Hostname: page-component-68945f75b7-wph62 Total loading time: 0 Render date: 2024-08-05T19:35:46.624Z Has data issue: false hasContentIssue false

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020

Part of: Surgery

Published online by Cambridge University Press:  20 November 2020

Caitlin E. King
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Elizabeth J. Thompson
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Henry P. Foote
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Kanecia O. Zimmerman
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Durham, NC, USA
Kevin D. Hill
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Reid Chamberlain
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
Christoph P. Hornik*
Affiliation:
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Durham, NC, USA
*
Author for correspondence: Christoph P. Hornik, MD, PhD, MPH, Department of Pediatrics, Duke University School of Medicine and Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715, USA. Tel: +1 919 684 8111; Fax: +1 919 681 9457. Email: christoph.hornik@duke.edu

Abstract

Background:

Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use.

Methods:

To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth – 18 years of age. Two reviewers independently reviewed studies to determine final eligibility.

Results:

The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses.

Conclusion:

Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.

Type
Review Article
Copyright
© The Author(s), 2020. 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

Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 18901900.CrossRefGoogle ScholarPubMed
Jacobs, JP, He, X, Mayer, JE Jr, et al. Mortality trends in pediatric and congenital heart surgery: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. Ann Thorac Surg 2016; 102: 13451352.CrossRefGoogle Scholar
Jacobs, ML, O’Brien, SM, Jacobs, JP, et al. An empirically based tool for analyzing morbidity associated with operations for congenital heart disease. J Thorac Cardiovasc Surg 2013; 145: 10461057.e1.CrossRefGoogle ScholarPubMed
Smith-Parrish, M, Schumacher, K, Gruppen, L, et al. The clinical factors agreed upon by pediatric cardiac intensivists to define low cardiac output syndrome. Circulation 2013; 128: A17441.Google Scholar
Parr, GV, Blackstone, EH, Kirklin, JW Cardiac performance and mortality early after intracardiac surgery in infants and young children. Circulation 1975; 51: 867874.CrossRefGoogle ScholarPubMed
Loomba, RS, Flores, S. Use of vasoactive agents in postoperative pediatric cardiac patients: insights from a national database. Congenit Heart Dis 2019; 14: 11761184.CrossRefGoogle ScholarPubMed
Roeleveld, PP, de Klerk, JCA. The perspective of the intensivist on inotropes and postoperative care following pediatric heart surgery: an international survey and systematic review of the literature. World J Pediatr Congenit Heart Surg 2018; 9: 1021.CrossRefGoogle ScholarPubMed
Torok, RD, Li, JS, Kannankeril, PJ, et al. Recommendations to enhance pediatric cardiovascular drug development: report of a multi-stakeholder think tank. J Am Heart Assoc 2018; 7: e007283.CrossRefGoogle ScholarPubMed
Burstein, DS, Rossi, AF, Jacobs, JP, et al. Variation in models of care delivery for children undergoing congenital heart surgery in the United States. World J Pediatr Congenit Heart Surg 2010; 1: 814.CrossRefGoogle ScholarPubMed
Ferrer-Barba, A, Gonzalez-Rivera, I, Bautista-Hernandez, V. Inodilators in the management of low cardiac output syndrome after pediatric cardiac surgery. Curr Vasc Pharmacol 2016; 14: 4857.CrossRefGoogle ScholarPubMed
