Pediatric Pharmacotherapy
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  • 1. PEDIATRICPHARMACOTHERAPYA Monthly Newsletter for Health Care Professionals from theChildren’s Medical Center at the University of VirginiaVolume 9 Number 2 February 2003 The Use of Milrinone in Infants and Children Marcia L. Buck, Pharm.D., FCCPT raditionally, catecholamines such as dopamine, dobutamine, epinephrine, and norepinephrine have been used for their Administration of milrinone produced a significant increase in cardiac index, from 2.1+0.5 at baseline to 3.0+0.8 L/min/m2 duringpositive inotropic effect in children with low treatment, with a decrease in mean atrial pressurecardiac output. These agents, however, produce from 66+12 to 57+10 mm Hg. Systemicseveral undesirable effects, including an increase vascular resistance decreased by an average ofin heart rate and myocardial oxygen 37% (2,136+432 to 1,336+400 dyne·sec/cm5·m2)consumption, down-regulation of beta- and pulmonary vascular resistance decreased byadrenergic receptors, and an increase in systemic 27% (488+160 to 360+120 dyne·sec/cm5·m2).vascular resistance. Unlike the catecholamines, Heart rate increased transiently during themilrinone produces a positive inotropic effect loading dose, but slowed during the infusion.with concurrent vasodilation and little Myocardial oxygen consumption waschronotropic effect. As a result of these unchanged.differences, milrinone has become a valuabletool in the treatment of children following In 1999, Bailey and colleagues studied thecardiac surgery and in the management of shock. effects of milrinone in 20 children between 3 and 22 months of age with low cardiac output afterMechanism of Action surgery.6 All patients received a 50 mcg/kgMilrinone, like its predecessor inamrinone loading dose. In 12 of the children, the loading(formerly called amrinone), is a bipyridine dose was followed by an infusion of 0.5 to 0.7inotrope/vasodilator. It is a selective inhibitor of mcg/kg/min. The loading dose produced anpeak III cyclic adenosine monophosphate average increase in cardiac index of 18%(cAMP) phosphodiesterase in cardiac and (mean+SE 2.0+0.2 to 3.4+0.3 L/min/m2) at avascular muscle. Inhibition of this enzyme mean serum concentration of 235 ng/ml. Meanresults in an accumulation of cAMP, producing blood pressure decreased by an average of 12%,an increase in intracellular ionized calcium in from 66.7+1.4 to 58.9+2 mm Hg. Heart rate, leftcardiac muscle which increases contractile force. atrial pressure, and central venous pressure wereIncreasing cAMP also produces relaxation of unchanged. Based on pharmacokineticvascular smooth muscle. Milrinone exhibits a simulations performed with the data from thisconcentration-dependent response, with optimal study, the authors suggest that a short-term,effects occurring between 100 and 300 ng/ml.1-3 high-dose infusion of 3 mcg/kg/min for 30 minutes may be beneficial prior to initiation of aUse After Cardiac Surgery 0.5 mcg/kg/min maintenance infusion to accountSeveral investigators have studied the effects of for the larger volume of distribution observed inmilrinone in reversing the low cardiac output children.frequently observed in infants and children aftercardiac surgery.4-8 In 1995, Chang and Since publication of these initial reports,colleagues conducted a prospective study of milrinone has gained acceptance as anmilrinone in ten neonates (3 to 27 days of age) alternative or supplement to catecholamines inwith low cardiac output following surgical repair the management of pediatric patients with lowof congenital heart defects.4 Patients were given cardiac output following repair of congenitala loading dose of 50 mcg/kg intravenously (IV) heart defects. Although the data available toover 15 minutes, followed by an infusion of 0.5 date have been promising, questions about themcg/kg/min for 30 minutes. The doses used optimal timing for initiation of therapy, dosing,were based on standard dosing for adults. and monitoring remain. A prospective
