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This Manual has been designed for use in the NICU at London Health Sciences Centre (LHSC), London, Ontario, Canada, and represents clinical practice at this institution. The information contained within the Manual may not be applicable to other centres. If users of this Manual are not familiar with a drug, it is recommended that the official monograph be consulted before it is prescribed and administered. Any user of this information is advised that the contributors, Editor and LHSC are not responsible for any errors or omissions, and / or any consequences arising from the use of the information in this Manual.

MILRINONE

Indication

Short-term support to increase cardiac output.

A small case series and anecdotal reports suggest that milrinone, in conjunction with inhaled nitric oxide, may be useful in the treatment of neonatal pulmonary hypertension.

Pharmacology

  • Has inotropic and vasodilatory properties, and enhances diastolic relaxation in heart muscle
  • Inhibits phosphodiesterase III (PDE-III), resulting in an accumulation of intracellular 3'-5' cyclic AMP and subsequently an increase in intracellular Ca.
    • In the myocardium PDE-III is the predominant form of phosphodiesterase, Inhibition of PDE-III by milrinone leads to an increased Ca uptake into cells, causing improved contractility, and an increased cardiac output (positive inotropy)
    • In vascular smooth muscles, this leads to increased calcium uptake into the sarcoplasmic reticulum, thereby reducing the amount of calcium available for muscle constriction. This leads to relaxation of the vessel wall and vasodilation
  • Onset of action (improved hemodynamic function) : 5 to 15 minutes

Pharmacokinetics

  • The following pharmacokinetic parameters were measured in neonates who had undergone cardiac surgery.
  • Volume of distribution (neonates) = 0.523 + 0.028 L/kg
  • Total Body Clearance (neonates) = 1.64 + 0.373 mL/kg/min
  • Half Life (neonates) ~ 3.7 hours
  • 83% of an administered dose is eliminated unchanged renally

Precautions

  • use with caution in patients with a history of heart dysrhythmias
  • use with caution and modify dose in patients with impaired renal function

Dose

A retrospective case series of 9 term neonates with severe persistent pulmonary hypertension, in whom milrinone was used in conjunction with inhaled nitric oxide, suggests that this combination may lead to an improvement in oxygenation without compromising hemodynamic status. (Ref # 8)
  • It has been estimated, through pharmacokinetic simulation, that if therapy is initiated at 0.75 mcg/kg/min (ie, NO loading dose) then it will take approximately 2 hours to reach 50% of the steady state concentration.

    Neonates

    Loading Dose = 50 mcg/kg IV over 15 minutes

    Maintenance = 0.25 mcg/kg/min infusion, titrating to effect (range: 0.25-0.75 mcg/kg/min)

    In our limited experience, a loading dose has usually not been required in neonates.

  • Compatible with both NaCl and Dextrose containing solutions.
  • Compatible with TPN.
  • Since milrinone is renally cleared, patients with decreased renal function may have an exaggerated effect to the given dose. Patient's response should be monitored closely. Maintenance dose may need to be lowered and dose should be titrated to effect.

Side Effects

  • Ventricular arrhythmias (12.1%)
  • Hypotension (2.9%)
  • Hypokalemia (0.6%)
  • Thrombocytopenia (0.4%)
  • Abnormal LFTs

Monitoring

  • Blood pressure (may decrease by 5-9% after starting dose)
    • If hypotensive during infusion, decrease infusion rate
  • Heart rate (may transiently increase by 5-10% after starting dose) and rhythm
  • Signs and symptoms of heart failure
  • Platelet count
  • Electrolytes
  • Renal function (over 80% of an administered dose is excreted in the urine as unchanged drug)
  • Liver function

Compatibility/Incompatibility

  • Incompatible with furosemide and imipenem (compatible with meropenem)
  • Compatible with 0.9% NaCl and Dextrose 5%

Supplied

  • Available as 1mg/mL in 10 or 20 mL vials
  • Store at room temperature, do not freeze

References

  1. Young TE, Mangum B. Neofax 2004. North Caroline: Acorn Publishing; 2001
  2. Taketomo CK, Hodding JH, Kraus D. Pediatric dosage handbook. 11th ed. Ohio: Lexi-comp Inc; 2004
  3. Roy R, Griffiths K, editors. The Hospital for Sick Children 2002-2004 formula. 21st Ed. Toronto: Hospital for Sick Children; 2002
  4. Bailey JM, Hoffman TM, Wessel DL, Nelson DP, Atz AM, Chang AC, et al. A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery. J Pharmacokinet Pharmacodyn. 2004; 31: 43-59.
  5. Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, et al. 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.
  6. Milrinone [database on internet]. United States of America: Thompson Micromedex. c2005 - [cited 20 May 2005]. Available from: http://www.lhsc.on.ca/mdxcgi/display.exe?CTL=/mdx/mdxcgi/MEGAT.SYS&SET=8357C1D5428E415135E3A0&SYS=1&T=1345
  7. Parenteral drug administration manual. London: London Health Sciences Centre; 2000
  8. McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent hypertension of the newborn. Journal of Critical Care 2006;21:217-23.

Prepared by : Ruth Law ,BScPhm, LHSC Pharmacy Resident, May 2005
Reviewed by : David Knoppert, MScPhm, Henry Roukema, MD, November 2005



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