Jocelyn R. Grunwell

Procedural Sedation Outside of the Operating Room Using Ketamine in 22,645 Children: A Report From the Pediatric Sedation Research Consortium

Objective: Most studies of ketamine administered to children for procedural sedation are limited to emergency department use. The objective of this study was to describe the practice of ketamine procedural sedation outside of the operating room and identify risk factors for adverse events. Design: Observational cohort review of data prospectively collected from 2007 to 2015 from the multicenter Pediatric Sedation Research Consortium. Setting: Sedation services from academic, community, free-standing children’s hospitals and pediatric wards within general hospitals. Patients: Children from birth to 21 years old or younger. Interventions: None. Measurements and Main Results: Describe patient characteristics, procedure type, and location of administration of ketamine procedural sedation. Analyze sedation-related adverse events and severe adverse events. Identify risk factors for adverse events using multivariable logistic regression. A total of 22,645 sedations performed using ketamine were analyzed. Median age was 60 months (range, < 1 mo to < 22 yr); 72.0% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedations were performed in dedicated sedation or radiology units (64.6%). Anticholinergics, benzodiazepines, or propofol were coadministered in 19.8%, 57.9%, and 35.4%, respectively. The overall adverse event occurrence rate was 7.26% (95% CI, 6.92–7.60%), and the frequency of severe adverse events was 1.77% (95% CI, 1.60–1.94%). Procedures were not completed in 39 of 19,747 patients (0.2%). Three patients experienced cardiac arrest without death, all associated with laryngospasm. Conclusions: This is a description of a large prospectively collected dataset of pediatric ketamine administration predominantly outside of the operating room. The overall incidence of severe adverse events was low. Risk factors associated with increased odds of adverse events were as follows: cardiac and gastrointestinal disease, lower respiratory tract infection, and the coadministration of propofol and anticholinergics.

Trend and Outcomes of Video Laryngoscope Use Across Picus.

Objective: Video (indirect) laryngoscopy is used as a primary tracheal intubation device for difficult airways in emergency departments and in adult ICUs. The use and outcomes of video laryngoscopy compared with direct laryngoscopy has not been quantified in PICUs or cardiac ICUs. Design: Retrospective review of prospectively collected observational data from a multicenter tracheal intubation database (National Emergency Airway Registry for Children) from July 2010 to June 2015. Setting: Thirty-six PICUs/cardiac ICUs across the United States, Canada, Japan, New Zealand, and Singapore. Patients: Any patient admitted to a PICU or a pediatric cardiac ICU and undergoing tracheal intubation. Interventions: Use of direct laryngoscopy versus video laryngoscopy for tracheal intubation. Measurements and Main Results: There were 8,875 tracheal intubations reported in the National Emergency Airway Registry for Children database, including 7,947 (89.5%) tracheal intubations performed using direct laryngoscopy and 928 (10.5%) tracheal intubations performed using video laryngoscopy. Wide variability in video laryngoscopy use exists across PICUs (median, 2.6%; range, 0–55%). Video laryngoscopy was more often used in older children (p < 0.001), in children with history of a difficult airway (p = 0.01), in children intubated for ventilatory failure (p < 0.001), and to facilitate the completion of an elective procedure (p = 0.048). After adjusting for patient-level covariates, a secular trend, and site-level variance, the use of video laryngoscopy significantly increased over a 5-year period compared with fiscal year 2011 (odds ratio, 6.7; 95% CI, 1.7–26.8 for fiscal year 2014 and odds ratio, 11.2; 95% CI, 3.2–38.9 for fiscal year 2015). The use of video laryngoscopy was independently associated with a lower occurrence of tracheal intubation adverse events (adjusted odds ratio, 0.57; 95% CI, 0.42–0.77; p < 0.001) but not with a lower occurrence of severe tracheal intubation adverse events (adjusted odds ratio, 0.86; 95% CI, 0.56–1.32; p = 0.49) or fewer multiple attempts at endotracheal intubation (adjusted odds ratio, 0.93; 95% CI, 0.71–1.22; p = 0.59). Conclusions: Using National Emergency Airway Registry for Children data, we described patient-centered adverse outcomes associated with video laryngoscopy compared with direct laryngoscopy for tracheal intubation in the largest reported international cohort of children to date. Data from this study may be used to design sufficiently powered prospective studies comparing patient-centered outcomes for video laryngoscopy versus direct laryngoscopy during endotracheal intubation.

Comparison of Glutathione, Cysteine, and Their Redox Potentials in the Plasma of Critically Ill and Healthy Children.

