John S. Giuliano

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.

Admission Angiopoietin Levels in Children with Septic Shock

Angiopoietin (angpt) 1 and angpt-2 are circulating proteins first ascribed opposing roles in embryonic angiogenesis. Both bind the tyrosine kinase with immunoglobulin-like loop and epidermal growth factor homology domains (Tie) 2 receptor on endothelial cells, but angpt-1 is a Tie-2 agonist, whereas angpt-2 antagonizes Tie-2 signaling. In the developed vasculature, angpt-1 protects against vascular leak, whereas angpt-2 promotes increased vascular permeability. Because alterations in vascular permeability are common in septic shock, we obtained plasma from critically ill children within 24 h of diagnosis of the systemic inflammatory response syndrome (SIRS, n = 20), sepsis (n = 20), or septic shock (n = 61), as well as 15 healthy controls. Plasma levels of angpt-1 and angpt-2 were measured via a commercially available enzyme-linked immunosorbent assay. Plasma angpt-2 levels were significantly elevated in children with septic shock when compared with healthy children, as well as critically ill children with either SIRS or sepsis, and circulating angpt-2 levels seemed to correlate with disease severity and outcome. In addition, plasma angpt-1 levels were significantly decreased in critically ill children with septic shock compared with critically ill children with either SIRS or sepsis. Given the contrasting effects of angpt-2 and angpt-1 on the vascular endothelium, these two factors may play an important role in the pathophysiology of septic shock in children, and further studies are warranted.

Level of Trainee and Tracheal Intubation Outcomes

BACKGROUND: Tracheal intubation is an important intervention to stabilize critically ill and injured children. Provider training level has been associated with procedural safety and outcomes in the neonatal intensive care settings. We hypothesized that tracheal intubation success and adverse tracheal intubation–associated events are correlated with provider training level in the PICU. METHODS: A prospective multicenter observational cohort study was performed across 15 PICUs to evaluate tracheal intubation between July 2010 to December 2011. All data were collected by using a standard National Emergency Airway Registry for Children reporting system endorsed as a Quality Improvement project of the Pediatric Acute Lung Injury and Sepsis Investigator network. Outcome measures included first attempt success, overall success, and adverse tracheal intubation–associated events. RESULTS: Reported were 1265 primary oral intubation encounters by pediatric providers. First and overall attempt success were residents (37%, 51%), fellows (70%, 89%), and attending physicians (72%, 94%). After adjustment for relevant patient factors, fellow provider was associated with a higher rate of first attempt success (odds ratio [OR], 4.29; 95% confidence interval [CI], 3.24–5.68) and overall success (OR, 9.27; 95% CI, 6.56–13.1) compared with residents. Fellow (versus resident) as first airway provider was associated with fewer tracheal intubation associated events (OR, 0.42; 95% CI, 0.31–0.57). CONCLUSIONS: Across a broad spectrum of PICUs, resident provider tracheal intubation success is low and adverse associated events are high, compared with fellows. More intensive pediatric resident procedural training is necessary before “live” tracheal intubations in the intensive care setting.

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.

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.

Use of procalcitonin for the prediction and treatment of acute bacterial infection in children.

Purpose of review Procalcitonin (PCT) is increasingly utilized to determine the presence of infection or to guide antibiotic therapy. This review will highlight the diagnostic and prognostic utility of serum PCT in children. Recent findings Recent studies endorse the use of serum PCT to detect invasive infection, to differentiate sepsis from noninfectious systemic inflammatory response syndrome, and to guide antibiotic therapy. Typical values for maximal sensitivity and specificity are less than 0.5 ng/ml for noninfectious inflammation and greater than 2.0 ng/ml for bacterial sepsis. PCT appears to be a reliable indicator of infection. PCT has performed better than C-reactive protein in some settings, though pediatric comparative data are lacking. PCT may aid in diagnosing infection in challenging patient populations such as those with sickle cell disease, congenital heart defects, neutropenia, and indwelling central venous catheters. Antibiotic therapy tailored to serial PCT measurements may shorten the antibiotic exposure without increasing treatment failure. Summary PCT is a reliable serum marker for determining the presence or absence of invasive bacterial infection and response to antibiotic therapy. Tailoring antibiotics to PCT levels may reduce the duration of therapy without increasing treatment failure, but more research is needed in children.

The Role Of Endogenously Produced Extracellular Hsp72 In Mononuclear Cell Reprogramming

Intracellular heat shock protein 72 (Hsp72) is known to serve a broad cytoprotective role. Recent data indicate that stressed cells can release Hsp72 into the extracellular compartment, although the biological function of extracellular Hsp72 remains to be fully elucidated. Because extracellular Hsp72 has been demonstrated to interact with Toll-like receptor 4, we hypothesized that endogenously produced and released Hsp72 would reprogram the mononuclear cell responses to LPS. THP-1 cells treated with LPS were used as a model for nuclear factor (NF)-&kgr;B activation. Heat shock conditions consisted of incubation at 43°C for 1 h. Control cells were incubated at 37°C. Twenty four hours after incubation, heat shock conditioned media (HSCM) and control media (CM) were centrifuged, and the respective cells were discarded. A separate group of naive THP-1 cells were then incubated with either HSCM or CM for 18 h and then stimulated with LPS (1 &mgr;g/mL). Heat shock significantly increased Hsp72 in HSCM compared with CM. In THP-1 cells transfected with an NF-&kgr;B luciferase reporter plasmid, the addition of HSCM attenuated subsequent LPS-mediated luciferase activity compared with cells incubated in CM. The addition of HSCM also attenuated LPS-mediated NF-&kgr;B-DNA binding and I&kgr;B&agr; degradation. Heat shock protein 72-mediated inhibition of NF-&kgr;B activation was further corroborated by a significant decrease in TNF-&agr; production. When HSCM and CM were subjected to Hsp72 depletion via adenosine triphosphate-agarose binding, LPS-mediated activation of NF-&kgr;B was partially restored, suggesting that Hsp72 is partially responsible for cellular reprogramming in response to HSCM. These data demonstrate that endogenously produced and released extracellular Hsp72 has the ability to reprogram the in vitro response to endotoxin in cultured human mononuclear cells.

