Chad A. Knoderer

Nonsteroidal Anti-Inflammatory Drugs Are an Important Cause of Acute Kidney Injury in Children

OBJECTIVE To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. STUDY DESIGN We conducted a retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code 584.5 or 584.9 from January 1999 to June 2010. Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development. RESULTS Patients (N=1015) were identified through International Classification of Diseases, Ninth Revision screening. Twenty-one children had clinical, laboratory, and radiographic studies suggesting NSAID-associated acute tubular necrosis and 6 had findings suggesting NSAID-associated acute interstitial nephritis, representing 2.7% (27 of 1015) of the total cohort with AKI and 6.6% when excluding complex patients with multifactorial AKI. Children with NSAID-associated AKI had a median (range) age of 14.7 years (0.5-17.7 years); 4 patients (15%) were <5 years old. Fifteen of 20 children (75%) for whom dosing data were available received NSAIDs within recommended dosing limits. Patients<5 years old were more likely to require dialysis (100% vs 0%, P<.001), intensive care unit admission (75% vs 9%, P=.013), and a longer length of stay (median 10 vs 7 days, P=.037). CONCLUSIONS NSAID-associated AKI accounted for 2.7% of AKI in this pediatric population. AKI typically occurred after the administration of correctly dosed NSAIDs. Young children with NSAID-associated AKI may have increased disease severity.

Sildenafil for the Treatment of Pulmonary Hypertension in Pediatric Patients

Sildenafil is a phosphodiesterase 5 inhibitor widely used for the treatment of pulmonary hypertension in children. Despite limited available safety and efficacy evidence, use of sildenafil continues to increase. To date, sildenafil use for pediatric pulmonary hypertension has been characterized for 193 children through 16 studies and 28 case series and reports. The primary efficacy data suggest that sildenafil is beneficial for facilitating the weaning of inhaled nitric oxide in children after cardiac surgery. Compiled safety data suggest that sildenafil is well tolerated among children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. This review summarizes the available data describing the use, safety, and efficacy of sildenafil for children with pulmonary hypertension.

Are Elevated Vancomycin Serum Trough Concentrations Achieved Within the First 7 Days of Therapy Associated With Acute Kidney Injury in Children

BACKGROUND In 2008, the empiric vancomycin dosing recommendation in children at our institution was changed from 40 to 60 mg/kg per day. Subsequently, an increased incidence of acute kidney injury (AKI) in patients receiving vancomycin was suspected. The objective of this study was to evaluate AKI in children receiving vancomycin and to determine risk factors for AKI development. METHODS Medical records of patients aged 30 days through 17 years who received vancomycin for at least 72 hours between January and December 2007 (40 mg/kg per day) and January and December 2010 (60 mg/kg per day) were reviewed. Patients with cystic fibrosis, an elevated baseline serum creatinine, or without a serum creatinine concentration obtained after receipt of vancomycin were excluded. Acute kidney injury was defined using adapted pediatric RIFLE criteria as an increase in serum creatinine from baseline of 50% or more. RESULTS Acute kidney injury occurred in 19.4% of the 859 children included, with no difference between the 2007 and 2010 periods (18.8% vs 20%, respectively; P = .636). Intensive care unit admission (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.20-2.94) and an initial vancomycin trough concentration ≥15 mg/L (OR, 2.18; 95% CI, 1.21-3.92) were determined to be significantly associated with AKI. CONCLUSIONS These results suggest an initial vancomycin serum trough concentration of ≥15 mg/L and intensive care unit admission are predictors of AKI in this pediatric population.