McFerson, MC, McCanta, AC, Pan, Z, et al. Tachyarrhythmias after the Norwood procedure: relationship and effect of vasoactive agents. Pediatr Cardiol. 2014; 35: 668675.CrossRefGoogle ScholarPubMed
Oualha, M, Urien, S, Spreux-Varoquaux, O, et al. Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children. Crit Care 2014; 18: R23.CrossRefGoogle ScholarPubMed
Watarida, S, Shiraishi, S, Sugita, T, et al. Effects of docarpamine on hemodynamics after open heart surgery in children. Ann Thorac Cardiovasc Surg 2000; 6: 106109.Google ScholarPubMed
de Souza, RL, de Carvalho, WB, Maluf, MA, Carvalho, AC. Assessment of splanchnic perfusion with gastric tonometry in the immediate postoperative period of cardiac surgery in children. Arq Bras Cardiol 2001; 77: 509519.CrossRefGoogle ScholarPubMed
Cavigelli-Brunner, A, Hug, MI, Dave, H, et al. Prevention of low cardiac output syndrome after pediatric cardiac surgery: a double-blind randomized clinical pilot study comparing dobutamine and milrinone. Pediatr Crit Care Med 2018; 19: 619625.CrossRefGoogle ScholarPubMed
Ebade, AA, Khalil, MA, Mohamed, AK. Levosimendan is superior to dobutamine as an inodilator in the treatment of pulmonary hypertension for children undergoing cardiac surgery. J Anesth 2013; 27: 334339.CrossRefGoogle ScholarPubMed
De Oliveira, NC, Ashburn, DA, Khalid, F, et al. Prevention of early sudden circulatory collapse after the Norwood operation. Circulation 2004; 110: II133–II138.CrossRefGoogle Scholar
Furck, AK, Hansen, JH, Uebing, A, Scheewe, J, Jung, O, Kramer, HH. The impact of afterload reduction on the early postoperative course after the Norwood operation – a 12-year single-centre experience. Eur J Cardiothorac Surg 2010; 37: 289295.Google ScholarPubMed
Lechner, E, Hofer, A, Mair, R, Moosbauer, W, Sames-Dolzer, E, Tulzer, G. Arginine-vasopressin in neonates with vasodilatory shock after cardiopulmonary bypass. Eur J Pediatr 2007; 166: 12211227.CrossRefGoogle ScholarPubMed
Agrawal, A, Singh, VK, Varma, A, Sharma, R. Intravenous arginine vasopressin infusion in refractory vasodilatory shock: a clinical study. Indian J Pediatr 2012; 79: 488493.CrossRefGoogle ScholarPubMed
Burton, GL, Kaufman, J, Goot, BH, da Cruz, EM. The use of arginine vasopressin in neonates following the Norwood procedure. Cardiol Young 2011; 21: 536544.CrossRefGoogle ScholarPubMed
Alten, JA, Borasino, S, Toms, R, Law, MA, Moellinger, A, Dabal, RJ. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. Pediatr Crit Care Med 2012; 13: 300304.CrossRefGoogle ScholarPubMed
Lu, Z, Wang, X, Yang, J, Li, S, Yan, J. Vasopressin in vasodilatory shock for both left and right heart anomalous pediatric patients after cardiac surgery. Shock 2018; 50: 173177.CrossRefGoogle ScholarPubMed
Mastropietro, CW, Davalos, MC, Seshadri, S, Walters, HL 3rd, Delius, RE. Clinical response to arginine vasopressin therapy after paediatric cardiac surgery. Cardiol Young 2013; 23: 387393.CrossRefGoogle ScholarPubMed
Davalos, MC, Barrett, R, Seshadri, S, et al. Hyponatremia during arginine vasopressin therapy in children following cardiac surgery. Pediatr Crit Care Med 2013; 14: 290297.CrossRefGoogle ScholarPubMed
Murray, L, Alford, H, Haney, AL, et al. Postoperative calcium chloride infusions in neonates undergoing cardiac surgery (Abstract F12). In: Selected abstracts from Cardiology 2019: 22nd Annual Update on Pediatric and Congenital Cardiovascular Disease. Huntington Beach, CA; February 13–17, 2019. World J Pediatr Congenit Heart Surg 2019; 10: NP30–NP31.Google Scholar
