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Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

ABSTRACT: BACKGROUND:Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the pharmacokinetics of fluconazole in infants on ECMO. METHODS:Infants <120 days of age received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected preoxygenator and postoxygenator around doses 1 and 2 to calculate pharmacokinetic indices and describe oxygenator extraction. A 1-compartment model was fit to the data using nonlinear regression. Surrogate pharmacodynamic targets for efficacy were evaluated. RESULTS:Ten infants were enrolled. After dose 1 (n = 9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg and the median exposure in the first 24 hours (area under the curve from 0 to 24 hours) was 322 h × mg/L. After multiple doses (n = 7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg and the area under the curve from 0 to 24 hours was 352 h × mg/L. After dose 1, 78% of infants achieved the prophylaxis target, whereas only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (-2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (?= -0.05). There were no adverse events related to fluconazole. CONCLUSIONS:Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.

SUBMITTER: Watt KM

PROVIDER: S-EPMC3444624 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

Watt Kevin M KM Benjamin Daniel K DK Cheifetz Ira M IM Moorthy Ganesh G Wade Kelly C KC Smith P Brian PB Brouwer Kim L R KL Capparelli Edmund V EV Cohen-Wolkowiez Michael M

The Pediatric infectious disease journal 20121001 10

<h4>Background</h4>Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the pharmacokinetics of fluconazole in infants on ECMO.<h4>Methods</h4>Infants <120 days of age received either intravenous fluconazole prophylaxis (25 mg/kg once a week) ...[more]

PMID: 22627870

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Project description:BACKGROUND:Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations. METHODS:This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96?h during infusion and 72?h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses. RESULTS:A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL?=?37.8?×?EXP (0.207?×?(temperature?-?36.9))?L h-1, central volume of distribution (V1)?=?229?L, V2?=?1640?×?(total plasma protein/4.5)2.46?L, and intercompartmental clearance (Q)?=?41?L?h-1. Based on Monte Carlo simulation results, an infusion of 17.5??g?h-1 seems to reach target sufentanil concentration (0.3-0.6??g?L-1) in most ECMO patients except hypothermic patients (33?°C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low. CONCLUSIONS:This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery. TRIAL REGISTRATION:Clinicaltrials.gov NCT02581280 , December 1st, 2014.

Project description:OBJECTIVES:To determine whether mortality differs between roller and centrifugal pumps used during extracorporeal membrane oxygenation in infants weighing less than 10?kg. DESIGN:Retrospective propensity-matched cohort study. SETTING:All extracorporeal membrane oxygenation centers reporting to the Extracorporeal Life Support Organization. PATIENTS:All patients less than 10?kg supported on extracorporeal membrane oxygenation during 2011-2016 within Extracorporeal Life Support Organization Registry. INTERVENTIONS:Centrifugal and roller pump recipients were propensity matched (1:1) based on predicted probability of receiving a centrifugal pump using demographic variables, indication for extracorporeal membrane oxygenation, central versus peripheral cannulation, and pre-extracorporeal membrane oxygenation patient management. MEASUREMENTS AND MAIN RESULTS:A total of 12,890 patients less than 10?kg were supported with extracorporeal membrane oxygenation within the Extracorporeal Life Support Organization registry during 2011-2016. Patients were propensity matched into a cohort of 8,366. Venoarterial and venovenous extracorporeal membrane oxygenation runs were propensity matched separately. The propensity-matched cohorts were similar except earlier year of extracorporeal membrane oxygenation (standardized mean difference, 0.49) in the roller pump group. Within the propensity-matched cohort, survival to discharge was lower in the centrifugal pump group (57% vs 59%; odds ratio, 0.91; 95% CI, 0.83-0.99; p = 0.04). Hemolytic, infectious, limb injury, mechanical, metabolic, neurologic, pulmonary, and renal complications were more frequent in the centrifugal pump group. Hemorrhagic complications were similar between groups. Hemolysis mediated the relationship between centrifugal pumps and mortality (indirect effect, 0.023; p < 0.001). CONCLUSIONS:In this propensity score-matched cohort study of 8,366 extracorporeal membrane oxygenation recipients weighing less than 10?kg, those supported with centrifugal pumps had increased mortality and extracorporeal membrane oxygenation complications. Hemolysis was evaluated as a potential mediator of the relationship between centrifugal pump use and mortality and met criteria for full mediation.

Project description:ObjectivesTo evaluate the association between bleeding from chest tubes and clinical outcomes in children supported by extracorporeal membrane oxygenation.DesignSecondary analysis of a large observational cohort study.SettingEight pediatric institutions within the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Collaborative Pediatric Critical Care Research Network.PatientsCritically ill children supported by extracorporeal membrane oxygenation.InterventionsNone.Measurements and main resultsDaily chest tube bleeding, results from hemostatic assays, transfusion volumes, 90-day PICU-free days, and mortality were collected prospectively by trained bedside extracorporeal membrane oxygenation specialists and research coordinators. Extracorporeal membrane oxygenation was employed in the care of 514 consecutive patients. Sixty percent of patients had at least one episode of chest tube bleeding (median chest tube blood volume over the entire extracorporeal membrane oxygenation course was 123 mL/kg [interquartile range, 47-319 mL/kg]). Twenty-six percent had at least 1 day of bleeding from the chest tube greater than 100 mL/kg/d. The number of days with chest tube bleeding greater than 60 mL/kg/d was independently associated with increased in-hospital mortality (adjusted odds ratio, 1.43; 95% CI, 1.05-1.97; p = 0.02) and decreased PICU-free days (beta coefficient, -4.2; 95% CI, -7.7 to -0.6; p = 0.02). The total amount of bleeding from chest tube were independently associated with increased mortality (per mL/kg/extracorporeal membrane oxygenation run; adjusted odds ratio, 1.002; 95% CI, 1.000-1.003; p = 0.04). Fibrinogen, weight, indication for extracorporeal membrane oxygenation, and need for hemodialysis were independently associated with chest tube bleeding, whereas platelet count, coagulation tests, heparin dose, and thrombotic events were not.ConclusionsIn children supported by extracorporeal membrane oxygenation, chest tube bleeding above 60 mL/kg/d was independently associated with worse clinical outcome. Low fibrinogen was independently associated with chest tube bleeding, whereas platelet count and hemostatic tests were not. Further research is needed to evaluate if interventions to prevent or stop chest tube bleeding influence the clinical outcome.

Dataset Information

Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

Publications

Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

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