Cefuroxime Pharmacokinetics in Pediatric Cardiovascular Surgery Patients Undergoing Cardiopulmonary Bypass

OBJECTIVES The objective of this study was to determine the pharmacokinetics of cefuroxime in children undergoing cardiopulmonary bypass (CPB) for cardiovascular surgery. DESIGN A prospective study. SETTING A tertiary pediatric teaching hospital. PARTICIPANTS Infants and children undergoing CPB were enrolled in the study. INTERVENTION An initial dose (mean, 24.2 ± 1.6 mg/kg) of cefuroxime was administered before surgical incision, and a second dose (mean, 14.4 ± 7.9 mg/kg) was administered in the CPB prime solution. Serial blood samples were obtained before, during, and after the CPB process. Samples were shipped on dry ice to the analytic laboratory and concentrations determined by a validated high-performance liquid chromatography method. A 2-compartment pharmacokinetic model was fitted to the data using maximum a priori-Bayesian estimation, with weight as a covariate. Monte Carlo simulations of a single-dose (25 mg/kg pre-CPB) approach and a 2-dose (25 mg/kg pre- and 12.5-mg/kg prime solution dose) approach were performed. MEASUREMENTS AND MAIN RESULTS Fifteen subjects (9 males/6 females) were enrolled in the study, with median (range) age and weight of 11 (3-34) months and 9.5 (4.5-15.4) kg, respectively. The median (range) duration of CPB was 136 (71-243) minutes. Median and range cefuroxime pharmacokinetic parameters were as follows: maximum concentration (Cmax) dose, 1: 328 (150-512) μg/mL; systemic clearance, 0.050 (0.041-0.058) L/h/kg; steady-state volume of distribution, 0.213 (0.081-0.423) L/kg; volume of distribution in the central compartment, 0.081 (0.046-0.162) L/kg; and elimination half-life, 3.76 (1.03-6.81) hours. The median 8-hour post-dose-simulated cefuroxime concentrations were 26.5 and 16.0 mg/L for the 2-dose and single-dose regimens, respectively. CONCLUSION Manufacturers recommend that pediatric doses of cefuroxime (25-50 mg/kg) can be used in infants and children undergoing CPB to maintain adequate serum concentrations for surgical-site infection prophylaxis. A second intraoperative dose, administered through the CPB circuit, provides no additional prophylactic advantage.

System-Wide Implementation of the Use of an Extended- Infusion Piperacillin/Tazobactam Dosing Strategy: Feasibility of Utilization From a Children's Hospital Perspective

BACKGROUND Use of extended infusions of piperacillin/tazobactam (PT) in adult patients has been described, but data in children are limited. OBJECTIVE The goal of this study was to determine the feasibility of using an extended-infusion PT dosing strategy as the standard of care in a childrens hospital. METHODS This was a prospective observational study of patients aged >30 days who received PT after admission to a freestanding, tertiary care childrens hospital. After institution of an extended-infusion PT dosing protocol as the standard dosing option, patients receiving PT were prospectively assessed for presence of and reasons for changes in dosing regimen. RESULTS A total of 332 patients, with a median age of 5 years (interquartile range, 1.9-12 years) and median weight of 19.9 kg (interquartile range, 11.7 - 37.6 kg) received PT (100 mg/kg based on piperacillin component). Extended-infusion PT was used for the duration of PT therapy in 92% (n = 304) of patients. Twenty-eight patients (8%) received a traditional infusion over 30 minutes, with 19 of 28 being changed from extended infusion and 9 of 28 being empirically prescribed traditional infusion PT. The most commonly encountered reason for not using extended infusions was coadministration of vancomycin (17 of 28 [61%]) and lack of compatibility data with PT. Dosing errors, which were voluntarily reported, were infrequent (1.8% [n = 6]). The few observed dosing errors were likely attributable to the overall ordering process at our institution, which requires ordering as the milligram per kilogram dose as total PT rather than based on piperacillin component as is commonly documented in pediatric dosing references. CONCLUSIONS Results of this study suggest that extended-infusion PT dosing was feasible in this specific childrens hospital. Ninety-two percent of patients received our institutions preferred dosing regimen; a small percentage of patients still needed to receive traditional infusion times.

