Faculty Bibliography

Meropenem, a broad-spectrum carbapenem, is commonly used for empirical and definitive therapy in the pediatric intensive care unit (ICU). Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or patients who are not in the ICU. Adult data demonstrate that pharmacokinetic parameters such as the volume of distribution and clearance can be significantly altered in individuals receiving extracorporeal membrane oxygenation (ECMO). Alterations in the volume of distribution and clearance of antimicrobials in patients with sepsis and septic shock have also been documented, and these patients have demonstrated lower than expected antimicrobial serum concentrations based on standard dosing regimens. Therefore, an understanding of the pharmacokinetic changes in critically ill children receiving ECMO is crucial to determining the most appropriate dose and dosing interval selection for any antimicrobial therapy. In this case report, we describe the pharmacokinetics of a continuous infusion of meropenem in a pediatric cardiac ICU patient who was receiving concurrent extracorporeal life support. The patient was an 8-month-old male infant who underwent a Glenn procedure and pulmonary artery reconstruction. Postoperatively, he required ECMO with a total run of 21 days. On day 11 of ECMO, a bronchoalveolar lavage was performed, and blood cultures from days 11 and 12 of ECMO grew Pseudomonas aeruginosa, with a meropenem minimum inhibitory concentration (MIC) of 0.5 mug/ml. On ECMO day 13, meropenem was initiated with a loading dose of 40 mg/kg and infused over 30 minutes, followed by a continuous infusion of 200 mg/kg/day. A meropenem serum concentration measured 8 hours after the start of the infusion was 46 mug/ml. Repeat levels were measured on days 3 and 9 of meropenem therapy and were 39 and 42 mug/ml, respectively. Repeat blood and respiratory cultures remained negative. This meropenem regimen (40-mg/kg bolus followed by a continuous infusion of 200 mg/kg/day) was successful in providing a target attainment of 100% for serum and lung concentrations above the MIC for at least 40% of the dosing interval and was associated with a successful clinical outcome.

We evaluated whether procalcitonin (PCT) might aid diagnosing serious bacterial infections in a general pediatric ICU population. 201 patients accounted for 332 PCT samples. A PCT >/=1.45 ng/mL had a positive predictive value of 30%, a negative predictive value of 93%, and a sensitivity of 72% and a specificity of 75%. These data suggest PCT can assist in identifying patients without serious bacterial infections and limit antimicrobial use.

OBJECTIVES: To report our experience with the use of IV enoxaparin in neonatal and pediatric patients in the ICU. DESIGN: We performed a case control from January 1, 2009, to June 30, 2012, comparing patients that received IV enoxaparin to controls that received subcutaneous enoxaparin. Cases were matched to controls in a 1:2 manner. IV enoxaparin doses were infused over 30 minutes and anti-Factor Xa levels were drawn 4 hours after the start of the IV infusion or 4 hours after a subcutaneous dose. SETTING: The pediatric and cardiac ICUs of a tertiary/quaternary, free-standing, academic children's hospital. PATIENTS: Forty-five neonatal and pediatric patients receiving prophylactic or therapeutic enoxaparin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifteen cases and 30 controls were included. Of 15 patients, 13 received IV enoxaparin for treatment and two received IV enoxaparin for prophylaxis as compared with 25 of 30 controls receiving subcutaneous enoxaparin for treatment and five receiving subcutaneous enoxaparin for prophylaxis. The ages for the cases ranged from 21 days to 16 years with a median weight of 5 kg, and the ages for controls ranged from 10 days to 23 years with a median weight of 31 kg. The median duration of IV therapy was 11 days (range, 1-120 d) and the median duration for subcutaneous therapy was 15 days (range, 3-85 d). The mean initial IV dose was 1.14 +/- 0.38 mg/kg/dose q12h, and the mean initial subcutaneous dose was 0.85 +/- 0.2 mg/kg/dose subcutaneous q12h (p = 0.003). The mean therapeutic IV dose was 1.31 +/- 0.52 mg/kg/dose q12h, and the mean therapeutic subcutaneous dose was 0.9 +/- 0.3 mg/kg/dose q12h (p = 0.016). There were no adverse events reported related to bleeding, thrombosis, or hypersensitivity in any of the cases or controls evaluated. CONCLUSION: The pharmacodynamics of a 30-minute IV enoxaparin infusion was found to produce therapeutic 4 hour anti-Factor Xa levels similar to subcutaneous doses. Although this was a small study, there were no adverse events, suggesting the safety profile of IV enoxaparin may be similar to subcutaneous dosing with the added benefit of less pain associated with IV dosing. These findings suggest that IV enoxaparin may be a viable option for anticoagulating critically ill children and its use warrants further study.

OBJECTIVE: Observed associations between fluid balance and septic shock outcomes are likely confounded by initial mortality risk. We conducted a risk-stratified analysis of the association between post-ICU admission fluid balance and pediatric septic shock outcomes. DESIGN: Retrospective analysis of an ongoing multicenter pediatric septic shock clinical and biological database. SETTING: Seventeen PICUs in the United States. PATIENTS: Three hundred and seventeen children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We stratified subjects into three mortality risk categories (low, intermediate, and high) using a validated biomarker-based stratification tool. Within each category, we assessed three fluid balance variables: total fluid intake/kg/d during the first 24 hours, percent positive fluid balance during the first 24 hours, and cumulative percent positive fluid balance up to 7 days. We used logistic regression to estimate the effect of fluid balance on the odds of 28-day mortality, and on complicated course, which we defined as either death within 28 days or persistence of two or more organ failures at 7 days. There were 40 deaths, and 91 subjects had a complicated course. Increased cumulative percent positive fluid balance was associated with mortality in the low-risk cohort (n = 204; odds ratio, 1.035; 95% CI, 1.004-1.066) but not in the intermediate- and high-risk cohorts. No other associations with mortality were observed. Fluid intake, percent positive fluid balance in the first 24 hours, and cumulative percent positive fluid balance were all associated with increased odds of a complicated course in the low-risk cohort but not in the intermediate- and high-risk cohorts. CONCLUSIONS: When stratified for mortality risk, increased fluid intake and positive fluid balance after ICU admission are associated with worse outcomes in pediatric septic shock patients with a low initial mortality risk but not in patients at moderate or high mortality risk.

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.

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.