The Core Outcome Measures in Effectiveness Trials (COMET) initiative aims to facilitate the development and application of ‘core outcome sets’ (COS). A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The overall aim of the Core Outcome Measurement Instrument Selection (COMIS) project is to develop a guideline on how to select outcome measurement instruments for outcomes included in a COS. As part of this project, we describe our current efforts to achieve a consensus on the methods for selecting outcome measurement instruments for outcomes to be included in a COS.
A Delphi study is being performed by a panel of international experts representing diverse stakeholders with the intention that this will result in a guideline for outcome measurement instrument selection. Informed by a literature review, a Delphi questionnaire was developed to identify potentially relevant tasks on instrument selection. The Delphi study takes place in a series of rounds. In the first round, panelists were asked to rate the importance of different tasks in the selection of outcome measurement instruments. They were encouraged to justify their choices and to add other relevant tasks. Consensus was reached if at least 70% of the panelists considered a task ‘highly recommended’ or ‘desirable’ and if no opposing arguments were provided. These tasks will be included in the guideline. Tasks that at least 50% of the panelists considered ‘not relevant’ will be excluded from the guideline. Tasks that were indeterminate will be taken to the second round. All responses of the first round are currently being aggregated and will be fed back to panelists in the second round. A third round will only be performed if the results of the second round require it.
Since the Delphi method allows a large group of international experts to participate, we consider it to be the preferred consensus-based method for our study. Based upon this consultation process, a guideline will be developed on instrument selection for outcomes to be included in a COS.
COMET; Core outcome set; Delphi study; Outcome measurement instruments; Selection; Protocol; Guideline
Considerable heterogeneity has been observed in the selection and reporting of disease-specific pediatric outcome measures in randomized controlled trials (RCTs). This makes interpretation of results and comparison across trials challenging. Outcome measures in pediatric anaphylaxis trials have never previously been systematically assessed. This systematic review (SR) identified and assessed outcome measures used in RCTs of anaphylaxis treatment in children. As a secondary objective, this SR assessed the evidence for current treatment modalities for anaphylaxis in the pediatric population.
We searched MEDLINE, EMBASE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL from 2001 until December 2012. We also searched websites listing ongoing trials. We included randomized and controlled trials of anaphylaxis treatment in patients 0–18 years of age. Two authors independently assessed articles for inclusion.
No published studies fulfilled the inclusion criteria.
There is an alarming absence of RCTs evaluating the treatments for anaphylaxis in children. High quality studies are needed and are possible to design, despite the severe and acute nature of this condition. Consensus about the selection and validation of appropriate outcome measures will enhance the quality of research and improve the care of children with anaphylaxis.
Previous studies have found that up to 60% of children with neurologic conditions have tried complementary and alternative medicine (CAM).
To assess the use of CAM among patients presenting to neurology clinics at two academic centers in Canada.
A survey instrument was developed to inquire about use of CAM products and therapies, including reasons for use, perceived helpfulness, and concurrent use with conventional medicine, and administered to patients or their parents/guardians at the Stollery Children's Hospital in Edmonton and the Children's Hospital of Eastern Ontario (CHEO) in Ottawa.
Overall CAM use at the Stollery was 78%, compared to 48% at CHEO. The most common CAM products used were multi-vitamins (84%), vitamin C (37%), homeopathic remedies (24%), and fish oil/omega 3 s (22%). The most common CAM practices used were massage (47%), chiropractic (37%), faith healing (18%), aromatherapy (16%), homeopathy (16%), and relaxation (16%). Many patients used CAM products at the same time as conventional medicine but just over half (57%) discussed this concurrent use with their physician.
CAM use is common in pediatric neurology patients and most respondents felt that it was helpful, with few or no harms associated. However, this use is often undisclosed, increasing possibility of interactions with conventional drugs. We urge clinicians to inquire about CAM use during routine history taking at every patient visit. Parents would clearly like more information about CAM from their specialty clinics; such information would be easier to share if more primary data were available about the safety and effectiveness of commonly used therapies.
To investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies.
Cross-sectional study of screened patients.
10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011.
The participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications.
Primary outcome measures
Patients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality.
Over a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE.
A substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based.
Complementary Medicine; Toxicology
Information about the safety of herbal medicine often comes from case reports published in the medical literature, thus necessitating good quality reporting of these adverse events. The purpose of this study was to perform a systematic review of the comprehensiveness of reporting of published case reports of adverse events associated with herb use in the pediatric population.
