Rainer Gedeit

Critically ill children during the 2009-2010 influenza pandemic in the United States.

BACKGROUND: The 2009 pandemic influenza A (H1N1) (pH1N1) virus continues to circulate worldwide. Determining the roles of chronic conditions and bacterial coinfection in mortality is difficult because of the limited data for children with pH1N1-related critical illness. METHODS: We identified children (<21 years old) with confirmed or probable pH1N1 admitted to 35 US PICUs from April 15, 2009, through April 15, 2010. We collected data on demographics, baseline health, laboratory results, treatments, and outcomes. RESULTS: Of 838 children with pH1N1 admitted to a PICU, the median age was 6 years, 58% were male, 70% had ≥1 chronic health condition, and 88.2% received oseltamivir (5.8% started before PICU admission). Most patients had respiratory failure with 564 (67.3%) receiving mechanical ventilation; 162 (19.3%) received vasopressors, and 75 (8.9%) died. Overall, 71 (8.5%) of the patients had a presumed diagnosis of early (within 72 hours after PICU admission) Staphylococcus aureus coinfection of the lung with 48% methicillin-resistant S aureus (MRSA). In multivariable analyses, preexisting neurologic conditions or immunosuppression, encephalitis (1.7% of cases), myocarditis (1.4% of cases), early presumed MRSA lung coinfection, and female gender were mortality risk factors. Among 251 previously healthy children, only early presumed MRSA coinfection of the lung (relative risk: 8 [95% confidence interval: 3.1–20.6]; P < .0001) remained a mortality risk factor. CONCLUSIONS: Children with preexisting neurologic conditions and immune compromise were at increased risk of pH1N1-associated death after PICU admission. Secondary complications of pH1N1, including myocarditis, encephalitis, and clinical diagnosis of early presumed MRSA coinfection of the lung, were mortality risk factors.

Protocolized Sedation vs Usual Care in Pediatric Patients Mechanically Ventilated for Acute Respiratory Failure: A Randomized Clinical Trial

IMPORTANCE Protocolized sedation improves clinical outcomes in critically ill adults, but its effect in children is unknown. OBJECTIVE To determine whether critically ill children managed with a nurse-implemented, goal-directed sedation protocol experience fewer days of mechanical ventilation than patients receiving usual care. DESIGN, SETTING, AND PARTICIPANTS Cluster randomized trial conducted in 31 US pediatric intensive care units (PICUs). A total of 2449 children (mean age, 4.7 years; range, 2 weeks to 17 years) mechanically ventilated for acute respiratory failure were enrolled in 2009-2013 and followed up until 72 hours after opioids were discontinued, 28 days, or hospital discharge. INTERVENTION Intervention PICUs (17 sites; n = 1225 patients) used a protocol that included targeted sedation, arousal assessments, extubation readiness testing, sedation adjustment every 8 hours, and sedation weaning. Control PICUs (14 sites; n = 1224 patients) managed sedation per usual care. MAIN OUTCOMES AND MEASURES The primary outcome was duration of mechanical ventilation. Secondary outcomes included time to recovery from acute respiratory failure, duration of weaning from mechanical ventilation, neurological testing, PICU and hospital lengths of stay, in-hospital mortality, sedation-related adverse events, measures of sedative exposure (wakefulness, pain, and agitation), and occurrence of iatrogenic withdrawal. RESULTS Duration of mechanical ventilation was not different between the 2 groups (intervention: median, 6.5 [IQR, 4.1-11.2] days; control: median, 6.5 [IQR, 3.7-12.1] days). Sedation-related adverse events including inadequate pain and sedation management, clinically significant iatrogenic withdrawal, and unplanned endotracheal tube/invasive line removal were not significantly different between the 2 groups. Intervention patients experienced more postextubation stridor (7% vs 4%; P = .03) and fewer stage 2 or worse immobility-related pressure ulcers (<1% vs 2%; P = .001). In exploratory analyses, intervention patients had fewer days of opioid administration (median, 9 [IQR, 5-15] days vs 10 [IQR, 4-21] days; P = .01), were exposed to fewer sedative classes (median, 2 [IQR, 2-3] classes vs 3 [IQR, 2-4] classes; P < .001), and were more often awake and calm while intubated (median, 86% [IQR, 67%-100%] of days vs 75% [IQR, 50%-100%] of days; P = .004) than control patients, respectively; however, intervention patients had more days with any report of a pain score ≥ 4 (median, 50% [IQR, 27%-67%] of days vs 23% [IQR, 0%-46%] of days; P < .001) and any report of agitation (median, 60% [IQR, 33%-80%] vs 40% [IQR, 13%-67%]; P = .003), respectively. CONCLUSIONS AND RELEVANCE Among children undergoing mechanical ventilation for acute respiratory failure, the use of a sedation protocol compared with usual care did not reduce the duration of mechanical ventilation. Exploratory analyses of secondary outcomes suggest a complex relationship among wakefulness, pain, and agitation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00814099.

