Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.

OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.

Perinatal Anesthesia Exposure and Autism Spectrum Disorders.

Epidural analgesia is frequently used during labor among pregnant people in the United States. Different factors have been associated with the development of autism spectrum disorder in the epidemiological literature: maternal health, infectious and pharmacological etiologies, social factors, and environmental exposures. Current data indicates no clear association between the use of epidural labor analgesia and the development of autism spectrum disorder in the offspring. This review presents the public health perspective on the postulated association between perinatal anesthesia exposure and autism spectrum disorders.

Impact of Anesthetic Exposures on the Neurocognitive Profiles of Pediatric Brain Tumor Survivors: A New Direction for Research and Multidisciplinary Collaboration.

Primary brain tumors are the most commonly diagnosed solid tumors in children, and pediatric brain tumor survivors experience lasting, pervasive deficits of neurocognitive functioning. Repeated exposure to anesthetic drugs is a necessary component not only of surgical resection but also of multimodal cancer care for the youngest patients with brain tumors. The potential for anesthetic neurotoxicity to worsen neurocognitive outcomes in this vulnerable group, therefore, warrants our attention and further study through multi-disciplinary collaboration. This review discusses neurocognitive functioning in pediatric brain tumor survivors, highlighting the findings of a recent study of children with tumors of the posterior fossa which identified treatment-related risk factors for neurocognitive difficulties, with those undergoing multimodal therapies (eg, chemotherapy and irradiation) experiencing the greatest deficits compared with healthy controls. The role of anesthetic neurotoxicity in long-term outcomes among pediatric brain tumor survivors is also reviewed.

Pediatric Intensive Care Unit Patients: Sedation, Monitoring, and Neurodevelopmental Outcomes.

The design and conduct of pediatric sedation studies in critically ill patients have historically been challenging due to the complexity of the pediatric intensive care unit (PICU) environment and the difficulty of establishing equipoise. Clinical trials, for instance, represent 1 important means of advancing our knowledge in this field, but there is a paucity of such studies in the literature. Accounting for ground-level factors in planning for each trial phase (eg, enrollment, intervention, assessment, and follow-up) and the presence of broader system limitations is of key importance. In addition, there is a need for early planning, coordination, and obtaining buy-in from individual study sites and staff to ensure success, particularly for multicenter studies. This review synthesizes the current state of pediatric sedation research and the myriad of challenges in designing and conducting successful trials in this particular area. The review poses consideration for future research directions, including novel study designs, and discusses electroencephalography monitoring and neurodevelopmental outcomes of PICU survivors.

Variability in Resource Utilization in the Evaluation and Management of Simple Febrile Seizures Inpatients in US Children's Hospitals.

OBJECTIVE: To characterize resource utilization in the evaluation and treatment of hospitalized simple febrile seizure (SFS) patients in US tertiary pediatric hospitals. METHODS: This is a retrospective cohort study using the Pediatric Health Information System from 2010 to 2015. Children 6 months to 5 years of age who were inpatients with a diagnosis of SFS. Children who had brain magnetic resonance imaging (MRI), electroencephalography (EEG), or received anticonvulsants were compared with those who did not have testing or anticonvulsant treatment. Hospital-level variation in the utilization rates of MRI, EEG, or treatment with anticonvulsants was also evaluated. RESULTS: In Pediatric Health Information System-participating institutions, 8.4% (n=3640) of children presenting to the emergency department with SFS were hospitalized. Among these SFS inpatients, 57.8% (n= 2104) did not receive further evaluation with MRI/EEG or treatment with anticonvulsants. There was evidence of wide inter-hospital variation in resource utilization rates. The median (interquartile range) utilization rate was 6.2% (3.0 to 11.0%) for MRI, 28.5% (16.0 to 46.3%) for EEG and 17.1% (10.9 to 22.3%) for treatment with anticonvulsants. CONCLUSION: No specific hospital-level factors were identified that contributed to the variation in resource utilization in the evaluation and management of hospitalized SFS patients.

Adverse Events in the Pediatric Cardiac Catheterization Suite: Does Having Pediatric Cardiac Anesthesiologists Make a Difference?

