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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. Objectives. Discuss pharmacologic principles of analgesia, sedation and paralysis - PowerPoint PPT Presentation
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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?