Medications in the PICU: Medications in the PICU:

The ECMO EffectThe ECMO Effect

Lizbeth Hansen, PharmD, BCPSLizbeth Hansen, PharmD, BCPS

Angie Skoglund, PharmD, BCPSAngie Skoglund, PharmD, BCPS

Clinical Pediatric PharmacistClinical Pediatric PharmacistUniversity of Minnesota Amplatz ChildrenUniversity of Minnesota Amplatz Children’’s Hospitals Hospital

Objectives

Discuss pharmacologic principles of Discuss pharmacologic principles of analgesia, sedation and paralysisanalgesia, sedation and paralysis

Review the current data that addresses Review the current data that addresses the effect of ECMO (extracorporeal the effect of ECMO (extracorporeal membranous oxygenation) on commonly membranous oxygenation) on commonly used medicationsused medications

Analgesia, Sedation & Paralysis

Opioid AnalgesicsOpioid Analgesics

Mechanism of ActionMechanism of Action Bind to opiate receptors (mu, gamma, kappa)Bind to opiate receptors (mu, gamma, kappa) Act on the descending inhibitory pathway in the Act on the descending inhibitory pathway in the

CNS to produce analgesiaCNS to produce analgesia

As dose increases, so do side effectsAs dose increases, so do side effects CNS depressionCNS depression Respiratory depressionRespiratory depression Nausea/VomitingNausea/Vomiting ConstipationConstipation Urinary retentionUrinary retention

Opioid AnalgesicsOpioid Analgesics

Morphine Hydromorphone Fentanyl

Initial dose (IV) 0.05-0.1 mg/kg 0.007-0.015 mg/kg 1-2 mcg/kg

Continuous Infusion 0.03 mg/kg/hr 0.005 mg/kg/hr 1 mcg/kg/hr

Onset of action 2-4 minutes 2-4 minutes 1-2 minutes

Duration of action 2-4 hours 3-6 hours 30-60 minutes

Equianalgesic dose 10 mg 1.5 mg 0.1 mg

Active Metabolite Yes No No

Clinical PearlsClinical Pearls Morphine – histamine release responsible for Morphine – histamine release responsible for

hypotensive effectshypotensive effects Fentanyl – too rapid administration of high doses can Fentanyl – too rapid administration of high doses can

cause cause ““rigid chestrigid chest”” phenomenon phenomenon

SedativesSedatives

BenzodiazepinesBenzodiazepines Bind to the GABABind to the GABAAA receptor to produce both receptor to produce both

anxiolytic and hypnotic effectsanxiolytic and hypnotic effects

BarbituratesBarbiturates Bind to a separate site on the GABA receptor Bind to a separate site on the GABA receptor

to produce CNS depression (sedation)to produce CNS depression (sedation)

SedativesSedatives

Midazolam Lorazepam Propofol

Initial Dose (IV) 0.05-0.1 mg/kg 0.05-0.1 mg/kg 1 mg/kg

Continuous Infusion

0.05 -0.1 mg/kg/hr 0.025-0.05 mg/kg/hr 25-50 mcg/kg/min

Onset of Action 2-4 minutes 15-30 minutes 30 seconds

Duration of Action 1-2 hours 4-6 hours 3-10 minutes

Active Metabolite Yes No No

Phenobarbital Pentobarbital

Initial Dose (IV) 1-3 mg/kg 1-3 mg/kg

Onset of Action 5 minutes 1 minute

Duration of Action 4-10 hours 15 minutes

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/hrAdverse Effects Hypotension (25-50%), bradycardia (5-15%)

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

Non-Depolarizing NMBs

Vecuronium Cisatracurium Rocuronium

Initial Dose (IV) 0.1 mg/kg 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/min 10-12 mcg/kg/min

Onset of Action 1-3 minutes 2-3 minutes 30-60 seconds

Duration of Action 30-40 minutes 35-45 minutes 20-40 minutes

Elimination Biliary (50%)Urine (25%)

Hofmann elimination

Biliary (70%)Urine (30%)

ECMO ECMO

Extracorporeal Extracorporeal Membrane OxygenationMembrane Oxygenation

Prolonged form of cardio-pulmonary Prolonged form of cardio-pulmonary bypass (on average 3-10 days)bypass (on average 3-10 days)

