Athena F. Zuppa

The effect of a thyroid hormone infusion on vasopressor support in critically ill children with cessation of neurologic function

Objective:To determine the impact of a thyroid hormone infusion (T4) on the vasopressor requirements in children with cessation of neurologic function (i.e., brain death) during evaluation for organ recovery Design:Retrospective cohort study. Setting:The 1998–2002 database of a regional organ recovery program. Patients:Children ≤18 yrs with cessation of neurologic function during evaluation for organ recovery (n = 171) were included. The treated group (n = 91) received a weight-based bolus and continuous infusion of T4 according to the organ procurement agency protocol. All other children (n = 80) were considered untreated. Interventions:T4 was administered at the clinician’s discretion. All children (treated and untreated) had identical goals for fluids, blood pressure, and organ function criteria. Vasopressor score ([dopamine × 1] + [dobutamine × 1] + [epinephrine × 100] + [norepinephrine × 100] + [phenylephrine × 100]) at the time of the program’s involvement (T0) and at organ recovery (TOR) were recorded. The Wilcoxon rank sum and Student’s two-sample t-test were used to compare the average vasopressor score at T0 vs. TOR. The Wilcoxon signed rank test was used to analyze the difference in median vasopressor score at T0 vs. TOR. Multivariable linear regression was used to assess the impact of T4 on the ability to wean vasopressor support while accounting for the effects of several potential confounders. Measurements and Main Results:One hundred seventy-one subjects were included in the final analysis. T4 administration was associated with an unadjusted decrease in the vasopressor score of 32 (95% confidence interval, 12–53; p = .002). After adjusting for steroid administration, fluid balance, and baseline vasopressor score, T4 administration was associated with a decrease in vasopressor score of 24 (95% confidence interval, 6–43; p = .011). Conclusions:T4 reduced vasopressor needs in children with cessation of neurologic function and hemodynamic instability. A prospective study of T4 in critically ill and hemodynamically unstable children appears warranted.

Critical care for pediatric asthma: Wide care variability and challenges for study

Objectives: To describe pediatric severe asthma care, complications, and outcomes to plan for future prospective studies by the Collaborative Pediatric Critical Care Research Network. Design: Retrospective cohort study. Setting: Pediatric intensive care units in the United States that submit administrative data to the Pediatric Health Information System. Patients: Children 1–18 yrs old treated in a Pediatric Health Information System pediatric intensive care unit for asthma during 2004-2008. Interventions: None. Measurements and Main Results: Thirteen-thousand five-hundred fifty-two children were studied; 2,812 (21%) were treated in a Collaborative Pediatric Critical Care Research Network and 10,740 (79%) were treated in a non-Collaborative Pediatric Critical Care Research Network pediatric intensive care unit. Medication use in individual Collaborative Pediatric Critical Care Research Network centers differed widely: ipratropium bromide (41%–84%), terbutaline (11%–74%), magnesium sulfate (23%–64%), and methylxanthines (0%–46%). Complications including pneumothorax (0%–0.6%), cardiac arrest (0.2%–2%), and aspiration (0.2%–2%) were rare. Overall use of medical therapies and complications at Collaborative Pediatric Critical Care Research Network centers were representative of pediatric asthma care at non-Collaborative Pediatric Critical Care Research Network pediatric intensive care units. Median length of pediatric intensive care unit stay at Collaborative Pediatric Critical Care Research Network centers was 1 to 2 days and death was rare (0.1%–3%). Ten percent of children treated at Collaborative Pediatric Critical Care Research Network centers received invasive mechanical ventilation compared to 12% at non-Collaborative Pediatric Critical Care Research Network centers. Overall 44% of patients who received invasive mechanical ventilation were intubated in the pediatric intensive care unit. Children intubated outside the pediatric intensive care unit had significantly shorter median ventilation days (1 vs. 3), pediatric intensive care unit days (2 vs. 4), and hospital days (4 vs. 7) compared to those intubated in the pediatric intensive care unit. Among children who received mechanical respiratory support, significantly more (41% vs. 25%) were treated with noninvasive ventilation and significantly fewer (41% vs. 58%) were intubated before pediatric intensive care unit care when treated in a Pediatric Health Information System hospital emergency department. Conclusions: Marked variations in medication therapies and mechanical support exist. Death and other complications were rare. More than half of patients treated with mechanical ventilation were intubated before pediatric intensive care unit care. Site of respiratory mechanical support initiation was associated with length of stay.

Population pharmacokinetics of dexmedetomidine in infants after open heart surgery.

