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Rapid Responses: Rapid Responses published:
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Ibuprofen is a marker of soft tissue infection more than its cause
- nicholas D Moore (25 September 2008)
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Ibuprofen and soft tissue infections
- Anthony Harnden (26 September 2008)
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Re: Ibuprofen and soft tissue infections
- Carlos A Calderon Ospina, Alejandra Salcedo (26 September 2008)
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What about GI bleed?
- David Taylor (28 September 2008)
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what about acute renal failure?
- oscar,m jolobe (29 September 2008)
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Adverse events in antipyretic medication
- Anthony Harnden (30 September 2008)
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Ibuprofen and soft tissue infections in children
- Samuel M. Lesko, Richard M. Vezina, Allen A. Mitchell (16 October 2008)
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nicholas D Moore, Director of Clinical Research/clinical pharmacology Bordeaux University Hospital, 33076
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I am very surprised at this misleading response to the previous paper, including its title, which affirms as a fact what is just an opinion or a hypothesis. It seems that the authors did not read the references that they cite to support the affirmation that ibuprofen increases the risk of soft tissue infection in varicella: to quote the authors of the more recent of these studies (1), the only one that is really methodologically sound: "These data do not support the hypothesis that nonsteroidal antiinflammatory drugs, or ibuprofen in particular, increase the risk of necrotizing GAS infections." The second paper cited (2) concludes "The risk of invasive Group A streptococcal infection was associated with demographic and environmental factors and persistent high fever. There was no association with the use of ibuprofen or paracetamol alone, but the use of both agents was significantly associated with streptococcal infection. These studies demonstrate that children with fever tolerate treatment with ibuprofen as well as treatment with paracetamol. Neither agent is associated with an increased risk of necrotising soft tissue infections." The conclusion is certainly not the one that the title of the response suggests, but clearly that persistent high fever in patients receiving ibuprofen or paracetamol after varicella is probably a sign of incipient soft tissue infection. Another study found an association also with antibiotics in parapneumonic empyema (3), also probably confounding by indication. Certainly more studies are needed, probably a large randomized clinical trial that is the only true way of avoiding confounding by indication in this case. Such misleading and unwarranted affirmations are unfortunate. Paracetamol is a good first-line product, but it is not as effective as ibuprofen, and it certainly is not as safe as most people would like. Unfortunately, excess fear of ibuprofen can lead to excess use of paracetamol, which in overdose and especially in children can be quite hepatotoxic (4,5). Unlike soft tissue infection with ibuprofen, this is a fact, not an opinion. Best Nicholas Moore 1. Lesko SM, O'Brien KL, Schwartz B, Vezina R, Mitchell AA. Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella. Pediatrics. 2001 May;107(5):1108-15. 2. Lesko SM. The safety of ibuprofen suspension in children. Int J Clin Pract Suppl. 2003 Apr(135):50-3. 3. Byington CL, Spencer LY, Johnson TA, Pavia AT, Allen D, Mason EO, et al. An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis. 2002 Feb 15;34(4):434-40. 4. Ranganathan SS, Sathiadas MG, Sumanasena S, Fernandopulle M, Lamabadusuriya SP, Fernandopulle BM. Fulminant hepatic failure and paracetamol overuse with therapeutic intent in febrile children. Indian J Pediatr. 2006 Oct;73(10):871-5. 5. James LP, Alonso EM, Hynan LS, Hinson JA, Davern TJ, Lee WM, et al. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006 Sep;118(3):e676-81. Competing interests: I have been involved in a number of studies including large clinical trials comparing ibuprofen to paracetamol. I have given expert advice to various pharmaceutical companies in the field of low- dose NSAIDs analgesia |
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Anthony Harnden, Unoversity Lecturer in General Practice Department of Primary Health Care, University of Oxford OX3 7LF
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I fully agree with Professor Moore. I am astonished that the BMJ have chosen to publish this unsubstantiated letter alongside Alastair Hay's research and my editorial and that Tony Delamothe chose to highlight the letter in the Editors choice. Please go back and read the original articles cited in the letter. I had carefully read through the these articles before writing 'Paracetamol and ibuprofen are safe for children when given at the recommended doses.' I would like to highlight one further issue. Since the BMJ published my editorial on line the Lancet have published in print Beasleys original research describing an association between paracetamol use in infancy and childhood and risk of atopic disease age 6-7. This attracted widespread media attention in the UK.The study has problems with confounding and doesn't change my message but I think your readers will be a bit perplexed that I didn't refer to the study in my commentary. The lag time between online publishing and the print version has created this problem. Competing interests: None declared |
