Milrinone 2016

Alert May cause hypotension. Caution advised when using loading dose.
Reduce infusion rate in infants with renal impairment and prematurity.
Indication Inotrope and vasodilator for:
• Treatment of low cardiac output states and as an adjunct to inhaled nitric oxide in neonates
1
with persistent pulmonary hypertension of the neonate .
2, 3
• Prevention of low cardiac output syndrome (LCOS) post cardiac surgery .
• Treatment of myocardial dysfunction in neonates and children with shock particularly in
4
context of enteroviral 71 infection .
Action Selective inhibitor of type 3 cAMP phosphodiesterase in cardiac and vascular muscle.
Drug Type Inotrope and vasodilator.

Trade Name Primacor, Milrinone GH.

Presentation 1 mg/mL (1000 microgram/mL) vial.

Dosage/Interval Term infants (NO loading dose)
Continuous IV infusion: 0.33 − 0.75 microgram/kg/minute.

Term infants (OPTIONAL loading dose)

Continuous IV infusion: 0.33 − 0.75 microgram/kg/minute.
OPTIONAL: Loading dose: 75 microgram/kg over 60 minutes (Caution - risk of hypotension with
loading dose).

Pre-term infants (NO loading dose)

Continuous IV infusion: 0.2 microgram/kg/minute.

Pre-term infants (OPTIONAL loading dose)

Continuous IV infusion: 0.2 microgram/kg/minute.
OPTIONAL: Loading dose: 135 microgram/kg over 3 hours (Caution - risk of hypotension with
loading dose).

Renal impairment (including hypoplastic left heart syndrome undergoing surgery)

Continuous IV infusion: 0.2 −0.33 microgram/kg/minute.

Route Continuous IV infusion.

Maximum Daily Dose Maximum IV Infusion rate: 1 microgram/kg/minute – caution as risk of drug accumulation over
time.
Preparation/Dilution Term infants
Draw up 1 mL/kg (1000 microgram/kg of milrinone) and make up to a final volume of 50 mL with
sodium chloride 0.9%.
Infusing at a rate of 1 mL/hour = 0.33 microgram/kg/minute.

OPTIONAL- Give a loading dose of 3.75 mL (75 microgram/kg) over 60 minutes (Note: risk of
hypotension with loading dose).

Pre-term infants and renal impairment

Draw up 0.6 mL/kg (600 microgram/kg of milrinone) and make up to a final volume of 50 mL
with sodium chloride 0.9%.
Infusing at a rate of 1 mL/hour = 0.2 microgram/kg/minute.

OPTIONAL - Give a loading dose of 11.25 mL (135 microgram/kg) over 3 hours (Note: risk of
hypotension with loading dose).

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 Milrinone 2016
Administration Continuous IV infusion preferably via a central line.
Adjust infusion rate based on haemodynamic and clinical response.
For term infants ─ if loading is not given, higher maintenance infusion may be required to reach
the steady state – range 0.5−0.75 microgram/kg/minute.
For preterm infants ─ if loading dose is not given, titrate the maximal infusion rate to
0.5 microgram/kg/minute if required. Avoid prolonged infusion > 0.2 microgram/kg/minute in
very preterm infants.
Monitoring Continuous heart rate, ECG and blood pressure monitoring preferable.
Assess urine output and peripheral perfusion frequently.
Monitor fluid and electrolytes.
Contraindications Severe obstructive aortic or pulmonary valvular disease or hypertrophic subaortic stenosis.
Hypersensitivity to milrinone, other 3,4'-bipyridines (inamrinone) or any other ingredient of the
formulation.
Precautions Ensure adequate circulating blood volume prior to commencement.
Loading dose: Considered optional depending on clinical circumstances. May cause
hypotension. Monitor BP and heart rate closely and ensure adequate volume replacement.
5
Prematurity: Long half-life reported (10 hours) in very preterm infants. Avoid prolonged higher
rate infusion (≥0.2 microgram/kg/minute).
Renal impairment: Significantly increases half-life of milrinone. A reduction in the infusion rate
in patients with renal impairment to prevent drug accumulation is advised.
Patient recovery: Improvement in cardiac output with resultant diuresis may necessitate a
reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose
digitalised patients to arrhythmias.
Drug Interactions None known.

