr J Prim Health Care Fam Med 2017;9(1):a1449. https://doi.org/10.4102/phcfm. v9i.1449 10. Duvivier RJ, Moulet JR, Opalek A, Norcini J. Overview of the world’s medical schools: An update. Med Educ 2014;48(9):860-869. https://doi.org/10.1111/medu.12499 11. Talib Z, van Schalkwyk S, Couper I, et al. Medical education in decentralized settings: How medical students contribute to health care in 10 sub-Saharan African countries. Acad Med 2017;92(12):17231732. https://doi.org/10.1097/ACM.0000000000002003

S Afr Med J 2018;108(6):451-452. DOI:10.7196/SAMJ.2018.v108i6.13214

How climate change can fuel listeriosis outbreaks in South Africa

The listeriosis outbreak that began in early 2017 in South Africa (SA) is the largest recorded globally.[1] The source of the outbreak was located in early March 2018, when traces of the Listeria monocytogenes bacterium were found in a food production facility in Polokwane, Limpopo Province, SA, which produces ready-to-eat processed meat products.[2] By the time the source was identified, about 950 cases of invasive disease had been confirmed and 180 deaths reported, almost certainly underestimates of the actual extent of the disease.[2] Actions to halt the outbreak, such as product recalls and closing implicated processing plants, are clearly an immediate priority, as are steps to enforce environmental health standards. It is also important, however, to pay attention to factors relating to the longer-term, structural environment in which such outbreaks unfold and which may contribute to an increased frequency of cases in the near future. One such factor is climate change, which has garnered little attention thus far in the discourse surrounding the outbreak. The wide-ranging environmental effects associated with global climate change markedly alter the epidemiology of food-borne diseases, including L. monocytogenes.[3] Even though Listeria species are ubiquitous within the natural environment, several features of the epidemiology and characteristics of the microbe make it especially climate sensitive. Spikes in ambient temperature and high summer temperature peaks, for example, have been linked to the occurrence of listeriosis, as with most diarrhoeal pathogens.[4-6] Hot weather extremes that become more common with climate change, augment the replication cycles of L. monocytogenes and could cause breakdowns in food cooling chains, with rapid rises in numbers of the bacteria on food products.[7] But, aside from temperature increases, altered rainfall patterns and lengthened dry seasons – as we have seen in the western regions of SA – may influence Listeria transmission. L. monocytogenes is classically associated with the food chain, during pre-harvesting and processing and at retail level.[8,9] Water scarcity can compromise hand hygiene, as well as cleaning and sanitising operations in the food products industry. Cleaning hands with sanitisers, increasingly the norm in drought-affected areas, is less effective than washing with soap and water.[10] More importantly, however, in food processing plants, water scarcity may hamper efforts to clean machines used for slicing, chopping or related processes. Intensive, deep cleaning is required to prevent persistence of L. monocytogenes on such machines, given that the bacterium can tolerate high salt and nitrate concentrations, desiccation, moderate heat, and

both acidic and alkaline conditions.[9] With incomplete cleaning, especially of machines that have ‘unhygienic’ designs or are damaged, L. monocytogenes can persist in harbourage sites (i.e. cracks, niches or other hard-to-reach places).[9] The organisms can adhere to all food contact surfaces, forming biofilms, which are hard to eliminate. In a study in Gauteng, for example, the microbe was isolated from stainless steel surfaces in food plants after they had been cleaned and disinfected using a range of cleaning methods.[11] As could be expected, several studies have detected L. monocytogenes in food samples of street vendors, who have limited access to water and cleaning equipment.[12,13] The bacterium has even been found in delicatessens in Johannesburg – in 10% of cleaning cloths.[14] These levels of contamination will possibly rise as water scarcity, which threatens much of the country, further reduces personal and industrial cleaning. Another way that climate change influences the spread of L. monocytogenes is through inducing a switch in the types and sources of water used for agriculture and domestic purposes. When supplies of potable municipal water become limited, both subsistence and commercial farmers resort to using surface water for irrigation, which often naturally harbours Listeria species.[15,16] In both rural and urban areas, roof-harvested rainwater is increasingly being used for irrigation and domestic purposes. A study of rainwater tanks in villages in three provinces of SA found that 22% of samples were contaminated with L. monocytogenes, possibly from bird faeces and debris on rooftops.[17] The organism also proliferates in water within drainage ditches, which may then contaminate fruits and vegetables when used for irrigation.[3,18] Changes in precipitation patterns wrought by large-scale climate disruption also impact on Listeria dispersal. Rainfall occurring in short bursts of 5 - 10 minutes favours the dispersal of Listeria and other pathogens from the soil onto plants, while lengthier downpours exert a washout effect.[3] As with fresh produce, run-off water may contaminate the water in fish farms, an effect especially noticeable during summer months.[19] As this water filters through the fishes’ gills, they become contaminated with L. monocytogenes, and the organism is then introduced into food processing plants.[20] In summary, long-term water scarcity can influence cleaning practices and alter water sources in ways that favour the persistence of Listeria in food-processing plants, but also in retail outlets and domestic settings. Much closer monitoring of food industry standards, changes in dietary habits of the public and heightened

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EDITORIAL

responses to listeriosis outbreaks are required, in conjunction with efforts to increase the volume of potable municipal water and to ensure that all citizens have access to this water. Ultimately, infectious disease outbreaks, which may become more frequent with rising ambient temperatures and water scarcity, are the proverbial canary in a coal mine. They serve as but one reminder of the devastating effects of climate change presently unfolding in SA. As with all nations, the country needs to takes rigorous steps to prepare for these changes. The high levels of carbon emissions in SA, especially its reliance on coal for power, may well worsen the impact of climate change. In SA, 93% of electricity production is still obtained from coal, more than double the global average (42%), and renewable energy sources account for ˂2% of electricity compared with a world average of 22%.[21] Also, challenges in public transport in the country, especially with train services,[22] have heightened the use of taxis, cars and other forms of carbon-intensive transport. Without concerted action to prepare for the health effects of climate change, and in the absence of efforts to reduce further environmental degradation, South Africans may face many more large outbreaks of infectious diseases in years to come. M F Chersich, F Scorgie, H Rees Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa mchersich@wrhi.ac.za C Y Wright Environment and Health Research Unit, South African Medical Research Council and Department of Geography, Geoinformatics and Meteorology, Faculty of Natural and Agricultural Sciences, University of Pretoria, South Africa 1. Spies D. WHO: South Africa’s listeriosis outbreak ‘largest ever’. News 24, 13 January 2018. https:// www.news24.com/SouthAfrica/News/who-south-africas-listeriosis-outbreak-largest-ever-20180113 (accessed 10 May 2018). 2. Motsoaledi A. Media statement by the Minister of Health Dr Aaron Motsoaledi regarding the update on the listeriosis outbreak in South Africa. 2017. http://www.kznhealth.gov.za/Listeriosis/Mediastatement-NDOH-04032018.pdf (accessed 15 May 2018). 3. Hellberg RS, Chu E. Effects of climate change on the persistence and dispersal of foodborne bacterial pathogens in the outdoor environment: A review. Crit Rev Microbiol 2016;42(4):548-572. https://doi. org/10.3109/1040841x.2014.972335 4. Goulet V, Jacquet C, Martin P, et al. Surveillance of human listeriosis in France, 2001 - 2003. Euro Surveill 2006;11(6):79-81.

5. Musengimana G, Mukinda FK, Machekano R, Mahomed H. Temperature variability and occurrence of diarrhoea in children under five-years-old in Cape Town metropolitan sub-districts. Int J Environ Res Public Health 2016;13(9):859. https://doi.org/10.3390/ijerph13090859 6. European Food Safety Authority, European Centre for Disease Prevention and Control. The European Union summary report on trends and sources of zoonoses, zoonotic agents and food-borne outbreaks in 2016. 2017. https://ecdc.europa.eu/sites/portal/files/documents/summary-report-zoonoses-foodborneoutbreaks-2016.pdf (accessed 10 May 2018). 7. Miettinen MK, Siitonen A, Heiskanen P, et al. Molecular epidemiology of an outbreak of febrile gastroenteritis caused by Listeria monocytogenes in cold-smoked rainbow trout. J Clin Microbiol 1999;37(7):2358-2360. 8. Henriques AR, Gama LT, Fraqueza MJ. Tracking Listeria monocytogenes contamination and virulence-associated characteristics in the ready-to-eat meat-based food products industry according to the hygiene level. Int J Food Microbiol 2017;242:101-106. https://doi.org/10.1016/j. ijfoodmicro.2016.11.020 9. Carpentier B, Cerf O. Review. Persistence of Listeria monocytogenes in food industry equipment and premises. Int J Food Microbiol 2011;145(1):1-8. https://doi.org/10.1016/j.ijfoodmicro.2011.01.005 10. Farber T. Day Zero may fan deadly listeriosis outbreak. Sunday Times, 28 January 2018. https:// www.timeslive.co.za/sunday-times/news/2018-01-27-day-zero-may-fan--deadly-listeriosis-outbreak/ (accessed 10 May 2018). 11. Lambrechts AA, Human IS, Doughari JH, Lues JF. Efficacy of low-pressure foam cleaning compared to conventional cleaning methods in the removal of bacteria from surfaces associated with convenience food. Afr Health Sci 2014;14(3):585-592. https://doi.org/10.4314/ahs.v14i3.13 12. Nyenje ME, Odjadjare CE, Tanih NF, Green E, Ndip RN. Foodborne pathogens recovered from ready-to-eat foods from roadside cafeterias and retail outlets in Alice, Eastern Cape Province, South Africa: Public health implications. Int J Environ Res Public Health 2012;9(8):2608-2619. https://doi. org/10.3390/ijerph9082608 13. Plessis EMD, Govender S, Pillay B, Korsten L. Exploratory study into the microbiological quality of spinach and cabbage purchased from street vendors and retailers in Johannesburg, South Africa. J Food Prot 2017;80(10):1726-1733. https://doi.org/10.4315/0362-028x.jfp-16-540 14. Christison CA, Lindsay D, von Holy A. Cleaning and handling implements as potential reservoirs for bacterial contamination of some ready-to-eat foods in retail delicatessen environments. J Food Prot 2007;70(12):2878-2883. 15. Olaniran AO, Nzimande SB, Mkize NG. Antimicrobial resistance and virulence signatures of Listeria and Aeromonas species recovered from treated wastewater effluent and receiving surface water in Durban, South Africa. BMC Microbiol 2015;15:234. https://doi.org/10.1186/s12866-015-0570-x 16. Odjadjare EE, Obi LC, Okoh AI. Municipal wastewater effluents as a source of listerial pathogens in the aquatic milieu of the Eastern Cape Province of South Africa: A concern of public health importance. Int J Environ Res Public Health 2010;7(5):2376-2394. https://doi.org/10.3390/ijerph7052376 17. Jongman M, Korsten L. Microbial quality and suitability of roof-harvested rainwater in rural villages for crop irrigation and domestic use. J Water Health 2016;14(6):961-971. https://doi.org/10.2166/ wh.2016.058 18. Markland SM, Ingram D, Kniel KE, Sharma M. Water for agriculture: The convergence of sustainability and safety. Microbiol Spectr 2017;5(3). https://doi.org/10.1128/microbiolspec.PFS-0014-2016 19. Miettinen H, Wirtanen G. Ecology of Listeria spp. in a fish farm and molecular typing of Listeria monocytogenes from fish farming and processing companies. Int J Food Microbiol 2006;112(2):138146. https://doi.org/10.1016/j.ijfoodmicro.2006.06.016 20. Miettinen H, Wirtanen G. Prevalence and location of Listeria monocytogenes in farmed rainbow trout. Int J Food Microbiol 2005;104(2):135-143. https://doi.org/10.1016/j.ijfoodmicro.2005.01.013 21. International Energy Agency. Statistics. 2014. http://www.iea.org/statistics/statisticssearch/ (accessed 10 May 2018). 22. Public Protector. ‘Derailed’. A report on an investigation into allegations of maladminstration relating to financial mismanagement, tender irregularities and appointment irregularities against the Passenger Rail Agency of South Africa (PRASA). Report No: 3 of 2015/2016. 2015. http://allafrica.com/ download/resource/main/main/idatcs/00091794:b2efdd85e08e1e087813a4b7a417f4e4.pdf (accessed 15 May 2018).

S Afr Med J 2018;108(6):453-454. DOI:10.7196/SAMJ.2018.v108i6.13274

June 2018, Print edition

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CME

GUEST EDITORIAL

Anaesthesia in South Africa ‘We ought to have saints’ days to commemorate the great discoveries which have been made for all mankind, and perhaps for all time – or for whatever time may be left to us. Nature … is a prodigal of pain. I should like to find a day when we can take a holiday, a day of jubilation when we can fête good Saint Anaesthesia and chaste and pure Saint Antiseptic … I should be bound to celebrate, among others, Saint Penicillin … .’ (Winston Churchill, speech at Guildhall, London, 10 September 1947[1]) Anaesthesia facilitates performance of surgical and other interventional procedures by quickly, safely and pleasantly producing analgesia, absence of awareness and anxiety, and adequate muscle relaxation. An important aspect of perioperative anaesthetic care is maintenance of physiological homeostasis, including haemodynamic stability, ventilation, oxygenation and temperature. The anaesthetic team may also provide additional services, such as preoperative evaluation, postoperative management in the postanaesthesia care unit or intensive care unit (ICU), and management of both acute and chronic perioperative pain. Before elective anaesthesia, all patients are evaluated by an anaesthesiologist to assess medical status and preparedness for the planned procedure, implement strategies to reduce risks and create an anaesthetic plan.[2] Fasting guidelines to prevent pulmonary aspiration of gastric contents are applied in all patients undergoing elective surgery, including procedures performed under general anaesthesia (GA), regional anaesthesia, and monitored anaesthesia care (MAC). Prediction of the degree of difficulty of airway management and ventilation is an important part of the preanaesthetic evaluation. The American Society of Anesthesiologists (ASA)’s physical status classification system is relatively simple. It has proven effective in stratifying overall perioperative risk of morbidity and mortality for patient-specific risk factors (Table 1).[3] Patients are classified according to the degree to which underlying medical problems produce functional limitations, and a higher ASA physical status is associated with increased risk of complications, unexpected hospital admission after surgery, postoperative admission to the ICU, longer duration of hospital stay, and higher costs and mortality due to patient- and surgery-specific factors.[3] Risk assessment tools that combine patient and surgical risk factors have been developed. In older adults, frailty predicts postoperative mortality, morbidity, Table 1. American Society of Anesthesiologists physical status classification system ASA physical status classification ASA I ASA II ASA III ASA IV ASA V ASA VI

Definition A normal healthy patient A patient with mild systemic disease A patient with severe systemic disease A patient with severe systemic disease that is a constant threat to life A moribund patient who is not expected to survive without the operation A declared brain-dead patient whose organs are being removed for donor purposes

ASA = American Society of Anesthesiologists.

discharge disposition and functional decline.[4] Anaesthesia-related mortality rates have decreased to 1 death per 200 000 - 300 000 anaesthetics in the last few decades,[5] primarily as a consequence of improvements in the understanding of physiology, anaesthesia equipment and monitoring, anaesthetic agents and techniques, and a greater focus on anaesthesia safety. Factors affecting the selection of appropriate anaesthetic techniques for an individual patient include surgical requirements for performance of the procedure, anticipated duration of surgery, patient comorbidities and preferences, plans for providing postoperative analgesia, and experience and preferences of the anaesthesia care provider. As a general rule, there are no clear-cut indications for one type of anaesthesia over another when either would be appropriate.[6] For major or prolonged procedures, GA with airway management using an endotracheal tube or supraglottic airway device is usually the most appropriate primary technique, particularly if a deep level of sedation is required and/or if airway access is limited. GA may also be selected for minor procedures, particularly if it is the patient’s preference. Depending on the location of the procedure, neuraxial anaesthesia (e.g. peripheral nerve block, intravenous regional anaesthesia), or local anaesthetic infiltration by the surgeon, may be selected. These techniques are often supplemented with lighter levels of sedation to maintain airway reflexes (i.e. sedation with MAC). There are benefits and risks to any type of anaesthetic. When assessing whether avoidance of GA is appropriate, considerations include the patient’s ability to lie motionless in the position required for the procedure, and whether the patient can co-operate, communicate and is willing to undergo the procedure, given the possibility of awareness with recall. In many cases, a combined technique (i.e. GA plus epidural or peripheral nerve block for supplemental analgesia) provides both optimal intraoperative conditions and excellent multimodal management of postoperative pain. Standard monitoring during anaesthesia includes basic physiological measures such as pulse oximetry, temperature, electrocardiography and non-invasive blood pressure devices.[7] Furthermore, for ventilated patients, measurement of end-tidal carbon dioxide and inspired oxygen concentration, as well as use of low oxygen concentration and ventilator disconnect alarms, is helpful. Quantitative monitoring of the volume of expired gas is strongly encouraged. In patients undergoing GA, end-tidal inhalation anaesthetic concentrations are measured to aid in monitoring anaesthetic depth and preventing awareness. Neuromonitoring with electroencephalography provides supplemental information. Invasive haemodynamic monitoring requires insertion of an intra-arterial, central venous or pulmonary artery catheter, or a transoesophageal echocardiography probe. Maintenance of perioperative haemodynamic stability, including fluid administration to maintain optimal intravascular volume status and use of vasoactive drugs when necessary, is based on assessment of standard and/or invasive haemodynamic monitoring parameters. Ideally, after having received anaesthesia, all patients should be monitored in a post-anaesthesia care unit that provides standardised assessment of recovery, including discharge criteria, resulting in reduced postoperative adverse events and streamlined postoperative care.[8] After MAC with minimal sedation, patients

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CME

who have completely recovered may proceed directly to the predischarge unit for more rapid discharge. Critically ill patients and those who are intubated are admitted directly to the ICU. Commenting on the state of surgery and anaesthesia in South Africa (SA), Patel et al.[9] remarked, ‘Considering the challenges identified, developing a national road map for surgery and anaesthesia is a colossal task. Objective assessment of population needs is vital to developing any strategies aimed at addressing deficiencies in the current profile of service delivery. This assessment demands accurate and regular data collection and reporting. In spite of the existing demands on service delivery providers, an ongoing assessment of needs and the effectiveness of policy interventions provides an opportunity for innovation and to develop the relationship between tertiary, regional, peripheral and primary levels of care.’ In an editorial in 2012, Diedericks[10] wrote, ‘In SA the majority of anaesthetics are provided by non-specialists. In most cases this involves anaesthesia for small, brief procedures. Many of these cases are anaesthesia for caesarean section. Unfortunately the reports on maternal death indicate that SA has a relatively high rate of deaths associated with anaesthesia for caesarean section. This may be an indicator of all anaesthesia care. Many factors contribute to this situation, but the loss of experienced practitioners in rural areas, inadequate training, and high turnover of personnel are factors that are important.’ In 2018, sadly, the state of anaesthesia in SA has not changed significantly from the description given above. In this issue of CME, several topics are reviewed that hold great relevance for non-specialists and specialists alike; it is hoped that these will improve the practice of anaesthesia in SA. First, advances in paediatric anaesthesia are considered. Availability of dedicated facilities with appropriate equipment, monitoring and specialised personnel trained in paediatric anaesthesia and resuscitation have contributed to the reduction in perioperative risk for paediatric patients. Bester et al.[11] provide guidance on the selection of suitable facilities for perioperative care, risk stratification and patient selection, safe selection of medication and standardisation of its use, and implementation of specific anaesthetic techniques that can minimise risk in the paediatric surgical population. Second, the management of spinal hypotension and associated complications following caesarean section is reviewed.[12] Spinal hypotension may be predicted by simple parameters such as age >25 years, preoperative heart rate >90 bpm and preoperative mean arterial pressure <90 mmHg. Heart rate variability and point-ofcare echocardiography predict hypotension with greater accuracy. Spinal anaesthesia is absolutely contraindicated if the patient is hypovolaemic. Left lateral tilt is advised. The dose of spinal bupivacaine should not be reduced in obese patients. Crystalloid co-loading is an adequate fluid strategy in most cases, but of limited efficacy in the prevention of hypotension. Early intervention with phenylephrine is the first-line approach for hypotension if heart rate is preserved under spinal anaesthesia. The vigilant use of phenylephrine boluses, targeting maternal heart rate as a surrogate for cardiac output, is effective. Third, the management of myocardial injury after non-cardiac surgery (MINS) is reviewed.[13] MINS is defined as an elevated postoperative cardiac troponin level resulting from myocardial ischaemia, without evidence of a non-ischaemic cause. The perioperative context contributes to the pathophysiology of relative myocardial hypoperfusion and ischaemia, which differentiates MINS from myocardial infarction in non-surgical patients. More than 80% of MINS patients

are asymptomatic for myocardial ischaemia, and therefore would not fulfil the universal definition of myocardial infarction, despite a similar prognosis. Accurate diagnosis of MINS therefore relies on routine postoperative cardiac troponin surveillance for 48 - 72 hours, which is cost-effective, even in SA. One in 10 patients with MINS dies within 30 days of surgery, and 1 in 5 sustains major cardiovascular complications. Simple treatment strategies could improve short- and long-term mortality, which include cardioprotective therapy intensification, and ensuring therapy with aspirin and statins. It is my hope that the series of articles included in the CME issues on perioperative medicine and anaesthesia will improve knowledge, enhance practice, and translate into improved care of SA patients. Funding. This manuscript is not funded. Prof. N Ntusi gratefully acknowledges support from the National Research Foundation and the Medical Research Council of South Africa, as well as the Harry Crossley Foundation. Conflicts of interest. None.

Ntobeko Ntusi Division of Cardiology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital; Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town; and Hatter Institute of Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa ntobeko.ntusi@uct.ac.za 1. Gaither CC, Cavazos-Gaither AE. Gaither’s Dictionary of Scientific Quotations. 2nd ed. New York: Springer, 2012:1382. 2. Committee on Standards and Practice Parameters, Apfelbaum JL, Connis RT, Nickinovich DG; American Society of Anesthesiologists Task Force on Preanesthesia Evaluation, Pasternak LR, Arens JF, Caplan RA, et al. Practice advisory for preanesthesia evaluation: An updated report by the American Society of Anesthesiologists Task Force on preanesthesia evaluation. Anesthesiology 2012;116(3):522538. https://doi.org/10.1097/ALN.0b013e31823c1067 3. Cohen MM, Duncan PG, Tate RB. Does anesthesia contribute to operative mortality? JAMA 1988;260(19):2859-2863. https://doi.org/10.1001/jama.1988.03410190107032 4. Kim SW, Han HS, Jung HW, et al. Multidimensional frailty score for the prediction of postoperative mortality risk. JAMA Surg 2014;149(7):633-640. https://doi.org/10.1001/jamasurg.2014.241 5. Botney R. Improving patient safety in anesthesia: A success story? Int J Radiat Oncol Biol Phys 2008;71(1 Suppl):S182-S186. https://doi.org/10.1016/j.ijrobp.2007.05.095 6. Urwin SC, Parker MJ, Griffiths R. General versus regional anaesthesia for hip fracture surgery: A meta-analysis of randomized trials. Br J Anaesth 2000;84(4):450-455. https://doi.org/10.1093/ oxfordjournals.bja.a013468 7. Committee of Origin: Standards and Practice Parameters. Standards for basic anesthetic monitoring. 2016. https://www.asahq.org/~/media/Sites/ASAHQ/Files/Public/Resources/standards-guidelines/standardsfor-basic-anesthetic-monitoring.pdf (accessed 6 May 2018). 8. Apfelbaum JL, Silverstein JH, Chung FF, et al.; American Society of Anesthesiologists Task Force on Postanesthetic Care. Practice guidelines for postanesthetic care: An updated report by the American Society of Anesthesiologists Task Force on postanesthetic care. Anesthesiology 2013;118(2):291-307. https://doi.org/10.1097/ALN.0b013e31827773e9 9. Patel N, Peffer M, Leusink A, Singh N, Smith M. Surgery and anaesthesia in the South African context: Looking forward. S Afr Med J 2016;106(2):135-136. https://doi.org/10.7196/SAMJ.2016.v106i2.10529 10. Diedericks J. Anaesthetics. CME 2012;30(6):192. 11. Bester K, Meyer H, Crowther M, Gray R. Anaesthesia for paediatric patients: Minimising the risk. S Afr Med J 2018;108(6):457-459. https://doi.org/10.7196/SAMJ.2018.v108i6.13351 12. Gibbs MW, van Dyk D, Dyer RA. Managing spinal hypotension during caesarean section: An update. S Afr Med J 2018;108(6):460-463. https://doi.org/10.7196/SAMJ.2018.v108i6.13373 13. Coetzee E, Biccard BM. Myocardial injury after non-cardiac surgery: Time to shed the ignorance. S Afr Med J 2018;108(6):464-467. https://doi.org/10.7196/SAMJ.2018.v108i6.13346

S Afr Med J 2018;108(6):455-456. DOI:10.7196/SAMJ.2018.v108i6.13384

June 2018, Print edition

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CME

Anaesthesia for paediatric patients: Minimising the risk K Bester, MB ChB, DA (SA), FCA (SA); H Meyer, MB ChB, FRCA; M Crowther, MB ChB, DA (SA), Dip Obst (SA); R Gray, MB ChB, DA (SA), FCA (SA) Division of Paediatric Anaesthesia, Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Corresponding author: K Bester (kotgel@gmail.com)

Advances in paediatric anaesthesia include the availability of dedicated facilities with appropriate equipment, monitoring and specialised personnel trained in paediatric anaesthesia and resuscitation. These developments have contributed to the reduction in perioperative risk for paediatric patients. However, access to all the resources available in dedicated paediatric facilities is limited in resource-constrained settings. The objective of this review is to provide guidance with regard to the selection of suitable facilities for perioperative care, risk stratification and patient selection, safe selection of medication and standardisation of its use, and implementation of specific anaesthetic techniques that can minimise risk in the paediatric surgical population. S Afr Med J 2018;108(6):457-459. DOI:10.7196/SAMJ.2018.v108i6.13351

On 28 January 1848, 15-year-old Hannah Greener died after receiving a chloroform anaesthetic for the removal of a toenail. This was the first recorded death attributed to anaesthesia. Subsequent advances in anaesthetic techniques, training, medication and monitoring have contributed significantly to a decline in anaesthesia-related mortality and morbidity.[1,2] The development of dedicated paediatric centres and paediatric specialties has also led to the improvement in outcomes seen in paediatric surgery.[3] The American Academy of Pediatrics Guidelines for the Pediatric Perioperative Anesthesia Environment suggest that a number of requirements should be met to minimise perioperative risk. These include staff, such as anaesthetists, nursing and technical personnel with dedicated paediatric training, and a treatment area with appropriate equipment and medication.[4] In resource-limited settings, the risks of providing surgical services to paediatric patients need to be offset against the need for optimal utilisation of national resources available for the provision of services. When considering the development of paediatric surgical services, the following principles can be applied to help to minimise risk in this patient population: • Facilities should be appropriately equipped to manage paediatric patients and the complications that may arise from the procedure(s) undertaken. • Risk stratification of paediatric patients for specific procedures in specific settings should be undertaken. • Standardised operating procedures and drug-dosing tables should be used to promote simplicity and safety. • Techniques employed by the anaesthetist should be chosen to minimise risk, and consideration must be given to appropriate postoperative analgesia and monitoring requirements.

<100 paediatric anaesthesia procedures annually than in groups performing >200 procedures.[5] In 2006, a major review of services for children in hospitals in the UK recommended that anaesthetists looking after children should maintain an annual caseload of ≥100 patients between the ages of 0 and 12 years.[6] All equipment should be the appropriate size and type for paediatric patients. Many facilities set up a ‘paediatric trolley’, which should have a list of the required equipment that should be checked regularly. Pre- and postoperative care facilities should also fulfil certain requirements. The recovery area should have one-onone patient-to-nurse ratios and the staff should be familiar with specific paediatric care and resuscitation protocols. Depending on the complexity of cases, the need for availability of overnight, high-care or intensive care facilities should be addressed. Many children in South Africa (SA) require surgery in small hospitals, and the challenge is to improve the structures and processes of care in those hospitals. The role of tertiary hospitals should be to support colleagues in smaller district hospitals by means of telephonic advice, the sharing of protocols and educational opportunities, and reviewing digitally transmitted images where possible.

Facilities

The neonatal period is associated with highest risk, and neonatal surgery should only be undertaken in specialist centres. Children <1 year of age undergoing surgery have been shown to have a 4.5 times increased risk of perioperative mortality compared with older children.[9] Risk of perioperative adverse events decreases with age, and the likelihood of having an adverse event in the perioperative period decreases by 3% for every 1-year increase in age.[10]

When planning services, a facility should aim to manage a minimum number of specified cases, ensure appropriate skills, and maintain equipment and drugs for their spectrum of practice – preferably written into policy. Clear recommendations with regard to these minimum numbers remain controversial, but complication rates have been reported to be significantly increased in groups performing

Risk stratification

Each facility should decide on their scope of practice based on their ability to deal with potential risks. The caseload will need to be estimated as accurately as possible and the type and complexity of surgery should be considered (Table 1).[7,8] Consideration should be given to the possibility of localising children’s surgery to one location or within a group of small/collegiate hospitals to achieve a sufficient workload to maintain competence.

Age

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gastrointestinal systems. Patients may also be at risk of adverse reactions to anaesthetic drugs, such as anaesthesia-induced rhabdomyolysis (AIR), malignant hyperthermia (MH) and mitochondrial dysfunction.[13] A history of prematurity should be elicited in all children. Prematurity may have many long-term consequences that will impact on perioperative management. These include chronic lung disease, acquired subglottic stenosis secondary to prolonged intubation, and cerebral palsy. Subglottic stenosis can result in difficulty with intubation and may require the use of a smaller endotracheal tube than anticipated.

Table 1. Recommendations for paediatric surgery (British Association of Paediatric Surgeons) Type of hospital Surgical procedure Elective Non-specialist paediatric surgery safe to be performed at Congenital inguinal hernia peripheral hospital[7] Congenital hydrocele Circumcision Orchidopexy Umbilical hernia repair Emergency Appendicectomy Correction of torsion of testis Repair of incarcerated hernia Less complex trauma Neonatal surgery Specialist paediatric surgery requiring specialist paediatric Complex surgical conditions centre[8] requiring special expertise Children with significant comorbidities Paediatric urology

Medication and standardisation

Planning for the true emergency

The need for urgent surgery has been shown to be a better predictor of risk than the type of surgery,[11] with emergent or urgent cases accounting for 83% of in-hospital perioperative deaths[9] and 88% of unplanned intensive care admissions.[12] While it may not be in the patients’ interests to defer emergent surgery and transfer them to an alternative facility, it may be preferable if the outcome is likely to be better in a centre where the expertise and resources are available. The decision to operate is based on the child’s age, availability of a competent team, geographical location or response to initial treatment. Examples of true emergencies, where it may be better for a relatively inexperienced team to operate immediately, include torsion of the testis, volvulus, expanding intracranial haemorrhage, fracture with neurovascular compromise or upper airway obstruction.

