Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-27T11:29:07.227Z Has data issue: false hasContentIssue false
  • English
  • Français

The relationship between simulated milrinone exposure and hypotension in children

Published online by Cambridge University Press:  05 August 2021

Sarah Jane Commander ,
Daniel Gonzalez ,
Karan R. Kumar ,
Tracy Spears ,
Michael Cohen-Wolkowiez ,
Kanecia O. Zimmerman ,
Stephen J. Balevic  and
Christoph P. Hornik Open the ORCID record for Christoph P. Hornik [Opens in a new window]
Sarah Jane Commander
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Surgery, Duke University Medical Center, Durham, NC, USA
Daniel Gonzalez
Affiliation:
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Karan R. Kumar
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Tracy Spears
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA
Michael Cohen-Wolkowiez
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Kanecia O. Zimmerman
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Stephen J. Balevic
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Christoph P. Hornik*
Affiliation:
Department of Pediatrics, Duke Clinical Research Institute, Durham, NC, USA Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
*
Author for correspondence: Christoph Hornik, MD, PhD, MPH, Department of Pediatrics, Duke University School of Medicine, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715 USA. Tel: 919-357-8145; Fax: 919-681-9457; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Introduction:

Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure–safety relationship is unknown.

Methods:

Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure–safety relationships.

Results:

We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01).

Conclusions:

We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure–response and –safety relationships.

