Sarah Curtis

Standard 6: Age Groups for Pediatric Trials

* Abbreviations: RCT — : randomized controlled trial SSRI — : selective serotonin reuptake inhibitor It has long been an axiom in clinical pediatrics that “children are not just little adults.” It has also been recognized that there are many changes from birth through childhood and the adolescent years. However, the full implications of pediatric age groupings for health care and research are still not adequately understood. There is still much to be discovered about children’s biological and psychological development and how these processes affect the effectiveness and efficacy of interventions. Trial design that accounts for age differences and promotes consistency in reporting of age-related data is essential to ensure the validity and clinical usefulness of pediatric trial data. A recent study highlighted variable treatment efficacy in children versus adults. In this study, 128 meta-analyses from Cochrane reviews, containing data on at least 1 adult and 1 pediatric randomized controlled trial (RCT) with a binary primary efficacy outcome, were reviewed.1 The authors found that in all except 1 case, the 95% confidence intervals could not exclude a relative difference in treatment efficacy between adults and children of >20%; in two-thirds of these cases, the relative difference in observed point estimates was >50%. The study also highlighted the paucity of RCTs in pediatrics; the median number of children per meta-analysis was 2.5 times smaller than the number of adults. Children and adults seem to have distinctive responses to treatments. For example, administration of phenobarbitones is useful for adults with cerebral malaria and is associated with decreased convulsions. However, in children, this drug is associated with increased 6-month mortality. Similarly, corticosteroids may offer survival benefit for adults with bacterial meningitis but not for children with the same condition. In acute traumatic brain injury, corticosteroids did not decrease mortality in adults, but there was a trend for increased mortality in children.1 In asthma, long-acting β2-agonists decreased … Address correspondence to Martin Offringa, MD, PhD, Senior Scientist and Program Head, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: martin.offringa{at}sickkids.ca

A randomized controlled trial of sucrose and/or pacifier as analgesia for infants receiving venipuncture in a pediatric emergency department

BackgroundAlthough sucrose has been accepted as an effective analgesic agent for procedural pain in neonates, previous studies are largely in the NICU population using the procedure of heel lance. This is the first report of the effect of sucrose, pacifier or the combination thereof for the procedural pain of venipuncture in infants in the pediatric emergency department population.MethodsThe study design was a double (sucrose) and single blind (pacifier), placebo-controlled randomized trial – factorial design carried out in a pediatric emergency department. The study population was infants, aged 0 – 6 months. Eighty-four patients were randomly assigned to one of four groups: a) sucrose b) sucrose & pacifier c) control d) control & pacifier. Each child received 2 ml of either 44% sucrose or sterile water, by mouth. The primary outcome measure: FLACC pain scale score change from baseline. Secondary outcome measures: crying time and heart rate change from baseline.ResultsSucrose did not significantly reduce the FLACC score, crying time or heart rate. However sub-group analysis revealed that sucrose had a much greater effect in the younger groups. Pacifier use reduced FLACC score (not statistically significant), crying times (statistically significant) but not heart rate. Subgroup analysis revealed a mean crying time difference of 76.52 seconds (p < 0.0171) (0–1 month) and 123.9 seconds (p < 0.0029) (1–3 month). For subgroup age > 3 months pacifier did not have any significant effect on crying time. Age adjusted regression analysis revealed that both sucrose and pacifier had significant effects on crying time. Crying time increased with both increasing age and increasing gestational age.ConclusionPacifiers are inexpensive, effective analgesics and are easy to use in the PED for venipuncture in infants aged 0–3 months. The benefits of sucrose alone as an analgesic require further investigation in the older infant, but sucrose does appear to provide additional benefit when used with a pacifier in this age group.Trial registrationCurrent Controlled Trials ISRCTN15819627

Clinical Features Suggestive of Meningitis in Children: A Systematic Review of Prospective Data

