Current Best Evidence: Translating Best Evidence into Best Care EDITOR’S NOTE: Studies for this issue were identified using alerts from Archives of Disease in Childhood-Education and Practice, Archives of Disease in Childhood-Fetal and Neonatal, Archives of Disease in Childhood, British Medical Journal, Journal of the American Medical Association, New England Journal of Medicine, Pediatric Infectious Disease Journal, Pediatrics, The Journal of Pediatrics, and The Lancet. Search terms were “paediatrics” [All Fields] OR “pediatrics” [All Fields] OR “pediatrics” [MeSH Terms]. In addition, studies also were identified using the Clinical Queries feature of PubMed. Cleo Pappas, MLIS, Library of the Health Sciences, University of Illinois at Chicago, contributed to the review and selection of this month’s abstracts. —Jordan Hupert, MD EVIDENCE-BASED MEDICINE PEARL: LONGITUDINAL LATENT CLASS ANALYSIS: Longitudinal latent class analysis, as it applies to medicine, is a method that detects subgroups among a large group. Each subgroup (or subclass) is defined by a set of characteristics (signs/symptoms), the probabilities of which statistically relate to one another. An example can be found in the article by Lodge et al (see piece by Collins on page 207 regarding article Lodge et al; J Pediatr 2014;164:289-94). The authors applied this type of analysis to early-life risk factors (eg, parental asthma, parental smoking, pets in the home) and the subsequent development of childhood wheezing in a large birth cohort. Although the probability of each of the risk factors for the overall birth cohort was easily measured over time, it was not known whether there were subclasses, each with a unique set of risk-factor probabilities. The statistical analysis was able to identify 5 subclasses of that birth cohort. The authors reviewed the subclass risk-factor-probability sets and they defined wheezing phenotypes for each: never/infrequent, transient, intermediate, late, and persistent wheezing. This type of analysis is termed “latent” as the subclasses (wheezing phenotypes) are “present but not apparent (a definition of latent).” The analysis was “longitudinal,” as patients were followed for wheezing patterns at discreet time points from 4 weeks until 7 years of age. —Jordan Hupert, MD LIBRARIAN PEARL: ALERTS: Alerts are tools that allow you to develop a search strategy, enter it into a database, and then have the database email you results on a regular basis. Alerts are useful for quality improvement initiatives, chronic illnesses, orphan illnesses, and long-term projects such as research articles or white papers. The first step in creating an alert is to set up a free email account that you will remember to check regularly. You may use any internet browser. To create an alert in Google, go to www.google.com/alerts. Enter your search query and examine the sample result to determine if your query is specific to your topic. Create the alert by entering your email address, the sources you want checked, and the frequency that you wish to receive results. For a tutorial, visit www. wikihow.com/Use-Google-Alerts. —Cleo Pappas, MLIS
Identification of early-life risk factor profiles for wheeze phenotypes Lodge CJ, Zaloumis S, Lowe AJ, Gurrin LC, Matheson MC, Axelrad C, et al. Early-life risk factors for childhood wheeze phenotypes in a high-risk birth cohort. J Pediatr 2014; 164:289-94. Question Among infants at high risk of allergy who are followed longitudinally, which early-life factors are associated with wheezing? Design Observational birth cohort. Setting Melbourne, Australia. Participants 620 infants at high risk of allergy followed up to 7 years of age. Outcomes Risk factors associated with 5 longitudinal-latentclass-analysis (LLCA)-identified wheeze classes: never/
infrequent, transient, intermediate, late, and persistent phenotypes. Main Results Lower respiratory tract infection (LRTI) and childcare by 1 year of age were associated with risk of transient wheeze. LRTI and aeroallergen sensitization increased the risk of early persistent wheeze. LRTI, eczema, aeroallergen sensitization, and food sensitization increased the risk of intermediate-onset wheeze. Heavy parental smoking at birth increased the risk of late-onset wheeze. Breastfeeding was protective in transient and late-onset wheeze. Conclusions These findings provide distinct early-life risk factor profiles for each wheeze phenotype. Commentary LLCA has allowed researchers to expand upon original 4 group classification of childhood wheeze by Martinez et al1 and better differentiate wheezing phenotypes.2 Lodge et al applied LLCA to 7 years of wheeze data from 207
