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Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation.

ABSTRACT: BACKGROUND:Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK). METHODS:To characterize micafungin pharmacokinetics and safety in infants on ECMO, we conducted an open-label pharmacokinetics trial. Infants on ECMO either received intravenous micafungin 4?mg/kg every 24 h for invasive candidiasis prophylaxis or 8?mg/kg every 24 h when a fungal infection was suspected or confirmed. We collected plasma samples after single and multiple micafungin doses. We defined the therapeutic target as the adult exposure associated with efficacy in phase III trials and the prophylactic target as one-half of the therapeutic target. RESULTS:We enrolled 12 infants (124 samples) with a median age of 59 days. Using a 1-compartment model, median weight-normalized volume of distribution and clearance were 0.64?L/kg and 0.041?L/kg/h, respectively. Dose-exposure simulations revealed that doses of 2.5 and 5?mg/kg every 24 h matched exposure targets for prophylaxis and treatment of invasive candidiasis, respectively. We did not observe any drug-related adverse events. CONCLUSIONS:In infants on ECMO, micafungin volume of distribution was higher and clearance was in the upper range of previously published values for infants not on ECMO. Based on these data, we recommend dosing of 2.5 and 5?mg/kg every 24 h for prophylaxis and treatment of invasive candidiasis, respectively, to match adult exposure proven effective against Candida spp.

SUBMITTER: Autmizguine J

PROVIDER: S-EPMC5071122 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation.

Autmizguine Julie J Hornik Christoph P CP Benjamin Daniel K DK Brouwer Kim L R KL Hupp Susan R SR Cohen-Wolkowiez Michael M Watt Kevin M KM

The Pediatric infectious disease journal 20161101 11

<h4>Background</h4>Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK).<h4>Methods</h4>To characterize micafungin pharmacokinetics and safety in infants on ECMO, we conducted an open-label pharmacokinetics trial. Infants on ECMO either received intravenous micafungin 4 mg/kg every 24 h for invasive candidiasis prophylaxis or 8 mg/kg every 24 h wh ...[more]

PMID: 27314826

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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.

Project description:ObjectiveTo evaluate the performance of the extracorporeal membrane oxygenation retrieval team at a high-volume extracorporeal membrane oxygenation center during the coronavirus disease 2019 pandemic.DesignObservational study including all adult patients with confirmed infection due to severe acute respiratory syndrome coronavirus-2 cannulated at other centers and transported on extracorporeal membrane oxygenation to the ICU of the Vall d'Hebron University Hospital between 15 March and 10 June 2020.SettingThe ICU (capacity expanded to 200 during the pandemic) of the Vall d'Hebron University Hospital (a 1,100-bed public university hospital in Barcelona), the referral center for extracorporeal respiratory support in Catalonia (7.5 million inhabitants).PatientsExtracorporeal membrane oxygenation was considered if the Pao2/Fio2 ratio less than 80 mm Hg (refractory to prone position) and/or Paco2 greater than 80 mm Hg and pH less than 7.25 for more than 6 hours, and no contraindications for extracorporeal support were present.InterventionsVenovenous extracorporeal membrane oxygenation was initiated in the primary center. Then, patients were transferred to the ICU of the Vall d'Hebron University Hospital where they received support until respiratory improvement. After decannulation, patients were discharged for rehabilitation at the primary center.Measurements and main resultsNineteen patients with severe acute respiratory syndrome coronavirus-2 infection and with a mean Pao2/Fio2 ratio of 71 mm Hg (57-118 mm Hg) despite prone positioning and a mean Paco2 of 70 mm Hg (47-110 mm Hg) were transferred to our center from their primary hospital after cannulation and received venovenous extracorporeal membrane oxygenation support. Prior to cannulation, six patients (31.5%) presented vascular thrombosis, and nine (47.4%) were already receiving anticoagulant therapy. Eighteen transfers were carried out with no significant complications. While on extracorporeal membrane oxygenation, thrombotic events were recorded in nine patients (47.4%) and hemorrhagic events in 13 (68.4%). Thirteen patients (68.4%) were successfully weaned, and 12 (63.1%) were discharged home.ConclusionsExtracorporeal membrane oxygenation retrieval can rescue young, previously healthy patients with severe coronavirus disease 2019 in whom all the conventional respiratory measures have failed. Thrombotic and hemorrhagic complications are frequent in this cohort.

Dataset Information

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation.

Publications

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation.

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