Abstract
Since its discovery in 1975 dobutamine has been used off-label for treating hemodynamic insufficiency in newborns and children. We present a structured literature review of pharmacokinetic and pharmacodynamic data for dobutamine in the pediatric population. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria. Where possible, results for the pharmacodynamic and pharmacokinetic effect of dobutamine were reported as pooled data. Forty-six papers met the inclusion criteria. With regard to pharmacodynamic data a number of studies reported significant increases in a number of clinical parameters such as heart rate, blood pressure, cardiac output across a wide range of pediatric populations. With regard to pharmacokinetic data studies reported that the infusion rate was positively correlated to plasma dobutamine concentration. There was great variability with regard to dobutamine clearance between individuals and as to whether it followed first- or zero-order elimination kinetics. While the pharmacodynamic effects of dobutamine appear to reflect the pharmacological profile of the drug, the pharmacokinetic data are difficult to interpret due to inhomogeneity between study populations ages, comorbidities, dobutamine dosages and methodologies. High-quality prospective pharmacokinetic and pharmacodynamic data especially in newborns are urgently required prior to a large randomized study.
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References
Alderliesten T, Lemmers PMA, van Haastert IC et al (2014) Hypotension in preterm neonates: low blood pressure alone does not affect neurodevelopmental outcome. J Pediatr 164:986–991. doi:10.1016/j.jpeds.2013.12.042
Aslan YY, Koca LL, Mutlu MM et al (2011) Apopitotic effects of dopamine and dobutamine on neutrophils of premature neonates. J Matern Fetal Neonatal Med 24:1155–1158. doi:10.3109/14767058.2010.545914
Ballabh P (2010) Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 67:1–8
Banner W, Vernon DD, Minton SD, Dean JM (1991) Nonlinear dobutamine pharmacokinetics in a pediatric population. Crit Care Med 19:871–873
Berg RAR, Padbury JFJ (1997) Sulfoconjugation and renal excretion contribute to the interpatient variation of exogenous catecholamine clearance in critically ill children. Crit Care Med 25:1247–1251
Berg RA, Donnerstein RL, Padbury JF (1993) Dobutamine infusions in stable, critically ill children: pharmacokinetics and hemodynamic actions. Crit Care Med 21:678–686
Berg RA, Padbury JF, Donnerstein RL et al (1993) Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents. J Pharmacol Exp Ther 265:1232–1238
Berner M, Oberhänsli I, Rouge JC et al (1989) Chronotropic and inotropic supports are both required to increase cardiac output early after corrective operations for tetralogy of Fallot. J Thorac Cardiovasc Surg 97:297–302
Bohn DJ, Poirier CS, Edmonds JF, Barker GA (1980) Hemodynamic effects of dobutamine after cardiopulmonary bypass in children. Crit Care Med 8:367–371
Clark RH, Bloom BT, Spitzer AR, Gerstmann DR (2006) Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 117:1979–1987. doi:10.1542/peds.2005-1707
Conroy S, Choonara I, Impicciatore P et al (2000) Survey of unlicensed and off label drug use in paediatric wards in European countries. European network for drug investigation in children. BMJ 320:79–82
Coté CJ, Kauffman RE, Troendle GJ, Lambert GH (1996) Is the “therapeutic orphan” about to be adopted? Pediatrics 98:118–123
Dalben M, Varkulja G, Basso M et al (2008) Investigation of an outbreak of Enterobacter cloacae in a neonatal unit and review of the literature. J Hosp Infect 70:7–14. doi:10.1016/j.jhin.2008.05.003
de Waal K, Kluckow M (2015) Functional echocardiography; from physiology to treatment. Early Hum Dev 86:149–154. doi:10.1016/j.earlhumdev.2010.01.030