  • 2. multicenter, randomized, double-blind, placebo- mean pulmonary artery pressure were decreased.controlled study is currently under development No significant changes were noted in heart rate,to address these questions.7 The Prophylactic systolic or diastolic blood pressure, meanIntravenous Use of Milrinone After Cardiac systemic arterial pressure, or pulmonaryOperation in Pediatrics (PRIMACORP) study capillary wedge pressure. All patients continuedwill compare a low-dose milrinone regimen on milrinone after the 4-hour trial, for a meanconsisting of a 25 mcg/kg loading dose followed duration of 48 hours. The authors concludedby an infusion of 0.25 mcg/kg/min, a high-dose that in volume-resuscitated pediatric patientsregimen with a 75 mcg/kg loading dose followed with septic shock, milrinone, used in conjunctionby an infusion of 0.75 mcg/kg/min, and placebo with traditional catecholamines, improvesfor up to 36 hours. Study end points will include cardiovascular function.mortality, cardiac indices, and length of hospitalstay. A pharmacokinetic assessment will also be Pharmacokineticsdone. In adults, milrinone has a volume of distribution of 0.3 to 0.4 L/kg, a terminal elimination half-While the PRIMACORP study addresses the life of 1.5 to 2.3 hours, and a clearance ofoptimal use of IV milrinone, other routes of approximately 2 ml/kg/min. It is excreted in theadministration are also being considered for the urine, as unchanged drug (83% of a dose) andpostoperative patient population. In a recent the glucuronide conjugate (12%).2,3,5study of adults with pulmonary hypertensionfollowing cardiac surgery, inhaled milrinone was As shown in the previous studies, theshown to produce additive pulmonary pharmacokinetics of milrinone are altered invasodilation when administered with inhaled infants and children. In 1998, Ramamoorthyprostacyclin.9 Compared with prostacyclin and colleagues studied the pharmacokinetics ofalone, inhaled milrinone in concentrations of milrinone after cardiac surgery in 19 children0.25, 0.5, and 1 mg/ml given with prostacyclin between 1 month and 11 years of age.5 Elevenproduced a significantly greater and longer of the children were enrolled into a low-dosereduction in pulmonary vascular resistance and protocol: two 25 mcg/kg bolus doses were given,an increase in stroke volume. Systemic vascular followed by an infusion titrated to a final rate ofresistance and mean arterial pressure were 0.5 mcg/kg/min. The remaining eight childrenunchanged. While this route of administration were placed on a high-dose protocol and given ahas not yet been studied in children, it may offer 50 mcg/kg bolus dose followed by a 25 mcg/kgan alternative to current therapies for pulmonary bolus dose and an infusion titrated to a final ratehypertension following cardiac surgery. of 0.75 mcg/kg/min. Blood samples were obtained over 24 hours. PharmacokineticUse in Septic Shock parameters were evaluated using traditional andIn addition to its use after cardiac surgery, non-linear mixed effects modeling techniques.milrinone may also be beneficial in themanagement of low cardiac output resulting The milrinone concentration data were best fit tofrom septic shock.10,11 Barton and colleagues a two-compartment pharmacokinetic model instudied the effects of milrinone in 12 children this trial. At steady-state, both groups hadwith septic shock (ages 9 months to 15 years) milrinone concentrations above the desired levelalready receiving catecholamine infusions.10 In of 100 ng/ml, with a mean of 113+39 ng/ml inthis prospective, double-blind trial, patients were the low-dose group and 206+74 ng/ml in therandomized to receive either a loading dose of high-dose group. The volume of distribution50 mcg/kg milrinone followed by an infusion of was significantly higher in these patients than0.5 mcg/kg/min or placebo. After two hours, reported in adults, with mean values of 0.9+0.4the patients were crossed over to the other arm and 0.7+0.2 L/kg in patients < 1 year and > 1and treated for an additional two hours. At the year of age, respectively. Likewise, clearanceend of this phase, patients could continue to was increased, with values of 3.8+1 and 5.9+2receive milrinone at their physician’s discretion. ml/kg/min in the two groups. Terminal elimination half-life was prolonged in the infantsMilrinone significantly increased cardiac index, (mean 3.15+2 hrs), but similar to adult values infrom an average of 3.7+0.8 L/min/m2 at baseline the older children (mean 1.86+2 hrs).to 5.5+1.6 L/min/m2 at 2 hours, while values inthe placebo group remained unchanged. Stroke In conjunction with their study of the efficacy ofvolume index and oxygen delivery were also milrinone in children with septic shock, Lindsay,significantly increased during the active Barton, and colleagues also conducted atreatment phase, while systemic vascular pharmacokinetic evaluation.11 Using a one-resistance, pulmonary vascular resistance, and compartment model, the authors calculated an
