Racial/Ethnic Minority Children With Cancer Experience Higher Mortality on Admission to the ICU in the United States.

OBJECTIVE: We investigated whether differences in survival exist between children of various racial/ethnic groups with cancer admitted to the PICU. DESIGN: A retrospective multicenter analysis was conducted using Virtual Pediatric Systems data from reporting centers. Demographic information, Pediatric Risk for Mortality III score, and outcome variables were analyzed using mixed-effects logistic regression modeling to assess for differences in mortality. SETTING: One hundred thirty-five PICUs in the United States. PATIENTS: Pediatric patients with cancer admitted to PICUs in the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study details the analysis of 23,128 PICU admissions of 12,232 unique oncology patients representing 3% of all PICU admissions with 1,610 deaths (7.0% case fatality). African American (8.5%) and Hispanic children (8.1%) had significantly higher mortality (p < 0.05) compared with Caucasian children (6.3%). Regional analysis showed Hispanic patients to have higher mortality in the West in the United States, whereas African American patients in the South in the United States had higher mortality. A pulmonary disease diagnosis in Hispanics increased odds of mortality (odds ratio, 1.39; 95% CI, 1.13-1.70), whereas a diagnosis of shock/sepsis increased risk for mortality in African Americans (odds ratio, 1.56; 95% CI, 1.11-2.20) compared with Caucasians. There were no differences between races/ethnic groups in the rates of limitations of care. After controlling for Pediatric Risk of Mortality III, PICU length of stay, stem cell transplant status, readmissions, cancer type (solid, brain, hematologic), mechanical ventilation days, and sex, Hispanic (odds ratio, 1.24; 95% CI, 1.05-1.47) and African Americans (odds ratio, 1.37; 95% CI, 1.14-1.66) had significantly higher odds of mortality compared with Caucasians. CONCLUSIONS: The results show that after controlling for severity and cancer type, a child's race, ethnicity, and region of presentation influence mortality in the PICU. This suggests that additional investigation is warranted along with a need to rethink our approach to the evaluation and treatment of critically ill African American and Hispanic children with cancer.

Hemoglobin Levels Across the Pediatric Critical Care Spectrum: A Point Prevalence Study.

OBJECTIVES: To determine the prevailing hemoglobin levels in PICU patients, and any potential correlates. DESIGN: Post hoc analysis of prospective multicenter observational data. SETTINGS: Fifty-nine PICUs in seven countries. PATIENTS: PICU patients on four specific days in 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients' hemoglobin and other clinical and institutional data. Two thousand three hundred eighty-nine patients with median age of 1.9 years (interquartile range, 0.3-9.8 yr), weight 11.5 kg (interquartile range, 5.4-29.6 kg), and preceding PICU stay of 4.0 days (interquartile range, 1.0-13.0 d). Their median hemoglobin was 11.0 g/dL (interquartile range, 9.6-12.5 g/dL). The prevalence of transfusion in the 24 hours preceding data collection was 14.2%. Neonates had the highest hemoglobin at 13.1 g/dL (interquartile range, 11.2-15.0 g/dL) compared with other age groups (p < 0.001). The percentage of 31.3 of the patients had hemoglobin of greater than or equal to 12 g/dL, and 1.1% had hemoglobin of less than 7 g/dL. Blacks had lower median hemoglobin (10.5; interquartile range, 9.3-12.1 g/dL) compared with whites (median, 11.1; interquartile range, 9.0-12.6; p < 0.001). Patients in Spain and Portugal had the highest median hemoglobin (11.4; interquartile range, 10.0-12.6) compared with other regions outside of the United States (p < 0.001), and the highest proportion (31.3%) of transfused patients compared with all regions (p < 0.001). Patients in cardiac PICUs had higher median hemoglobin than those in mixed PICUs or noncardiac PICUs (12.3, 11.0, and 10.6 g/dL, respectively; p < 0.001). Cyanotic heart disease patients had the highest median hemoglobin (12.6 g/dL; interquartile range, 11.1-14.5). Multivariable regression analysis within diagnosis groups revealed that hemoglobin levels were significantly associated with the geographic location and history of complex cardiac disease in most of the models. In children with cancer, none of the variables tested correlated with patients' hemoglobin levels. CONCLUSIONS: Patients' hemoglobin levels correlated with demographics like age, race, geographic location, and cardiac disease, but none found in cancer patients. Future investigations should account for the effects of these variables.

Multicenter Analysis of the Factors Associated With Unplanned Extubation in the PICU.