Ricci, Z, Garisto, C, Favia, I, Vitale, V, Di Chiara, L, Cogo, PE. Levosimendan infusion in newborns after corrective surgery for congenital heart disease: randomized controlled trial. Intensive Care Med 2012; 38: 11981204.CrossRefGoogle ScholarPubMed
Amiet, V, Perez, MH, Longchamp, D, et al. Use of levosimendan in postoperative setting after surgical repair of congenital heart disease in children. Pediatr Cardiol 2018; 39: 1925.CrossRefGoogle ScholarPubMed
Tkachuk, V, Chernyshuk, S, Chasovskyi, K, Zhovnir, V. Levosimendan in complex treating of low cardiac output syndrome in neonates after open heart surgery. Intensive Care Med 2011; 37: S64.Google Scholar
Giordano, R, Palma, G, Palumbo, S, et al. Single center experience with levosimendan administration after pediatric cardiac surgery. G Ital Cardiol 2013; 14: 35S36S.Google Scholar
Osthaus, WA, Boethig, D, Winterhalter, M, et al. First experiences with intraoperative Levosimendan in pediatric cardiac surgery. Eur J Pediatr 2009; 168: 735740.CrossRefGoogle ScholarPubMed
Wang, A, Cui, C, Fan, Y, et al. Prophylactic use of levosimendan in pediatric patients undergoing cardiac surgery: a prospective randomized controlled trial. Crit Care 2019; 23: 428.CrossRefGoogle ScholarPubMed
Momeni, M, Rubay, J, Matta, A, et al. Levosimendan in congenital cardiac surgery: a randomized, double-blind clinical trial. J Cardiothorac Vasc Anesth 2011; 25: 419424.CrossRefGoogle ScholarPubMed
Basto-Duarte, MC, Flores-Rodriguez, CX, Bermon, A, Mendoza-Crespo, SE. Clinical outcomes with the use of levosimendan in patients with hypoplastic left heart syndrome brought to norwood procedure. Cardiol Young 2017; 27: S191S192.Google Scholar
Pellicer, A, Riera, J, Lopez-Ortego, P, et al. Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery. Pediatr Res 2013; 73: 95103.CrossRefGoogle ScholarPubMed
Jadhav, M, Bobhate, P, Garekar, S, et al. Levosimendan versus milrinone after corrective open-heart surgery in children. Ann Pediatr Cardiol 2012; 5: 104105.Google Scholar
Lechner, E, Hofer, A, Leitner-Peneder, G, et al. Levosimendan versus milrinone in neonates and infants after corrective open-heart surgery: a pilot study. Pediatr Crit Care Med 2012; 13: 542548.CrossRefGoogle ScholarPubMed
Thorlacius, EM, Suominen, PK, Wahlander, H, et al. The effect of levosimendan versus milrinone on the occurrence rate of acute kidney injury following congenital heart surgery in infants: a randomized clinical trial. Pediatr Crit Care Med 2019; 20: 947956.CrossRefGoogle ScholarPubMed
Duggal, B, Pratap, U, Slavik, Z, Kaplanova, J, Macrae, D. Milrinone and low cardiac output following cardiac surgery in infants: is there a direct myocardial effect? Pediatr Cardiol 2005; 26: 642645.CrossRefGoogle Scholar
Hoffman, TM, Wemovsky, 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: 9961002.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: 951957.CrossRefGoogle ScholarPubMed
Barnwal, NK, Umbarkar, SR, Sarkar, M, Dias, R. Randomized comparative study of intravenous infusion of three different fixed doses of milrinone in pediatric patients with pulmonary hypertension undergoing open heart surgery. Ann Card Anaesth 2017; 20: 318322.CrossRefGoogle ScholarPubMed
Chu, CC, Lin, SM, New, SH, et al. Effect of milrinone on postbypass pulmonary hypertension in children after tetralogy of Fallot repair. Zhonghua Yi Xue Za Zhi (Taipei) 2000; 63: 294300.Google ScholarPubMed
