Derek S. Wheeler

Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children

BACKGROUND Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS We conducted this trial of two targeted temperature interventions at 38 childrens hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

The host response to sepsis and developmental impact.

Invasion of the human by a pathogen necessitates an immune response to control and eradicate the microorganism. When this response is inadequately regulated, systemic manifestations can result in physiologic changes described as “sepsis.” Recognition, diagnosis, and management of sepsis remain among the greatest challenges shared by the fields of neonatology and pediatric critical care medicine. Sepsis remains among the leading causes of death in both developed and underdeveloped countries and has an incidence that is predicted to increase each year. Despite these sobering statistics, promising therapies derived from preclinical models have universally failed to obviate the substantial mortality and morbidity associated with sepsis. Thus, there remains a need for well-designed epidemiologic and mechanistic studies of neonatal and pediatric sepsis to improve our understanding of the causes (both early and late) of deaths attributed to the syndrome. In reviewing the definitions and epidemiology, developmental influences, and regulation of the host response to sepsis, it is anticipated that an improved understanding of this host response will assist clinician-investigators in identifying improved therapeutic strategies.

Extracellular Hsp72, an endogenous DAMP, is released by virally infected airway epithelial cells and activates neutrophils via Toll-like receptor (TLR)-4

BackgroundNeutrophils play an important role in the pathophysiology of RSV, though RSV does not appear to directly activate neutrophils in the lower airways. Therefore locally produced cytokines or other molecules released by virally-infected airway epithelial cells are likely responsible for recruiting and activating neutrophils. Heat shock proteins (HSPs) are generally regarded as intracellular proteins acting as molecular chaperones; however, HSP72 can also be released from cells, and the implications of this release are not fully understood.MethodsHuman bronchial epithelial cells (16HBE14o-) were infected with RSV and Hsp72 levels were measured by Western blot and ELISA. Tracheal aspirates were obtained from critically ill children infected with RSV and analyzed for Hsp72 levels by ELISA. Primary human neutrophils and differentiated HL-60 cells were cultured with Hsp72 and supernatants analyzed for cytokine production. In some cases, cells were pretreated with polymyxin B prior to treatment with Hsp72. IκBα was assessed by Western blot and EMSAs were performed to determine NF-κB activation. HL-60 cells were pretreated with neutralizing antibody against TLR4 prior to Hsp72 treatment. Neutrophils were harvested from the bone marrow of wild type or TLR4-deficient mice prior to treatment with Hsp72.ResultsInfection of 16HBE14o- with RSV showed an induction of intracellular Hsp72 levels as well as extracellular release of Hsp72. Primary human neutrophils from normal donors and differentiated HL-60 cells treated with increasing concentrations of Hsp72 resulted in increased cytokine (IL-8 and TNFα) production. This effect was independent of the low levels of endotoxin in the Hsp72 preparation. Hsp72 mediated cytokine production via activation of NF-κB translocation and DNA binding. Using bone marrow-derived neutrophils from wild type and TLR4-mutant mice, we showed that Hsp72 directly activates neutrophil-derived cytokine production via the activation of TLR4.ConclusionCollectively these data suggest that extracellular Hsp72 is released from virally infected airway epithelial cells resulting in the recruitment and activation of neutrophils.

Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children.

Reliable prediction of severe acute kidney injury (AKI) has the potential to optimize treatment. Here we operationalized the empiric concept of renal angina with a renal angina index (RAI) and determined the predictive performance of RAI. This was assessed on admission to the pediatric intensive care unit, for subsequent severe AKI (over 200% rise in serum creatinine) 72 h later (Day-3 AKI). In a multicenter four cohort appraisal (one derivation and three validation), incidence rates for a Day 0 RAI of 8 or more were 15-68% and Day-3 AKI was 13-21%. In all cohorts, Day-3 AKI rates were higher in patients with an RAI of 8 or more with the area under the curve of RAI for predicting Day-3 AKI of 0.74-0.81. An RAI under 8 had high negative predictive values (92-99%) for Day-3 AKI. RAI outperformed traditional markers of pediatric severity of illness (Pediatric Risk of Mortality-II) and AKI risk factors alone for prediction of Day-3 AKI. Additionally, the RAI outperformed all KDIGO stages for prediction of Day-3 AKI. Thus, we operationalized the renal angina concept by deriving and validating the RAI for prediction of subsequent severe AKI. The RAI provides a clinically feasible and applicable methodology to identify critically ill children at risk of severe AKI lasting beyond functional injury. The RAI may potentially reduce capricious AKI biomarker use by identifying patients in whom further testing would be most beneficial.

