Person:

Randolph, Adrienne

The randomized controlled trial (RCT) remains the highest-ranked study design when grading recommendations for clinical practice. In the previous issue of Critical Care, Duffett and colleagues published a scoping review of RCTs in pediatric critical care medicine and identified some serious gaps in the body of research underlying the field. Relatively few published RCTs were identified, and they were mostly small and potentially susceptible to bias. High patient heterogeneity, relatively low prevalence of specific disorders such as acute respiratory distress syndrome or septic shock, along with relatively low mortality rates, all make it difficult to improve this situation without the collaboration of pediatric critical care research networks internationally. Designing a robust RCT that can impact clinical practice has always been challenging. First, one must assess current clinical practice and disease prevalence, refine definitions and measurements, and pilot-test the intervention to be studied. The first step, however, is to rigorously assess what has already been done. This step will be facilitated by the now available, innovative, online, searchable repository of RCTs in pediatric critical care on the Evidence in Pediatric Critical Care website.

Sepsis is the leading cause of death in children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics. This article highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. We review how the capacity of the immune system to respond to infection develops over early life. We also bring attention to primary immune deficiencies that should be considered in children recurrently infected with specific types of organisms. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. It is important for clinicians to be aware of infection-related syndromes that primarily affect children. Although children in developed countries are more likely to survive severe infections than adults, many survivors have chronic health impairments.

Sepsis is associated with significant morbidity and mortality if not promptly recognized and treated. Since the development of early goal-directed therapy, mortality rates have decreased, but sepsis remains a major cause of death in patients arriving at the emergency department or staying in hospital. In this forum article, we asked clinicians and researchers with expertise in sepsis care to discuss the importance of rapid detection and treatment of the condition, as well as special considerations in different patient groups.

Introduction: The objective of this laboratory study was to measure the effect of decreased lung compliance and endotracheal tube (ETT) leakage on measured exhaled tidal volume at the airway and at the ventilator, in a research study with a test lung. Methods: The subjects were infant, adult and pediatric test lungs. In the test lung model, lung compliances were set to normal and to levels seen in acute respiratory distress syndrome. Set tidal volume was 6 ml/kg across a range of simulated weights and ETT sizes. Data were recorded from both the ventilator light-emitting diode display and the CO2SMO Plus monitor display by a single observer. Effective tidal volume was calculated from a standard equation. Results: In all test lung models, exhaled tidal volume measured at the airway decreased markedly with decreasing lung compliance, but measurement at the ventilator showed minimal change. In the absence of a simulated ETT leak, calculation of the effective tidal volume led to measurements very similar to exhaled tidal volume measured at the ETT. With a simulated ETT tube leak, the effective tidal volume markedly overestimated tidal volume measured at the airway. Conclusion: Previous investigators have emphasized the need to measure tidal volume at the ETT for all children. When ETT leakage is minimal, it seems from our simulated lung models that calculation of effective tidal volume would give similar readings to tidal volume measured at the airway, even in small patients. Future studies of tidal volume measurement accuracy in mechanically ventilated children should control for the degree of ETT leakage.

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Association between whole-genome sequencing (WGS) of the virus and death in patients with SARS-CoV-2 is one potential method of early identification of highly pathogenic strains to target for containment. We analyzed 7,548 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 4.09e-09 and 4.41e-23, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations alter amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development. Identification of these highly significant associations, unlikely to occur by chance, may assist with COVID-19 early containment of strains that are potentially highly pathogenic.

Rationale: Effective immunomodulatory therapies for children with life-threatening “cytokine storm” triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis. Objectives: To compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications. Methods: Children with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO. Measurements and main results Modules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p < 10−4], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002), were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes. Conclusion: We identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective therapies may need to target mediators of both inflammation and repair.