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620 children in the Melbourne Atopy Cohort Study (MACS) and their 23 data points far exceed most previous LLCA studies. The identification of a 5-class model, noted above, largely agrees with previous studies, as do the identified associations. The intermediate-onset phenotype is strongly linked to atopy. The increased prevalence of significant wheeze in this high risk birth cohort (60% MACS vs 41% The Avon Longitudinal Study of Parents an Children3) is almost entirely accounted for by intermediate-onset wheeze (20.7% MACS vs 3% The Avon Longitudinal Study of Parents an Children). The conclusions are hampered by the lack of a standardized questionnaire. For example, “cough” was included under 2 years and “episodes of asthma” from 3 to 7 years. However, the findings remain consistent with previous studies. The authors also postulate some causative mechanisms for their phenotypes but fail to take account of the crucial role that earlylife lung function has been shown to play in the classification of pre-school wheeze phenotypes.1,2 Samuel A. Collins, BA, MA, MBBS, MRCPCH University of Southampton Southampton, United Kingdom
References 1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133-8. 2. Collins SA, Pike KC, Inskip HM, Godfrey KM, Roberts G, Holloway JW, et al. Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitization data in the first 6 years of life: evidence from the Southampton Women’s survey. Pediatr Pulmonol 2013;48: 683-92. 3. Savenije OE, Granell R, Caudri D, Koppelman GH, Smit H, Wijga A, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol 2011;127:1505-12.
Topical antibiotics are superior to oral antibiotics in children with acute tympanostomy tube otorrhea van Dongen TM, van der Heijden GJ, Venekamp RP, Rovers MM, Schilder AG. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med 2014; 370:723-33. Question Among children with acute tympanostomy tube otorrhea (TTO), what is the efficacy of topical intra-aural antibiotics, compared with oral antibiotics, in resolution of TTO? Design Randomized, controlled, 3-group trial.
Vol. 165, No. 1 Outcomes Presence of otorrhea after 2 weeks of treatment, assessed otoscopically. Main Results 2 weeks after treatment, 5% of children treated with antibiotic–glucocorticoid eardrops had otorrhea compared with 44% of those treated with oral antibiotics (number needed to treat, 3; 95% CI, 2 to 4) and 55% of those treated with initial observation (number needed to treat, 2; 95% CI, 2 to 3). Conclusions Antibiotic–glucocorticoid eardrops were more effective than oral antibiotics and initial observation in children with TTO. Commentary The benefits of topical antibiotic therapy for acute TTO have been recently reviewed, leading to a recommendation that “clinicians should prescribe topical antibiotic eardrops only, without oral antibiotics, for children with uncomplicated acute TTO.”1 The trial by van Dongen et al bolsters this recommendation with high quality evidence and a placebo control group. Although 55% of the placebo group had otorrhea by otoscopy 2 weeks after treatment, there was no difference in generic quality of life among groups and differences in otitis-specific quality of life were small, suggesting a potential role for observation and aural toilet (eg, cleaning otorrhea from the ear canal with a nasal aspirator) in some children with mild discharge, minimal symptoms, and good quality of life. Children with persistent or more symptomatic TTO are best treated with topical antibiotic drops, approved for use in the middle ear, as recommended in the previously cited clinical practice guideline1 and reinforced in the Choosing Wisely campaign2 from the American Board of Internal Medicine. Richard M. Rosenfeld, MD, MPH State University of New York Downstate Medical Center Brooklyn, New York
References 1. Rosenfeld RM, Schwartz SR, Pynnonen MA, Tunkel DE, Hussey HM, Fichera JS, et al. Clinical practice guideline: tympanostomy tubes in children. Otolaryngol Head Neck Surg 2013;149(Suppl 1):S1-35. 2. American Academy of Otolaryngology—Head and Neck Surgery. Choosing Wisely: Five things physicians and patients should question. Available at: http://www.choosingwisely.org/doctor-patient-lists/americanacademy-of-otolaryngology-head-and-neck-surgery-foundation/. Accessed March 3, 2014.
Transcranial magnetic stimulation may improve symptoms of hemiparesis
Participants Children, 1–10 years of age, with up to 1 week of TTO.
Gillick BT, Krach LE, Feyma T, Rich TL, Moberg K, Thomas W, et al. Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized controlled trial. Dev Med Child Neurol 2014;56:44-52.
