Janice E. Sullivan

Clinical Report—Fever and Antipyretic Use in Children

Fever in a child is one of the most common clinical symptoms managed by pediatricians and other health care providers and a frequent cause of parental concern. Many parents administer antipyretics even when there is minimal or no fever, because they are concerned that the child must maintain a “normal” temperature. Fever, however, is not the primary illness but is a physiologic mechanism that has beneficial effects in fighting infection. There is no evidence that fever itself worsens the course of an illness or that it causes long-term neurologic complications. Thus, the primary goal of treating the febrile child should be to improve the childs overall comfort rather than focus on the normalization of body temperature. When counseling the parents or caregivers of a febrile child, the general well-being of the child, the importance of monitoring activity, observing for signs of serious illness, encouraging appropriate fluid intake, and the safe storage of antipyretics should be emphasized. Current evidence suggests that there is no substantial difference in the safety and effectiveness of acetaminophen and ibuprofen in the care of a generally healthy child with fever. There is evidence that combining these 2 products is more effective than the use of a single agent alone; however, there are concerns that combined treatment may be more complicated and contribute to the unsafe use of these drugs. Pediatricians should also promote patient safety by advocating for simplified formulations, dosing instructions, and dosing devices.

Population Pharmacokinetics of Fluconazole in Young Infants

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Prevalence of adverse events in pediatric intensive care units in the United States.

Objectives: Selection of relevant patient safety interventions for the pediatric intensive care (PICU) requires identification of the types and severity of adverse events (AEs) and adverse drug events (ADEs) that occur in this setting. The studys objectives were to: 1) determine the rates of AEs/ADEs, including types, severity, and preventability, in PICU patients; 2) identify population characteristics associated with increased risk of AEs/ADEs; 3) develop and test a PICU specific trigger tool to facilitate identification of AEs/ADEs. Design, Setting, Patients: Retrospective, cross-sectional, randomized review of 734 patient records who were discharged from 15 U.S. PICUs between September and December 2005. Intervention: A novel PICU-focused trigger tool for AE/ADE detection. Measurements and Results: Sixty-two percent of PICU patients had at least one AE. A total of 1488 AEs, including 256 ADEs, were identified. This translates to a rate of 28.6 AEs and 4.9 ADEs per 100 patient-days. The most common types of AEs were catheter complications, uncontrolled pain, and endotracheal tube malposition. Ten percent of AEs were classified as life-threatening or permanent; 45% were deemed preventable. Higher adjusted rates of AEs were found in surgical patients (p = .02), patients intubated at some point during their PICU stay (p = .002), and patients who died (p < .001). Surgical patients had higher preventable adjusted AE (p = .01) and ADE rates (p = .02). The adjusted cumulative risk of an AE per PICU day was 5.3% and 1.6% for an ADE alone. There was a 4% increase in adjusted ADEs rates for every year increase in age. Conclusions: AEs and ADEs occur frequently in the PICU setting. These data provide areas of focus for evidence-based prevention strategies to decrease the substantial risk to this vulnerable pediatric population.

Evaluation of a low-dose lidocaine lontophoresis system for topical anesthesia in adults and children: A randomized, controlled trial

BACKGROUND Commonly used classes of topical anesthetics require 30 to 60 minutes to provide effective anesthesia. A new low-dose lidocaine iontophoresis system (LDLIS) may provide topical anesthesia in 10 minutes at a lower dose than previous systems, thereby limiting adverse events. METHODS This was a prospective, randomized, multicenter, double-blind, placebo-controlled, clinical trial. Adults and children aged 5 to 17 years (inclusive) received a 10-minute ionntophoretic treatment with either lidocaine or a saline placebo before venipuncture or venous cannulation. Intensity of pain associated with venipuncture or venous cannulation was assessed using either a 10-cm Visual Analog Scale (VAS) for adults and children aged 12 to 17 years or the Facial Affective Scale (FAS) for all children enrolled. RESULTS Five hundred forty-eight patients (276 adults, 272 children) participated. Mean (SD) VAS pain scores were lower in adults who received iontophoresis with lidocaine rather than with placebo (0.77 [1.49] vs 2.52 [2.30], P < 0.001) and in children aged 12 to 17 years (1.50 [1.87] vs 2.58 [2.26], P = 0.001). FAS pain scores were lower among children who received iontophoresis with lidocaine rather than with placebo (0.36 [0.26] vs 0.51 [0.27], P < 0.001). Similar results were found for children stratified by age group (5-7 years: 0.40 [0.30] vs 0.60 [0.31], P = 0.011; 8-11 years: 0.35 [0.27] vs 0.48 [0.27], P = 0.021; 12-17 years: 0.33 [0.21] vs 0.48 [0.24], P = 0.001). Mean (SD) parental ratings of pain on the FAS for children aged 5 to 11 years were also lower for the lidocaine group (0.45 [0.28] vs 0.55 [0.25], P = 0.018). Adverse events were similar between groups and included skin erythema and edema. One patient in the study experienced a partial-thickness burn. CONCLUSION In this study of adults and children, the LDLIS provided effective topical anesthesia for venipuncture and venous cannulation within 10 minutes.