Adverse Reactions Ventricular arrhythmias in cardiac patients.

Patent ductus arteriosus has been reported.
May cause hypotension.

Compatibility Fluids: Glucose 5%, sodium chloride 0.9%.

Y-site: Amino acid solutions, adrenaline (epinephrine) hydrochloride, amiodarone, atracurium,

bivalirudin, calcium gluconate monohydrate, caspofungin, dexmedetomidine, digoxin,
dobutamine, dopamine, doripenem, fentanyl, glyceryl trinitrate, heparin sodium, insulin (short-
acting), magnesium sulfate heptahydrate, metoprolol, midazolam, morphine sulfate
pentahydrate, noradrenaline (norepinephrine), pancuronium, potassium chloride, ranitidine,
rocuronium, sodium nitroprusside, vecuronium, verapamil.
Incompatibility Fluids: Sodium bicarbonate.

Y-site: Bumetanide, esmolol, furosemide (frusemide), imipenem + cilastatin, ondansetron.

Stability Diluted solution: Store below 30°C and use within 24 hours.

Storage Vials: Store below 25°C.Protect from light. Discard remainder after use.

Special Comments Discard admixtures exhibiting colour change.

Evidence summary Efficacy:

Treatment of pulmonary hypertension in near term infants: Case series report improvements in
pulmonary and systemic haemodynamics and oxygenation in infants with pulmonary
1, 6, 7
hypertension treated with nitric oxide. (LOE IV GOR C)
Treatment of very pre-term infants: An RCT found no difference in measures of systemic blood
8
flow when used preventatively in extremely premature infants. Case series reported
improvement in oxygenation and a fall in blood pressure in pre-term infants with pulmonary
9
hypertension treated with nitric oxide. There are insufficient data to determine the efficacy
and safety of milrinone in pre-term infants with pulmonary hypertension and/or myocardial
10 8
dysfunction. (LOE II , GOR C)

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 Milrinone 2016
Neonates and infants undergoing cardiac surgery: A single RCT found high dose milrinone
2, 3
reduced the risk of LCOS post cardiac surgery. (LOE II, GOR B) An historical control study
11
reported use of milrinone post ductal ligation improved ventilation and reduced inotrope use
(LOE IV, GOR C).
Infants and children with shock associated with myocardial dysfunction: An RCT found milrinone
0.5 microgram/kg/min reduced mortality in children with enterovirus 71-induced pulmonary
4
oedema and/or shock. A loading dose was not used. (LOE II, GOR B)

Safety:
Reports of arrhythmias, tachycardia, hypotension and hypokalaemia, bronchospasm, headaches,
thrombocytopenia, anaemia and elevated serum liver enzymes. In neonates treated with
2, 6
milrinone, hypotension and intraventricular haemorrhage have been observed. (LOE IV)