Comorbidities

Significant pathological conditions, such as the presence of a syndrome, a large burn injury or a cardiac lesion, are usually clearly evident. However, there are several comorbidities that may have a significant impact on the perioperative course, which may only become evident when actively sought. These include the irritable airway, presence of obstructive sleep apnoea (OSA), neuromuscular disease and a history of premature birth. Airways may be irritable in patients with a history of upper respiratory tract infection (URTI) during the preceding 2 weeks, or a personal or family history of asthma or atopy. These patients have a higher incidence of laryngospasm, bronchospasm, stridor, desaturation and other airway complications. On average, very young children will have 6 - 8 URTIs every year. While it may be possible to delay elective surgery, the decision to proceed must be balanced against the urgency of the procedure and potential risk for the patient. OSA and obesity are associated with an increased risk of respiratory depression and adverse airway events.[10] OSA may also be complicated by pulmonary hypertension and cor pulmonale. Patients with severe OSA are not suitable for day surgery, require reduced opioid doses and postoperative apnoea and oxygen saturation monitoring for 24 - 48 hours. Neuromuscular disease can complicate the perioperative course owing to involvement of the cardiovascular, respiratory and

The administration of medication to paediatric patients requires meticulous attention to detail. Use of drug tables, calculators and cross-checking by healthcare workers can lessen potential errors.[4] A simple chart that lists doses of emergency drugs and recipes for mixture of inotropic infusions can be of great assistance. It is also helpful to display algorithms for the management of emergency situations. Duplication of drug administration between the theatre and ward is a common problem and systems should be in place to avoid such errors. Halothane causes an increased incidence of bradycardia and myocardial depression in children compared with sevoflurane. Standard vaporisers allow for seven times the effective dose of halothane to be delivered, which explains the high incidence of intraoperative cardiac arrests owing to overdose of inhalational agents reported in the older literature.[1,2] It should be noted that sevoflurane overdose can also result in cardiac arrest, and 8% sevoflurane should be used with caution. One should be cognisant of potential side-effects when administering neuromuscular-blocking agents. Muscle relaxation is required less frequently in children, and intubation may often be safely achieved with the use of medications other than muscle relaxants. Suxamethonium may offer superior intubating conditions to the non-depolarising muscle relaxants, but it can cause lifethreatening hyperkalaemia in susceptible patients, and may cause bradycardia.[3] In young children who may suffer from undiagnosed myopathies and muscle dystrophies, the risk of AIR and MH is of concern wherever volatiles or suxamethonium are used.[13] Muscle relaxants should always be reversed in doses titrated to findings on neuromuscular monitoring to reduce the risk of respiratory complications. The volumes of fluid used during administration of medication may represent a significant proportion of the total volume administered, particularly in younger patients. It is important that the anaesthetist is aware of the volume of dead space in intravenous systems. Every drug should be flushed in with a specified volume, and care should be taken to ensure that the system is completely cleared of medication before the patient leaves theatre. A small volume of medication may correlate to a significant dose of the drug in a small patient. Practitioners must be vigilant in their assessment of a patient’s volume status and blood loss. Underestimation of preoperative or intraoperative blood loss can lead to hypovolaemic cardiac arrest in children. Reports of cardiac arrest due to hypovolaemia were often related to operations where blood loss might have been difficult to estimate or could go unnoticed, e.g. craniectomies and spinal surgery.[2] Where there is a high risk of bleeding, advanced haemodynamic monitoring should be employed, e.g. invasive blood pressure monitoring, echocardiography and near-infrared spectroscopy. It is important to recognise that the use of advanced monitoring should not delay the ongoing resuscitation in these patients.

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Techniques

Airway management

Respiratory complications in children are more common than cardiac complications, and younger children are more vulnerable to such events.[1] Respiratory episodes are frequently responsible for unexpected intensive care unit admissions and cardiac arrest.[2,12] A history of URTI or atopy, surgery to the neck and airway, and younger age (˂6 years) increases the risk of adverse respiratory episodes.[2,10,14] The most appropriate technique should be chosen and the anaesthetist must be prepared to manage such potential adverse events. Adverse airway episodes are not limited to the operating room. It has been shown that ~50% of all cardiac arrests in the recovery area are caused by adverse respiratory events.[14] The type of airway device used can impact on the risk of adverse respiratory events. The use of a face mask only reduces the risk of respiratory complications. The use of a supraglottic device may decrease complications in the recovery room,[14] but it may increase adverse respiratory events intraoperatively, especially in children weighing <12 kg. Complications experienced with supraglottic devices tended to be more mechanical in nature (difficulty with placement and ventilation, dislodgement), while tracheal tubes more commonly caused laryngospasm and bronchospasm.[15] Cuffed tracheal tubes, especially where the cuff pressure is monitored, are associated with fewer perioperative respiratory complications.[14] Desflurane may increase the risk of adverse respiratory events in children and should be avoided in susceptible patients.

Ultrasound

Ultrasound may enhance the success rate and decrease complications when used for vascular access and regional techniques.[16] In our experience, it can be an invaluable tool when vascular access is difficult. While guidelines from North America and the UK recommend that ultrasound imaging be used for vascular access in children,[16] it may not be readily available in many hospitals. It therefore remains important that clinicians maintain their skills in both ultrasound-guided and landmark techniques.

Human factors

Human factors contribute significantly to adverse events. A study showed that insufficient practical application of techniques contributed more to critical events than lack of knowledge.[1] A retrospective analysis by Marcus[17] highlighted the significant role of poor clinical decision-making, inadequate checking, practical task failures, lack of experience, poor communication and distraction with regard to adverse events. Although dedicated paediatric anaesthetists and centres lead to better outcomes, these resources are insufficient to accommodate the needs of paediatric patients in SA. Every institution that can contribute towards the care of paediatric patients should therefore evaluate their system and choose to manage an appropriate number of suitable cases, using the correct equipment and medication.

Maintaining paediatric anaesthetic skills may be achieved by refresher courses at larger units and attending advanced paediatric life support courses – an 18-month interval has been suggested.

Conclusion

Facilities providing surgery to paediatric patients should be able to manage all perioperative aspects of patient care, including potential complications. A culture of critical review and redress will ensure that facilities maintain adequate standards of care. Co-operation, partnerships and networks are indispensable in the pursuit of excellence in paediatric anaesthesia. Acknowledgements. None. Author contributions. KB: substantial contribution to conception, initial and further writing, revision and final approval of work. HM and RG: substantial contribution to further writing, revision and final approval of work. MC: contribution to research for and writing of a section, i.e. Techniques. Funding. None. Conflicts of interest. None. 1. Gonzalez LP, Pignaton W, Kusano PS, Módolo NSP, Braz JRC, Braz LG. Anesthesia-related mortality in pediatric patients: A systematic review. Clinics (Sao Paulo) 2012;67(4):381-387. https://doi. org/10.6061/clinics/2012(04)12 2. Morray JP. Cardiac arrest in anesthetized children: Recent advances and challenges for the future. Paediatr Anaesth 2011;21(7):722-729. https://doi.org/10.1111/j.1460-9592.2010.03440.x 3. Somri M, Coran AG, Hadjittofi C, et al. Improved outcomes in paediatric anaesthesia: Contributing factors. Pediatr Surg Int 2012;28(6):553-561. https://doi.org/10.1007/s00383-012-3101-y 4. Village EG. Guidelines for the pediatric perioperative anesthesia environment. Pediatrics 1999;103(2):512515. https://doi.org/10.1542/peds.103.2.512 5. Auroy Y, Ecoffey C, Messiah A, Rouvier B. Relationship between complications of pediatric anesthesia and volume of pediatric anesthetics. Anesth Analg 1997;84:228-236. https://doi.org/10.1097/00000539199701000-00060 6. Healthcare Commission. Improving services for children in hospital. 2007. http://www.ehealthnurses. org.uk/pdf/ChildrenReportFeb07.pdf (accessed 20 April 2018). 7. British Association of Paediatric Surgeons. A Guide for Purchasers and Providers of Paediatric Surgical Services. Edinburgh: The Royal College of Surgeons of Edinburgh, 1995. 8. Arul G, Spicer R, McDonald P, Robinson P, Spitz L. Where should paediatric surgery be performed? Arch Dis Child 1998;79(1):65-72. https://doi.org/10.1136/adc.79.1.65 9. Meyer HM, Thomas J, Wilson GS, de Kock M. Anesthesia-related and perioperative mortality: An audit of 8 493 cases at a tertiary pediatric teaching hospital in South Africa. Pediatr Anesth 2017;27(10):1021-1027. https://doi.org/10.1111/pan.13214 10. Habre W, Disma N, Virag K, et al. Incidence of severe critical events in paediatric anaesthesia (APRICOT): A prospective multicentre observational study in 261 hospitals in Europe. Lancet Respir Med 2017;5(5):412-425. https://doi.org/10.1016/ S2213-2600(17)30116-9 11. Nasr VG, DiNardo JA, Faraoni D. Development of a pediatric risk assessment score to predict perioperative mortality in children undergoing noncardiac surgery. Anesth Analg 2017;124(5):1514-1519. https://doi.org/10.1213/ane.0000000000001541 12. Gibson AR, Limb J, Bell G. Retrospective audit of unplanned admissions to pediatric high dependency and intensive care after surgery. Paediatr Anaesth 2014;24(4):372-376. https://doi.org/ 10.1111/pan.12343 13. Gray RM. Anaesthesia and the paediatric muscle disorders. South Afr J Anaesth Analg 2013;19(1):20-23. https://doi.org/10.1080/22201173.2013.10872885 14. Von Ungern-Sternberg BS. Respiratory complications in the pediatric postanesthesia care unit. Anesthesiol Clin 2014;32(1):45-61. https://doi.org/10.1016/j.anclin.2013.10.004 15. Bordet F, Allaouchiche B, Lansiaux S, et al. Risk factors for airway complications during general anaesthesia in paediatric patients. Paediatr Anaesth 2002;12(9):762-769. https://doi.org/10.1046/j.14609592.2002.00987.x 16. Kamra K, Hammer GB. Central venous catheter placement in children: ‘How good is good enough?’ Paediatr Anaesth 2013;23(11):971-973. https://doi.org/10.1111/pan.12228 17. Marcus R. Human factors in pediatric anesthesia incidents. Paediatr Anaesth 2006;16(3):242-245. https://doi.org/10.1111/j.1460-9592.2005.01771.x

Accepted 18 April 2018.

June 2018, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

CME

Managing spinal hypotension during caesarean section: An update M W Gibbs, MB ChB, DA (SA), FCA (SA), MMed (Anaes); D van Dyk, MB ChB, DA (SA), FCA (SA); R A Dyer, FCA (SA), PhD Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: M W Gibbs (matthew.gibbs@uct.ac.za)

Hypotension is common after spinal local anaesthesia for caesarean section. However, the substandard treatment of spinal hypotension and associated complications are responsible for up to two-thirds of deaths that occur in South Africa (SA) for caesarean section under spinal anaesthesia. In some cases, spinal hypotension may be predicted by simple parameters such as age >25 years, preoperative heart rate >90 bpm and preoperative mean arterial pressure <90 mmHg. Heart rate variability and point-of-care echocardiography also predict hypotension with greater accuracy, but are limited by equipment and training issues. Spinal anaesthesia is absolutely contraindicated if the parturient is hypovolaemic. Left lateral tilt is still advised, despite the absence of strong supporting evidence. The dose of spinal bupivacaine should not be reduced in obese patients. Crystalloid co-loading is an adequate fluid strategy in most cases, but is of limited efficacy in the prevention of hypotension. It is imperative that immediately after the patient is placed supine, close attention is paid to communication with her, heart rate changes and pulse volume. Early intervention with phenylephrine is the first-line approach for hypotension if heart rate is preserved under spinal anaesthesia. Phenylephrine infusions (25 - 50 µg/min) are easy to administer, maintain baseline maternal haemodynamics and are applicable to the SA context. The vigilant use of phenylephrine boluses (50 - 100 µg), targeting maternal heart rate as a surrogate for cardiac output, is also effective. Noradrenaline has been used successfully to prevent spinal hypotension, but evidence does not yet suggest practice change. Local and international guidelines have recently been published. S Afr Med J 2018;108(6):460-463. DOI:10.7196/SAMJ.2018.v108i6.13373

What is the magnitude of the problem?

Despite the significant shift in practice from general to spinal anaesthesia for caesarean section, avoidable anaesthetic deaths in South Africa (SA) persist. In the triennium 2011 - 2013, 71% of 105 anaesthesia-related deaths involved spinal anaesthesia, the majority of which were deemed avoidable.[1] Given that more than half (55.1%) of these deaths occurred at district-level hospitals, these institutions should be targeted for support and education, with context-sensitive solutions based on up-to-date evidence-based guidelines. This brief review summarises the most recent data regarding hypotension during spinal anaesthesia for caesarean section. The authors discuss new insights into the predictors of hypotension, venous and arterial components of haemodynamic changes, dosing controversies and up-to-date treatment modalities.

How do we predict spinal hypotension?

Hypotension after spinal anaesthesia for caesarean section is a common clinical finding and causes major morbidity, and indeed, mortality, depending on the context. Predicting which parturients will experience major spinal hypotension remains a target of ongoing research. In 2014, an in-depth review was published locally, and further recent articles from SA have shed light on the matter. Research has shown a specific pattern of heart rate variability to be a risk factor for spinal hypotension. Bishop et al.[2] performed Holter continuous electrocardiogram (ECG) recordings for ≥5 minutes preoperatively on 102 elective patients due to undergo caesarean section. They investigated the low-frequency/ high-frequency (LFHF) ratio, a measure of heart rate variability, and compared this with baseline heart rate and body mass index (BMI)

as other predictors. A logistic regression analysis was performed, which showed that an LFHF threshold of 2.0 was predictive of spinal hypotension (defined as systolic blood pressure <90 mmHg), with an odds ratio of 1.478 (p=0.046). In comparison, BMI and baseline heart rate were less predictive. A further observational trial by the same authors[3] found that preoperative heart rate, mean arterial pressure (MAP) and maternal age were also predictive of spinal hypotension. A scoring system based on these variables (pulse rate >90 bpm, age >25 years, MAP <90 mmHg – the PRAM score) showed good discrimination, and patients had a 53% chance of developing spinal hypotension if all three factors were present. This simple scoring system, although not validated in larger studies, is probably a more useful practical tool in resource-constrained environments compared with LFHF measurements. In other studies, a BMI >25 kg/m2 has been shown to be a predictor of hypotension, but this was not supported by the PRAM study group. Recent data showed the benefit of point-of-care echocardiography in the prediction of spinal hypotension. A prospective observational trial assessing changes in the sub-aortic velocity time integral (VTI) after a 45° passive leg raise, found that when the change in VTI was >21%, the area under the receiver operating characteristics (ROC) curve for predicting spinal hypotension was highly predictive at 0.8 (confidence interval 0.6 - 0.9; p=0.0001). Until point-of-care echocardiography and the associated skills become more widely available, this will remain a research tool.

What is the correct spinal anaesthesia dose?

What, then, is the safe and effective dose of intrathecal local anaesthetic? Although a smaller dose is attractive in terms of a lower

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incidence of hypotension and nausea and vomiting, it is associated with increased breakthrough pain. A meta-analysis of 12 randomised control trials comparing low-dose bupivacaine (i.e. <8 mg/<1.8 mL) with a normal dose of ≥8 mg, showed a 3-fold increase in the need for analgesic supplementation intraoperatively; the number-neededto-treat for additional harmful outcomes was 4.[4] Historically, there has been a perception that a non-adjusted spinal dose in obese patients would cause a higher and unpredictable block owing to previous articles suggesting increased block height in such patients. This is concerning in our country, where nearly 70% of women are overweight or obese. After a recent article suggesting that the effective dose 95% (ED95) for intrathecal local anaesthesia for obese and normal BMI parturients is similar, a 2016 study performed by Ngaka et al.[5] specifically addressed this issue. These authors compared a group of patients at term with a BMI of <32 kg/m2 with another whose BMI was >40 kg/m2, each receiving identical doses of local anaesthetic. Although the temperature block was two dermatomes higher at 25 minutes in the morbidly obese group, and there was a 20-minute greater block regression time, there were no block levels higher than T1, and no differences in phenylephrine requirements or in reduction of peak flow rate after spinal anaesthesia. Other studies showed no correlation between height, weight, BMI and block height with standard (12 mg) doses of spinal bupivacaine. Subsequent reviews have thus concluded that dose adjustment of hyperbaric bupivacaine is unnecessary in obese patients.

What is the effect of aortocaval compression on spinal hypotension?

Left lateral tilt (15°) of the parturient after spinal anaesthesia to ensure displacement of the gravid uterus and subsequent aortocaval compression has been standard practice since the 1970s. Lee et al.[6] recently called this practice into question, randomising 100 women to either the supine position or 15° left lateral tilt. Maternal blood pressure was maintained with titrated phenylephrine infusions or boluses in both groups. There was no difference in the primary outcome, i.e. neonatal acid base balance. However, the mean phenylephrine requirement was higher and mean cardiac output decreased in the supine group. An accompanying editorial urges caution in abandoning the classic approach, as some patients have an exaggerated response to aortocaval compression, including occasional reflex bradycardia and precipitous hypotension.

How does the venous circulation affect spinal hypotension?

Due to the physiological changes of pregnancy, healthy women at term have an increase in plasma volume of ~40%, which usually compensates for the sympathectomy associated with spinal anaesthesia. However, after haemorrhage, sympathectomy, as well as the usual arteriolar dilatation associated with spinal anaesthesia, results in venodilatation and rapid decompensation as blood shifts from the stressed volume to the unstressed volume in the splanchnic circulation. In a recent meta-analysis, Melchor et al.[7] demonstrated that the use of colloids, either as a preload or a co-load, is associated with significantly reduced rates of hypotension compared with crystalloids. However, no method of fluid administration effectively prevents hypotension. Therefore, additional means of maintaining maternal blood pressure are required. In the past 10 - 12 years, research focused on the arterial component of spinal hypotension, the effect of regional anaesthesia on the systemic vascular resistance (SVR) in both healthy women and those with pre-eclampsia, as well as the physiological effect of vasopressors on the SVR. In healthy

women undergoing caesarean section under spinal anaesthesia, minimally invasive cardiac output measurements showed that when the MAP decreases by 20%, the SVR decreases by 35% and the heart rate, stroke volume and cardiac output increase by 12%, 9% and 22%, respectively.[8] The same article showed that phenylephrine restores haemodynamics to baseline, compared with ephedrine, which further increases cardiac output and is associated with a delay to peak pressor effect (undesirable in terms of nausea and vomiting). There is little information on the effects of spinal anaesthesia on the venous circulation in the fluid-replete parturient. Kuhn et al.[9] used leg wrapping after spinal anaesthesia to reduce hypotension instead of no intervention, and showed that venodilatation does contribute to spinal hypotension. This was, however, a far lesser effect than that of the arteriolar component, and of the effect of phenylephrine infusion in counteracting this decrease in SVR.

Why should phenylephrine be used in spinal hypotension?

It is now well accepted that the best approach to spinal hypotension is by means of a combination of intravenous crystalloid co-load and phenylephrine. This is the most effective method of ensuring maternal safety and comfort and preventing neonatal acidosis. In a randomised double-blind trial comparing varying set rates of phenylephrine infusion, 100 µg/min decreased maternal cardiac output and heart rate by up to 20%. An infusion at a rate of 25 - 50 µg/min was therefore sufficient to maintain appropriate maternal haemodynamics without exposing the fetus to large doses of phenylephrine and is the current recommendation. Although ephedrine is a commonly used drug in the management of spinal hypotension, it has concerning effects on the fetus as a result of stimulation of fetal metabolism after placental transfer of ephedrine and the resulting stimulation of fetal beta-adrenergic receptors. In a study of 109 elective caesarean section patients at term comparing high-dose ephedrine with phenylephrine infusions, titrating the latter to systolic blood pressure resulted in better fetal blood gases (umbilical artery pH 7.25 v. 7.34, base deficit −4.8 v. −1.9 mmol/L, and lactate 4.2 v. 2.2 mmol/L, respectively). A recent meta-analysis reported a 5-fold increase in the risk of fetal acidosis and larger base deficit with ephedrine than with phenylephrine.[10] A recent randomised trial on the haemodynamics of vasopressors during spinal anaesthesia in cases of pre-eclampsia, demonstrated a significant difference in the effect of vasopressors on SVR, with phenylephrine rapidly restoring SVR to baseline, and ephedrine, even in large doses, being less effective. Phenylephrine also reduces cardiac output, but as an appropriate response to the increase in cardiac output resulting from the spinal anaesthesia (Fig. 1).[11] Another trial comparing two groups of women with severe preeclampsia and fetal compromise, who were treated with ephedrine and phenylephrine boluses, revealed no significant differences in the primary outcome of umbilical artery base excess (mean −4.9 (standard deviation (SD) 3.7) v. −6.0 (4.6) mmol/L for ephedrine and phenylephrine, respectively; p=0.29).[12] There were also no differences in 1-minute Apgar scores or lactate levels, suggesting that in women with severe pre-eclampsia and fetal compromise, the choice of vasopressor does not affect fetal acid base status. Anaesthetists should also bear in mind that cardiac output response to phenylephrine is preload dependent. Work done in a porcine general anaesthesia model demonstrated that cardiac output decreases in response to phenylephrine administration when the patient is fluid replete and increases if the animal is fluid depleted. Therefore, what is the best method of administering phenylephrine? Simple titrated phenylephrine infusions initiated immedi-

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Change from pre-vaso period, %

-20 Time, seconds

Fig. 1. Percentage change in haemodynamic variables over 150 seconds after administration of phenylephrine 50 (range 50 - 150) µg or ephedrine 15 (range 7.5 - 37.5) mg for spinal hypotension. (Adapted from Dyer et al.,[11] with permission. HR = heart rate; CO = cardiac output; MAP = mean arterial pressure; SV = stroke volume; SVR = systemic vascular resistance; pre-vaso = mean value immediately prior to treatment of spinal hypotension.)

ately after the induction of spinal anaesthesia are certainly less labour intensive, are safe and are associated with a low incidence of maternal nausea and vomiting. Closed-loop, feedback computer-controlled phenylephrine infusions provide even tighter blood pressure control. However, this method requires specialised equipment and is not practicable in limited-resource environments. Phenylephrine boluses (50 - 100 µg) may be equally effective in preventing and treating spinal hypotension. The importance lies in choosing the best method appropriate to the maternal condition, local context and physician skill and experience. All the potential administration methods and doses have been well summarised in a recent review.[13]

Should one consider noradrenaline?

There are now several articles advocating the use of noradrenaline rather than phenylephrine for the treatment of spinal hypotension because of its moderate beta-adrenergic effects on maternal heart rate. In a randomised study of 104 healthy patients undergoing caesarean delivery under spinal anaesthesia, at 5 minutes after local anaesthetic injection a noradrenaline infusion maintained maternal cardiac output and heart rate better than a phenylephrine infusion. Maternal blood pressures and neonatal Apgar scores were similar with regard to the relevant infusions. Further work determined that phenylephrine 100 µg equals noradrenaline 8 µg. A subsequent editorial called into question the need for change to a more potent drug, suggesting that the burden of proof for noradrenaline to replace phenylephrine has not as yet been met, in contrast to the proven benefit of phenylephrine over ephedrine.[14]

What is the approach to a patient who develops bradycardia under spinal anaesthesia?

It is imperative that immediately after a spinal local anaesthetic has been injected, close attention is paid to communication with the patient, heart rate changes and pulse volume. Hypotension and bradycardia should be treated with ephedrine and/or anticholinergic agents after increasing left lateral tilt, if necessary. Bradycardia is not an uncommon occurrence when a patient with spinal hypotension is treated with the enthusiastic administration of

phenylephrine. The use of prophylactic glycopyrrolate in conjunction with a phenylephrine infusion was shown to improve cardiac output and heart rate, but at the cost of increased hypertension and an increased incidence of dry mouth. Baroreceptor-mediated bradycardia in response to an increased blood pressure after the administration of phenylephrine should not be treated with anticholinergics, as this may result in tachycardia and hypertension, particularly in pre-eclampsia. A recent meta-analysis demonstrated that prophylactic ondansetron reduced the incidence of spinal hypotension, vasopressor consumption and nausea and vomiting in the obstetric and nonobstetric populations, but the clinical significance is uncertain. The exact mechanism is unclear; however, it is suggested that 5-hydroxytryptamine (5-HT3)-receptor antagonism during the sympathectomy induced by spinal blockade may decrease the risk of mechanoreceptor activation in the left ventricle, which could have resulted in the subsequent activation of the Bezold-Jarisch reflex, with hypotension and bradycardia.

Are there any practice guidelines available?

Internationally, a consensus statement has recently been published, which emphasises the importance of pattern recognition of the haemodynamic changes associated with spinal anaesthesia, and describes in detail the management of spinal hypotension with vasopressors during caesarean section.[10] Recommendations for best practice include the use of alpha1-agonists for the treatment and prevention of hypotension (using boluses or infusions); left lateral uterine displacement and crystalloid co-loading or colloid preloading in addition to vasopressors for maintenance of the systolic blood pressure at ≤90% of baseline, and targeting maternal heart rate as a surrogate marker for cardiac output, i.e. tight haemodynamic control; and the use of phenylephrine infusions at 25 - 50 mg/min immediately after intrathecal injection. In patients with pre-eclampsia, fewer vasopressors are usually required, probably secondary to the vasoconstrictor state associated with this condition.[15] Guidelines have recently been published on the diagnosis and management of spinal anaesthesia with high sensorimotor block.[16] The main principles remain: (i) preparation for and anticipation of high spinal anaesthesia, including drawing up appropriate drugs; (ii) early recognition; (iii) respiratory support and prompt administration of ephedrine (due to the likelihood of cardiac deafferentation); (iv) avoidance of cardiorespiratory depressants, such as propofol or thiopentone; (v) administration of adrenaline via a peripheral vein if necessary to maintain cardiac output; and (vi) ongoing monitoring of the patient for haemodynamic instability and recovery from respiratory failure.

‘Context is king’

[17]

Much of the mechanistic research performed on the haemodynamic effects of spinal anaesthesia, and of vasopressors for spinal hypotension, has been carried out in high-resource environments. These findings have greatly improved knowledge and understanding. However, the application of the findings to a resource-limited situation remains challenging. The use of simple phenylephrine infusions has been successfully demonstrated to good effect in the SA context[18] and should encourage SA researchers who are appropriately applying up-to-date information. Ongoing data collection and context-sensitive research are to be encouraged, and audits such as the Confidential Enquiry into Maternal Deaths in SA and initiatives such as the SA Perioperative Research Outcomes Group (SAPORG) are specifically targeting the improvement of obstetric and perinatal

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care. Given that the recent continent-wide African Surgical Outcomes Study (ASOS) reported caesarean section as the most commonly performed procedure,[19] and that the mortality associated with spinal anaesthesia remains significant, spinal hypotension should ideally be avoided. When it does occur, it is critical that the associated clinical deterioration is immediately identified and appropriate management rapidly initiated.

Key points

• Substandard treatment of spinal hypotension and associated complications are responsible for a large proportion of deaths in SA for caesarean section under spinal anaesthesia. • Spinal anaesthesia is absolutely contraindicated if the parturient is hypovolaemic. • Spinal hypotension may in some cases be predicted by simple parameters, such as age, preoperative heart rate and preoperative mean arterial pressure. • Left lateral tilt is still advised, despite the absence of strong supporting evidence. • The dose of spinal bupivacaine should not be reduced in obese patients. • Crystalloid co-loading is an adequate fluid strategy in most cases, but is of limited efficacy in the prevention of hypotension. • It is imperative that immediately after the patient is placed supine, close attention is paid to communication with her, heart rate changes and pulse volume. • Early intervention with phenylephrine is the first-line approach for hypotension if the heart rate is preserved under spinal anaesthesia. • Phenylephrine boluses (50 - 100 µg) or infusions (25 - 50 µg/min) are easy to administer and maintain baseline maternal haemodynamics, and are applicable to the SA context. • Noradrenaline has been used successfully to prevent spinal hypotension, but evidence does not yet suggest a change of practice. Acknowledgements. None. Author contributions. All authors contributed to the intellectual input, contents and editing process. Funding. None. Conflicts of interest. None.

