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The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation.

Shekar K, Roberts JA, Smith MT, Fung YL, Fraser JF - BMC Anesthesiol (2013)

Bottom Line: Mixed-effects regression models will be used to estimate the drug loss over time in ex vivo studies.Data from animal and clinical studies will be analysed using non-linear mixed-effects models.ACTRN12612000559819.

View Article: PubMed Central - HTML - PubMed

Affiliation: Critical Care Research Group, Adult Intensive Care Services, The Prince Charles, Hospital and The University of Queensland, Brisbane, QLD, 4032, Australia. kiran_shekar@health.qld.gov.au.

ABSTRACT

Background: Extracorporeal membrane oxygenation (ECMO) is a supportive therapy and its success depends on optimal drug therapy along with other supportive care. Emerging evidence suggests significant interactions between the drug and the device resulting in altered pharmacokinetics (PK) of vital drugs which may be further complicated by the PK changes that occur in the context of critical illness. Such PK alterations are complex and challenging to investigate in critically ill patients on ECMO and necessitate mechanistic research. The aim of this project is to investigate each of circuit, drug and critical illness factors that affect drug PK during ECMO.

Methods/design: An incremental research plan that encompasses ex vivo experiments for drug stability testing in fresh human and ovine whole blood, ex vivo drug disposition studies in standard and modified adult ECMO circuits primed with fresh human or ovine whole blood, PK studies in healthy and critically ill ovine models of ECMO with appropriate non ECMO controls and an international mutli-centre clinical population PK study will be utilised to comprehensively define the PK alterations that occur in the presence of ECMO. Novel drug assays that will allow quantification of multiple drugs in small volumes of plasma will also be developed. Mixed-effects regression models will be used to estimate the drug loss over time in ex vivo studies. Data from animal and clinical studies will be analysed using non-linear mixed-effects models. This will lead to generation of PK data that enables the development evidence based guidelines for antibiotic, sedative and analgesic drug therapy during ECMO.

Discussion: Systematic research that integrates both mechanistic and clinical research is desirable when investigating the complex area of pharmacokinetic alterations during ECMO. The above research approach will provide an advanced mechanistic understanding of PK during ECMO. The clinical study when complete will result in development robust guidelines for prescription of 18 commonly used antibiotic, sedative and analgesic drugs used in ECMO patients. This research may also pave the way for further refinements in circuitry, drug chemistry and drug prescriptions during ECMO.

Trial registration: ACTRN12612000559819.

No MeSH data available.


Related in: MedlinePlus

Significant sequestration of drugs in the ECMO circuit increases their volumes of distribution leading to suboptimal drug concentrations in the body. A mere increase in administered dose for all drugs during ECMO may not suffice, as the less sequestered drugs may reach toxic levels. A - PVC tubing, B- pump, C- oxygenator (Reproduced with Permission, Shekar et al Journal of Crit Care 2012).
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Figure 2: Significant sequestration of drugs in the ECMO circuit increases their volumes of distribution leading to suboptimal drug concentrations in the body. A mere increase in administered dose for all drugs during ECMO may not suffice, as the less sequestered drugs may reach toxic levels. A - PVC tubing, B- pump, C- oxygenator (Reproduced with Permission, Shekar et al Journal of Crit Care 2012).

Mentions: In critically ill patients not receiving ECMO, it has been shown PK changes can result in highly significant changes to drug exposure through interactions between the patient, pathology and the drug [9-12]. The ECMO system introduces additional variables, which are the circuit itself, and the effects of systemic inflammation due to the prolonged use of an extracorporeal circuit. Sequestration of drugs in the circuit, increased volume of distribution (Vd) and decreased clearance (CL) are the major PK changes associated with ECMO [8], although the extent of change remains poorly characterised. Published data from neonatal circuit studies highlight the influence that drug properties such as molecular size, degree of ionization at physiological pH, lipophilicity and plasma protein binding have on drug disposition during ECMO [13,14]. In a manner analogous to the lung it mimics, ECMO is critically dependent upon the large surface area of the oxygenator and associated tubing to ensure adequate blood flows through the circuit and facilitate gas transfer. This bio-synthetic interface results in significant sequestration of the administered drugs resulting in a compartmental effect on PK (FigureĀ 2). The type and age of circuit components including type of the pump, oxygenator and tubing as well as circuit priming may influence the level of drug sequestration [15-18]. Patient factors such as systemic inflammation, haemodilution, bleeding and transfusion, organ dysfunction and renal replacement therapy all add to the clinical challenges of drug dosing during ECMO [8].