CONTEXT: Clinical diagnosis of pediatric meningitis is fundamental; therefore, familiarity with evidence underscoring clinical features suggestive of meningitis is important. OBJECTIVE: To seek evidence supporting accuracy of clinical features of pediatric bacterial meningitis. METHODS: A review of Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, Web of Science, and PubMed was conducted for all articles of relevance. Articles contained prospective data of clinical features in children with laboratory-confirmed bacterial meningitis and in comparison groups of those without it. Two authors independently assessed quality and extracted data to calculate accuracy data of clinical features. RESULTS: Of 14 145 references initially identified, 10 met our inclusion criteria. On history, a report of bulging fontanel (likelihood ratio [LR]: 8.00 [95% confidence interval (CI): 2.4–26]), neck stiffness (7.70 [3.2–19]), seizures (outside febrile-convulsion age range) (4.40 [3.0–6.4]), or reduced feeds (2.00 [1.2–3.4]) raised concern about the presence of meningitis. On examination, jaundice (LR: 5.90 [95% CI: 1.8–19]), being toxic or moribund (5.80 [3.0–11]), meningeal signs (4.50 [2.4–8.3]), neck stiffness (4.00 [2.6–6.3]), bulging fontanel (3.50 [2.0–6.0]), Kernig sign (3.50 [2.1–5.7]), tone up (3.20 [2.2–4.5]), fever of >40°C (2.90 [1.6–5.5]), and Brudzinski sign (2.50 [1.8–3.6]) independently raised the likelihood of meningitis. The absence of meningeal signs (LR: 0.41 [95% CI: 0.30–0.57]) and an abnormal cry (0.30 [0.16–0.57]) independently lowered the likelihood of meningitis. The absence of fever did not rule out meningitis (LR: 0.70 [95% CI: 0.53–0.92]). CONCLUSIONS: Evidence for several useful clinical features that influence the likelihood of pediatric meningitis exists. No isolated clinical feature is diagnostic, and the most accurate diagnostic combination is unclear.

Music to Reduce Pain and Distress in the Pediatric Emergency Department: A Randomized Clinical Trial

IMPORTANCE Many medical procedures aimed at helping children cause them pain and distress, which can have long-lasting negative effects. Music is a form of distraction that may alleviate some of the pain and distress experienced by children while undergoing medical procedures. OBJECTIVE To compare music with standard care to manage pain and distress. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted in a pediatric emergency department with appropriate sequence generation and adequate allocation concealment from January 1, 2009, to March 31, 2010. Individuals assessing the primary outcome were blind to treatment allocation. A total of 42 children aged 3 to 11 years undergoing intravenous placement were included. INTERVENTIONS Music (recordings selected by a music therapist via ambient speakers) vs standard care. MAIN OUTCOMES AND MEASURES The primary outcome was behavioral distress assessed blinded using the Observational Scale of Behavioral Distress-Revised. The secondary outcomes included child-reported pain, heart rate, parent and health care provider satisfaction, ease of performing the procedure, and parental anxiety. RESULTS With or without controlling for potential confounders, we found no significant difference in the change in behavioral distress from before the procedure to immediately after the procedure. When children who had no distress during the procedure were removed from the analysis, there was a significantly less increase in distress for the music group (standard care group = 2.2 vs music group = 1.1, P < .05). Pain scores among children in the standard care group increased by 2 points, while they remained the same in the music group (P = .04); the difference was considered clinically important. The pattern of parent satisfaction with the management of childrens pain was different between groups, although not statistically significant (P = .07). Health care providers reported that it was easier to perform the procedure for children in the music group (76% very easy) vs the standard care group (38% very easy) (P = .03). Health care providers were more satisfied with the intravenous placement in the music group (86% very satisfied) compared with the standard care group (48%) (P = .02). CONCLUSIONS AND RELEVANCE Music may have a positive impact on pain and distress for children undergoing intravenous placement. Benefits were also observed for the parents and health care providers. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00761033.

A descriptive analysis of a representative sample of pediatric randomized controlled trials published in 2007