Electronic literature search included 7 databases and a manual search of retrieved articles from inception through 2010. We included published case reports and case series that reported an adverse event associated with exposure to an herbal product by children under the age of 18 years old. We used descriptive statistics. Based on the International Society of Epidemiology's “Guidelines for Submitting Adverse Events Reports for Publication,” we developed and assigned a guideline adherence score (0-17) to each case report.
Ninety-six unique journal papers were identified and represented 128 cases. Of the 128 cases, 37% occurred in children under 2 years old, 38% between the ages of 2 and 8 years old, and 23% between the ages of 9 and 18 years old. Twenty-nine percent of cases were the result of an intentional ingestion while 36% were from an unintentional ingestion. Fifty-two percent of cases documented the Latin binomial of the herb ingredients; 41% documented plant part. Thirty-two percent of the cases reported laboratory testing of the herb, 20% documented the manufacturer of the product, and 22% percent included an assessment of the potential concomitant therapies that could have been influential in the adverse events. Mean guideline adherence score was 12.5 (range 6-17).
There is considerable need for improvement in reporting adverse events in children following herb use. Without better quality reporting, adverse event reports cannot be interpreted reliably and do not contribute in a meaningful way to guiding recommendations for medicinal herb use.
Herbs; adverse events; pediatric; systematic review
To perform a systematic review of adverse events associated with herb use in the pediatric population. Since many health care providers get their information about the safety of herbal medicine from case reports published in the medical literature, it is important to assess the quality of these case reports.
Electronic literature search included 7 databases and a manual search of retrieved articles from inception through 2010. We included case reports and case series that reported an adverse event associated with exposure to an herbal product by children under the age of 18 years old. Based on the International Society of Epidemiology's “Guidelines for Submitting Adverse Events Reports for Publication”, we assigned a guideline adherence score (0-17) to each case report.
Ninety-six unique journal papers were identified and represented 128 cases. Of the 128 cases, 37% occurred in children under 2 years old, 38% between the ages of 2 – 8 years old, and 23 % between the ages 9-18 years old. In a few cases, the child used a product that was contaminated (5%) or adulterated (2%). Twenty-nine percent of cases were the result of an intentional ingestion while 36% were from an unintentional ingestion. Mean guideline adherence score was 12.5 (range 6 – 17).
There is considerable need for improvement in reporting adverse events in children following herb use. Without better quality reporting, adverse event reports cannot be interpreted reliably, and do not contribute in a meaningful way to guiding clinical recommendations.
herbs; adverse events; pediatric; systematic review
Background. The use of complementary and alternative medicine (CAM) is high among children and youths with chronic illnesses, including cancer. The objective of this study was to assess prevalence and patterns of CAM use among pediatric oncology outpatients in two academic clinics in Canada. Procedure. A survey was developed to ask patients (or their parents/guardians) presenting to oncology clinics at the Stollery Children's Hospital in Edmonton and the Children's Hospital of Eastern Ontario (CHEO) in Ottawa about current or previous use of CAM products and practices. Results. Of the 137 families approached, 129 completed the survey. Overall CAM use was 60.5% and was not significantly different between the two hospitals. The most commonly reported reason for not using CAM was lack of knowledge about it. The most common CAM products ever used were multivitamins (86.5%), vitamin C (43.2%), cold remedies (28.4%), teething remedies (27.5%), and calcium (23.0%). The most common CAM practices ever used were faith healing (51.0%), massage (46.8%), chiropractic (27.7%), and relaxation (25.5%). Many patients (40.8%) used CAM products at the same time as prescription drugs. Conclusion. CAM use was high among patients at two academic pediatric oncology clinics. Although most respondents felt that their CAM use was helpful, many were not discussing it with their physicians.
Background. Use of complementary and alternative medicine (CAM) by children with cancer is high; however, pediatric best cases are rare. Objectives. To investigate whether best cases exist in pediatric oncology using a three-phase approach and to compare our methods with other such programs. Methods. In phase I, Children's Oncology Group (COG) oncologists were approached via email and asked to recall patients who were (i) under 18 when diagnosed with cancer, (ii) diagnosed between 1990 and 2006, (iii) had unexpectedly positive clinical outcome, and (iv) reported using CAM during or after cancer treatment. Phase II involved partnering with CAM research networks; patients who were self-identified as best cases were asked to submit reports completed in conjunction with their oncologists. Phase III extended this partnership to 200 CAM associations and training organizations. Results. In phase I, ten cases from three COG sites were submitted, and most involved use of traditional Chinese medicine to improve quality of life. Phases II and III did not yield further cases. Conclusion. Identification of best cases has been suggested as an important step in guiding CAM research. The CARE Best Case Series Program had limited success in identifying pediatric cases despite the three approaches we used.
