Medications in the PICU: The ECMO Effect

1. Medications in the PICU: The ECMO Effect Lizbeth Hansen, PharmD, BCPS Angie Skoglund, PharmD, BCPS Clinical Pediatric Pharmacist University of Minnesota Amplatz Children’s Hospital

2. Objectives Discuss pharmacologic principles of analgesia, sedation and paralysis Review the current data that addresses the effect of ECMO (extracorporeal membranous oxygenation) on commonly used medications

3. Analgesia, Sedation & Paralysis

4. Opioid Analgesics • Mechanism of Action • Bind to opiate receptors (mu, gamma, kappa) • Act on the descending inhibitory pathway in the CNS to produce analgesia • As dose increases, so do side effects • CNS depression • Respiratory depression • Nausea/Vomiting • Constipation • Urinary retention

5. Opioid Analgesics • Clinical Pearls • Morphine – histamine release responsible for hypotensive effects • Fentanyl – too rapid administration of high doses can cause “rigid chest” phenomenon

6. Sedatives • Benzodiazepines • Bind to the GABAA receptor to produce both anxiolytic and hypnotic effects • Barbiturates • Bind to a separate site on the GABA receptor to produce CNS depression (sedation)

7. Sedatives

8. Dexmedetomidine • MOA: highly selective alpha2 agonist • Activation of alpha2 receptors in brain stem • Sedation • Activation of alpha2 receptors in spinal cord • Analgesia • Loading dose: 1 mcg/kg over 10 minutes then 0.2-0.7 mcg/kg/hr • Adverse Effects • Hypotension (25-50%), bradycardia (5-15%)

9. Paralytics • Depolarizing Neuromuscular Blockers • Succinylcholine • 1-1.5 mg/kg IV/IO RSI • Onset: 2-3 minutes, Duration: 10-30 minutes • Adverse effects: hyperkalemia, incr ICP, malignant hyperthermia

10. Non-Depolarizing NMBs

11. ECMO

12. Extracorporeal Membrane Oxygenation Prolonged form of cardio-pulmonary bypass (on average 3-10 days) Used to support patients with life-threatening respiratory or cardiac failure Provides a decrease in workload and adequate oxygen to the patient while allowing time for the lungs and/or heart to “rest” or heal

13. The ECMO Circuit

14. The ECMO Circuit • Components: • Venous cannula (thru RIJ into RA), venous reservoir (bladder), roller pump, membrane oxygenator, heat exchanger, arterial cannula (thru RCA into AA) • VA vs VV ECMO: • Venoarterial ECMO bypasses lungs • Venovenous ECMO does not provide cardiac support

15. Indications • Neonates • Primary pulmonary hypertension, meconium aspiration, respiratory distress syndrome, group B streptococcal sepsis, congenital diaphragmatic hernia • Infants & Children • Low CO following repair of CHD • Unable to wean off cardiac bypass in OR • Bridge to cardiac surgery or transplant

16. Complications Clots in circuit (19%) Oxygenator failure Seizures, intracranial bleeding Hemolysis & coagulopathy (SIRS) Arrhythmias Oliguria (within 24-48h) Metabolic acidosis

17. Weaning Attempted daily by assessing systemic arterial and venous saturations when decreasing flow thru the bypass circuit When the required level of bypass flow is approx 10% of cardiac output, a trial period of ECMO should be done If patient able to maintain adequate gas exchange & acceptable hemodynamic parameters, decannulation can occur

18. Medications Used in ECMO Inotropes and vasopressors for additional cardiac support Heparin to prevent clotting of ECMO circuit Antibiotics for prophylaxis and treatment of infection (vancomycin & 3rd gen ceph) Electrolyte supplementation Sedatives & analgesics for comfort

19. Pharmaco-kinetic & -dynamic changes during ECMO • Increased circulating blood volume • Blood volumes needed to prime the circuit (300-400 mL) are more than double of the infant’s own blood volume (200-250 mL) • Drug binding interactions with circuit • Drug adsorption and sequestration onto plastic cannulae and/or silicone oxygenator • Altered renal, hepatic & cerebral blood flow • Non-pulsatile blood flow • Previous injury to organs pre-ECMO

20. Drug Administration into the ECMO circuit Dagan, et al (1993) showed decreases in serum concentrations while circulating through the ECMO circuit The amount of drug lost to the circuit appears to be related to how new the circuit is

21. Drug Administration into the ECMO circuit, cont’d Mulla et al (2000) showed significant decreases in serum concentrations due to uptake by the PVC tubing of ECMO circuit When albumin was used to prime the circuit, they found an additional 10% increase in uptake of the sedatives

22. Drug Administration into the ECMO circuit, cont’d • Green, et al (1990) showed the clearance rate of heparin doubled while on ECMO compared to when decannulated • 3.8 mL/kg/min vs 1.6 mL/kg/min • Nearly 50% of the heparin dose was lost in the circuit

23. Analgesics • Fentanyl • Up to 70% of the dose has been sequestered by the silicone membrane oxygenator • Saturation kinetics – once the binding sites are saturated, less drug is needed to maintain sedation • Morphine • Dagan et al (1994) showed a decrease in clearance of morphine while on ECMO • 34 mL/kg/min vs 63 mL/kg/min • Authors postulated this may be an effect of decreased hepatic blood flow

24. Phenobarbital In vitro studies have shown up to a 17% loss of a dose in a new circuit Increase in the Vd to 1.2 L/kg also leads to decreased concentrations in the blood Very important for serum drug monitoring to ensure patient is within therapeutic goal to prevent seizure activity

25. Antibiotics • Vancomycin • Hoie (1990) & Amaker (1996) both showed an increase in Vd (0.68-1.1 L/kg) along with increase in half-life (7.7-16.9 hrs) • Dose: 15-20 mg/kg IV q24h • Gentamicin • Cohen (1990) & Batt-Mehta (1992) both showed an increase in Vd (0.51-0.67 L/kg) along with increase in half-life (5.7-10 hrs) • Dose: 2.5-3.5 mg/kg IV q18-24h

26. Other drugs Due to lack of studies, it is unknown what pharmacokinetic changes occur during administration of other medications used to support the patient on ECMO

27. Questions?