Pharmacotherapy Management in Patients with Extracorporeal ... ECLS...¢  Pharmacotherapy Management

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  • Pharmacotherapy Management in Patients with Extracorporeal Membrane Oxygenation

    Ayesha Ather, PharmD, BCPS, BCCP Program Director, PGY2 Cardiology Pharmacy Residency

    Assistant Adjunct Professor, College of Pharmacy University of Kentucky

  • Faculty Disclosure

    • I have no conflicts of interest to disclose.

  • • Gap = Lack of treatment guidelines and published research often leave providers with no clear way to optimally treat patients

    • Need = Our learners need strategies to manage patients on extracorporeal membrane oxygenation (ECMO)

    Educational Need/Practice Gap

  • Upon completion of this educational activity, you will be able to:

    1. Identify alterations in pharmacokinetics (PK) associated with ECMO

    2. Review dose adjustments and monitoring of analgesics, sedatives, and antimicrobials in critically ill patients on ECMO

    3. Evaluate the anticoagulation management and monitoring practices in patients on ECMO

    Objectives

  • • What is the desired change/result in practice resulting from this educational intervention?

    • As a result of the information/tools provided in this activity, learners should be better able to utilize appropriate pharmacologic therapies to manage patients on ECMO

    Expected Outcome

  • ECLS Registry Report: International Summary 2019

  • Pharmacokinetic Alterations

    Drug Factors Disease Factors

    Extracorporeal Factors

  • Critical Illness

    Augmented Cardiac Output

    Leaky Capillaries/Volume

    Resuscitation

    Altered Protein Binding

    End-organ Dysfunction

    Increased Clearance Increased Volume of Distribution

    Decreased Plasma

    Concentrations

    Decreased Clearance

    Increased Plasma

    Concentrations

    Dzierba et al. Crit Care. 2017:21;21(1):66

  • Extracorporeal Membrane Oxygenation

    Augmented Cardiac Output Hemodilution Drug Sequestration

    End-organ Dysfunction

    Increased Clearance Increased Volume of Distribution

    Decreased Plasma

    Concentrations

    Decreased Clearance

    Increased Plasma

    Concentrations

    Dzierba et al. Crit Care. 2017:21;21(1):66

  • • ECMO Circuit • Tubing type • Oxygenator membrane • Priming solution • Age of the circuit

    Extracorporeal Membrane Oxygenation

    A: Tubing/Pump B: Oxygenator C: Priming solution

    A

    B C

    Preston et al. J Extra Corpor Technol 2010 S;42(3):199-202 Shekar et al. J Crit Care 2012; 27(6): 741.e9-18

    Wildschut et al. Intensive Care Med 2010; 36(12): 2109-2116

  • Drug Factors - Analgesics and Sedatives

    Dzierba AL et al. Pharmacotherapy 2019 Mar;39(3):355-368

    Lipophilicity (log p value) and protein-binding properties of common opioids and sedatives

  • Analgesics and Sedatives

    0

    20

    40

    60

    80

    100

    120

    Morphine Midazolam Fentanyl Propofol

    Pe rc

    en ta

    ge

    Simulated Adult ECMO Circuit

    0 Minutes 1440 Minutes

    Shekar et al. Crit Care. 2012;16(5):R194 Lemaitre et al. Critical Care. 2015;19:40

  • How to Manage Pain and Sedation

  • Routine assessment of pain, agitation and delirium

    Pain should be treated before sedation

    Target light sedation (vs deep sedation)

    Propofol or dexmedetomidine preferred over benzodiazepines for sedation

    Performing rehabilitation or mobilization

    Key Guideline Concepts

    Barr J, et al. Crit Care Med 2013;41(1):263-306 Devlin JW, et al. Crit Care Med 2018;46(9):e825-e873

  • 48-hrs post VV ECMO

    initiation (n=45)

    Deeply sedated, n (%) 43 (96) Continuous infusion sedative, n (%) 43 (96) Continuous infusion opioid, n (%) 44 (98) Daily propofol dose in mg, median (IQR)

    3,380 (1,105–4,110)

    Daily midazolam equivalents dose in mg, median (IQR)

    202 (103–247)

    Daily fentanyl equivalents dose in mcg, median (IQR)

    4,800 (3,000–5,820)

    Application of Guidelines

    24-hrs before VV ECMO

    discontinuation (n=35) 8 (23)

    16 (46) 24 (69) 1,760

    (960–2,960) 32

    (14–81) 1,625

    (610–3,345)

    48-hrs post VV ECMO

    discontinuation (n=30) 1 (3)

    8 (27) 12 (40)

    660 (540–2,220)

    32 (10–122)

    720 (150–1,660)

    DeBacker J, et al. ASAIO J 2018;64:544-551

    IQR: interquartile range

  • Initial Preferred Opioid n=221 (%)

    Fentanyl 171 (77)

    Hydromorphone 36 (16)

    Morphine 10 (5)

    Current Practice and Perceptions Second Preferred

    Opioid n=221 (%)