Cervical artery dissection (CAD) and stroke are serious harms that are sometimes associated with cervical spinal manipulation therapy (cSMT). Because of the relative rarity of these adverse events, studying them prospectively is challenging. As a result, systematic review of reports describing these events offers an important opportunity to better understand the relation between adverse events and cSMT. Of note, the quality of the case report literature in this area has not yet been assessed.
1) To systematically collect and synthesize available reports of CAD that have been associated with cSMT in the literature and 2) assess the quality of these reports.
A systematic review of the literature was conducted using several databases. All clinical study designs involving CADs associated with cSMT were eligible for inclusion. Included studies were screened by two independent reviewers for the presence/absence of 11 factors considered to be important in understanding the relation between CAD and cSMT.
Overall, 43 articles reported 901 cases of CAD and 707 incidents of stroke reported to be associated with cSMT. The most common type of stroke reported was ischemic stroke (92%). Time-to-onset of symptoms was reported most frequently (95%). No single case included all 11 factors.
This study has demonstrated that the literature infrequently reports useful data toward understanding the association between cSMT, CADs and stroke. Improving the quality, completeness, and consistency of reporting adverse events may improve our understanding of this important relation.
To synthesise existing knowledge of the efficacy and safety of long-acting versus short-acting methylphenidate for paediatric attention deficit hyperactivity disorder (ADHD).
Systematic review and meta-analysis.
Electronic literature search of CENTRAL, MEDLINE, PreMEDLINE, CINAHL, EMBASE, PsychINFO, Scopus and Web of Science for articles published in the English language between 1950 and 2012. Reference lists of included studies were checked for additional studies.
Randomised controlled trials of paediatric ADHD patients (<18 years), comparing a long-acting methylphenidate form to a short-acting methylphenidate form.
Two authors independently selected trials, extracted data and assessed risk of bias. Continuous outcomes were compared using standardised mean differences (SMDs) between treatment groups. Adverse events were compared using risk differences between treatment groups. Heterogeneity was explored by subgroup analysis based on the type of long-acting formulation used.
Thirteen RCTs were included; data from 882 participants contributed to the analysis. Meta-analysis of three studies which used parent ratings to report on hyperactivity/impulsivity had an SMD of −0.30 (95% CI −0.51 to −0.08) favouring the long-acting forms. In contrast, three studies used teacher ratings to report on hyperactivity and had an SMD of 0.29 (95% CI 0.05 to 0.52) favouring the short-acting methylphenidate. In addition, subgroup analysis of three studies which used parent ratings to report on inattention/overactivity indicate that the osmotic release oral system generation long-acting formulation was favoured with an SMD of −0.35 (95% CI −0.52 to −0.17), while the second generation showed less efficacy than the short-acting formulation with an SMD of 0.42 (95% CI 0.17 to 0.68). The long-acting formulations presented with slightly more total reported adverse events (n=578) as compared with the short-acting formulation (n=566).
The findings from this systematic review indicate that the long-acting forms have a modest effect on the severity of inattention/overactivity and hyperactivity/impulsivity according to parent reports, whereas the short-acting methylphenidate was preferred according to teacher reports for hyperactivity.
Attention deficit/hyperactivity disorder
Many consumers use natural health products (NHPs) concurrently with prescription medications. As NHP-related harms are under-reported through passive surveillance, the safety of concurrent NHP-drug use remains unknown. To conduct active surveillance in participating community pharmacies to identify adverse events related to concurrent NHP-prescription drug use.
Participating pharmacists asked individuals collecting prescription medications about (i) concurrent NHP/drug use in the previous three months and (ii) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional information after obtaining additional verbal consent and documenting so within the interview form. Over a total of 112 pharmacy weeks, 2615 patients were screened, of which 1037 (39.7%; 95% CI: 37.8% to 41.5%) reported concurrent NHP and prescription medication use. A total of 77 patients reported a possible AE (2.94%; 95% CI: 2.4% to 3.7%), which represents 7.4% of those using NHPs and prescription medications concurrently (95%CI: 6.0% to 9.2%). Of 15 patients available for an interview, 4 (26.7%: 95% CI: 4.3% to 49.0%) reported an AE that was determined to be “probably” due to NHP use.