Devictor D, Verlhac S, Pariente D, Huault G (1988) Hemodynamic effects of dobutamine in asphyxiated newborn infants. Arch Fr Pediatr 45:467–470
Driscoll DJ (1987) Use of inotropic and chronotropic agents in neonates. Clin Perinatol 14:931–949
Driscoll DJ, Gillette PC, Duff DF et al (1979) Hemodynamic effects of dobutamine in children. Am J Cardiol 43:581–585
EMA (2010) Revised priority list for studies into off-patent paediatric medical products. European Medicines Agency, London, EMA/480197/2010, pp 1–8
Filippi L, Pezzati M, Poggi C et al (2007) Dopamine versus dobutamine in very low birthweight infants: endocrine effects. Arch Dis Child Fetal Neonatal Ed 92:F367–F371. doi:10.1136/adc.2006.098566
Gauthier M, van Doesburg N, Lacroix J, Rousseau E (1984) The pharmacology of cardiorespiratory resuscitation in children. Union Med Can 113:106–111
Greenough A, Emery EF (1993) Randomized trial comparing dopamine and dobutamine in preterm infants. Eur J Pediatr 152:925–927
Gupta S, Donn SM (2014) Neonatal hypotension: dopamine or dobutamine? Semin Fetal Neonatal Med 19:54–59. doi:10.1016/j.siny.2013.09.006
Gupte S (2002) Perspectives in neonatal shock. Perinatology 4:264–275
Habib DM, Padbury JF, Anas NG et al (1992) Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care patients. Crit Care Med 20:601–608
Hamamichi Y, Ichida F, Tsubata S et al (2002) Dobutamine stress radionuclide ventriculography reveals silent myocardial dysfunction in Kawasaki disease. Circ J 66:63–69
Harada K, Tamura M, Ito T et al (1996) Effects of low-dose dobutamine on left ventricular diastolic filling in children. Pediatr Cardiol 17:220–225
Harada K, Tamura M, Toyono M, Yasuoka K (2002) Effect of dobutamine on a Doppler echocardiographic index of combined systolic and diastolic performance. Pediatr Cardiol 23:613–617. doi:10.1007/s00246-002-0017-7
Hayabuchi YY, Matsuoka SS, Kuroda YY (1999) Plasma concentrations of atrial and brain natriuretic peptides and cyclic guanosine monophosphate in response to dobutamine infusion in patients with surgically repaired tetralogy of fallot. Pediatr Cardiol 20:343–350
Hentschel R, Hensel D, Brune T et al (1995) Impact on blood pressure and intestinal perfusion of dobutamine or dopamine in hypotensive preterm infants. Biol Neonate 68:318–324
Hunt RW, Evans N, Rieger I, Kluckow M (2004) Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. J Pediatr 145:588–592. doi:10.1016/j.jpeds.2004.06.056
Hurwitz RA, Siddiqui A, Caldwell RL et al (1990) Assessment of ventricular function in infants and children. Response to dobutamine infusion. Clin Nucl Med 15:556–559
Jose AB, Niguidula DF, Botros S et al (1981) Hemodynamic effects of dobutamine in children. Anaesthesiology 55:25
Kates RE, Leier CV (1978) Dobutamine pharmacokinetics in severe heart failure. Clin Pharmacol Ther 24:537–541
Klarr JM, Faix RG, Pryce CJ, Bhatt-Mehta V (1994) Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. J Pediatr 125:117–122. doi:10.1016/S0022-3476(94)70137-7
Kleiber N, Tromp K, Mooij MG et al (2014) Ethics of drug research in the pediatric intensive care unit. Paediatr Drugs. doi:10.1007/s40272-014-0101-5
Kluckow M (2005) Low systemic blood flow and pathophysiology of the preterm transitional circulation. Early Hum Dev 81:429–437. doi:10.1016/j.earlhumdev.2005.03.006
Kwapisz MM, Neuhäuser C, Scholz S et al (2009) Hemodynamic effects of dobutamine and dopexamine after cardiopulmonary bypass in pediatric cardiac surgery. Paediatr Anaesth 19:862–871. doi:10.1111/j.1460-9592.2009.03101.x
Lorenz JM, Kleinman LI, Ahmed G, Markarian K (1995) Phases of fluid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics 96:484–489
Martinez AM, Padbury JF, Thio S (1992) Dobutamine pharmacokinetics and cardiovascular responses in critically ill neonates. Pediatrics 89:47–51