Used to support patients with life-Used to support patients with life-threatening respiratory or cardiac failurethreatening respiratory or cardiac failure

Provides a decrease in workload and Provides a decrease in workload and adequate oxygen to the patient while adequate oxygen to the patient while allowing time for the lungs and/or heart to allowing time for the lungs and/or heart to ““restrest”” or heal or heal

The ECMO CircuitThe ECMO Circuit

The ECMO CircuitThe ECMO Circuit

Components:Components: Venous cannula (thru RIJ into RA), venous Venous cannula (thru RIJ into RA), venous

reservoir (bladder), roller pump, membrane reservoir (bladder), roller pump, membrane oxygenator, heat exchanger, arterial cannula oxygenator, heat exchanger, arterial cannula (thru RCA into AA)(thru RCA into AA)

VA vs VV ECMO:VA vs VV ECMO: Venoarterial ECMO bypasses lungsVenoarterial ECMO bypasses lungs Venovenous ECMO does not provide cardiac Venovenous ECMO does not provide cardiac

support support

IndicationsIndications

NeonatesNeonates Primary pulmonary hypertension, meconium Primary pulmonary hypertension, meconium

aspiration, respiratory distress syndrome, aspiration, respiratory distress syndrome, group B streptococcal sepsis, congenital group B streptococcal sepsis, congenital diaphragmatic herniadiaphragmatic hernia

Infants & ChildrenInfants & Children Low CO following repair of CHDLow CO following repair of CHD Unable to wean off cardiac bypass in ORUnable to wean off cardiac bypass in OR Bridge to cardiac surgery or transplantBridge to cardiac surgery or transplant

ComplicationsComplications

Clots in circuit (19%)Clots in circuit (19%)

Oxygenator failureOxygenator failure

Seizures, intracranial bleedingSeizures, intracranial bleeding

Hemolysis & coagulopathy (SIRS)Hemolysis & coagulopathy (SIRS)

ArrhythmiasArrhythmias

Oliguria (within 24-48h) Oliguria (within 24-48h)

Metabolic acidosisMetabolic acidosis

WeaningWeaning

Attempted daily by assessing systemic Attempted daily by assessing systemic arterial and venous saturations when arterial and venous saturations when decreasing flow thru the bypass circuitdecreasing flow thru the bypass circuit

When the required level of bypass flow is When the required level of bypass flow is approx 10% of cardiac output, a trial approx 10% of cardiac output, a trial period of ECMO should be doneperiod of ECMO should be done

If patient able to maintain adequate gas If patient able to maintain adequate gas exchange & acceptable hemodynamic exchange & acceptable hemodynamic parameters, decannulation can occurparameters, decannulation can occur

Medications Used in ECMOMedications Used in ECMO

Inotropes and vasopressors for additional Inotropes and vasopressors for additional cardiac supportcardiac support

Heparin to prevent clotting of ECMO circuitHeparin to prevent clotting of ECMO circuit

Antibiotics for prophylaxis and treatment of Antibiotics for prophylaxis and treatment of infection (vancomycin & 3infection (vancomycin & 3rdrd gen ceph) gen ceph)

Electrolyte supplementationElectrolyte supplementation

Sedatives & analgesics for comfortSedatives & analgesics for comfort

Pharmaco-kinetic & -dynamic Pharmaco-kinetic & -dynamic changes during ECMOchanges during ECMO

Increased circulating blood volumeIncreased circulating blood volume Blood volumes needed to prime the circuit (300-400 Blood volumes needed to prime the circuit (300-400

mL) are more than double of the infantmL) are more than double of the infant’’s own blood s own blood volume (200-250 mL)volume (200-250 mL)

Drug binding interactions with circuitDrug binding interactions with circuit Drug adsorption and sequestration onto plastic Drug adsorption and sequestration onto plastic

cannulae and/or silicone oxygenatorcannulae and/or silicone oxygenator

Altered renal, hepatic & cerebral blood flowAltered renal, hepatic & cerebral blood flow Non-pulsatile blood flowNon-pulsatile blood flow Previous injury to organs pre-ECMOPrevious injury to organs pre-ECMO

