Inpatient management of children with severe acute malnutrition: a review of WHO guidelines

XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651 | doi: http://dx.doi.org/10.2471/BLT.15.162867 Research 642 Inpatient management of children with severe acute malnutrition: a review of WHO guidelines Kirkby D Tickella & Donna M Dennob Introduction Each year, severe acute malnutrition – defined as a weight-for- height z-score of less than −3 or a mid-upper arm circumfer- ence of less than 115 mm – is the direct cause of an estimated 540 000 child deaths and an important underlying contributor to many other child deaths, especially those due to pneumonia and diarrhoea.1,2 The prevalence of – and case fatality rate for – malnutrition are particularly high in infants.3,4 Severe acute malnutrition without medical complications can now be effectively managed in the community, with ready-to-use thera- peutic foods.5 The presence of complications such as anorexia, infections or metabolic dysfunction still warrants inpatient management. The World Health Organization (WHO) indi- cates that, by following its inpatient management guidelines, less than 10% of children with complicated severe acute mal- nutrition should die.2 However, despite reported compliance with these guidelines, health centres in sub-Saharan Africa have reported mortality rates of 10–40% among severely malnour- ished hospitalized children.3,6 The corresponding published rates in Asia tend to be lower, possibly because: Asian health systems are generally stronger than their African counterparts; therapeutic innovations have been introduced in some Asian facilities that have not yet been used in Africa; and children with uncomplicated severe malnutrition are sometimes admitted to Asian health facilities – but not, generally, to African health facilities.7,8 In sub-Saharan Africa, human immunodeficiency virus (HIV) is believed to contribute greatly to malnutrition- related mortality – although, a recent meta-analysis demon- strated an overall case fatality rate of 15% among paediatric inpatients with severe malnutrition without HIV infection.6 It is unlikely that severe acute malnutrition will be eliminated in the foreseeable future, as preventative interven- tions would have to reach the 52 million children who have moderate acute malnutrition.1 Optimizing the management of complicated severe malnutrition therefore remains an im- portant strategy for reducing malnutrition-related mortality. WHO’s first guidelines on the management of malnu- trition – published in 1981 and focused on protein-energy malnutrition9– were replaced in 1999 by guidelines on the management of severe acute malnutrition.10 These two documents summarized decades of clinical experience and described the achievement of low malnutrition-related case fatality rates in some specific settings.9-11 Further guideline revisions were made in 20032 and 2013.4 Relevant joint state- ments from WHO and other United Nations agencies were issued in 20075 and 2009.12 The combination of these joint statements, the 1999 guidelines and the revisions of 2003 and 2013 constitutes the current WHO severe acute malnutrition guidelines and underpins WHO’s related training material.13 Although weak health systems and the inadequate imple- mentation of guidelines undoubtedly contribute to the high number of preventable deaths attributed to complicated severe acute malnutrition,14 this condition causes high case fatality even in relatively well resourced centres that report full imple- mentation of the WHO guidelines. This review attempts to identify evidence gaps within the guidelines on inpatient man- agement of severe acute malnutrition that, if filled, may help reduce mortality below the levels that can be accomplished solely by adherence to existing guidelines. We reviewed each individual recommendation contained within current WHO guidelines – including those relating to the post-discharge Objective To understand how the World Health Organization’s (WHO’s) guidelines on the inpatient care of children with complicated severe acute malnutrition may be strengthened to improve outcomes. Methods In December 2015, we searched Google scholar and WHO’s website for WHO recommendations on severe acute malnutrition management and evaluated the history and cited evidence behind these recommendations. We systematically searched WHO International Clinical Trials Registry Platform, clinicaltrials.gov and the Controlled Trials metaRegister until 10 August 2015 for recently completed, ongoing, or pending trials. Findings WHO’s guidelines provide 33 recommendations on the topic. However, 16 (48.5%) of these recommendations were based solely on expert opinion – unsupported by published evidence. Another 11 (33.3%) of the recommendations were supported by the results of directly relevant research – i.e. either randomized trials (8) or observational studies (3). The other six recommendations (18.2%) were based on studies that were not conducted among children with complicated severe malnutrition or studies of treatment that were not identical to the recommended intervention. Trials registries included 20 studies related to the topic, including nine trials of alternative feeding regimens. Acute medical management and follow-up care studies were minimally represented. Conclusion WHO’s guidelines on the topic have a weak evidence base and have undergone limited substantive adjustments over the past decades. More trials are needed to make that evidence base more robust. If the mortality associated with severe malnutrition is to be reduced, inpatient and post-discharge management trials, supported by studies on the causes of mortality, are needed. a Department of Epidemiology, University