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

5. Opioid Analgesics MorphineHydromorphoneFentanyl Initial dose (IV)0.05-0.1 mg/kg0.007-0.015 mg/kg1-2 mcg/kg Continuous Infusion0.03 mg/kg/hr0.005 mg/kg/hr1 mcg/kg/hr Onset of action2-4 minutes 1-2 minutes Duration of action2-4 hours3-6 hours30-60 minutes Equianalgesic dose10 mg1.5 mg0.1 mg Active MetaboliteYesNo 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 GABA A receptor to produce both anxiolytic and hypnotic effects Bind to the GABA A receptor to produce both anxiolytic and hypnotic effectsBarbiturates Bind to a separate site on the GABA receptor to produce CNS depression (sedation) Bind to a separate site on the GABA receptor to produce CNS depression (sedation)

7. Sedatives MidazolamLorazepamPropofol Initial Dose (IV)0.05-0.1 mg/kg 1 mg/kg Continuous Infusion 0.05 -0.1 mg/kg/hr0.025-0.05 mg/kg/hr25-50 mcg/kg/min Onset of Action2-4 minutes15-30 minutes30 seconds Duration of Action1-2 hours4-6 hours3-10 minutes Active MetaboliteYesNo PhenobarbitalPentobarbital Initial Dose (IV)1-3 mg/kg Onset of Action5 minutes1 minute Duration of Action4-10 hours15 minutes

8. Dexmedetomidine MOA: highly selective alpha 2 agonist Activation of alpha 2 receptors in brain stem Sedation Activation of alpha 2 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 VecuroniumCisatracuriumRocuronium Initial Dose (IV)0.1 mg/kg 0.6-1 mg/kg Continuous Infusion 1-1.5 mcg/kg/min (0.05 -0.1 mg/kg/hr) 1-4 mcg/kg/min10-12 mcg/kg/min Onset of Action1-3 minutes2-3 minutes30-60 seconds Duration of Action30-40 minutes35-45 minutes20-40 minutes EliminationBiliary (50%) Urine (25%) Hofmann elimination Biliary (70%) Urine (30%)

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. Components: Venous cannula (thru RIJ into RA), venous reservoir (bladder), roller pump, membrane oxygenator, heat exchanger, arterial cannula (thru RCA into AA) 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 Venoarterial ECMO bypasses lungs Venovenous ECMO does not provide cardiac support 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 Primary pulmonary hypertension, meconium aspiration, respiratory distress syndrome, group B streptococcal sepsis, congenital diaphragmatic hernia Infants & Children Low CO following repair of CHD Low CO following repair of CHD Unable to wean off cardiac bypass in OR Unable to wean off cardiac bypass in OR Bridge to cardiac surgery or transplant 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 & 3 rd 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) 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 Drug adsorption and sequestration onto plastic cannulae and/or silicone oxygenator Altered renal, hepatic & cerebral blood flow Non-pulsatile blood flow Non-pulsatile blood flow Previous injury to organs pre-ECMO 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 % changeMorphinePhenytoinVancomycinGentamicinPhenobarb New circuit 36%43%36%10%17% Used circuit (5 days) 16%--11%0%6%

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 % DecreaseMidazolamLorazepamDiazepamPropofol No albumin68%40%88%98% Albumin76%52%96%99%

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 3.8 mL/kg/min vs 1.6 mL/kg/min Nearly 50% of the heparin dose was lost in the circuit 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 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 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) 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 Dose: 15-20 mg/kg IV q24hGentamicin 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) 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 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?