The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation.

Shekar K, Roberts JA, Smith MT, Fung YL, Fraser JF - BMC Anesthesiol (2013)

Significant sequestration of drugs in the ECMO circuit increases their volumes of distribution leading to suboptimal drug concentrations in the body. A mere increase in administered dose for all drugs during ECMO may not suffice, as the less sequestered drugs may reach toxic levels. A - PVC tubing, B- pump, C- oxygenator (Reproduced with Permission, Shekar et al Journal of Crit Care 2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643838&req=5

Figure 2: Significant sequestration of drugs in the ECMO circuit increases their volumes of distribution leading to suboptimal drug concentrations in the body. A mere increase in administered dose for all drugs during ECMO may not suffice, as the less sequestered drugs may reach toxic levels. A - PVC tubing, B- pump, C- oxygenator (Reproduced with Permission, Shekar et al Journal of Crit Care 2012).
Mentions: In critically ill patients not receiving ECMO, it has been shown PK changes can result in highly significant changes to drug exposure through interactions between the patient, pathology and the drug [9-12]. The ECMO system introduces additional variables, which are the circuit itself, and the effects of systemic inflammation due to the prolonged use of an extracorporeal circuit. Sequestration of drugs in the circuit, increased volume of distribution (Vd) and decreased clearance (CL) are the major PK changes associated with ECMO [8], although the extent of change remains poorly characterised. Published data from neonatal circuit studies highlight the influence that drug properties such as molecular size, degree of ionization at physiological pH, lipophilicity and plasma protein binding have on drug disposition during ECMO [13,14]. In a manner analogous to the lung it mimics, ECMO is critically dependent upon the large surface area of the oxygenator and associated tubing to ensure adequate blood flows through the circuit and facilitate gas transfer. This bio-synthetic interface results in significant sequestration of the administered drugs resulting in a compartmental effect on PK (FigureĀ 2). The type and age of circuit components including type of the pump, oxygenator and tubing as well as circuit priming may influence the level of drug sequestration [15-18]. Patient factors such as systemic inflammation, haemodilution, bleeding and transfusion, organ dysfunction and renal replacement therapy all add to the clinical challenges of drug dosing during ECMO [8].

Bottom Line: Mixed-effects regression models will be used to estimate the drug loss over time in ex vivo studies.Data from animal and clinical studies will be analysed using non-linear mixed-effects models.ACTRN12612000559819.

View Article: PubMed Central - HTML - PubMed

Affiliation: Critical Care Research Group, Adult Intensive Care Services, The Prince Charles, Hospital and The University of Queensland, Brisbane, QLD, 4032, Australia. kiran_shekar@health.qld.gov.au.

ABSTRACT

Background: Extracorporeal membrane oxygenation (ECMO) is a supportive therapy and its success depends on optimal drug therapy along with other supportive care. Emerging evidence suggests significant interactions between the drug and the device resulting in altered pharmacokinetics (PK) of vital drugs which may be further complicated by the PK changes that occur in the context of critical illness. Such PK alterations are complex and challenging to investigate in critically ill patients on ECMO and necessitate mechanistic research. The aim of this project is to investigate each of circuit, drug and critical illness factors that affect drug PK during ECMO.

Methods/design: An incremental research plan that encompasses ex vivo experiments for drug stability testing in fresh human and ovine whole blood, ex vivo drug disposition studies in standard and modified adult ECMO circuits primed with fresh human or ovine whole blood, PK studies in healthy and critically ill ovine models of ECMO with appropriate non ECMO controls and an international mutli-centre clinical population PK study will be utilised to comprehensively define the PK alterations that occur in the presence of ECMO. Novel drug assays that will allow quantification of multiple drugs in small volumes of plasma will also be developed. Mixed-effects regression models will be used to estimate the drug loss over time in ex vivo studies. Data from animal and clinical studies will be analysed using non-linear mixed-effects models. This will lead to generation of PK data that enables the development evidence based guidelines for antibiotic, sedative and analgesic drug therapy during ECMO.

Discussion: Systematic research that integrates both mechanistic and clinical research is desirable when investigating the complex area of pharmacokinetic alterations during ECMO. The above research approach will provide an advanced mechanistic understanding of PK during ECMO. The clinical study when complete will result in development robust guidelines for prescription of 18 commonly used antibiotic, sedative and analgesic drugs used in ECMO patients. This research may also pave the way for further refinements in circuitry, drug chemistry and drug prescriptions during ECMO.

Trial registration: ACTRN12612000559819.

No MeSH data available.


Related in: MedlinePlus