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Protecting Young Children from Life-Threatening Drug Toxicity
EDITORIALS
November 2013
Protecting Young Children from Life-Threatening Drug Toxicity
T
here is nothing more devastating than losing the life of by studying the responses of physicians and parents.8 Among a young child because of toxicity caused by the very physicians, 25% did not agree with the recommendations. drug that was supposed to cure or relieve his/her sympAmong parents, 70% believed that these agents relieve symptoms. Yet, every year large numbers of neonates and toddlers toms and 68% stated that they are not dangerous. Fifteen succumb to such therapeutic misadventures. percent of parents of children younger than 2 years declared Young children are more susceptible to that they will continue to use them, and 61% See related article, p 1372 drug errors; because of their small sizes, of parents of children 2-11 years will even a 10-fold error in dose calculation or administration continue to do so. Of interest, 21% of parents were more can be small enough to “look OK.”1 For the same reason, likely to request an antibiotic from the physician. accidental ingestion of 1 adult dose unit by a toddler can We must recognize these concerns, as this under stream, if be fatal in the case of tricyclic antidepressants, antipsychotics, not addressed through education and parent’s health literacy, quinine derivatives, calcium channel blockers, opioids, and may endanger the achievements of the OTC restriction. In oral hypoglycemic.2 this context it is interesting to note that scientific evidence Cough and cold remedies have been very widely used for the effectiveness of OTC cold remedies has not been agents in young children. Containing antihistamines, deconproven despite very wide use and a market of billions of dolgestants, expectorants, and antitussives, these combinations lars a year. We accept high rates of toxicities of anticancer have been regarded as safe when used in the recommended drugs in children because their efficacy and effectiveness doses. However, because of their very wide use, fatal cases have been proven. We cannot accept toxicity of OTC cough of misuse and overdose have continued to occur.3 and cold remedies in young children if their clinical advanStarting in 2007, the Food and Drug Administration tages are unproven or questionable. (FDA) and the Consumer Healthcare Products Association The positive energy generated by the success of this FDA have moved toward advising physicians and parents not to initiative should inspire us to move into other areas where use these agents in young children. In 2008, both organizayoung children’s safety is endangered. For example, Amertions issued specific warnings against use of these agents in ican and Canadian children are still endangered by parents children younger than 2 years (FDA), or 4 years (Consumer using camphorated oils as a cold remedy. This traditional Healthcare Products Association). practice results in poisoning of significant numbers of young In this issue of The Journal, Mazer-Amishrahi et al quantify children, without any proven benefit.9,10 Let us create a new therapeutic culture in which the printhe effect of these restrictions on the rates of toddlers’ ciples of risk vs benefit prevail, ensuring that young children poisoning, using the unique data collected by National Poiare not endangered by drugs that have not been proven effecson Data System from poison centers throughout the US.4 They record dramatic decline in every aspect measured: untive for them. n intentional ingestions of over-the-counter (OTC) cough Gideon Koren, MD, FRCPC, FACMT and cold medications, therapeutic errors, referrals to health Division of Clinical Pharmacology-Toxicology care facilities for unintentional ingestions, and moderate to Department of Pediatrics severe outcomes. The authors had relevant data from 2000 The Hospital for Sick Children up to 2010. University of Toronto The results of the present study corroborate previous studies 5-7 Toronto, Ontario, Canada that have used different systems. Such corroboration is important because these are retrospective analyses, and it is always theoretically possible that the changes might have resulted from other factors, unaccounted for in the analysis. This dramatic change marks a major victory for public health as related to the well being of young children. Yet, there are challenges that must be identified and acknowledged while celebrating this achievement; young children continue to have cold symptoms, and the pressure on pediatricians to prescribe for them has not decreased. In a recent study, Garbutt et al assessed the impact of the FDA advisory not to use OTC cough and cold products in young children
FDA OTC
Food and Drug Administration Over-the-counter
Reprint requests: Gideon Koren, MD, FRCPC, FACMT, Division of Clinical Pharmacology-Toxicology, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave, Toronto, ON, Canada M5G 1X8. E-mail: [email protected]
References 1. Koren G, Barzilay Z, Greenwald M. Tenfold errors in administration of drug doses: a neglected iatrogenic disease in pediatrics. Pediatrics 1986; 77:848-9.
The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.05.039
1249
THE JOURNAL OF PEDIATRICS
www.jpeds.com
2. Bar-Oz B, Levichek Z, Koren G. Medications that can be fatal for a toddler with one tablet or teaspoonful: a 2004 update. Pediatr Drugs 2004;6:123-6. 3. U.S. Food and Drug Administration Briefing Information. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4323b1-00-index. htm. Accessed May 6, 2013. 4. Mazer-Amirshahi M, Reid N, van den Aker J, Litovitz T. Effects of cough and cold medication restriction and label changes on pediatric ingestions reported to US poison centers. J Pediatr 2013;163:1372-6. 5. Klein-Schwartz W, Sorkin JD, Doyon S. Impact of the voluntary withdrawal of over-the-counter cough and cold medications on pediatric ingestions reported to poison centers. Pharmacoepidemiol Drug Safety 2010;19:819-24.
