Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation

Mulla, Hussain; McCormack, P. D.; Lawson, Graham; Firmin, Richard K.; Upton, David

doi:10.1097/00000542-200308000-00008

Cited by 73 publications

(53 citation statements)

References 37 publications

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“…The expanded circulating volume and sequestration by plastic components of the circuit have been shown to influence the pharmacokinetics of theophylline and midazolam [4,5]. In addition, there is a suggestion that recirculation of blood during venovenous cannulation may also contribute to altered drug disposition [4].…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation

Mulla¹,

Pooboni

2005

Brit J Clinical Pharma

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112

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AimsExtracorporeal membrane oxygenation (ECMO) is a life support system used during severe respiratory or cardiorespiratory failure. The objective of this study was to characterize the population pharmacokinetics of vancomycin during ECMO. MethodsA population model was developed using WinNonMix (Version 2.0.1) from a total of 366 plasma observations in 45 patients, including term neonates, older children and adults. The study utilized both rich prospective and sparse retrospective data. Prospective samples were drawn at baseline and then 30, 60,90, 120, 180, 240, 300, 360 and 420 min postinfusion. Steady state concentrations were obtained retrospectively from an assay database, cross-referencing with the patients' medical records. ResultsData were examined using a two-compartment model with an additive and proportional residual error. Model fit improved substantially when clearance, CL (l kg -1 h -1 ) was modelled as a nonlinear function of serum creatinine (Cr) m mol l -1 . There was a linear relationship between CL and age up to 1000 days: CL (Age < 1000 days) = [2.4 + 0.0018 ¥ Age (days)]/Cr; CL (Age > 1000 days) = 4.3/Cr. Age also influenced central volume ( V 1) when included in the model as a dichotomous variable: V 1 (Age < 4000 days) = 0.45 l kg -1 ; V 1 (Age > 4000 days) = 0.36 l kg -1 . Intercompartmental clearance and tissue volume were estimated to be 0.09 l kg -1 h -1 and 0.25 l kg -1 , respectively. Model validation in a separate group of 20 patients revealed a bias of -7.7% and a precision of 26.7%. ConclusionsThe clearance of vancomycin was decreased and its volume of distribution increased in patients receiving ECMO, suggesting altered drug disposition during this treatment.

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Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation

Mulla¹,

Pooboni

2005

Brit J Clinical Pharma

Self Cite

112

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“…PK changes attributed to ECMO support include increased volume of distribution (V) and decreased clearance (CL), but these vary by drug and are not consistently predicted using drug physicochemical properties (5)(6)(7)(8). This study describes the population PK of fluconazole in children supported by ECMO and provides rational dosing recommendations for the prevention and treatment of invasive candidiasis in this vulnerable population.…”

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confidence: 99%

Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

Watt

González

Benjamin

et al. 2015

Antimicrob Agents Chemother

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f Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance ( Extracorporeal membrane oxygenation (ECMO) is life-saving in children with refractory cardiorespiratory failure. ECMO is a cardiopulmonary bypass device that provides complete respiratory and cardiac support. Mechanically, blood is drained from the venous system, pumped through an artificial lung membrane in which oxygen is added and carbon dioxide is removed, and then returned to either venous or arterial circulation. ECMO has been used successfully to support children with multiple disease processes, including meconium aspiration syndrome, fulminant myocarditis, and sepsis (1). Despite these successes, children supported by ECMO are at high risk for ECMO-related complications, especially nosocomial infections (2).Invasive candidiasis is common and fatal in children on ECMO. In this population, Candida species are the most common infectious organism (2). The incidence of infection varies by center, and rates as high as 10% have been reported (2, 3). Candida infections cause substantial morbidity and mortality (3) and are difficult to eradicate due to the ability of the organism to adhere to indwelling catheters. For this reason, routine management of candidiasis consists not only of the use of antifungal agents but also the removal of catheters (4). Catheter removal for children on ECMO is often impossible, because the ECMO cannulas connect the child to the ECMO circuit. Therefore, therapy on ECMO relies on either the prevention of invasive candidiasis or optimal therapeutic dosing in children with infection.Optimal dosing for prevention or treatment of candidiasis in children on ECMO can differ greatly from that with other populations due to the pharmacokinetic (PK) changes induced by the ECMO circuit. PK changes attributed to ECMO support include increased volume of distribution (V) and decreased clearance (CL), but these vary by drug and are not consistently predicted using drug physicochemical properties (5-8). This study describes the population PK of fluconazole in children supported by ECMO and provides rational dosing recommendations for the prevention and treatment of invasive candidiasis in this vulnerable population. MATERIALS AND METHODSStudy design. Fluconazole samples were obtained from three prospective trials. Study 1 was a single-center open-label PK study of fluconazole in children on ECMO (n ϭ 20) (9), study 2 was a single-center PK study of a fluconazole loading dose in critically ill children (n...