Pharmacokinetics:
Extremely pre-term infants for prevention of low systemic blood flow: T ½ averaged 10 hours.
Milrinone loading infusion 0.75 microgram/kg/min for 3 hours followed by maintenance infusion
5
0.2 microgram/kg/min achieved target (180–300 nanogram/mL). (LOE IV GOR C)
Term infants with pulmonary hypertension: Half-life (t½) averaged 4 hours. Loading dose 50
microgram/kg resulted in sub-therapeutic concentrations. Maintenance infusion 0.33–0.99
1
microgram/kg/min resulted in concentrations above target range (180–300 nanogram/mL).
(LOE IV GOR C)
Term newborns with hypoplastic left heart undergoing surgery: Neonates received an initial
dose of either a 100 or 250 microgram/kg of milrinone into the cardiopulmonary bypass circuit.
A constant infusion of 0.5 microgram/kg/min resulted in drug accumulation during the initial 12
h of drug administration. Postoperatively, milrinone clearance was significantly impaired. Initial
loading dose of 100 microgram/kg on CPB resulted in plasma concentrations similar to those
observed in other therapeutic settings. In the postoperative setting of markedly impaired renal
12
function, an infusion rate of 0.2 microgram/kg/min should be considered.
Paediatric patients with septic shock: T½ averaged 1.47 hours (range, 0.62 to 10.85 hours).
Loading dose 75 microgram/kg and starting infusion rates 0.75–1.0 microgram/kg/min for
13
patients with normal renal function recommended.
Prevention of low cardiac output syndrome post cardiac surgery in infants: Loading dose 50
microgram/kg then infusion 3 microgram/kg/min for 30 minutes and then a maintenance
14
infusion 0.5 microgram/kg/min, with adjustment for age. (LOE IV GOR C).
References 1. McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A. Pharmacology of milrinone in
neonates with persistent pulmonary hypertension of the newborn and suboptimal response to
inhaled nitric oxide. Pediatric critical care medicine : a journal of the Society of Critical Care
Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
2013;14:74-84.
2. Burkhardt BE, Rucker G, Stiller B. Prophylactic milrinone for the prevention of low cardiac
output syndrome and mortality in children undergoing surgery for congenital heart disease. The
Cochrane database of systematic reviews. 2015;3:CD009515.
3. Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM, Akbary A, Kocsis
JF, Kaczmarek R, Spray TL, Wessel DL. Efficacy and safety of milrinone in preventing low cardiac
output syndrome in infants and children after corrective surgery for congenital heart disease.
Circulation. 2003;107:996-1002.
4. Chi CY, Khanh TH, Thoa le PK, Tseng FC, Wang SM, Thinh le Q, Lin CC, Wu HC, Wang JR, Hung
NT, Thuong TC, Chang CM, Su IJ, Liu CC. Milrinone therapy for enterovirus 71-induced
pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Critical
care medicine. 2013;41:1754-60.
5. Paradisis M, Jiang X, McLachlan AJ, Evans N, Kluckow M, Osborn D. Population
pharmacokinetics and dosing regimen design of milrinone in preterm infants. Archives of disease
in childhood Fetal and neonatal edition. 2007;92:F204-9.
6. James AT, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF. The effect of milrinone on
right and left ventricular function when used as a rescue therapy for term infants with
pulmonary hypertension. Cardiology in the young. 2015:1-10.

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 Milrinone 2016
7. McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates
with severe persistent pulmonary hypertension of the newborn. Journal of critical care.
2006;21:217-22.
8. Paradisis M, Evans N, Kluckow M, Osborn D. Randomized trial of milrinone versus placebo for
prevention of low systemic blood flow in very preterm infants. The Journal of pediatrics.
2009;154:189-95.
9. James AT, Bee C, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF. Treatment of
premature infants with pulmonary hypertension and right ventricular dysfunction with
milrinone: a case series. Journal of perinatology : official journal of the California Perinatal
Association. 2015;35:268-73.
10. Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary
hypertension of the newborn. The Cochrane database of systematic reviews. 2010:CD007802.
11. Jain A, Sahni M, El-Khuffash A, Khadawardi E, Sehgal A, McNamara PJ. Use of targeted
neonatal echocardiography to prevent postoperative cardiorespiratory instability after patent
ductus arteriosus ligation. The Journal of pediatrics. 2012;160:584-9 e1.
12. Zuppa AF, Nicolson SC, Adamson PC, Wernovsky G, Mondick JT, Burnham N, Hoffman TM,
Gaynor JW, Davis LA, Greeley WJ, Spray TL, Barrett JS. Population pharmacokinetics of milrinone
in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction. Anesthesia
and analgesia. 2006;102:1062-9.
13. Lindsay CA, Barton P, Lawless S, Kitchen L, Zorka A, Garcia J, Kouatli A, Giroir B.
Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic
shock. The Journal of pediatrics. 1998;132:329-34.
14. Bailey JM, Miller BE, Lu W, Tosone SR, Kanter KR, Tam VK. The pharmacokinetics of milrinone
in pediatric patients after cardiac surgery. Anesthesiology. 1999;90:1012-8.
15. MIMS accessed via CIAP on 4th November 2015
14. Australian Injectable Drugs Handbook, 6th Edition, Society of Hospital Pharmacists of
Australia 2015.
th
16. Neofax accessed on www.neofax.micromedex.solutions.com on 28 October 2015
17. Micromedex 2.0 accessed via CIAP on 4th November 2015

Original version Date: 5/12/2015 Author: NeoMed Consensus Group

Current Version number: 2 Version Date: 16/02/2016
Risk Rating: Medium Due for Review: 16/02/2019
Approval by: As per Local policy Approval Date:

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