Keywords

Milrinonehypotensionpopulation pharmacokineticssimulated concentrationreal-world data
Type
Original Article
Information
Cardiology in the Young , Volume 32 , Issue 5 , May 2022 , pp. 782 - 788
Check for updates
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Giaccone, A, Zuppa, AF, Sood, B, et al. Milrinone pharmacokinetics and pharmacodynamics in neonates with persistent pulmonary hypertension of the newborn. Am J Perinatol 2017; 34: 749–758.Google ScholarPubMed
Milrinone [package insert]. Irvine, CA: B. Braun Medical Inc., 2006.Google Scholar
Bishara, T, Seto, WT, Trope, A, Parshuram, CS. Use of milrinone in critically ill children. Can J Hosp Pharm 2010; 63: 420–428.Google ScholarPubMed
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. Cochrane Database Syst Rev 2015; 3: CD009515.Google Scholar
Lindsay, CA, Barton, P, Lawless, S, et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr 1998; 132: 329–334.CrossRefGoogle ScholarPubMed
Cox, ZL, Calcutt, MW, Morrison, TB, Akers, WS, Davis, MB, Lenihan, DJ. Elevation of plasma milrinone concentrations in stage D heart failure associated with renal dysfunction. J Cardiovasc Pharmacol Ther 2013; 18: 433–438.CrossRefGoogle Scholar
Taniguchi, T, Shibata, K, Saito, S, Matsumoto, H, Okeie, K. Pharmacokinetics of milrinone in patients with congestive heart failure during continuous venovenous hemofiltration. Intensive Care Med 2000; 26: 1089–1093.CrossRefGoogle ScholarPubMed
Young, RA, Ward, A. Milrinone. A preliminary review of its pharmacological properties and therapeutic use. Drugs 1988; 36: 158–192.CrossRefGoogle ScholarPubMed
Hornik, CP, Yogev, R, Mourani, PM, et al. Population pharmacokinetics of milrinone in infants, children, and adolescents. J Clin Pharmacol 2019; 59: 1606–1619.CrossRefGoogle ScholarPubMed
Bailey, JM, Levy, JH, Kikura, M, Szlam, F, Hug, CC Jr Pharmacokinetics of intravenous milrinone in patients undergoing cardiac surgery. Anesthesiology 1994; 81: 616–622.CrossRefGoogle ScholarPubMed
Garcia Guerra, G, Joffe, AR, Senthilselvan, A, Kutsogiannis, DJ, Parshuram, CS. Incidence of milrinone blood levels outside the therapeutic range and their relevance in children after cardiac surgery for congenital heart disease. Intensive Care Med 2013; 39: 951–957.CrossRefGoogle ScholarPubMed
Gist, KM, Mizuno, T, Goldstein, SL, Vinks, A. Retrospective evaluation of milrinone pharmacokinetics in children with kidney injury. Ther Drug Monit 2015; 37: 792–796.CrossRefGoogle ScholarPubMed
Hoffman, TM, Wernovsky, G, Atz, AM, 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.CrossRefGoogle ScholarPubMed
Larsson, R, Liedholm, H, Andersson, KE, Keane, MA, Henry, G. Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment. Eur J Clin Pharmacol 1986; 29: 549–553.CrossRefGoogle ScholarPubMed
Ramamoorthy, C, Anderson, GD, Williams, GD, Lynn, AM. Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery. Anesth Analg 1998; 86: 283–289.CrossRefGoogle ScholarPubMed
Hallik, M, Ilmoja, ML, Tasa, T, et al. Population pharmacokinetics and dosing of milrinone after patent ductus arteriosus ligation in preterm infants. Pediatr Crit Care Med 2019; 20: 621–629.CrossRefGoogle ScholarPubMed
Ku, LC, Wu, H, Greenberg, RG, et al. Use of therapeutic drug monitoring, electronic health record data, and pharmacokinetic modeling to determine the therapeutic index of phenytoin and lamotrigine. Ther Drug Monit 2016; 38: 728–737.CrossRefGoogle ScholarPubMed
Hornik, CP, Atz, AM, Bendel, C, et al. Creation of a multicenter pediatric inpatient data repository derived from electronic health records. Appl Clin Inform 2019; 10: 307–315.Google ScholarPubMed
Schwartz, GJ, Work, DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 2009; 4: 1832–1843.CrossRefGoogle ScholarPubMed
Kleinman, ME, Chameides, L, Schexnayder, SM, et al. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122 (18 Suppl 3): S876–S908.Google ScholarPubMed
Keizer, RJ, van Benten, M, Beijnen, JH, Schellens, JH, Huitema, AD. Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed 2011; 101: 72–79.CrossRefGoogle ScholarPubMed
B. Braun Medical, Inc. Milrinone Lactate in Dextrose (B. Braun Medical Inc.): FDA Package Insert, Page 4 of 4. https://medlibrary.org/lib/rx/meds/milrinone-lactate-in-dextrose/page/4/. Published October 29, 2007. Accessed September 29, 2020.Google Scholar
Nanimatsu, H, Saikawa, T, Maeda, T, Fukuoka, Y, Takaki, R. Hemodynamic effects of milrinone in patients with congestive heart failure--short- and long-term follow up studies. Jpn Circ J 1993; 57: 91–101.CrossRefGoogle Scholar
Baruch, L, Patacsil, P, Hameed, A, Pina, I, Loh, E. Pharmacodynamic effects of milrinone with and without a bolus loading infusion. Am Heart J 2001; 141: 266–273.CrossRefGoogle ScholarPubMed
Mizuno, T, Gist, KM, Gao, Z, et al. Developmental pharmacokinetics and age-appropriate dosing design of milrinone in neonates and infants with acute kidney injury following cardiac surgery. Clin Pharmacokinet 2019; 58: 793–803.CrossRefGoogle ScholarPubMed
Vogt, W. Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug-disease model. Clin Pharmacokinet 2014; 53: 51–72.CrossRefGoogle ScholarPubMed
Remme, WJ, van Hoogenhuyze, DC, Kruijssen, HA, Pieper, PG, Bruggeling, WA. Preload-dependent hemodynamic effects of milrinone in moderate heart failure. Cardiology 1992; 80: 132–142.CrossRefGoogle ScholarPubMed
Shipley, JB, Tolman, D, Hastillo, A, Hess, ML. Milrinone: basic and clinical pharmacology and acute and chronic management. Am J Med Sci 1996; 311: 286–291.CrossRefGoogle ScholarPubMed
Seino, Y, Takano, T, Hayakawa, H, et al. Hemodynamic effects and pharmacokinetics of oral milrinone for short-term support in acute heart failure. Cardiology 1995; 86: 34–40.CrossRefGoogle ScholarPubMed
Sato, N. Phosphodiesterase III inhibitor—characteristics, mechanisms of action, pharmacokinetics, indications, contraindications, clinical trials, and side effects. Nihon Rinsho 2007; 65 (Suppl 5): 43–48.Google ScholarPubMed
Smith, PB, Benjamin, DK Jr, Murphy, MD, et al. Safety monitoring of drugs receiving pediatric marketing exclusivity. Pediatrics 2008; 122: e628–e633.CrossRefGoogle ScholarPubMed
Supplementary material: File

Commander et al. supplementary material

Commander et al. supplementary material

Download Commander et al. supplementary material(File)
File 12.5 KB