Intervention Hydrocortisone-bacitracin-colistin eardrops or oral amoxicillin-clavulanate suspension or observation.
Question Among children with congenital hemiparesis, what is the therapeutic efficacy of repetitive transcranial magnetic
Setting Utrecht, Amsterdam, and Nijmegen in The Netherlands.
208
CURRENT BEST EVIDENCE
July 2014 stimulation (rTMS), compared with sham rTMS, in enhancing function of the affected limb? Design Randomized, controlled trial. Setting Gillette Children’s Specialty Healthcare, Saint Paul, Minnesota. Participants Children with congenital hemiparesis. Intervention rTMS or sham rTMS; all patients also received constraint-induced movement therapy (CIMT). Outcomes Primary outcome was spontaneous performance in bimanual functional activities as evaluated with the Assisting Hand Assessment (AHA) test. Main Results Improvement in AHA differed significantly between groups (P = .007). Eight of 10 participants in the rTMS/CIMT group showed improvement greater than the smallest detectable difference, but only 2 of 9 in the sham rTMS/CIMT group showed such improvement (number needed to treat, 2; 95% CI, 2-5). Conclusions Primed, low-frequency rTMS combined with CIMT is efficacious in pediatric hemiparesis. Commentary This study combines a validated behavioral intervention with an augmented form of inhibitory rTMS. It adds to the growing consensus on both techniques, but does not demonstrate superiority of primed rTMS or show whether the treatments are synergistic or merely additive. If rTMS temporarily relieves the injured hemisphere from competition so it can learn new outputs (my belief), then it should be done right before CIMT. If it remodels the brain on its own, it does not matter. Susceptibility to TMS changes with development1 and varies significantly between individuals. Therefore, response variables (eg, motor evoked potential threshold and the degree of inhibition from rTMS) might have been reported and tested as covariates to strengthen and better interpret the results. rTMS has existed for 25 years, and substantial preliminary data on the effectiveness of contralesional inhibition have been published,2 yet there have been neither large trials nor apparent interest in commercialization for the treatment of hemiparesis. Results such as these must be followed-up aggressively if they are to provide a just return on investment. Eric Wassermann, MD National Institutes of Health Bethesda, Maryland
References 1. Garvey MA, Mall V. Transcranial magnetic stimulation in children. Clin Neurophysiol 2008;119:973-84. 2. Wassermann EM, Zimmermann T. Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther 2012;133: 98-107.
Acetaminophen: a possible alternative to ibuprofen in patent ductus arteriosus closure
Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014;164:510-4. Question Among premature infants with a patent ductus arteriosus (PDA), what is the therapeutic efficacy of acetaminophen, compared with ibuprofen, on the PDA closure rate? Design Randomized, controlled trial. Setting Neonatal intensive care unit, Ankara, Turkey. Participants Preterm infants < 30 weeks’ gestational age, birthweight < 1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed significant PDA. Intervention Oral acetaminophen versus oral ibuprofen. Outcomes PDA closure rate. Main Results The PDA closed in 31 (77.5%) of the patients assigned to the oral ibuprofen group vs 29 (72.5%) of those enrolled in the acetaminophen group (absolute risk reduction [ARR] 5%, 95% CI, -13.95% to 23.95%, not significant). The reopening rate was higher in the acetaminophen group than in the ibuprofen group, but not statistically different (ARR 6%, 95% CI, -9.48% to 25.48%, not significant). Conclusions Acetaminophen may be a medical alternative in the management of PDA. Commentary Despite intense study, indecision surrounds treatment of the preterm infant with a PDA. Who should be treated, when, and with what? Oncel et al provide pilot evidence suggesting a role for oral acetaminophen to close the PDA. Interestingly, the most premature infants—those at highest risk for complications secondary to a PDA— appeared to have the highest rates of ductal closure with acetaminophen when compared to oral ibuprofen. This trial was powered to detect an unrealistic 25% difference in PDA closure rates between the two therapies, and found an insignificant difference of merely 5%. Additionally, the trial was far too small to detect important yet uncommon adverse effects of acetaminophen. Finally, eligibility was based primarily on echocardiographic evidence of significant PDA. It is increasingly clear that many PDAs close spontaneously, and expectant management is safe.1 Routine screening echocardiography, as performed in this study, will likely lead to overtreatment.2 One can hope that oral acetaminophen will prove to have higher efficacy and less toxicity than indomethacin or ibuprofen. Such novel therapies are crucially important because the ultimate decision about which infants will benefit most from treatment of the PDA hinges completely on the risk:benefit of the available therapies. Sara B. DeMauro, MD, MSCE University of Pennsylvania Philadelphia Pennsylvania Clyde J. Wright, MD University of Colorado School of Medicine Aurora, Colorado 209
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References 1. Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. J Pediatr 2012;160:929-35.e1. 2. DeMauro SB, Cohen MS, Ratcliffe SJ, Abbasi S, Schmidt B. Serial echocardiography in very preterm infants: a pilot randomized trial. Acta Paediatr 2013;102:1048-53.
