![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](https://image.slidesharecdn.com/adjustingdrugdosingecmocriticalcareconferenceegypt-170125124122/75/Adjusting-drug-dosing-in-ECMO-patients-24-2048.jpg)
Uploaded byDr.Mahmoud Abbas
Adjusting drug dosing in ECMO patients
The document discusses optimizing drug dosing for patients on extracorporeal membrane oxygenation (ECMO), outlining the effects of ECMO on drug pharmacokinetics and providing recommendations for various medications used during ECMO treatment. Key factors influencing drug disposition include drug stability, lipophilicity, and protein binding, with specific suggestions for antibiotics, sedatives, and analgesics dosages. Ongoing research aims to develop appropriate dosing guidelines to improve therapeutic outcomes in critically ill patients receiving ECMO support.
More Related Content
Similar to Adjusting drug dosing in ECMO patients
Adjusting drug dosing in ECMO patients
- 1. Optimizing Drug Dosingfor 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 ofECMO 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 ECMOCircuit Ha MA, Sieg AC. Pharmacotherapy.2016
- 6. Factors Influencing PharmacokineticAlterations 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 duringECMO Altered Volume of distribution Altered renal or hepatic Clearance Altered Serum drug Concentration Altered half life
- 8.
- 9. ECMO and Drugs Pharmacologic Support Safetyand Efficacy
- 10. Type of Studies Invitro Ex Vivo In vivo Animal studies Clinical Trials Case Reports
- 11. Commonly Studied Medicationsin ECMO Anticoagulants Antimicrobials Sedatives and analgesics
- 12.
- 13. Antibiotics Concentration dependent antibiotics Aminoglycosides Quinolones Time dependentantibiotics β-Lactams Penicillins Cephalosporins Carbapenems Macrolides Vancomycin, Linezolid
- 14.
- 15. In vitro, Exvivo 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 andVancomycin Tron C. et al. Clin. Exp. Pharmacol. Physiol.2016; 43:281–28 Shekar et al. Critical Care (2012) 16:R194
- 17. Meropenem (MEM) andPiperacillin/Tazobactam (TZP) Donadello K. et al. International Journal of Antimicrobial Agents (2015) 45: 278–282
- 18. Meropenem Simulated mean meropenemlogarithmic 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 MeropenemTreatment 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/TazobactamTreatment 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 of2 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 associatedwith 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 DeGradoJR. 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 DeGradoet al. 2017 Nigoghossian et al. 2016 Shekar . et al. 2012 Mediandailydoseofbenzodiazepineequivalents(mg)
- 29.
- 30. Heparin vs Bivalirudin PieriM. et al. J Cardiothorac Vasc Anesth. 2013; 27: 30-4
- 31. Dosing of Anticoagulantsin 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 PKProject 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 inthe 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 Dosesof 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 cansignificantly 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 drugdosage 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.
- 40. Therapeutic Drug MonitoringDose Individualization
- 41.
- 42.
- 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