INTRODUCTION: It has been suggested that anesthesiologists with subspecialty expertise in pediatric cardiac anesthesia are best qualified to care for patients with complex congenital cardiac anomalies and manage the complex physiology frequently encountered in the pediatric cardiac catheterization lab. We evaluated the incidence of adverse events in our pediatric cardiac catheterization lab, comparing care provided by cardiac and noncardiac pediatric attending anesthesiologists. METHODS: Data were collected on each anesthetic in the pediatric cardiac catheterization lab from January 1, 2016 to December 31, 2019. A generalized linear mixed effect model was used to identify associations between pediatric cardiac and noncardiac anesthesiologists and the presence of adverse events adjusting for age, American Society of Anesthesiologists physical status, emergency status, and interventional versus diagnostic procedures. RESULTS: A total of 3,761 procedures involving 1,729 patients were included in the study. There was no significant difference between noncardiac and cardiac anesthesia attendings for overall adverse events (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.82 to 1.75 P=0.349). Specific respiratory adverse events (OR, 1.22; 95%, CI 0.73 to 2.03 P=0.443) or cardiac adverse events (OR, 1.26; 95% CI, 0.64 to 2.48 P=0.502) were also not significantly different with respect to noncardiac compared with cardiac attending anesthesiologists. CONCLUSIONS: In our analysis, the incidence of adverse events in the pediatric cardiac catheterization lab during the study period was not statistically different, whether anesthesia care was provided by a cardiac or a noncardiac anesthesiologist.

Children with Congenital Heart Disease Show Increased Behavioral Problems Compared to Healthy Peers: A Systematic Review and Meta-Analysis.

Millions of children and adults are living with congenital heart disease (CHD). Their risk for behavioral problems has not been the subject of a meta-analysis. We performed a systematic review and meta-analysis of measures of behavioral problems in people born with CHD compared to peers without CHD. We searched Pubmed, CINAHL, Embase, PsycInfo, and the Cochrane Library from January 1, 1986 to November 15, 2021. We included studies that reported a measure of behavioral problems in patients with CHD in children and adults older than 3 years of age. We screened 26,343 search results, and 24 studies met inclusion criteria. The quality of evidence was generally low. Subjects with CHD had a small increase in internalizing problems [standardized mean difference (SMD): 0.198, p = 0.02] and total behavior problems (SMD: 0.287, p = 0.013), but no difference in externalizing behavioral problems. There was significant heterogeneity in all three domains of behavior problems analyzed, and it could not be explained by variables such as age, severity, assessor, or assessment tool. There are small increases in parent- and self-reported overall behavioral problems and internalizing problems in patients with CHD compared to healthy controls. Wide confidence intervals in the meta-analyses leave open the possibility that certain factors may increase the risk of behavioral problems in this group, and future studies with important attention paid to potential confounders may help identify risk factors.

Accuracy of diagnostic codes for prenatal opioid exposure and neonatal opioid withdrawal syndrome.

OBJECTIVE: Determine the accuracy of diagnostic codes in identifying Prenatal Opioid Exposure (POE) and Neonatal Opioid Withdrawal Syndrome (NOWS). STUDY DESIGN: A cross-sectional study of 374,222 mother-infant dyads with delivery from 01/01/2010 to 12/31/2019. We ascertained maternal diagnostic codes for opioid use during pregnancy and infant diagnostic codes for drug exposure and withdrawal. We assessed sensitivity and positive predictive value (PPV) for POE and NOWS, defined using laboratory, pharmacy, and clinical data. RESULTS: Maternal codes had low sensitivity (36.4%) and PPV (34.7%) for POE. Infant codes for drug exposure were neither sensitive for POE (14%) nor NOWS (31.6%) and had low PPV. Codes for newborn withdrawal had low sensitivity (31.6%) for detecting NOWS, but high PPV (85%). Sensitivity improved (95.1%) for NOWS requiring pharmacologic treatment. CONCLUSIONS: Diagnostic codes identify POE and NOWS poorly. Improved case identification would include pharmacy and laboratory results, and clearly defined criteria for evidence of withdrawal.

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.