  • 3. average volume of distribution at steady-state for of children undergoing cardiac surgery withoutmilrinone of 1.47+1.03 L/kg, a clearance of milrinone, 25% developed thrombocytopenia.11+9.6 ml/kg/min, and a terminal elimination Liver function tests, BUN, and creatinine in thehalf-life of 2.88+3.21 hours. Like the data from milrinone patients were within normal limits.Ramamoorthy5, this study documented a largervolume of distribution in children than reported Other pediatric milrinone studies reported noin adults. These studies, together with the paper significant adverse effects. In the study byby Bailey6, suggest that a larger loading dose, Chang4, one child had occasional prematureand perhaps a greater initial infusion rate, may atrial beats, but there were no sustainedbe necessary in children to achieve serum tachyarrhythmias. No patients in the studies byconcentrations within the desired range and Bailey6 and Barton10 exhibited arrhythmias.produce an optimal cardiovascular response. Dosing RecommendationsAdverse Effects Milrinone (Primacor; Sanofi-Synthelabo) isAs with other positive inotropes, the available in a 1 mg/ml concentration in 10, 20,phosphodiesterase inhibitors have the potential and 50 ml single-dose vials, 5 mg/5mlto produce arrhythmias. Milrinone produces a Carpuject sterile cartridges, and in 200 mcg/mlslight shortening of atrioventricular node premixed 100 and 200 ml bags.3conduction time, which may result in anincreased ventricular response rate in patients Based on the studies presented, thewith atrial flutter or fibrillation. In Phase II and recommended loading dose of milrinone inIII clinical trials of adults, ventricular infants and children is 50 to 75 mcg/kg given IVarrhythmias were reported in 12% of patients. In over 15 to 60 minutes. The loading dose may bethese patients, 8.5% experienced ventricular reduced to 25 mcg/kg or omitted in patients atectopic activity, 2.8% had nonsustained risk for hypotension. Immediately after the load,ventricular tachycardia, 1% had sustained a continuous infusion of 0.375 to 0.75ventricular tachycardia, and 0.2% had mcg/kg/min may be started. Administration ofventricular fibrillation (some patients had more milrinone within this range should producethan one type of arrhythmia). Supraventricular serum concentrations above the minimumarrhythmias occurred in 3.8% of patients. desired concentration of 100 ng/ml. TheHypokalemia has been reported in 0.6% of maintenance infusion rate should be titrated topatients receiving milrinone and may predispose patient response. Serum concentrationthem to the development of arrhythmias.1-3 monitoring is not routinely available in most institutions.Other adverse effects associated with milrinoneuse in adult clinical trials include: hypotension Infusion rates should be decreased in patients(2.9%) seen most often with rapid administration with renal impairment.1-3 Although no specificof the loading dose, headaches (2.9%), angina recommendations have been published for(1.2%), tremor (0.4%), and thrombocytopenia children with renal dysfunction, the following(0.4%). The incidence of thrombocytopenia is table of recommendations for adults may be usedsubstantially less than that seen with inamrinone as a general reference.(2.4%). Post-marketing surveillance hasincluded case reports of bronchospasm and Table 1. Dose Adjustment for Renal Impairmentelevations in liver function tests in patients Creatinine Clearance Milrinone Ratereceiving milrinone.1-3 50 ml/min/1.73m2 0.43 mcg/kg/min 40 ml/min/1.73m2 0.38 mcg/kg/minWhile only a small number of pediatric patients 30 ml/min/1.73m2 0.33 mcg/kg/minhave been evaluated in clinical trials, the adverse 20 ml/min/1.73m2 0.28 mcg/kg/mineffect profile of milrinone in children appears 10 ml/min/1.73m2 0.23 mcg/kg/minsimilar to that of adults. In the pharmacokinetic 5 ml/min/1.73m2 0.2 mcg/kg/minstudy by Ramamoorthy, 2 of the 19 children(11%) developed arrhythmias.5 Both patients Drug Interactions and Compatibilitywere infants; one underwent repair for tetralogy The loading dose of milrinone may be givenof Fallot and the other for an atrioventricular undiluted or diluted to 10 to 20 ml. For infusion,canal defect. Both developed junctional ectopic milrinone should be diluted to a concentration oftachycardia requiring discontinuation of 200 to 400 mcg/ml with D5W, 0.9% sodiummilrinone. Eleven patients (58%) developed chloride, 0.45% sodium chloride, or lactatedthrombocytopenia; however, the authors suggest Ringer’s solution. Milrinone is compatible withthat this adverse effect may be more the result of many other drugs commonly used in thesurgery than milrinone. In a comparison group intensive care setting. The following table lists
