Pharmacokinetics and ECMO

OVERVIEW

• ECMO support has potential implications for pharmacotherapy in the critically ill, the significance of which are poorly defined
• Pharmacokinetic effects of ECMO vary with:
  • different drugs and drug characteristics
  • different types and compositions of ECMO circuit components
• The effect of ECMO on pharmacokinetics may contribute to
  • therapeutic failure
  • drug toxicity, and/or
  • antimicrobial resistance

CHARACTERISTICS OF PATIENTS RECEIVING ECMO

• severe critically illness, with either respiratory failure (VV-ECMO) or circulatory failure (VA-ECMO), or both
• multi-organ dysfunction syndrome (MODS) is common (including AKI and the need for RRT)
• presence of an extracoporeal circuit (oxygenator, pump, circuit tubing and cannulae)
  • drug sequestration in extracorporeal circuit
  • increased volume of distribution and hemodilution
  • altered blood flow (may be non-pulsatile in VA-ECMO; regional differences)
  • SIRS response to extracoporeal circuit
• often receiving multiple medications, with potential for drug interactions

PHARMACOKINETIC EFFECTS OF ECMO

Mixing of priming volume with the patient’s own blood volume increase effective circulating volume

• causes acute hemodilution and decrease in total blood concentration of drugs
• pharmacological impact depends on:
  • apparent volume of distribution (Vd) of the drugs
  • degree of protein binding, and
  • the extent of equilibration between tissue and plasma concentrations on initiation of ECMO
• Drugs with small Vd (e.g. gentamicin) are significantly affected compared to drugs with large Vd (e.g. amiodarone)
• Depletion of plasma protein (e.g. albumin) may affect plasma and tissue protein binding and plasma concentrations of drugs (typically transient due to administration of albumin and blood products)

Changes in blood flow affect clearance of drugs during ECMO

• Non-pulsatile flow in VA-ECMO can alter perfusion of tissues, reduce capillary circulation and aerobic metabolism
• Kidneys interpret pulseless blood flow as hypotension thus activating the renin-angiotensin system (leads to reduced urine production and impaired sodium excretion)
• Regional blood flow changes in the liver can affect drug clearance (especially those with a high extraction ratio e.g. propranolol)
• Decreased pulmonary blood flows, especially during VA ECMO, may affect sequestration and metabolism of many sedative and analgesic drugs by the lungs
• SIRS response to ECMO results in autonomic, endocrine and local cytokine factors that alter tissue distribution of drugs as well as clearance

Drug adsorption to components of the ECMO circuit

• Drug properties may influence the degree of binding to the circuit components
• Important drug properties include:
  • molecular size
  • degree of ionization
  • lipophilicity
  • plasma protein binding
• the circuit may continue to release the sequestrated molecules once a particular drug infusion is ceased
• it is unclear how priming of a circuit with different fluids affects drug sequestration
• Centrifugal pump circuits with hollow-fibre membrane oxygenators show less absorption for all drugs, most pronounced for lipophilic drugs

Summary table from Shekar et al (2012):

SPECIFIC DRUGS

Some examples:

• Antifungals — voriconazole is sequestered; caspofungin is usual dose
• Sedatives — Midazolam hashigher Vd and CL on ECMO, absorptive drug loss could be a cause of higher dose requirements. Propofol, which is lipophilic and highly protein bound, is significantly sequestered in the circuit
• Analgesics — fentanyl extensively binds to ECMO circuit after 24h, requiring higher doses; morphine preferred for longer term use

DRUG DOSING CONSIDERATIONS

From Erstad (2015):

• Drug dosing recommendations for an adult on ECMO are unlikely to be evidenced-based
• Data from neonatal case reports, case series or studies may not apply to adults
• Data from one drug may not be applicable to another even from the same class
• Drug regimen recommendations in critical care guidelines may not apply to patients on ECMO
• Organ dysfunction apart from the lung and heart complicate interpretation of literature
• The contribution of distinct physicochemical properties of drugs to sequestration is unclear
• Hydrophilicity or lipophilicity appear to be important factors affecting pharmacokinetics
• The therapeutic actions of drugs are not consistently predictable by pharmacokinetics
• The design and properties of the equipment change over time with implications for dosing
• The priming solution such as blood or blood-derived products may affect dosing

Therapeutic implications

• pharmacokinetic effects of ECMO are less problematic for drugs that can be titrated to endpoints (e.g. vasopressors, sedation), but are problematic for those that cannot (e.g. antibiotics)
• use therapeutic drug monitoring to individualise pharmacotherapy of ECMO patients if possible

References and Links

LITFL

• CCC – Everything ECMO
• CCC – ECMO troubleshooting
• CCC – Own the ECMO (presentation by Hergen Buescher, 2011)

Journal articles

• Erstad BL. Designing drug regimens for special intensive care unit populations. World journal of critical care medicine. 4(2):139-51. 2015. [pubmed]
• Mousavi S, Levcovich B, Mojtahedzadeh M. A systematic review on pharmacokinetic changes in critically ill patients: role of extracorporeal membrane oxygenation. Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 19(5):312-21. 2011. [pubmed]
• Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. Journal of critical care. 27(6):741.e9-18. 2012. [pubmed]