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The safety, efficacy, and pharmacokinetics of esmolol for blood pressure control immediately after repair of coarctation of the aorta in infants and children: A multicenter, double-blind, randomized trial

2008; Elsevier BV; Volume: 136; Issue: 2 Linguagem: Inglês

10.1016/j.jtcvs.2007.09.086

1097-685X

Sarah Tabbutt, Susan C. Nicolson, Peter C. Adamson, Xuemei Zhang, Marc L. Hoffman, Winfield Wells, Carl L. Backer, Francis X. McGowan, James S. Tweddell, Paula M. Bokesch, Mark S. Schreiner,

Hemodynamic Monitoring and Therapy

ObjectivesBlood pressure control is important after repair of coarctation of the aorta. We report the first prospective multi-institutional trial addressing the safety and efficacy of esmolol after repair of coarctation of the aorta in infants and children.MethodsThe primary objective of this phase IIIb, multicenter, double-blind, randomized, dose-ranging trial was the efficacy of esmolol to control hypertension. Candidates included subjects younger than 6 years and weighing 2.5 kg or more who underwent surgical intervention for coarctation of the aorta and required therapy for systemic hypertension. One hundred sixteen subjects received esmolol: 36 received a low dose (125 μg/kg), 43 received a medium dose (250 μg/kg), and 37 received a high dose (500 μg/kg). The primary outcomes were the change in systolic blood pressure and the need for additional antihypertensive rescue medication 5 minutes after the initiation of esmolol.ResultsAll dose groups showed a significant decrease from baseline in systolic blood pressure (−9.6 ± 16.3 mm Hg, P < .001). There were no differences in systolic blood pressure response at 5 minutes between dose groups (high, medium, or low) or age groups. The need for rescue medication at 5 minutes was not different between dose groups. All dose groups showed similar incidences of adverse events. There were no serious adverse events.DiscussionEsmolol can be administered safely to patients younger than 6 years after repair of coarctation of the aorta. In the dose range of 125 to 500 μg/kg, esmolol significantly decreased systolic blood pressure. Blood pressure control is important after repair of coarctation of the aorta. We report the first prospective multi-institutional trial addressing the safety and efficacy of esmolol after repair of coarctation of the aorta in infants and children. The primary objective of this phase IIIb, multicenter, double-blind, randomized, dose-ranging trial was the efficacy of esmolol to control hypertension. Candidates included subjects younger than 6 years and weighing 2.5 kg or more who underwent surgical intervention for coarctation of the aorta and required therapy for systemic hypertension. One hundred sixteen subjects received esmolol: 36 received a low dose (125 μg/kg), 43 received a medium dose (250 μg/kg), and 37 received a high dose (500 μg/kg). The primary outcomes were the change in systolic blood pressure and the need for additional antihypertensive rescue medication 5 minutes after the initiation of esmolol. All dose groups showed a significant decrease from baseline in systolic blood pressure (−9.6 ± 16.3 mm Hg, P < .001). There were no differences in systolic blood pressure response at 5 minutes between dose groups (high, medium, or low) or age groups. The need for rescue medication at 5 minutes was not different between dose groups. All dose groups showed similar incidences of adverse events. There were no serious adverse events. Esmolol can be administered safely to patients younger than 6 years after repair of coarctation of the aorta. In the dose range of 125 to 500 μg/kg, esmolol significantly decreased systolic blood pressure. Earn CME credits at http://cme.ctsnetjournals.orgCoarctation of the aorta (CoA) comprises approximately 6% of all congenital heart disease.1Samanek M. Slavik Z. Zborilova B. Hrobonova V. Voriskova M. Skovranek J. Prevalence, treatment and outcome of heart disease in live-born children: a prospective analysis of 91,823 live-born children.Pediatr Cardiol. 