1. National Committee for the Confidential Enquiries into Maternal Deaths. Saving Mothers 2011 - 2013: Sixth Report on the Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: National Department of Health, 2014. 2. Bishop DG, Cairns C, Grobbelaar M, Rodseth RN. Heart rate variability as a predictor of hypotension following spinal for elective caesarean section: A prospective observational study. Anaesthesia 2017;72(5):603-608. https://doi.org/10.1111/anae.13813 3. Bishop DG, Cairns C, Grobbelaar M, Rodseth RN. Obstetric spinal hypotension: Preoperative risk factors and the development of a preliminary risk score – the PRAM score. S Afr Med J 2017;107(12):1127-1131. https://doi.org/10.7196/SAMJ.2017.v107i12.12390 4. Arzola C, Wieczorek PM. Efficacy of low-dose bupivacaine in spinal anaesthesia for caesarean delivery: Systematic review and meta-analysis. Br J Anaesth 2011;107(3):308-318. https://doi.org/10.1093/bja/ aer200 5. Ngaka TC, Coetzee JF, Dyer RA. The influence of body mass index on sensorimotor block and vasopressor requirement during spinal anesthesia for elective cesarean delivery. Anesth Analg 2016;123(6):1527-1534. https://doi.org/10.1213/ANE.0000000000001568 6. Lee AJ, Landau R, Mattingly JL, et al. Left lateral table tilt for elective cesarean delivery under spinal anesthesia has no effect on neonatal acid-base status. Anesthesiology 2017;127(2):241-249. https://doi. org/10.1097/ALN.0000000000001737 7. Melchor JR, Espinosa A, Hurtado EM, et al. Colloids versus crystalloids in the prevention of cesarean section. A systematic review and meta-analysis. Minerva Anestesiol 2015;81(9):1019-1030. 8. Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009;111(4):753-766. https://doi.org/10.1097/ALN.0b013e3181b437e0 9. Kuhn JC, Hauge TH, Rosseland LA, Dahl V, Langesæter E. Hemodynamics of phenylephrine infusion versus lower extremity compression during spinal anesthesia for cesarean delivery: A randomized, double-blind, placebo-controlled study. Anesth Analg 2016;122(4):1120-1129. https://doi.org/10.1213/ ANE.0000000000001174 10. Kinsella SM, Carvalho B, Dyer RA, et al. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia 2018;73(1):71-92. https://doi.org/10.1111/anae.14080 11. Dyer RA, Daniels A, Vorster A, et al. Maternal cardiac output response to colloid preload and vasopressor therapy during spinal anaesthesia for caesarean section in patients with severe preeclampsia: A randomised, controlled trial. Anaesthesia 2018;73(1):23-31. https://doi.org/10.1111/ anae.14040 12. Dyer RA, Emmanuel A, Adams SC, et al. A randomised comparison of bolus phenylephrine and ephedrine for the management of spinal hypotension in patients with severe preeclampsia and fetal compromise. Int J Obstet Anesth 2018;33:23-31. https://doi.org/10.1016/j.ijoa.2017.08.001 13. Lee JE, George RB, Habib AS. Spinal-induced hypotension: Incidence, mechanisms, prophylaxis, and management: Summarizing 20 years of research. Best Pract Res Clin Anaesthesiol 2017;31(1):57-68. https://doi.org/10.1016/j.bpa.2017.01.001 14. Carvalho B, Dyer RA. Norepinephrine for spinal hypotension during cesarean delivery: Another paradigm shift? Anesthesiology 2015;122(4):728-730. https://doi.org/10.1097/ALN.0000000000000602 15. Dyer RA, Piercy JL, Reed AR, Lombard CJ, Schoeman LK, James MF. Hemodynamic changes associated with spinal anesthesia for cesarean delivery in severe preeclampsia. Anesthesiology 2008;108(5):802-811. https://doi.org/10.1097/01.anes.0000311153.84687.c7 16. Van Rensburg G, van Dyk D, Bishop D, et al. The management of high spinal anaesthesia in obstetrics: Suggested clinical guideline in the South African context. S Afr J Anaesth Analg 2016;22(1) (Suppl 1):51-53. 17. Bishop DG, Rodseth RN, Dyer RA. Context is king – obstetric anaesthesia management strategies in limited resource settings. Int J Obstet Anesth 2017;31:1-4. https://doi.org/10.1016/j.ijoa.2017.04.010 18. Bishop DG, Cairns C, Grobbelaar M, Rodseth RN. Prophylactic phenylephrine infusions to reduce severe spinal anesthesia hypotension during cesarean delivery in a resource-constrained environment. Anesth Analg 2017;125(3):904-906. https://doi.org/10.1213/ANE.0000000000001905 19. Biccard BM, Madiba TE, Kluyts H-L, et al. Perioperative patient outcomes in the African Surgical Outcomes Study: A 7-day prospective observational cohort study. Lancet 2018;391(10130):1589-1598. https://doi.org/10.1016/S0140-6736(18)30001-1

Accepted 26 April 2018.

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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Myocardial injury after non-cardiac surgery: Time to shed the ignorance E Coetzee, MB ChB, DA (SA), FCA (SA), MMed (Anaesth); B M Biccard, MB ChB, FFARCSI, FCA (SA), MMedSci, PhD Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, Groote Schuur Hospital and University of Cape Town, South Africa Corresponding author: E Coetzee (ettiennec@gmail.com)

Perioperative cardiovascular complications are common and place a significant burden on public healthcare systems. A large proportion of such complications are due to a new clinical entity, i.e. myocardial injury after non-cardiac surgery (MINS). It is important to understand MINS, its prognosis and management in the perioperative period. A literature review of MINS was done. MINS is defined as an elevated postoperative cardiac troponin level that was considered as resulting from myocardial ischaemia without evidence of a non-ischaemic cause for the troponin elevation. The perioperative milieu (surgical stress response, sympathetic activation, hypercoagulability, hypotension, bleeding, anaemia and pain) contributes to the pathophysiology of a relative myocardial hypoperfusion and ischaemia, which differentiates MINS from myocardial infarction in non-surgical patients. Globally, >7% of adults ≥45 years of age suffer MINS, with South African (SA) studies confirming similar event rates. More than 80% of MINS patients are asymptomatic for myocardial ischaemia, and therefore would not fulfil the universal definition of myocardial infarction, despite having a similar prognosis to those with the latter condition. Accurate diagnosis of MINS therefore relies on routine daily postoperative cardiac troponin surveillance for 48 - 72 hours postoperatively in patients with a >5% risk of major perioperative cardiovascular complications. This approach is cost-effective in SA. One in 10 patients with MINS dies within 30 days of surgery, and 1 in 5 develops major cardiovascular complications. Short- and long-term mortality could be improved by simple treatment strategies, including cardiovascular therapy intensification, and by ensuring aspirin use and statin therapy. All recommendations promote the involvement of a multidisciplinary team. MINS is a common, serious perioperative cardiovascular complication with public healthcare implications that has been underappreciated in SA. A multidisciplinary approach with simple treatment strategies should be adopted. S Afr Med J 2018;108(6):464-467. DOI:10.7196/SAMJ.2018.v108i6.13346

Case vignette

A clinical entry, after specialist referral of a patient who experienced a postoperative troponin elevation, reads as follows: ‘Thank you for the referral. Reason for referral: postoperative troponin elevation following total hip replacement. According to the history, the patient was asymptomatic and comfortable in the ward. No ischaemic symptoms or electrocardiogram [ECG] changes noted. Vital signs were within normal limits. Assessment: isolated troponin elevation, expected in this patient population and not clinically significant. Recommendation: review patient for symptoms, no specific therapy required.’ After an uneventful hospital stay, the patient was discharged on the 4th postoperative day, but died 5 days later at home. The global surgical volume has increased to >300 million procedures per annum.[1] Cardiovascular complications contribute to one-third of major perioperative morbidity and mortality, with perioperative myocardial infarction and myocardial injury after non-cardiac surgery (MINS) accounting for 39% of all deaths within 30 days of non-cardiac surgery.[2] These deaths are distributed equally between patients who sustain a postoperative myocardial infarction and MINS.[2] The burden of perioperative cardiovascular complications, therefore, has a major public health importance. The paucity of clinicians with an appreciation of the importance of perioperative myocardial injuries and the associated prognosis, and the knowledge necessary to manage this public healthcare burden, needs to be addressed.[3]

Methods

A literature search on MINS in the perioperative period was conducted using MEDLINE and the following search terms: ‘myocardial injury’,

‘noncardiac surgery’, ‘mortality’, ‘perioperative complications’, ‘treatment’, ‘prevention’ and ‘guidelines’. Additional reports were obtained by reviewing reference lists from the literature. Studies involving large cohorts with clear inclusion criteria and outcome data were reviewed. Reviews and smaller studies with local significance were also included.

MINS

MINS occurs when myocardial ischaemia-related cellular damage occurs in the perioperative period. It has been defined as an elevated cardiac troponin T (cTnT) level that was considered as resulting from myocardial ischaemia without evidence of a non-ischaemic cause of cTnT elevation (Table 1).[4] The pathophysiology of MINS in surgical patients differs from that of myocardial infarction in medical (non-surgical) patients.[5] Surgical patients are exposed to a unique environment that includes sympathetic activation, bleeding, anaemia, pain, hypotension and hypercoagulability during the perioperative period. Another distinctive clinical feature of MINS is that it most commonly presents within the first 3 postoperative days, strengthening its association with the early postoperative pathophysiological environment, in contrast to postoperative atherosclerotic plaque rupture that tends to occur more randomly during the weeks after surgery, and more closely resembles a traditional medical (non-surgical) myocardial infarction.[5]

Incidence of MINS

International data estimate that >100 million adults ≥45 years of age undergo non-cardiac surgery per annum.[2] In the recent Vascular Events In Non-cardiac Surgery Patients Cohort Evaluation (VISION)

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study non-cardiac surgical patients were studied for perioperative complications.[6] More than 40 000 patients were enrolled, of whom 7% experienced MINS.[4,7] MINS is therefore a common perioperative complication, especially when one considers the nonselective nature of the VISION study’s inclusion criteria: ≥45 years of age and the need to spend a night in hospital following surgery, thereby providing a representative sample of perioperative outcomes in unselected surgical patients. Therefore, about 1 in 14 in-hospital patients ≥45 years old, who undergo non-cardiac surgery, will experience MINS as a perioperative complication. Factors that increase the risk for experiencing MINS occur commonly in our surgical population. These include increasing age, patients with known cardiovascular disease or known risk factors for cardiovascular disease, and operations associated with an elevated risk (typically intermediate and major surgical severity, and all nonelective surgery) (Table 2).[4]

universal definition of myocardial infarction; only 7% presented with ischaemic symptoms and 15% had nonspecific ECG changes.[4,7] The majority of troponin elevations occur within 48 hours of surgery, and the patient’s prognosis is positively correlated with the peak troponin level.[4,7] Studies of the high-sensitivity cTnT (hs-cTnT) test found that a small absolute increase in hs-cTnT from the preoperative to the postoperative period has prognostic use (Table 1).[7] Furthermore, observational data have shown that ~50% of patients demonstrate an early 24-hour postoperative window, where the troponin levels remain low before a subsequent rise in these levels, highlighting the need for serial troponin surveillance in the postoperative period.[10] As most of the prognostically significant troponin elevations occur asymptomatically, it is inappropriate to depend on ECG changes or ischaemic symptomatology to alert a clinician to MINS, as this will result in the majority (>80%) of diagnoses being missed.[4]

Clinical presentation of MINS in the postoperative period

Cardiac troponin T thresholds should be considered according to clinical context

To diagnose medical (non-surgical) myocardial infarction, the diagnostic criteria require documented elevated cardiac biomarkers and features of ischaemia (clinical, electrocardiographic or imaging).[8] Current studies employ cTnT, as it is universally standardised.[9] In contrast to medical myocardial infarction, clinical features of ischaemia are notoriously absent in surgical patients. Therefore, the diagnosis of MINS hinges on perioperative troponin elevation, and the exclusion of known non-ischaemic causes of perioperative troponin elevation, e.g. sepsis and pulmonary embolism.[4] More than 93% of patients who experienced MINS, did not fulfil the diagnostic criteria for the Table 1. MINS diagnostic criteria and hs-cTnT thresholds independently associated with 30-day mortality[7] MINS diagnostic criteria (only one required) Any peak hs-cTnT ≥65 ng/L An absolute increase in hs-cTnT of 5 ng/L, with peak cTnT 20 - 64 ng/L hs-cTnT thresholds associated with 30-day mortality Adjusted hazard hs-cTnT, ng/L ratio (95% CI)* 30-day mortality, % 14 - <20 9.1 (3.8 - 22.1) 1.1 20 - <65 23.6 (10.3 - 54.1) 3.0 65 - <1 000 70.3 (30.6 - 161.7) 9.1 227.0 (87.4 - 589.9) 29.6 ≥1 000 MINS = myocardial injury after non-cardiac surgery; hs-cTnT = high-sensitivity cardiac troponin T; CI = confidence interval. *All p<0.001.

Table 2. Perioperative risk factors for the development of MINS[4] Risk factor Increasing age Current atrial fibrillation Diabetes Hypertension Congestive heart failure Coronary artery disease Peripheral vascular disease Stroke Decreasing renal function Urgent or emergency surgery

The diagnostic troponin thresholds for MINS differ from those used to diagnose medical patients with myocardial infarction.[4,7,8] Before cardiac biomarkers are used in clinical practice, their diagnostic thresholds need to be determined by investigating specific reference populations.[8] The clinical environment of surgical and medical patients differs, which influences the sensitivity and specificity of these tests for specific outcomes and therefore requires populationspecific investigation.[9] The literature investigating different troponin assays in perioperative patients has provided assay-specific troponin levels that are of prognostic relevance in the surgical patient (i.e. independently associated with 30-day mortality),[4,7] but may not be typically associated with an adverse prognosis in the non-surgical patient (Table 1).

Prognosis of surgical patients with MINS

MINS has a 30-day mortality of 10%.[4] One in 10 patients with MINS dies, and 1 in 5 patients suffers a major cardiovascular complication (congestive cardiac failure, non-fatal cardiac arrest and stroke) within 30 days of surgery.[4] Various investigators have reported similar outcomes, as demonstrated by two meta-analyses independently associating postoperative troponin elevation with long- and shortterm mortality.[3] A recent study found that the incidence of MINS in a South African (SA) patient population was comparable with those of large international cohorts.[11] The 1 500 SA patients included in the VISION cohort also suggested findings that could be compared with those of other international cohorts, and showed no evidence of differences between clusters.[6,7] It is therefore reasonable to assume that the SA patient population has a similar risk for MINS and outcomes after MINS to that in the literature. Patients who develop MINS postoperatively, have prognostic risk factors independently associated with 30-day mortality (Table 3).[4] A point system allows for prediction of the risk of 30-day mortality: Table 3. Independent predictors of 30-day mortality in patients who experience MINS[4] Independent predictors Age ≥75 years ST elevation or new LBBB Anterior ischaemic changes on ECG

Adjusted odds ratio (95% CI)* 2.06 (1.33 - 3.37) 3.96 (1.54 - 9.14) 2.33 (1.42 - 3.70)

MINS = myocardial injury after non-cardiac surgery; LBBB = left bundle branch block; ECG = electrocardiogram; CI = confidence interval. *All p<0.01.

MINS = myocardial injury after non-cardiac surgery.

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0 points (5%), 1 point (10%), 2 points (20%), 3 points (30%) and 4 points (50%).[4] The cTnT diagnostic thresholds required for MINS, along with the 30-day prognostic impact, are shown in Table 1. The prognostically significant impact of MINS in the perioperative period is thus clear and therefore demands that clinicians understand the clinical entity of MINS and its associated diagnostic criteria, prognosis, prognostic markers and the need for active therapeutic intervention. The consultation example shown in the introduction of this article can therefore no longer be accepted.

Proposed management of MINS

The most recently published perioperative cardiovascular guidelines propose postoperative troponin surveillance for patients who have a >5% risk of a perioperative major adverse cardiovascular event. The following criteria apply: (i) any patient ≥65 years of age; (ii) patients between 45 and 64 years of age with a revised cardiac risk index (RCRI) of ≥1; or (iii) any patient with an elevated preoperative natriuretic peptide (including brain natriuretic peptide or N-terminal probrain natriuretic peptide).[12] The recent Canadian guidelines on cTnT surveillance and RCRI score are summarised in Table 4. As complications are common in the first week after MINS, we would advocate early intervention.[13] Evidence from randomised controlled trials is lacking, but we expect this to change over the next few years.[3] The Management of Myocardial Injury After Noncardiac Surgery Trial (MANAGE) (clinicaltrials.gov/ct2/show/NCT01661101) results are currently in press, but initial reports indicate improved primary endpoints. MANAGE evaluated the impact of anticoagulation on perioperative vascular complications after MINS. The final results will provide more insight into therapeutic options. Current observational data suggest that simple therapeutic measures could improve outcomes once MINS occurs. The literature supports the use of postoperative aspirin administration and statin therapy to reduce 30-day mortality after MINS.[14] Furthermore, intensification of therapy (defined as introducing or increasing any of the following cardiovascular drug groups: antiplatelet agents, beta-blockers, statins or angiotensin converting enzyme inhibitors) during the postoperative period has been shown to be associated with an improved 1-year survival.[15] However, deciding on a specific therapy should be part of a multidisciplinary approach. The potential benefits of therapies should be

weighed against potential risks on an individual basis. After initiation of treatment intensification, surveillance for additional prognostic information should continue (Table 3).[4] Increased postoperative monitoring (i.e. continuous invasive haemodynamic monitoring and a high-care facility) and optimised myocardial oxygen balance (i.e. haemodynamic support, correction of anaemia and electrolyte disturbances) could be of additional benefit, but is currently only supported by recommendations.[13] A pharmacoeconomic study showed that troponin surveillance in the SA context should be cost-effective for all patients ≥45 years of age who undergo non-cardiac surgery, but only when combined with active intervention once MINS is diagnosed.[16]

An adapted proposed algorithm for MINS management is depicted in Fig. 1.

Conclusion

MINS commonly occurs in non-cardiac surgical patients ≥ 45 years of age. Ten percent of patients who experience MINS die within 30 days of surgery. MINS can be easily diagnosed if routine, postoperative hs-cTnT surveillance is conducted, as recommended by current international guidelines, and it is likely to be cost-effective in SA. Once MINS is diagnosed, institution of simple therapies may improve outcome. Large studies are expected to provide more therapeutic insight in the near future. Screening and treatment of MINS need to be incorporated into routine postoperative surgical management.

Table 4. Postoperative troponin surveillance recommendations from the Canadian Cardiovascular Society Guidelines[12,17] Daily postoperative cTnT surveillance for 48 - 72 hours if baseline risk >5% for cardiovascular death or non-fatal myocardial infarction at 30 days after surgery, including:[12] Elevated preoperative NT-proBNP or BNP measurement RCRI score ≥1* Age 45 - 64 years, with significant cardiovascular disease* Age ≥65 years* RCRI[17] High-risk-type surgery (intraperitoneal, intrathoracic or supra-inguinal vascular) Ischaemic heart disease History of congestive heart failure History of cerebrovascular disease Insulin therapy for diabetes Preoperative serum creatinine >2.0 mg/dL (177 µmol/L) RCRI = revised cardiac risk index; NT-proBNP = N-terminal probrain natriuretic peptide; BNP = brain natriuretic peptide; cTnT = cardiac troponin T; CI = confidence interval. *If preoperative NT-proBNP or BNP not available.

Oxygen Optimise haemoglobin Aspirin ± clopidogrel Statin ACE inhibitor or ARB Anticoagulation ± morphine, ± nitroglycerine

Haemodynamically stable

Haemodynamically unstable

Beta-blockade

Manage hypotension and dysrhythmias Add beta-blocker when stable

Consider coronary angiogram if: (i) ST elevation (ii) ST depression with recurrent symptoms and no contraindication to heparin

Fig. 1. Proposed algorithm for the management of patients with MINS. (Adapted from Biccard.[18] MINS = myocardial injury after non-cardiac surgery; ACE inhibitor = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker.)

June 2018, Print edition

CME

Acknowledgement. None. Author contributions. The draft article was produced by EC and all subsequent versions were edited and proofread by BMB and EC. Funding. None. Conflicts of interest. None.

1. Weiser TG, Haynes AB, Molina G, et al. Estimate of the global volume of surgery in 2012: An assessment supporting improved health outcomes. Lancet 2015;385(S11). https://doi.org/10.1016/ S0140-6736(15)60806-6 2. Devereaux PJ, Sessler DI. Cardiac complications in patients undergoing major noncardiac surgery. N Engl J Med 2015;373(23):2258-2269. https://doi.org/10.1056/NEJMra1502824 3. Mauermann E, Puelacher C, Lurati Buse G. Myocardial injury after noncardiac surgery. Curr Opin Anaesthesiol 2016;29(3):403-412. https://doi.org/10.1097/ACO.0000000000000336 4. Botto F, Alonso-Coello P, Chan MTV, et al. Myocardial injury after noncardiac surgery. Anesthesiology 2014;120(3):564-578. https://doi.org/10.1097/ALN.0000000000000113 5. Biccard BM, Rodseth RN. The pathophysiology of peri-operative myocardial infarction. Anaesthesia 2010;65(7):733-741. https://doi.org/10.1111/j.1365-2044.2010.06338.x 6. Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA 2012;307(21):2295-2304. https://doi.org/10.1001/jama.2012.5502 7. Devereaux PJ, Biccard BM, Sigamani A, et al. Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA 2017;317(16):1642-1651. https://doi.org/10.1001/jama.2017.4360 8. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012;126(16):2020-2035. https://doi.org/10.1161/CIR.0b013e31826e1058

9. Apple FS, Collinson PO. Analytical characteristics of high-sensitivity cardiac troponin assays. Clin Chem 2012;58(1):54-61. https://doi.org/10.1373/clinchem.2011.165795 10. Le Manach Y, Perel A, Coriat P, et al. Early and delayed myocardial infarction after abdominal aortic surgery. Anesthesiology 2005;102(5):885-891. https://doi.org/10.1097/00000542-200505000-00004 11. Coetzee E, Biccard BM, Dyer RA, et al. Incidence of myocardial injury after non-cardiac surgery: Experience at Groote Schuur Hospital, Cape Town, South Africa. S Afr Med J 2018;108(5):408-412. https://doi.org/10.7196/SAMJ.2018.v108i5.12784 12. Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular Society guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery. Can J Cardiol 2017;33(1):17-32. https://doi.org/10.1016/j.cjca.2016.09.008 13. Biccard BM. Detection and management of perioperative myocardial ischemia. Curr Opin Anaesthesiol 2014;27(3):336-343. https://doi.org/10.1097/ACO.0000000000000071 14. Devereaux P. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery. Ann Intern Med 2011;154(8):523-528. https://doi.org/10.7326/0003-4819154-8-201104190-00003 15. Foucrier A, Rodseth R, Aissaoui M, et al. The long-term impact of early cardiovascular therapy intensification for postoperative troponin elevation after major vascular surgery. Anesth Analg 2014;119(5):1053-1063. https://doi.org/10.1213/ANE.0000000000000302 16. Torborg A, Ryan L, Kantor G, Biccard BM. The pharmacoeconomics of routine postoperative troponin surveillance to prevent and treat myocardial infarction after non-cardiac surgery. S Afr Med J 2014;104(9):619-623. https://doi.org/10.7196/SAMJ.7654 17. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100(10):1043-1049. https://doi.org/10.1161/01.CIR.100.10.1043 18. Biccard B. Peri-operative myocardial infarction. S Afr J Anaesth Analg 2010;16(1):44-46. https://doi. org/10.1080/22201173.2010.10872633

Accepted 3 April 2018.

June 2018, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

CASE REPORT

Prolonged paralysis in a child with organophosphate pesticide poisoning K Balme,1 MB ChB, MSc (Paed); M McCulloch,2 MB BCh, FCPaed (SA); C Stephen,1 MB ChB, DCH (SA) 1 2

Poisons Information Centre, Red Cross War Memorial Children’s Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Paediatric Intensive Care Unit, Red Cross War Memorial Children’s Hospital and Faculty of Health Sciences, University of Cape Town, South Africa

Corresponding author: K Balme (kate.balme@uct.ac.za)

A 17-month-old boy presented to a local community health centre in Cape Town, South Africa, with severe organophosphate pesticide poisoning (OPP), necessitating the use of intravenous atropine to control cholinergic symptoms, as well as emergency intubation for ongoing respiratory distress. He required prolonged ventilatory support in the intensive care unit at his referral hospital and had subsequent delayed neurological recovery, spending 8 days in hospital.We present this case to emphasise the importance of adequate atropinisation in the management of severe OPP and to highlight the dangers of inappropriate use of suxamethonium for intubation in patients with OPP. S Afr Med J 2018;108(6):468-470. DOI:10.7196/SAMJ.2018.v108i6.12994

Organophosphates are registered for use as pesticides in the agricultural sector in South Africa (SA). Unfortunately, many products are sold illegally for use as domestic rodenticides, where young children may be at risk of accidental exposure.[1] In SA, data on organophosphate pesticide poisoning (OPP) in children are scarce.[2-5] A review of cases (2003 - 2008) seen at Red Cross War Memorial Children’s Hospital, Cape Town, SA, showed that of 311 pesticide incidents, 203 were caused by cholinergic pesticides (organophosphates and carbamates), leading to a median hospital stay of 3 days for symptomatic patients (n=195/203).[2] Of these cholinergic incidents, 120 (59%) patients required admission to a high-care or intensive care unit (ICU); 5 of them died. The severity of presentation of this cohort shows that more than half of paediatric patients may require respiratory support, including assisted ventilation, in addition to the administration of atropine for control of muscarinic symptoms. Adequate knowledge of appropriate ventilatory resuscitation and early medical management for patients with OPP is essential for medical practitioners providing emergency care. We describe a case of severe OPP with prolonged apnoea and paralysis, most likely due to suboptimal atropinisation and the use of suxamethonium for airway intubation.

Case report

A 17-month-old well-grown boy was found acutely ill at home. He was vomiting, sweating, drowsy and breathing with difficulty. In the morning, his mother had put out rat poison mixed with rice and left the boy in the care of his 12-year-old sibling. The child was rushed to the local community health centre. On arrival, he had a respiratory rate (RR) of 30 breaths per minute, oxygen saturation levels of 100%, heart rate (HR) of 137 bpm, and was drowsy with pinpoint pupils and bronchorrhoea. A diagnosis of presumed OPP was made. He was given an intravenous (IV) atropine test dose of 0.01 mg/kg. At 5 - 10-minute intervals further bolus doses of 0.2 mg, 0.2 mg, 0.2 mg and 0.3 mg were administered intravenously. The child showed some response to atropine with tachycardia and clearing of secretions, but still had pinpoint pupils. While awaiting the ambulance for transfer to the referral hospital, his oxygen saturation decreased to 85% and the decision was taken to

intubate and ventilate him. Rapid sequence induction was performed using IV midazolam 0.2 mg (0.02 mg/kg) and suxamethonium 20 mg (1.7 mg/kg); he improved with manual ventilation with a self-inflating bag and 40% oxygen. The patient was tranferred by ambulance on a transport ventilator and with an atropine infusion (0.017 mg/kg/h). He remained sweaty, had pinpoint pupils and was noted to have sudden reductions in HR – from 186 to 95 bpm. Although he had bilateral crepitations on chest auscultation, he maintained oxygen saturation levels of 98% throughout his transfer. No further atropine bolus doses were given en route to the referral hospital. On arrival at the receiving hospital, 2 hours after initiating medical resuscitation, he was assessed as being severely ill, with an HR of 97 bpm, blood pressure of 153/70 mmHg, pinpoint pupils, some oral secretions, severe bilateral crepitations and an oxygen saturation level of 62%, despite an ongoing atropine infusion. Arterial blood gas showed: pH 6.9, pCO2 11.1 kPa, pO2 8.0 kPa, bicarbonate 12.6 mmol/L and base excess 13.9 mmol/L. His oxygen saturation improved to 100% after manual ventilation with a self-inflating bag and 40% oxygen. He was given IV Ringer’s lactate solution 120 mL and further IV atropine bolus doses of 0.2 mg and 0.4 mg. The clinical notes indicated an inadequate response to atropine, as his pupils remained pinpoint, but did not report on the clearing of secretions in the lungs. Additional medical treatment included IV ceftriaxone 1.2 g and acyclovir 240 mg for management of possible sepsis. The patient was taken to the ICU for a continued atropine infusion of 0.017 mg/kg/h and intermittent positive pressure ventilation (IPPV). On arrival in the ICU, he had crepitations in the left lung, but good air entry bilaterally. His body was washed and gastric lavage was performed. Despite receiving no ongoing sedation, the child was noted to be completely paralysed with gasping respirations on the ventilator >20 hours after receiving medical attention. He had good air entry bilaterally, his pupils remained pinpoint, with no reaction to light, and he had no spontaneous movements. His atropine infusion was increased to 0.02 mg/kg/h. Later that day, he started making spontaneous movements with flexion of the upper extremities and

June 2018, Print edition

IN PRACTICE

withdrawal to painful stimuli, but there was minimal movement of the lower limbs and no spontaneous eye opening. At this point, his atropine infusion was decreased to 0.004 mg/kg/h. Overnight, he was given diazepam and clonidine for marked restlessness and the following morning his atropine infusion was again increased to 0.017 mg/kg/h. Almost 3 days after presenting to hospital, the patient became more responsive, his pupils were 3 - 4 mm and sluggishly reactive, and he was therefore electively extubated. He subsequently had mild respiratory distress with a RR of 55 breaths per minute, subcostal recessions, alar flaring and stridor, but good air entry bilaterally. The patient was given dexamethasone, nebulised with adrenaline, placed on continuous positive airway pressure (CPAP) for 1 day, with ongoing clonidine and diazepam for sedation, and atropine was weaned to 0.004 mg/kg/h. The following day his level of consciousness was assessed as 10/15 on the Glascow Coma Scale (GCS), his pupils were 4 - 5 mm and reactive, and he had good air entry bilaterally. His atropine infusion was discontinued and he was transferred to the general medical ward on nasal-prong oxygen. On reception in the ward, he was restless and drowsy, with tachypnoea, bilateral crepitations and an HR of 90 bpm. No further doses of atropine were administered. His sedation was stopped and after 2 days on nasal-prong oxygen he could breathe adequately in room air. The suspicion of OPP was confirmed by a pseudocholinesterase level of <1 000 U/L (laboratory reference range 4 620 - 11 500 U/L) on two occasions 48 hours apart. Although the rodenticide active ingredient was not identified by laboratory analysis, the severity of presentation, low pseudocholinesterase level and duration of symptoms suggest it was an organophosphate and not a carbamate pesticide; treatment would, however, have been identical for both. No electromyographic studies were performed. Serum salicylate levels were negative. His blood gas steadily improved and renal function was normal. His clotting parameters and liver enzymes were slightly deranged initially; neither required active management. The patient’s procalcitonin was 6.36 µg/L and a chest radiograph showed perihilar infiltrates more marked on the left. He developed a low-grade fever and Klebsiella pneumonia was cultured on a tracheal aspirate. He completed 7 days of IV cefotaxime and acyclovir. Of particular mention is the patient’s protracted neurological recovery. In the ICU, there had been concern of a hypoxic brain injury due to his longer than anticipated ventilatory requirements and reduced movements. A computed axial tomography (CAT) brain scan showed subtle effacement of the superior surface sulci and basal cisterns only, but no cerebral oedema and no intracranial pathology. No abnormalities were detected in his lumbar puncture aspirate. Once all sedation was discontinued in the general ward, only spontaneous eye opening and some purposeful movements were evident, as he remained hypotonic with marked head lag, a weak cry and unable to push up or sit unsupported. He progressed slowly over a few days and was able to walk, albeit with an unsteady gait, on discharge. He was not attended to by a physiotherapist during his hospital admission. There is no comment on his gag reflex, but continuous nasogastric feeds were started when he was in the ICU; these progressed to bolus feeds and finally to normal eating before discharge. His case was reported to the City of Cape Town Health Department. A social worker assessed the home circumstances and his parents were given home safety counselling before discharge of the patient. Subsequent telephonic contact with the family confirmed that the child was ‘doing well’, but no formal neurological follow-up examination has been undertaken.

