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PRACTICE: Rajesh Khanna, Monica Lakhanpaul, Shona Burman-Roy, M Stephen Murphy on behalf of the Guideline Development Group and the technical team Diarrhoea and vomiting caused by gastroenteritis in children under 5 years: summary of NICE guidance BMJ 2009; 338: b1350 [Full text]

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Use of antiemetics treatment in paediatrics acute gastroenteritis

Federico Marchetti, Anna Erenbourg, Luca Ronfani   (28 April 2009)

Re: Use of antiemetics treatment in paediatrics acute gastroenteritis

Umesh Prabhu   (29 April 2009)

Use of antiemetics treatment in paediatrics acute gastroenteritis

Mohammed Aman Samaei   (29 April 2009)

Diarrhoea and vomiting caused by gastroenteritis: clinical guideline--a critique

Alastair R Michell, London EC1 6BQ   (8 May 2009)

Use of antiemetics treatment in paediatrics acute gastroenteritis 28 April 2009
Federico Marchetti, Attending physician Department of Pediatrics, Institute of Child Health, IRCCS Burlo Garofolo, Trieste, Anna Erenbourg, Luca Ronfani Send response to journal: Re: Use of antiemetics treatment in paediatrics acute gastroenteritis	EDITOR, Khanna R et al. reported the NICE current practice recommendations to treat paediatric acute gastroenteritis (AG) without including pharmacological treatment for vomiting (1). However, vomiting from AG is distressing for patients and their families. In addition, vomiting is not only a direct cause of fluid loss but can also hamper successful oral rehydration therapy (ORT) and it is a major factor of ORT failure. Many physicians believe that vomiting is a contraindication to ORT. Paediatricians providing care in the emergency department, consistently favour intravenous fluid therapy (IVT) for mild or moderate dehydration when vomiting is the major symptom (2). Thus, effective treatment for vomiting would lead to an important reduction in IVT use. In clinical practice, antiemetic drugs are frequently used in children with AG. A recent retrospective survey retrieved data from 4 national and international databases and showed that prescription of antiemetic medications varied considerably (3). In particular, between 2% and 23% of children with AG received prescriptions for antiemetic medications. Antihistamines were most frequently used in Germany and Canada, whereas promethazine was preferentially prescribed in United States. In France, Spain and Italy domperidone was the favourite antiemetic treatment. Ondansetron was chosen in a minor proportion of antiemetic prescriptions. As demonstrated in recently published meta-analysis, the literature evaluating the efficacy of symptomatic drugs in reducing acute vomiting for AG in paediatric age is methodologically limited and focuses mainly on ondansetron (4,5). The same evidence showed that an adequate evaluation of anti-emetic drugs largely used in clinical practice, such as domperidone, is completely missing. The Cochrane reviewers explicitly indicated that further research is needed to assess the effectiveness and cost- effectiveness of antiemetic drugs use (4). In light of these considerations, further randomised controlled trials aiming to compare the efficacy of ondansetron and other antiemetic drugs, such as domperidone, for the symptomatic treatment of vomiting in AG are needed. The study could answer to the following clinical questions: a) would anti-emetic agents reduce the percentage of children who keeps vomiting? b) would anti-emetic treatment favour the ORT and reduce the need for nasogastric or IVT? c) would the treatment reduce the percentage of children accessing health services and needing hospital admission? We believe that the results of such a trial could significantly impact current clinical practice. Federico Marchetti, Anna Erenbourg, Luca Ronfani Department of Pediatrics, Institute of Child Health, IRCCS Burlo Garofolo, University of Trieste, via dell’Istria 65/1. 34100 Trieste, Italy Corresponding Author: Federico Marchetti, MD. marchetti@burlo.trieste.it REFERENCES 1. Khanna R, Lakhanpaul M, Burman-Roy S, Murphy MS; Guideline Development Group and the technical team. Diarrhoea and vomiting caused by gastroenteritis in children under 5 years: summary of NICE guidance. BMJ. 2009;338:b1350. doi: 10.1136/bmj.b1350. 