BACKGROUND: Dexmedetomidine is a highly selective &agr;2-agonist with hypnotic, analgesic, and anxiolytic properties. In adults, it provides sedation while preserving respiratory function facilitating extubation. Only limited pharmacokinetic data are available for pediatric patients. The primary aim of this study was to determine the pharmacokinetics of dexmedetomidine in infants after open heart surgery. METHODS: We evaluated 36 infants, aged 1 to 24 months, after open heart surgery. Cohorts of 12 infants requiring mechanical ventilation after open heart surgery were enrolled sequentially to 1 of the 3 initial loading dose—continuous IV infusion (CIVI) regimens: 0.35–0.25, 0.7–0.5, or 1–0.75 &mgr;g/kg-&mgr;g/kg/h. The initial loading dose was administered over 10 minutes immediately postoperatively followed by a CIVI of up to 24 hours. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. RESULTS: Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight on drug clearance, intercompartmental clearance, central and peripheral volume of distributions, total bypass time as a covariate on clearance and central volume of distribution, and age and ventricular physiology as covariates on clearance. Infants demonstrated a clearance of 28.1 mL/min/kg0.75, intercompartmental clearance of 93.4 mL/min/kg0.75, central volume of distribution of 1.2 L/kg, and peripheral volume of distribution of 1.5 L/kg. CONCLUSIONS: Dexmedetomidine clearance increased with weight, age, and single-ventricle physiology, whereas total bypass time was associated with a trend toward decreasing clearance, and central volume of distribution increased as a function of total bypass time. The dependence of clearance on body weight supports current practice of weight-based dexmedetomidine dosing, whereas the clinical impact of the remaining covariate effects requires further investigation. Initial loading doses in the range of 0.35 to 1 &mgr;g/kg over 10 minutes and CIVI of 0.25 to 0.75 &mgr;g/kg/h were well tolerated in this infant population.

Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction

We performed a blinded, randomized pharmacokinetic study of milrinone in 16 neonates with hypoplastic left heart undergoing stage I reconstruction to determine the impact of cardiopulmonary bypass and modified ultrafiltration on drug disposition and to define the drug exposure during a continuous IV infusion of drug postoperatively. Neonates received an initial dose of either a 100 or 250 &mgr;g/kg of milrinone into the cardiopulmonary bypass circuit at the start of rewarming. Postoperatively, milrinone was infused to clinical needs. A mixed-effect modeling approach was used to characterize milrinone pharmacokinetics during cardiopulmonary bypass, modified ultrafiltration, and postoperatively using the NONMEM algorithm. All patients in this study demonstrated a modified ultrafiltration concentrating effect that occurred despite a modified ultrafiltration drug clearance of 3.3 mL · kg−1 · min−1. The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 &mgr;g · kg−1 · min−1 resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL · kg−1 · min−1), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL · kg−1 · min−1) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 &mgr;g · kg−1 · min−1 should be considered.

Fatal and Near-Fatal Asthma in Children: The Critical Care Perspective

OBJECTIVE To characterize the clinical course, therapies, and outcomes of children with fatal and near-fatal asthma admitted to pediatric intensive care units (PICUs). STUDY DESIGN This was a retrospective chart abstraction across the 8 tertiary care PICUs of the Collaborative Pediatric Critical Care Research Network (CPCCRN). Inclusion criteria were children (aged 1-18 years) admitted between 2005 and 2009 (inclusive) for asthma who received ventilation (near-fatal) or died (fatal). Data collected included medications, ventilator strategies, concomitant therapies, demographic information, and risk variables. RESULTS Of the 261 eligible children, 33 (13%) had no previous history of asthma, 218 (84%) survived with no known complications, and 32 (12%) had complications. Eleven (4%) died, 10 of whom had experienced cardiac arrest before admission. Patients intubated outside the PICU had a shorter duration of ventilation (median, 25 hours vs 84 hours; P < .001). African-Americans were disproportionately represented among the intubated children and had a shorter duration of intubation. Barotrauma occurred in 15 children (6%) before admission. Pharmacologic therapy was highly variable, with similar outcomes. CONCLUSION Of the children ventilated in the CPCCRN PICUs, 96% survived to hospital discharge. Most of the children who died experienced cardiac arrest before admission. Intubation outside the PICU was correlated with shorter duration of ventilation. Complications of barotrauma and neuromyopathy were uncommon. Practice patterns varied widely among the CPCCRN sites.

Incidence and Outcomes of Cardiopulmonary Resuscitation in PICUs.