of Washington, Seattle, United States of America (USA). b Departments of Pediatrics and Global Health, University of Washington, 6200 NE 74th Street, Suite 110, Box 354920, Seattle, WA 98115, USA. Correspondence to Donna M Denno (email: ddenno@uw.edu). (Submitted: 30 September 2015 – Revised version received: 1 March 2016 – Accepted: 1 March 2016 – Published online: 8 July 2016 ) R search XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867 643 Research Inpatient management of severe acute malnutritionKirkby D Tickell & Donna M Denno care that forms an integral extension of hospital management. We traced the lineage and quantified the evidence cited in support of each recommendation. We also searched trials registries systemati- cally, to determine which evidence gaps may be closed by the results of ongoing or recently completed trials. Methods We identified WHO’s recommendations for severe acute malnutrition manage- ment by searching Google Scholar – using “severe acute malnutrition” and “author:WHO” as the search terms – and by downloading the publications on the WHO nutrition website in December 2015.15 Full texts were reviewed if they represented a relevant guideline – as classified by WHO’s guideline review committee – or guideline update.16 Documents specific to humanitarian crises and those without inpatient or post-discharge management recommen- dations – e.g. the 2007 and 2009 joint statements5,12 – were excluded. Each included guideline was parsed into indi- vidual recommendations. We excluded diagnosis and admission criteria and care principles that are applicable to all hospitalized children – e.g. the monitor- ing of blood glucose after treatment of hypoglycaemia. We traced each recommendation’s evolution through the development of the guidelines and noted any modifica- tions and references cited in support of the recommendation. The full texts of all potentially relevant citations were reviewed. To determine the origins of each recommendation further, we reviewed three documents predating the current guidelines: WHO’s 1981 severe protein-energy malnutrition recommendations,9 and two textbooks commonly used before the publication of WHO’s first severe malnutrition guidelines in 1999.17,18 According to formal GRADE (grad- ing of recommendations, assessment, development and evaluation) assess- ment, each of the recommendations we investigated was of low, very low or unclassifiable quality. We evaluated each recommendation using GRADE’s directness assessment, as this provided meaningfully differentiated categories of evidence quality.16 Recommendations that were not supported by any cited evidence were considered to be based entirely on expert opinion. Recom- mendations were defined as indirectly supported if all of the cited studies were either among populations other than children with complicated severe acute malnutrition – e.g. HIV care guidance derived from studies of HIV-infected children without concurrent malnutri- tion – or only based on a treatment that was similar, but not identical, to the WHO recommended treatment – e.g. commercial ready-to-use therapeutic foods recommended on the basis of tri- als of locally produced versions of such foods. If at least one study concerning the endorsed intervention in a popula- tion of children with complicated severe acute malnutrition was cited in support of a recommendation, then that recom- mendation was considered to be directly supported. Direct evidence was further categorized as an observational study or a randomized trial. To determine the aims and extent of any recently completed, ongoing, or pending trials relevant to the man- agement of complicated severe acute malnutrition, we searched the WHO International Clinical Trials Registry Platform, the United States National Institutes of Health’s clinicaltrials. gov database and the Controlled Tri- als metaRegister systematically, using the search terms “malnutrition” and “wasting”. We completed this search on 10 August 2015. We fully reviewed all records with relevant or non-specific titles and included interventional trials among children with complicated severe acute malnutrition. We excluded trials already cited in WHO guidelines and those stopped before subject enrolment. We investigated the publication status and results of relevant trials by searching PubMed for the corresponding registra- tion numbers. Results Eight documents containing 33 current recommendations met our inclusion criteria (Fig. 1).2,9,10,17–20 The lineage of the 33 recommendations is summa- rized in Table 1. Expert opinion, in the absence of published evidence, was the basis for 16 (48.5%) of the recommen- dations. Three (9.1%) and six (18.2%) of the recommendations were drawn from direct observational or indirect evidence, respectively. The remaining eight recommendations (24.2%) were each supported by at least one direct randomized trial. Fig. 1. Flowchart of the search for guidelines and recommendations on the inpatient management of severe acute malnutrition, 2015 379 records identified through search: • 279 from WHO nutrition publication list • 100 from Google Scholar 6 records excluded: • 5 not addressing inpatient management • 1 not a guideline 368 records excluded: • 13 duplicates • 350 not addressing SAM • 5 specific to humanitarian crisis 183 recommendations excluded: • 49 duplicates • 28 not relevant to inpatients • 65 not specific to SAM • 41 superseded by later advice 14 full-text records reviewed for eligibility 8 records included – covering 216 recommendations 33 recommendations included in qualitative analysis 3 records not captured by search SAM: severe acute malnutrition. XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: | JobID: | Title: | Copyright Year 2016 | Volume 94 | | Issue 9 | pub-date 09 2016 Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867644 Research Inpatient management of severe acute malnutrition Kirkby D Tickell & Donna M Denno Table 1. Ancestry of evidence cited in support of the World Health Organization’s recommendations on the inpatient management of children with severe acute malnutrition Recommendation History Evidence base, year published First released Last modified Direct RCT Direct observational Indirect Micronutrients 200 000 IU of vitamin A for patients with eye signs of deficiencya 1981 – 1998, 2007, 2012 – – 200 000 IU of vitamin A for patients with measles1 2003 – 1998, 2007, 2012 – – 200 000 IU of vitamin A for patients not receiving vitamin A via feeds or other supplementsa 2013 – 1998, 2007, 2012 – – 5000 IU of vitamin A per daya 2013 – 1998, 2007, 2012 – – Zinc for patients with diarrhoea unless receiving zinc-fortified feeds 2013 – – – – No difference in zinc and vitamin A dosing based on HIV statusb 2013 – – – 2010 Copper, folic acid, iron, magnesium and potassium to be given daily for at least 2 weeks 1992 1996 – – – Feeding Feed immediately on admission, then every 2–3 hours. Transition from F-75 therapeutic milk feed to RUTF when patient stable, with appetite and decreasing oedemac 2003 – – 1998 1989, 1998,a 1998,b 1998,c 2009 Transition from F-100 therapeutic milk feed to RUTF when weight gain is rapid and patient accepting dietc 2003 – – 1998 1989, 1998,a 1998,b 1998,c 2009 For patient aged < 6 months, support breastfeeding – or relactate – with supplementary feeds and do not give undiluted F-100d 1981 2013 2009 2000 2009 No difference in feeding approach based on HIV status 2013 – – – – Can give RUTF in acute or persistent diarrhoea cases 2013 – – – 1994, 1995,1997, 2002, 2005 Fluid management Give ReSoMal for mild–moderate dehydration in non-cholera cases 1999 – 2003 2000 1999, 2000, 2001 Give standard low-osmolarity ORS for mild– moderate dehydration in suspected cases of cholera 2013 – 2009 – – For shock or severe dehydration, give intravenous Ringer’s lactate solution or half-strength Darrow’s solution, each supplemented with 5% dextrosee 1999 2013 2010 – – Every 5–10 minutes, monitor patients receiving intravenous fluids to check for overload 1999 – – – – Give blood transfusion, at 10 ml/kg, for shock if no improvement after 1 hour of intravenous therapy, and for severe anaemia 1999 – – – – Do not give blood transfusions > 24 hours post- admission 2013 – – 2006 – ART Start lifelong ART if patient aged < 24 months9 2013 – – – 2009, 2010 Start lifelong ART, based on CD4 counts or clinical staging, if patient aged ≥ 24 monthsf 2013 – – – 2009, 2010 Start ART after stabilization of complications 2013 – – – 2009, 2011, 2012 Hypoglycaemia and hypothermia If patient conscious, give 50 ml bolus of 10% dextrose – by mouth or nasogastric tube – then F-75 every 30 minutes for 2 hours 1969 or before 1996 – – – If patient unconscious, lethargic or convulsing, give 10% dextrose intravenously, at 5 ml/kg, and then 50 ml of 10% dextrose by mouth 1969 or before 1996 – – – (continues. . .) XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Kirkby D Tickell & Donna M Denno Inpatient management of severe acute malnutrition Research 645Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867 XSL Version: | JobID: | Title: | Copyright Year 2016 | Volume 94 | | Issue 9 | pub-date 09 2016 Twenty-three (69.7%) recommen- dations had been added or revised since the original guideline published in 1999.10 Only six (26.1%) of these 23 were supported by a directly relevant randomized trial. Three (13.0%) and six (26.1%) were supported by at least one direct observational or indirect study, respectively, while no references were cited in support of the remaining eight (34.8%) recommendations. The 1999 guidelines10 presented a 10-step manage- ment protocol – as originally proposed in the article Ten steps to recovery that was published in 1996.11 Five (15.2%) of the 33 current recommendations are identical to – or slight modifications of – the recommendations first proposed in this 1996 article. Seven (21.2%) of the current recommendations originated before 1996 – although five of these have since been slightly revised. Recommendation age and quality The age of the recommendation and quality of supporting evidence varied according to the involved clinical area. Micronutrients Micronutrient recommendations were largely based on expert opinion, al- though three randomized trials23–25 directly supported two of the recom- mendations made in the 2013 update: low-dose vitamin A administration, reserving high-dose vitamin A for those with eye signs of deficiency or measles.4 Collectively, the trials demonstrated that either dose of vitamin A was superior to placebo, and that high-dose vitamin A offered no benefit compared with low-dose and might be associated with nosocomial diarrhoea and pneumonia. The 2013 update also recommended that HIV-infected children receive the same zinc and vitamin A doses as uninfected peers.4 This recommendation was sup- ported by a systematic review of studies among HIV-infected children and adults without malnutrition, which indicated that HIV infection should not alter zinc requirements.26 Specific recommenda- tions on the broader micronutrient package, which have remained constant for over 20 years, are all based on expert opinion. Feeding Indirectly related studies were the pre- dominant reference type cited in support Recommendation History Evidence base, year published First released Last modified Direct RCT Direct observational Indirect Infection Give empiric ampicillin and gentamycin and then, if no response, chloramphenicol 1969 or before 