BackgroundRandomized controlled trials (RCTs) are the gold standard for trials assessing the effects of therapeutic interventions; therefore it is important to understand how they are conducted. Our objectives were to provide an overview of a representative sample of pediatric RCTs published in 2007 and assess the validity of their results.MethodsWe searched Cochrane Central Register of Controlled Trials using a pediatric filter and randomly selected 300 RCTs published in 2007. We extracted data on trial characteristics; outcomes; methodological quality; reporting; and registration and protocol characteristics. Trial registration and protocol availability were determined for each study based on the publication, an Internet search and an author survey.ResultsMost studies (83%) were efficacy trials, 40% evaluated drugs, and 30% were placebo-controlled. Primary outcomes were specified in 41%; 43% reported on adverse events. At least one statistically significant outcome was reported in 77% of trials; 63% favored the treatment group. Trial registration was declared in 12% of publications and 23% were found through an Internet search. Risk of bias (ROB) was high in 59% of trials, unclear in 33%, and low in 8%. Registered trials were more likely to have low ROB than non-registered trials (16% vs. 5%; p = 0.008). Effect sizes tended to be larger for trials at high vs. low ROB (0.28, 95% CI 0.21,0.35 vs. 0.16, 95% CI 0.07,0.25). Among survey respondents (50% response rate), the most common reason for trial registration was a publication requirement and for non-registration, a lack of familiarity with the process.ConclusionsMore than half of this random sample of pediatric RCTs published in 2007 was at high ROB and three quarters of trials were not registered. There is an urgent need to improve the design, conduct, and reporting of child health research.

Ultrasonographically Guided Peripheral Intravenous Cannulation of Children and Adults: A Systematic Review and Meta-analysis

STUDY OBJECTIVE Peripheral intravenous cannulation is procedurally challenging and painful. We perform a systematic review to evaluate ultrasonographic guidance as an aid to peripheral intravenous cannulation. METHODS We searched MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, ClinicalTrials.gov, and Google.ca. We included randomized trials evaluating ultrasonographically guided peripheral intravenous cannulation and reporting risk of peripheral intravenous cannulation failure, number of attempts, procedure time, or time from randomization to peripheral intravenous cannulation. We separately analyzed pediatric and adult data and emergency department (ED), ICU, and operating room data. Quality assessment used the Cochrane Risk of Bias Tool. RESULTS We identified 4,664 citations, assessed 403 full texts for eligibility, and included 9 trials. Five had low risk, 1 high risk, and 3 unclear risk of bias. A pediatric ED trial found that ultrasonography decreased mean difference (MD) in the number of attempts (MD -2.00; 95% confidence interval [CI] -2.73 to -1.27) and procedure time (MD -8.10 minutes; 95% CI -12.48 to -3.72 minutes). In an operating room pediatric trial, ultrasonography decreased risk of first-attempt failure (risk ratio 0.23; 95% CI 0.08 to 0.69), number of attempts (MD -1.50; 95% CI -2.52 to -0.48), and procedure time (MD -5.95; 95% CI -10.21 to -1.69). Meta-analysis of adult ED trials suggests that ultrasonography decreases the number of attempts (MD -0.43; 95% CI -0.81 to -0.05). Ultrasonography decreased risk of failure (risk ratio 0.47; 95% CI 0.26 to 0.87) in an adult ICU trial. CONCLUSION Ultrasonography may decrease peripheral intravenous cannulation attempts and procedure time in children in ED and operating room settings. Few outcomes reached statistical significance. Larger well-controlled trials are needed.

Empirical Evaluation of Age Groups and Age-Subgroup Analyses in Pediatric Randomized Trials and Pediatric Meta-analyses

BACKGROUND: An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed. METHODS: We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported. RESULTS: The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8–10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance. CONCLUSIONS: We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.

A systematic review and meta-analysis of new interventions for peripheral intravenous cannulation of children.

Objective Establishing intravenous access in children is often challenging for health professionals. Multiple attempts at peripheral intravenous cannulation (PIVC) cause increased pain and delayed delivery of therapy. Our objective was to synthesize and evaluate the best evidence for novel interventions designed to improve pediatric PIVC. Methods We searched for published and unpublished studies using MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Web of Science, ClinicalTrials.gov, and Google.ca. We included studies for meta-analysis if they were randomized, evaluated an intervention other than ultrasound, and reported on 1 of 3 primary outcome measures: success or failure of PIVC, number of attempts to successful cannulation, and procedure time. Two blinded reviewers assessed studies for eligibility and applied a data extraction form to those included. Study quality was assessed using the Cochrane Risk of Bias Tool. Results Seven studies met the inclusion criteria. Randomized controlled trials (RCTs) of 3 different interventions were identified. A meta-analysis of 3 RCTs found that use of a transilluminator was associated with a decreased risk of first-attempt PIVC failure (risk ratio, 0.66; confidence interval, 0.41–1.06). Meta-analysis of 3 other RCTs found that near-infrared light devices do not impact the risk of first-attempt PIVC failure (risk ratio, 0.99; confidence interval, 0.74–1.33). Conclusions Near-infrared light devices might be efficacious in selected subpopulations, but the available evidence does not support an overall benefit in the pediatric population. Transilluminators modestly improve pediatric PIVC, but the clinical significance of this benefit is questionable. Nitroglycerin ointments may increase the risk of PIVC failure and are associated with adverse effects.