Active surveillance markedly improves identification and reporting of adverse events associated with concurrent NHP-drug use. Although not without challenges, active surveillance is feasible and can generate adverse event data of sufficient quality to allow for meaningful adjudication to assess potential harms.
Integrative medicine is defined as relationship-centered care that focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals and disciplines to achieve optimal health and healing, including evidence-based complementary and alternative medicine. Pediatric integrative medicine (PIM) develops and promotes this approach within the field of pediatrics. We conducted a survey to identify and describe PIM programs within academic children’s hospitals across North America. Key barriers and opportunities were identified for the growth and development of academic PIM initiatives in the US and Canada.
Academic PIM programs were identified by email and eligible for inclusion if they had each of educational, clinical, and research activities. Program directors were interviewed by telephone regarding their clinical, research, educational, and operational aspects.
Sixteen programs were included. Most (75%) programs provided both inpatient and outpatient services. Seven programs operated with less than 1 FTE clinical personnel. Credentialing of complementary and alternative medicine (CAM) providers varied substantially across the programs and between inpatient and outpatient services. Almost all (94%) programs offered educational opportunities for residents in pediatrics and/or family medicine. One fifth (20%) of the educational programs were mandatory for medical students. Research was conducted in a range of topics, but half of the programs reported lack of research funding and/or time. Thirty-one percent of the programs relied on fee-for-service income.
Pediatric integrative medicine is emerging as a new subspecialty to better help address 21st century patient concerns.
Complementary and alternative medicine (CAM) is commonly used by children, but estimates of that use vary widely partly due to the range of questionnaires used to assess CAM use. However, no studies have attempted to appraise measurement properties of these questionnaires. The aim of this systematic review was to critically appraise and summarize measurement properties of questionnaires of CAM use in pediatrics.
A search strategy was implemented in major electronic databases in March 2011 and conference websites, scientific journals and experts were consulted. Studies were included if they mentioned a questionnaire assessing the prevalence of CAM use in pediatrics. Members of the team independently rated the methodological quality of the studies (using the COSMIN checklist) and measurement properties of the questionnaires (using the Terwee and Cohen criteria).
A total of 96 CAM questionnaires were found in 104 publications. The COSMIN checklist showed that no studies reported adequate methodological quality. The Terwee criteria showed that all included CAM questionnaires had indeterminate measurement properties. According to the Cohen score, none were considered to be a well-established assessment, two approached the level of a well-established assessment, seven were promising assessments and the remainder (n = 87) did not reach the score’s minimum standards.
None of the identified CAM questionnaires have been thoroughly validated. This systematic review highlights the need for proper validation of CAM questionnaires in pediatrics, which may in turn lead to improved research and knowledge translation about CAM in clinical practice.
Rhodiola rosea (R. rosea) is grown at high altitudes and northern latitudes. Due to its purported adaptogenic properties, it has been studied for its performance-enhancing capabilities in healthy populations and its therapeutic properties in a number of clinical populations. To systematically review evidence of efficacy and safety of R. rosea for physical and mental fatigue.
Six electronic databases were searched to identify randomized controlled trials (RCTs) and controlled clinical trials (CCTs), evaluating efficacy and safety of R. rosea for physical and mental fatigue. Two reviewers independently screened the identified literature, extracted data and assessed risk of bias for included studies.
Of 206 articles identified in the search, 11 met inclusion criteria for this review. Ten were described as RCTs and one as a CCT. Two of six trials examining physical fatigue in healthy populations report R. rosea to be effective as did three of five RCTs evaluating R. rosea for mental fatigue. All of the included studies exhibit either a high risk of bias or have reporting flaws that hinder assessment of their true validity (unclear risk of bias).
Research regarding R. rosea efficacy is contradictory. While some evidence suggests that the herb may be helpful for enhancing physical performance and alleviating mental fatigue, methodological flaws limit accurate assessment of efficacy. A rigorously-designed well reported RCT that minimizes bias is needed to determine true efficacy of R. rosea for fatigue.
Some cruciferous plants may serve as preventive treatments for several medical conditions; our objective was to systematically investigate their safety in humans. Four electronic databases were searched, and, of 10,831 references identified, 50 were included. Data were extracted by two independent reviewers, whereafter the association between interventions and adverse events was assessed. Adverse events in 53 subjects were identified through clinical trials; of these, altered drug metabolism was rated as certainly/likely caused by cruciferous plants. Adverse events in 1247 subjects were identified through observational studies, of which none received high causality ratings. Adverse events in 35 subjects were identified through case reports, of which allergies and warfarin resistance were rated as certainly/likely caused by cruciferous plants. We conclude that cruciferous plants are safe in humans, with the exception of allergies. Individuals treated with warfarin should consult their physician. Further investigation of uses of cruciferous plants in preventative medicine is warranted.