Prophylactic use of probiotics ameliorates infantile colic Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr 2014;168:228-33. Question Among newborns, what is the prophylactic efficacy of probiotics, compared with placebo, in preventing/ameliorating infantile colic? Design Randomized, controlled trial. Setting 9 neonatal units in Italy. Participants Full-term babies. Intervention Lactobacillus reuteri Diagnostic and Statistical Manual (DSM) 17938 or placebo. Outcomes Reduction of daily crying time, regurgitation, and constipation during the first 3 months of life. Main Results At 3 months of age, the mean duration of crying time (38 vs 71 minutes; P < .01), the mean number of regurgitations per day (2.9 vs 4.6; P < .01), and the mean number of evacuations per day (4.2 vs 3.6; P < .01) for the L reuteri DSM 17938 and placebo groups, respectively, were significantly different. Conclusions Prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders. Commentary Infantile colic, though self-resolving, increases healthcare and emotional costs. Those with infantile colic are
210
Vol. 165, No. 1 at a significantly increased risk for developing recurrent abdominal pain, allergic diseases, and psychological disorders.1 Though the etiology is unknown, evidence suggests the gut microbiome may play a role in the generation of symptoms.2 Indrio et al employed a double blind, placebocontrolled multicenter prophylactic strategy for infant crying using the probiotic L reuteri DSM 17938. Interpretation of the beneficial effects of the probiotic is limited by the few details regarding randomization among the centers, how study material was supplied to each center and subjects, and the use of a nonvalidated diary. Despite these limitations, this study lends increasing support for the use of L reuteri DSM 17938 for infantile colic. However, at least two important questions remain. First, what is the mechanism of action of L reuteri DSM 17938, as it does not appear to change gut microbiome composition?3 Answering this question may lead to therapies without the need for administration of live organisms. Second, what, if any, are the long-term health consequences of using this (or any) probiotic in infancy? Future studies will ideally re-examine children several years after treatment. Bruno P. Chumpitazi, MD, MPH Robert J. Shulman, MD Baylor College of Medicine Houston, Texas
References 1. Savino F, Castagno E, Bretto R, Brondello C, Palumeri E, Oggero R. A prospective 10-year study on children who had severe infantile colic. Acta Paediatr Suppl 2005;94:129-32. 2. de Weerth C, Fuentes S, de Vos WM. Crying in infants: On the possible role of intestinal microbiota in the development of colic. Gut Microbes 2013;4:416-21. 3. Roos S, Dicksved J, Tarasco V, Locatelli E, Ricceri F, Grandin U, et al. 454 pyrosequencing analysis on faecal samples from a randomized DBPC trial of colicky infants treated with Lactobacillus reuteri DSM 17938. PLoS One 2013;8:e56710.