Vol. 163, No. 5 6. Forrester MB. Effect of cough and cold medication withdrawal and warning on ingestions by young children reported to Texas poison centers. Pediatr Emerg Care 2012;28:510-3. 7. Shehab N, Schaefer MK, Kegler SR, Budnitz DS. Adverse events from cough and cold medications after a market withdrawal of products labeled for infants. Pediatrics 2010;126:1100-7. 8. Garbutt JM, Sterkel R, Banister C, Walbert C, Strunk RC. Physician and parent response to the FDA advisory about use of over-the-counter cough and cold medications. Acad Pediatr 2010;10:64-9. 9. Theis JG, Koren G. Camphorated oil: still endangering the lives of Canadian children. CMAJ 1995;152:1821-4. 10. Flaman Z, Pellechia-Clarke S, Bailey B, McGuigan M. Unintentional exposure of young children to camphor and eucalyptus oils. Pediatr Child Health 2001;6:80-3.
Prevention of Excessive Crying by Intestinal Microbiota Programming
F
or reasons that are not clear, human infants are born (compared with infants without colic), in addition to signifwith a well-developed capacity to cry.1 This first cry icantly greater BH2 levels after a lactose meal.8 In several is particularly well-received as an indication that the studies, however, neither treatment of breast milk nor forbaby is alive and well, but, in many ways, it is different mula with lactase resolved the problem of colic or did so in than any other cry that follows. Subsequent cries may not only some of the infants.9,10 The authors of other studies have found that several infants with colic be as well-received! Unexplained and severe See related article, p 1272 respond to cow’s milk protein elimination crying affects 3%-28% of breastfed or from their own diet if formula fed,11 or their mother’s diet, formula-fed (otherwise-healthy) young infants.2 Although excessive, inconsolable crying and colic are considered to if breastfed.12 In one study, authors found that crying in infants with colic was correlated with preprandial BH2, which be a benign, self-resolving problem, they can be very distresscould be indicative of small bowel bacterial overgrowth or ing and lead to marital conflict and parental exhaustion.3 Infantile colic is defined as paroxysmal, excessive, inconsolable excessive gas production from carbohydrate from the previcrying without an identifiable cause in an otherwise-healthy ous meal.13 Perhaps a more relevant finding of that study was that levels of fecal calprotectin, a marker of colonic inflaminfant occurring in the first 3 months of life and lasting a mation, were increased approximately 2-fold in infants minimum of 3 hours per day, 3 days per week, for 3 weeks. with colic compared with that of infants without colic, with Mothers of infants with colic have been reported as feeling values in a range comparable with levels of calprotectin in less competent as mothers, in addition to having more sepachildren with active inflammatory bowel disease. ration anxiety than mothers of infants without colic.4 Infantile colic at 2 months of age has been associated with high Enter intestinal microbiota. Infants with colic have been maternal depression scores 4 months later.5 In a small study, found to be more frequently colonized with Clostridium diffi26% of mothers of infants with colic admitted thoughts of cile during the time of colic than were age-matched coninfanticide during their infant’s colic episodes.6 trols,14 less frequently colonized by Lactobacillus spp., and The pathogenesis of excessive crying is considered to be more frequently by anaerobic gram-negative bacteria,15 multifactorial with behavioral, social, and neurodevelopparticularly gas-forming coliform bacteria, (ie, Escherichia mental components involved in the gut brain interaction. coli).16 Another study showed that stools of infants with colic had fewer identifiable bands on denaturing gradient gel elecCrying episodes have been associated with gastrointestinal trophoresis, and Klebsiella species were detected in more padysmotility and feeding difficulties, immaturity of immune tients with colic than in controls (8 vs 1, P = .02)13 but also and barrier gut functions, visceral hyperalgesia, and aberrant 7 that Lactobacillus brevis and Lactobacillus lactis lactis might responses to stress. Intestinal distension by gas or swallowed air could be a be involved in the pathogenesis by increasing meteorism possible explanation for the crying. Gas results from bacterial and abdominal distension.17 The few existing studies differ in their findings regarding fermentation of dietary carbohydrate that reaches the colon. the microbiota identified. In any case, if an abnormal fecal One such gas is hydrogen, which can be measured in the breath hydrogen excretion (BH2). Significantly greater baseline BH2 values have been reported in some infants with colic The author has received honoraria for talks and scientific advice from the Nestle Nutrition Institute and Sequoia z.o.o. (Poland), and holds stock in Mead Johnson Nutrition.