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Carlos A Calderon Ospina, Assistant Professor Pharmacology Unit. Faculty of Medicine. Universidad del Rosario. Bogota. Colombia., Alejandra Salcedo
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We think that there is an unfortunate misunderstanding about our letter recently published by the BMJ. If the readers take a look at our original response that was published online on September 11th, they will see that we only wrote about an association between the use of ibuprofen and soft-tissue infections in children, but in any moment we mentioned a causative effect about this adverse event. Actually we reviewed the references cited, but unfortunately, the ones that show the association did not appear in the print issue of the journal. We must say that we completely agree with Professor Moore about the fact that a large randomized clinical trial is needed to clarify the existence of a possible causative relationship between ibuprofen and soft- tissue infections in children. Finally, we allow ourselves to publish our original response (including the title) again, in order to clarify the misunderstood. Thanks for all of your comments, these are very valuable for us. Increased risk of soft tissue infections in children who take ibuprofen and ibuprofen and paracetamol "Recently, the BMJ published a clinical study according to which the combination of ibuprofen and paracetamol is more effective in going temperature down in children with fever (1). In turn, ibuprofen is more effective as monotherapy than paracetanol in controlling this symptom; that is why the authors conclude that for discomfort feverish children; first it should be administrate ibuprofen and then consider adding paracetamol for 24 hours in case of do not obtain the expected recovery. However, there are a few reports that suggest an association between the intake of ibuprofen or ibuprofen and paracetamol and an increased risk to suffer from soft-tissue infections, some of them very serious such as necrotizing fasciitis (2,4,5,6). Some of these studies shown an increase of the risk arose from the intake of ibuprofen as monotherapy (2,5,6), or the combination between ibuprofen and paracetamol (3,4); but at the same time a few of them are very emphatic showing that there is not an increase in the risk associated to the intake of paracetamol alone (3,4,7). The main risk factors for suffering from necrotizing fasciitis associated to nonsteroideal anti-inflammatory drugs (NSAIDs) include age (children) and a viral disease during the treatment. In fact, a French, case (patients with soft tissue necrotizante infection)-control study, published recently (6), documented that among 38 cases that were reported to the National System of Pharmacovigilance between 2000 and 2004, 25 patients were exposed to ibuprofen and 24 patients had have chickenpox. In the same study patients had a median age of 4 years old, and the adjusted odds ratios for exposure to NSAIDs and for viral infection were 31,38 (IC 95% 6,40 – 153,84) and 17,55 (IC 95% 3,47 – 88,65) respectively. It is quite interesting that in Hay´s et. al. study (1), 57 children with viral diseases were included (36,5%), and although it says that five children were hospitalized due to adverse serious events, it is not clear how these events happened or none extra information besides the medication taken is given. To conclude, we think that is not possible to ignore the available evidence, and although the combination of ibuprofen and paracetamol could be more effective for treating fever in children, precautions have to be taken when administrating this combination in children with viral infections, especially in children with chickenpox, and in this population the administration of paracetamol should be considered as monotherapy, decreasing the risk of suffering from soft tissue infections such as necrotizing fasciitis. References 1. Hay A, Costelloe C, Redmond N, Montgomery A, Fletcher M, Hollinghurst S, Peters T. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ. 2008; 337: a1302. 2. Zerr DM, Alexander ER, Duchin JS, Koutsky LA, Rubens CE. A case- control study of necrotizing fasciitis during primary varicella. Pediatrics. 1999; 103: 783 - 790. 3. Lesko SM, O'Brien KL, Schwartz B, Vezina R, Mitchell AA. Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella. Pediatrics. 2001; 107:1108 -1115. 4. Lesko SM. The safety of ibuprofen suspension in children. Int J Clin Pract Suppl. 2003; 135: 50 - 53. 5. Leroy S, Mosca A, Landre-Peigne C, Cosson MA, Pons G. Ibuprofen in childhood: evidence-based review of efficacy and safety. Arch Pediatr. 2007; 14: 477 - 484. 6. Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M; French Network of Pharmacovigilance Centres. Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs. Clin Exp Dermatol. 2008; 33: 249 -255. 7. Mikaeloff Y, Kezouh A, Suissa S. Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease. Br J Clin Pharmacol. 2008; 65: 203 - 209." Competing interests: None declared |
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David Taylor, GP principal Birmingham UK B31
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Thank you for your article. I have always been put off ibuprofen by dire tales from a paediatric nephrologist of dialysing toddlers who had taken ibuprofen during a normal childhood illness. I have advised parents of anorexic febrile children to avoid ibuprofen. This is all anecdotal, has anybody got any comment? Competing interests: None declared |