Identification of early-life risk factor profiles for wheeze phenotypes Lodge CJ, Zaloumis S, Lowe AJ, Gurrin LC, Matheson MC, Axelrad C, et al. Early-life risk factors for childhood wheeze phenotypes in a high-risk birth cohort. J Pediatr 2014; 164:289-94. Question Among infants at high risk of allergy who are followed longitudinally, which early-life factors are associated with wheezing? Design Observational birth cohort. Setting Melbourne, Australia. Participants 620 infants at high risk of allergy followed up to 7 years of age. Outcomes Risk factors associated with 5 longitudinal-latentclass-analysis (LLCA)-identified wheeze classes: never/
infrequent, transient, intermediate, late, and persistent phenotypes. Main Results Lower respiratory tract infection (LRTI) and childcare by 1 year of age were associated with risk of transient wheeze. LRTI and aeroallergen sensitization increased the risk of early persistent wheeze. LRTI, eczema, aeroallergen sensitization, and food sensitization increased the risk of intermediate-onset wheeze. Heavy parental smoking at birth increased the risk of late-onset wheeze. Breastfeeding was protective in transient and late-onset wheeze. Conclusions These findings provide distinct early-life risk factor profiles for each wheeze phenotype. Commentary LLCA has allowed researchers to expand upon original 4 group classification of childhood wheeze by Martinez et al1 and better differentiate wheezing phenotypes.2 Lodge et al applied LLCA to 7 years of wheeze data from 207
THE JOURNAL OF PEDIATRICS
www.jpeds.com
620 children in the Melbourne Atopy Cohort Study (MACS) and their 23 data points far exceed most previous LLCA studies. The identification of a 5-class model, noted above, largely agrees with previous studies, as do the identified associations. The intermediate-onset phenotype is strongly linked to atopy. The increased prevalence of significant wheeze in this high risk birth cohort (60% MACS vs 41% The Avon Longitudinal Study of Parents an Children3) is almost entirely accounted for by intermediate-onset wheeze (20.7% MACS vs 3% The Avon Longitudinal Study of Parents an Children). The conclusions are hampered by the lack of a standardized questionnaire. For example, “cough” was included under 2 years and “episodes of asthma” from 3 to 7 years. However, the findings remain consistent with previous studies. The authors also postulate some causative mechanisms for their phenotypes but fail to take account of the crucial role that earlylife lung function has been shown to play in the classification of pre-school wheeze phenotypes.1,2 Samuel A. Collins, BA, MA, MBBS, MRCPCH University of Southampton Southampton, United Kingdom
References 1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133-8. 2. Collins SA, Pike KC, Inskip HM, Godfrey KM, Roberts G, Holloway JW, et al. Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitization data in the first 6 years of life: evidence from the Southampton Women’s survey. Pediatr Pulmonol 2013;48: 683-92. 3. Savenije OE, Granell R, Caudri D, Koppelman GH, Smit H, Wijga A, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol 2011;127:1505-12.
Topical antibiotics are superior to oral antibiotics in children with acute tympanostomy tube otorrhea van Dongen TM, van der Heijden GJ, Venekamp RP, Rovers MM, Schilder AG. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med 2014; 370:723-33. Question Among children with acute tympanostomy tube otorrhea (TTO), what is the efficacy of topical intra-aural antibiotics, compared with oral antibiotics, in resolution of TTO? Design Randomized, controlled, 3-group trial.
Vol. 165, No. 1 Outcomes Presence of otorrhea after 2 weeks of treatment, assessed otoscopically. Main Results 2 weeks after treatment, 5% of children treated with antibiotic–glucocorticoid eardrops had otorrhea compared with 44% of those treated with oral antibiotics (number needed to treat, 3; 95% CI, 2 to 4) and 55% of those treated with initial observation (number needed to treat, 2; 95% CI, 2 to 3). Conclusions Antibiotic–glucocorticoid eardrops were more effective than oral antibiotics and initial observation in children with TTO. Commentary The benefits of topical antibiotic therapy for acute TTO have been recently reviewed, leading to a recommendation that “clinicians should prescribe topical antibiotic eardrops only, without oral antibiotics, for children with uncomplicated acute TTO.”1 The trial by van Dongen et al bolsters this recommendation with high quality evidence and a placebo control group. Although 55% of the placebo group had otorrhea by otoscopy 2 weeks after treatment, there was no difference in generic quality of life among groups and differences in otitis-specific quality of life were small, suggesting a potential role for observation and aural toilet (eg, cleaning otorrhea from the ear canal with a nasal aspirator) in some children with mild discharge, minimal symptoms, and good quality of life. Children with persistent or more symptomatic TTO are best treated with topical antibiotic drops, approved for use in the middle ear, as recommended in the previously cited clinical practice guideline1 and reinforced in the Choosing Wisely campaign2 from the American Board of Internal Medicine. Richard M. Rosenfeld, MD, MPH State University of New York Downstate Medical Center Brooklyn, New York
References 1. Rosenfeld RM, Schwartz SR, Pynnonen MA, Tunkel DE, Hussey HM, Fichera JS, et al. Clinical practice guideline: tympanostomy tubes in children. Otolaryngol Head Neck Surg 2013;149(Suppl 1):S1-35. 2. American Academy of Otolaryngology—Head and Neck Surgery. Choosing Wisely: Five things physicians and patients should question. Available at: http://www.choosingwisely.org/doctor-patient-lists/americanacademy-of-otolaryngology-head-and-neck-surgery-foundation/. Accessed March 3, 2014.