BH2
Breath hydrogen excretion
0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.06.034
1250
November 2013
Protecting Young Children from Life-Threatening Drug Toxicity
T
here is nothing more devastating than losing the life of by studying the responses of physicians and parents.8 Among a young child because of toxicity caused by the very physicians, 25% did not agree with the recommendations. drug that was supposed to cure or relieve his/her sympAmong parents, 70% believed that these agents relieve symptoms. Yet, every year large numbers of neonates and toddlers toms and 68% stated that they are not dangerous. Fifteen succumb to such therapeutic misadventures. percent of parents of children younger than 2 years declared Young children are more susceptible to that they will continue to use them, and 61% See related article, p 1372 drug errors; because of their small sizes, of parents of children 2-11 years will even a 10-fold error in dose calculation or administration continue to do so. Of interest, 21% of parents were more can be small enough to “look OK.”1 For the same reason, likely to request an antibiotic from the physician. accidental ingestion of 1 adult dose unit by a toddler can We must recognize these concerns, as this under stream, if be fatal in the case of tricyclic antidepressants, antipsychotics, not addressed through education and parent’s health literacy, quinine derivatives, calcium channel blockers, opioids, and may endanger the achievements of the OTC restriction. In oral hypoglycemic.2 this context it is interesting to note that scientific evidence Cough and cold remedies have been very widely used for the effectiveness of OTC cold remedies has not been agents in young children. Containing antihistamines, deconproven despite very wide use and a market of billions of dolgestants, expectorants, and antitussives, these combinations lars a year. We accept high rates of toxicities of anticancer have been regarded as safe when used in the recommended drugs in children because their efficacy and effectiveness doses. However, because of their very wide use, fatal cases have been proven. We cannot accept toxicity of OTC cough of misuse and overdose have continued to occur.3 and cold remedies in young children if their clinical advanStarting in 2007, the Food and Drug Administration tages are unproven or questionable. (FDA) and the Consumer Healthcare Products Association The positive energy generated by the success of this FDA have moved toward advising physicians and parents not to initiative should inspire us to move into other areas where use these agents in young children. In 2008, both organizayoung children’s safety is endangered. For example, Amertions issued specific warnings against use of these agents in ican and Canadian children are still endangered by parents children younger than 2 years (FDA), or 4 years (Consumer using camphorated oils as a cold remedy. This traditional Healthcare Products Association). practice results in poisoning of significant numbers of young In this issue of The Journal, Mazer-Amishrahi et al quantify children, without any proven benefit.9,10 Let us create a new therapeutic culture in which the printhe effect of these restrictions on the rates of toddlers’ ciples of risk vs benefit prevail, ensuring that young children poisoning, using the unique data collected by National Poiare not endangered by drugs that have not been proven effecson Data System from poison centers throughout the US.4 They record dramatic decline in every aspect measured: untive for them. n intentional ingestions of over-the-counter (OTC) cough Gideon Koren, MD, FRCPC, FACMT and cold medications, therapeutic errors, referrals to health Division of Clinical Pharmacology-Toxicology care facilities for unintentional ingestions, and moderate to Department of Pediatrics severe outcomes. The authors had relevant data from 2000 The Hospital for Sick Children up to 2010. University of Toronto The results of the present study corroborate previous studies 5-7 Toronto, Ontario, Canada that have used different systems. Such corroboration is important because these are retrospective analyses, and it is always theoretically possible that the changes might have resulted from other factors, unaccounted for in the analysis. This dramatic change marks a major victory for public health as related to the well being of young children. Yet, there are challenges that must be identified and acknowledged while celebrating this achievement; young children continue to have cold symptoms, and the pressure on pediatricians to prescribe for them has not decreased. In a recent study, Garbutt et al assessed the impact of the FDA advisory not to use OTC cough and cold products in young children
FDA OTC
Food and Drug Administration Over-the-counter
Reprint requests: Gideon Koren, MD, FRCPC, FACMT, Division of Clinical Pharmacology-Toxicology, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave, Toronto, ON, Canada M5G 1X8. E-mail: [email protected]
References 1. Koren G, Barzilay Z, Greenwald M. Tenfold errors in administration of drug doses: a neglected iatrogenic disease in pediatrics. Pediatrics 1986; 77:848-9.
The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.05.039
1249
THE JOURNAL OF PEDIATRICS
www.jpeds.com
2. Bar-Oz B, Levichek Z, Koren G. Medications that can be fatal for a toddler with one tablet or teaspoonful: a 2004 update. Pediatr Drugs 2004;6:123-6. 3. U.S. Food and Drug Administration Briefing Information. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4323b1-00-index. htm. Accessed May 6, 2013. 4. Mazer-Amirshahi M, Reid N, van den Aker J, Litovitz T. Effects of cough and cold medication restriction and label changes on pediatric ingestions reported to US poison centers. J Pediatr 2013;163:1372-6. 5. Klein-Schwartz W, Sorkin JD, Doyon S. Impact of the voluntary withdrawal of over-the-counter cough and cold medications on pediatric ingestions reported to poison centers. Pharmacoepidemiol Drug Safety 2010;19:819-24.