Acid-Suppressing Agents and Risk for Clostridium difficile Infection in Pediatric Patients

Background. Acid-suppressing agents have been associated with increased Clostridium difficile infection (CDI) in adults. The objective of this study was to evaluate the association of acid-suppressing therapy with the development of CDI in the pediatric population. Methods. This was a retrospective case-control study. Children aged 1 through 17 years with a positive C difficile polymerase chain reaction (PCR) result obtained between June 1, 2008, and June 1, 2012, were randomly matched to a control population selected from patients with negative PCR. Results. A total of 458 children were included. No difference was observed in acid-suppressive therapy prior to PCR in CDI-positive versus -negative patients (n = 131 [57.2%] vs n = 121 [52.8%], P = .348). Among patients receiving acid-suppressing therapy prior to obtaining a PCR, no difference was observed in proton pump inhibitor use (45% vs 46.3%, P = .843), but histamine-2 receptor antagonist (H2RA) use was greater in the CDI-positive patients (32.8% vs 14.9%, P = .001). Logistic regression analysis demonstrated that H2RA therapy at home (odds ratio = 4.6; 95% confidence interval = 1.5-14.5) was an independent CDI predictor. Conclusion. In this pediatric population, CDI risk in children receiving home acid-suppressive therapy with H2RAs is nearly 4.5 times greater than that of children not receiving H2RA therapy. These results suggest the need for continued monitoring and study of H2RA therapy in children.

A Randomized, Controlled Trial of Catheter-Related Infectious Event Rates Using Antibiotic-Impregnated Catheters Versus Conventional Catheters in Pediatric Cardiovascular Surgery Patients

: We conducted a randomized, controlled clinical trial to determine whether a difference in catheter-associated blood stream infection (CABSI) incidence existed between children who underwent cardiac surgery and had a central venous catheter impregnated with minocycline and rifampin versus those who had a conventional, nonimpregnated catheter after cardiac surgery. Due to a lower number of infections than expected, the study was terminated early. Among 288 evaluable patients, the rates of CABSI and line-related complications were similar between the 2 groups.

Assessment of the validity of reported antibiotic allergic reactions in pediatric patients.

Study Objective. To determine whether a reported antibiotic allergy was likely to have been immunologically mediated.

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

ABSTRACT The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

Y-Site Compatibility of Vancomycin and Piperacillin/ Tazobactam at Commonly Utilized Pediatric Concentrations

Background Vancomycin and piperacillin/tazobactam are common empiric antibiotics in hospitalized pediatric patients. Studies evaluating intravenous (IV) compatibility at various concentrations show inconsistent results. Objective The objective of this study was to determine the Y-site compatibility of vancomycin 10 mg/mL and piperacillin/tazobactam 112.5 mg/mL. Methods Vancomycin (10 g vial) was reconstituted using sterile water for injection (SWFI) and diluted with 5% dextrose in water (D5W) to a final concentration of 10 mg/mL in an evacuated IV bag. Piperacillin/tazobactam (40.5 g vial) was reconstituted and diluted with SWFI to a final concentration of 112.5 mg/mL (100 mg/mL piperacillin) in an evacuated IV bag. Both antibacterial stock solutions were then stored in a refrigerator at 4°C (39.2°F). Initial solution appearances, including color, clarity, and particulates, were documented. Diluted solutions were mixed in a quantity of 3 mL of each vancomycin and piperacillin/tazobactam in glass test tubes. Subsequent evaluation included pH assessment and visual evaluation with unaided eye, magnifying glass, high-beam light, and via Spec-20 turbidimeter. Solution mixtures were evaluated upon mixing and again at 30 minutes, 1 hour, and 4 hours after mixing. Results Initial combination of vancomycin and piperacillin/tazobactam resulted in a milky precipitate, visible to the unaided eye, which dissipated 15 seconds after mixing. No precipitate was visualized via any method at any additional time point. Turbidimetry and pH readings did not demonstrate differences from baseline measurements. Conclusions A combination of vancomycin 10 mg/mL and piperacillin/tazobactam 112.5 mg/mL demonstrated precipitation immediately upon mixing. Co-infusion of vancomycin and piperacillin/tazobactam via Y-site should be considered incompatible.