Lecture presented by Dr Naglaa Bazan at the Egyptian ECMO day -Egyptian African Critical Care Summit held at Cairo, Egypt

1. Optimizing Drug Dosing for Patients on
Extracorporeal membrane oxygenation
(ECMO)
Dr. Naglaa Bazan
PhD in Clinical Pharmacy- Cairo University
Fellow and Head of Clinical Pharmacy
Critical Care Medicine Department
Cairo University Hospitals

2. Objectives
• Effect of ECMO support on Drugs
• Changes in drug pharmacokinetics during ECMO
• Summary of literature evaluating different drugs used during ECMO
• Current ongoing research and recommendations for optimizing drug
dosing during ECMO in adult patients

5. Components of ECMO Circuit
Ha MA, Sieg AC. Pharmacotherapy.2016

6. Factors Influencing Pharmacokinetic Alterations
ECMO circuit
factors
Drug Factors
Patient
Factors
Drug sequestration
Circuit Priming
Circuit Age
Altered Blood Flow
Drug sequestration
Serum protein
Acid-base disorders
Volume status
Systemic Inflammation
Organ Dysfunction

7. Pharmacokinetic Alterations during ECMO
Altered
Volume of
distribution
Altered renal
or hepatic
Clearance
Altered Serum
drug
Concentration
Altered half
life

8. ECMO and Drugs
Toxicity

9. ECMO and Drugs
Pharmacologic
Support
Safety and
Efficacy

10. Type of Studies
In vitro
Ex Vivo
In vivo
Animal studies
Clinical Trials
Case Reports

11. Commonly Studied Medications in ECMO
Anticoagulants
Antimicrobials
Sedatives and
analgesics

12. Antimicrobials

13. Antibiotics
Concentration dependent
antibiotics
Aminoglycosides
Quinolones
Time dependent antibiotics
β-Lactams
Penicillins
Cephalosporins
Carbapenems
Macrolides
Vancomycin, Linezolid

14. Pharmacokinetic and Pharmacodynamic
Parameters

15. In vitro, Ex vivo and In vivo animal Studies
Drug Lipophilicity/Hydrophilicity Protein binding Sequestration
Vancomycin Hydrophilic 55% Non-significant
Meropenem Hydrophilic 2% unstable at
physiological
temperature
Ceftriaxone Hydrophilic 95 %
Ciprofloxacin lipophilic 20-40% Non- significant
Linezolid Hydrophilic 31 % Non-Significant
Gentamicin Hydrophilic 0-30% NA
Caspofungin Hydrophilic 97%
Voriconazole Lipophilic 58%
Fluconazole Hydrophilic 11-12% Non- Significant

16. Cephalosporins, Carbapenems and Vancomycin
Tron C. et al. Clin. Exp. Pharmacol. Physiol.2016; 43:281–28 Shekar et al. Critical Care (2012) 16:R194

17. Meropenem (MEM) and Piperacillin/Tazobactam (TZP)
Donadello K. et al. International Journal of Antimicrobial Agents (2015) 45: 278–282

18. Meropenem
Simulated mean meropenem logarithmic
Concentrations in a critically ill patient on ECMO
With CrCL of 20, 50, 80, 120 and 180 mL/min for
(a) 500 mg IV 8-hourly,
(b) 1 g IV 8-hourly and
(c) 2 g IV 8-hourly
Shekar K. et al. Critical Care. 2014;18(6):565.
Meropenemconc.(mg/L)Meropenemconc.(mg/L)Meropenemconc.(mg/L)

19. Optimization of Meropenem Treatment during
ECMO/Critical Illness
More frequent dosing
Dose increase
Prolonged infusion
Ideally, meropenem should be infused
continuously over 24 h but, it is relatively
unstable at room temperature
3-hour infusion is safe
Routine target concentrations >2 mg/L are maintained with standard
dosing (1 g IV 8-hourly). However, an increase in dose may be necessary
when targeting higher concentrations or in patients with elevated
creatinine clearance
Shekar et al. Crit Care. 2014 Dec 12;18(6):565

20. Optimization of Pipracillin/Tazobactam Treatment
during ECMO/Critical Illness
Administering the antibiotic over half the dosing interval ( 3 h if given
QID), or administering the total daily dose as a continuous infusion over
24 h after an initial loading dose
Cota et al. Crit Care. 2016; 20: 163
Therapeutic Drug
Monitoring