2. Ozuah PO, Avner JR, Stein RE. Oral rehydration, emergency physicians, and practice parameters: a national survey. Pediatrics 2002;109(2):259-261. 3. Pfeil N, Uhlig U, Kostev K, et al. Antiemetic medications in children with presumed infectious gastroenteritis--pharmacoepidemiology in Europe and Northern America. J Pediatr 2008;153(5):659-62. 4. Alhashimi D, Alhashimi H, Fedorowicz Z. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database Syst Rev 2009;(2):CD005506. 5. DeCamp LR, Byerley JS, Doshi N, Steiner MJ. Use of antiemetic agents in acute gastroenteritis: a systematic review and meta-analysis. Arch Pediatr Adolesc Med 2008;162(9):858-865 Competing interests: None declared
Re: Use of antiemetics treatment in paediatrics acute gastroenteritis 29 April 2009
Umesh Prabhu, Consultant Paediatrician Fairfield Hospital., Bury BL9 7TA Send response to journal: Re: Re: Use of antiemetics treatment in paediatrics acute gastroenteritis	Thank you very much for your comment. Practice varies a lot from country to country. I was trained in India and use of antiemetic was very common and in 1982 I came to UK and not used antiemetic in any patients. In 1989 I took my son to India on a holiday and he was sick for 2 days with Gastro-enteritis and was dehydrated. Indian Paediatrician gave him one dose of anti-emetic and he settled very well. May be just a co-incidence. However, here since 1982 I have not used anti-emetic in any child and all children have settled after a couple of days. Does anti-emetic shorten the vomiting, do parents find it useful, does it help children to recover quickly, is it cost effective and will we make more children ill by anti-emetics? These are the questions we have probably got to consider. However, I am not convinced that anti-emetic has a huge role and all children with Gastro-enteritis will settle provided we keep a watch on their hydration. Competing interests: None declared
Use of antiemetics treatment in paediatrics acute gastroenteritis 29 April 2009
Mohammed Aman Samaei, FY2 Aelfgar Surgey WS15 2AB Send response to journal: Re: Use of antiemetics treatment in paediatrics acute gastroenteritis	In response to the EDITOR, Khanna R et al regarding the use of antiemetics in AG, I would like to say that I agree with the author as we need more studies to find out about the effects and importance of using antiemetics in AG.As weather is getting warmer and we will expect more cases of AG,the use of antiemetic is going to be more needed. Working in paediatrics and general Practice, I gained the experience that antiemetics like Ondansetron is quite useful and may significantly reduce the admission and prevention of dehydration. Competing interests: None declared
Diarrhoea and vomiting caused by gastroenteritis: clinical guideline--a critique 8 May 2009
Alastair R Michell, Professor of Comparative Medicine [ Univ. of London] Dept Biochemical Pharmacology, Harvey Institute, Barts Hospital, London EC1 6BQ Send response to journal: Re: Diarrhoea and vomiting caused by gastroenteritis: clinical guideline--a critique	Diarrhoea and vomiting caused by gastroenteritis: clinical guideline for the NHS (April 2009)--a critique Treatment of diarrhoea should rest on understanding of the underlying pathophysiology: evidence-based medicine is essential to confirm the validity of such an approach, not to replace it, especially when the available evidence is fallible. O’Shaugnessy[1,2], who pioneered the use of rationally based oral and parenteral fluid therapy for acute diarrhoea in 1832 appreciated the importance of treating what we now call acidosis; the new Clinical Guideline on the treatment of diarrhoea commissioned by NICE [RCOG Press, April 2009] seems not to and that is not its only defect. The fundamental nature of diarrhoea The Guideline includes several clinical definitions of diarrhoea. An additional pathophysiological definition would illuminate the rationale for oral rehydration therapy [ORT]: diarrhoea is fundamentally a failure of enteric salt and water uptake sufficient to overwhelm the compensatory capacity of the colon [3]. A well formulated oral rehydration solution [ORS], has an appropriate sodium:glucose ratio for intestinal cotransport, promoting intestinal sodium and water uptake, so attacking the underlying problem; it is not simply symptomatic treatment. Metabolic acidosis With mild dehydration, restoration of extracellular fluid [ECF] volume, through improved renal perfusion, may correct acidosis without provision of bicarbonate precursor. In severe diarrhoea, bicarbonate precursor is important in both oral and parenteral therapy- as already noted by O’Shaugnessy by 1832. Indeed, the lethal potential of acidosis was expounded 90 years ago by the American humorist H. L. Mencken ‘Life is a struggle, not against sin, not against money power, but against hydrogen ions…The dying man doesn’t struggle much and he isn’t much afraid. As his alkalies give out he succumbs to a blest stupidity. His mind fogs. His will power vanishes. He submits decently. He scarcely gives a damn.’ [3] Neglecting acidosis in discussing the treatment of severe diarrhoea, however, is unblest stupidity; the Guideline scarcely gives a damn; it advocates saline for ECF volume replacement. Saline is appropriate treatment for metabolic alkalosis; it can not also be correct for acidosis. What evidence establishes that rapid i/v rehdyration with saline, 40 ml/kg is appropriate even with shock [p72] ? With both severe diarrhoea and shock, metabolic alkalosis is improbable: acidosis, with its associated hyperkalaemia, is potentially dangerous. The suggested dose, equivalent to 200ml of bicarbonate-free fluid per litre of ECF, would dilute plasma bicarbonate eg from 12 mmol/l to 10 mmol/l, increasing base deficit by 17%. Suggesting even 50-100 mmol/l could increase base deficit by 50%. Although Table 5.4 [p68] includes 4 studies utilising lactated Ringers, their efficacy in correcting acidosis is not discussed. Sodium in ORSs The sodium concentration of an ORS reflects the optimum for enteric uptake, not faecal sodium loss or ‘normal’ intake. Clinical anxiety about hypernatraemia rests substantially on the misapprehension that it is caused by excess sodium intake: actually it reflects predominant water loss or inadequate water intake. Every litre of ECF deficit inescapably requires 140 mmol of sodium to correct it: the less per litre of ORS, the more ORS will be needed unless, improbably, reduced sodium is outweighed by enhanced absorbtion. The Guideline, commendably, acknowledges the excessive preoccupation with hypernatraemia [p71]. Indeed, although the differences are not statistically significant, the failure rate [need for supplementation with i/v fluids] for low Na ORS [45mmol/l] was double that with high Na [90 mmol/l] ORS [p62]. Nevertheless the verdict favours low Na ORSs, essentially influenced by a Cochrane Review by Hahn et al [cited as 2007, but analysed in detail by Michell in 2005[4];the essential data remain unchanged, May 2009]. Of 13 studies providing this key evidence, which has directed paediatric ORT towards hypotonic solutions, 9 aroused serious reservations. Glutamine A glutamine-containing ORS has been used to treat neonatal diarrhoea in calves for over 10 years, because it supports recovery of villus architecture, whereas a conventional glutamine-free WHO-type ORS was associated with deterioration of villus architecture[5-7].If children responded similarly, glutamine would seem particularly important, especially if they are already malnourished, before their diarrhoea. Carneiro-Filhoe et al[8] refer to its ‘great potential in oral rehydration for diarrhoea’ and a BMJ article in 2005[9] advocated research on this solution for paediatric use. The Guideline has several recommendations for research, but no mention of glutamine. Issues for research From what has already been said, these should include • Would diarrhoeic children, especially those who are malnourished, benefit from a glutamine-containing ORS ? • Is saline, as opposed to lactated Ringers solution, appropriate i/v therapy in the face of metabolic acidosis; if so, how severe can the dehydration and the acidosis be for replacement of ECF volume with solutions lacking a bicarbonate precursor to be effective in