Smith, AH, Owen, J, Borgman, KY, Fish, FA, Kannankeril, PJ. Relation of milrinone after surgery for congenital heart disease to significant postoperative tachyarrhythmias. Am J Cardiol 2011; 108: 16201624.CrossRefGoogle ScholarPubMed
Costello, JM, Dunbar-Masterson, C, Allan, CK, et al. Impact of empiric nesiritide or milrinone infusion on early postoperative recovery after Fontan surgery: a randomized, double-blind, placebo-controlled trial. Circ Heart Fail 2014; 7: 596604.CrossRefGoogle ScholarPubMed
Simsic, JM, Scheurer, M, Tobias, JD, et al. Perioperative effects and safety of nesiritide following cardiac surgery in children. J Intensive Care Med 2006; 21: 2226.CrossRefGoogle ScholarPubMed
Moffett, BS, Price, JF. Evaluation of sodium nitroprusside toxicity in pediatric cardiac surgical patients. Ann Pharmacother 2008; 42: 16001604.CrossRefGoogle ScholarPubMed
Pekkarinen, A, Hortling, H. The effect of continuous intravenous infusion of adrenaline on the circulation and blood chemistry. Acta Endocrinol (Copenh) 1951; 6: 193214.CrossRefGoogle ScholarPubMed
Bibile, SW, Perera, GK, Jansz, AW, Williams, T. The principal actions of noradrenaline on man and its use in the treatment of surgical shock. Ceylon Med J 1954; 2: 175182.Google Scholar
Silverberg, AB, Shah, SD, Haymond, MW, Cryer, PE. Norepinephrine: hormone and neurotransmitter in man. Am J Physiol 1978; 234: E252E256.Google ScholarPubMed
Steen, PA, Tinker, JH, Pluth, JR, Barnhhorst, DA, Tarhan, S. Efficacy of dopamine, dobutamine, and epinephrine during emergence from cardiopulmonary bypass in man. Circulation 1978; 57: 378384.CrossRefGoogle ScholarPubMed
Mueller, HS. Effects of dopamine on haemodynamics and myocardial energetics in man: comparison with effects of isoprenaline and L-noradrenaline. Resuscitation 1978; 6: 179189.CrossRefGoogle ScholarPubMed
Nakazawa, M, Takahashi, Y, Aiba, S, Okuda, H, Ohta, H, Takao, A. Acute hemodynamic effects of dopamine, dobutamine, and isoproterenol in congested infants or young children with large ventricular septal defect. Jpn Circ J 1987; 51: 10101015.CrossRefGoogle ScholarPubMed
Mills, KI, Costello, JM, Almodovar, MC. A review of systemic vasodilators in low cardiac output syndrome following pediatric cardiac surgery. Curr Vasc Pharmacol 2016; 14: 2936.CrossRefGoogle ScholarPubMed
Fowler, NO, Holmes, JC, Gaffney, TE, Privitera, PJ, Grupp, G. Hemodynamic effects of phenoxybenzamine in anesthetized dogs. J Clin Invest 1970; 49: 20362050.CrossRefGoogle ScholarPubMed
Mossad, E, Motta, P, Sehmbey, K, Toscana, D. The hemodynamic effects of phenoxybenzamine in neonates, infants, and children. J Clin Anesth 2008; 20: 9498.CrossRefGoogle Scholar
Das, PK, Parratt, JR. Myocardial and haemodynamic effects of phentolamine. Br J Pharmacol 1971; 41: 437444.CrossRefGoogle ScholarPubMed
Collier, JG, Nachev, C, Robinson, BF. Comparison of blockade at alpha-adrenoceptors by thymoxamine and phentolamine in peripheral arteries and veins of man. Br J Pharmacol 1972; 44: 294300.CrossRefGoogle Scholar
Silva, MRE Jr, Rosenberg, M. The release of vasopressin in response to haemorrhage and its role in the mechanism of blood pressure regulation. J Physiol 1969; 202: 535557.CrossRefGoogle Scholar
Kaplan-Albuquerque, N, Di Salvo, J. Protein kinase C: modulation of vasopressin-induced calcium influx and release in A7r5 vascular smooth muscle cells. Arch Biochem Biophys 1998; 359: 209214.CrossRefGoogle ScholarPubMed
Barrett, LK, Singer, M, Clapp, LH. Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med 2007; 35: 3340.CrossRefGoogle ScholarPubMed