21. Imipenem
A report of 2 patients supported with venovenous ECMO for refractory acute
respiratory distress syndrome following single lung transplantation for pulmonary
fibrosis
Treated empirically with 1 g of imipenem intravenously every 6 h
Enterobacter cloacae was isolated from the respiratory sample
Treated empirically with 1 g of imipenem intravenously every 6 h
Klebsiella pneumoniae was isolated from the respiratory sample
Welsch et al. Transpl Infect Dis. 2015 Feb;17(1):103-5
Patient 1
Patient 2
An elevated dosing regimen (4 g/24 h)
is more likely to optimize drug
exposure, and therapeutic drug
monitoring is recommended, where
available

22. Vancomycin
Efficacy is associated with
maintaining an AUC/MIC ratio
of ≥ 400.
The goal trough is 15 to 20
mg/mL
Moore et al.CPT Pharmacometrics Syst Pharmacol. 2016 Sep; 5(9): 495–502
Mulla et al. Br J Clin Pharmacol (2005) 60:265–275
• Recent adult data have largely shown that ECMO does not
significantly affect vancomycin V and CL
Vancomycin PK alteration
Priming
volume
Transfusion
and
hemodilution
Decreasing
renal
function
Sequestering
drugs in the
ECMO circuit

23. Vancomycin Pharmacokinetics
Wu CC. et al. J Formos Med Assoc. 2016;115(7):560-70

24. Vancomycin
ECMO Control
Subtherapeutic trough
Concentration (<10 mg/dl)
54% >50%
Supratherapeutic trough
concentrations (> 20 mg/dl)
18.2% NA
Efficacy is associated with
maintaining an AUC/MIC ratio
of ≥ 400.
The goal trough is 15 to 20
mg/mL
Maintenance dose (mg/kg/24 hours) =
0.684 * CLCr (mL/ min/1.73 m2) - 6.408]
New Dosing Method
(CLCr > 20 mL/ min/1.73 m) + Continous infusion
+ Therapeutic Drug Monitoring
Wu CC. et al. J Formos Med Assoc. 2016;115(7):560-70

25. Antivirals: Oseltamivir
Lemaitre F. et al. Therapeutic Drug Monitoring. 2012; 34:171–5
Group 1: patients with ECMO + CVVHD. Group 2: patients with ECMO alone
Mulla H.et al. Anaesth Intensive Care. 2013;41(1):66-73

26. Sedatives and Analgesics: In vitro, Ex vivo and
In vivo animal Studies
Drug Lipophilicity/Hydrophilicity Protein
binding
Sequestration
Midazolam Lipophilic 92 %
Fentanyl Lipophilic 85 %
Propofol Lipophilic 95-99 %
+ Oxidation
Morphine Hydrophilic 30% Non- significant
Thiopental Lipophilic 80%

27. Sedatives and Analgesics
DeGrado JR. et al. J Crit Care. 2017;37:1-6
Name of the
Study
•DeGrado JR, Hohlfelder B, Ritchie BM. et al. Evaluation of sedatives, analgesics, and
neuromuscular blocking agents in adults receiving extracorporeal membrane
oxygenation. J Crit Care. 2017;37:1-6
•Settings: Brigham and Women's Hospital , a 793-bed tertiary care facility
Aim
•Evaluate the use of sedative, analgesic, and neuromuscular blocking agents (NMBAs)
in patients undergoing extracorporeal membrane oxygenation (ECMO) support
Patients and
Methods
•A 2-year, prospective, observational study of adult intensive care unit patients on
ECMO support for more than 48 hours
•Patients: 32 including 15 receiving VA (venoarterial) ECMO and 17 VV (venovenous)
ECMO
Conclusion
•Patients received relatively low doses of sedatives and analgesics while at a light level
of sedation on average. Patients rarely required neuromuscular blockade.
•The hypothesis that patients on ECMO require high doses of sedatives and analgesics
should be further investigated

28. Sedatives and Analgesics
24
118
175
0
20
40
60
80
100
120
140
160
180
200
DeGrado et al. 2017 Nigoghossian et al. 2016 Shekar . et al. 2012
Mediandailydoseofbenzodiazepineequivalents(mg)

29. Anticoagulants
Heparin
Bivalirudin
Argatroban

30. Heparin vs Bivalirudin
Pieri M. et al. J Cardiothorac Vasc Anesth. 2013; 27: 30-4

31. Dosing of Anticoagulants in ECMO
Name
Altered pharmacokinetics Dosing recommendation during
ECMO (Adults)
Heparin Adsorption by circuit
or by blood
components in circuit
bolus of 50-100 units per kg body
weight at the time of
cannulation, then continuous
infusion, target aPTT
Argatroban Unknown 0.15–0.2 µg/kg/min was effective.
Usual dosage of 2µg/kg/min
resulted in excessive bleeding
Or 0.35 µg/kg/min starting dose,
continuous infusion
0.25–1.6 µg/kg/min (aPTT)
Bivalirudin Unknown Bolus 0.5 mg/kg, Infusion of 0.5
mg/kg/h was successful
Or bolus
0.5 mg/kg, initial infusion after
bolus 0.5 mg/kg/h,
continuous infusion during ECMO
0.05–0.15 mg/kg/h (aPTT)