1996 – – – Patients aged < 6 months should receive same antibiotics as older children 2013 – – – – Give measles vaccine to non-immunized children aged ≥ 6 months 1996 – – – – Discharge from inpatient or outpatient care Transfer to outpatient care on clinical condition rather than anthropometry 2013 – – – – Move patients aged < 6 months to outpatient care if their daily weight gain exceeds the median growth velocity standard or is > 5 mg/kg/day for 3 days 2013 – – – – Discharge from outpatient care when WHZ is ≥ –2 or MUAC is ≥ 125 mm 2013 – – – – The anthropometric measure that qualified a child for admission should be used to monitor the child’s outpatient progressg 2013 – – – – If oedema was the only observed complication, normal anthropometrics can be used to monitor outpatient progress 2013 – – – – Discharge from outpatient care should not be based on percentage weight gain 2013 – – – 2004, 2012 Emotional support Provide patient with emotional and sensory support 1969 or before – – – – ART: antiretroviral therapy; HIV: human immunodeficiency virus; IU: international unit; MUAC: mid-upper arm circumference; ORS: oral rehydration solution; RCT: randomized controlled trial; RUTF: ready-to-use therapeutic foods; WHZ: weight-for-height z-score. a All vitamin A recommendations are supported by the same randomized trials. b Citation for vitamin A and zinc dosing in HIV infection is a Cochrane review of five vitamin A and two zinc randomized trials indirectly related to the management of complicated severe acute malnutrition. c The F-75 and F-100 therapeutic milk feeding recommendations are supported by the same studies. d If maternal breastfeeding is not possible, wet nursing should be encouraged. e If neither solution available, use 0.45% saline with 5% dextrose. f Based on indirect evidence discussed in two sets of World Health Organization guidelines.21,22 g That is, if the diagnosis was made on low MUAC, use MUAC – and not WHZ – to quantify recovery. (. . .continued) XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867646 Research Inpatient management of severe acute malnutrition Kirkby D Tickell & Donna M Denno of the feeding recommendations. Rec- ommendations for the use of therapeutic milk feeds – i.e. F-75 and F-100 – and the criteria for transition to ready-to-use therapeutic foods were last updated in 20032 and were based on the results of six studies. Five of these studies demon- strated an association between refeeding syndrome and death among adolescents with eating disorders, children with neurological dysphagia, children with parent-imposed starvation, and critical- ly ill adults in high-income settings.27–31 The 2013 update4 advised against use of undiluted F-100 among young infants, based on a direct study that indicated a possible connection between undiluted F-100 and renal solute overload, hyper- natraemia and death.32 Specific advice on breastfeeding has remained largely unchanged for almost half a century.18 Fluid management Three of the six recommendations on fluid management – including the specification of low-osmolarity salts for cholera – had been revised in the 2013 update.4 Recom- mendations for the treatment of shock or severe dehydration underwent a relatively minor re-ordering in the preference of intravenous fluids, based on a direct randomized trial of 62 children, in which Ringer’s lactate solution with 5% dextrose was compared with half-strength Dar- row’s solution with 5% dextrose. Neither of these fluids was found to correct shock sufficiently and the choice of fluid had no significant effect on mortality.33 Finally, the study that was cited in support of limiting the timing, indications and infu- sion rates for transfusions demonstrated a strong association between mortality and transfusion – although adjustment for confounding by indication may have been insufficient.34 Antiretroviral treatment Although three recommendations on antiretroviral treatment were added in the 2013 update,4 none was supported by direct evidence. Antiretroviral initiation recommendations referenced WHO’s guidelines on the management of child- hood HIV infection.21,22 The advice to initiate antiretrovirals after clinical stabi- lization cited two pharmacokinetic stud- ies among children with varying degrees of malnutrition35,36 and one retrospective study that demonstrated faster recovery when antiretroviral treatment was initi- ated within 21 days of the diagnosis of uncomplicated severe malnutrition.37 Other clinical problems Recommendations on the management of hypoglycaemia, hypothermia and acute infections – including specifics related to antimicrobial treatment – were made in the Ten steps to recovery article.11 They remain unchanged and are not supported by any cited evidence. Discharge and follow-up Six recommendations on discharge from hospital and outpatient care were added in the 2013 update4 and were almost exclusively drawn from expert opin- ion. Supporting citations were limited to two indirect retrospective studies demonstrating that mid-upper arm circumference was an adequate measure of outpatient progress.38,39 The results of these studies led to the recommendation to eliminate percentage weight gain as a criterion for discharge from outpatient follow-up. Ongoing or recent trials Our search of trials registries yielded the full records of 58 trials – after re- view of trial titles (Fig. 2). Twenty of these trials met our inclusion criteria (Table 2). Fifteen of the 20 trials had been completed – and the results of four had been published – by the time of our search.40–43 Two had reported statistically significant results; one demonstrated that community follow-up increased linear growth and clinic attendance43 and the other that