Michelfelder EC, Witt SA, Khoury P, Kimball TR (2003) Moderate-dose dobutamine maximizes left ventricular contractile response during dobutamine stress echocardiography in children. J Am Soc Echocardiogr 16:140–146. doi:10.1067/mje.2003.3
Mielgo V, Soler AVI, Rey-Santano C (2014) Dobutamine in paediatric population: a systematic review in juvenile animal models. PLoS ONE 9:e95644
Milsap RL, Jusko WJ (1994) Pharmacokinetics in the infant. Environ Health Perspect 102(Suppl 11):107–110
Nakazawa M, Takahashi Y, Aiba S et al (1987) Acute hemodynamic effects of dopamine, dobutamine, and isoproterenol in congested infants or young children with large ventricular septal defect. Jpn Circ J 51:1010–1015
NEOCIRC Consortium (2012) Dobutamine for NEOnatal CIRCulatory failure defined by novel biomarkers. www.neocirculation.eu. In: http://neocirculation.eu. Accessed 28 Feb 2014
Osborn D, Evans N, Kluckow M (2002) Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow. J Pediatr 140:183–191. doi:10.1067/mpd.2002.120834
Osborn DAD, Evans NN, Kluckow MM (2007) Left ventricular contractility in extremely premature infants in the first day and response to inotropes. Pediatr Res 61:335–340. doi:10.1203/pdr.0b013e318030d1e1
Osborn DA, Evans N, Kluckow M et al (2007) Low superior vena cava flow and effect of inotropes on neurodevelopment to 3 years in preterm infants. Pediatrics 120:372–380. doi:10.1542/peds.2006-3398
Osborn DA, Paradisis M, Evans N (2007) The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow. Cochrane Database Syst Rev. doi:10.1002/14651858.CD005090.pub2
Pellicer A (2007) Hipotensión y soporte cardiovascular en el recién nacido de bajo peso. Anales de Pediatría Continuada 5:361–365. doi:10.1016/S1696-2818(07)74160-4
Perkin RM, Levin DL, Webb R et al (1982) Dobutamine: a hemodynamic evaluation in children with shock. J Pediatr 100:977–983
Platz H, Fries R, Hudec M et al (1983) The prognostic relevance of various factors at the time of the first admission of the patient: retrospective DÖSAK study on carcinoma of the oral cavity. J Maxillofac Surg 11:3–12. doi:10.1016/S0301-0503(83)80005-8
Pushparajah K, Wong J, Bellsham-Revell HR et al (2013) MRI catheter stress haemodynamics in hypoplastic left heart syndrome after Fontan completion. Cardiol Young 23:S1–S144
Razavi RS, Baker A, Qureshi SA et al (2001) Hemodynamic response to continuous infusion of dobutamine in Alagille’s syndrome. Transplantation 72:823–828
Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (2006) Official Journal of the European Union. L 378/1
Robel-Tillig E, Knüpfer M, Pulzer F, Vogtmann C (2007) Cardiovascular impact of dobutamine in neonates with myocardial dysfunction. Early Hum Dev 83:307–312. doi:10.1016/j.earlhumdev.2006.06.005
Rozé JC, Tohier C, Maingueneau C et al (1993) Response to dobutamine and dopamine in the hypotensive very preterm infant. Arch Dis Child 69:59–63. doi:10.1136/adc.69.1_Spec_No.59
Ruelas-Orozco G, Vargas-Origel A (2000) Assessment of therapy for arterial hypotension in critically ill preterm infants. Am J Perinatol 17:95–99
Ruggieri L, Giannuzzi V, Baiardi P et al (2014) Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines. Eur J Pediatr. doi:10.1007/s00431-014-2398-z
Sakata Y, Iijima T, Yoshida I et al (1991) Effects of dopamine and dobutamine on systemic hemodynamics and myocardial metabolism in children after open heart surgery. Kyobu Geka 44:461–466
Sakata Y, Anzai T, Iijima T et al (1992) Effects of dobutamine and isoproterenol on systemic hemodynamics and myocardial metabolism in children after open heart surgery. Kokyu To Junkan 40:65–70
Schranz D, Stopfkuchen H, Jüngst BK et al (1982) Hemodynamic effects of dobutamine in children with cardiovascular failure. Eur J Pediatr 139:4–7
