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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

Ex vivo ECMO circuit model. A -reservoir bladder, B- oxygenator, C- centrifugal pump, D-drug injection and sampling port, E- circuit tubing.
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Figure 5: Ex vivo ECMO circuit model. A -reservoir bladder, B- oxygenator, C- centrifugal pump, D-drug injection and sampling port, E- circuit tubing.

Mentions: A validated ex vivo model of ECMO has been previously published [38,39]. Briefly, Maquet PLS ECMO circuits will be used (Maquet Cardiopulmonary AG, Hechinger Straße, Germany). A reservoir bladder (Medtronic R38) will allow sampling from the closed circuit (Figure 5). The circuit will be primed with Plasmalyte, 4% albumin followed by fresh whole blood to obtain a post oxygenator pressure of 230–250 mmHg. The final estimated volume of the pressurised circuit is 668 mL. A centrifugal pump maintained a circuit flow rate of 4–5 L /min. Oxygen tension and circuit temperature and pH will be maintained at 100–150 mm Hg and 37°C. Carbon dioxide gas or sodium bicarbonate solution will be added to the circuit to maintain the pH of the circulating blood in the range 7.25–7.55. Study drugs (Table 1) will be injected post oxygenator to achieve clinically relevant concentrations in the circuit. Serial samples will be obtained post oxygenator over 24 hours. For re-dose PK studies, study drugs will be reinjected at 6, 8 or 12 hours (as per clinical dosing guidelines). This will further investigate potential saturation of the circuit with time and its affect on drug disposition during ECMO.


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)

Ex vivo ECMO circuit model. A -reservoir bladder, B- oxygenator, C- centrifugal pump, D-drug injection and sampling port, E- circuit tubing.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Ex vivo ECMO circuit model. A -reservoir bladder, B- oxygenator, C- centrifugal pump, D-drug injection and sampling port, E- circuit tubing.
Mentions: A validated ex vivo model of ECMO has been previously published [38,39]. Briefly, Maquet PLS ECMO circuits will be used (Maquet Cardiopulmonary AG, Hechinger Straße, Germany). A reservoir bladder (Medtronic R38) will allow sampling from the closed circuit (Figure 5). The circuit will be primed with Plasmalyte, 4% albumin followed by fresh whole blood to obtain a post oxygenator pressure of 230–250 mmHg. The final estimated volume of the pressurised circuit is 668 mL. A centrifugal pump maintained a circuit flow rate of 4–5 L /min. Oxygen tension and circuit temperature and pH will be maintained at 100–150 mm Hg and 37°C. Carbon dioxide gas or sodium bicarbonate solution will be added to the circuit to maintain the pH of the circulating blood in the range 7.25–7.55. Study drugs (Table 1) will be injected post oxygenator to achieve clinically relevant concentrations in the circuit. Serial samples will be obtained post oxygenator over 24 hours. For re-dose PK studies, study drugs will be reinjected at 6, 8 or 12 hours (as per clinical dosing guidelines). This will further investigate potential saturation of the circuit with time and its affect on drug disposition during ECMO.

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