Discussion

Organophosphates bind irreversibly to acetylcholinesterase and plasma cholinesterase, rendering them unable to cleave acetylcholine at pre- and postsynaptic junctions and at skeletal muscle and central nervous system receptors. This results in a clinical syndrome of cholinergic overstimulation. During the acute cholinergic crisis, respiratory embarrassment is due to bronchorrhoea, bronchospasm, respiratory muscle weakness and central nervous system depression with loss of central respiratory drive.[6,7] Any ongoing respiratory difficulty and neurological weakness may be due to delayed neurotoxic effects, such as intermediate syndrome,[6,8] or complications secondary to the acute crisis, e.g. hypoxic brain injury or aspiration.[8] Treatment of OPP requires particular attention to supportive care of the respiratory, neurological and cardiovascular systems. Antidotes may be used; atropine provides relief of muscarinic and central nervous system symptoms,[8] and the clinical efficacy of oximes is contested as current evidence is insufficient.[9] With appropriate treatment, clinical reversal of symptoms in the acute cholinergic phase should occur within hours, but the response to and duration of treatment are also dependent on the route of exposure, amount and type of organophosphate.[10] Although thorough topical decontamination is required, gut decontamination (activated charcoal and gastric lavage) should only be done if the patient presents within 1 - 2 hours of ingestion of a potentially life-threatening amount of organophosphate.[6,11] The case described had an atypical clinical course, as the child showed prolonged neuromuscular blockade and apnoea beyond what would be expected of the acute cholinergic crisis after decontamination and atropinisation. It is likely that a variety of mechanisms contributed to his slower than usual recovery. A possible cause for this patient’s prolonged morbidity is suboptimal treatment with atropine. There was a delay in optimising atropinisation; static rather than incremental bolus atropine doses were given and once an infusion was started, only two further bolus doses were administered despite ongoing muscarinic symptoms. In moderate-to-severe OPP, the current recommendation is to double the dose of atropine every 5 - 10 minutes until clinical improvement occurs, particularly the drying of respiratory secretions, reversal of bronchospasm and improvement in HR and blood pressure.[6,12] Pupils may take a little longer to dilate. Once stabilised, an atropine infusion is started, calculated at an hourly rate of 10 - 20% of the total amount required to stabilise the patient, and titrated according to clinical response. Any breakthrough of muscarinic symptoms requires bolus doses in addition to, or even with an increase in, the atropine infusion.[12] Regular review of patients is critical to assess response to atropine. It has been shown that rapid atropinisation results in reduced mortality, shorter time to atropinisation, less atropine toxicity and less intermediate syndrome.[8,13] In severely poisoned patients, large quantities of atropine may be required with the potential to deplete the available hospital stock. Fortunately, atropine is inexpensive and has an 18-month expiry period. This more aggressive approach to atropinisation would possibly have contributed to a speedier recovery and even obviated the need for emergency intubation and ventilation in this patient. Furthermore, the timeous use of oximes may have aided in reversing any nicotinic effects such as respiratory muscle weakness, but because of the ongoing controversy surrounding their role in acute OPP[8,9] and their expense, they are rarely available or used in our setting. Prolonged paralysis can be associated with the use of suxamethonium, a depolarising muscle relaxant, which is commonly used for patient intubation owing to its short duration of action.

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IN PRACTICE

Both suxamethonium and the non-depolarising muscle relaxant mivacurium are metabolised by plasma cholinesterases; [7,14] therefore, their metabolism is reduced in the presence of OPP, resulting in an exaggerated iatrogenic paralysis. This phenomenon has been reported in adults[15,16] and children[17-19] with OPP and suxamethonium use, and may have been a contributing factor to this child’s prolonged apnoea. Where muscle relaxants are required for airway intubation in patients with OPP, depolarising agents not metabolised by plasma cholinesterases are preferable. Other causes of reduced cholinesterase activity, which can contribute to increased OPP severity but were not present in this patient, are malnutrition, liver and renal disease, malignancy, burns, heart disease, oral contraceptive use, pregnancy, hypothyroidism, use of cholinesterase inhibitors (e.g. pyridostigmine) and plasmapheresis.[7,14] Our patient’s clinical course was not typical of an intermediate syndrome sometimes seen in OPP, as his respiratory function did not regress after initial recovery, he had generalised muscle weakness rather than predominantly proximal weakness, and he did not develop any cranial nerve palsies. It is however possible that any recovery period between the acute cholinergic crisis and the development of intermediate syndrome was masked by the prolonged suxamethonium-induced paralysis. Intermediate syndrome usually presents 1 - 4 days after apparent recovery from severe, acute OPP. Patients develop muscle weakness, especially of the muscles of respiration (including neck flexors and bulbar muscles) and proximal muscles, as well as cranial nerve palsies. It is thought to be owing to neuromuscular junction dysfunction and perhaps inadequate oxime therapy. Patients present with worsening respiratory function, but recover fully with ventilatory support.[6,7] A central cause for our patient’s respiratory depression may have been due to hypoxic brain injury. Although the CAT scan did not completely exclude this possibility, it is less likely, as at last contact the child had fully recovered with no crude cognitive impairment. Other options for his unusual clinical course include that he was homozygous for atypical plasma cholinesterase and therefore presented with a more severe clinical picture,[7,14] or that the unidentified organophosphate agent was highly lipophilic, resulting in ongoing toxicity.

Conclusion

Optimising resuscitation efforts is vital in ensuring improved outcomes for patients with OPP. Early aggressive atropinisation with incremental atropine bolus doses followed by infusion improves outcomes and may even reduce the need for intubation and ventilation in patients with severe OPP. Where emergency airway protection is required, the weakness caused by OPP may obviate the need for any muscle relaxant. However, if a muscle relaxant is clinically needed, suxamethonium and mivacurium should be avoided and alternative agents be made available as emergency stock for such patients. Alternative muscle relaxants, as determined by local availability and cost, include rocuronium (rapid speed of onset), cisatracurium (non-organdependent elimination) and vecuronium.

Teaching points

• In patients with severe OPP, rapid atropinisation with initial doubling of bolus doses, followed by an atropine infusion, improves outcomes. Regular assessment of treatment response is required. • Acute respiratory failure in OPP is due to bronchorrhoea, bronchospasm, respiratory muscle weakness and central nervous system depression. • Suxamethonium and mivacurium for intubation should not be used in patients with OPP, and alternative muscle relaxants should be considered. Where suxamethonium has been used for airway management, prolonged paralysis must be anticipated. Acknowledgements. Consent to write this case report was obtained by KB by telephonic conversation with the patient’s mother. Author contributions. KB and CS wrote the initial manuscript, and MM made expert contributions to the discussion and clinical teaching points. Funding. None. Conflicts of interest. None. 1. London L. Childhood pesticide poisoning – a clarion call for action on children’s vulnerability. S Afr Med J 2005;95(9):673-674. 2. Balme KH, Roberts JC, Glasstone M, et al. Pesticide poisonings at a tertiary children’s hospital in South Africa: An increasing problem. Clin Toxicol (Phila) 2010;48(9):928-934. https://doi.org/10.3109/155 63650.2010.534482 3. Dippenaar R, Diedericks R. Paediatric organophosphate poisoning – a rural hospital experience. S Afr Med J 2005;95(9):678-681. 4. Veale DJH, Wium CA, Muller GJ. Toxicovigilance I: A survey of acute poisonings in South Africa based on Tygerberg Poison Information Centre data. S Afr Med J 2013;103(5):293-297. https://doi. org/10.7196%2Fsamj.6647 5. Marks CJ, van Hoving DJ. A 3-year survey of acute poisoning exposures in infants reported in telephone calls made to the Tygerberg Poison Information Centre, South Africa. S Afr J Child Health 2016;10(1):43-46. https://doi.org/10.7196%2Fsajch.2016.v10i1.1045 6. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet 2008;371(9612):597-607. https://doi.org/10.1016%2Fs0140-6736%2807%2961202-1 7. Karalliedde L. Organophosphorus poisoning and anaesthesia. Anaesthesia 1999;54(11):1073-1088. https://doi.org/10.1046%2Fj.1365-2044.1999.01061.x 8. Eddleston M, Chowdhury FR. Pharmacological treatment of organophosphorus insecticide poisoning: The old and the (possible) new. Br J Clin Pharmacol 2015;81(3):462-470. https://doi.org/ 10.1111%2Fbcp.12784 9. Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev 2011;(2):CD005085. https://doi.org/10.1002/14651858. CD005085.pub2 10. Peter JV, Sudarsan TI, Moran JL. Clinical features of organophosphate poisoning: A review of different classification systems and approaches. Indian J Crit Care Med 2014;18(11):735-745. https://doi.org/ 10.4103%2F0972-5229.144017 11. Benson BE, Hoppu K, Troutman WG, et al. Position paper update: Gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila) 2013;51(3):140-146. https://doi.org/10.3109% 2F15563650.2013.770154 12. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self-poisoning with organophosphorus or carbamate pesticide – a treatment protocol for junior doctors. Crit Care 2004;8(6):R391-R397. https://doi.org/10.1186/cc2953 13. Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol 2012;8(2):108-117. https://doi.org/10.1007%2Fs13181-012-0214-6 14. Davis L, Britten JJ, Morgan M. Cholinesterase. Its significance in anaesthetic practice. Anaesthesia 1997;52(3):244-260. https://doi.org/10.1111%2Fj.1365-2044.1997.084-az0080.x 15. Jaksa RJ, Palahniuk RJ. Attempted organophosphate suicide: A unique cause of prolonged paralysis during electroconvulsive therapy. Anesth Analg 1995;80(4):832-833. https://doi.org/10.1097% 2F00000539-199504000-00032 16. Guillermo FP, Pretel CMM, Royo FT, et al. Prolonged suxamethonium-induced neuromuscular blockade associated with organophosphate poisoning. Br J Anaesth 1988;61(2):233-236. https://doi. org/10.1093%2Fbja%2F61.2.233 17. Selden BS, Curry SC. Prolonged succinylcholine-induced paralysis in organophosphate insecticide poisoning. Ann Emerg Med 1987;16(2):215-217. https://doi.org/10.1016%2Fs0196-0644%2887%2980018-5 18. Weeks DB, Ford D. Prolonged suxamethonium-induced neuromuscular block associated with organophosphate poisoning. Br J Anaesth 1989;62(2):237. https://doi.org/10.1093%2Fbja%2F62.2.237-a 19. Sener EB, Ustun E, Kocamanoglu S, Tur A. Prolonged apnea following succinylcholine administration in undiagnosed acute organophosphate poisoning. Acta Anaesthesiol Scand 2002;46(8):1046-1048. https://doi.org/10.1034%2Fj.1399-6576.2002.460821.x

Accepted 8 January 2018.

June 2018, Print edition

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

IN PRACTICE

MEDICINE AND THE LAW

Posthumous conception: Recent legal developments in South Africa D W Thaldar, PhD School of Law, Howard College, University of KwaZulu-Natal, Durban, South Africa Corresponding author: D W Thaldar (ThaldarD@ukzn.ac.za)

Posthumous conception – when a deceased person’s gametes are used for procreative purposes – made its debut in South African (SA) courts in NC v Aevitas Fertility Clinic. A widow was granted the right to use her deceased husband’s sperm for procreation. Against the background of legislative ambiguity, this case creates legal certainty that posthumous conception is legally permissible in SA – at least where deceased persons provided written consent that their gametes can be used by their surviving spouses or life partners after their death, and where there is no controversy about such consent. S Afr Med J 2018;108(6):471-473. DOI:10.7196/SAMJ.2018.v108i6.13182

It has happened since time immemorial that men conceive children, but then die before the birth of their children. However, the possibility of conceiving children after death is relatively new. Posthumous conception is made possible by modern reproductive technology – in particular the cryopreservation of sperm and eggs. While the legislation of some comparative jurisdictions specifically deals with posthumous conception, this is not the case in South Africa (SA). The legislation in SA is not only ambiguous on whether posthumous conception is legal, but gives rise to uncertainty regarding the nature of the legal relationship between the surviving spouse or life partner and the fertility clinic where the gametes are stored. This medicolegal conundrum was solved in the recent case of NC v Aevitas Fertility Clinic (NC).[1]

Legal issues

Background[2]

The parties to the lawsuit

NC centres on the reproductive intentions and tragedies of a couple who married in 2008 and planned to have children. However, in 2010 the wife was diagnosed with Gitelman syndrome, making a pregnancy life-threatening for her. They decided to use a surrogate mother, but before these plans came to fruition the husband fell ill with cancer. Anticipating chemotherapy in 2013, he stored his sperm with Aevitas Fertility Clinic (Aevitas). They provided him with their standard sperm storage form, which offered four options for the stored sperm in the event of his death: (i) thawing and discarding it; (ii) assigning it to the ‘care’ of his wife or partner; (iii) using it for scientific research; or (iv) donating it to another couple. He selected that the stored sperm should be assigned to his wife’s care. He completed the form and provided a sample of his sperm to Aevitas. Although the husband’s prognosis was good, the couple discussed the possibility of his death and its impact on their reproductive plans. They decided that should he die, his wife would have a child using his stored sperm. Despite the chemotherapy, the husband’s health deteriorated, and it became evident that he would not survive the cancer. In this context, the couple again discussed the possibility of the wife having a child after the husband’s death using his stored sperm and again agreed that she should proceed. The husband died in January 2017 and his widow set in motion their plans to have a child using his sperm, which Aevitas supported.

The main legal question was whether posthumous conception is at all legal in SA. If legal in principle, the next question is whether the law should require certain conditions to be met, and whether such conditions were in fact met in the specific case. A potentially complicating factor was the nature of the legal relationship between Aevitas and the widow concerning the deceased husband’s sperm. Was Aevitas legally obligated to provide her with access to the sperm? The widow’s legal representatives advised her to approach the court to obtain legal certainty.[2] She applied to the Western Cape High Court for a declaratory order – a legally binding form of preventive adjudication – that she had the legal right to use her deceased husband’s sperm.[3]

The widow, as applicant, cited Aevitas as respondent. Apart from being in possession of the sperm, Aevitas was also its legal owner. However, at common law, the human body, or parts of it, are not susceptible to ownership.[4,5] Breaking with this principle, the Regulations Relating to Artificial Fertilisation of Persons[6] (the Regulations) made in terms of the National Health Act[7] (the Act) provide that human gametes and embryos can be legally owned. Regulation 18(1)(a) provides that sperm not intended for the artificial fertilisation of the donor’s spouse is owned by the ‘authorised institution’. As the applicant was diagnosed with Gitelman syndrome, the couple intended to use a surrogate to have a child using the husband’s stored sperm. Therefore, Aevitas (the ‘authorised institution’) legally owned the sperm. Ownership is the most comprehensive right that a person has in relation to an object, which includes the right to use, alienate and even destroy the object. An owner’s rights in this respect can be limited through various legal means. However, a fertility clinic’s ownership of sperm is created and mandated through statute, raising the question of whether this ownership can be transferred, wholly or partially, through a private transaction such as a contract between the fertility clinic and a man who wants to store his sperm with them. If the answer is in the affirmative, was there a contract that transferred any constituent rights of Aevitas’s ownership of the sperm? Although

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IN PRACTICE

Aevitas supported the applicant’s plans of posthumous conception, this is not determinative of the parties’ legal rights. A fertility clinic owning sperm may feel ethically compelled to provide a person in the applicant’s position with access to the sperm, but without a legally binding obligation there is no guarantee that a change in circumstances may not lead to a change in its position. Should persons in the applicant’s position be content to have access to the stored sperm of their deceased husbands or life partners at the pleasure of a fertility clinic? The applicant decided to obtain certainty regarding her rights concerning her deceased husband’s sperm, meaning that her rights would be defined vis-à-vis Aevitas’s rights. Aevitas was cited as respondent – not as an antagonist in the lawsuit, but as a de facto possessor and statutory owner of the deceased husband’s sperm, within the context of legal uncertainty brought about by the Regulations.

Is posthumous conception legal?

The Act provides: ‘56. (1) A person may use tissue or gametes removed or blood or a blood product withdrawn from a living person only for such medical or dental purposes as may be prescribed.’ The Regulations mirror the Act: ‘These regulations only apply to the withdrawal of gametes from and for use in living persons.’ The ambiguity in these provisions is evident: should the sperm donor be living only at the stage of donating the sperm (so-called ‘withdrawal’), or at the stage of using the sperm for in vitro fertilisation, or at the stage of embryo transfer? While posthumous retrieval of sperm is clearly banned, is posthumous use of sperm also banned? The applicant argued that the legislative provisions only require that a sperm donor must be living at the stage when gametes are withdrawn. Had the legislature intended to ban posthumous use, the formulation of the statutory provisions would have been different. For instance, the provisions might have been ‘withdrawn from a person who is still alive when the gametes are to be used’. The applicant therefore argued that posthumous conception is legal in SA law.

What are the conditions for posthumous conception?

The applicant argued that SA statutory law does not specifically deal with posthumous conception. Therefore, general legal principles must be applied. Referring to established precedent in medical law,[8] the applicant submitted that the principle of autonomy should guide the court. Autonomy is a principle of SA medical law and the SA Constitution.[9] Applied to posthumous conception, autonomy requires that deceased persons must have consented to their gametes being used posthumously. Where such consent by the deceased is evident, posthumous conception should be allowed. The impact of the principle of autonomy is stronger than allowing posthumous conception: autonomy translates into a legal right of the surviving spouse or life partner to use the deceased spouse or life partner’s gametes (subject to their consent). The literature suggests that posthumous conception should be regulated as surrogacy applications.[10] However, implicit in the applicant’s argument based on autonomy, is that to require further conditions for allowing posthumous conception, e.g. requiring judicial oversight informed by psychological reports as for surrogacy applications, would restrict the surviving spouse or life partner’s autonomy and would be prima facie unconstitutional. The applicant’s argument was simple: if posthumous conception is willed by the surviving spouse or life partner, consent by the deceased person is a necessary and sufficient requirement for posthumous conception. In this case, there was clearly consent: Aevitas’s sperm storage agreement that was filled out and signed by the applicant’s deceased husband provided documentary proof.

Aevitas’s affidavit

Aevitas filed a short affidavit in support of the applicant.[11] The gist of the affidavit was that Aevitas respects its patients’ autonomy, in particular the autonomy of the men who store their sperm with Aevitas to determine the fate of their sperm after their deaths. Interestingly, given this ethical position, Aevitas states that it had in fact in 2015 performed posthumous conception for another patient (and deceased patient). Although this fact shows Aevitas’s ethical consistency, it had to be handled carefully by the applicant, for at least two reasons. First, it may have been damaging to her case if she was perceived to rely on the fact of the previous posthumous conception as implicitly having any normative effect on the lawsuit. The fact that something has been done does not make it legal to do it. The applicant avoided any insinuation of posthumous conception being a fait accompli in our law. Second, it could have damaged the applicant’s case if she was perceived to rely on Aevitas’s ethical judgement to influence the court’s legal judgment. Although Aevitas’s 2015 posthumous conception was recorded in the papers, the applicant did not rely on it in argument, and the court did not bring up the issue.

The judgment and its meaning

During oral argument in open court, the court observed that the applicant’s deceased husband clearly consented to his sperm being used posthumously and granted the relief sought, declaring that the applicant had the right to use her deceased husband’s sperm for procreation.[12] NC therefore created legal certainty regarding the basic aspects of posthumous conception. It is now established that the relevant legislation allows posthumous conception, and that the surviving spouse or life partner has a legal right to use the stored gametes for conception. This right may be subject to the consent by the deceased person, but this is not a valid inference from the judgment. What can be inferred from the judgment is that consent by the deceased person is sufficient as condition for allowing posthumous conception, and that the evidence before the court in NC was sufficient to prove such consent. However, uncertainty still remains whether consent is a necessary condition. Regarding a fertility clinic’s statutory ownership of sperm, the right of the surviving spouse or life partner to use the deceased spouse or life partner’s stored gametes for posthumous conception renders a fertility clinic’s statutory ownership, where applicable, mere nominal ownership.

Conclusion: Implications for the practice of reproductive medicine

In cases that are analogous to the NC case, in other words where deceased persons provided written consent that their gametes can be used by their surviving spouse or life partner after their death, and where there is no controversy about such consent, fertility clinics may legally assist the surviving spouse or life partner with posthumous conception. In such cases, it will not be necessary to approach the court – the legal position has now been sufficiently established. However, in cases that differ from the facts of NC, e.g. where there was no written consent or no evidence of consent, it would be advisable to approach the court before proceeding with posthumous conception, as this requires further development of the law. A practical step for fertility clinics is to include the same options in their gamete storage agreements, in the event of death, as did Aevitas. Acknowledgements. None. Author contributions. Sole author. Funding. None. Conflicts of interest. None. The author was legal counsel in the case under discussion.

June 2018, Print edition

IN PRACTICE

1. NC v. Drs Aevitas Inc t/a Aevitas Fertility Clinic (23236/2017) [2018] ZAWCHC (23 January 2018). 2. NC v. Drs Aevitas Inc t/a Aevitas Fertility Clinic (23236/2017) [2018] ZAWCHC (23 January 2018). Applicant’s founding affidavit. 3. NC v. Drs Aevitas Inc t/a Aevitas Fertility Clinic (23236/2017) [2018] ZAWCHC (23 January 2018). Notice of motion. 4. Grotius. Inleidinge tot de Hollandsche Rechts-Geleerdheid. 2.1.3. 5. Digesta 9.2.13 pr. 6. Regulations Relating to Artificial Fertilisation of Persons GN R1165 GG 40312, 30 September 2016. 7. South Africa. National Health Act 61 of 2003. 8. Castell v. De Greef 1994 (4) SA 408 (C) 421C–D. 9. British American Tobacco South Africa (Pty) Ltd v. Minister of Health [2012] ZASCA 107, [2012] 3 All SA 593 (SCA) [13].

10. Kruuse H. From the Grave to the Cradle: The Possibility of Post-Mortem Gamete Retrieval and Reproduction in South Africa?. S Afr J Hum Rights 2012;28(3):532-552. https://doi.org/10.1080/199 62126.2012.11865059. 11. NC v. Drs Aevitas Inc t/a Aevitas Fertility Clinic (23236/2017) [2018] ZAWCHC (23 January 2018). Respondent’s affidavit. 12. NC v. Drs Aevitas Inc t/a Aevitas Fertility Clinic (23236/2017) [2018] ZAWCHC (23 January 2018). Court order.

Accepted 22 March 2018.

SAMF

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RESEARCH

Staphylococcus aureus and Escherichia coli levels on the hands of theatre staff in three hospitals in Johannesburg, South Africa, before and after handwashing D O Matuka,1,2 MSc Med; B Binta,1 MSc Med; H A Carman,1 MB BCh, FCDerm (SA); T Singh,1,2 PhD Immunology and Microbiology, National Institute for Occupational Health, National Health Laboratory Service, Johannesburg, South Africa 2 Department of Clinical Microbiology and Infectious Disease, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: D O Matuka (onnicah.matuka@nioh.nhls.ac.za) Background. Hand hygiene is a fundamental component of infection control. Hand contamination with Staphylococcus aureus and Escherichia coli may contribute to infections. Objectives. To assess the effectiveness of different handwashing methods in reducing the levels of bacterial flora, especially S. aureus and E. coli, on the hands of theatre staff. Methods. A cross-sectional study was conducted among 70 staff in surgical theatres of three randomly chosen hospitals in Johannesburg, South Africa. Samples were taken before and after handwashing using the modified glove juice method and the fingernail press technique. Standard microbiological techniques were used to identify bacteria. Descriptive statistics and non-parametric analysis were used to compare the differences between hospitals and to determine the effects of handwashing on microbial flora and skin irritation. Results. S. aureus organisms were isolated in the prewash samples of 29 (41%) and in the postwash samples of 20 (29%) workers. Of the 29 with positive prewash cultures, 19 (65.5%) showed decreased postwash counts, while 10 (34.5%) showed no change or increased counts. Four workers with a negative prewash count had a positive postwash count. No statistical differences were found between postwash counts categorised by the type of cleansing formula used and the washing technique. E. coli organisms were identified in the prewash count of the fingertip press of one worker. Conclusions. Almost half of the theatre staff carried S. aureus isolates on their hands prior to handwashing and approximately one-third after handwashing. Closer monitoring of handwashing techniques should be introduced. S Afr Med J 2018;108(6):474-476. DOI:10.7196/SAMJ.2018.v108i6.12485

Hospital theatres are considered to be one of the most complex and hazardous environments that pose a high risk of infection to medical staff (and patients) owing to long exposures to biological agents.[1] Hospital-acquired infections (HAIs) are a serious health issue and an economic burden worldwide, as they present a risk to healthcare workers (HCWs), patients and the community. The main sources of HAIs are contaminated air, contact surfaces and hands of medical staff. HCWs can also acquire these pathogens during direct contact with patients or contaminated environmental surfaces.[2,3] In spite of hand hygiene protocols and policies in healthcare facilities, poor handwashing compliance continues to exist among medical professionals.[4] Skin flora contains resident bacteria that inhabit the deeper skin layers and are difficult to eradicate (e.g. Micrococcus spp.), as well as transient flora that colonise the superficial layer of the skin and are responsible for nosocomial infections, although they are easily removed by handwashing.[5] Numerous reports reflect the necessity for handwashing using various techniques to prevent the spread of pathogenic organisms to patients.[6] Staphylococcus aureus organisms cultured from healthy hands of medical professionals (10%) and from damaged hands (16.7%) were also noted.[3] Studies reported high levels of S.aureus on the hands of female and male HCWs, ranging from 5% to 20%.[7-9] S. aureus is a dangerous pathogen that can cause serious and life-threatening diseases, such as severe septicaemia, pneumonia,

meningitis, septic arthritis, folliculitis, impetigo, osteomyelitis and toxic shock syndrome.[4,10] Furthermore, methicillin-resistant S. aureus has become common in hospitals and communities.[11] From January to July 2012, there were 1 148 South African (SA) cases of confirmed S. aureus bacteraemia.[12] Of these, 619 (54%) were reported in Gauteng, and 289 (44%) were resistant to oxacillin/ methicillin, with compliance of only 40% in intensive care units. The objective of this study was to assess the efficacy of different handwashing techniques in reducing the levels of bacterial flora, especially S. aureus and Escherichia coli, on the hands of theatre workers.

Methods

A cross-sectional study was conducted from October to December 2013 and in July 2014 among 70 surgical theatres staff of three hospitals in Johannesburg, SA. These hospitals were selected randomly by their proximity to the testing laboratory and the willingness of management to participate in the study. To test for bacteria on the skin at the beginning of the work shift, the dominant hand of each participant was inserted into and massaged for 1 minute in a sterile polyethylene bag containing 75 mL of tryptic soy broth (TSB) with neutralisers (0.1% polysorbate 80, 0.03% lecithin and sodium thiosulphate). The procedure was performed before handwashing and repeated immediately after washing and before drying of the hands. The samples were transported on the same day in a cooler

June 2018, Print edition

RESEARCH

bag with ice to the National Institute for Occupational Health, Johannesburg, for microbiological analysis. Standard microbiological techniques were employed for bacterial quantification and identification of S. aureus and E. coli. After vigorous mixing, TSB was diluted (1:10 and 1:100) and 0.1 mL was plated onto a tryptic soy agar (TSA) medium, 5% blood agar with gentamicin and mannitol salt agar (Diagnostic Media Products, SA) for isolation of S. aureus, using the aseptic spreading method. The inoculated culture plates were incubated aerobically at 37°C. Total bacterial count enumeration was performed after 72 hours and reported as colony-forming units (CFU) per mL. The 5 fingertips of the less dominant hand of participants were pressed with equal pressure onto half plates containing 5% blood agar and MacConkey agar for 5 seconds to isolate Gram-negative bacteria (no bacterial counts were done). Isolated bacterial colonies from the agar plates were identified by conventional techniques (morphology, haemolysis, lactose fermentation, Gram-staining and microscopy) using a study guide on diagnostic bacteriology.[13] Descriptive statistics and non-parametric analysis using Stata 11 (StataCorp., USA) were employed to compare the differences between handwashing techniques and between hospitals. The level of significance was p<0.05.

Results

Seventy individuals (40 females, 30 males) took part in the study, of whom 32 were nurses, 31 medical doctors and 7 other participants. A total of 280 samples (140 hands and 140 fingerprints) for both pre- and postwashing were collected. Of the 70 participants, 8 had an increase, 58 had a decrease and 4 had no change in total bacterial counts after handwashing. There were no statistically significant differences between the prewash and postwash arithmetic mean counts of S. aureus (Table 1) or by hospital (p≤0.10). S. aureus organisms were isolated in the prewash samples of 29/70 (41%) workers and in 20/70 (29%) postwash samples. Of the 29 who had positive cultures of S. aureus before washing, 19 (65.5%) showed a decrease in the postwash count and 10 (34.5%) an increase or no change in bacterial load of the postwash count. The proportion of workers with S. aureus in the prewash samples differed between hospitals, even though the difference was not statistically significant (exact test, p=0.08). S. aureus was identified in 12/30 (40%) workers in hospital A, 5/20 (25%) in hospital B and 12/20 (60%) in hospital C. Four workers with a negative prewash count had a positive postwash count. No statistical differences were found between postwash counts categorised by the type of cleansing formula used and between different techniques (scrub with a brush, scrub without a brush and ordinary handwashing). Chlorhexidine gluconate (Hibiscrub) washing solution was used by 54/69 (78%) participants, povidone iodine (Betadine) by 13 (19%) and 4% chlorhexidine gluconate (MediScrub) by 2 (3%). One person (2%) of the total number of participants (N=70) did not report the use of any soap; S. aureus was not isolated from this worker. No difference was seen in workers with and without S. aureus for postwash samples based on the type of handwashing agent used (exact test, p=0.153). Table 1. Mean Staphylococcus aureus CFUs before and after handwashing Arithmetic mean, CFU/mL Mean log10, CFU/mL*

Prewash (n=29) 1.9 × 103 3.28

Postwash (n=20) 0.5 × 103 2.70

CFU = colony-forming units. *Zero count values are excluded from the mean log10 calculations.