Background Oxidative stress is known to play a role in critical illness due to an imbalance in reactive oxygen species and reactive nitrogen species, and the body’s ability to detoxify pro-oxidants using small molecule anti-oxidants and anti-oxidant enzymes. Objective To compare the concentrations of plasma redox metabolites and redox potentials for the Cys/CySS and GSH/GSSG thiol/disulfide pairs in critically ill children with healthy control children. Methods We performed a prospective clinical observational study of children ages ≤18 years and weight ≥6 kg, who were hospitalized between January 2010 and April 2012 in a 30-bed multidisciplinary medical-surgical pediatric intensive care unit (PICU). We measured the plasma concentrations of Cys, CySS, GSH, and GSSG within the first 24 h of PICU arrival, and we calculated the redox potential for the Cys/CySS (Eh Cys/CySS) and GSH/GSSG (Eh GSH/GSSG) thiol/disulfide pairs in the plasma of 61 critically ill children and 16 healthy control children. Results Critically ill children have less Cys (p = 0.009), less CySS (p = 0.011), less Total Cys ([Cys] + 2[CySS], p = 0.01), more GSSG (p < 0.001), and more oxidized Eh GSH/GSSG (p < 0.001) compared to healthy children. Conclusion Our results demonstrate that in the presence of pediatric critical illness, the Total Cys/CySS thiol pool decreases while GSH is likely one component of the cellular redox system that reduces CySS back to Cys, thus maintaining Eh Cys/CySS. The Total Cys pool is more abundant than the Total GSH pool in the plasma of children. Further investigation is needed to elucidate the differences in redox potentials in subgroups of critically ill children, and to determine whether differences in redox metabolite concentrations and redox potentials correlate with severity of critical illness and clinical outcomes.

Vitamin D deficiency is associated with an oxidized plasma cysteine redox potential in critically Ill children

Critically ill populations incur high levels of oxidative stress and commonly present with vitamin D deficiency. This study aimed to investigate the relationship between vitamin D status and plasma markers of glutathione (GSH) and cysteine (Cys) redox and immunity in critically ill children. This was a cross-sectional study of n=50 PICU patients. Subjects were categorized according to their plasma 25-hydroxyvitamin D [25(OH)D] concentrations: (<20, 20-30, and ≥30ng/dL). Plasma GSH, glutathione disulfide (GSSG), Cys, and cystine (CySS) were measured with high-performance liquid chromatography, and their associated redox potentials determined (EhGSSG and EhCySS, respectively). Plasma LL-37, an indicator of innate immune function, was assayed with ELISA. Data were analyzed using general linear regression before and after adjustment for age, sex, and race. Results showed that EhCySS was more reduced in subjects with plasma 25(OH)D concentrations ≥30ng/mL compared to those with 25(OH)D concentrations <20ng/mL (P=0.009). Plasma GSH, GSSG, and total GSH decreased with increasing 25(OH)D category (P=0.06, 0.03, and 0.01, respectively), and plasma glutamine levels were lowest in subjects with plasma 25(OH)D concentrations ≥30ng/mL (P=0.004). Plasma LL-37 concentrations did not significantly differ by vitamin D status (P=0.08). In conclusion, vitamin D sufficiency was associated with more reduced plasma EhCySS, indicative of lower oxidative stress in critically ill children. Plasma GSH, GSSG, and glutamine, however, were lower in the vitamin D sufficient group. The role of vitamin D in maintaining redox status during pediatric critical illness requires further study.

Differential expression of the Nrf2-linked genes in pediatric septic shock.

IntroductionExperimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock.MethodsWe conducted a focused analysis of 267 Nrf2-linked genes using a multicenter, genome-wide expression database of 180 children with septic shock 10 years of age or younger and 53 healthy controls. The analysis involved RNA isolated from whole blood within 24 h of pediatric intensive care unit admission for septic shock and a false discovery rate of 5 %. We compared differentially expressed genes from (1) patients with septic shock and healthy controls and (2) across validated gene expression–based subclasses of pediatric septic shock (endotypes A and B) using several bioinformatic methods.ResultsWe found upregulation of 123 Nrf2-linked genes in children with septic shock. The top gene network represented by these genes contained primarily enzymes with oxidoreductase activity involved in cellular lipid metabolism that were highly connected to the peroxisome proliferator activated receptor and the retinoic acid receptor families. Endotype A, which had higher organ failure burden and mortality, exhibited a greater downregulation of Nrf2-linked genes than endotype B, with 92 genes differentially regulated between endotypes.ConclusionsOur findings indicate that Nrf2-linked genes may contribute to alterations in oxidative signaling and intermediary metabolism in pediatric septic shock.

Hyperchloremia Is Associated with Complicated Course and Mortality in Pediatric Patients with Septic Shock

Objective: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock. Design: Retrospective analysis of a pediatric septic shock database. Setting: Twenty-nine PICUs in the United States. Patients: Eight hundred ninety children 10 years and younger with septic shock. Interventions: None. Measurements and Main Results: We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1–3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0–6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3–3.5; p = 0.002). The secondary analysis yielded similar results. Conclusion: Hyperchloremia is independently associated with poor outcomes among children with septic shock.