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“…Extracorporeal membrane oxygenation (ECMO) can alter the pharmacokinetics of some medications through increased total blood volume and drug adsorption to the tubing or oxygenator. 2,3 Many children receiving ECMO also receive continuous renal replacement therapies (CRRTs), adding an additional source of drug clearance. One published case series detailed the pharmacokinetics of a 4 mg/kg dose of oseltamivir in three children who received ECMO and continuous venovenous hemofiltration (CVVH); however, oseltamivir binding to the ECMO oxygenator and the contribution of CVVH to oseltamivir clearance were not assessed.…”

Section: Introductionmentioning

confidence: 99%

The Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in a Critically Ill Pediatric Patient Receiving Extracorporeal Membrane Oxygenation and Continuous Venovenous Hemodialysis

Eyler

Klein

Mueller

2012

The Journal of Pediatric Pharmacology and Therapeutics

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This report details the pharmacokinetics of oseltamivir and oseltamivir carboxylate following administration of high-dose oseltamivir in a critically ill child receiving extracorporeal membrane oxygenation (ECMO) and continuous venovenous hemodialysis (CVVHD). A 6-year-old critically ill male patient suffering from a presumed viral illness was transferred to our institution's pediatric intensive care unit from an outside hospital after developing respiratory failure and cardiomegaly. ECMO and oseltamivir therapy were initiated upon admission, and CVVHD was started on hospital day 3. Pharmacokinetic sampling occurred at an oseltamivir dose of approximately 4 mg/kg on hospital day 6. The patient's oseltamivir and oseltamivir carboxylate area under the plasma concentration time curves for the 12-hour dosing interval (AUC 0-12 ) were 30.5 and 905 ng/mLhr, respectively. Drug clearance by CVVHD was 31.6 mL/min for oseltamivir and 26.9 mL/min for oseltamivir carboxylate. Pre-and postoxygenator oseltamivir and oseltamivir carboxylate plasma concentrations did not differ substantially. The patient's oseltamivir carboxylate plasma concentrations remained well above the reported mean 50% inhibitory concentration for 2009 pandemic H1N1 virus. However, despite receiving twice the standard dose of oseltamivir, the oseltamivir carboxylate AUC 0-12 in our patient was less than that reported in noncritically ill pediatric subjects. The reduced oseltamivir carboxylate AUC 0-12 found in our patient was most likely due to decreased drug absorption.INDEX TERMS continuous renal replacement therapy, dialysis, extracorporeal membrane oxygenation, influenza, oseltamivir J Pediatr Pharmacol Ther 2012;17(2):173-176

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Pharmacokinetics of Midazolam in Neonates Undergoing Extracorporeal Membrane Oxygenation

Abstract: These results reveal significantly increased volume of distribution and plasma half-life in neonates receiving extracorporeal membrane oxygenation. Altered kinetics may reflect sequestration of midazolam by components of the extracorporeal membrane oxygenation circuit.

Cited by 73 publications

References 37 publications

Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation

Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation

Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

The Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in a Critically Ill Pediatric Patient Receiving Extracorporeal Membrane Oxygenation and Continuous Venovenous Hemodialysis

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