Objectives:To determine the incidence of cardiopulmonary resuscitation in PICUs and subsequent outcomes. Design, Setting, and Patients:Multicenter prospective observational study of children younger than 18 years old randomly selected and intensively followed from PICU admission to hospital discharge in the Collaborative Pediatric Critical Care Research Network December 2011 to April 2013. Results:Among 10,078 children enrolled, 139 (1.4%) received cardiopulmonary resuscitation for more than or equal to 1 minute and/or defibrillation. Of these children, 78% attained return of circulation, 45% survived to hospital discharge, and 89% of survivors had favorable neurologic outcomes. The relative incidence of cardiopulmonary resuscitation events was higher for cardiac patients compared with non-cardiac patients (3.4% vs 0.8%, p <0.001), but survival rate to hospital discharge with favorable neurologic outcome was not statistically different (41% vs 39%, respectively). Shorter duration of cardiopulmonary resuscitation was associated with higher survival rates: 66% (29/44) survived to hospital discharge after 1-3 minutes of cardiopulmonary resuscitation versus 28% (9/32) after more than 30 minutes (p < 0.001). Among survivors, 90% (26/29) had a favorable neurologic outcome after 1-3 minutes versus 89% (8/9) after more than 30 minutes of cardiopulmonary resuscitation. Conclusions:These data establish that contemporary PICU cardiopulmonary resuscitation, including long durations of cardiopulmonary resuscitation, results in high rates of survival-to-hospital discharge (45%) and favorable neurologic outcomes among survivors (89%). Rates of survival with favorable neurologic outcomes were similar among cardiac and noncardiac patients. The rigorous prospective, observational study design avoided the limitations of missing data and potential selection biases inherent in registry and administrative data.

Safety and Population Pharmacokinetic Analysis of Intravenous Acetaminophen in Neonates, Infants, Children, and Adolescents With Pain or Fever

OBJECTIVES The administration of acetaminophen via the oral and rectal routes may be contraindicated in specific clinical settings. Intravenous administration provides an alternative route for fever reduction and analgesia. This phase 1 study of intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, Inc., San Diego, CA) in inpatient pediatric patients with pain or fever requiring intravenous therapy was designed to assess the safety and pharmacokinetics of repeated doses over 48 hours. METHODS Neonates (full-term to 28 days) received either 12.5 mg/kg every 6 hours or 15 mg/kg every 8 hours. Infants (29 days to <2 years), children (2 to <12 years) and adolescents (≥12 years) received either 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours. Both noncompartmental and population nonlinear mixed-effects modeling approaches were used. Urinary metabolite data were analyzed, and safety and tolerability were assessed. RESULTS Pharmacokinetic parameters of acetaminophen were estimated using a two-compartment disposition model with weight allometrically expressed on clearances and central and peripheral volumes of distribution (Vds). Postnatal age, with a maturation function, was a significant covariate on clearance. Total systemic normalized clearance was 18.4 L/hr per 70 kg, with a plateau reached at approximately 2 years. Total central and peripheral Vds of acetaminophen were 16 and 59.5 L/70 kg, respectively. The drug was well tolerated based on the incidence of adverse events. The primary and minor pathways of elimination were acetaminophen glucuronidation, sulfation, and glutathione conjugate metabolites across all age groups. CONCLUSIONS Intravenous acetaminophen in infants, children, and adolescents was well tolerated and achieved plasma concentrations similar to those achieved with labeled 15 mg/kg body weight doses by oral or rectal administration.

Pharmacokinetics and pharmacodynamics in the critically ill child.

An understanding of pharmacokinetics and pharmacodynamics can allow for a rational approach to prescribing medications for critically ill children. Absorption, distribution, metabolism, elimination, and the response to medications are affected by age and disease state. Various medications are used in the care of critically ill children. Many medications are prescribed for children based on dosing guidance from adult studies, however. Care providers must be cautious of the high risk for drug interactions and adverse reactions in the intensive care setting.

Population pharmacokinetics of ketorolac in neonates and young infants.

Although ketorolac is commonly used as an analgesic in the pediatric population, there is no information on the pharmacokinetics of ketorolac available for children less than 6 months of age. The objective of this analysis was to construct a population pharmacokinetic model to describe ketorolac disposition in young children. Three neonates and 9 infants, median (range) age 0.4-32 weeks, were administered with 0.5 mg/kg of ketorolac. The data were best described by a 2-compartment model, with an allometric expression to describe body weight effects on clearance. Estimated parameters were clearance [2.8 mL·min-1·(kg0.75)-1], intercompartmental clearance (11.5 mL/min), volume of distribution of the central compartment (535 mL), and volume of distribution of the peripheral compartment (322 mL). The clearance values in these neonates and younger group of infants are greater than that reported for older children and adults.

Drug Utilization in the Pediatric Intensive Care Unit: Monitoring Prescribing Trends and Establishing Prioritization of Pharmacotherapeutic Evaluation of Critically Ill Children

The primary objective of this study was to characterize the drug exposure for children hospitalized in the authors’ institutions pediatric intensive care unit for the year 2002. Secondary objectives included the examination of drug utilization differences among various age criteria and the suitability of the most prevalent resources for pediatric dosing guidance. Many of the most commonly prescribed agents in the pediatric intensive care unit fall into the broad categories of pain management/sedation and anti‐infectives. Based on the generally narrow windows afforded by each of these drug classes, it is obvious that more, well‐defined investigations in critically ill children are warranted. The existing dosing guidance for many of these agents is neither generalizable nor sufficient to accommodate the diversity in pediatric intensive care unit patients, and the current drug monographs fall short of any practical dosing information.