long-chain n-3 poly- unsaturated fatty acid in erythrocytes increased among severely malnour- ished children who were given ready- to-use therapeutic food enriched with polyunsaturated fatty acid.42 The other two published trials, which detected no significant differences, compared alternative formulations of ready-to-use therapeutic food with standard formula- tions. Of the 16 unpublished trials, nine and two had been designed to investigate alternative feeding regimens and the use of probiotics, respectively. One each had been designed to investigate pancre- atic enzyme replacement, antioxidants, intravenous rehydration, stool output assessment, and antiretroviral pharma- cokinetics. Three unpublished antibiotic trials – completed between 2008 and 2014 – examined ciprofloxacin pharma- cokinetics, ceftriaxone for concurrent pneumonia, and post-discharge pro- phylaxis with co-trimoxazole (Table 2). Discussion The 2013 update stated that “major research gaps were identified in each of the sections covered”.4 Our analysis shows that such gaps persist and extend across the entire spectrum of guidance on the management of complicated severe acute malnutrition. The absence of relevant published data has forced a reliance on expert opinion. The evidence that was cited in support of many recom- mendations was of very low quality and often did not specifically pertain to the recommended treatment. These deficits demonstrate that guideline reforms have been driven by an overwhelming clinical need – rather than by a body of compelling evidence. This is not criti- cism of WHO or the guidelines’ authors, who should be commended for creating pragmatic management documents by threading together the little solid evidence available and expert opinion. Fig. 2. Flowchart of the search for recent or current trials relevant to the inpatient management of severe acute malnutrition, 2015 1868 trials excluded as not relevant to the management of SAM 38 trials excluded as not relevant to the inpatient management of SAM 1926 trials listed in trials registries 58 trials assessed for eligibility via full-text records 20 trials included in qualitative analysis SAM: severe acute malnutrition. XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867 647 Research Inpatient management of severe acute malnutritionKirkby D Tickell & Donna M Denno It should be noted that recommen- dations supported by weak evidence or expert opinion are not necessarily incor- rect. Many of the recommendations are grounded in the results of basic science research and careful clinical observa- tions, much of which was made before the 1996 seminal Ten steps to recovery article. However, the population of pae- diatric inpatients with severe malnutri- tion has dramatically changed in the last 10–20 years. Over that period, HIV has emerged as an important contributing problem, younger infants have come to represent an increasing proportion of malnourished children and, for cases without complications, outpatient care has eclipsed hospital management.3,4 Data from previous eras may therefore not be generalizable to the modern child with complicated severe acute malnutrition. In some areas the absence of clini- cal data is particularly concerning. For example, given that the largest burden of mortality from malnutrition is in sub-Saharan Africa, where the prevalence of HIV infection is relatively high, the lack of evidence to guide the management of HIV-infected children with malnutrition is worrying.1 A 2009 meta-analysis found that, among severely malnourished children, HIV infection was associated with a threefold increased risk of mortality.6 In a cohort study of severely malnourished children admitted to Queen Elizabeth Hospital in Malawi, HIV-infected children rep- resented 64% of the deaths. The same study found that 67% of infants died.3 In the absence of data addressing these two populations – i.e. young infants and HIV-infected children with complicated severe malnutrition – the guidelines’ authors have been forced to generalize the management practices from other populations, without evidence that this is optimal or even appropriate.4 Fur- thermore, in the Malawian study, 25% of the children who were discharged died in the following 12 months and these deaths represented 44% of the total recorded mortality.3 Post-discharge mortality rates are high and their causes are poorly understood. This knowledge gap warrants urgent attention. Antimicrobial therapy for severely malnourished inpatients represents another conspicuous knowledge gap. Empiric antibiotics have been recom- mended since at least 196918 and the cur- rently endorsed regimen has remained unchanged since it was standardized to ampicillin and gentamicin in 1996.11 A 1996 trial demonstrated the superiority of ampicillin and gentamicin compared with previously endorsed protocols relying on co-trimoxazole or penicillin and gentamicin.44We are not aware of any subsequent studies comparing the currently recommended regimen with other antimicrobials. In the care of severe acute malnutrition, fluid man- Table 2. Registered clinical trials addressing the inpatient or post-discharge management of children with complicated severe acute malnutrition, 2015 Topic, title, country Registry identifier Date of last updatea Statusa Antibiotics Antibiotics in concurrent pneumonia, Bangladesh NCT00968370 14 July 2013 Complete Post-discharge co-trimoxazole prophylaxis, Kenya NCT00934492 15 August 2014 Complete Oral ciprofloxacin, Kenya ISRCTN31079753 2 February 2009 Complete Antiretrovirals Steady-state pharmacokinetics in concurrent HIV infection, Uganda, United Republic of Tanzania and Zimbabwe NCT01818258 5 August 2015 Not yet recruiting Feeding Comparison of RUTF with 10% and 