E. coli organisms were isolated from the prewashed fingertip sample of 1 HCW. Staphylococcus spp. were isolated from fingertips, but could not be identified further for S. aureus using half-plates (MacConkey/blood agar).

Discussion

This is the first SA report to quantify the microbiological burden on the hands of theatre workers and to identify S. aureus and E. coli. The overall minimal bacterial counts for prewashing ranged from 0 to 4.3 × 105 CFU/mL, whereas counts after handwashing ranged from 0 to 1.4 × 105 CFU/mL. The mean log10 CFU/mL of S. aureus was 3.28 and 2.70 pre- and postwashing, respectively. In contrast to our findings of 74% total bacterial reduction, in another study a decrease of 95 - 99% in bacterial load was demonstrated after performing hand hygiene.[14] The percentage of HCWs with S. aureus contamination on their hands is higher in our study than levels previously described.[3,7,15] However, Singh and Singh[14] isolated S. aureus in 70% of nurses, 60% of students and 40% of attendants. Persistent skin colonisation with S. aureus was reported,[8] and was associated with certain body sites and the environment. The different hospitals showed no statistical differences in the arithmetic mean counts between prewashing and postwashing counts. This may be attributed to the small sample sizes. The handwashing protocols approved by theatre management did not differ between hospitals. In 4 cases across the hospitals, the postwash count of S. aureus was elevated, although the prewash count was zero. Of the HCWs with S. aureus isolates on their hands, 10 had increased counts after handwashing. The elevation in bacterial counts could be owing to the hypothesis that transient microbes are easily removed from the hands by washes of ˂30 seconds, whereas resident bacteria embedded in deeper layers of the skin are not easily removed, regardless of the length of time spent handwashing.[16] The elevated postwash counts may have been due to cross-contamination with contaminated surfaces and/or equipment in theatres and between departments, as proven by researchers.[2-4] In 3 HCWs no bacteria were isolated from their hands for both pre- and postwashing, which could be due to handwashing prior to sampling, even though they had stated that they had not washed their hands – possibly for fear of being excluded. However, in 2 of the 3 workers, Staphylococcus spp. were isolated from their fingerprints before handwashing. This suggests that although their palms or hands were not colonised by bacteria, their fingernails were contaminated. Transient organisms such as S. aureus and Gram-negative bacteria are acquired by HCWs during contact with patients and contaminated surfaces and could lead to HAIs.[17] Our findings may be indicative of contamination of the soap dispenser lid, the hand lever or the soap residual at the tip of the container, which may have been contaminated by air particles. Studies showed that taps and door knobs are rarely cleaned and therefore contain the highest microbial load.[4] The presence of S. aureus on the hands of a large proportion of theatre staff, even after handwashing, should be reason for concern, as gloves are not puncture proof and there may be bacterial transmission to surgical sites from exposed skin. This is also supported by a study investigating handwashing practices of medical students, which showed an increase in bacterial load on the hands of those who washed with soap after toilet use; this increase was attributed to touching the toilet door knobs.[4] Workers carrying S. aureus organisms on their hands may harbour these on other body sites, notably in the nose. Persistence of the organisms found on cultures after handwashing may imply that they are not easily removed from the hands and may be resident.[4] Hand

June 2018, Print edition

RESEARCH

cleansing should be performed as per the ‘5 moments of hand hygiene’ recommended by the World Health Organization (WHO), equipment should be decontaminated after use, and environmental sites should be regularly and effectively cleaned.[18] Staphylococcus spp. were isolated from both prewash and postwash fingertip samples of the less dominant hand. Although not confirmed, it is possible that S. aureus was among the Staphylococcus spp. found on the fingertips. De Alwis et al.[4] found high bacterial loads on the dominant hand after toilet use. Two previous studies demonstrated the presence of S. aureus using the fingertip method.[19,20] The current study showed that a higher percentage (23%) of HCWs who scrubbed their hands with a brush had skin irritation, even though the percentage was not statistically significant. While it is generally accepted that nosocomial infections in patients may be acquired from HCWs, and the importance of hand hygiene is stressed throughout the literature, the former is not always the case. For instance, although a previous study demonstrated postsurgical wound infection with S. aureus in 24 of 214 patients, genetic typing showed that HCWs were not the source of infection.[21] E. coli were isolated from the fingerprints of only 1 HCW (1%); this finding is similar to that of Singh and Singh,[14] who also reported 1% in a study done in India. A major drawback of the current study is the small sample size. Furthermore, methicillin-resistant S. aureus was not identified and should be investigated in a larger population. The study warrants further research into the determinants of poor handwashing outcomes, such as duration of washing, amount of antimicrobial agent used and lather formation, sources of cross-contamination (e.g. taps and detergent containers) and behaviour practices.[21]

Conclusion

S. aureus contamination remains a challenge in healthcare facilities. It was found on the hands of almost half of theatre staff before handwashing for theatre and approximately one-third after handwashing. This may be regarded as medically significant. The type of handwashing technique was not shown to be a key determinant in reducing S. aureus counts; however, it may play a role in skin irritation. Handwashing has been reported as the most effective and inexpensive way to prevent transmission, and more advocacy is needed to ensure that HCWs adhere to strict handwashing and hand-care protocols in view of their fundamental role in infection control. In conclusion, our findings may be used to inform other hospitals that handwashing protocols should be reassessed at regular intervals and further analysed for adequacy. This may help to prevent potential S. aureus outbreaks in healthcare settings. Continuing education on behavioural changes to improve hygiene habits of all staff should be encouraged. Acknowledgements. The assistance provided by Dr A Mayekisa, O Kgasha, A Fourie and Z Kirsten for fieldwork is gratefully acknowledged. We thank the management of the three hospitals and the participants.

Author contributions. HAC initiated the project and contributed to the manuscript. TS contributed to the conceptualisation of the study and provided intellectual input. BB and DOM analysed samples, interpreted the microbiological information and contributed to the content and revision of the article. Funding. The study was conducted as part of a research project supported by the National Institute for Occupational Health/National Health Laboratory Service and funded by Galderma and Aspen through the Dermatology Society of South Africa awards. Conflicts of interest. None. 1. Laham NA. Prevalence of bacterial contamination in general operating theatres in selected hospitals in the Gaza Strip, Palestine. J Infect Publ Health 2012;5(1):43-51. https://doi.org/10.1016/j. jiph.2011.10.006 2. Bardaquim VA, Oliveira-de-Souza CW, de-Melo-Martins D, Soares CA, Paiva de Sousa C. Micobiological characterization of the surface contamination in surgical room areas in a hospital in Sao Paulo (Brazil). Infectio 2014;18(4):130-134. https://doi.org/10.1016/j.infect.2014.05.004 3. Li-sha S, Chun-juan X, Hong-bing J, Wei C, Xiao-feng Z, Xiu-hua L. Spread of Staphylococcus aureus between medical staff and high-frequency contact surfaces in a large metropolitan hospital. Int J Nurs Sci 2015;2(4):366-370. https://doi.org/10.1016/j.ijnss.2015.11.001 4. De Alwis WR, Pakirisamy P, San LW, Xiaofen EC. A study of hand contamination and handwashing practices among medical students. Int Scholar Res Net 2012:1-5. https://doi.org/10.5402/2012/251483 5. Otto M. Staphylococcus colonization of the skin and antimicrobial peptides. Expert Rev Dermatol 2010;5(2):183-195. 6. Centers for Disease Control and Prevention. Guideline for hand hygiene in health care settings: Recommendation of the Health Care Infection Control Practices Advisory Committee and the HICPAC/ SHEA/APIC/IDSA in Hand Hygiene Task Force. Morbid Mortal Wkly Rep 2002;51(RR16):1-45. 7. Cespedes C, Miller M, Quagliarello B, Vavagiakis P, Klein RS, Lowry FD. Differences between Staphyloccus aureus isolates from medical and non-medical hospital personnel. J Clin Microbiol 2002;40(7):2594-2597. https://doi.org/10.1128/JCM.40.7.2594-2597.2002 8. Dascher FD. How cost effective is the present use of antiseptics? J Hosp Infect 1988;11(Suppl A):227-235. 9. Tammelin A, Hambraeus A, Stahle E, Ransjo U. Nasal and hand carriage of Staphyloccus aureus in staff at a department for thoracic and cardiovascular surgery: Endogenous or exogenous source. Infect Control Hosp Epidemiol 2003;24(9):686-689. https://doi.org/10.1086/502277 10. Lowy FI. Staphyloccus aureus infections. N Engl J Med 1998;339(8):520-532. https://doi.org/10.1056/ NEJM199808203390806 11. Chambers HF. The changing epidemiology of Staphylococcus aureus. Emerg Infect Dis 2001;7(2):178182. https://doi.org/10.3201/eid0702.700178 12. National Institute for Communicable Diseases. Germs South Africa Annual Report. 2012. http://www. nicd.ac.za (accessed 4 May 2018). 13. Bartlett MA. Diagnostic Bacteriology: A Study Guide. Philadelphia, USA: FA Davis, 2000:53-61. 14. Singh S, Singh AK. Prevalence of bacteria contaminating the hands of healthcare workers during routine patient care: A hospital-based study. J Acad Clin Microbiol 2016;18(1):60-62. https://doi. org/10.4103/0972-1282.184764 15. Rocha LA, Ferreira de Almeida E, Borges L, Gontijo Filho PP. Changes in hands microbiota associated with skin damage because of hand hygiene procedures on the health care workers. Am J Infect Control 2009;37(2):155-159. https://doi.org/10.1006/j.ajic.2008.04.251 16. Jensen D, Macinga D, Shumaker D, Bellino R, Arogast J, Schaffner D. Quantifying the effects of water temperature, soap volume, lather time and antimicrobial soap as variables in the removal of Escherichia coli ATCC 11229 from hands. J Food Protect 2017;80(6):1022-1031. https://doi.org/10.4315/0362028X.JFP-16-370 17. Nicolay CR. Hand hygiene: An evidence-based review for surgeons. Int J Surg 2006;4(1):53-65. https:// doi.org/10.1016/j.jhin.2005.06.002 18. Curran ET. Outbreak column 14: Staphylococcus aureus – new outbreaks of old infections. J Infect Prevent 2014;15(4):148-153. https://doi.org/10.1177//1757177414536942 19. Creamer E, Dorrian S, Dolan A, et al. When are the hands of health care workers positive for methicillin-resistant Staphylococcus aureus? J Hosp Infect 2010;75(2):107-111. https://doi.org/10.1016/ j.jhin.2009.12.005 20. Pittet D, Dharan S, Touveneau S, Sauvan V, Perneger TV. Bacterial contamination of the hands of hospital staff during routine patient care. Arch Intern Med 1999;159(8):821-826. https://doi. org/10.1001/archinte.159.8.821 21. Ahmed AO, van Belkum A, Fahal AH, et al. Nasal carriage of Staphylococcus aureus and epidemiology of surgical site infections in a Sudanese university hospital. J Clin Microbiol 1998;36(12):3614-3618.

Accepted 21 December 2017.

June 2018, Print edition

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RESEARCH

Economic evaluation of safety-engineered devices and training in reducing needlestick injuries among healthcare workers in South Africa P de Jager,1,2,3 MB ChB, MMed (PHM), FCPHM (SA), MSc, DA (SA), DCH (SA); M Zungu,4,5 MB ChB, MMed (PHM), FCPHM (SA); R E Dyers,6,7 MB ChB, MMed (PHM), FCPHM (SA), MSc Department of Anaesthesia, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Department of Social Policy, London School of Economics and Political Science, London, UK 4 HIV/TB Unit, National Institute for Occupational Health, National Health Laboratory Services, Johannesburg, South Africa 5 School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa 6 Division of Health Systems and Public Health, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa 7 Western Cape Government: Health, South Africa 1 2

Corresponding author: Pieter de Jager (pieter.dejager@wits.ac.za) Background. Healthcare workers (HCWs) are at increased risk of contracting various communicable diseases. Needlestick injuries (NSIs) are a common mechanism of exposure. Training in basic universal precautions and utilisation of safety-engineered devices (SEDs) are interventions known to reduce the risk of NSI. Objectives. To assess the cost-utility of SEDs v. a training programme in universal precautions (TP) v. a combination strategy to reduce NSIs among South African HCWs. Methods. A Markov model comparing SEDs v. a TP v. a combination strategy against current practice was developed. A hypothetical cohort of HCWs working in the SA public sector was followed from a payerâ&#x20AC;&#x2122;s perspective for a period of 45 years, and discounted costs and benefits were assessed. Data were obtained from the National Department of Health, suppliers and published literature. One-way and probabilistic sensitivity analysis was conducted. Results. Over the study time horizon, our model estimated that 2Â 209, 3 314 and 4 349 needlestick injuries per 1 000 HCWs could be prevented if a TP, SEDs or a combination strategy, respectively, was adopted compared with current practice. All three candidate interventions were cost-effective at a willingness to pay (WTP) of one times the gross domestic product per capita (USD6 483.90/qualityadjusted life-year (QUALY) gained). SEDs as a stand-alone intervention was dominated by a combination strategy. Compared with current practice, the incremental cost-effectiveness of training was USD32.90/QALY v. USD432.32/QALY for SEDs and USD377.08/QALY for a combination strategy. Results were sensitive to the effectiveness of the interventions. Probabilistic sensitivity analysis showed that at a WTP of USD6 483.90/QALY gained, a combination strategy would be cost-effective 95.4% of the time. Conclusions. A combination strategy in which both SEDs and a TP are adopted is preferred. S Afr Med J 2018;108(6):477-483. DOI:10.7196/SAMJ.2018.v108i6.12913

Healthcare workers (HCWs) are at increased risk of contracting infectious diseases owing to workplace exposure.[1,2] High disease prevalence and reduced investment in and availability of adequate safety measures place HCWs in developing countries at disproportionate risk compared with their counterparts in highincome countries.[3] HCWs in these settings are at particular risk of contracting tuberculosis and blood-borne pathogens such as HIV, hepatitis B and hepatitis C.[1,4] An important mechanism of exposure to blood-borne pathogens is accidental needlestick injury (NSI). The incidence of NSI varies across settings, and significant underreporting to occupational and public health authorities affects the validity of estimates. Studies from South Africa (SA) place the incidence of NSI between 24% in primary care nurses and up to 69% among junior doctors per annum.[5,6] Risk factors for sustaining an NSI vary depending on the context. Less-experienced staff and those who have not received training in universal precautions have consistently been found to be at increased risk of sustaining an NSI. [7-9] In developed countries, the evidence indicates that

doctors are at higher risk of NSI than nurses.[10] However, given the clinical load placed on mid-level HCWs in low- and middle-income countries, this is not necessarily the case in developing countries.[7] Given their risk and severity, the most important potential consequences of an NSI are acquiring HIV or hepatitis B or C. The transmission probability following an occupational NSI is 6 - 30% for hepatitis B and up to 2.83% for HIV.[11,12] Globally, 4.4% of HIV, 37% of hepatitis C and 39% of hepatitis B infections in HCWs are attributable to NSI.[13] Furthermore, HCWs commonly experience a range of psychological symptoms following occupational exposure to blood or body fluids.[14] NSIs also impose economic costs on health systems and society.[15-20] Training in universal precautions and adoption of safetyengineered devices (SEDs) are two key interventions that have been shown to reduce NSIs.[21-25] On pooled analysis of five studies, Harb et al.[22] reported an effectiveness of 46% (relative risk (RR) 0.54, 95% CI 0.41 - 0.71) for SEDs in reducing NSIs among HCWs.[22] Similarly, Tarigan et al.[23] estimated that SEDs were 49% (RR 0.51,

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95% CI 0.40 - 0.64), training 44% (RR 0.66, 95% CI 0.50 - 0.89), and a combination of training and SEDs 62% (RR 0.38, 95% CI 0.28 - 0.50) effective in reducing NSIs among HCWs. In contrast, a fourth review found only low-quality evidence to suggest that SEDs may reduce NSIs, but moderate (statistically non-significant) evidence that they could increase blood splashes by 60% (RR 1.6, 95% CI 0.08 - 2.36).[24] The few studies that have attempted to assess the cost-effectiveness of SEDs or training in reducing NSIs were either single-centre studies with limited cost perspectives[26-29] or did not undertake any uncertainty analysis.[27] With these limited cost perspectives, lack of methodological robustness and the fact that these studies were all done in high-income settings with a low HIV prevalence, there is currently insufficient evidence to guide decision-making on the adoption of SEDs and training programmes (TPs) in SA.

Objectives

To assess the cost-utility of SEDs, a basic universal precautions TP or a combination of both interventions v. current practice in the SA public healthcare sector.

Methods

Ethics review was not required for this study, as it did not require the collection or analysis of any primary data. Findings are reported in compliance with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS).[30]

Study setting

SA, a middle-income country with a gross domestic product (GDP) per capita in 2014 of USD6 483.90, has the largest HIV-positive population in the world, with an estimated prevalence among the general population of 12.2%.[31,32] There are no national policies or regulations aimed at

reducing sharps injuries in HCWs. However, current SA HIV guidelines provide for triple-therapy post-exposure prophylaxis (PEP) in cases where HCWs are exposed or potentially exposed to HIV.[33]

Study design

A decision analytical Markov model with 1-year cycles was developed to assess the cost-utility, from a public payer perspective, of current practice v.: (i) a stand-alone biennial universal precautions TP; (ii)Â adoption of SEDs as a stand-alone intervention; or (iii) a TP and SEDs in combination. A hypothetical HIV-uninfected cohort of HCWs, defined as doctors and nurses joining the SA public sector in 2015, transition through seven possible Markov states over a 45-year time horizon from the age of 20 as new entrants to the workforce (in 2015) to the retirement age of 65. Medical and nursing students in SA commence clinical rotations, and therefore become at risk to exposure, during their second or third year of study. In this analysis we only included devices utilised for: (i) initiating a peripheral intravenous infusion; (ii) delivering an injection (intramuscular and/or subcutaneous); or (iii) phlebotomy. Based on our estimates, only 7.2% (in terms of volume) of devices purchased by the public sector in 2015 were SEDs; however, our epidemiological data precede 2015 and reflect a much lower market share of SEDs. Training was defined as basic training in universal precautions. To our knowledge, with the exception of one tertiary academic hospital, there is currently no routine training on universal health precautions in the public sector. We therefore assumed the current practice (basecase) scenario to have no training and 0% coverage in SEDs.

Transition probabilities

Transition probabilities are summarised in Table 1. Self-reported incidence data of NSIs suffer from significant under-reporting, so

Table 1. Cohort and population characteristics and transition probabilities Characteristic Age (years) Time horizon (years) Cost perspective Cohort composition, % Doctors Nurses Transition probabilities* Annual attrition rate Annual probability of NSI Year 1 Year 10 Year 20 Year 30 Year 45 Prevalence of HIV, % HIV transmission Effectiveness PEP HIV progression Asymptomatic to symptomatic Symptomatic to AIDS Annual mortality rate (probability*) Asymptomatic HIV Symptomatic HIV AIDS

Base case 20 - 65 45 Public payer

Sensitivity analysis -

Source Assumption Assumption, working life Assumption

13.2 86.8

[44,45]

0.031

0.024 - 0.038

[44]

0.69 0.50 0.37 0.22 0.10 30 0.0023 0.81

0.600 - 0.78 0.270 - 0.73 0.280 - 0.47 0.002 - 0.53 0.000 - 0.28 Beta Beta 0.43 - 0.94

[46,47]

[5,6,34-36]

[37-40] [41] [42,43]

0.32 0.20

[48]

0.0148 0.0169 0.21

[49]

[48]

[49] [49]

NSI = needlestick injury; PEP = post-exposure prophylaxis. *1 = absolute certainty an event will occur, 0 = absolute certainty an event will not occur.

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we did not use any hospital surveillance or administrative data in estimating the probability of NSIs. All epidemiological input data for the model were obtained from published literature. An important determinant in the probability of sustaining an NSI and transitioning from the ‘well’ to the ‘NSI’ state is work experience (see Fig. 1 for the Markov model and the appendix (available from the corresponding author on request, email pieter.dejager@wits.ac.za) for the transition probability matrix).[7-9] To account for work experience, transition to the NSI state was time-dependent and based on pooled estimates from available SA epidemiological studies (see appendix for pooled estimate results).[5,6,34-36] Linear interpolation was used to estimate probabilities between years. After sustaining an NSI, transition back to the ‘well’ state or progression to the ‘HIV-exposed’ state occurred as a function of the estimated HIV prevalence rates found in outpatient department and hospitalised patients in SA. Based on a pooled estimate of available studies, we estimated this to be 30% (95% CI 15 - 47)[37-40] (see appendix for additional details). Transition probability from ‘HIV-exposed’ to ‘HIV-infected’ was obtained from a meta-analysis estimating the probability of seroconversion following an NSI where the source patient is HIVinfected (0.23%).[41] In our model we assumed that there is universal access to timely PEP for all exposed HCWs, and we therefore adjusted the probability of seroconversion by the efficacy of PEP (81%).[42,43] Transition from ‘HIV asymptomatic’ to ‘HIV symptomatic’ and finally ‘AIDS’ was based on epidemiological estimates of transition from SA.[49] It was possible to transition from the ‘well’, ‘NSI’ and ‘HIV-exposed’ states to the absorptive state ‘exit’, the probability of which was taken to be the estimated annual mean attrition rate for doctors (3.8%) and nurses (2.4%) from the public sector.[44,46] In contrast, transition from ‘HIV symptomatic’, ‘HIV asymptomatic’ and ‘AIDS’ to the saturation state ‘exit’ was taken to be the mortality rate for these groups[49,50] plus the background attrition rate.[44,46] Fig. 1 provides a schematic summary of the Markov model.

Costs

The cost perspective of this study is that of the public payer, namely the National Department of Health (NDoH), as the purchaser of devices and primary employer of all HCWs in the public sector. All cost data were adjusted for inflation and converted to US dollars to allow for international comparison, and are reported in 2015 terms. [51] Costs were attributed to HCWs to obtain cost per HCW estimates. It is estimated that there were ~106 822 doctors (13.2%) and nurses (86.8%) employed in the public sector in SA in

Well

NSI

HIV exposed

HIV asymp.

Exit

HIV symp.

AIDS

Fig. 1. Schematic summary of the Markov model. (NSI = needlestick injury; asymp. = asymptomatic; symp. = symptomatic.)

2015. [44-46,52] In the public sector, HCWs are salaried workers with wage scales published annually by the Department of Public Service Administration.[53] From these data, we estimated that the weighted mean daily wage of doctors and nurses in 2015 was USD101.14. Wage data were included in the model to account for the opportunity cost of training and absenteeism costs resulting from HIV exposure and subsequent side-effects of taking PEP. Cost items and quantities required in the management of HIV PEP were identified through the review of current clinical management guidelines adopted in SA.[54] Laboratory costs were obtained from the National Health Laboratory Service (NHLS), the sole laboratory service provider for the public sector (NHLS State Price List 2015, obtained from the NHLS). For pharmaceutical costs, single-exit prices for antiretroviral drugs were obtained from the NDoH.[55] Other PEP programme costs included in the analysis were pre- and post-test counselling and occupational health follow-up visits. Treatment costs for HIV were obtained from the literature and differentiated between asymptomatic, symptomatic and AIDS care. [48] For our analysis, in line with World Health Organization (WHO) recommendations, we assumed that all HCWs who seroconvert are initiated on highly active antiretroviral treatment at the time of diagnosis, regardless of CD4+ count.[56] Obtaining estimates from both suppliers and the NDoH, we triangulated cost data for SED and non-SED devices. Devices are purchased on a tender system by provincial departments of health, so there is heterogeneity in the pricing of various items across provincial administrations. We estimated the total volume for each category of devices (i.e. devices utilised for initiating a peripheral intravenous infusion, delivering an injection, or used for phlebotomy) purchased by the public sector in 2015 stratified by SED and non-SED. We obtained low and high price estimates for each device category for both SED and non-SED devices. From these data we calculated the total cost for each category under two scenarios: zero SED coverage and 100% SED coverage. By applying the estimated number of HCWs employed in the public sector in 2015, we calculated the cost per HCW for each device category and each scenario. Training costs were estimated from current training courses available in SA. Under the training intervention, we assumed that HCWs would attend biennial full-day training on basic universal precautions to be provided on-line. On-line courses are available and are undergoing further refinement by SA universities.[59] Table 2 provides a summary of the cost components included in the model.

Effectiveness

Benefits accrued under each scenario were measured in qualityadjusted life-years (QALYs). QALYs are utility-based composite measures of morbidity and mortality associated with given health states and allow for comparability across studies and health outcomes. We assumed the ‘well’ state to be associated with perfect health and therefore assigned a utility score of 1. No studies were found that reported QALYs for NSI, but this event is typically associated with localised pain and psychological distress.[60] We therefore assigned a conservative, near-perfect level of health (QALY 0.98, sensitivity range 0.95 - 1) to the ‘NSI’ health state and assessed this assumption in both the univariate and probabilistic sensitivity analysis. Utility scores for being HIV-exposed had previously been estimated through expert consultation as reported by Haddix et al.[61] QALYs for asymptomatic, symptomatic and advanced (AIDS) HIV were obtained from a meta-analysis by Tengs and Wallace.[62] A recent systematic review and meta-analysis by Tarigan et al.[23] estimated the pooled effectiveness of SEDs, training and combined training and SEDs in reducing NSIs among healthcare workers. [23]

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Table 2. Economic model inputs (costs expressed in 2015 USD) Cost component Discount rate, % USD conversion Opportunity costs Weighted mean daily wage, USD Absentee days, n Training time, n days per annum HIV occupational exposure costs, USD HIV ELISA Serum creatinine PEP ARV costs* Pre- and post-test counselling Occupational health consult Cost of HIV treatment, USD Asymptomatic Symptomatic AIDS Intervention costs per HCW, USD Non-SED SED TP

Base case

Sensitivity analysis

Source

3 12.54

0-6 -

[57]

101.14 3.5 0.5

Log-normal 0-7 -

[53]

47.71 26.24 103.41 4.00 15.95

Log-normal -

†

416.78 421.28 455.07

Log-normal Log-normal Log-normal

[48]

51.59 274.89 23.92

Log-normal Log-normal Log-normal

‡

[58]

Assumption Assumption

† [55] [53] [53]

[48] [48]

‡ [59]

ELISA = enzyme-linked immunosorbent assay; PEP = post-exposure prophylaxis; ARV = antiretroviral; HCW = healthcare worker; SED = safety-engineered device; TP = training programme; NHLS = National Health Laboratory Service. *USD103.41 is the total cost of 28 days of treatment as per national guidelines (tenovofir 300 mg/d, emtricitabine 200 mg/d plus raltegravir 400 mg twice a day). † NHLS State Price List 2015, obtained from the NHLS. ‡ These costs were obtained from suppliers.

Table 3. Utility scores for various health states Health state Well NSI HIV-exposed HIV asymptomatic HIV symptomatic AIDS

QALY 1 0.98 0.95 0.88 0.822 0.64

Standard deviation 0 0.014 0.021794 0.19 0.224 0.0735

Sensitivity Probability distribution Beta Beta Beta Beta Beta

Source Assumed Assumed [61] [62] [62] [62]

QALY = quality-adjusted life-year; NSI = needlestick injury.

Table 4. Effectiveness of interventions Interventions Training SEDs SEDs and TP PEP

Base case, % reduction 0.34 0.49 0.62 0.81

Sensitivity, uniform distributions 0.11 - 0.5 0.36 - 0.6 0.5 - 0.72 0.43 - 0.94

Source [23] [23] [23] [42,43]

SEDs = safety-engineered devices; TP = training programme; PEP = post-exposure prophylaxis.

Table 5. Cost-effectiveness of three intervention strategies compared with current practice to reduce NSIs among SA public sector HCWs

Intervention Current practice TP only SEDs only SEDs and TP

Cost per HCW (USD) 1 163.29 1 247.64 3 151.17 3 619.04

Incremental cost (USD) 84.34 1 987.87 2 455.74

Effectiveness (QALYs) 15.3 17.69 19.73 21.64

Incremental effectiveness (QALYs) 2.56 4.60 6.51

ICER (USD/ QALY) 32.90 432.32 377.08

CE 76.90 70.53 159.75 167.24

NSI = needlestick injury; SA = South African; HCWs = healthcare worker; QALYs = quality-adjusted life-years; ICER = incremental cost-effectiveness ratio; CE = cost-effectiveness; TP = training programme; SEDs = safety-engineered devices.

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The pooled estimates are based on 17 studies, 16 of which were before-and-after in design, while one was a randomised controlled trial.[25] The effectiveness of HIV PEP was obtained from two casecontrol studies.[42,43] Tables 3 and 4 provide a summary of the utility scores and effectiveness data, respectively.

compared with current practice at an additional discounted cost of USD2 455.74. Therefore, under the base case, SEDs in combination with a TP was the preferred intervention with an ICER of USD377.08 per QALY gained.

Analysis

The effectiveness of SEDs, training and training in combination with SEDs were the most important variables on univariate sensivity analysis, impacting on the ICERs for each strategy. Net benefit oneway sensitvity analysis was used to take account of effectiveness, cost and WTP as the input variable changes. Although the effectiveness of training, SEDs and a combination of training and SEDs impacted on the net benefit, the impact was not sufficient to change the strategy. Varying the effectiveness of each intervention strategy within plausible ranges, a combination strategy of both SEDs and training remains the strategy of choice at a WTP threshold of USD6 483.90 per QALY gained (see appendix). Results from the Monte Carlo probabilistic sensitivity analysis, whereby all the uncertainty captured by the model inputs was assessed simultaneously, are reported in Fig. 3. A combination strategy is prefered at a WTP threshold of USD6 483.9 per QALY gained, where it would be a cost-effective strategy 95.4% of the time.

