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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

Validated ovine ECMO model. Reproduced with permission, Fung et al, ISBT Science Series 2012.
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Figure 6: Validated ovine ECMO model. Reproduced with permission, Fung et al, ISBT Science Series 2012.

Mentions: Following 12 hours of ventilation and PK sampling the healthy control sheep will be maintained on ECMO for 24 h. We have recently published a detailed description of our ovine model (Figure 6) of ECMO [39]. Cannulation will be performed in the supine position by rewiring the previously placed IJV venous sheaths. A 21Fr (50 cm) femoral Carmeda Bioactive Surface coated (CBAS®) venous cannula (Medtronic Inc, Minneapolis, MN, USA) will be inserted into the right IJV using a Seldinger technique and positioned using intra cardiac echocardiography (ICE) [47] in the proximal inferior vena cava (IVC). A 19Fr (50 cm) Carmeda coated femoral venous cannula will be used for return blood and also inserted in the right IJV and positioned at the mid right atrium using ICE. Pump speeds will be titrated to target flows at least 2/3rd of pre-ECMO CO (or 60–80 mL/kg). Sedative study drug infusions will be titrated to clinical effect. Antibiotics will be infused over 30 mins upon commencement of ECMO and at 8 and 12 h (for re-dose PK) to obtain serial blood samples for drug assays using validated LC-MS/MS methods, and subsequent PK analysis.


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)

Validated ovine ECMO model. Reproduced with permission, Fung et al, ISBT Science Series 2012.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Validated ovine ECMO model. Reproduced with permission, Fung et al, ISBT Science Series 2012.
Mentions: Following 12 hours of ventilation and PK sampling the healthy control sheep will be maintained on ECMO for 24 h. We have recently published a detailed description of our ovine model (Figure 6) of ECMO [39]. Cannulation will be performed in the supine position by rewiring the previously placed IJV venous sheaths. A 21Fr (50 cm) femoral Carmeda Bioactive Surface coated (CBAS®) venous cannula (Medtronic Inc, Minneapolis, MN, USA) will be inserted into the right IJV using a Seldinger technique and positioned using intra cardiac echocardiography (ICE) [47] in the proximal inferior vena cava (IVC). A 19Fr (50 cm) Carmeda coated femoral venous cannula will be used for return blood and also inserted in the right IJV and positioned at the mid right atrium using ICE. Pump speeds will be titrated to target flows at least 2/3rd of pre-ECMO CO (or 60–80 mL/kg). Sedative study drug infusions will be titrated to clinical effect. Antibiotics will be infused over 30 mins upon commencement of ECMO and at 8 and 12 h (for re-dose PK) to obtain serial blood samples for drug assays using validated LC-MS/MS methods, and subsequent PK analysis.

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