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.

Cytokines and Toxicity in Acetaminophen Overdose

Several cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme‐linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alanine aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N‐acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity.

Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants

ABSTRACT Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations.

Efficacy, Safety, and Pharmacokinetics of Candesartan Cilexetil in Hypertensive Children Aged 6 to 17 Years

This 4‐week randomized, double blind, placebo‐controlled study (N=240), 1‐year open label trial (N=233), and single‐dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy‐one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8–11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo‐corrected 4.9/3.0–7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6‐ to 12‐ and 12‐ to 17‐year‐olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well‐tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 &mgr;g/mL for 50% of the dose interval and >2 &mgr;g/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148). Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Comparison of end-tidal CO2 and Paco2 in children receiving mechanical ventilation.

Objective To determine whether end-tidal CO2 (Petco2) measurement provides a reliable estimate of ventilation in critically ill children who are mechanically ventilated. Design Prospective, nonrandomized, consecutive enrollment study. Setting A university-affiliated children’s hospital pediatric intensive care unit. Patients All intubated, mechanically ventilated pediatric patients. Interventions All Petco2-Paco2 pairs were from patients ventilated with a Servo 300 Ventilator (Siemens-Elema AB, Stockholm, Sweden). When a blood gas sample was obtained, Petco2 as measured by a continuous mainstream Petco2 capnograph was recorded. Measurements The results of blood gas measurements and corresponding Petco2 measurements were recorded. Demographic data and primary diagnosis were noted. Petco2-Paco2 pairs obtained from patients with intracardiac shunts or obtained during high-frequency oscillation or extracorporeal membrane oxygenation at the time of measurement were excluded from analysis. Linear regression was used to analyze Petco2-Paco2 pairs. Repeated measure analysis of variance with the mixed-model algorithm in SAS software (SAS Institute, Carey, NC) was used to analyze the trend in the Petco2 and Paco2 relationship. Chi-square was used to analyze categorical data. Statistical significance was considered p < .05. Results A total of 129 children were enrolled, and 1708 paired Paco2 and Petco2 measurements were recorded. The mean age ± sd was 4.1 ± 5.6 yrs. Paco2 positively correlated with Petco2. The linear equation for the regression analysis was y = 0.71 x (95% confidence interval, 0.69–0.73) + 8.93 (95% confidence interval, 7.89–9.97), with r2 = .716 and p < .001. The Petco2-Paco2 difference was ≤5 mm Hg (0.67 kPa) in 54% and ≤10 mm Hg (1.33 kPa) in 80% of paired data. Increased lung disease had a negative effect on Petco2 correlation with Paco2. A total of 223 of 640 (35%) blood gases (defined by Pao2/Fio2 ratio of <200) had >10 mm Hg (1.33 kPa) difference between the Petco2 and Paco2. However, only 111 of 1068 (10%) Petco2-Paco2 pairs had a difference of >10 mm Hg (1.33 kPa) in patients with a Pao2/Fio2 ratio >200. Trend analysis showed the Petco2-Paco2 difference increased with increasing duration of mechanical ventilation. Conclusion In most intubated, mechanically ventilated infants and children, Petco2 reliably estimates ventilation.