Drug Administration into the Drug Administration into the ECMO circuitECMO circuit

Dagan, et al (1993) showed decreases in Dagan, et al (1993) showed decreases in serum concentrations while circulating serum concentrations while circulating through the ECMO circuitthrough the ECMO circuit

The amount of drug lost to the circuit appears The amount of drug lost to the circuit appears to be related to how new the circuit isto be related to how new the circuit is

% change Morphine Phenytoin Vancomycin Gentamicin Phenobarb

New circuit 36% 43% 36% 10% 17%

Used circuit (5 days)

16% -- 11% 0% 6%

Drug Administration into the Drug Administration into the ECMO circuit, contECMO circuit, cont’’dd

Mulla et al (2000) showed significant Mulla et al (2000) showed significant decreases in serum concentrations due to decreases in serum concentrations due to uptake by the PVC tubing of ECMO circuit uptake by the PVC tubing of ECMO circuit

When albumin was used to prime the When albumin was used to prime the circuit, they found an additional 10% circuit, they found an additional 10% increase in uptake of the sedativesincrease in uptake of the sedatives

% Decrease Midazolam Lorazepam Diazepam Propofol

No albumin 68% 40% 88% 98%

Albumin 76% 52% 96% 99%

Drug Administration into the Drug Administration into the ECMO circuit, contECMO circuit, cont’’dd

Green, et al (1990) showed the clearance Green, et al (1990) showed the clearance rate of heparin doubled while on ECMO rate of heparin doubled while on ECMO compared to when decannulatedcompared to when decannulated 3.8 mL/kg/min vs 1.6 mL/kg/min3.8 mL/kg/min vs 1.6 mL/kg/min Nearly 50% of the heparin dose was Nearly 50% of the heparin dose was

lost in the circuitlost in the circuit

AnalgesicsAnalgesics

FentanylFentanyl Up to 70% of the dose has been sequestered Up to 70% of the dose has been sequestered

by the silicone membrane oxygenatorby the silicone membrane oxygenatorSaturation kinetics – once the binding sites are Saturation kinetics – once the binding sites are saturated, less drug is needed to maintain sedationsaturated, less drug is needed to maintain sedation

MorphineMorphine Dagan et al (1994) showed a Dagan et al (1994) showed a decreasedecrease in in

clearance of morphine while on ECMOclearance of morphine while on ECMO34 mL/kg/min vs 63 mL/kg/min34 mL/kg/min vs 63 mL/kg/min

Authors postulated this may be an effect of Authors postulated this may be an effect of decreased hepatic blood flow decreased hepatic blood flow

PhenobarbitalPhenobarbital

In vitro studies have shown up to a 17% In vitro studies have shown up to a 17% loss of a dose in a new circuitloss of a dose in a new circuit

Increase in the Vd to 1.2 L/kg also leads to Increase in the Vd to 1.2 L/kg also leads to decreased concentrations in the blooddecreased concentrations in the blood

Very important for serum drug monitoring Very important for serum drug monitoring to ensure patient is within therapeutic goal to ensure patient is within therapeutic goal to prevent seizure activityto prevent seizure activity

AntibioticsAntibiotics

VancomycinVancomycin Hoie (1990) & Amaker (1996) both showed an Hoie (1990) & Amaker (1996) both showed an

increase in Vd (0.68-1.1 L/kg) along with increase in Vd (0.68-1.1 L/kg) along with increase in half-life (7.7-16.9 hrs)increase in half-life (7.7-16.9 hrs)

Dose: 15-20 mg/kg IV q24hDose: 15-20 mg/kg IV q24h

GentamicinGentamicin Cohen (1990) & Batt-Mehta (1992) both showed Cohen (1990) & Batt-Mehta (1992) both showed

an increase in Vd (0.51-0.67 L/kg) along with an increase in Vd (0.51-0.67 L/kg) along with increase in half-life (5.7-10 hrs)increase in half-life (5.7-10 hrs)

Dose: 2.5-3.5 mg/kg IV q18-24hDose: 2.5-3.5 mg/kg IV q18-24h

Other drugsOther drugs

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

Questions?