In this study we used event-related brain potentials (ERP) as neural markers of cognitive operations to examine emotion and attentional processing in a population of high-risk adolescents with mental health problems that included attention deficit and hyperactivity disorder (ADHD), anxiety, and depression. We included a healthy control group for comparison purposes, and employed a modified version of the emotional oddball paradigm, consisting of frequent distracters (scrambled pictures), infrequent distracters (sad, fearful, and neutral pictures), and infrequent targets (circles). Participants were instructed to make a right hand button press to targets and a left hand button press to all other stimuli. EEG/ERP recordings were taken using a high-density 256-channel recording system. Behavioral data showed that for both clinical and non-clinical adolescents, reaction time (RT) was slowest in response to the fearful images. Electrophysiological data differentiated emotion and target processing between clinical and non-clinical adolescents. In the clinical group we observed a larger P100 and late positive potential (LPP) in response to fearful compared to sad or neutral pictures. There were no differences in these ERPs in the healthy sample. Emotional modulation of target processing was also identified in the clinical sample, where we observed an increase in P300 amplitude, and a larger sustained LPP in response to targets that followed emotional pictures (fear and sad) compared to targets that followed neutral pictures or other targets. There were no differences in these target ERPs for the healthy participants. Taken together, we suggest that these data provide important and novel evidence of affective and attention dysfunction in this clinical population of adolescents, and offer an example of the disruptive effects of emotional reactivity on basic cognition.
ADHD; adolescents; anxiety; attention; depression; emotion; event-related potentials
Despite many studies confirming that the use of complementary and alternative medicine (CAM) by children is common, few have assessed related adverse events.
To conduct a national survey to identify the frequency and severity of adverse events associated with paediatric CAM use.
Survey questions were developed based on a review of relevant literature and consultation with content experts. In January 2006, the Canadian Paediatric Surveillance Program distributed the survey to all paediatricians and paediatric subspecialists in active practice in Canada.
Of the 2489 paediatricians who received the survey, 583 (23%) responded. Respondents reported that they asked patients about CAM use 38% of the time and that patients disclosed this information before being questioned only 22% of the time. Forty-two paediatricians (7%) reported seeing adverse events, most commonly involving natural health products, in the previous year. One hundred five paediatricians (18%) reported witnessing cases of delayed diagnosis or treatment (n=488) that they attributed to the use of CAM.
While serious adverse events associated with paediatric CAM appear to be rare, delays in diagnosis or treatment seem more common. Given the lack of paediatrician-patient discussion regarding CAM use, our findings may under-represent adverse events. A lack of reported adverse events should not be interpreted as a confirmation of safety. Active surveillance is required to accurately assess the incidence, nature and severity of paediatric CAM-related adverse events. Patient safety demands that paediatricians routinely inquire about the use of CAM.
Adverse effects; Complementary therapies; Health survey; Manipulation; Natural products; Paediatrics; Spinal
Exogenous melatonin has been increasingly used in the management of sleep disorders.
To conduct a systematic review of the efficacy and safety of exogenous melatonin in the management of primary sleep disorders.
A number of electronic databases were searched. We reviewed the bibliographies of included studies and relevant reviews and conducted hand-searching.
Randomized controlled trials (RCTs) were eligible for the efficacy review, and controlled trials were eligible for the safety review.
One reviewer extracted data, while the other verified data extracted. The Random Effects Model was used to analyze data.
Melatonin decreased sleep onset latency (weighted mean difference [WMD]: −11.7 minutes; 95% confidence interval [CI]: −18.2, −5.2)); it was decreased to a greater extent in people with delayed sleep phase syndrome (WMD: −38.8 minutes; 95% CI: −50.3, −27.3; n=2) compared with people with insomnia (WMD: −7.2 minutes; 95% CI: −12.0, −2.4; n=12). The former result appears to be clinically important. There was no evidence of adverse effects of melatonin.
There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less); however, additional large-scale RCTs are needed before firm conclusions can be drawn. There is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome with short-term use. There is evidence to suggest that melatonin is safe with short-term use (3 months or less).
melatonin; sleep; primary; review