Results Base case

Current practice SEDs SEDs and TP TP Undominated

Effectiveness, %

Fig. 2. Cost-effectiveness of three intervention strategies to reduce NSI among HCWs compared with current practice at a WTP of USD6 483.90. (NSI = needlestick injury; HCWs = healthcare workers; WTP = willingness to pay; SEDs = safety-engineered devices; TP = training programme.) 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 00

00 70

00 20

Current practice SEDs SEDs and TP TP

Cost-effective iterations, %

Both SEDs and training as stand-alone interventions or in combination improve health outcomes in HCWs by reducing the number of NSI events, HIV exposures and the lifetime probability of contracting HIV due to NSIs. Over a 45-year working life, it is estimated that 2 209, 3 314 and 4 349 NSI per 1 000 HCWs would be prevented if a TP alone, SEDs alone, or training and SEDs in combination, respectively, were to be adopted in the public sector compared with current practice. This translates into 672, 1 009 and 1 325 HIV exposure events averted and reductions in the cumulative probability of seroconversion from 0.91% (current practice) to 0.66% (TP), 0.53% (SEDs) and 0.41% (SEDs and TP). All three intervention strategies were more costly than current practice (Table 5 and Fig. 2). The average annual discounted cost per HCW under current practice was estimated at USD1 163.29 compared with USD1 247.64, USD3 151.17 and USD3 619.04 per HCW for a stand-alone TP, SEDs alone or training and SEDs in combination, respectively. Compared with current practice, a standalone TP would increase discounted QALYs by 2.56 at an additional discounted cost of USD84.34. Training was found to be a highly cost-effective intervention, with an ICER of USD32.90/QALY gained. Although cost-effective, the SEDs-only strategy was dominated by a combination strategy of both SEDs and training. SEDs alone were estimated to increase discounted QALYs by 4.90 at an additional discounted cost of USD1 987.87 and an ICER of USD432.32/QALY gained. It is estimated that adopting a combination strategy of both SEDs and training would increase discounted QALYs by 6.51

3 800 3 600 3 400 3 200 3 000 2 800 2 600 2 400 2 200 2 000 1 800 1 600 1 400 1 200 1 000

WTP = 6 483.9

Cost (USD)

We developed and analysed our decision analytical Markov model in TreeAge Pro 2015 (TreeAge Software, USA). Costs and benefits accruing to each Markov state under each of the four scenarios under consideration were calculated by conducting a cohort simulation (N=10 000). From this analysis we estimated the number of NSI and HIV exposure events under each scenario over the 45-year time horizon as well as the cumulative probability of contracting HIV due to NSIs. Following WHO guidelines, all costs and benefits were discounted at 3% and varied between 0% and 6% in the sensitivity analysis.[57] To avoid overestimating the final cycle’s lifetime, halfcycle corrections were applied to all costs and benefits. Incremental cost-effectiveness ratios (ICERs) were calculated to assess the costeffectiveness of each intervention scenario with current practice. There are currently no willingness to pay (WTP) thresholds for SA, so we adopted WHO guidelines to assess cost-effectiveness.[63] The per capita GDP for SA in 2014 was USD6 483.90 and was taken as the cost-effectiveness threshold.[63,64] In order to assess the robustness of our estimates, we conducted one-way and probabilistic sensitivity analysis. One-way sensitivity analysis was undertaken to assess the effects of biasing input parameters to upper and lower limits. Multi-way Monte Carlo simulation (probabilistic sensitivity analysis) consisting of 10 000 simulations in which all input parameters were varied simultaneously as a function of their underlying probability distributions was undertaken (see appendix for additional details).

Sensitivity analysis

WTP (USD)

Fig. 3. Results of probabilistic sensitivity analysis. (SEDs = safety-engineered devices; TP = training programme; WTP = willingness to pay.)

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Discussion

Our study assessed the cost-utility of three strategies, compared with current practice, aimed at reducing NSIs among HCWs in a high HIV prevalence setting. We found that a combination strategy of adopting both SEDs and training in universal precautions would be the preferred strategy, with an ICER of USD377.08 per QALY gained. This is significantly lower than SA’s per capita GDP (USD6 483.90), making it a highly cost-effective option in reducing NSIs among doctors and nurses working in the public sector. A combination strategy would reduce the number of NSIs and exposure events and reduce the number of occupational HIV cases. Prüss-Üstün et al.[13] estimated that globally there are 1 000 (range 200 - 5 000) cases of HIV per year in HCWs due to NSI, with 720 (range 130 - 3 510) occurring in Africa.[13] Over a 45-year time horizon, we found that a combination strategy would reduce the cumulative probability of acquiring HIV from NSI by 54.9% (from 0.91% to 0.41%). Based on our model estimates, we calculate that there are, under current practice, ~20 cases of HIV per annum in HCWs in SA and that this could be reduced to nine cases if a combination strategy were to be implemented. There are no published statistics available in SA on the number of occupationally acquired cases of HIV infection in HCWs. Given that there were 56 confirmed and 136 possible cases of occupationally acquired HIV cases in US HCWs between 1985 and 1999 and it is estimated that in Europe there are 7 cases per annum,[13] our calculation of 20 cases per year is probably an under-estimation due to our model assumption that there is 100% access and compliance to timely diagnostics and PEP. This is the first study to assess the cost-effectiveness of SEDs in a developing country context. All the previous studies were conducted in single centres in high-income countries, with limited costing perspectives and no utilisation of uncertainty and sensitivity analysis and expressed effectiveness as cost per NSI averted, thus limiting the comparability of previous findings with ours.[26-29] Nevertheless, we estimate that the cost per NSI averted would be USD38.18, USD599.84 and USD564.67 for training alone, SEDs alone or a combination strategy, respectively. Previous estimates of the costeffectiveness of SEDs from the USA have ranged from USD789 to USD2 571, and in Europe it has been calculated that savings would range from EUR2.65 to EUR869.79 per NSI averted. [26-29] Our estimates, although not directly comparable, fall within the ranges estimated in the European study, but are lower than those from the USA.

Study limitations

Our study had a number of limitations. First, we did not take account of all the costs and consequences of NSI. To make our model more manageable, we did not consider hepatitis B or C, even though together with HIV they are the most common bloodborne pathogens transmitted through NSI – with a prevalence of >8% in the general population, hepatitis B is endemic in SA.[65] Further, we only included doctors and nurses from the time they are students in our analysis, but other HCWs such as laboratory technicians and cleaning staff are also at risk of NSI. In settings with inadequate medical waste management, communities are also at risk of sustaining NSI. Therefore, excluding the costs of other infectious diseases and HCWs or communities affected by NSI from our model, we have probably underestimated the true cost-effectiveness of the interventions. Second, we assumed that HIV prevalence in the source population would remain constant over the 45-year period and varied it within a constant range in the sensitivity analysis. The age-standardised prevalence of HIV

has stabilised in SA, increasing by only 0.002 per 100 000 between 2005 and 2015,[31] so this assumption will probably not affect the model estimates greatly. Third, the evidence on the effectiveness of the interventions was largely based on observational studies. We took estimates from the most recent and complete meta-analysis on the effectiveness of SEDs, training and a combination of the two strategies and varied these in the sensitivity analysis. Fourth, there are limited epidemiological studies investigating the incidence of NSI in SA. We searched the literature and pooled the estimates from all available studies, stratified estimates based on work experience and varied these estimates in the sensitivity analysis. Finally, there are no available utility estimates for NSI events per se, so we assumed NSI to be associated with a QALY of 0.98 and varied this assumption in the sensitivity analysis.

Highlights

• HCWs are at increased risk of contracting infectious diseases, including HIV secondary to accidental NSI. Although SEDs and training in universal precautions are known to reduce NSIs, it is not known whether these would be cost-effective interventions in a middle-income country with a high HIV burden. • Our economic evaluation shows that a combination strategy that includes both the adoption of SEDs and a biannual TP for HCWs in SA’s public sector would be cost-effective from a public payer’s perspective. • Our findings provide policy guidance on an important yet often overlooked aspect of health policy in SA, the health of HCWs.

Conclusions

Our study shows that a combination strategy in which both SEDs and a basic universal precautions TP are adopted is the preferred strategy to reduce NSIs in HCWs in SA’s public sector. Given the lack of policy on the prevention of NSI in SA, our study provides important evidence to inform decision-making. As a starting point the SA NDoH is currently engaged in policy processes on occupational health for health workers in respect of HIV and tuberculosis, and our study is very pertinent to that process, especially in advocating for the inclusion of a policy tenant on NSI prevention. Since procurement in SA may be centralised in some provincial departments of health, the authors would encourage improved communication with infection prevention and control and occupational health and safety. Finally, our findings or model may also be applicable to other settings with similar levels of economic development and where there is a high burden of HIV. Acknowledgements. We express our gratitude to Dr Spo Kgalamono, Prof. David Rees and Ms Busisiwe Nyantumbu, colleagues at the National Institute for Occupational Health, for assisting with the collection of cost data. Drs Diana Quirmbach and Jeroen Luyten from the London School of Economics and Political Science provided feedback on an earlier draft. Author contributions. PJ: conceptualisation, model development, data collection, statistical analysis, drafting manuscript, interpretation of results, review and approval of final manuscript; MZ: data collection, interpretation of findings, review and approval of final manuscript; RED: data collection, interpretation of findings, review and approval of final manuscript. Funding. The School of Public Health at the University of the Witwatersrand provided partial funding for this project. Conflicts of interest. None.

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Kruger WH. Needlestick injuries among nurses in a regional hospital in South Africa. 2012. http:// reference.sabinet.co.za/sa_epublication_article/ohsa_v18_n3_a4 (accessed 8 September 2015). 7. Nsubuga FM, Jaakkola MS. Needle stick injuries among nurses in sub-Saharan Africa. Trop Med Int Health 2005;10(8):773-781. https://doi.org/10.1111/j.1365-3156.2005.01453.x 8. Bekele T, Gebremariam A, Kaso M, Ahmed K. Factors associated with occupational needle stick and sharps injuries among hospital healthcare workers in Bale Zone, Southeast Ethiopia. PLoS One 2015;10(10):e0140382. https://doi.org/10.1371/journal.pone.0140382 9. Makary MA, Al-Attar A, Holzmueller CG, et al. Needlestick injuries among surgeons in training. N Engl J Med 2007;356(26):2693-2699. https://doi.org/10.1097/01.sa.0000296372.51242.0a 10. Wicker S, Jung J, Allwinn R, Gottschalk R, Rabenau HF. Prevalence and prevention of needlestick injuries among health care workers in a German university hospital. Int Arch Occup Environ Health 2007;81(3):347-354. https://doi.org/10.1007/s00420-007-0219-7 11. Beltrami EM, Williams IT, Shapiro CN, Chamberland ME. Risk and management of blood-borne infections in health care workers. Clin Microbiol Rev 2000;13(3):385-407. https://doi.org/10.1128/ cmr.13.3.385-407.2000 12. Baggaley RF, Boily M-C, White RG, Alary M. Risk of HIV-1 transmission for parenteral exposure and blood transfusion: A systematic review and meta-analysis. AIDS 2006;20(6):805-812. https://doi. org/10.1097/01.aids.0000218543.46963.6d 13. Prüss-Üstün A, Rapiti E, Hutin Y. Estimation of the global burden of disease attributable to contaminated sharps injuries among health-care workers. Am J Ind Med 2005;48(6):482-490. https:// doi.org/10.1002/ajim.20230 14. Gershon RRM, Flanagan PA, Karkashian C, et al. Health care workers’ experience with postexposure management of bloodborne pathogen exposures: A pilot study. Am J Infect Control 2000;28(6):421428. https://doi.org/10.1067/mic.2000.109907 15. Trueman P, Taylor M, Twena N, Chubb B. The cost of needlestick injuries associated with insulin administration. Br J Commun Nurs 2008;13(9):413-417. https://doi.org/10.12968/bjcn.2008.13.9.30911 16. Mannocci A, de Carli G, di Bari V, et al. How much do needlestick injuries cost? A systematic review of the economic evaluations of needlestick and sharps injuries among healthcare personnel. Infect Control Hosp Epidemiol 2016;37(6):635-646. https://doi.org/10.1017/ice.2016.48 17. Glenngård AH, Persson U. Costs associated with sharps injuries in the Swedish health care setting and potential cost savings from needle-stick prevention devices with needle and syringe. Scand J Infect Dis 2009;41(4):296-302. https://doi.org/10.1080/00365540902780232 18. Oh HS, Yoon Chang SW, Choi JS, Park ES, Jin HY. Costs of postexposure management of occupational sharps injuries in health care workers in the Republic of Korea. Am J Infect Control 2013;41(1):61-65. https://doi.org/10.1016/j.ajic.2012.01.030 19. Leigh JP, Gillen M, Franks P, et al. Costs of needlestick injuries and subsequent hepatitis and HIV infection. Curr Med Res Opin 2007;23(9):2093-2105. https://doi.org/10.1185/030079907x219517 20. Ekwueme DU, Weniger BG, Chen RT. Model-based estimates of risks of disease transmission and economic costs of seven injection devices in sub-Saharan Africa. Bull World Health Organ 2002;80(11):859-870. http://www.who.int/bulletin/archives/80(11)859.pdf 21. Tuma S, Sepkowitz KA. Efficacy of safety-engineered device implementation in the prevention of percutaneous injuries: A review of published studies. Clin Infect Dis 2006;42(8):1159-1170. https:// doi.org/10.1086/501456 22. Harb AC, Tarabay R, Diab B, Ballout RA, Khamassi S, Akl EA. Safety engineered injection devices for intramuscular, subcutaneous and intradermal injections in healthcare delivery settings: A systematic review and meta-analysis. BMC Nurs 2015;14:71. https://doi.org/10.1186/s12912-015-0119-1 23. Tarigan LH, Cifuentes M, Quinn M, Kriebel D. Prevention of needle-stick injuries in healthcare facilities: A meta-analysis. Infect Control Hosp Epidemiol 2015;36(7):823-829. https://doi. org/10.1017/ice.2015.50 24. Reddy VK, Lavoie MC, Verbeek JH, Pahwa M. Devices for preventing percutaneous exposure injuries caused by needles in healthcare personnel. Cochrane Database Syst Rev 2017, Issue 11. Art. No.: CD009740. https://doi.org/10.1002/14651858.cd009740.pub3 25. Van der Molen HF, Zwinderman KAH, Sluiter JK, Frings-Dresen MHW. Better effect of the use of a needle safety device in combination with an interactive workshop to prevent needle stick injuries. Saf Sci 2011;49(8-9):1180-1186. https://doi.org/10.1016/j.ssci.2011.03.010 26. Mendelson MH, Short LJ, Schechter CB, et al. Study of a needleless intermittent intravenous-access system for peripheral infusions: Analysis of staff, patient, and institutional outcomes. Infect Control Hosp Epidemiol 1998;19(6):401-406. https://doi.org/10.1086/647839 27. Orenstein R, Reynolds L, Karabaic M, Lamb A, Markowitz SM, Wong ES. Do protective devices prevent needlestick injuries among health care workers? Am J Infect Control 1995;23(6):344-351. https://doi.org/10.1016/0196-6553(95)90264-3 28. Roudot-Thoraval F, Montagne O, Schaeffer A, Dubreuil-Lemaire M-L, Hachard D, Durand-Zaleski I. Costs and benefits of measures to prevent needlestick injuries in a university hospital. Infect Control Hosp Epidemiol 1999;20(9):614-617. https://doi.org/10.1086/501681 29. Armadans Gil L, Cano F, Isabel M, et al. Safety-engineered devices to prevent percutaneous injuries: Cost-effectiveness analysis on prevention of high-risk exposure. Gac Sanit 2006;20(5):374-381. https:// doi.org/10.1157/13093206 30. Husereau D, Drummond M, Petrou S, et al. Consolidated health economic evaluation reporting standards (CHEERS) statement. BMC Med 2013;11(1):80. https://doi.org/10.1186/1741-7015-11-80 31. Wang H, Wolock TM, Carter A, et al. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980 - 2015: The Global Burden of Disease Study 2015. Lancet HIV 2016;3(8):e361-e387. https://doi.org/10.1016/S2352-3018(16)30087-X

32. Shisana O, Labadarios D, Simbayi LC, et al. South African national HIV prevalence, incidence and behaviour survey, 2012. 2015. http://ecommons.hsrc.ac.za/handle/123456789/2490 (accessed 23 June 2016). 33. Venter F. Post-exposure prophylaxis. South Afr J HIV Med 2008;37(Winter):36-45. http://sahivsoc. org/Files/Guidelines%20for%20post-exposure%20prophylaxis%20(2008).pdf (accessed 7 May 2018). 34. Rabbitts JA. Occupational exposure to blood in medical students. S Afr Med J 2003;93(8):621-624. 35. Marais B, Cotton M. Occupational exposure to human immunodeficiency virus in pediatricians: A previously undescribed high risk group. Pediatr Infect Dis J 2003;22(4):382-383. https://doi. org/10.1097/01.inf.0000059963.24260.e9 36. Nyantumbu B, Geyer N, Botham L, Eijkemans G. WHO-ICN project: Preventing needle-stick injury in healthcare workers. No. E1-4. International Occupational Hygiene Association (IOHA), Pilanesberg National Park, South Africa, 19 - 23 September 2005. 37. Shisana O, Hall EJ, Maluleke R, Chauveau J, Schwabe C. HIV/AIDS prevalence among South African health workers. S Afr Med J 2004;94(10):846-850. 38. Rollins N, Dedicoat M, Danaviah S, et al. Prevalence, incidence, and mother-to-child transmission of HIV-1 in rural South Africa. Lancet 2002;360(9330):389-390. https://doi.org/10.1016/s01406736(02)09599-5 39. Rollins NC, Coovadia HM, Bland RM, et al. Pregnancy outcomes in HIV-infected and uninfected women in rural and urban South Africa: J Acquir Immune Defic Syndr 2007;44(3):321-328. https:// doi.org/10.1097/qai.0b013e31802ea4b0 40. Parikh A, Veenstra N. The evolving impact of HIV/AIDS on outpatient health services in KwaZuluNatal, South Africa. S Afr Med J 2008;98(6):468-472. 41. Patel P, Borkowf CB, Brooks JT, Lasry A, Lansky A, Mermin J. Estimating per-act HIV transmission risk: A systematic review. AIDS 2014;28(10):1509-1519. https://doi.org/10.1097/qad.0000000000000298 42. Young T, Arens FJ, Kennedy GE, Laurie JW, Rutherford GW. Antiretroviral post-exposure prophylaxis (PEP) for occupational HIV exposure. Cochrane Database Syst Rev 2007, Issue 1. Art. No.: CD002835. https://doi.org/10.1002/14651858.cd002835.pub3 43. Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med 1997;337(21):1485-1490. https://doi.org/10.1056/ nejm199711203372101 44. Econex. The human resource supply constraint: The case of doctors. 2010. http://econex.co.za/ publication/health-reform-note-8/ (accessed 19 November 2015). 45. Econex. Update GP and specialist numbers: 2011 and 2012. 2013. http://www.hpcsa.co.za/Uploads/ editor/UserFiles/downloads/service_fees-tariff/submissions/sappf_f_econex_updated_gp_specialist_ numbers_27%2003%202013.pdf (accessed 19 November 2015). 46. Econex. The human resource supply constraint: The case of nurses. 2010. http://econex.co.za/ publication/health-reform-note-9/ (accessed 19 November 2015). 47. Wildschut A, Mqolozana T. Shortage of nurses in South Africa: Relative or absolute? 2008. http:// www.lmip.org.za/sites/default/files/documentfiles/nursesshortage.pdf (accessed 19 November 2015). 48. Moodley N, Gray G, Bertram M. The case for adolescent HIV vaccination in South Africa: A costeffectiveness analysis. Medicine 2016;95(4):e2528. https://doi.org/10.1097/md.0000000000002528 49. Brinkhof MWG, Boulle A, Weigel R, et al. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: Comparison with HIV-unrelated mortality. PLOS Med 2009;6(4):e1000066. https://doi.org/10.1371/journal.pmed.1000066 50. Statistics South Africa. Mortality and causes of death in South Africa, 2013: Findings from death notification. 2014. http://www.statssa.gov.za/publications/P03093/P030932013.pdf (accessed 13 November 2015). 51. Statistics South Africa. Consumer price inflation 1960 onwards. 2016. http://www.statssa.gov.za/ publications/P0141/CPIHistory.pdf? (accessed 13 November 2015). 52. Econex. Updated GP and specialist numbers for SA. 2010. http://econex.co.za/publication/healthreform-note-7/ (accessed 19 November 2015). 53. Department of Public Service Administration. Remuneration documents. 2015. http://www.dpsa.gov. za/dpsa2g/r_documents.asp (accessed 25 May 2016). 54. Moorhouse M, Bekker LG, Black V, et al. Guideline on the management of occupational and nonoccupational exposure to the human immunodeficiency virus and recommendations for postexposure prophylaxis: 2015 update. South Afr J HIV Med 2015;16(1):1-14. https://doi.org/10.4102/ hivmed.v16i1.399 55. National Department of Health, South Africa. South African medicine price registry: Single exit price database. 2015. http://www.mpr.gov.za/PublishedDocuments.aspx#DocCatId=21 (accessed 25 November 2015). 56. World Health Organization. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng. pdf (accessed 25 May 2016). 57. Tan-Torres Edejer T, Baltussen R, Adam T, et al. Making choices in health: WHO guide to costeffectiveness analysis. 2003. http://agris.fao.org/agris-search/search.do?recordID=XF2015015286 (accessed 25 May 2016). 58. South African Reserve Bank. ZAR to USD exchange rate. 2016. http://wwwrs.resbank.co.za/ webindicators/SDDSDetail.aspx?DataItem=BOP5329M (accessed 25 May 2016). 59. Stellenbosch University – Unit for Infection Prevention and Control. http://sun025.sun.ac.za/portal/ page/portal/UIPC/INDEX (accessed 25 May 2016). 60. Lee JM, Botteman MF, Xanthakos N, Nicklasson L. Needlestick injuries in the United States: Epidemiologic, economic, and quality of life issues. AAOHN J 2005;53(3):117-133. https://doi. org/10.1177/216507990505300311 61. Haddix AC, Teutsch SM, Corso PS. Prevention Effectiveness: A Guide to Decision Analysis and Economic Evaluation. New York: Oxford University Press, 2003. 62. Tengs TO, Wallace A. One thousand health-related quality-of-life estimates. Med Care 2000;38(6):583637. https://doi.org/10.1097/00005650-200006000-00004 63. Sachs JD. Macroeconomics and health: Investing in health for economic development. Rev Panam Salud Publica 2002;12(2):143-144. https://doi.org/10.1590/s1020-49892002000800017 64. World Bank. GDP per capita (current US$) | Data | Table. http://data.worldbank.org/indicator/ NY.GDP.PCAP.CD (accessed 27 May 2016). 65. Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: Epidemiology and vaccination. Epidemiol Rev 2006;28(1):112-125. https://doi.org/10.1093/epirev/mxj009

Accepted 12 January 2018.

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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Medical students’ perspectives on euthanasia and physician-assisted suicide and their views on legalising these practices in South Africa R K Jacobs, MB ChB; M Hendricks, BA Hons (Psych), HDE, MA (Clin Psych), LLB; MPhil (Bioethics) Centre for Medical Ethics and Law, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Corresponding author: R K Jacobs (ryankjacobs16@gmail.com) Background. Euthanasia/physician-assisted suicide have been a controversial and sometimes taboo topic for a long time, not only in South Africa (SA) but also internationally. A recent (SA) judicial case has seen the topic debated again. Consensus on accepting or abolishing these practices in SA has yet to be reached. All relevant role players need to be adequately engaged before policy can be informed. Objectives. To determine the views of future doctors (medical students) regarding euthanasia and physician-assisted suicide (PAS) and to ascertain their stance on its legalisation in South Africa (SA). Methods. A paper-based, semi-quantitative descriptive study design consisting of 16 questions, using convenience sampling of third- to fifth-year medical students at Stellenbosch University, was used. Results. The overall response rate was 69.3% (N=277). In total, 52.7% of participants (n=146) felt that the practices of euthanasia/PAS should be legalised in SA. Responses varied depending on patient morbidities. If a patient had terminal disease with intractable suffering, 41.9% of participants would terminate the patient’s life upon request. A further 36.1% of participants stated that they would have no part in ending a patient’s life, while 35.0% said that they would be comfortable with providing the patient with the correct means to end their life (PAS). The majority (80.1%) of participants indicated that they would prefer a dedicated ethics committee to decide who receives euthanasia/PAS. Many factors influenced participants’ responses, but differences in opinion between and within the various religious groups were particularly evident in the responses received. Conclusions. More than half the respondents in this study were open to legalising euthanasia/PAS, substantially more than in previous studies. However, only 41.9% of respondents would consider actually performing euthanasia/PAS, for certain patients. Views of other healthcare workers as well as the public are required before policy can be informed. S Afr Med J 2018;108(6):484-489. DOI:10.7196/SAMJ.2018.v108i6.13089

The medical practice of euthanasia and physician-assisted suicide (PAS) remains a controversial topic, not only in South Africa (SA) but throughout the world. Euthanasia and PAS are defined as two distinct means by which an end to a patient’s life can be brought about. According to Materstvedt et al.,[1] euthanasia is defined as ‘a doctor intentionally killing a person by the administration of drugs, at that person’s voluntary and competent request’. While PAS is defined as ‘a doctor intentionally helping a person commit suicide by providing drugs for self-administration, at that person’s voluntary and competent request’,[1] SA law regards both euthanasia and PAS as forms of active euthanasia.[2] The South African Law Commission[3] holds that ‘such an act [euthanasia and/or PAS] would undoubtedly be unlawful and the person giving the assistance could be convicted of murder’, as both euthanasia and PAS contain the definitional elements of murder. Despite the fact that 34% of SA doctors surveyed in 2011[4] had already had patients request life-ending interventions, it is evident that fear of prosecution contributes to doctors’ reluctance to perform these procedures. Given past requests for euthanasia and PAS, the time to consider legislative change is fast approaching, and to pre-empt the legislative review it is prudent to explore the attitudes of doctors towards these life-ending practices.[5] In the past, various cases have been brought before the SA judicial system. Two cases, S v De Bullocq[6] and S v Hartmann,[7] dealt with acts of active euthanasia, in which the motive for killing was to end useless existence and (intractable) suffering, respectively. In both cases it was found that the accused acted unlawfully. Judgment passed

in these cases found the accused guilty of murder. However, lighter sentences (i.e. no imprisonment, the usual sentence for murder) were imposed, indicating the court’s sympathy for the plight of the accused and the deceased. Most recently, SA courts had to consider a request for PAS from Advocate Stransham-Ford. In 2015, an application was brought to the North Gauteng High Court for assistance in dying (PAS), with the subsequent exoneration of the physician. [8] The application was granted, but the applicant died just hours before the ruling was passed. [8] The SA Supreme Court overturned the High Court’s decision on appeal, but acknowledged euthanasia as ‘a doctrine which may be in the womb of time, but whose birth is distant’.[5] The euthanasia discourse is re-emerging against the backdrop of an ageing population[9] and the advancement of medical technologies that ultimately ensure longevity under dire medical circumstances, including longevity of patients with intractable mental illnesses.[10] So far the courts have taken centre stage in the euthanasia debate, but with the recent developments, particularly in the Stransham-Ford case, the need to engage medical professionals has become urgent.

Objectives

To ascertain the views of future doctors on euthanasia and PAS in SA.

Methods Design

A paper-based, semi-quantitative descriptive study design was used

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to assess the views of third- to fifth-year medical students at Stellenbosch University on euthanasia and PAS in SA.

Ethical considerations and approval

The study was approved by the Stellenbosch University Undergraduate Research Ethics Committee (ref. no. U16/03/004). Institutional approval was granted by the Stellenbosch University Institutional Research and Planning Division. The participant information sheet as well as a briefing from the principal investigator reiterated the voluntary and anonymous nature of participation in this study. Written informed consent was obtained, as per individual questionnaires. Question 1 sought consent in the form of a pre-flight checklist and subsequent tick-box.

Sampling

Convenience sampling was used. The principal investigator sought the views of a sample of third- to fifth-year medical students who were present in a lecture hall on the days when the data were collected. Students who were absent were excluded. Final-year medical students were excluded because they were not available. Third- to fifth-year medical students have already covered most of their theoretical modules (including an introductory or more formal bioethics module) and have been exposed to the working or clinical environment to varying degrees. They were deemed suitable candidates for this study as they (theoretically) have a better appreciation of the subject matter than their junior (first- and second-year) counterparts.

The questionnaire

A questionnaire containing 16 questions was used. Some questions used in the questionnaire were adapted from a survey conducted by Leppert et al.[11] Three main categories of questions were used in the questionnaire. Table 1 elaborates on the specifics of each question relating to the topic. Questions 1 - 5 dealt with demographic

information on the participants, namely consent, gender, ethnicity, year of study and religious affiliation. The questionnaire was piloted on 20 random third- to final-year medical students, for validation.

Data collection and analysis

The study was conducted from April 2016 to April 2017. Owing to the semi-quantitative descriptive study design, data collection and interpretation were two-fold. The quantitative data were captured and recorded in a Microsoft Excel (2016) workbook (Microsoft, USA) and subsequently analysed using descriptive statistics by means of frequency tables. Qualitative data were grouped and summarised (using thematic analysis) in a Microsoft Word (2016) document (Microsoft, USA). Each questionnaire was read and scrutinised twice by the primary investigator, to avoid missing or repeating any aspects that would skew the results.

Results

Of the 400 questionnaires that were distributed, 277 (69.3%) were returned completed. ‘Incomplete’ questionnaires were not included in data analysis. Of the 277 completed questionnaires, 33 (11.9%) were responses from third-year students while 99 (35.7%) and 145 (52.3%) were responses from fourth- and fifth-year students, respectively. Fig. 1 shows the religious affiliations of the respondents.

Category 1 questions

Category 1 questions explored students’ attitudes towards life-ending requests and the legalisation of life-ending interventions in SA. The majority of the participants (57.0%, n=158) believed that the patient should have the final decision in choosing to end their life, but only 47.7% (n=132) believed that doctors should be allowed to help these patients fulfil their requests. Most participants (52.7%, n=146) were in favour of legalising the practice of euthanasia and PAS in SA, but 63.5% (n=176) would still attempt to persuade a patient to choose a palliative treatment method instead of a life-ending intervention.

Table 1. Questionnaire category details Category 1

Question no. 6 7 14 15

16* 8*

9* 10* 11* 3

12*

13*

Question A patient should have a choice in deciding to end his/her life. Doctors should be able to help patients to die if they wish to die. If somebody I know and love suffered from a life-threatening, painful illness. I would support their decision to die. I would attempt to persuade the patient (seeking life-ending interventions) to opt for palliative therapy, rather than life-ending interventions. I believe that euthanasia/physician-assisted suicide should be legalised in South Africa. A patient known to have a painful, incurable disease (e.g. metastatic cancer), who is likely to die from the condition, seeks life-ending intervention. Would you fulfil his/her wish to end his/her life prematurely? A patient known to have a painful, incurable disease (e.g. metastatic cancer) but who is unlikely to die soon seeks life-ending intervention. Would you fulfil his/her wish to end his/her life? A patient presents to you with no known disease, but seeks life-ending intervention. Would you fulfil his/her wish to end his/her life? Should a patient with a known (medically resistant) psychiatric condition also be granted end-of-life options – as for those with terminal medical conditions? A patient known to have a painful, incurable disease (e.g. metastatic cancer) seeks life-ending interventions. Would you be willing to be the person administering the lethal medication (active euthanasia) or facilitate the process of dying by prescribing the lethal medication (physician-assisted suicide)? Regarding performing euthanasia/physician-assisted suicide (for all patients seeking it), I would prefer to:

*Questions requiring elaboration.