25% milk, Malawi ISRCTN54186063 4 June 2009 Completeb Reformulated F-75 therapeutic milk feed, Kenya and Malawi NCT02246296 6 January 2015 Ongoing Rehabilitation with undiluted F-100 or diluted F-100, Bangladesh NCT01558440 26 July 2015 Complete RUTF based on sorghum, soybean and maize, Malawi PACTR201505001101224 15 April 2015 Not yet recruiting RUTF based on soybean, Bangladesh NCT01634009 4 March 2015 Ongoing RUTF enriched with n-3 PUFA, Kenya NCT01593969 15 August 2014 Completeb Three dietary regimes, Malawi ISRCTN13916953 14 January 2013 Complete Three new formulations of RUTF, Malawi ISRCTN19364765 23 July 2009 Completeb Whole milk during initial management, India CTRI/2011/07/001853 3 May 2012 Complete Fluids Slow versus rapid rehydration, Bangladesh NCT02216708 20 August 2014 Complete Follow-up Community-based follow-up, Bangladesh NCT01157741 7 July 2010 Completeb Stool output Stool frequency, Malawi ISRCTN11571116 15 January 2014 Complete Supplements Antioxidants and oxidants, Jamaica NCT00069134 27 January 2015 Ongoing Pancreatic exocrine replacement therapy, Malawi ISRCTN57423639 14 April 2014 Complete Probiotics in recovery, Uganda ISRCTN16454889 12 May 2014 Complete Spirulina supplementation, Niger PACTR201406000810205 9 April 2014 Complete HIV: human immunodeficiency virus; PUFA: polyunsaturated fatty acids; RUTF: ready-to-use therapeutic food. a As recorded on 10 August 2015. b Results published before 10 August 2015. XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867648 Research Inpatient management of severe acute malnutrition Kirkby D Tickell & Donna M Denno agement also remains unresolved and understudied. For ethical or practical reasons, some guidance areas are simply not amenable to clinical trials. Beyond vi- tamin A and zinc, the composition of the recommended micronutrient pack- age has remained constant for decades and is underpinned by estimated daily requirements and observed micronutri- ent deficiencies in severe malnutrition. It would be impractical to run factorial trials for all micronutrients. However, this does not preclude the improvement of micronutrient packages via obser- vational studies and targeted clinical trials, particularly given the etiological, environmental and social changes that have occurred in the decades since the foundational micronutrient research was conducted. Our quantitative gap analysis builds on other reviews,45,46 including a 2012 systematic review46 – conducted in preparation for WHO’s 2013 update – that concluded: “For many of the most highly ranked questions evidence was lacking or inconclusive”.4 Our review of trials registries revealed that most of the upcoming, ongoing or recently completed relevant trials were focused on feeding and nutrition – areas not identified as priorities in the 2013 up- date4 or supporting systematic review.46 Furthermore, the areas in highest need of evidence – e.g. intravenous fluids, antimicrobials, the treatment of infants younger than six months and HIV- infected children, and post-discharge management – were very modestly represented. Therefore, it is unlikely that currently registered trials will address many of the critical knowledge gaps related to the inpatient management of severe acute malnutrition. The paucity of relevant research may arise from a misconception that further work is unnecessary because adequate guidelines exist. As we have described, however, the underlying evidence for most management areas is weak. The current global undernutri- tion research agenda is largely focused on reducing the burden of stunting and moderate acute malnutrition – impor- tant and justifiable areas of concern. However, we should not neglect the half a million children who die from severe acute malnutrition annually.1 Epidemiological studies that define the etiologies of illness and mortal- ity form an important foundation for interventional trials. Recent such studies have challenged long-standing beliefs about the relative importance of specific pathogens in pneumonia and diarrhoeal disease. For example, a South African study found cytomegalovirus, Mycobacterium tuberculosis and Pneu- mocystis jiroveci to be frequent causes of treatment failure among children with severe pneumonia47 while the Global Enteric Multicentre Study demonstrated Cryptosporidium, enterotoxigenic Esch- erichia coli, rotavirus and Shigella to be leading causes of childhood diarrhoeal death.48 These findings have spurred interventional trials that hopefully will improve management and save lives. A few studies have evaluated the causes of infection or death among children admitted for severe acute malnutri- tion.49,50 However, we are aware of no recent or robustly sampled investigation of the causes – including non-infectious etiologies – of mortality among such children during hospitalization or post- discharge. The failure of many trials to find statistically significant results may stem from a superficial understand- ing of the contemporary etiologies of such mortality. For example, if children with environmental enteric dysfunc- tion require specific treatment more than children who are affected by food insecurity alone, then including both groups of children in trials of ready- to-use therapeutic foods could lead to attenuated estimates of efficacy and reduced statistical power. An improved understanding of the epidemiology of complicated severe acute malnutrition will facilitate the efficient design of clini- cal trials and catalyse the discovery of new and effective interventions. This paper is not a detailed sys- tematic review but rather a tracing of the lineage of each recommendation and its supporting citations. We did not review evidence that was not refer- enced in the relevant