Schwartz PH, Eldadah MK, Newth CJ (1991) The pharmacokinetics of dobutamine in pediatric intensive care unit patients. Drug Metab Dispos 19:614–619
Seri I (2001) Neonatal shock: etiology, pathophysiology and management. Prenat Neonatal Med 6:15–26. doi:10.1080/13598630108500263
Steinberg C, Notterman DA (1994) Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors. Clin Pharmacokinet 27:345–367. doi:10.2165/00003088-199427050-00003
Stopfkuchen H, Schranz D, Huth R, Jüngst BK (1987) Effects of dobutamine on left ventricular performance in newborns as determined by systolic time intervals. Eur J Pediatr 146:135–139
Stopfkuchen H, Queisser-Luft A, Vogel K (1990) Cardiovascular responses to dobutamine determined by systolic time intervals in preterm infants. Crit Care Med 18:722–724
Stowe CD, Storgion SA, Lee KR, Phelps SJ (1996) Hemodynamic response to intentionally altered flow continuity of dobutamine and dopamine by an infusion pump in infants. Pharmacotherapy 16:1018–1023. doi:10.1002/j.1875-9114.1996.tb03027.x
Subhedar NV, Shaw NJ (2003) Dopamine versus dobutamine for hypotensive preterm infants. Cochrane Database Syst Rev 3:CD001242
Trifonova NA, Ismail-Zade IA, Michelson VA (1994) Value of dobutamine in children surgically treated for portal hypertension. Apropos of 23 cases. Cah Anesthesiol 42:577–581
van den Broek MPH, Groenendaal F, Egberts ACG, Rademaker CMA (2010) Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet 49:277–294. doi:10.2165/11319360-000000000-00000
Yan M, Webster LT, Blumer JL (2002) 3-O-methyldobutamine, a major metabolite of dobutamine in humans. Drug Metab Dispos 30:519–524. doi:10.1124/dmd.30.5.519
Acknowledgments
A special thanks to Tom Roper and Sarah Butler, Clinical librarians at The Brighton and Sussex University Hospitals NHS Trust, for their help with searching strategies for this review. This literature review will be presented to the European Medicines Agency as part of a Pediatric Investigations Plan for the Neo-Circulation Project. The members of the consortium are outlined below: Chief Investigator: Adelina Pellicer, Madrid, Spain. Principal Project Coordinator: Heike Rabe, Brighton, UK. Local Investigators: Philip Amess, Neil Aiton, David Crook, Ramon Fernandez, Liam Mahoney, Heike Rabe, Hector Rojas-Anaya, Brighton, UK; Vincent Jullien, Thomas Le Saux, Gerard Pons, Paris, France; Frank Biertz, Wolfgang Büter, Armin Koch, Hannover, Germany; Victoria Mielgo, Adolf Valls-i-Soler (in memoriam), Bizkaia, Spain; Wolfgang Göpel, Christoph Härtel, Lübeck, Germany; Haris Kotidis, Mark Turner, Michael Weindling, Liverpool, UK; Claudia Roll, Datteln, Germany; Maria Carmen Bravo, Fernando Cabanas, Madrid, Spain; Simon Bryson, Chesire, UK; Alexandrina Tatu, Adrian Toma, Bucharest, Romania; Gabriela Zaharie, Cluj-Napoca , Romania; Géza Bokodi, Miklós Szabó, Budapest, Hungary; Tibor Ertl, Simone Funke, Pécs, Hungary; Ebru Ergenekon, Kivilcim Gücüyener, Şebnem Soysal, Ankara, Turkey; Christiane Dammann, Olaf Dammann, Jennifer Lee, Boston, US; Neo-Circulation Expert Advisory Board: Tonse N. K. Raju, Bethesda, USA; Nicholas Evans, Sydney, Australia; Stephanie Läer, Düsseldorf, Germany; Silke Mader, Karlsfeld, Germany; Monika Seibert-Grafe, Mainz, Germany. Neo-Circulation Ethics Advisory and Data Monitoring Board: Gorm Greisen, Copenhagen, Denmark; Lena Hellström-Westas, Uppsala, Sweden; Josef Högel, Ulm, Germany.
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Mahoney, L., Shah, G., Crook, D. et al. A Literature Review of the Pharmacokinetics and Pharmacodynamics of Dobutamine in Neonates. Pediatr Cardiol 37, 14–23 (2016). https://doi.org/10.1007/s00246-015-1263-9
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DOI: https://doi.org/10.1007/s00246-015-1263-9