OBJECTIVE: To identify factors associated with unplanned extubation in PICUs. DESIGN: A prospective, case-controlled multicenter study. SETTING: Eleven Pediatric Intensive Care Units collaborating through the National Association of Children's Hospitals and Related Institutions PICU focus group. PATIENTS: Patients with unplanned extubation events and control patients without unplanned extubation. INTERVENTIONS: Unplanned extubation events were prospectively tracked for 1 year at 11 centers. When an unplanned extubation occurred, up to four controls were randomly identified of other intubated patients in the unit. For each event and control, data associated with unplanned extubation events, reintubation, and outcomes were collected. MEASUREMENTS AND MAIN RESULTS: One hundred eighty-nine unplanned extubation events occurred out of 25,500 endotracheal tube days in the study (0.74 unplanned extubations/100 endotracheal days; 95% CI, 0.64-0.85), with 654 associated controls. Unplanned extubation rates ranged by site from 0.3 to 2.1 unplanned extubations/100 endotracheal days. Children less than 6 years had an increased rate of unplanned extubation (0.83 for < 6 yr vs 0.45 for ≥ 6 yr; p = 0.001). After multivariate analysis, inadequate patient sedation (odds ratio, 9.1; 95% CI, 4.5-18.5), loose or slimy endotracheal tube (odds ratio, 10.4; 95% CI, 5.0-22.2), a planned extubation in the next 12 hours (odds ratio, 2.3; 95% CI, 1.3-4.1), and a nurse pulled from another unit (odds ratio, 3.8; 95% CI, 1.4-9.9) were associated with unplanned extubation. Sixty percent of unplanned extubations required reintubation. CONCLUSIONS: The rate of unplanned extubation is higher in patients aged less than 6 years. Patient factors, such as decreased level of sedation, loose or slimy endotracheal tube, and staffing factors such as floating nurse from another unit, contribute to unplanned extubation in children.

The safety of propofol sedation for elective nonintubated esophagogastroduodenoscopy in pediatric patients.

OBJECTIVES: To evaluate the safety of deep sedation provided by pediatric intensivists for elective nonintubated esophagogastroduodenoscopy. DESIGN: Retrospective observational study. SETTING: The sedation program at the Helen DeVos Children's Hospital. PATIENTS: A 4-year retrospective analysis was done on all outpatient elective pediatric esophagogastroduodenoscopy procedures performed in an intensivist run sedation program. Safety was examined by reviewing the occurrence of minor and major adverse effects during esophagogastroduodenoscopy sedation. Interventions were studied and reported. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 12,447 sedations were performed by the pediatric sedation program for various procedures. Two thousand one hundred forty-seven patients received 2,325 sedations (18.6%) for esophagogastroduodenoscopies performed for various indications. During the same time period, 53 (one for every 40 esophagogastroduodenoscopy sedations) were screened, found unsuitable for nonintubated sedation, and referred for general anesthesia. There were 2,254 sedations with propofol, 65 methohexital, five ketamine, and one fentanyl/midazolam sedation. Propofol sedation proved safe with a 2.1% prevalence of minor adverse events and no major events. Methohexital, on the other hand, had higher rate (p < 0.001) of minor events and one patient developed an anaphylactic reaction to its use. Regression analysis showed that other sedative agents were 8.6 times more likely to be associated with complications than propofol (odds ratio, 8.6; 95% CI, 4.1-18.2; p < 0.001). CONCLUSIONS: This study demonstrates that deep sedation for elective esophagogastroduodenoscopies can be provided safely in the appropriately screened patient by nonanesthesiologist physicians in a sedation program. These data suggest that propofol is a safe and effective agent for esophagogastroduodenoscopy sedation.

Cost and safety of pediatric intensive care physician-placed broviac catheters.

OBJECTIVE: To compare the cost and safety of placement of Broviac catheters in children by pediatric intensivists in a sedation suite versus placement by pediatric surgeons in the operating room. DESIGN: Single-center retrospective analysis. SETTING: Pediatric sedation suite and operating rooms in a tertiary care children's hospital. PATIENTS: All pediatric patients with Broviac catheters placed (n = 253) at this institution over a 3-year period from 2007 to 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We reviewed the charts of all pediatric patients with Broviac catheters placed, either by intensivists or surgeons, and compared cost and outcomes. Procedure safety was assessed and categorized into immediate, short-term (within 2 wk of procedure), and long-term outcomes. Anesthetic safety and billing data for the procedure were also collected. Among similar patient populations, immediate complications, such as pneumothorax, procedure failure (p > 0.999), and anesthetic complications (p = 0.60), were not significantly different. Short-term outcomes, including infection (p = 0.27) and catheter malfunction (p > 0.999), were not different. Long-term outcomes, including mean indwelling catheter days (p = 0.60) and removal due to catheter infection (p = 0.09), were not different between the groups. Overall cost of the procedure was significantly different: $7,031 (± $784) when performed by surgeons and $3,565 (± $311) when performed by intensivists (p < 0.001). CONCLUSIONS: Pediatric critical care physicians can place Broviac catheters as safely as pediatric surgeons and at a lower cost in a defined patient population.

Nitric oxide-endothelin-1 interactions after surgically induced acute increases in pulmonary blood flow in intact lambs.