TGF-β1 Suppresses the Type I IFN Response and Induces Mitochondrial Dysfunction in Alveolar Macrophages

TGF-β1 is a pleiotropic cytokine with an established role in fibrosis; however, the immunosuppressive effects of TGF-β1 are less characterized. Elevated levels of TGF-β1 are found in patients with acute and chronic lung diseases, and the underlying disease processes are exacerbated by respiratory viral infections. The alveolar macrophage is the first line of cellular defense against respiratory viral infections, and its response to infections is dependent on environmental cues. Using the mouse alveolar macrophage line, MH-S, and human CD14+ monocyte-derived macrophages, we examined the effects of TGF-β1 on the type I IFN antiviral response, macrophage polarization, and mitochondrial bioenergetics following a challenge with human respiratory syncytial virus (RSV). Our results showed that TGF-β1 treatment of macrophages decreased the antiviral and proinflammatory response, and suppressed basal, maximal, spare mitochondrial respiration, and mitochondrial ATP production. Challenge with RSV following TGF-β1 treatment further exacerbated mitochondrial dysfunction. The TGF-β1 and TGF-β1+RSV–treated macrophages had a higher frequency of apoptosis and diminished phagocytic capacity, potentially through mitochondrial stress. Disruption of TGF-β1 signaling or rescue of mitochondrial respiration may be novel therapeutically targetable pathways to improve macrophage function and prevent secondary bacterial infections that complicate viral respiratory infections.

Outcomes following implementation of a pediatric procedural sedation guide for referral to general anesthesia for magnetic resonance imaging studies

Guidelines for referral of children to general anesthesia (GA) to complete MRI studies are lacking. We devised a pediatric procedural sedation guide to determine whether a pediatric procedural sedation guide would decrease serious adverse events and decrease failed sedations requiring rescheduling with GA.

Comments on Baranwal et al: Dexamethasone pretreatment for 24 h versus 6 h for prevention of postextubation airway obstruction in children

Dear Editor, I read with interest the paper of Baranwal et al. [1] on the use of a 24-h versus a 6-h pre-extubation (pretreatment) protocol of dexamethasone (24hPD vs. 6hPD) to prevent postextubation airway obstruction (PEAO) in children in a resourcelimited pediatric intensive care unit. The primary outcome of the study was the occurrence of clinically significant PEAO, as defined by a composite indicator comprised of a modified version of Westley’s croup score (mWCS) of C4, which required adrenaline nebulization treatment(s) and/or reintubation during the 48-h post-extubation period. As I was evaluating the paper, I noticed that the relative risk (RR) for the primary outcome was incorrectly calculated. Based on the information provided in the paper, the 2 9 2 table is:

Impaired defenses of neonatal mouse alveolar macrophage with cftr deletion are modulated by glutathione and TGFβ1

Our understanding of the intrinsic effects of cystic fibrosis (CF) transmembrane conductance regulator (cftr) deletion on resident neonatal alveolar macrophage (AM) remains limited. We previously demonstrated that diminished glutathione (GSH) or excessive AM transforming growth factor beta one (TGFβ1) contributes to AM dysfunction in a variety of disease states. In this study, using a gut‐corrected cftr neonatal knockout (KO) mouse model and a siRNA‐manipulated macrophage‐like cell line (THP‐1 cell), we hypothesized (1) that cftr mutation alone increases neonatal AM oxidant stress and cellular TGFβ1 signaling via altered GSH, thereby impairing cellular function, and (2) that exogenous GSH attenuates AM alterations and dysfunction in the KO AM. In neonatal KO mice, the baseline bronchoalveolar lavage fluid demonstrated a near doubling in mixed disulfides (P ≤ 0.05) and oxidized GSSG (P ≤ 0.05) without concurrent inflammation compared to WT littermates. KO AM demonstrated diminished AM thiols (P ≤ 0.05), increased AM mitochondrial ROS (P ≤ 0.05), increased AM TGFβ1 (P ≤ 0.05) with increased TGFβ1 signaling (P ≤ 0.05), and impaired phagocytosis (P ≤ 0.05). KO AM mitochondrial ROS was modulated by exogenous GSH (P ≤ 0.05). Conversely, TGFβ1 was reduced (P ≤ 0.05) and impaired phagocytosis was rescued (P ≤ 0.05) by exogenous GSH in the KO AM. These results suggest that an altered neonatal AM phenotype may contribute to the initiation of lung inflammation/infection in the CF lung. Modulation of the AM in the neonatal CF lung may potentially alter progression of disease.