    Hydromorphone 106 (48)

    Morphine 48 (21)

    Fentanyl 38 (17)

    Initial Preferred Sedative for Deep

    Sedation n=221 (%)

    Propofol 155 (70)

    Benzodiazepines 54 (24)

    Dexmedetomidine 9 (4)

    Ketamine 2 (1)

    Initial Preferred Sedative for Light

    Sedation n=221 (%)

    Dexmedetomidine 100 (45)

    Propofol 85 (39)

    Benzodiazepine infusion 16 (7)

    Benzodiazepine prn 9 (4)

    Second Preferred Sedative for Deep

    Sedation n=221 (%)

    Benzodiazepines 90 (41)

    Dexmedetomidine 52 (23)

    Propofol 41 (19)

    Ketamine 27 (12)

    Second Preferred Sedative for Light

    Sedation n=221 (%)

    Dexmedetomidine 81 (37)

    Benzodiazepine prn 49 (22)

    Propofol 45 (20)

    Ketamine 12 (5)

    Perception that opioid dosing is higher with VV-ECMO = 121 (55) Perception that sedation dosing is higher with VV-ECMO = 131 (59)

    Dzierba et al. J Crit Care. 2019 Oct;53:98-106

  • • Drug dosing recommendations are unlikely to be evidence- based

    • Use published pharmacokinetic data in critically ill patients to make dosage adjustments

    • Set daily sedation goals and consider daily interruption of sedatives

    • Lipophilicity and protein binding appear to be important factors affecting pharmacokinetics

    Analgesia and Sedation Considerations

  • • Therapeutic failure

    • Potential emergence of resistant microorganisms

    • Toxicity

    Antimicrobial Dosing Considerations

    HA et al. Pharmacotherapy. 2017;37(2):221-235

  • Drug Factors - Antimicrobials

    Lipophilicity (log p value) and protein-binding properties of common antimicrobials

    Dzierba AL et al. Pharmacotherapy 2019 Mar;39(3):355-368

  • Vancomycin Patients Endpoints

    11 ECMO 11 Controls No difference in

    clearance or volume of distribution

    20 ECMO 60 Controls 11 ECMO 11 Controls

    Antimicrobials and ECMO

    Amikacin Patients Endpoints

    50 ECMO 50 Controls

    No difference in Cmax and Cmin Cmax

  • • Case control cohort: Total of 41 therapeutic drug monitoring (TDM) results

    β-Lactam Pharmacokinetics in ECMO

    Meropenem (n=27)

    Piperacillin/Tazobactam (n=14)

    ECMO Control ECMO Control Volume of Distribution (L/kg) 0.46 (0.26–0.92) 0.60 (0.42–0.90) 0.33 (0.26–0.46) 0.31 (0.21–0.41)

    Elimination half life (h) 3.0 (2.1–4.8) 2.9 (2.4–3.7) 2.0 (1.1–4.2) 1.6 (1.0–4.7)

    Total drug clearance (mL/min) 125 (63–198) 144 (97–218) 156 (91–213) 134 (47–179)

    Donadello et al. Int J Antimicrob Agents. 2015;45(3):278-82

  • β-Lactam Pharmacokinetics in ECMO

    Donadello et al. Int J Antimicrob Agents. 2015;45(3):278-82

  • Drug Protein Binding Log p Volume of

    Distribution Expected

    Effect Dose

    Adjustment

    Ceftriaxone 85-90% -0.01 5.78–13.5 L Moderate sequestration Not required

    Vancomycin 50% -4.4 28–70 L Minimal sequestration Not required

    Levofloxacin 24–38% 0.65 88.9 L Minimal to moderate

    sequestration Not required

    Gentamicin/ Tobramycin/ Amikacin

    < 30% < 0.0 14–21 L Minimal sequestration Not required

    Voriconazole 58% 2.56 322 L Moderate to high sequestration Yes

    Dose Adjustments for Select Agents

    HA et al. Pharmacotherapy. 2017;37(2):221-235

  • • PK data in adult patients on ECMO are sparse

    • Consider loading dose for drugs with moderate to high

    sequestration

    • Dose guided by therapeutic drug monitoring when applicable

    • Monitor for signs of infections

    Antimicrobial Dosing Considerations

  • Bleeding and Thrombosis Complications

    • Meta-analysis: 12 studies (1763) patients

    • Any bleeding (33%)

    • Hemolysis (18%)

    • Venous thrombosis (10%)

    • Gastrointestinal bleeding (7%)

    • Disseminated intravascular coagulation (5%)

    Zangrillo et al. Crit Care Resusc. 2013;15(3):172-178

  • The Clinical Challenge

    ThrombosisBleeding Which

    Anticoagulant?

    Zangrillo et al. Crit Care Resusc. 2013;15(3):172-178

  • Guidelines

    “These guidelines describe useful and safe practice, but these are not necessarily consensus recommendations. These guidelines are not

    intended as a standard of care, and are revised at regular intervals as new information, devices, medications, and techniques become available