Transcranial magnetic stimulation may improve symptoms of hemiparesis
Participants Children, 1–10 years of age, with up to 1 week of TTO.
Gillick BT, Krach LE, Feyma T, Rich TL, Moberg K, Thomas W, et al. Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized controlled trial. Dev Med Child Neurol 2014;56:44-52.
Intervention Hydrocortisone-bacitracin-colistin eardrops or oral amoxicillin-clavulanate suspension or observation.
Question Among children with congenital hemiparesis, what is the therapeutic efficacy of repetitive transcranial magnetic
Setting Utrecht, Amsterdam, and Nijmegen in The Netherlands.
208
CURRENT BEST EVIDENCE
July 2014 stimulation (rTMS), compared with sham rTMS, in enhancing function of the affected limb? Design Randomized, controlled trial. Setting Gillette Children’s Specialty Healthcare, Saint Paul, Minnesota. Participants Children with congenital hemiparesis. Intervention rTMS or sham rTMS; all patients also received constraint-induced movement therapy (CIMT). Outcomes Primary outcome was spontaneous performance in bimanual functional activities as evaluated with the Assisting Hand Assessment (AHA) test. Main Results Improvement in AHA differed significantly between groups (P = .007). Eight of 10 participants in the rTMS/CIMT group showed improvement greater than the smallest detectable difference, but only 2 of 9 in the sham rTMS/CIMT group showed such improvement (number needed to treat, 2; 95% CI, 2-5). Conclusions Primed, low-frequency rTMS combined with CIMT is efficacious in pediatric hemiparesis. Commentary This study combines a validated behavioral intervention with an augmented form of inhibitory rTMS. It adds to the growing consensus on both techniques, but does not demonstrate superiority of primed rTMS or show whether the treatments are synergistic or merely additive. If rTMS temporarily relieves the injured hemisphere from competition so it can learn new outputs (my belief), then it should be done right before CIMT. If it remodels the brain on its own, it does not matter. Susceptibility to TMS changes with development1 and varies significantly between individuals. Therefore, response variables (eg, motor evoked potential threshold and the degree of inhibition from rTMS) might have been reported and tested as covariates to strengthen and better interpret the results. rTMS has existed for 25 years, and substantial preliminary data on the effectiveness of contralesional inhibition have been published,2 yet there have been neither large trials nor apparent interest in commercialization for the treatment of hemiparesis. Results such as these must be followed-up aggressively if they are to provide a just return on investment. Eric Wassermann, MD National Institutes of Health Bethesda, Maryland
References 1. Garvey MA, Mall V. Transcranial magnetic stimulation in children. Clin Neurophysiol 2008;119:973-84. 2. Wassermann EM, Zimmermann T. Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther 2012;133: 98-107.