33. The ECMO Pharmacokinetic (PK) Project
Trial
Registration
• Trial registered on ANZCTR , ID: ACTRN12612000559819, Trial acronym: ASAP-ECMO
Scientific
Title
• Pharmacokinetic modelling of antibiotic, sedative and analgesic drugs and their relevant metabolites in critically
ill patients receiving extracorporeal membrane oxygenation (ECMO) and development of dosing guidelines to
optimise drug therapy during ECMO
Inclusion
criteria
• Currently undergoing ECMO for respiratory +/- cardiac dysfunction
• Clini-cal indication of the studied drugs
• Age:18-89 years
Exclusion
Criteria
•- No valid consent
- Known allergy to study drug
- Pregnancy
- S. Bilirubin >150
- Ongoing massive blood loss and blood product transfusion
- Therapeutic plasma exchange in the last 24 hours
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347691
Sample size 160

34. The ECMO PK Project
Location
• Australia: The Prince Charles, Hospital, St Vincent's Hospital (Darlinghurst) , The Alfred – Prahran.
• New Zealand
Aim
• Understand the combined effects of the ECMO circuit and severe illness on drug treatment. The results will allow to
develop guidelines to assist doctors in administering the right dose of the right drug at the right time to patients on
ECMO
1ry
Outcomes
• Develop population PK models for antibiotic, sedative, analgesic and drugs and their relevant metabolites in
critically ill patients receiving ECMO
• Develop guidelines to optimise the dosing of sedative, analgesic and antibiotic drugs during ECMO
2ry
Outcomes
• Improving sedation practices during ECMO
• Developement of ECMO specific sedation protocols

35. Drugs Included in the Study
• Antibiotics
Ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum,
ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir
• Sedatives and analgesics
Midazolam
Morphine
Fentanyl
Propofol
Dexmedetomidine
Thiopentone

36. Recommended Starting Doses of Sedatives
and Analgesics in the ECMO PK Project
Drug (IV bolus/infusion) Dose Comment
Morphine 10-30 mg/hr Titrated to a Richmond Agitation
Sedation Scale (RASS) of -3 to -4
and a bispectral index (BIS) of 40-
45.
Patient ventilator interactions may
also be used as a guide to titrate
sedation especially in patients on
venovenous ECMO
Midazolam 10-30 mg/hr
Propofol 10-200 mg/hr Additional intravenous sedation if
required may be provided with
one of the following agents
Dexmeditomedine 1 mcg/kg bolus and 0.1 -1.5
mcg/kg/min
Fentanyl if morphine is
discontinued for clinical reasons.
50-300 mcg/hour
Thiopentone ( 100-200 mg/hour)* 100-200 mg/hour

37. Conclusions
• ECMO can significantly alter drug pharmacokinetics by different
mechanisms
• Drug stability, lipophilicity and protein binding are the three key drug
factors that influence drug disposition in ECMO circuits
• PK alterations of hydrophilic drugs might be more likely due to the
haemodilution mechanism associated with the additional
compartment represented by the circuit or high volume of fluid
supplementation requested in intensive care patients
• Optimal drug prescription during ECMO remains a developing science

38. Conclusions
• Altered drug dosage regimens may be necessary in both pediatric and adult
patients
• Dose requirements may change throughout treatment course
• Morphine being less lipophilic than fentanyl, making it a potentially superior
option when managing patients receiving ECMO
• Don’t rely on the one size fits all’ paradigm when choosing the antibiotic dose
• Meropenem may be a better drug for adults on ECMO
• Vancomycin and antifungal dosing should be guided by therapeutic drug
monitoring
• Unlike bivalirudin, argatroban's primary route of elimination is via the liver,
making it potentially attractive in patients with renal dysfunction
• Dexmedetomidine may be a promising sedative and analgesic in ECMO