Developing a clinically feasible personalized medicine approach to pediatric septic shock.

RATIONALE Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock. OBJECTIVES To develop and validate a real-time subclassification method for septic shock. METHODS Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132). MEASUREMENTS AND MAIN RESULTS The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval [CI95] = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011). CONCLUSIONS We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.

Testing the Prognostic Accuracy of the Updated Pediatric Sepsis Biomarker Risk Model

Background We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort. Objective To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort. Methods Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system. Results Mortality in the test cohort was 13.2%. Using a risk cut-off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62–95), specificity was 75% (68–82), positive predictive value was 34% (22–47), and negative predictive value was 97% (91–99). The area under the receiver operating characteristic curve was 0.81 (0.70–0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47–1.35; p<0.001). Conclusions The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system.

Cumulative fluid intake minus output is not associated with ventilator weaning duration or extubation outcomes in children

Objective: The effect of fluid balance on respiratory outcomes for critically ill children has not been evaluated. The only indicator of fluid balance routinely recorded across our intensive care units was estimated fluid intake and output. We sought to determine whether cumulative intake minus output (I-O) at the start of weaning predicted weaning duration and whether cumulative I-O at extubation predicted extubation failure. Design: Prospective observational study. Setting: Ten pediatric intensive care units. Patients: Cumulative I-O was recorded daily for 301 mechanically ventilated children (<18 yrs of age) from November 1999 through April 2001. Interventions: Cumulative I-O was recorded during a study of weaning strategies and extubation failure in which mechanical ventilation of the majority of patients during weaning and extubation was managed according to a protocol that did not include fluid balance indicators. Outcomes were the time to successful removal of ventilatory support and the rate of initial extubation failure. Measurements and Main Results: Relationships between cumulative I-O and outcomes were assessed by means of proportional hazards and logistic regression. The mean cumulative I-O per kilogram of ideal body weight at the start of weaning was 101 mL (sd, 180). Cumulative I-O at the time weaning was initiated did not predict duration of mechanical ventilator weaning. The mean cumulative I-O per kilogram of ideal body weight at extubation was 136 mL (sd, 237). Cumulative I-O at extubation did not predict extubation outcome. There was an association between cumulative I-O at extubation and the duration of weaning in cases not managed by a protocol. Conclusion: Although routinely recorded, cumulative fluid I-O does not appear to have clinical utility in cases managed according to a mechanical ventilator protocol in which tidal volume and oxygenation on minimal levels of ventilator support are systematically tested.

Failure of aggressive therapy to alter outcome in pediatric near-drowning.

Objectives: To identify predictors of outcome in pediatric near-drowning victims, and to measure the effectiveness of therapy in pediatric near-drowning victims by assessing clinical outcome as a function of injury severity at presentation and therapeutic interventions during hospitalization. Design: Retrospective chart review at a tertiary care university associated Childrens Hospital from January 1976 to July 1992 Measurements and Main Results: Initial intensive care unit (ICU) assessment included a Glasgow Coma Score (GCS) and a Pediatric Risk of Mortality (PRISM) Score. Outcome was assessed using a standard scoring system classifying functional abilities at hospital discharge as no functional disability, independent, partially independent, or total dependence on caregivers for function. Forty (49%) of 81 died. Of the survivors, 26 (63%) had no functional disability or were partially dependent at hospital discharge Of the 47 (64%) patients with a GCS ≤ 4 on presentation to the ICU, 37 (79%) died and 10 (21%) were dependent in all areas of function at discharge. Of the 40 (60%) patients who had a PRISM score < 20, 98% either died or were completely dependent at discharge. Of the 49 patients who were asystolic upon arrival to the emergency department (ED), 76% died, and the rest were completely dependent. Logistic regression showed that therapy had no independent effect on outcome when disease severity was accounted for Conclusions: Severity of illness measured by GCS and PRISM score in the ICU can be useful in predicting outcome. For patients cared for in a Pediatric Intensive Care Unit, those with asystole on arrival at the ED had uniformly poor outcome. Currently available therapies do not alter outcome