Salsburey, DJ, Brown, DR. Effect of parenteral calcium treatment on blood pressure and heart rate in neonatal hypocalcemia. Pediatrics 1982; 69: 605609.Google ScholarPubMed
Hvarfner, A, Mörlin, C, Wide, L, Ljunghall, S. Interactions between indices of calcium metabolism and blood pressure during calcium infusion in humans. J Hum Hypertens 1989; 3: 211220.Google ScholarPubMed
Sorsa, T, Heikkinen, S, Abbott, MB, et al. Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem 2001; 276: 93379343.CrossRefGoogle ScholarPubMed
Ferrer-Barba, A, Gonzalez-Rivera, I, Bautista-Hernandez, V. Inodilators in the management of low cardiac output syndrome after pediatric cardiac surgery. Curr Vasc Pharmacol 2016; 14: 4857.CrossRefGoogle ScholarPubMed
Bowman, P, Haikala, H, Paul, RJ. Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. J Pharmacol Exp Ther 1999; 288: 316325.Google ScholarPubMed
Farah, AE, Frangakis, CJ. Studies on the mechanism of action of the bipyridine milrinone on the heart. Basic Res Cardiol 1989; 1: 85103.CrossRefGoogle Scholar
Colucci, WS. Myocardial and vascular actions of milrinone. Eur Heart J 1989; 10 (Suppl C): 3238.CrossRefGoogle ScholarPubMed
Ito, M, Tanaka, T, Saitoh, M, Masuoka, H, Nakano, T, Hidaka, H. Selective inhibition of cyclic AMP phosphodiesterase from various human tissues by milrinone, a potent cardiac bipyridine. Biochem Pharmacol 1988; 37: 20412044.Google ScholarPubMed
Silver, PJ, Lepore, RE, O’Connor, B, et al. Inhibition of the low Km cyclic AMP phosphodiesterase and activation of the cyclic AMP system in vascular smooth muscle by milrinone. J Pharmacol Exp Ther 1988; 247: 3442.Google Scholar
Song, DL, Kohse, KP, Murad, F. Brain natriuretic factor. Augmentation of cellular cyclic GMP, activation of particulate guanylate cyclase and receptor binding. FEBS Lett 1988; 232: 125129.CrossRefGoogle ScholarPubMed
Zhou, HL, Fiscus, RR. Brain natriuretic peptide (BNP) causes endothelium-independent relaxation and elevation of cyclic GMP in rat thoracic aorta. Neuropeptides 1989; 14: 161169.CrossRefGoogle ScholarPubMed
Gmeiner, R, Riedl, J, Baumgartner, H. Effect of sodium nitroprusside on myocardial performance and venous tone. Eur J Pharmacol 1975; 31: 287291.CrossRefGoogle ScholarPubMed
Page, IH, Corcoran, AC, Dustan, HP, Koppanyi, T. Cardiovascular actions of sodium nitroprusside in animals and hypertensive patients. Circulation 1955; 11: 188198.CrossRefGoogle ScholarPubMed
Kamisaki, Y, Waldman, SA, Murad, F. The involvement of catalytic site thiol groups in the activation of soluble guanylate cyclase by sodium nitroprusside. Arch Biochem Biophys 1986; 251: 709714.CrossRefGoogle ScholarPubMed
Kartha, VM, Jacobs, JP, Vener, DF, et al. National benchmarks for proportions of patients receiving blood transfusions during pediatric and congenital heart surgery: an analysis of the STS Congenital Heart Surgery Database. Ann Thorac Surg 2018; 106: 11971203.CrossRefGoogle ScholarPubMed
Zimmerman, K, Gonzalez, D, Swamy, GK, Cohen-Wolkowiez, M. Pharmacologic studies in vulnerable populations: using the pediatric experience. Semin Perinatol 2015; 39: 532536.CrossRefGoogle ScholarPubMed
Thomas, M, Menon, K. Consenting to pediatric critical care research: understanding the perspective of parents. Dynamics 2013; 24: 1824.Google ScholarPubMed
Kleiber, N, Tromp, K, Mooij, MG, van de Vathorst, S, Tibboel, D, de Wildt, SN. Ethics of drug research in the pediatric intensive care unit. Paediatr Drugs 2015; 17: 4353.CrossRefGoogle ScholarPubMed
Fanaroff, AC, Califf, RM, Harrington, RA, et al. Randomized trials versus common sense and clinical observation: JACC Review Topic of the Week. J Am Coll Cardiol 2020; 76: 580589.CrossRefGoogle Scholar
