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
Review the current data that addresses
the effect of ECMO (extracorporeal
membranous oxygenation) on commonly
used medications
Analgesia, Sedation &
Paralysis
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
Opioid 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
2-4 minutes
2-4 minutes
1-2 minutes
2-4 hours
3-6 hours
30-60 minutes
10 mg
1.5 mg
0.1 mg
Yes
No
No
Onset of action
Duration of action
Equianalgesic dose
Active Metabolite
Clinical Pearls


Morphine – histamine release responsible for
hypotensive effects
Fentanyl – too rapid administration of high doses can
cause “rigid chest” phenomenon
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)
Sedatives
Initial Dose (IV)
Continuous
Infusion
Onset of Action
Midazolam
Lorazepam
Propofol
0.05-0.1 mg/kg
0.05-0.1 mg/kg
1 mg/kg
0.05 -0.1 mg/kg/hr 0.025-0.05 mg/kg/hr 25-50 mcg/kg/min
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/hr
Adverse 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
Initial Dose (IV)
Continuous
Infusion
Onset of Action
Duration of Action
Elimination
Vecuronium
Cisatracurium
Rocuronium
0.1 mg/kg
0.1 mg/kg
0.6-1 mg/kg
1-1.5 mcg/kg/min
(0.05 -0.1 mg/kg/hr)
1-4 mcg/kg/min
10-12 mcg/kg/min
1-3 minutes
2-3 minutes
30-60 seconds
30-40 minutes
35-45 minutes
20-40 minutes
Biliary (50%)
Urine (25%)
Hofmann
elimination
Biliary (70%)
Urine (30%)
ECMO
Extracorporeal
Membrane Oxygenation
Prolonged form of cardio-pulmonary
bypass (on average 3-10 days)
Used to support patients with lifethreatening 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
The ECMO Circuit
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
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
Complications
Clots in circuit (19%)
Oxygenator failure
Seizures, intracranial bleeding
Hemolysis & coagulopathy (SIRS)
Arrhythmias
Oliguria (within 24-48h)
Metabolic acidosis
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
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
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
Drug Administration into the
ECMO circuit
Dagan, et al (1993) showed decreases in
serum concentrations while circulating
through the ECMO circuit
% change
New circuit
Used circuit
(5 days)
Morphine
Phenytoin
Vancomycin
Gentamicin
Phenobarb
36%
43%
36%
10%
17%
16%
--
11%
0%
6%
The amount of drug lost to the circuit appears
to be related to how new the circuit is
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
% Decrease
Midazolam
Lorazepam
Diazepam
Propofol
No albumin
68%
40%
88%
98%
Albumin
76%
52%
96%
99%
When albumin was used to prime the
circuit, they found an additional 10%
increase in uptake of the sedatives
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
lost in the circuit
was
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
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
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
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
Questions?