The temporal kinetics of circulating angiopoietin levels in children with sepsis.

Objective: Capillary integrity continues to challenge critical care physicians worldwide when treating children with sepsis. Vascular growth factors, specifically angiopoietin-1 and angiopoietin-2, play opposing roles in capillary stabilization in patients with sepsis. We aim to determine whether pediatric patients with severe sepsis/shock have persistently high angiopoietin-2/1 ratios when compared with nonseptic PICU patients over a 7-day period. Design: Prospective observational study. Patients were classified within 24 hours of admission into non–systemic inflammatory response syndrome, systemic inflammatory response syndrome/sepsis, or severe sepsis/shock. Plasma levels of angiopoietin-1 and angiopoietin-2 were measured via enzyme-linked immunosorbent assay. The angiopoietin-2/1 ratio was graphically plotted and determined whether patients fell into “constant” or “variable” patterns. Setting: Tertiary care center PICU. Patients: Critically ill pediatric patients with varying sepsis severity. Interventions: None. Measurements and Main Results: Forty-five patients were enrolled (nine non–systemic inflammatory response syndrome, 19 systemic inflammatory response syndrome/sepsis, and 17 severe sepsis/shock). Gender, age, weight, comorbidities, and PICU length of stay were not significantly different between the groups. Admission pediatric risk stratification scores and net fluid ins/outs were significantly elevated in the severe sepsis/shock group when compared (all p < 0.05). Admission angiopoietin-2 levels and angiopoietin-2/1 ratios were significantly different in the severe sepsis/shock group when all groups were compared (both p < 0.05). Additionally, the latter were significantly elevated in the severe sepsis/shock group at multiple time points (all p ⩽ 0.05) with the peak occurring on day 2 of illness. In a separate analysis, 32% of systemic inflammatory response syndrome/sepsis and 82% of severe sepsis/shock had variable angiopoietin-2/1 ratio patterns compared with none in the control group (p < 0.001). Conclusions: Pediatric patients with severe sepsis and septic shock possess significantly elevated angiopoietin-2/1 ratios during their first 3 days of illness, which peak at day 2 of illness. A subset of these patients demonstrated variable angiopoietin-2/1 ratio patterns.

Development of a Quality Improvement Bundle to Reduce Tracheal Intubation–Associated Events in Pediatric ICUs

Advanced airway management in the pediatric intensive care unit (PICU) is hazardous, with associated adverse outcomes. This report describes a methodology to develop a bundle to improve quality and safety of tracheal intubations. A prospective observational cohort study was performed with expert consensus opinion of 1715 children undergoing tracheal intubation at 15 PICUs. Baseline process and outcomes data in tracheal intubation were collected using the National Emergency Airway Registry for Children reporting system. Univariate analysis was performed to identify risk factors associated with adverse tracheal intubation–associated events. A multidisciplinary quality improvement committee was formed. Workflow analysis of tracheal intubation and pilot testing were performed to develop the Airway Bundle Checklist with 4 parts: (1) risk factor assessment, (2) plan generation, (3) preprocedure time-out to ensure that providers, equipment, and plans are prepared, (4) postprocedure huddle to identify improvement opportunities. The Airway Bundle Checklist developed may lead to improvement in airway management.

Transport Disposition Using the Transport Risk Assessment in Pediatrics (TRAP) Score

Abstract Background. Determining appropriate disposition for referred pediatric patients is difficult, since it relies primarily on a telephone description of the patient. In this study, we evaluate the Transport Risk Assessment in Pediatrics (TRAP) scores ability to assist in appropriate placement of these patients. This novel tool is derived from physiologic variables. Objectives. To determine the feasibility of calculating a TRAP score and whether a higher score correlates with pediatric intensive care unit (PICU) admission. Methods. We performed an observational study of pediatric patients transported by a specialized team to a tertiary care center and the feasibility of implementing the TRAP tool. Patients were eligible if transported by the pediatric specialty transport team for direct admission to the childrens hospital. The TRAP score was obtained either through chart review of the transport teams initial assessment or in real time by the transport team. Results. A total of 269 patients were identified, with 238 patients included in the study. Using logistic regression, higher TRAP scores were associated with PICU admission (odds ratio [OR] 1.40, p < 0.001). Patients with a higher score were also less likely to leave the PICU within 24 hours (OR 0.79, p < 0.001). Conclusion. The TRAP score is a novel objective pediatric transport assessment tool where an elevated score is associated with PICU admission for more than 24 hours. This score may assist with the triage decisions for transported pediatric patients.