Combining Functional and Tubular Damage Biomarkers Improves Diagnostic Precision for Acute Kidney Injury After Cardiac Surgery

BACKGROUND Increases in serum creatinine (ΔSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication. OBJECTIVES This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI. METHODS Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (≥100% ΔSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline ≤48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to ΔSCr increases of ≥50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values [Corrected]. RESULTS Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than ΔSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL-/pCysC+ composite was superior to ΔSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than ΔSCr strata. CONCLUSIONS Composites of functional and tubular damage biomarkers are superior to ΔSCr for predicting discrete characteristics of AKI.

Renal angina: an emerging paradigm to identify children at risk for acute kidney injury

Acute kidney injury (AKI) leads to high rates of morbidity and independently increases mortality risk. Therapy for AKI is likely limited by the inability to reliably diagnose AKI in its early stages, and, importantly, small changes in serum creatinine may be associated with poor outcomes and severe AKI. Whereas AKI biomarker research seeks to identify more sensitive and timely indices of kidney dysfunction, AKI lacks physical signs and symptoms to trigger biomarker assessment in at-risk patients, limiting biomarker efficacy. Accurate models of AKI prediction are unavailable. Severity of illness (SOI) scoring systems and organ dysfunction scores (OD), which stratify patients by prediction of mortality risk, are AKI reactive, not predictive. Kidney-specific severity scores do not account for AKI progression, and stratification models of AKI severity are not predictive of AKI. Thus, there is a need for a kidney scoring system that can help predict the development of AKI. This review highlights the concept of renal angina, a combination of patient risk factors and subtle AKI, as a methodology to predict AKI progression. Fulfillment of renal angina criteria will improve the efficiency of AKI prediction by biomarkers, in turn expediting early therapy and assisting in creation of AKI-predictive scoring systems.

High-reliability emergency response teams in the hospital: improving quality and safety using in situ simulation training

Introduction In situ simulation training is a team-based training technique conducted on actual patient care units using equipment and resources from that unit, and involving actual members of the healthcare team. We describe our experience with in situ simulation training in a major childrens medical centre. Materials and methods In situ simulations were conducted using standardised scenarios approximately twice per month on inpatient hospital units on a rotating basis. Simulations were scheduled so that each unit participated in at least two in situ simulations per year. Simulations were conducted on a revolving schedule alternating on the day and night shifts and were unannounced. Scenarios were preselected to maximise the educational experience, and frequently involved clinical deterioration to cardiopulmonary arrest. Results We performed 64 of the scheduled 112 (57%) in situ simulations on all shifts and all units over 21 months. We identified 134 latent safety threats and knowledge gaps during these in situ simulations, which we categorised as medication, equipment, and/or resource/system threats. Identification of these errors resulted in modification of systems to reduce the risk of error. In situ simulations also provided a method to reinforce teamwork behaviours, such as the use of assertive statements, role clarity, performance of frequent updating, development of a shared mental model, performance of independent double checks of high-risk medicines, and overcoming authority gradients between team members. Participants stated that the training programme was effective and did not disrupt patient care. Conclusions In situ simulations can identify latent safety threats, identify knowledge gaps, and reinforce teamwork behaviours when used as part of an organisation-wide safety programme.