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Variations among participants with different religious affiliations were noted. Most respondents in all the groups (52.3% of Christians (n=102), 73.9% of Islamic students (n=34), 57.1% of Hindus (n=4), 87% of agnostics (n=20) and 100% (n=6) of those who did not list a religious affiliation agreed that euthanasia/PAS should be legalised in SA. Higher proportions of respondents in most of these groups felt that patients should be allowed to decide if they want to end their lives prematurely, and that doctors should be allowed to assist them. However, while the majority of Islamic students (56.5%, n=26) felt that euthanasia/PAS should be legalised in SA, the same proportion also felt that doctors should not assist patients in ending their lives prematurely. Some Islamic students (39.1%, n=18) maintained that patients should not be allowed to decide to end their lives prematurely. In contrast, nearly half of the agnostic medical students (43.5%, n=10), presumably with a naturalistic world view, would not attempt to persuade the patient to opt for palliative care. Fig. 2 highlights the differences in the numbers of participants who would 2% 3%

8% Christianity (n=195) Islam (n=46)

17%

Hinduism (n=7) Agnostic (n=23)

70%

Unspecified (n=6)

120

Yes

Undecided

Arguments supporting and opposing euthanasia/PAS

The main arguments presented by respondents in support of and opposing the legalisation of euthanasia/PAS in SA are outlined in Table 2. The results indicate that the views of these future SA doctors on this topic resonate with those of medical practitioners nationally and internationally.[11-17] These arguments are covered in greater detail in the discussion section of this article.

Category 2 questions

These questions explored students’ opinions regarding patient groups in which they would be more or less likely to perform or assist with active euthanasia or PAS. Four scenarios briefly detailing the morbidity of the patient who wished to hasten their death were presented. Results were largely unanimous across each specific question. With regard to the two questions on patients with painful, incurable disease, where the scenarios were similar but with a minor difference relating to duration of life remaining, responses were significantly different, 41.9% (n=116) of participants stating that they would assist in hastening death in a terminally ill patient with intractable suffering who was unlikely to live for much longer, but 71.1% (n=197) indicating that they would not hasten the death of a patient with the same morbidity (terminally ill with intractable suffering) if the patient had a longer time to live – although no exact time frame was provided. Nearly all the students (90.6%) (n=251) said that they would not assist a patient with life-ending interventions if the patient had no known treatable medical illness, and 54.2% (n=150) said that they would not assist a psychiatric patient to end their life prematurely. Participants of Islamic religious affiliation were largely opposed to assisting patients in hastening their death in any of the above scenarios. Reasons provided by respondents regarding which patients they would or would not consider assisting with euthanasia/PAS are set out in Table 3.

Category 3 questions

ec ifi (n= ed 6)

nd Hi

Undecided

Yes

Ag no (n= stic 23 )

Undecided

ui (n= sm 7)

Undecided

Yes

ris ti (n= anit 19 y 5)

Is (n= lam 46 )

46 29

Undecided

140 120 100 80 60 40 20 0

Yes

Participants, n

Fig. 1. Religious affiliations of respondents (N=277) (no respondent listed Judaism as their religious affiliation).

or would not attempt to persuade a patient to opt for palliative care, according to religious affiliation. Of the group as a whole, 50.2% (n=139) said that they would be supportive of a loved one who wanted to end their life prematurely owing to intractable disease. Islamic students differed from their peers in this regard, with only 23.9% (n=11) stating that they would be supportive of such a decision taken by a loved one.

Religious affiliation

Fig. 2. Numbers of participants from the different religious affiliations who would attempt to persuade a patient to opt for palliative care (N=277).

These questions explored students’ preferences for consultation regarding decision-making for patients requesting life-ending interventions. The majority of participants (80.1%, n=222) indicated that they would prefer to have a dedicated ethics team decide on which patient is eligible for euthanasia/PAS. Only 10.1% (n=28) of the respondents said that they would prefer to refer the patient, and the remaining 9.8% (n=27) indicated that they would choose either to decide for themselves or to consult a colleague. Responses to the question relating to who should decide if a patient should be granted their wish to hasten their death are outlined in Table 4.

Table 2. Main arguments of medical students with regard to legalising euthanasia/physician-assisted suicide In support Patient autonomy Relief of suffering In opposition Doctor’s oath to preserve life Morally wrong – against personal/religious world view ‘Slippery slope’ towards active involuntary euthanasia

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Table 3. Reasons for performing or not performing euthanasia/physician-assisted suicide in specific patients Patient with terminal (medical) illness with intractable suffering Yes Respect for patient autonomy To end suffering No Goes against religious/personal beliefs and morals Pro-life (i.e. a doctor’s job is to prolong life, not shorten/end it) Patient with no known medical condition Yes Respect for patient autonomy No No (real) indication to terminate life Patient with an intractable psychiatric condition Yes Quality of life over quantity No Psychiatric condition may not be treated adequately (therefore clouding patient’s judgement)

Table 4. Most common reasons relating to decision-making for euthanasia/physician-assisted suicide Ethics committee Team decisions are generally better than individually based decisions Ethics committees are generally better equipped than individuals to deal with and come to an objective decision regarding who is eligible for life-ending interventions A decision taken by an ethics team ensures that the doctor is protected from whatever consequences may ensue Refer the patient Not to be ‘burdened’ by the decision Consult a colleague/decide self Ethics committees take too long

Table 5. Reasons for preferred method of hastening death, or not wishing to do so Active euthanasia (10.5%) More control over situation with less room for error Physician-assisted suicide (35.0%) Not directly involved in the patient’s death (some participants felt that active euthanasia is equivalent to murder) Individual will have a ‘clear conscience’ (because of not being directly involved) None (36.1%) Goes against religious/personal morals/beliefs A doctor should aim to preserve life, not shorten/end it Undecided (18.4%) No reason provided

Method of hastening death

There were variations among respondents regarding methods by which they would assist a patient to hasten their death. Only 10.5% of students (n=29) indicated that they would opt for active euthanasia, while 35.0% (n=97) indicated that PAS would be their preferred method of hastening a patient’s death. Notably, 36.1% (n=100) indicated that they would rather not have any part in ending a patient’s life, if they were afforded this option. Reasons for the students’ choices of method of hastening death are set out in Table 5.

the opinion that doctors should be allowed to help patients hasten their death upon a competent patient’s request. In the only other SA study, conducted in 2011,[4] it was found that the majority of doctors were opposed to legalising PAS and active euthanasia. The results of the 2011 study concur with those of international studies, which focused on both qualified doctors and medical students. International studies conducted from 2006 to 2015[11-17] reported that the majority of respondents were opposed to either legalising or practising euthanasia/PAS.

Discussion

Arguments supporting legalisation of euthanasia/PAS

The findings of this study differ from equivalent studies conducted both locally and internationally. In our study, which explored the views of 277 medical students, 47.7% of students (n=132) were of

At present, the most widely used argument supporting the legalisation of euthanasia/PAS, both by respondents in this study and those reported in international articles, is that of respect for patient

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autonomy. The word autonomy, deriving from the Greek auto (self) and nomos (rule), refers to a person’s ability to make independent choices about his/her life. Autonomous, competent individuals have a fundamental right to decide what they deem to be good and necessary for themselves after reviewing all their options, with specific reference to healthcare and, by extension, life.[18-20] In SA, a patient’s autonomy is recognised as part of their inalienable constitutional rights, as expressed in the Constitution of South Africa[21] and the National Health Act.[22] Proponents of patient autonomy argue that the right to decide when one dies is or should be included in the understanding of this legislation. Internationally, patient autonomy and the significance thereof with regard to terminal illness and the wish for euthanasia/PAS are recognised and comprehensively detailed in the World Medical Association Declaration of Venice on Terminal Illness.[23] A second argument used in support of euthanasia/PAS is that of the prevention of or relief from intractable suffering, related to the autonomous person’s right to a dignified life and death.[19] The right to dignity is acknowledged in and one of the founding values in the Constitution (section 10).[21] Furthermore, it is widely held that no one should have to be constrained by or live with extreme suffering, if it is believed that the only way in which the suffering can be relieved is through death.[19] Offering the patient the option of euthanasia or PAS could therefore be seen as allowing the patient to die with dignity.[20]

Arguments opposing legalisation of euthanasia/PAS

Arguments opposing the legalisation of euthanasia/PAS by students in this study concur with international data. Euthanasia/PAS are considered wrong on the basis of personal and religious morality and on the basis of the universally acceptable principles of biomedical ethics. The biomedical ethics principles of beneficence (to act in the best interests of your patient) and non-maleficence (to ensure that no harm befalls your patient following your actions) are often used as arguments opposing the legalisation of euthanasia/PAS. The merits of these principles, when viewed (by some) in isolation, seem strong enough to oppose the legalisation of euthanasia/PAS. Additionally, the ‘slippery slope’ argument presented by respondents in this study follows international trends opposing euthanasia. The slippery slope argument infers that the consequences of certain actions (such as legalising euthanasia and/or PAS) may, on their own, be worse than the actual anticipated consequences of prohibiting the said action.[24] The single most widely used slippery slope argument states that by legalising (active) euthanasia and/or PAS, one is at direct risk of pushing the society concerned down a slope that would ultimately resemble that of Nazi Germany.[25] The Nazi Germany analogy aims to accentuate the point that those who practise euthanasia and/or PAS may become ‘dehumanised’, resulting in non-beneficent killing.

What type of patient would medical students assist with euthanasia or PAS?

The majority of the participants in this study were opposed to assisting patients with no known medical condition and those with psychiatric conditions to hasten their death. Most participants expressed the view that they would be more likely to assist a patient with a known terminal illness and intractable suffering with a poorer prognosis, compared with patients with the same morbidity but a better prognosis (i.e. a longer remaining duration of life). This finding concurs with the earlier SA study,[4] in which respondents indicated that they would not consider PAS/euthanasia for a patient without a terminal illness.

The seemingly high percentage of respondents who exhibited reluctance to assist with life-ending interventions to patients with intractable psychiatric illness raises questions regarding the teaching medical students receive on treating intractable psychiatric illnesses: namely, would these (and future) students be more liberal in their opinions about euthanasia/PAS for patients with intractable psychiatric illness if they better understood the concept of futility of treatment in psychiatry, thereby aligning their views with those held internationally – where there is an increase in support and lobbying for these life-ending interventions, as seen in the mental health literature.[10,26]

How would students choose to participate in euthanasia/PAS?

The proportion of participants who indicated that they would participate in either euthanasia or PAS differed from the earlier SA study,[4] in that participants in the current study were more willing to perform euthanasia/PAS.

Conclusions

This study explored medical students’ attitudes towards euthanasia and PAS and the prospects of legalising these practices in SA. In light of the renewed interest in the debate and the changing legal landscape, it was considered important to ascertain the views and opinions of these future doctors with regard to euthanasia and PAS, as it is believed that their views may determine their behaviour towards patients and peers.[12] Furthermore, should euthanasia/PAS be legalised, these young doctors, even though they are not obliged to implement the policies, would potentially need to perform or assist in these procedures and practices.[5] From this study it is evident that there is a difference in attitude towards the practice and legalisation of euthanasia/PAS between future SA doctors and present doctors (i.e. those who participated in the 2011 study). While concerns regarding the legalisation of euthanasia/ PAS do exist (for the reasons given above), if the information provided by this study holds true for medical practitioners, it is safe to accept that SA will not proceed down the slippery slope, as the majority of respondents demonstrated that they are fairly discriminatory about who to perform these life-ending interventions for. Additionally, safeguards such as developing a dedicated ethics committee to rule on case-specific applications, as well as adhering to the safeguards already outlined in the South African Law Commission’s report,[3] would further prevent the ‘misuse’ of these practices in SA. However, since SA is a democratic country, the views of the public should also be considered before moving to legalise or completely abolish these practices – as the SA Constitution regards individualism as equivalent to communitarianism.[27]

Recommendation

Although the responses garnered were largely unanimous across all questions, variations exist between respondents from different religious groups. These differences within as well as between various religious groups should be considered when discussing life-ending matters. These differences in opinion should be explored further in future research relating to euthanasia/PAS, as religion and culture have a significant influence on individuals’ opinions and responses.[28,29] Acknowledgements. The authors express their heartfelt gratitude to Prof. Keymanthri Moodley, Professor and Director, Centre for Medical Ethics and Law, Department of Medicine, Faculty of Health Sciences,

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Stellenbosch University, for her constant and continuous support in this research project and for assisting in obtaining both institutional and ethics approval. This article would not have been possible without her invaluable support and input. Author contributions. RKJ: principal investigator; study conception and design; data acquisition, analysis and interpretation; article drafting. MH: supervisor; study conception and design; article revision and final approval. Funding. None. Conflicts of interest. None. 1. Materstvedt LJ, Clark D, Ellershaw J, et al. Euthanasia and physician-assisted suicide: A view from an EAPC Ethics Talk Force. Palliat Med 2003;17(2):97-101. https://doi.org/10.1191/0269216303pm673oa 2. Scott H. Assisted suicide and the South African constitutional order. Responsa Meridiana 1998;1-17. 3. South African Law Commission. Euthanasia and the artificial preservation of life. Paper 71 Project 86, 1997. www.justice.gov.za/salrc/dpapers/dp71_prj86_1997.pdf (accessed 5 May 2015). 4. Ethics Institute of South Africa. Survey of Doctors’ Attitudes to Assisted Dying. Johannesburg: Ethics Institute of South Africa, 2011. 5. Stransham-Ford v the Minister of Justice and Correctional Services and Others 30 April 2015, Case no. 27401/15 (NGHC). 6. S v De Bellocq 1975 (3) SA 538 (T). 7. S v Hartmann 1975 (3) SA 532 (C). 8. Minister of Justice and Correctional Services v Estate Stransham-Ford (531/2015) 2016 ZASCA 197 (6 December 2016). 9. Bongaarts J, Feeney G. How long will we live? Popul Dev Rev 2006;32(4):605-628. https://doi. org/10.1111/j.1728-4457.2002.00013.x 10. Pienaar W. Developing the language of futility in psychiatry with care. S Afr J Psychiatry 2016;22(1):a978. https://doi.org/10.4102/sajpsychiatry.v22i1.978 11. Leppert W, Majkowicz M, Forycka M. Attitudes of Polish physicians and medical students toward breaking bad news, euthanasia and morphine administration in cancer patients. J Cancer Educ 2013;28(4):603-610. https://doi.org/10.1007/s13187-013-0553-2 12. Ahmed AM, Kheir MM. Attitudes towards euthanasia among final-year Khartoum University medical students. East Mediterr Health J 2006;12(3/4):391-397. http://www.who.int/iris/handle/10665/117098 (accessed 5 May 2015).

13. Karlsson M, Strang P, Milberg A. Attitudes toward euthanasia among Swedish medical students. Palliat Med 2007;21(7):615-622. https://doi.org/10.1177/0269216307081940 14. Clemens KE, Klein E, Jaspers B. Attitudes toward active euthanasia among medical students at two German universities. Support Care Cancer 2007;16(6):539-545. https://doi.org/10.1007/s00520-0080427-z 15. Seale C. Legalisation of euthanasia or physician-assisted suicide: Survey of doctors’ attitudes. Palliat Med 2009;23(3):205-212. https://doi.org/10.1177/0269216308102041 16. Leppert W, Gottwald L, Majkowicz M, et al. A comparison of attitudes toward euthanasia among medical students at two Polish universities. J Cancer Educ 2013;28(2):384-391. https://doi.org/10.1007/ s13187-012-0414-4 17. Zenz J, Tryba M, Zenz M. Palliative care professionals’ willingness to perform euthanasia or physician assisted suicide. BMC Palliat Care 2015;14(1):60. https://doi.org/10.1186/s12904-015-0058-3 18. McQuoid-Mason DJ. Stransham-Ford v. Minister of Justice and Correctional Services and Others: Can active voluntary euthanasia and doctor-assisted suicide be legally justified and are they consistent with the biomedical ethical principles? Some suggested guidelines for doctors to consider. South Afr J Bioethics Law 2015;8(2):34-40. https://doi.org/10.7196/SAJBL.446 19. Landman WA. The ethics of physician-assisted suicide and euthanasia. S Afr Med J 1997;87(7):866869. 20. Egan A. Should the state support the ‘right to die’? South Afr J Bioethics Law 2008;1(2):47-52. 21. South Africa. Constitution of the Republic of South Africa. Pretoria: Government Gazette, 1996. 22. South Africa. National Health Act No. 61 of 2003. 23. World Medical Association. Declaration of Venice on Terminal Illness. World Medical Association, 2006. https://www.wma.net/policies-post/wma-declaration-of-venice-on-terminal-illness// (accessed 7 May 2015). 24. Burgess JA. The great slippery-slope argument. J Med Ethics 1993;19(3):169-174. https://doi. org/10.1136/medethics-2012-100678 25. Lamb D. The slippery slope argument. In: Lamb D, ed. Down the Slippery Slope: Arguing in Applied Ethics. London: Croom Helm, 1988. 26. Berghmans R, Widdershoven G, Widdershoven-Heerding I. Physician-assisted suicide in psychiatry and loss of hope. Int J Law Psychiatry 2013;36(5-6):436-443. https://doi.org/10.1016/j.ijlp.2013.06.020 27. Wing AK. Communitarianism vs. individualism: Constitutionalism in Namibia and South Africa. Wisconsin Int Law J 1992;295(11):295-380. http://ir.uiowa.edu/law_pubs/1495 (accessed 12 May 2015). 28. Bullock K. The influence of culture on end-of-life decision making. J Soc Work End Life Palliat Care 2011;7(1):83-98. https://doi.org/10.1080/15524256.2011.548048 29. Gielen J, van den Branden S, Broeckaert B. Religion and nurses’ attitudes to euthanasia and physician assisted suicide. Nurs Ethics 2009;16(3):303-318. https://doi.org/10.1177/0969733009102692

Accepted 1 February 2018.

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Poor anticoagulation control in patients taking warfarin at a tertiary and district-level prothrombin clinic in Cape Town, South Africa I Ebrahim,1 MB ChB, FC Clin Pharmacol (SA); A Bryer,2 MB BCh, FCP (SA), MMed (Neurology), FC Neurology (SA), PhD; K Cohen,1 MB ChB, MMed (Clin Pharmacol), FCFP (SA), MSc (Epidemiol), Dip HIV Man, Dip Obst; J P Mouton,1 MB ChB; W Msemburi,3 BSc Statistics, BSc Hons, MPhil (Demography); M Blockman,1 MB ChB, BPharm, PG Dip Int Res Ethics, MMed (Clin Pharmacol) Division of Clinical Pharmacology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa Division of Neurology, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 3 Clinical Research Institute, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, South Africa 1 2

Corresponding author: I Ebrahim (ismaeel.ebrahim@uct.ac.za) Background. Warfarin is the most commonly used anticoagulant for both primary and secondary prevention of thromboembolism. For anticoagulation efficacy, the international normalised ratio (INR) needs to be within the therapeutic range for at least 65% of time on warfarin. Objectives. To describe INR control in patients on long-term warfarin and identified predictors of good INR control at two dedicated warfarin follow-up clinics in Cape Town, South Africa (SA). Methods. We reviewed clinical records of patients in care at the INR clinics at Mitchell’s Plain Community Health Centre and Groote Schuur Hospital. We included patients who had been on warfarin therapy for at least 27 months and excluded patients with <6 months of INR monitoring data or a >70-day gap between INR tests in the calculation period, and if >25% of follow-up time was at an alternative site. The time in therapeutic range (TTR) over 180 days using the Rosendaal method was calculated, and we categorised INR control as good if the TTR was ≥65%. We constructed a multivariate logistic regression model to identify associations with good INR control. Results. We included 363 patients, with a median age of 55 years (interquartile range (IQR) 44 - 64), of whom 65.6% were women. The most common indications for warfarin were valvular heart disease (45.7%) and atrial fibrillation (25.1%). The mean TTR was 47%, with only 91/363 patients having good INR control. In a multivariate model adjusted for age, sex, clinic and target INR, patients aged ≥55 years were more likely to have good INR control than younger patients (adjusted odds ratio 1.69, 95% confidence interval 1.03 - 2.79). Poorly controlled patients had more frequent INR monitoring than those with good INR control, with a median of 8 INRs (IQR 6 - 10) v. 6 INRs (IQR 5 - 8) in the 180-day period (p<0.0001). Conclusions. Only 25.1% of patients in our study achieved good INR control, despite regular INR monitoring. There is an urgent need to improve anticoagulation control of patients receiving warfarin in SA. Validated dosing algorithms are required, and access to lower warfarin dosage formulations may optimise individual dose titration. Advocacy for these formulations is advised. S Afr Med J 2018;108(6):490-494. DOI:10.7196/SAMJ.2018.v108i6.13062

Atrial fibrillation (AF) and valvular heart disease (VHD) increase the risk of thrombus-related morbidity and cardioembolic stroke.[1] Stroke is one of the top four causes of death and adult disability in South Africa (SA).[2,3] Appropriately dosed anticoagulation therapy decreases morbidity and mortality due to cardioembolic stroke.[4-6] Warfarin is the most widely used oral anticoagulant for primary and secondary stroke prevention[7] and is the only vitamin K antagonist (VKA) available in SA.[8] Alternative oral anticoagulants are not routinely available in public sector healthcare facilities owing to their high cost.[9] Aspirin is a poor alternative in patients with AF, as it is much less effective at preventing cardioembolic events.[7,10] Warfarin has unpredictable pharmacokinetics and dynamics, and requires individualised dosing to achieve optimal anticoagulation. Warfarin has a narrow therapeutic range, placing patients at risk of bleeding if the target is exceeded and at risk of thromboembolic complications if subtherapeutic.[5,10] Warfarin is a leading cause of adverse drug reaction (ADR)-related medical admissions in SA.[11] Time in the therapeutic range (TTR) is a calculation that reflects the duration of time in which a patient’s international normalised ratio (INR) values were within the desired range and is used

to evaluate the effectiveness of warfarin therapy. For effective anticoagulation, patients on warfarin should achieve an INR in the therapeutic range for ≥65% of the follow-up time.[10] Patients with TTR <65% have reduced warfarin efficacy.[10] Low TTR is also associated with an increased risk of both bleeding and thromboembolic complications. [10] Two multinational multicentre clinical trials (ACTIVE W and RE-LY) that included patients from SA found poor INR control in SA patients receiving warfarin.[10,12]

Objectives

We quantified anticoagulation control over a 6-month period for patients on long-term warfarin managed at two dedicated INR clinics in Cape Town, SA. Specific objectives were to determine the proportion of patients achieving a TTR ≥65%, and to identify predictors of adequate control (TTR ≥65%).

Methods

We reviewed folders of patients attending the warfarin anticoagulation monitoring clinics at Mitchell’s Plain Community Health Centre (MPC) and Groote Schuur Hospital (GSH) in Cape Town. These

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outpatient clinics assess the INR at patient visits and adjust the warfarin dose in response to the INR result. At GSH, INR results are available within hours and dose modification occurs immediately. At MPC, INR results are available the next day and dose adjustment instructions are given to patients telephonically. Both facilities use the same, unvalidated dosing algorithm to guide dose adjustments. We identified patients who were on longterm warfarin therapy, which we defined as at least 2 years on warfarin, after an initial 3-month dose-stabilisation period to achieve the required INR. The INR monitoring results were reviewed, and we excluded patients with <6 months of consecutive INR data and those who visited both or other sites and had >25% of follow-up visits at an alternative site. We also excluded patients who had >70 days between INR quantification.[13] Patient follow-up at clinics occurs at least every 2 months (56 days) and we allowed for patients to be 14 days late for routine follow-up. We excluded patients with larger gaps between INRs as this may affect the accuracy of TTR quantification and under- or overestimate the TTR.[13] We powered the study to detect a 15% difference in the mean TTR between the two sites (with α=0.05 and 80% power) and calculated that we would need 173 patients from each site for a total sample size of 346. We calculated the TTR using the widely accepted Rosendaal method.[13] The calculation assumes a linear relationship (increase or decrease) between consecutive INR values to determine the proportion of time within the therapeutic range.[13] We calculated TTR over 6 months (180 days) and excluded the first 90 days of regular INR monitoring data from the TTR calculation, to allow patients newly initiated on warfarin to achieve stability. TTR was therefore calculated starting from the first INR result after the 90-day window. The target INR range for patients taking warfarin for AF and most other indications is 2.0 - 3.0. The target INR range for VHD is 2.5 - 3.5.[14] The therapeutic range for the patient’s clinical condition was used as the target for that patient in the TTR calculation. In patients with an unknown indication for warfarin therapy, we assumed a target INR range of 2.0 - 3.0. We defined poor control as TTR <65% over the 180-day period, and good control as TTR ≥65%.[10]

Statistical analysis

We summarised continuous variables as means (standard deviation (SD)) if normally

distributed and as medians with interquartile ranges (IQRs) if abnormally distributed, and used the Wilcoxon rank-sum test for between-group comparisons of continuous variables. Univariate associations between categorical variables were explored using the χ2 test. We constructed a multivariate logistic regression model of associations with good anticoagulation (TTR ≥65%), and included age, sex, site and target INR in the model based on an a priori decision. Age was split into two groups at the median and included in the model as a binary variable. A p-value <0.05 was considered statistically significant. Stata SE 13.1 (StataCorp, USA) was used for the analyses.

Ethical considerations

The study was approved by the Human Research Ethics Committee at the University of Cape Town (ref. no. 658/2014) and the Western Cape Health Research Committee (ref. no. WC_2015RP8_111). Permission to conduct the research was given by hospital management of MPC and GSH. The study was conducted in accordance with the Declaration of Helsinki (last updated 2013)[15] and the Guideline for Good Clinical Practice.[16]

Results

We screened the clinical records of 949 patients, of whom 586 were excluded and 363 were included in the analysis (Fig. 1). Screening took place in September 2014. INR data were reviewed between 2009 and 2014, and all participants with more than 27 months of INR data were included in the study.

Patient characteristics are set out in Table 1. The most common indications for warfarin therapy were AF (25.1%) and VHD (45.7%). Other indications were pulmonary embolus, venous thromboembolism, systemic lupus erythematosus, hypercoagulable states and atrial flutter. An indication was not documented in 10.5% of patients. The mean (SD) TTR was 47.0% (24.0%) and did not differ significantly between sites (Fig. 2). In 272/363 patients (74.9%) the TTR was <65%. Poorly controlled patients had more frequent INR monitoring than those with good control, with a median of 8 readings (IQR 6 - 10) and 6 readings (IQR 5.0 - 8.0) over the 6-month period, respectively (rank-sum p<0.0001). Patients aged <55 years had a mean TTR of 43% (95% confidence interval (CI) 40 - 47) compared with a mean of 50% for those aged ≥55 years (95% CI 46 - 53) (p=0.0105). In the multivariate analysis, age ≥55 years was associated with better INR control (Table 2).

Discussion

The majority of patients in our study had poor INR control – only 25.1% had a TTR ≥65%. Older age was associated with better control, but even in patients aged ≥55 years, only 30.6% achieved a TTR of ≥65% (Table 2). This is a concerning finding. Despite regular follow-up, most patients did not achieve adequate INR control for efficacy and are at risk of warfarin adverse effects. Even under clinical trial conditions, anticoagulation control of South Africans taking warfarin was poor. SA partici-

Patient records screened N=949

Patients excluded, n=483 • <27 months on warfarin

INR monitoring results reviewed n=466 patients Patients excluded, n=103 • <6 months INR monitoring, n=60 • >70 days between consecutive INRs, n=23 • >25% of follow-up time at alternative clinic, n=20 Patients included in the analysis n=363 (MPC n=151, GSH n=212)

Fig. 1. Selection of patients included in the analysis. (INR = international normalised ratio; MPC = Mitchell’s Plain Community Health Centre; GSH = Groote Schuur Hospital.)

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Table 1. Characteristics of included patients (N=363) Patients, n (%) Female sex Age (years), median (IQR) Target INR range, n (%) 2.0 - 3.0* 2.5 - 3.5†

MPC 151 (41.3) 100 (66.2) 57 (48 - 66)

GSH 212 (58.4) 138 (65.1) 53 (41 - 62)

121 (80.1) 30 (19.9)

76 (35.9) 136 (64.2)

MPC = Mitchell’s Plain Community Health Centre; GSH = Groote Schuur Hospital; IQR = interquartile range; INR = international normalised ratio. *Target INR range of 2.0 - 3.0 for patients anticoagulated with warfarin because of atrial fibrillation, pulmonary embolus, venous thromboembolism, systemic lupus erythematosus, hypercoagulable states, atrial flutter or undocumented indication. † Target INR range of 2.5 - 3.5 for patients anticoagulated with warfarin because they had valvular heart disease.