WHO guidelines. Early guidelines were published at a time when evidence citation was uncommon. Any relevant evidence available to these guidelines’ authors will not have been captured by our review unless cited in subsequent updates. Additionally, it is impossible to quantify the cumulative clinical experience of the many experts who have contributed to the guidelines. This paper does not address why se- verely malnourished children admitted to Asian hospitals seem to experience different mortality rates to their coun- terparts in African facilities. It would be useful to determine, in various settings, the proportion of cases of severe malnu- trition that present with complications. In conclusion, we found that the evidence base for the management of complicated severe acute malnutrition is heavily reliant on expert opinion in the absence of published data, that the relevant recommendations have under- gone very limited substantive revision over the past two or more decades and that few ongoing clinical trials are be- ing conducted in high priority areas. Although enhanced implementation of current guidelines would improve outcomes, a renewed and even modest investment in relevant epidemiological and clinical research is likely to lead to more effective recommendations and lower mortality. ■ Competing interests: None declared. صخلم :ىفشتسلما لخاد ديدشو داح ةيذغت ءوسب ينباصلما لافطلأا نم ضىرلما ةرادإ ةيلماعلا ةحصلا ةمظنمب ةصالخا ةيهيجوتلا ئدابملل ةعجارم ةحصلا ةمظنمب ةصالخا ةيهيجوتلا ئدابلما زيزعت نكمي فيك مهف ضرغلا ءوس نم ةدقعم تلااحب ينباصلما لافطلأا نم ضىرلما ةياعر لوح ةيلماعلا .تلاّصحلما ينستح لجأ نم ىفشتسلما لخاد ديدشلاو دالحا ةيذغتلا ثحابلا في ثحبلاب انمق ،2015 ماع نم برمسيد رهش في ةقيرطلا ةمظنمب صالخا نيوتركللإا عقولماو Google scholar نم يملعلا ةرادإ نأشب ةيلماعلا ةحصلا ةمظنم تايصوت ةفرعلم ةيلماعلا ةحصلا خيراتلا مييقتب انمقو ديدشلاو دالحا ةيذغتلا ءوسب ةباصلإا تلااح في يجهنم لكشب انثحبو .تايصوتلا هذله ةجيتن ةدراولا ةلدلأاو ،ةيريسرلا براجتلل ةيلودلا تلاجسلل ةيلماعلا ةحصلا ةمظنم برنم “metaRegister” ماعلا لجسلاو clinicaltrials.gov وهو براجتلل 2015 سطسغأ 10 ىتح دهاوشلاب ةطبضلما براجتلل .ةقّلعلما وأ ةيرالجا وأ اًرخؤم ةلمتكلما XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867 649 Research Inpatient management of severe acute malnutritionKirkby D Tickell & Donna M Denno 33 ةيلماعلا ةحصلا ةمظنمب ةصالخا ةيهيجوتلا ئدابلما رفوت جئاتنلا هذه نم ةيصوت 16 تدنتسا ،كلذ عمو .عوضولما نأشب ةيصوت ةموعدم يرغ ،اهدحو ءابرلخا ءارآ لىع )48.5% ةبسنب( تايصوتلا تايصوتلا نم ىرخأ ةيصوت 11 معد متو .ةروشنلما ةلدلأا بناج نم يأ ،ةشرابلما ةلصلا تاذ ثوحبلا جئاتن بناج نم )% 33.3( ةبسنب تدنتسا .)3( ةيدصرلا تاساردلا وأ )8( ةاشعلما براجتلا امإ متي لم تاسارد لىع )% 18.2 ةبسنب( ىرخلأا تسلا تايصوتلا ةيذغتلا ءوس نم ةدقعم تلااحب ينباصلما لافطلأا ينب اهؤارجإ .هب صىوُلما لخدتلل ةلثامم نكت لم يتلا جلاعلا تاسارد وأ ديدشلا نم ،عوضولماب ةقلعتم ةسارد 20 لىع براجتلا تلاجس تلمتشا ةصالخا تاساردلا تناك .ةليدبلا ةيذغتلا ةمظنلأ براتج عست اهنيب دلحاب ةلثمم ضىرملل ةقحلالا ةياعرلاو ةدالحا ةيبطلا تلاالحا ةرادإب .ىندلأا ةحصلا ةمظنمب ةصالخا ةيهيجوتلا ئدابلما ىدل دجوي جاتنتسلاا تلايدعتلا ضعبل تعضخو ةـلدلأا نم ةفيعض ةدعاق ةيلماعلا مهاست نأ حجرلما نمو .ةيضالما دوقعلا رادم لىع ةدودحلما ةيعوضولما ناك اذإ .يرثكب ىوقأ ةلدلأا ةدعاق لعج في ةلجسلما براجتلا ضعب ،ضافخنلال هقيرط في دالحا ةيذغتلا ءوسب طبترلما تايفولا لدعم دعبو ىفشتسلما لخاد ضىرلما ةرادإ براتج ءارجإ لىإ ةجاح كانهف .تايفولا بابسأ لوح تاساردب ةموعدم ،ىفشتسلما نم جورلخا 摘要 严重急性营养不良儿童住院管理 ：WHO 指南回顾 目的 了解如何加强世界卫生组织 (WHO) 严重营养不 良儿童住院治疗指南，以改善治疗结果。 方法 2015 年 12 月，我们在谷歌学术和 WHO 网站上 搜索了关于严重急性营养不良管理的 WHO 建议，并 且评估了这些建议背后的历史和引用的证据。 我们在 2015 年 8 月 10 日之前在 WHO 国际临床试验注册平 台 (clinicaltrials.gov) 和临床对照试验 (mRCT) 上进行了 系统性搜索，以查找最近完成的、正在进行的或即将 进行的试验。 结果 WHO 指南针对这一课题提出 33 条建议。 然而， 这些建议中，有 16 条 (48.5%) 仅基于专家意见——无 公开发表的证据支持。 另外 11 条建议 (33.3%) 基于直 接相关研究的结果——即随机试验 (8) 或观察性研究 (3)。 还有 6 条建议 (18.2%) 基于未在复杂严重营养不 良儿童身上进行的研究或不同于所建议干预措施的治 疗研究。 试验注册平台上包含 20 项与本课题相关的 研究，包括 9 项替代性供餐计划试验。 关于急性医疗 管理和后续护理的研究数量很少。 结论 WHO 指南在该课题证据基础薄弱，并且在过去 数十年仅进行了有限的实质性调整。 需要进行更多试 验以增强证据基础。 要想降低与严重营养不良相关的 死亡率，我们需要进行由死亡原因研究支持的住院和 出院后管理试验。 Résumé Prise en charge des enfants hospitalisés pour malnutrition aiguë sévère: un examen des lignes directrices de l’OMS Objectif Comprendre comment renforcer les lignes directrices de l’Organisation mondiale de la Santé (OMS) relatives à la prise en charge des enfants hospitalisés pour malnutrition aiguë sévère avec complications en vue d’améliorer les résultats. Méthodes En décembre 2015, nous avons recherché les recommandations de l’OMS concernant la prise en charge de la malnutrition aiguë sévère dans Google Scholar et sur le site Internet de l’OMS, puis évalué l’historique et les éléments invoqués à l’appui de ces recommandations. Nous avons systématiquement recherché les essais récemment effectués, en cours ou en attente, jusqu’au 10 août 2015, dans le Système d’enregistrement international des essais cliniques de l’OMS, sur ClinicalTrials.gov et dans le metaRegister of Controlled Trials. Résultats Les l ignes directr ices de l ’OMS contiennent 33 recommandations à ce sujet. Cependant, 16 (48,5%) d’entre elles s’appuyaient uniquement sur une opinion d’expert non étayée par des données publiées. Onze (33,3%) autres étaient corroborées par les résultats de recherches présentant un intérêt direct, c’est-à-dire des essais randomisés (8) ou des études observationnelles (3). Les six dernières (18,2%) reposaient quant à elles sur des études n’ayant pas été menées auprès d’enfants atteints de malnutrition sévère avec complications ou sur des études de traitement non conforme à l’intervention recommandée. Les essais enregistrés incluaient 20 études en lien avec le sujet, dont neuf essais de régimes alimentaires alternatifs. Les études sur la prise en charge médicale urgente et les soins