Quality Improvement Initiative to Reduce Serious Safety Events and Improve Patient Safety Culture

BACKGROUND AND OBJECTIVE: Many thousands of patients die every year in the United States as a result of serious and largely preventable safety events or medical errors. Safety events are common in hospitalized children. We conducted a quality improvement initiative to implement cultural and system changes with the goal of reducing serious safety events (SSEs) by 80% within 4 years at our large, urban pediatric hospital. METHODS: A multidisciplinary SSE reduction team reviewed the safety literature, examined recent SSEs, interviewed internal leaders, and visited other leading organizations. Senior hospital leaders provided oversight, monitored progress, and helped to overcome barriers. Interventions focused on: (1) error prevention; (2) restructuring patient safety governance; (3) a new root cause analysis process and a common cause database; (4) a highly visible lessons learned program; and (5) specific tactical interventions for high-risk areas. Our outcome measures were the rate of SSEs and the change in patient safety culture. RESULTS: SSEs per 10 000 adjusted patient-days decreased from a mean of 0.9 at baseline to 0.3 (P < .0001). The days between SSEs increased from a mean of 19.4 at baseline to 55.2 (P < .0001). After a worsening of patient safety culture outcomes in the first year of intervention, significant improvements were observed between 2007 and 2009. CONCLUSIONS: Our multifaceted approach was associated with a significant and sustained reduction of SSEs and improvements in patient safety culture. Multisite studies are needed to better understand contextual factors and the significance of specific interventions.

Intracellular delivery of HSP70 using HIV-1 Tat protein transduction domain.

Heat shock protein 70 (HSP70) is an intracellular stress protein that confers cytoprotection to a variety of cellular stressors. Several lines of evidence have suggested that augmentation of the heat shock response by increasing the expression of HSP70 represents a potential therapeutic strategy for the treatment of critically ill patients. The Tat protein of human immunodeficiency virus 1 (HIV-1) has been used previously to deliver functional cargo proteins intracellularly when added exogenously to cultured cells. We generated a Tat-HSP70 fusion protein using recombinant methods and treated HSF -/- cells with either Tat-HSP70 or recombinant HSP70 prior to exposure to hyperoxia or lethal heat shock. We showed that biologically active, exogenous HSP70 can be delivered into cells using the HIV-1 Tat protein, and that the Tat-mediated delivery of HSP70 confers cytoprotection against thermal stress and hyperoxia and may represent a novel approach to augmenting intracellular HSP70 levels.

Incorporation of Biomarkers with the Renal Angina Index for Prediction of Severe AKI in Critically Ill Children

BACKGROUND AND OBJECTIVES Novel AKI biomarkers carry variable performance for prediction of AKI in patients with heterogeneous illness. Until utility is demonstrated in critically ill patients outside of the cardiopulmonary bypass population, AKI biomarkers are unlikely to gain widespread implementation. Operationalization of an AKI risk stratification methodology, termed renal angina, was recently reported to enhance prediction at the time of intensive care unit admission for persistent severe AKI. The renal angina index (RAI) was developed to provide the clinical context to direct AKI biomarker testing. This study tested the hypothesis that incorporation of AKI biomarkers in patients fulfilling renal angina improves the prediction of persistent severe AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a multicenter study of 214 patients admitted to the pediatric intensive care unit with sepsis, the discrimination of plasma neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-8 (MMP-8), and neutrophil elastase-2 (Ela-2) were determined individually and in combination with the RAI for severe AKI. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated. RESULTS Individual biomarkers demonstrated marginal discrimination for severe AKI (area under curve [AUC]: NGAL, 0.72; MMP-8, 0.68; Ela-2, 0.72), inferior to prediction by the clinical model of the RAI (AUC=0.80). Incorporation of each biomarker significantly added to the renal angina model AKI prediction (AUC=0.80, increased to 0.84-0.88; P<0.05 for each). The inclusion of each biomarker with the RAI demonstrated NRI (0.512, 0.428, and 0.545 for NGAL, MMP-8, and Ela-2, respectively; all P<0.03) and IDI (0.075 for Ela-2). The inclusion of both Ela-2 and NGAL with RAI demonstrated an NRI of 0.871 (P<0.001) and an IDI of 0.1 (P=0.01). CONCLUSIONS This study shows that incorporation of AKI biomarkers into the RAI improves discrimination for severe AKI. The RAI optimizes the utility of AKI biomarkers in a heterogeneous, critically ill patient population.