Acetaminophen: a possible alternative to ibuprofen in patent ductus arteriosus closure
Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014;164:510-4. Question Among premature infants with a patent ductus arteriosus (PDA), what is the therapeutic efficacy of acetaminophen, compared with ibuprofen, on the PDA closure rate? Design Randomized, controlled trial. Setting Neonatal intensive care unit, Ankara, Turkey. Participants Preterm infants < 30 weeks’ gestational age, birthweight < 1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed significant PDA. Intervention Oral acetaminophen versus oral ibuprofen. Outcomes PDA closure rate. Main Results The PDA closed in 31 (77.5%) of the patients assigned to the oral ibuprofen group vs 29 (72.5%) of those enrolled in the acetaminophen group (absolute risk reduction [ARR] 5%, 95% CI, -13.95% to 23.95%, not significant). The reopening rate was higher in the acetaminophen group than in the ibuprofen group, but not statistically different (ARR 6%, 95% CI, -9.48% to 25.48%, not significant). Conclusions Acetaminophen may be a medical alternative in the management of PDA. Commentary Despite intense study, indecision surrounds treatment of the preterm infant with a PDA. Who should be treated, when, and with what? Oncel et al provide pilot evidence suggesting a role for oral acetaminophen to close the PDA. Interestingly, the most premature infants—those at highest risk for complications secondary to a PDA— appeared to have the highest rates of ductal closure with acetaminophen when compared to oral ibuprofen. This trial was powered to detect an unrealistic 25% difference in PDA closure rates between the two therapies, and found an insignificant difference of merely 5%. Additionally, the trial was far too small to detect important yet uncommon adverse effects of acetaminophen. Finally, eligibility was based primarily on echocardiographic evidence of significant PDA. It is increasingly clear that many PDAs close spontaneously, and expectant management is safe.1 Routine screening echocardiography, as performed in this study, will likely lead to overtreatment.2 One can hope that oral acetaminophen will prove to have higher efficacy and less toxicity than indomethacin or ibuprofen. Such novel therapies are crucially important because the ultimate decision about which infants will benefit most from treatment of the PDA hinges completely on the risk:benefit of the available therapies. Sara B. DeMauro, MD, MSCE University of Pennsylvania Philadelphia Pennsylvania Clyde J. Wright, MD University of Colorado School of Medicine Aurora, Colorado 209
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References 1. Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. J Pediatr 2012;160:929-35.e1. 2. DeMauro SB, Cohen MS, Ratcliffe SJ, Abbasi S, Schmidt B. Serial echocardiography in very preterm infants: a pilot randomized trial. Acta Paediatr 2013;102:1048-53.
Prophylactic use of probiotics ameliorates infantile colic Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr 2014;168:228-33. Question Among newborns, what is the prophylactic efficacy of probiotics, compared with placebo, in preventing/ameliorating infantile colic? Design Randomized, controlled trial. Setting 9 neonatal units in Italy. Participants Full-term babies. Intervention Lactobacillus reuteri Diagnostic and Statistical Manual (DSM) 17938 or placebo. Outcomes Reduction of daily crying time, regurgitation, and constipation during the first 3 months of life. Main Results At 3 months of age, the mean duration of crying time (38 vs 71 minutes; P < .01), the mean number of regurgitations per day (2.9 vs 4.6; P < .01), and the mean number of evacuations per day (4.2 vs 3.6; P < .01) for the L reuteri DSM 17938 and placebo groups, respectively, were significantly different. Conclusions Prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders. Commentary Infantile colic, though self-resolving, increases healthcare and emotional costs. Those with infantile colic are
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Vol. 165, No. 1 at a significantly increased risk for developing recurrent abdominal pain, allergic diseases, and psychological disorders.1 Though the etiology is unknown, evidence suggests the gut microbiome may play a role in the generation of symptoms.2 Indrio et al employed a double blind, placebocontrolled multicenter prophylactic strategy for infant crying using the probiotic L reuteri DSM 17938. Interpretation of the beneficial effects of the probiotic is limited by the few details regarding randomization among the centers, how study material was supplied to each center and subjects, and the use of a nonvalidated diary. Despite these limitations, this study lends increasing support for the use of L reuteri DSM 17938 for infantile colic. However, at least two important questions remain. First, what is the mechanism of action of L reuteri DSM 17938, as it does not appear to change gut microbiome composition?3 Answering this question may lead to therapies without the need for administration of live organisms. Second, what, if any, are the long-term health consequences of using this (or any) probiotic in infancy? Future studies will ideally re-examine children several years after treatment. Bruno P. Chumpitazi, MD, MPH Robert J. Shulman, MD Baylor College of Medicine Houston, Texas
References 1. Savino F, Castagno E, Bretto R, Brondello C, Palumeri E, Oggero R. A prospective 10-year study on children who had severe infantile colic. Acta Paediatr Suppl 2005;94:129-32. 2. de Weerth C, Fuentes S, de Vos WM. Crying in infants: On the possible role of intestinal microbiota in the development of colic. Gut Microbes 2013;4:416-21. 3. Roos S, Dicksved J, Tarasco V, Locatelli E, Ricceri F, Grandin U, et al. 454 pyrosequencing analysis on faecal samples from a randomized DBPC trial of colicky infants treated with Lactobacillus reuteri DSM 17938. PLoS One 2013;8:e56710.