Wernovsky, G, Kuijpers, M, Van Rossem, MC, et al. Postoperative course in the cardiac intensive care unit following the first stage of Norwood reconstruction. Cardiol Young 2007; 17: 652665.CrossRefGoogle ScholarPubMed
Miyamoto, SD, Stauffer, BL, Polk, J, et al. Gene expression and β-adrenergic signaling are altered in hypoplastic left heart syndrome. J Heart Lung Transplant 2014; 33: 785793.CrossRefGoogle ScholarPubMed
Garcia, AM, Nakano, SJ, Karimpour-Fard, A, et al. Phosphodiesterase-5 is elevated in failing single ventricle myocardium and affects cardiomyocyte remodeling in vitro. Circ Heart Fail 2018; 11: e004571.CrossRefGoogle ScholarPubMed
Skarsgard, ED. The value of patient registries in advancing pediatric surgical care. J Pediatr Surg 2018; 53: 863867.CrossRefGoogle ScholarPubMed
Kelly, LE, Dyson, MP, Butcher, NJ, et al. Considerations for adaptive design in pediatric clinical trials: study protocol for a systematic review, mixed-methods study, and integrated knowledge translation plan. Trials 2018; 19: 572.CrossRefGoogle ScholarPubMed
Peters, MJ, Argent, A, Festa, M, et al. The intensive care medicine clinical research agenda in paediatrics. Intensive Care Med 2017; 43: 12101224.CrossRefGoogle ScholarPubMed
Lasky, T, Carleton, B, Horton, DB, et al. Real-world evidence to assess medication safety or effectiveness in children: systematic review. Drugs Real World Outcomes 2020; 7: 97107.CrossRefGoogle ScholarPubMed
Choong, K, Duffett, M, Cook, DJ, Randolph, AG. The impact of clinical trials conducted by research networks in pediatric critical care. Pediatr Crit Care Med 2016; 17: 837844.CrossRefGoogle ScholarPubMed
Hill, KD, Baldwin, HS, Bichel, DP, et al. Rationale and design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial. Am Heart J 2020; 220: 192202.CrossRefGoogle ScholarPubMed
Pletcher, MJ, Forrest, CB, Carton, TW. PCORnet’s collaborative research groups. Patient Relat Outcome Meas 2018; 9: 9195.CrossRefGoogle ScholarPubMed
Kim, KK, Helfand, M. Engagement in PCORnet research networks. Med Care 2018; 56 (10 Suppl 1): S1S3.CrossRefGoogle ScholarPubMed
Selby, JV, Grossman, C, Zirkle, M, Barbash, S. Multistakeholder engagement in PCORnet, the national patient-centered clinical research network. Med Care 2018; 56 (10 Suppl 1): S4S5.CrossRefGoogle ScholarPubMed
Ali, J, Califf, R, Sugarman, J. Anticipated ethics and regulatory challenges in PCORnet: the national patient-centered clinical research network. Account Res 2016; 23: 7996.CrossRefGoogle ScholarPubMed
Forrest, CB, Margolis, PA, Bailey, LC, et al. PEDSnet: a national pediatric learning health system. J Am Med Inform Assoc 2014; 21: 602606.CrossRefGoogle ScholarPubMed
Huser, V, Kahn, MG, Brown, JS, Gouripeddi, R. Methods for examining data quality in healthcare integrated data repositories. Pac Symp Biocomput 2018; 23: 628633.Google ScholarPubMed
Klonoff, DC. The new FDA Real-World Evidence Program to support development of drugs and biologics. J Diabetes Sci Technol 2020; 14: 345349.CrossRefGoogle ScholarPubMed
Jacobs, JP, O’Brien, SM, Pasquali, SK, et al. Variation in outcomes for risk-stratified pediatric cardiac surgical operations: an analysis of the STS Congenital Heart Surgery Database. Ann Thorac Surg 2012; 94: 564571; discussion 71–72.CrossRefGoogle ScholarPubMed
Gaies, M, Anderson, J, Kipps, A, et al. Cardiac Networks United: an integrated paediatric and congenital cardiovascular research and improvement network. Cardiol Young 2019; 29: 111118.CrossRefGoogle ScholarPubMed