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oscar,m jolobe, retired geriatrician manchester medical society, c/o john rylands university library, oxford road, manchester, M13 9PP
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The point is well made by Dr Taylor that administration of non-steroidal anti-inflammatory drugs(NSAID's) can precipitate, not only gastrointestinal bleeding, but, also, renal failure requiring dialysis(1). In one department of paediatric nephrology, over a period of 20 months, acute renal failure(ARF) was documented in six children without pre-existing renal disease aged, 4, 5, 9, 13, 15, and 15, respectively, who had been prescribed NSAID's 1-5 days previously. Ibuprofen was used in five instances, and ketoprofen in one instance. The underlying disorder was gastro-enteritis in 3 instances, varicella with asociated vomiting in one instance, and fracture, and pneumonia, respectively, in the other two instances(2). The authors drew attention to the fact that NSAID-related inhibition of prostaglandin synthesis and, hence, diminution of prostaglandin-related renal perfusion, increases the risk of ARF in the event of volume depletion from whatever cause, and that volume depletion, itself, is often underestimated(2). Relevant causes of volume depletion in children include, not only gastroenteritis, but also insensible loss of fluid via the skin during a pyrexial illness, and via the respiratory tract during tachypnoea. Accordingly, it is always worth remembering that "using NSAID in volume depleted children can precipitate acute renal failure", and that NSAID-related renal dysfunction may be underreported because many patients improve spontaneously when NSAID's are discontinued(3). References (1) Taylor,D What about GI bleed? Rapid response British Medical Journal 28/9/08 (2) Ulinski T., Guigonis V., Dunam O., Bensman A Acute renal failure after treatment with non-steroidal anti-inflammatory drugs European Journal of Pediatrics 2004:163:148-50 (3) Mathews C.,Shukla R., Jones C Using NSAID in volume depleted children can precipitate acute renal failure Archives of Disease in Childhood 2007:92:524-6 Competing interests: None declared |
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Anthony Harnden, University Lecturer in General Practice Department of Primary Health Care, Oxford University. OX3 7LF
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Whilst important to report adverse events, we should be cautious in assuming a causal association between drug and event in small case series of febrile children. Neither of the two references (1,2) reporting trial data in very large numbers of children support a difference in adverse effects between paracetamol and ibuprofen when used for short courses in children. 1. Perrott DA, Piira T, Goodenough B, Champion GD.Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis. Arch Pediatr Adolesc Med. 2004 Jun;158(6):521-6. 2. Lesko SM, Mitchell AA.The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics. 1999 Oct;104(4):e39 Competing interests: None declared |
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Samuel M. Lesko, Medical Director and Director of Research Northeast Regional Cancer Institute, 334 Jefferson Ave, Scranton, PA 18510, Richard M. Vezina, Allen A. Mitchell
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We read with interest the letter by Calderon Ospina and Salcedo citing our research as evidence that ibuprofen increases the risk of soft tissue infections in children with a febrile illness.(1,2) However, we believe it is important to clarify the results of our study, in which we studied the risk of invasive group A streptococcal infection (necrotizing and non-necrotizing soft tissue infections) in children with varicella. As we stated in the abstract, risk of these infectious complications overall was increased only among children exposed to ibuprofen and acetaminophen in combination, and use of this combination was strongly associated with severity of the underlying varicella illness. Neither did we find evidence of increasing risk of soft tissue infection with exposure to an increasing number of ibuprofen doses. These observations suggest the possibility that confounding by severity of the underlying illness may account, at least in part, for the observed association. Further in a sub -analysis, use of ibuprofen was only associated with risk of non- necrotizing soft tissue infections. Contrary to the writers’ inference, we do not believe our study provides evidence that ibuprofen use increases the risk of necrotizing fasciitis or other necrotizing soft tissue infections. Rather, we suspect that severity of the child’s underlying febrile illness is the primary risk factor for these infections. As we observed in our data, children who are treated with a combination of acetaminophen and ibuprofen for fever control are likely to be more seriously ill than those treated with either medication alone, and such children should be evaluated and monitored for adverse clinical outcomes particularly carefully because of their underlying disease severity, not because antipyretic medications themselves increase their risks. 1. Calderon Ospina CA, Salcedo A. Ibuprofen increases soft tissue infections in children. (Letter) BMJ 2008;337:a1767. 2. Lesko SM, O’Brien KL, Schwartz B, Vezina R, Mitchell AA. Invasive group A streptococcal infection and nonsteroidal anti-inflammatory drug use among children with primary varicella. Pediatrics 2001;107:1109-15. Competing interests: Our study was supported by funding from McNeil Consumer Healthcare and Wyeth Consumer Healthcare. |
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