Several congenital heart defects require surgery that acutely increases pulmonary blood flow (PBF). This can lead to dynamic alterations in postoperative pulmonary vascular resistance (PVR) and can contribute to morbidity and mortality. Thus the objective of this study was to determine the role of nitric oxide (NO), endothelin (ET)-1, and their interactions in the alterations of PVR after surgically induced increases in PBF. Twenty lambs underwent placement of an aortopulmonary vascular graft. Lambs were instrumented to measure vascular pressures and PBF and studied for 4 h. Before and after shunt opening, lambs received an infusion of saline (n = 9), tezosentan, an ETA- and ETB -receptor antagonist (n = 6), or Nomega-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor (n = 5). In control lambs, shunt opening increased PBF by 117.8% and decreased PVR by 40.7% (P < 0.05) by 15 min, without further changes thereafter. Plasma ET-1 levels increased 17.6% (P < 0.05), and total NOS activity decreased 61.1% (P < 0.05) at 4 h. ET-receptor blockade (tezosentan) prevented the plateau of PBF and PVR, such that PBF was increased and PVR was decreased compared with controls at 3 and 4 h (P < 0.05). These changes were associated with an increase in total NOS activity (+61.4%; P < 0.05) at 4 h. NOS inhibition (L-NNA) after shunt placement prevented the sustained decrease in PVR seen in control lambs. In these lambs, PVR decreased by 15 min (P < 0.05) but returned to baseline by 2 h. Together, these data suggest that surgically induced increases in PBF are limited by vasoconstriction, at least in part by an ET-receptor-mediated decrease in lung NOS activity. Thus NO appears to be important in maintaining a reduction in PVR after acutely increased PBF.

Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension.

Clinically significant increases in pulmonary vascular resistance (PVR) have been noted upon acute withdrawal of inhaled nitric oxide (iNO). Previous studies in the normal pulmonary circulation demonstrate that iNO increases endothelin-1 (ET-1) levels and decreases endogenous nitric oxide synthase (NOS) activity, implicating an endothelial etiology for the increase in resistance upon iNO withdrawal. However, the effect of iNO on endogenous endothelial function in the clinically relevant pulmonary hypertensive circulation is unknown. The objective of this study was to determine the effects of iNO on endogenous NO-cGMP and ET-1 signaling in lambs with preexisting pulmonary hypertension secondary to increased pulmonary blood flow. Eight fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt lambs). After delivery (4 wk), the shunt lambs were mechanically ventilated with iNO (40 ppm) for 24 h. After 24 h of inhaled NO, plasma ET-1 levels increased by 34.8% independently of changes in protein levels (P < 0.05). Contrary to findings in normal lambs, total NOS activity did not decrease during iNO. In fact, Western blot analysis demonstrated that tissue endothelial NOS protein levels decreased by 43% such that NOS activity relative to protein levels actually increased during iNO (P < 0.05). In addition, the beta-subunit of soluble guanylate cyclase decreased by 70%, whereas phosphodiesterase 5 levels were unchanged (P < 0.05). Withdrawal of iNO was associated with an acute increase in PVR, which exceeded baseline PVR by 45%, and a decrease in cGMP concentrations to levels that were below baseline. These data suggest that the endothelial response to iNO and the potential mechanisms of rebound pulmonary hypertension are dependent upon the underlying pulmonary vasculature.

Tezosentan, a combined parenteral endothelin receptor antagonist, produces pulmonary vasodilation in lambs with acute and chronic pulmonary hypertension.

OBJECTIVE: To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension. DESIGN: Prospective, randomized experimental study. SETTING: University-based research laboratory. SUBJECTS: Lambs with and without pulmonary hypertension. INTERVENTIONS: Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age. MEASUREMENTS AND MAIN RESULTS: At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% +/- 4.7 to 16.0% +/- 10.7; p < .05) and pulmonary vascular resistance (from 6.2% +/- 8.0 to 21% +/- 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation. CONCLUSIONS: Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted approximately 5-10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.

Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow.

BACKGROUND: Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. METHODS AND RESULTS: Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. CONCLUSIONS: Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Nitric oxide-endothelin-1 interactions after acute ductal constriction in fetal lambs.

Acute partial compression of the fetal ductus arteriosus (DA) results in an initial increase in pulmonary blood flow (PBF) that is followed by acute vasoconstriction. The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA. Twelve late-gestation fetal lambs (132-140 days) were instrumented to measure vascular pressures and left PBF. After a 24-h recovery period, acute constriction of the DA was performed by partially inflating a vascular occluder, and the hemodynamic variables were observed for 4 h. In control lambs (n = 7), acute ductal constriction initially increased PBF by 627% (P < 0.05). However, this was followed by active vasoconstriction, such that PBF was restored to preconstriction values by 4 h. This was associated with a 43% decrease in total NO synthase (NOS) activity (P < 0.05) and a 106% increase in plasma ET-1 levels (P < 0.05). Western blot analysis demonstrated no changes in lung tissue endothelial NOS, preproET-1, endothelin-converting enzyme-1, or ET(B) receptor protein levels. The infusion of PD-156707 (an ET(A) receptor antagonist, n = 5) completely blocked the vasoconstriction and preserved NOS activity. These data suggest that the fetal pulmonary vasoconstriction after acute constriction of the DA is mediated by NO-ET-1 interactions. These include an increase in ET(A) receptor-mediated vasoconstriction and an ET(A) receptor-mediated decrease in NOS activity. The mechanisms of these NO-ET-1 interactions, and their role in mediating acute changes in PBF, warrant further studies.