39. Recommendations

40. Therapeutic Drug Monitoring Dose Individualization

41. Research

42. Multidisciplinary Team

44. References
• Sherwin J, Travis Heath T, Watt K. Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on
Extracorporeal Membrane Oxygenation: A Review of the Current Literature. Clinical Therapeutics.2016; 38: 9.
• Pereira JG, Oliveira B. Antibiotics and extracorporeal circulation – one size does not fit all Critical Care. 2014;
18:695
• Shekar K, Roberts JA, Mcdonald CI. et al. Protein-bound drugs are prone to sequestration in
the extracorporeal membrane oxygenation circuit: resultsfrom an ex vivo study. Crit Care. 2015;19:164
• Donadello K, Antonucci E, et al. β-Lactam pharmacokinetics during extracorporeal membraneoxygenation
therapy: A case–control study. Int J Antimicrob Agents. 2015;45(3):278-82
• Lemaitre F, Luyt CE. et al. Impact of extracorporeal membrane
oxygenation and continuous venovenous hemodiafiltration on the
pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug
Monit.2012;34:171-5
• HA MA., Sieg AC. Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal
Membrane Oxygenation. Pharmacotherapy. 2016. doi: 10.1002/phar.1882
• Mulla H, Peek GJ, Harvey C, et al. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal
membrane oxygenation support. Anaesth Intensive Care. 2013;41(1):66-73

45. References
• Lemaitre F, Luyt CE, Roullet-renoleau F, et al. Impact of extracorporeal membrane oxygenation and continuous
venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic
(H1N1) influenza. Ther Drug Monit 2012;34(2):171-5.
• Donadello K, Antonucci E, Cristallini S, et al. β-Lactam pharmacokinetics during extracorporeal membrane oxygenation
therapy: A case-control study. Int J Antimicrob Agents 2015;45(3):278- 82
• Shekar K, Fraser JF, Taccone FS, et al. The combined effects of extracorporeal membrane oxygenation and renal
replacement therapy on meropenem pharmacokinetics: a matched cohort study. Critical Care. 2014;18(6):565.
• Tron C, Leven C, Fillâtre P. et al. Should we fear tubing adsorption of antibacterial drugs in extracorporeal membrane
oxygenation? An answer for cephalosporins and carbapenems. CEPP. 2016; 43:281–283
• Rybak M., Lomaestro B., Rotschafer J.,et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of
the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of
Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66: 82–98.
• Shekar K, Roberts JA, Smith MT. et al. The ECMO PK Project: an incremental research approach to advance understanding
of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation. BMC
Anesthesiology 2013, 13:7

46. References
• Lemaitre F, Hasni N, Leprince P. et al. Propofol, midazolam, vancomycin and cyclosporin therapeutic drug monitoring
in extracorporealmembrane oxygenation circuits primed with whole human blood. Crit Care. 2015 ;19:40.
• Shekar K, Robersts JA, Mcdonald CI. et al. Sequestration of drugs in the circuit may lead to therapeutic failure during
extracorporeal membrane oxygenation. Critical Care. 2012; 16:R194.
• Shekar K, Roberts JA, Mcdonald CI. et al. Protein-bound drugs are prone to sequestration in the extracorporeal membrane
oxygenation circuit: results from an ex vivo study. Critical Care. 2015; 19:164.
• Shekar K, Roberts JA, Barnett AG. et al. Can physicochemical properties of antimicrobials be used to predict their
pharmacokinetics during extracorporeal membrane oxygenation? Illustrative data from ovine models. Critical Care. 2015;
19:437.
• DeGrado JR, Hohlfelder B, Ritchie BM. et al. Evaluation of sedatives, analgesics, and neuromuscular blocking agents in
adults receiving extracorporeal membrane oxygenation. J Crit Care. 2017 Feb;37:1-6
• Shekar K, Roberts JA, Mullany DV, Corley A, Fishquet S, Bull TN, et al. Increased sedation requirements in patients receiving
extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intensive Care 2012;40:648–
55.

47. References
• Wu CC, Shen LJ, Hsu LF, et al. Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation J
Formos Med Assoc. 2016;115(7):560-70
• Mulla H, Pooboni S. Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane
oxygenation. Br J Clin Pharmacol 2005;60:265e75
• Moore JN, Healy JR, Peahota MM, et al. A Population Pharmacokinetic Model for Vancomycin in Adult Patients Receiving
Extracorporeal Membrane Oxygenation Therapy. CPT Pharmacometrics Syst Pharmacol. 2016 Sep; 5(9): 495–502
• Nigoghossian CD, Dzierba AL, Etheridge J, et al. Effect of extracorporeal membrane oxygenation use on sedative
requirements in patients with severe acute respiratory distress syndrome. Pharmacotherapy 2016;36(6):606–16.
• Shekar K, Fraser JF, Taccone FS, et al. The combined effects of extracorporeal membrane oxygenation and renal
replacement therapy on meropenem pharmacokinetics: a matched cohort study. Critical Care 2014, 18:565.
• Cotta MO, Jason A, Roberts JA, Lipman J. We need to optimize piperacillintazobactam dosing in critically ill patients—but
how? Critical Care. 2016; 20:163