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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

Proposed methods to understand the pharmacokinetic changes and optimise drug therapy during extracorporeal membrane oxygenation (ECMO).
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Figure 4: Proposed methods to understand the pharmacokinetic changes and optimise drug therapy during extracorporeal membrane oxygenation (ECMO).

Mentions: Although data from clinical studies of the impact of ECMO on altering the PK of drugs used in patients on ECMO will have great applicability for optimisation of pharmacotherapy, mechanistic research is required to identify the specific factors contributing to these PK changes. To gain insight into these factors, research using simulated circuits and large animal models are required so that individual variables can be altered in a systematic manner enabling the impact of each change to be quantified in an accurate and cost-effective manner. Additionally, this will define the interplay between critical illness and the extracorporeal circuit that result in altered PK during ECMO. The new knowledge to be generated has major implications for improving patient outcomes during ECMO therapy and extracorporeal technology in general. A proposed research plan that is being currently being implemented uses an incremental approach as shown schematically in and Figures 3 and 4. The study drugs are tabulated in Table 1.


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)

Proposed methods to understand the pharmacokinetic changes and optimise drug therapy during extracorporeal membrane oxygenation (ECMO).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Proposed methods to understand the pharmacokinetic changes and optimise drug therapy during extracorporeal membrane oxygenation (ECMO).
Mentions: Although data from clinical studies of the impact of ECMO on altering the PK of drugs used in patients on ECMO will have great applicability for optimisation of pharmacotherapy, mechanistic research is required to identify the specific factors contributing to these PK changes. To gain insight into these factors, research using simulated circuits and large animal models are required so that individual variables can be altered in a systematic manner enabling the impact of each change to be quantified in an accurate and cost-effective manner. Additionally, this will define the interplay between critical illness and the extracorporeal circuit that result in altered PK during ECMO. The new knowledge to be generated has major implications for improving patient outcomes during ECMO therapy and extracorporeal technology in general. A proposed research plan that is being currently being implemented uses an incremental approach as shown schematically in and Figures 3 and 4. The study drugs are tabulated in Table 1.

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