Vol. 163, No. 5 6. Forrester MB. Effect of cough and cold medication withdrawal and warning on ingestions by young children reported to Texas poison centers. Pediatr Emerg Care 2012;28:510-3. 7. Shehab N, Schaefer MK, Kegler SR, Budnitz DS. Adverse events from cough and cold medications after a market withdrawal of products labeled for infants. Pediatrics 2010;126:1100-7. 8. Garbutt JM, Sterkel R, Banister C, Walbert C, Strunk RC. Physician and parent response to the FDA advisory about use of over-the-counter cough and cold medications. Acad Pediatr 2010;10:64-9. 9. Theis JG, Koren G. Camphorated oil: still endangering the lives of Canadian children. CMAJ 1995;152:1821-4. 10. Flaman Z, Pellechia-Clarke S, Bailey B, McGuigan M. Unintentional exposure of young children to camphor and eucalyptus oils. Pediatr Child Health 2001;6:80-3.
Prevention of Excessive Crying by Intestinal Microbiota Programming
F
or reasons that are not clear, human infants are born (compared with infants without colic), in addition to signifwith a well-developed capacity to cry.1 This first cry icantly greater BH2 levels after a lactose meal.8 In several is particularly well-received as an indication that the studies, however, neither treatment of breast milk nor forbaby is alive and well, but, in many ways, it is different mula with lactase resolved the problem of colic or did so in than any other cry that follows. Subsequent cries may not only some of the infants.9,10 The authors of other studies have found that several infants with colic be as well-received! Unexplained and severe See related article, p 1272 respond to cow’s milk protein elimination crying affects 3%-28% of breastfed or from their own diet if formula fed,11 or their mother’s diet, formula-fed (otherwise-healthy) young infants.2 Although excessive, inconsolable crying and colic are considered to if breastfed.12 In one study, authors found that crying in infants with colic was correlated with preprandial BH2, which be a benign, self-resolving problem, they can be very distresscould be indicative of small bowel bacterial overgrowth or ing and lead to marital conflict and parental exhaustion.3 Infantile colic is defined as paroxysmal, excessive, inconsolable excessive gas production from carbohydrate from the previcrying without an identifiable cause in an otherwise-healthy ous meal.13 Perhaps a more relevant finding of that study was that levels of fecal calprotectin, a marker of colonic inflaminfant occurring in the first 3 months of life and lasting a mation, were increased approximately 2-fold in infants minimum of 3 hours per day, 3 days per week, for 3 weeks. with colic compared with that of infants without colic, with Mothers of infants with colic have been reported as feeling values in a range comparable with levels of calprotectin in less competent as mothers, in addition to having more sepachildren with active inflammatory bowel disease. ration anxiety than mothers of infants without colic.4 Infantile colic at 2 months of age has been associated with high Enter intestinal microbiota. Infants with colic have been maternal depression scores 4 months later.5 In a small study, found to be more frequently colonized with Clostridium diffi26% of mothers of infants with colic admitted thoughts of cile during the time of colic than were age-matched coninfanticide during their infant’s colic episodes.6 trols,14 less frequently colonized by Lactobacillus spp., and The pathogenesis of excessive crying is considered to be more frequently by anaerobic gram-negative bacteria,15 multifactorial with behavioral, social, and neurodevelopparticularly gas-forming coliform bacteria, (ie, Escherichia mental components involved in the gut brain interaction. coli).16 Another study showed that stools of infants with colic had fewer identifiable bands on denaturing gradient gel elecCrying episodes have been associated with gastrointestinal trophoresis, and Klebsiella species were detected in more padysmotility and feeding difficulties, immaturity of immune tients with colic than in controls (8 vs 1, P = .02)13 but also and barrier gut functions, visceral hyperalgesia, and aberrant 7 that Lactobacillus brevis and Lactobacillus lactis lactis might responses to stress. Intestinal distension by gas or swallowed air could be a be involved in the pathogenesis by increasing meteorism possible explanation for the crying. Gas results from bacterial and abdominal distension.17 The few existing studies differ in their findings regarding fermentation of dietary carbohydrate that reaches the colon. the microbiota identified. In any case, if an abnormal fecal One such gas is hydrogen, which can be measured in the breath hydrogen excretion (BH2). Significantly greater baseline BH2 values have been reported in some infants with colic The author has received honoraria for talks and scientific advice from the Nestle Nutrition Institute and Sequoia z.o.o. (Poland), and holds stock in Mead Johnson Nutrition.
BH2
Breath hydrogen excretion
0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.06.034
1250