correcting the acidosis ? • Stool output is a notoriously fallible guide to the efficacy of rehdration1 yet it is widely used as a criterion in judging ORSs; should such papers be excluded from systematic reviews ? Meta-analysis of fallible criteria Meta-analysis of unreliable data can not create reliable conclusions. The feasible measurements in paediatric cases of severe diarrhoea, especially in epidemics in isolated communities, are very restricted. The fallibility of clinical criteria in assessing severity of dehydration and success of rehydration are well known[4] and reaffirmed in the Guidance [17, 42-48]. Even loss of bodyweight has pitfalls as an index of severity of dehydration. Death can occur with relatively little loss of weight if there is a huge accumulation of fluid within the gut, causing lethal hypovolaemia before the output of fluid faeces can increase[10]. In contrast, ORT in calves rests on a line of research which defined the therapeutic targets which demarcate likely death from likely survival10, and then evaluated the beneficial effects of ORSs of different composition on plasma and ECF volume, plasma Na, K and pH, GFR, PCV (not just an index of hypovolaemia; in shock a raised PCV reminds us that blood viscosity rises exponentially with PCV, further impeding tissue perfusion) and villus architecture. It also corroborated the fallibility of stool output as a guide to effective rehydration. This is not surprising; if most of the ORS restores ECF volume, loss of the remainder as increased faecal output is inefficient but clinically unimportant. Moreover faecal output becomes normal before the small intestine, because of the compensatory capacity of the colon. Calves are not children, but unlike adult cattle, they are non-herbivorous, non-ruminant, functionally simple stomached; prima facie they offer a valid model for the evaluation of ORT in acute diarrhoea. Effectiveness of ORSs in improving plasma electrolytes, pH, plasma volume and GFR in diarrhoeic calves reflected adequate content of Na and bicarbonate precursor; improvement of pH and GFR were also potentiated by glutamine. This debate is not simply academic: for millions of children throughout the world it is a matter of life and death. Ten thousand die of this eminently treatable disease daily, mostly in poor countries: the media are missing the real medical headlines. The burden of proof is not whether calves are like children; since more reliable data are obtainable from calves the burden of proof is to establish, with due precautions, whether similar principles could save children’s’ lives[7]. A.R. Michell, Dept Biochemical Pharmacology, Harvey Institute, Barts & the London School of Medicine & Dentistry, London EC1M 6BQ. 1 O’Shaugnessy. WB Lancet 1831; 1: 490. 2 O’Shaugnessy. WB Report on the chemical pathology of malignant cholera. London: S.Wiley, 1832 3 Michell AR. The clinical biology of sodium Oxford, Elsevier. Chapter 3. 1995 4 Michell AR. Why has oral rehydration for calves and children diverged: direct vs indirect criteria of efficacy. Research in Veterinary Science 2005; 79:177-81. 5 Brooks HW, Hall, GA, Wagstaff AJ, MichellAR. Detrimental effects on villus form and function during conventional oral rehydration for diarrhoea in calves: . alleviation by a nutrient oral rehydration solution containing glutamine. Veterinary Journal 1998; 155: 263-274. 6 Michell AR. Oral rehydration for diarrhoea: symptomatic treatment or fundamental therapy Journal of Comparative Pathology 1998; 118: 175-193. 7 Michell AR. How may advances in oral rehydration therapy for animals benefit children ? Pharmaceutical Journal 2004; 272: 580-581. 8 Carneiro-Filho BA, Bushen OY, Brito GA, Lima AA, Guerrant RL. Glutamine analogues as adjunctive therapy for infectious diarrhoea. Current Infectious Disease Reports 2003; 5: 114-119 9 Michell AR. Why shouldn’t children benefit from oral rehydration solutions for calves ? British Medical Journal 2005; 331: 1267 10 Groutides CP, Michell AR. Changes in plasma composition in calves surviving or dying from diarrhoea. British Veterinary Journal 1990; 146: 205-210. Competing interests: Consultant on oral rehydration to veterinary pharmaceutical companies