Interpretation of Cerebrospinal Fluid White Blood Cell Counts in Young Infants With a Traumatic Lumbar Puncture

Study objective We determine the optimal correction factor for cerebrospinal fluid WBC counts in infants with traumatic lumbar punctures. Methods We performed a secondary analysis of a retrospective cohort of infants aged 60 days or younger and with a traumatic lumbar puncture (cerebrospinal fluid RBC count ≥10,000 cells/mm3) at 20 participating centers. Cerebrospinal fluid pleocytosis was defined as a cerebrospinal fluid WBC count greater than or equal to 20 cells/mm3 for infants aged 28 days or younger and greater than or equal to 10 cells/mm3 for infants aged 29 to 60 days; bacterial meningitis was defined as growth of pathogenic bacteria from cerebrospinal fluid culture. Using linear regression, we derived a cerebrospinal fluid WBC correction factor and compared the uncorrected with the corrected cerebrospinal fluid WBC count for the detection of bacterial meningitis. Results Of the eligible 20,319 lumbar punctures, 2,880 (14%) were traumatic, and 33 of these patients (1.1%) had bacterial meningitis. The derived cerebrospinal fluid RBCs:WBCs ratio was 877:1 (95% confidence interval [CI] 805 to 961:1). Compared with the uncorrected cerebrospinal fluid WBC count, the corrected one had lower sensitivity for bacterial meningitis (88% uncorrected versus 67% corrected; difference 21%; 95% CI 10% to 37%) but resulted in fewer infants with cerebrospinal fluid pleocytosis (78% uncorrected versus 33% corrected; difference 45%; 95% CI 43% to 47%). Cerebrospinal fluid WBC count correction resulted in the misclassification of 7 additional infants with bacterial meningitis, who were misclassified as not having cerebrospinal fluid pleocytosis; only 1 of these infants was older than 28 days. Conclusion Correction of the cerebrospinal fluid WBC count substantially reduced the number of infants with cerebrospinal fluid pleocytosis while misclassifying only 1 infant with bacterial meningitis of those aged 29 to 60 days.

Ultrasound or near-infrared vascular imaging to guide peripheral intravenous catheterization in children: a pragmatic randomized controlled trial

Background: Peripheral intravenous catheterization in children is challenging, and success rates vary greatly. We conducted a pragmatic randomized controlled trial to determine whether the use of ultrasound or near-infrared vascular imaging to guide catheterization would be more effective than the standard approach in achieving successful catheter placement on the first attempt. Methods: We enrolled a convenience sample of 418 children in a pediatric emergency department who required peripheral intravenous catheterization between June 2010 to August 2012. We stratified them by age (≤ 3 yr and > 3 yr) and randomly assigned them to undergo the procedure with the standard approach, or with the help of either ultrasound or near-infrared vascular imaging. The primary outcome was the proportion of patients who had successful placement of a catheter on the first attempt. Results: The rate of successful first attempts did not differ significantly between either of the 2 intervention groups and the standard approach group (differences in proportions −3.9%, 95% confidence interval [CI] −14.2% to 6.5%, for ultrasound imaging; −8.7%, 95% CI −19.4% to 1.9%, for near-infrared imaging). Among children 3 years and younger, the difference in success rates relative to standard care was also not significant for ultrasound imaging (−9.6%, 95% CI −29.8% to 10.6%), but it was significantly worse for near-infrared imaging (−20.1%, 95% CI −40.1% to −0.2%). Among children older than 3 years, the differences in success rates relative to standard care were smaller but not significant (−2.3%, 95% CI −13.6% to 9.0%, for ultrasound imaging; −4.1%, 95% CI −15.7% to 7.5%, for near-infrared imaging). None of the pairwise comparisons were statistically significant in any of the outcomes. Interpretation: Neither technology improved first-attempt success rates of peripheral intravenous catheterization in children, even in the younger group. These findings do not support investment in these technologies for routine peripheral intravenous catheterization in children. Trial registration: ClinicalTrials.gov, no. NCT01133652.