  • 4. drugs physically compatible with milrinone for a 3. Primacor product information. Sanofi-Synthelabo, Inc.period of 4 hours.12,13 October 2000. Available at 4. Chang AC, Atz AM, Wernovsky G, et al. Milrinone:Table 2. Drugs Compatible with Milrinone systemic and pulmonary hemodynamic effects in neonatesacyclovira magnesium sulfateb after cardiac surgery. Crit Care Med 1995;23:1907-14.amikacin a meropenema 5. Ramamoorthy C, Anderson GD, Williams GD, et al. a Pharmacokinetics and side effects of milrinone in infants andampicillin methylprednisolonea children after open heart surgery. Anesth Analg 1998;86:283- batracurium metronidazolea 9. bbumetanide midazolamb 6. Bailey JM, Miller BE, Lu W, et al. The pharmacokinetics acalcium chloride morphinea,b of milrinone in pediatric patients after cardiac surgery. a,b Anesthesiology 1999;90:1012-8.calcium gluconate nitroglycerinb 7. Chu CC, Lin SM, New SH, et al. Effect of milrinone on acefazolin norepinephrineb postbypass pulmonary hypertension in children after acefepime oxacillina tetralogy of Fallot repair. Chung Hua I Hsueh Tsa Chih acefotaxime pancuroniumb 2000;63:294-300. a 8. Hoffman TM, Wernovsky G, Atz AM, et al. Prophylacticceftazidime parenteral nutritiona,b intravenous use of milrinone after cardiac operation in acefuroxime piperacillina pediatrics study. Am Heart J 2002;143:15-21. bcimetidine piperacill./tazobactama 9. Haraldsson A, Kieler-Jensen N, Ricksten S. The additive aciprofloxacin potassium chlorideb pulmonary vasodilatory effects of inhaled prostacyclin and a inhaled milrinone in postcardiac surgical patients withclindamycin propofolb pulmonary hypertension. Anesth Analg 2001;93:1439-45. adexamethasone ranitidineb 10. Barton P, Garcia J, Kouatli A, et al. Hemodynamic effects bdiltiazem rocuroniumb of IV milrinone lactate in pediatric patients with septic shock. bdobutamine sodium bicarbonateb Chest 1996;109:1302-12. b 11. Lindsay CA, Barton P, Lawless S, et al. Pharmacokineticsdopamine sodium nitroprussideb and pharmacodynamics of milrinone lactate in pediatric bepinephrine theophyllineb patients with septic shock. J Pediatr 1998;132:329-34. bfentanyl ticarcillina 12. Akkerman SR, Zhang H, Mullins RE, et al. Stability of agentamicin ticarcillin/clavulanatea milrinone lactate in the presence of 29 critical care drugs and b 4 IV solutions. Am J Health-Syst Pharm 1999;56:63-8.heparin tobramycina 13. Veltri MA, Conner KG. Physical compatibility ofinsulin, human torsemideb milrinone lactate injection with intravenous drugs commonly bregular used in the pediatric intensive care unit. Am J Health-Systisoproterenolb vancomycina Pharm 2002;59:452-4. a,blorazepam vecuroniumba tested with milrinone 200 mcg/ml13 Pharmacology Literature Review b tested with milrinone 400 mcg/ml12 Once-daily aminoglycosides in children Although frequently used in adults, once-dailyMilrinone should not be infused with aminoglycoside dosing has failed to become afurosemide. A chemical interaction occurs standard practice in pediatrics. The authors ofbetween these drugs resulting in formation of a this review provide reasons for this resistanceprecipitate. Mixing of milrinone and imipenem- and suggest areas for future study. Knoderercilastatin results in a change in the color of the CA, Everett JA, Buss WF. Clinical issuessolution from light to dark yellow. While the surrounding once-daily aminoglycoside dosingclinical significance of this color change has not in children. Pharmacotherapy 2003;23:44-56.been assessed, it may indicate druginactivation.2,13 Formulary Update The following actions were taken by theSummary Pharmacy and Therapeutics Committee at theirWith its combined inotropic and vasodilatory meeting on 1/31/03:effects, milrinone provides a useful alternative to 1. Secretin (SecreFlo) was added to thetraditional catecholamines in children with low Formulary to aid in the diagnosis of pancreaticcardiac output. Although several small-scale dysfunction or gastrinoma and to facilitatestudies in children are available, more research is cholangiopancreatography.needed to evaluate long-term effects, better 2. Two chemotherapeutic agents, oxaliplatindefine the adverse effect profile, and determine (Eloxatin) and yttrium90 ibritumomab tiuxetanan optimal dosing strategy. (Zevalin), were added to the Formulary.References Contributing Editor:Marcia L. Buck, Pharm.D.1. Levy JH, Bailey JM, Deeb GM. Intravenous milrinone in Editorial Board: Anne E. Hendrick, Pharm.D.cardiac surgery. Ann Thorac Surg 2002;73:325-30. Michelle W. McCarthy, Pharm.D.2. Burnham TH, ed. Drug Facts and Comparisons. 2003. St. Kristi N. Hofer, Pharm.D.Louis: Facts and Comparisons, Inc. : 403-4. If you have comments or suggestions for future issues, please contact us at Box 800674, UVA
  • 5. Health System, Charlottesville, VA 22908 orby e-mail to Thisnewsletter is also available