The Temporal Version of the Pediatric Sepsis Biomarker Risk Model

Background PERSEVERE is a risk model for estimating mortality probability in pediatric septic shock, using five biomarkers measured within 24 hours of clinical presentation. Objective Here, we derive and test a temporal version of PERSEVERE (tPERSEVERE) that considers biomarker values at the first and third day following presentation to estimate the probability of a “complicated course”, defined as persistence of ≥2 organ failures at seven days after meeting criteria for septic shock, or death within 28 days. Methods Biomarkers were measured in the derivation cohort (n = 225) using serum samples obtained during days 1 and 3 of septic shock. Classification and Regression Tree (CART) analysis was used to derive a model to estimate the risk of a complicated course. The derived model was validated in the test cohort (n = 74), and subsequently updated using the combined derivation and test cohorts. Results A complicated course occurred in 23% of the derivation cohort subjects. The derived model had a sensitivity for a complicated course of 90% (95% CI 78–96), specificity was 70% (62–77), positive predictive value was 47% (37–58), and negative predictive value was 96% (91–99). The area under the receiver operating characteristic curve was 0.85 (0.79–0.90). Similar test characteristics were observed in the test cohort. The updated model had a sensitivity of 91% (81–96), a specificity of 70% (64–76), a positive predictive value of 47% (39–56), and a negative predictive value of 96% (92–99). Conclusions tPERSEVERE reasonably estimates the probability of a complicated course in children with septic shock. tPERSEVERE could potentially serve as an adjunct to physiological assessments for monitoring how risk for poor outcomes changes during early interventions in pediatric septic shock.

Factors predicting prolonged hospital stay for infants with bronchiolitis.

BACKGROUND Prior prediction models for length of stay (LOS) in bronchiolitis have focused more on birth- and disease-related risk factors than on early hospital course factors, particularly common clinical markers including respiratory status and caloric intake. OBJECTIVES 1) Study the associations of various clinical markers and LOS; and 2) develop a LOS prediction model. DESIGN Retrospective cohort study. SETTING Childrens Hospital of Wisconsin. PATIENTS Inclusion criteria were: age < 365 days old; admission between November 1, 2004 and April 15, 2005; final diagnosis of bronchiolitis; placement on the bronchiolitis treatment protocol; and lack of concurrent condition impacting LOS. RESULTS During the study period, 272/347 infants admitted with bronchiolitis met inclusion criteria. On hospital day 2, infants in the prolonged LOS group (≥ 108 hours) had a significantly greater number of hours on supplemental oxygen, maximum supplemental oxygen use, minimum supplemental oxygen use, maximum respiratory rate, mean respiratory score, and number of times suctioned. They had significantly lower minimum oxygen saturation and caloric intake. Recursive partitioning demonstrated five variables (hours of supplemental oxygen, maximum respiratory rate, minimum supplemental oxygen use, gestation, and caloric intake) to predict short or prolonged LOS with an area under the receiver-operator characteristic curve of 0.89/0.72 in the learning/test trees; sensitivity, 0.85; and specificity, 0.82. CONCLUSIONS There are important differences between infants with bronchiolitis having short and prolonged hospital stays, including several clinical markers identifiable on hospital day 2. This model may be a useful prediction tool for targeting early interventions for high-risk infants.

Control and variability of gastric pH in critically ill children

To determine the effect of illness severity and acute central nervous system injury on the control and variability of gastric pH in pediatric intensive care unit (ICU) patients receiving ranitidine. Design:Prospective, descriptive study. Setting:Pediatric ICU of a childrens hospital. Patients:Fourteen pediatric ICU patients. Interventions:Ranitidine (4 mg/kg/day) was administered to all patients. Measurements and Main Results:Patients enrolled in the study were divided into two groups based on illness type and severity. Illness severity was measured by the Pediatric Risk of Mortality (PRISM) score, with a PRISM score of >20 defining severe illness. Illness type was designated as central nervous system or noncentral nervous system. Gastric pH was continuously monitored in all patients using an intragastric, pH-sensitive electrode. Poor control of gastric pH was defined as a pH of <4.0 for >20% of the time monitored. The statistical significance of the differences between groups was measured using the Wilcoxon two-sample test or Fishers exact test. Patients with severe illness or acute central nervous system injury had a lower mean gastric pH than all other patients (4.6 vs. 6.4;p = .008) and spent more time with a gastric pH of <4.0 than other patients (47.5% of time monitored vs. 12.5% of time monitored; p = .003). Poor control of gastric pH occurred in 100% of patients with severe illness or acute central nervous system injury, while only 20% of the remaining patients had poor control of gastric pH (p = .01). Using power-spectrum analysis to evaluate gastric pH variability, gastric pH in patients receiving bolus ranitidine was more variable than gastric pH in patients receiving ranitidine continuously (p = .045). Illness severity or type had no effect on gastric pH variability (p = .78). Conclusions:a) Continuous infusion of ranitidine decreases variability of gastric pH in pediatric ICU patients; b) gastric pH variability may make intermittent monitoring of gastric pH inaccurate; c) children with acute central nervous system injury or PRISM scores of ≥20 have poor control of gastric pH; d) type of injury and PRISM scores predict response to ranitidine therapy. (Crit Care Med 1993; 21:1850–1855)

Combining Prognostic and Predictive Enrichment Strategies to Identify Children with Septic Shock Responsive to Corticosteroids

Objectives:Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids. Design:We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype. Measurements and Main Results:Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01–0.54; p = 0.007). Conclusions:A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.