Figure 2. Scatter plot of percentage of time that INR was in therapeutic range over 6 months of warfarin therapy

TTR over 6 months, %

anticoagulation) had a mean TTR of 46%.[10] In the RELY trial (randomised evaluation of long-term anticoagulation therapy), which randomised participants with AF to dabigatran or warfarin, 100 the mean TTR of SA participants was 58%.[12] In keeping with our findings, in an earlier study[17] only 50% of patients in Cape Town receiving warfarin for rheumatic heart disease had good anticoagulation control as measured by TTR calculated by the Rosendaal method, but only three INR readings were used in this study. A cross-sectional study at Victoria Hospital in Cape Town 50 found that only 49% of patients had a therapeutic INR.[18] There are few African studies outside SA. In an Ethiopian cross-sectional study, only 30.3% of patients had a therapeutic INR.[19] These cross-sectional studies are limited in their design by the fact that they only provide a snapshot of INR control at a single time point. The association between older age and improved control that we observed is in keeping with findings from other studies.[18,20] The Victoria Hospital 0 study in Cape Town found that patients aged ≥60 years were more MPC GSH likely than younger patients to have a therapeutic INR. A Swedish study also found a correlation between improved TTR and older age. [18,20] Healthcare facility We found no association between INR control and sex, similar to the study at Victoria Hospital.[18] INR control did not differ between the two clinics in our study. Fig. 2. Scatter plot of the percentage of time the INR was in the therapeutic Patients with poor anticoagulation control (TTR <65%) had more range over 6 months of warfarin therapy. Solid bars represent means and than those with good control, but despite standard S o l i d b deviations. a r s r e p r e The s e n dotted t s m e line a n s is a atn the d s TTR t a n d target a r d d (INR e v i a int i therapeutic o n . T h e d o t t frequent e d l i n e i INR s a t monitoring th e regular monitoring to guide dose adjustments, INR control was poor range for 65% of the time). TTR below the target indicates inadequate INR T T R t a r g e t ( I N R i n t h e r a p e u t i c r a n g e f o r 6 5 % o f t h e t i m e ) . T in T R these b e l patients. o w t h e tThis a r g e may t i n d reflect i c a t e sflaws in the unvalidated algorithm control. (INR = international normalised ratio; TTR = time in therapeutic irange; n a d e MPC q u a t =e Mitchell’s I N R c o n Plain t r o l . Community Health Centre; GSH = Groote used to guide warfarin dose adjustment at our study sites. Poor INR control may result in serious clinical consequences. A Schuur Hospital.) recent SA survey found that warfarin was the fourth most commonly implicated drug in ADR-related admissions and the most commonly pants with AF randomised to warfarin in the international implicated drug in preventable ADR-related admissions.[11] A median multicentre ACTIVE-W trial (dual antiplatelet therapy v. warfarin Table 2. Multivariate logistic regression model of associations with good anticoagulation control (TTR ≥65%) over 6 months (363 patients included in the model) Variable Age Sex Site INR target

Category <55 years ≥55 years Female Male MPC GSH 2 - 3* 2.5 - 3.5†

Univariate analysis OR (95% CI) Wald test p-value ref 1.86 (1.14 - 3.02) 0.013 ref 1.26 (0.77 - 2.07) 0.351 ref 0.69 (0.43 - 1.12) 0.132 ref 0.63 (0.39 - 1.03) 0.065

TTR ≥65%, n (%) 34/177 (19.2) 57/186 (30.6) 56/238 (23.5) 35/125 (28.0) 44/151 (29.1) 47/212 (22.2) 57/197 (28.9) 34/166 (20.5)

Multivariate analysis Adjusted OR (95% CI) Wald test p-value ref 1.69 (1.03 - 2.79) 0.039 ref 1.21 (0.73 - 1.99) 0.451 ref 0.85 (0.50 - 1.46) 0.560 ref 0.75 (0.43 - 1.30) 0.312

TTR = time in therapeutic range; INR = international normalised ratio; OR = odds ratio; CI = confidence interval; MPC = Mitchell’s Plain Community Health Centre; GSH = Groote Schuur Hospital. *INR target 2 - 3: atrial fibrillation, pulmonary embolus, venous thromboembolism, systemic lupus erythematosus, hypercoagulable states, atrial flutter. † INR target 2.5 - 3.5: valvular heart disease.

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hospital stay of 6 days (IQR 4 - 8.5) for all bleeds related to warfarin and non-steroidal anti-inflammatory drugs was recorded. [11] In an American study, INR instability was associated with higher healthcare utilisation, driven by increased length of hospital stay.[21] Direct oral anticoagulants (DOACs) are an alternative to warfarin. DOACs have a number of advantages, but are expensive when the direct cost is considered and therefore currently not routinely available in the SA public sector. DOACs have more rapid onset than warfarin, do not require heparin bridging, have fixed doses, are less susceptible to food and drug-drug interactions and do not require routine anticoagulation monitoring.[9,22-24] A meta-analysis of stroke prevention in AF patients comparing three DOACs (rivaroxaban, dabigatran and apixaban) with VKAs, published in 2017, found a significantly lower risk of intracranial haemorrhage with DOACs, with similar efficacy to that of DOACs.[25] However, warfarin therapy is likely to remain an important anticoagulant option in our setting, as DOACs are currently not easily accessed in the public healthcare sector. In addition, poor TTR control may be compounded by suboptimal warfarin dose adjustment practice. In SA, healthcare workers may prescribe half-tablet dosages in order to achieve a warfarin dose less than the only available 5 mg strength. A study comparing warfarin measured half-tablet drug content against target drug content found that a third of half-tablets fell outside of the proxy United States Pharmacopeia specification.[26] These findings suggest that warfarin may not always be uniformly distributed within the tablets, which may contribute to the variability and difficulty in achieving effective warfarin dose titration. Individualised small incremental dose adjustments may therefore not always be possible.

Study limitations

Our study has several limitations. We did not have data on some covariates such as concomitant comorbid disease, including hepatic or cardiac dysfunction, interacting medications and diet, which could affect anticoagulation control. Data on warfarin adherence, dosing recommendations or adherence to dose adjustment recommendations were not available. Patients with >70-day gaps between INRs were excluded, in line with recommendations for the Rosendaal method. [13] This may bias towards inclusion of more adherent patients, as patients missing clinic visits would be excluded. Despite this potential for bias, TTR was low in our included patients. Patients with <27 months of follow-up were not included, and this exclusion may also have introduced some bias, as patients with an indication for long-term anticoagulation who died before 27 months were not eligible for inclusion. For patients with ‘unknown indication’ we assumed a lower INR target level. This may have biased TTR control positively if the higher target (INR 2.5 - 3.5) was required. Although our total sample from the two sites exceeded the 346 patients required based on our power calculation, we were only able to include 152 patients who were eligible for inclusion from the MPC site. We therefore did not meet the power requirement to detect a 15% TTR difference between the two sites. The Rosendaal method to calculate TTR, which is the widely recommended method for describing anticoagulation control, also has certain limitations, particularly when individual INR values are far outside the recommended therapeutic range, as it assumes that the change in INR over time is linear between each time-point, which may not always be true. Our TTR target of ≥65% is derived from studies in AF, and may be too conservative for patients with VHD. Despite these limitations, this study provides good evidence in clinical practice of inadequate anticoagulation control in patients attending two high-volume INR clinics located in an urban SA community healthcare centre and at a tertiary academic hospital.

Conclusions

We found poor levels of anticoagulation control in our longitudinal study at two large urban dedicated SA INR clinics. Poor INR control places patients at risk of complications due to toxicity or lack of efficacy of therapy. Further research identifying predictors of poor control is required. The impact of poor anticoagulation control on clinical outcomes and healthcare costs in SA patients requires quantification. Warfarin therapy is likely to remain an important anticoagulant option in our setting, until the affordability and hence accessibility of alternative agents in SA conditions have been formally assessed. Evidence-based, locally validated algorithms to guide warfarin dose adjustment are urgently needed. The only warfarin formulation currently available in the public sector is the 5 mg tablet. Lower warfarin dosage formulations may optimise individual dose titration, and advocacy for these formulations is advised. Acknowledgements. The authors gratefully acknowledge the study patients and the nursing staff at the two prothrombin clinics, MPC and GSH. Special acknowledgement goes to Dr J P Mouton and Mr William Msemburi for their support in statistics and extraction of the data. We also thank Annemie Stewart for creating the data base, Nicky Kramer for her contribution during the protocol development and Dawn Rossiter for editing. Lastly, we thank the National Health Laboratory Service for providing patient INR data. Author contributions. Study concept and design: IE, MB and AB. Drafting of the manuscript: IE, MB, AB and KC. Statistical analysis and statistical support: IE, JPM, WM and KC. Interpretation of the data: all authors. Critical revision of the manuscript for important intellectual content: all authors. Funding. None. Conflicts of interest. None. 1. Singer D, Albers G, James D, et al. Antithrombotic therapy in atrial fibrillation. Chest 2008;133(6):546S-592S. https://doi.org/10.1378/chest.08-0678 2. South African Medicine Research Council. South African Burden of Disease report 2000. www.mrc. ac.za/bod (accessed 16 January 2016). 3. Horton R. Global disease burden GBD 2010: Understanding disease, injury, and risk. Lancet 2012;380(9859):2053-2054. https://doi.org/10.1016/S0140-6736(12)62133-3 4. Whayne TF. A review of the role of anticoagulation in the treatment of peripheral arterial disease. Int J Angiol 2012;21(4):187-194. https://doi.org/10.1055/s-0032-1330232 5. Hylek EM. Vitamin K antagonists and time in the therapeutic range: Implications, challenges, and strategies for improvement. J Thromb Thrombolysis 2013;35(3):333-335. https://doi.org/10.1007/s11239013-0900-5 6. Cannegieter S, Rosendaal F, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994;89:635-641. https://doi.org/10.1161/01.CIR.89.2.635 7. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999;131(7):492-501. https://doi.org/10.7326/0003-4819131-7-199910050-00042 8. Bryer A. New antithrombotic drugs? A revolution in stroke management (Editorial). Cardiovasc J Afr 2012;23(2):61-62. http://www.cvja.co.za/onlinejournal/vol23/vol23_issue2/files/assets/basic-html/index. html#7 (accessed 24 April 2018). 9. Sardar P, Chatterjee S, Chaudhari S, et al. New oral anticoagulants in elderly adults: Evidence from a metaanalysis of randomized trials. J Am Geriatr Soc 2014;62(5):857-864. https://doi.org/10.1111/jgs.12799 10. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029-2037. http://doi. org/10.1161/CIRCULATIONAHA.107.750000 11. Mouton JP, Njuguna C, Kramer N, et al. Adverse drug reactions causing admission to medical wards. Medicine (Baltimore) 2016;95(19):1-10. https://doi.org/10.1097/MD.0000000000003437 12. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: An analysis of the RE-LY trial. Lancet 2010;376(9745):975-983. https://doi.org/10.1016/S01406736(10)61194-4 13. Rosendaal FR, Cannegieter SC, van der Meer FJ, et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993;69(3):236-239. 14. Wan Y, Heneghan C, Perera R, et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: A systematic review. Circ Cardiovasc Qual Outcomes 2008;1:84-91. https://doi. org/10.1161/CIRCOUTCOMES.108.796185 15. World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA 2013;310(20):2191-2194. https://doi.org/10.1001/ jama.2013.281053 16. ICH harmonized tripartite guideline: Guideline for Good Clinical Practice. J Postgrad Med 2001;47(1):4550. http://www.jpgmonline.com/text.asp?2001/47/1/45/235 (accessed 3 August 2017). 17. Barth DD, Zühlke LJ, Joachim A, et al. Effect of distance to health facility on the maintenance of INR therapeutic ranges in rheumatic heart disease patients from Cape Town? No evidence for an association. BMC Health Serv Res 2015;15(219):1-7. https://doi.org/10.1186/s12913-015-0890-4

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18. Sonuga BO, Hellenberg DA, Cupido CS, Jaeger C. Profile and anticoagulation outcomes of patients on warfarin therapy in an urban hospital in Cape Town, South Africa. Afr J Primary Health Care Fam Med 2016;8(1):1-8. https://doi.org/10.4102/phcfm.v8i1.1032 19. Teklay G, Shiferaw N, Legesse B, Bekele ML. Drug-drug interactions and risk of bleeding among inpatients on warfarin therapy? A prospective observational study. Thromb J 2014;12:20. https://doi. org/10.1186/1477-9560-12-20 20. Wieloch M, Sjlander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. Anticoagulation control in Sweden: Reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011;32(18):2282-2289. https://doi. org/10.1093/eurheartj/ehr134 21. Laliberté F, Pilon D, Raut MK, et al. Is rivaroxaban associated with lower inpatient costs compared to warfarin among patients with non-valvular atrial fibrillation? Curr Med Res Opin 2014;30(8):15211528. https://doi.org/10.1185/03007995.2014.916159 22. Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation? A systematic review and meta-analysis of subgroups. Thrombosis 2013 (2013), Article ID 640723. https://doi.org/10.1155/2013/640723

23. Ymer M, Agon M, Shkelzen D, et al. New oral anticoagulants? Their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015;11:967-977. https://doi.org/10.2147/TCRM.S84210 24. Verheugt FA. The new oral anticoagulants. Neth Heart J 2010;18(6):314-318. https://doi.org/10.1182/ blood-2009-09-241851 25. Ntaios G, Papavasileiou V, Makaritsis K, Vemmos K, Michel P, Lip G. Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation: A systematic review and meta-analysis. Stroke 2017;48(9):2494-2503. https://doi. org/10.1161/STROKEAHA.117.017549 26. Hill S, Varker AS, Karlage K, Myrdal PB. Analysis of drug content and weight uniformity for halftablets of 6 commonly split medications. J Manag Care Spec Pharm 2009;15(3):253-261. https://doi. org/10.18553/jmcp.2009.153.253

Accepted 2 February 2018.

Phenotypic and genotypic correlation of carbapenememase-producing Enterobacteriaceae and problems experienced in routine screening This open-access article is distributed under CC-BY-NC 4.0.

A Singh-Moodley,1,2 BSc, BMedSc Hons, MMedSc, PhD; O Perovic,1,2 MD, DTM&H, FC Path (SA) (Microbiol), MMed (Microbiol)

Centre for Healthcare-associated infections, Antimicrobial Resistance and Mycoses, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa 2 Department of Clinical Microbiology and Infectious Diseases, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1

Corresponding author: A Singh-Moodley (ashikas@nicd.ac.za) Background. The emergence and transmission of carbapenem-resistant Enterobacteriaceae (CRE) is a concern in both the clinical and public health arenas. Reliable and accurate detection of these organisms is required for patient management and infection prevention and control purposes. In the routine laboratory, phenotypic methods are utilised for identification of CRE. Objectives. To investigate the phenotypic profiles of suspected carbapenemase-producing Enterobacteriaceae (CPE) isolates generated by the automated MicroScan Walkaway system making use of the Clinical and Laboratory Standards Institute (CLSI) guidelines, and correlate these with carbapenemase production by molecular methods. Methods. Antimicrobial susceptibility testing was performed using the MicroScan Walkaway system, and the presence of six carbapenemase genes (blaNDM, blaVIM, blaIMP, blaOXA-48 and variants, blaGES and blaKPC) was screened for using a multiplex real-time polymerase chain reaction. Results. A total of 2 678 isolates were evaluated. Klebsiella pneumoniae accounted for 62.9% of the isolates (n=1 685), followed by Enterobacter cloacae (n=361, 13.5%). Carbapenemases accounted for 75.2% of isolates; blaOXA-48 and its variants predominated (n=978, 36.5%), followed by blaNDM (n=904, 33.8%), blaVIM (n=108, 4.0%), blaIMP (n=35, 1.3%), blaGES (n=24, 0.9%) and blaKPC (n=18, 0.7 %). Conclusions. A considerable number of isolates expressing a carbapenemase or carbapenemases (the majority of which were blaOXA-48 producing) were susceptible to third-and fourth-generation cephalosporins and carbapenems, demonstrating that confirmed carbapenemase-producing isolates are not presenting as possible carriers of carbapenemases using routine diagnostic methods. Similar results were obtained when CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints were applied and are suitable for the purpose of patient management. However, since genotyping assays are costly, it is suggested that routine laboratories first perform comprehensive phenotypic screening for CPE. S Afr Med J 2018;108(6):495-501. DOI:10.7196/SAMJ.2018.v108i6.12878

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i6.12878

June 2018, Print edition

These open-access articles are distributed under Creative Commons licence CC-BY-NC 4.0.

RESEARCH

Is adrenal suppression in asthmatic children reversible? A case series E W Zöllner, PhD, MMed, MB ChB, DCH, DTM&H, DCH Endocrine Unit, Department of Paediatrics, Tygerberg Children’s Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Corresponding author: E W Zöllner (zollner@sun.ac.za) Background. Six hypocortisolaemic asthmatic children on steroids given at physiological doses were identified during a previous study. Objectives. To establish whether hypothalamic-pituitary-adrenal axis suppression (HPAS) could be reversed in hypocortisolaemic asthmatic children treated with steroids without sacrificing asthma control. Methods. In this case series, treatment of six hypocortisolaemic patients was modified by introducing steroid-sparing asthma medications. Serum cortisol and repeat overnight metyrapone tests (ONMTPTs) were done until HPAS was reversed in all patients. A retrospective folder review was performed and the following data were extracted: body mass index standard deviation score (BMI SDS), adherence, daily steroid type and dose, treatment modification, serum cortisol, final ONMTPT result and time taken to achieve normalisation. Results. The median serum cortisol level recovered to 311 nmol/L after 0.9 years (median). The ONMTPT normalised within 3.3 years (median). Steroid load decreased from 9.2 to 5.0 hydrocortisone equivalent mg/m2/d (medians), while asthma score improved from 1.42 to 0.85 (medians). Poor adherence was noted in two children before and four after treatment modification. BMI SDS decreased from –0.08 to –0.16 (medians). Conclusions. Hypocortisolaemia and HPAS could be reversed in asthmatic children treated with physiological doses of steroids by reducing steroid load by 40% and supplementing therapy with steroid-sparing medication. Poor adherence may have either contributed to or retarded HPA recovery. Simultaneously, asthma control improved. Confirmation by a prospective study would be ideal, but may not be feasible. S Afr Med J 2018;108(6):502-505. DOI:10.7196/SAMJ.2018.v108i6.13031

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i6.13031

Outcomes of outpatient ureteral stenting without fluoroscopy at Groote Schuur Hospital, Cape Town, South Africa S Sinha,1 MBBS, MS, FRCS (Glasg), FC Urol (SA); S Z Jaumdally,2,3 PhD; F Cassim,1 MB ChB, MMed (Urol), FC Urol (SA); J Wicht,1 MB ChB, MMed (Urol), FC Urol (SA); L Kaestner,1 MB ChB, MMed (Urol), FC Urol (SA); A Panackal,1 MD, FC Urol (SA); C H Jehle,1 MB ChB, MRCS (Lond), MMed (Urol), FC Urol (SA); P Govender,1 MB ChB, MMed (Urol), FC Urol (SA); S de Jager,1 MB ChB; E de Wet,1 MB ChB; M Dewar,1 MB ChB, MMed (Urol), FC Urol (SA); M E Kolia,1 MB ChB, FC Urol (SA); S Salukazana,1 MB ChB; C Moolman,1 MB ChB, MMed (Urol), FCUrol (SA); A P van den Heever,1 MB ChB, FC Urol (SA); B Kowlessur,1 MBBS, FC Urol (SA); G Pinto,1 MD, FC Urol (SA); J Lazarus,1 MB ChB, MMed (Urol), FC Urol (SA) Division of Urology, Department of Surgery, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa 2 Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 3 School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: S Sinha (s.sinha@uct.ac.za) Background. Ureteral stenting is generally a theatre-based procedure that requires a multidisciplinary team and on-table imaging. Limited hospital bed numbers and theatre time in our centre in Cape Town, South Africa, have led us to explore an alternative approach.

June 2018, Print edition

RESEARCH

Objectives. To see whether outpatient insertion of ureteric stents under local anaesthesia without fluoroscopy was a possible and acceptable alternative to theatre-based ureteral stenting. Methods. Ureteral stenting (double-J stents and ureteric catheters) was performed with flexible cystoscopy under local anaesthesia and chemoprophylaxis, but without fluoroscopic guidance, in an outpatient setting. Every patient had an abdominal radiograph and an ultrasound scan of the kidney after the procedure to confirm stent position. Results. Three hundred and sixteen procedures (276 double-J stents and 40 ureteric catheters) were performed in 161 men and 155 women. The overall success rate for the procedures was 85.4%, independent of gender (p=0.87), age (p=0.13), type of device inserted (p=0.81) or unilateral/bilateral nature of the procedure (p=1.0). Procedures with a successful outcome were performed in a significantly (p<0.0001) shorter median time (10 minutes (interquartile range (IQR) 5 - 15)) than failed procedures (20 minutes (IQR 10 - 30)). Patients with a pain score of >5 experienced a significantly (p=0.02) greater proportion of failure (27.3%) than patients with a pain score of â&#x2030;¤5 (12.5%). Difficulties were encountered in 23.7% of procedures, with a significantly higher proportion being registered in failed interventions compared with successful ones (82.6% v. 13.7%; p<0.0001). Conclusions. The procedure was easily mastered and technically simple, and represents savings in cost, time and human resources in our setting. S Afr Med J 2018;108(6):506-510. DOI:10.7196/SAMJ.2018.v108i6.12983

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i6.12983

Predictors of unplanned pregnancies among female students at South African Technical and Vocational Education and Training colleges: Findings from the 2014 Higher Education and Training HIV and AIDS survey N Mbelle, MA ELT, MPH; M Mabaso, MSc, PhD; G Setswe, MPH, PhD; S Sifunda, MPH, PhD HIV/AIDS, STIs and TB (HAST) Programme, Human Sciences Research Council, Pretoria, South Africa Corresponding author: N Mbelle (nmbelle@hsrc.ac.za) Background. Unplanned pregnancies among college/tertiary female students pose a serious public health concern in South Africa (SA) and are associated with adverse health and social outcomes that impact negatively on educational progress and future career prospects. Objectives. To examine the potential predictors of unplanned pregnancy among female students at Technical and Vocational Education and Training (TVET) colleges in SA. Methods. This analysis used data drawn from the 2014 Higher Education and Training HIV and AIDS survey, which was a nationally representative survey of TVET college students in SA. Associations between unplanned pregnancy and the explanatory variables were assessed using bivariate analysis. Multivariate logistic regression analysis was used to identify the effect of several independent predictors of unplanned pregnancy. Results. Of 1 002 female students who responded to the question on unplanned pregnancy, 74.6% reported having had an unplanned pregnancy. Predictors significantly associated with a reduced likelihood of unplanned pregnancy among female TVET students included living with a husband (odds ratio (OR) 0.28, 95% confidence interval (CI) 0.13 - 0.62; p=0.002), having two (OR 0.45, 95% CI 0.23 - 0.88; p=0.003) or three (OR 0.07, 95% CI 0.01 - 0.39; p=0.003) previous pregnancies, and not having had an abortion (OR 0.16, 95% CI 0.04 - 0.62; p=0.008). Conclusions. The high level of unplanned pregnancies is indicative of the state of womenâ&#x20AC;&#x2122;s reproductive health services at SA TVET colleges. The findings suggest that certain groups of female students are at increased risk of unplanned pregnancy and would benefit from targeted family planning interventions tailored to their needs. S Afr Med J 2018;108(6):511-516. DOI:10.7196/SAMJ.2018.v108i6.12744

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i6.12744

June 2018, Print edition

RESEARCH

High risk of suicide among high-school learners in uMgungundlovu District, KwaZulu-Natal Province, South Africa N Khuzwayo,1 PhD; M Taylor,2 PhD; C Connolly,2 MPH 1 2

Discipline of Rural Health, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Discipline of Public Health Medicine, School of Nursing and Public Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

Corresponding author: N Khuzwayo (khuzwayone@ukzn.ac.za) Background. Worldwide, suicide affects the most vulnerable populations, including adolescents and young adults. It is estimated that suicide will contribute more than 2% to the global burden of disease by 2020. Information about the prevalence of suicidal behaviour and the sociodemographic characteristics and risk factors associated with suicide in the South African (SA) rural context is important for local and national policy and contributes to global understanding of the phenomenon. Objective. To investigate key demographic factors and behaviours associated with planning and attempting suicide among high-school learners. Methods. In a cross-sectional study, we used stratified random sampling to select 16 schools in uMgungundlovu District, KwaZulu-Natal Province, SA. All grade 10 learners (N=1 759) at these schools completed a self-administered questionnaire (Centers for Disease Control and Prevention (CDC) Youth Risk Behavior Surveillance System). Data analysis was carried out with Stata 13 statistical software using generalised estimating equations. Results. In total, 222 learners (12.6% of the 1 759) had made plans to attempt suicide during the previous 12 months, 261 (14.8%) had actually attempted suicide, and 218 attempts had resulted in the learner being treated by a doctor or nurse (12.4%). The risk of planning suicide increased with age. For male learners, being threatened with a weapon on school property (adjusted odds ratio (AOR) 3.7, 95% confidence interval (CI) 1.9. - 7.1; p<0.01) or bullied through Facebook or WhatsApp (AOR 3.1, 95% CI 1.5 - 7.1; p<0.01) significantly increased the likelihood of making a suicide attempt that resulted in treatment by a doctor or nurse. For female learners, engaging in risk behaviours increased this likelihood, risk factors including being physically hurt by someone they were dating (1 - 3 times AOR 3.3, 95% CI 1.9 - 5.7; p<0.01, â&#x2030;Ľ4 times AOR 10.0, 95% CI 2.5 â&#x20AC;&#x201C; 40.2 (p<0.01) and number of drinks consumed in the past month (AOR 2.0, 95% CI 1.4 - 3.0; p<0.01). Conclusions. The prevalence of suicide attempts among these SA learners was high and was influenced by multiple factors. Routine surveillance systems are urgently required to develop context-based interventions for male and female learners at uMgungundlovu District rural high schools. S Afr Med J 2018;108(6):517-523. DOI:10.7196/SAMJ.2018.v108i6.12843

Full article available online at https://doi.org/10.7196/SAMJ.2018.v108i6.12843

June 2018, Print edition

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Die Van Heerden apteek groep bied n uitstekende sake geleentheid vir n Algemene Praktisyn, Psigiater en / of Dermatoloog met n bestaande praktyk wat n nuwe perseel benodig of addisionele kapasiteit beskikbaar het. Die geleenthede is by 2 van die apteke in Pretoria Oos en 1 apteek in Modimolle beskikbaar en die opsies is buigbaar volgens behoefte van praktyk. Die beoogde persele is onmiddelik beskikbaar by ons Apteke. Die oogmerk is n multi-dissplin re span waar die pasi nt toegang het tot die dokter(s), sowel as medikasie by dieselfde punt van sorg. Goeie mense verhoudinge, respek en samewerking word as grondslag vir die ooreenkoms beskou. Die praktyk se ure moet verkieslik in ooreenstemming wees met die handelsure van die apteek, teneinde optimaal diens te kan lewer. n ormele ontmoeting tussen belangstellende partye sal gereel word waarin verdere inligting sal verskaf word. Bystand met strukturele komponent sal verleen word, dit sluit in oprigting van kantore / spasie volgens unieke praktyk behoefte. Telefoon, elefoon, Internet en toerusting is u eie verantwoordelikheid.

ir eer inligting kontak Clarice Steen erg

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083 410 0353 clarice vhadmin.co.za

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CPD

June 2018

The CPD programme for SAMJ is administered by Medical Practice Consulting. CPD questionnaires must be completed online at www.mpconsulting.co.za.

True (A) or false (B): SAMJ Staphylococcus aureus and Escherichia coli levels on the hands of theatre staff in three hospitals in Johannesburg, South Africa (SA), before and after handwashing 1. The main sources of hospital-acquired infections are contaminated air, contact surfaces and hands of medical staff. 2. Skin flora contains transient flora that colonise the superficial layer of the skin and are responsible for nosocomial infections, which are not easily removed by handwashing. Medical students’ perspectives on euthanasia and physicianassisted suicide and their views on legalising these practices in SA 3. Euthanasia and physician-assisted suicide are defined as two distinct means by which an end to a patient’s life can be brought about. 4. Euthanasia is defined as ‘a doctor intentionally killing a person by the administration of drugs, at that person’s voluntary and competent request’. 5. PAS is defined as ‘a doctor intentionally helping a person commit suicide by providing drugs for self-administration, at that person’s voluntary and competent request’. 6. SA law regards both euthanasia and physician-assisted suicide as forms of active euthanasia. Poor anticoagulation control in patients taking warfarin at a tertiary and district-level prothrombin clinic in Cape Town, SA 7. Appropriately dosed anticoagulation therapy decreases morbidity and mortality due to cardioembolic stroke. 8. Warfarin has a narrow therapeutic range, placing patients at risk of bleeding if the target is exceeded and at risk of thromboembolic complications if subtherapeutic. 9. Warfarin is a leading cause of adverse drug reaction-related medical admissions in SA. Phenotypic and genotypic correlation of carbapenememaseproducing Enterobacteriaceae and problems experienced in routine screening 10. There is an increase in the detection of Enterobacteriaceae strains with resistance observed against beta-lactams, fluoroquinolones, aminoglycosides and polymyxins.

CME Anaesthesia for paediatric patients: Minimising the risk 11. Complication rates have been reported to be significantly increased in groups performing ˂100 paediatric anaesthesia procedures annually compared with groups performing >200 procedures. 12. The recovery area should have one-on-one patient-to-nurse ratios and the staff should be familiar with specific paediatric care and resuscitation protocols. 13. The neonatal period is associated with highest risk, and neonatal surgery should only be undertaken in specialist centres. Managing spinal hypotension during caesarean section: An update 14. The substandard treatment of spinal hypotension and associated complications are responsible for up to two-thirds of deaths that occur in SA for caesarean section under spinal anaesthesia. 15. In some cases, spinal hypotension may be predicted by simple parameters such as age >25 years, preoperative heart rate >90 bpm and preoperative mean arterial pressure <90 mmHg. 16. Crystalloid co-loading is an adequate fluid strategy in most cases, but is of limited efficacy in the prevention of hypotension. Myocardial injury after non-cardiac surgery: Time to shed the ignorance 17. Myocardial injury after non-cardiac surgery (MINS) is defined as an elevated postoperative cardiac troponin level that is considered as resulting from myocardial ischaemia without evidence of a non-ischaemic cause for the troponin elevation. 18. Globally, >7% of adults ≥45 years of age suffer MINS. 19. A relative myocardial hypoperfusion and ischaemia perioperatively differentiate MINS from myocardial infarction in non-surgical patients. 20. One in 10 patients with MINS dies within 30 days of surgery, and 1 in 5 develops major cardiovascular complications.

Readers please note: Articles may appear in summary/abstract form in the print edition of the Journal, with the full article available online at www.samj.org.za

A maximum of 3 CEUs will be awarded per correctly completed test.

INSTRUCTIONS 1. Read the journal. All the answers will be found there, in print or online. 2. Go to www.mpconsulting.co.za to answer the questions. Accreditation number: MDB015/033/01/2018

June 2018, Print edition

Makes colon cleansing plain sailing...

Sodium Picosulphate Oral Powder for Solution. For bowel cleansing in conjunction with: Intravenous Pyelograms (IVP) Bowel Evacuation Abdominal X-Ray Examinations Surgery Colonoscopy S0 Each sachet contains: Sodium Picosulphate 10mg, Magnesium Oxide Ph Eur 3.5g, Citric Acid Ph Eur 12.0g, Aspartame 36mg. Reg.No A38/11.5/0389.