de suivi n’étaient que très peu représentées. Conclusion Les lignes directrices de l’OMS sur le sujet s’appuient sur des données insuffisantes et n’ont fait l’objet que d’ajustements substantiels limités au cours des dernières décennies. Il est nécessaire de réaliser davantage d’essais afin de rendre cet ensemble de données plus fiable. Pour réduire la mortalité associée à la malnutrition sévère, il est nécessaire de réaliser des essais sur la prise en charge des enfants pendant et après leur hospitalisation, et de les étayer par des études sur les causes de la mortalité. Резюме Ведение детей с тяжелой острой недостаточностью питания в условиях стационара: обзор руководящих принципов ВОЗ Цель Определить возможные способы усовершенствования руковод ящих принципов Всемирной организации здравоохранения (ВОЗ) по ведению детей, страдающих тяжелой острой недостаточностью питания с осложнениями, в условиях стационара для улучшения конечных результатов. Методы В декабре 2015 года авторы статьи провели поиск в системе Google Scholar и на веб-сайте ВОЗ на предмет рекомендаций ВОЗ по ведению тяжелой острой недостаточности и проанализировали историю изменений этих рекомендаций и цитируемые факты, лежащие в их основе. До 10 августа 2015 года XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date XSL Version: xslver | JobID: JobID | Title: journal-title | Copyright Year 2 | Volume 87 | | Issue issue | pub-date pub-date Bull World Health Organ 2016;94:642–651| doi: http://dx.doi.org/10.2471/BLT.15.162867650 Research Inpatient management of severe acute malnutrition Kirkby D Tickell & Donna M Denno также выполнялся систематический поиск на Международной платформе для регистрации клинических испытаний (International Clinical Trials Registry Platform) ВОЗ, clinicaltrials.gov, а также в Метарегистре контролируемых исследований (Controlled Trials metaRegister) на предмет недавно завершенных, текущих или еще не завершенных исследований. Результаты Руководящие принципы ВОЗ содержат 33 рекомендации по данной теме. Однако 16 (48,5%) из этих рекомендаций основывались исключительно на экспертном мнении, не подтвержденном опубликованными фактическими данными. Еще 11 (33,3%) из этих рекомендаций были подкреплены результатами непосредственно относящегося к ним исследования, рандомизированного (8) или наблюдательного (3). Остальные шесть рекомендаций (18,2%) основывались на исследованиях, которые проводились не среди детей с осложненной тяжелой недостаточностью питания, или на исследованиях лечения, которое не было идентично рекомендуемому вмешательству. Реестры исследований включали 20 исследований, относящихся к данной теме, в том числе девять исследований альтернативных рационов. Исследования неотложной медицинской помощи и последующего ухода были практически не представлены. Вывод Руководящие принципы ВОЗ по данной теме имеют слабо подкрепленную доказательную базу, и их содержание незначительно изменялось в течение последних десятилетий. Необходимо выполнить больше исследований для того, чтобы укрепить соответствующую доказательную базу. Для снижения смертности, связанной с тяжелой недостаточностью питания, потребуются исследования ведения пациентов в условиях стационара и наблюдения после выписки, подкрепленные изучением причин смертности. Resumen Gestión hospitalaria de niños con malnutrición aguda grave: un análisis de las directrices de la OMS Objetivo Comprender cómo deben fortalecerse las directrices de la Organización Mundial de la Salud (OMS) sobre la atención hospitalaria de niños con malnutrición aguda grave complicada con el fin de mejorar los resultados. Métodos En diciembre de 2015, se realizaron búsquedas de recomendaciones eruditas en Google y en el sitio web de la OMS en relación con la gestión de la malnutrición aguda grave y se evaluó el historial y se citaron las pruebas detrás de estas recomendaciones. De forma sistemática, se realizaron búsquedas de ensayos completados, en proceso o pendientes hasta el 10 de agosto de 2015 en la Plataforma Internacional de Registros de Ensayos Clínicos (International Clinical Trials Registry Platform) de la OMS, en clinicaltrials.gov y en el Metarregistro de Ensayos Clínicos Controlados (Controlled Trials metaRegister). Resultados Las directrices de la OMS ofrecen 33 recomendaciones sobre el tema. No obstante, 16 (48,5%) de estas recomendaciones se basaron únicamente en opiniones de expertos, sin el respaldo de pruebas publicadas. Otras 11 (33,3%) recomendaciones estaban respaldadas por los resultados de investigaciones directamente relevantes, es decir, ensayos aleatorizados (8) o estudios de observación (3). Las otras 6 recomendaciones (18,2%) se basaban en estudios que no se realizaron en niños con malnutrición grave complicada o en estudios de tratamientos que no eran idénticos a la intervención recomendada. Los registros de los ensayos incluían 20 estudios relacionados con el tema, incluyendo 9 ensayos de regímenes de alimentación alternativos. La gestión médica aguda y los estudios de casos de seguimiento obtuvieron una representación mínima. Conclusión Las directrices de la OMS sobre el tema tienen una base de pruebas deficiente y han sufrido pocos ajustes importantes durante las últimas décadas. Es preciso realizar más ensayos para que esta base de pruebas sea mucho más firme. Si se pretende reducir la mortalidad asociada a la malnutrición grave, se necesitan ensayos de gestión hospitalaria y tras el alta, con el apoyo de estudios basados en las causas de la mortalidad. References 1. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al.; Maternal and Child Nutrition Study Group. Maternal and child undernutrition and overweight in low-income and middle-income countries. 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