1989; 10: 205-211Crossref PubMed Scopus (217) Google Scholar The surgical mortality of isolated coarctation is low at 0.5% to 2.5%.2Wood A.E. Javadpour H. Duff D. Oslizlok P. Walsh K. Is extended arch aortoplasty the operation of choice for infant coarctation? Results of 15 years' experience in 181 patients.Ann Thorac Surg. 2004; 77: 1353-1358Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 3Wright G.E. Nowak C.A. Goldberg C.S. Ohye R.G. Bove E.L. Rocchini A.P. Extended resection and end-to-end anastomosis for aortic coarctation in infants: results of a tailored surgical approach.Ann Thorac Surg. 2005; 80: 1453-1459Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Hypertension occurs in more than 65% of subjects during the postoperative period after surgical CoA repair.4Sealey W.C. Paradoxical hypertension after repair of coarctation of the aorta: a review of its causes.Ann Thorac Surg. 1990; 50: 323-329Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 5Rocchini A.P. Rosenthal A. Barger A.C. Castaneda A.R. Nadas A.S. Pathogenesis of paradoxical hypertension after coarctation resection.Circulation. 1976; 54: 382-387Crossref PubMed Scopus (88) Google Scholar, 6Gidding S.S. Rocchini A.P. Beekman R. Szpunar C.A. Moorehead C. Behrendt D. et al.Therapeutic effect of propranolol on paradoxical hypertension after repair of coarctation of the aorta.N Engl J Med. 1985; 312: 1224-1228Crossref PubMed Scopus (58) Google Scholar The short-acting and selective β1-antagonist esmolol hydrochloride (esmolol) has been shown to achieve early and predictable steady-state blood levels and to have a short duration of action.7Angaran D.M. Schultz N.J. Tschida V.H. Esmolol hydrochloride: an ultrashort-acting, beta-adrenergic blocking agent.Clin Pharm. 1986; 5: 288-303PubMed Google Scholar, 8Cuneo B.F. Zales V.R. Blahunka P.C. Benson D.W. Pharmacodynamics and pharmacokinetics of esmolol, a short-acting beta-blocking agent, in children.Pediatr Cardiol. 1994; 15: 296-301Crossref PubMed Scopus (36) Google Scholar Esmolol has been shown to control hypertension in children after cardiac surgery9Wiest D.B. Garner S.S. Uber W.E. Sade R.M. Esmolol for the management of pediatric hypertension after cardiac operations.J Thorac Cardiovasc Surg. 1998; 115: 890-897Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar and specifically after CoA repair (in both case reports10Smerling A. Gersony W.M. Esmolol for severe hypertension following repair of aortic coarctation.Crit Care Med. 1990; 18: 1288-1290Crossref PubMed Scopus (25) Google Scholar and small series9Wiest D.B. Garner S.S. Uber W.E. Sade R.M. Esmolol for the management of pediatric hypertension after cardiac operations.J Thorac Cardiovasc Surg. 1998; 115: 890-897Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 11Vincent R.N. Click L.A. Willliams H.M. Plauth W.H. Williams W.H. Esmolol as an adjunct in the treatment of systemic hypertension after operative repair of coarctation of the aorta.Am J Cardiol. 1990; 65: 941-943Abstract Full Text PDF PubMed Scopus (19) Google Scholar). This article is the first multicenter report of the dose response and safety of esmolol for the treatment of hypertension in infants and children after CoA repair. The primary aim was 2-fold: (1) the change in blood pressure from baseline and (2) the need for antihypertensive rescue medications. The secondary aims were (1) dose dependence, (2) age dependence, (3) pharmacokinetics, and (4) safety assessment. Earn CME credits at http://cme.ctsnetjournals.org This phase IIIb, multicenter, double-blind, randomized, active control, dose-ranging study was conducted at 20 institutions in North America; the institutional review board at each site approved the study. This study (protocol no. 20,015-004 entitled "A multi-center study to evaluate the efficacy, safety and pharmacokinetics of esmolol hydrochloride (Brevibloc) for treatment of hypertension in infants and children after surgical repair of coarctation of the aorta") was approved by the US Food and Drug Administration's (FDA) Division of Cardio-Renal Drug Products and monitored by the FDA's Bioresearch Monitoring Program. The steering committee, composed of cardiac anesthesiologists and cardiac intensivists from 3 high-volume pediatric centers (Children's Hospital of Philadelphia, Boston Children's Hospital, and Cleveland Clinic), assisted in the study design to ensure consistency with standard of care. Pediatric patients younger than 6 years and weighing 2.5 kg or more scheduled for surgical repair of CoA through a lateral thoracotomy were screened for eligibility. Participation in the study required a 2-stage eligibility process. Patients were evaluated in the preoperative phase to determine whether they were eligible for enrollment. Patients meeting screening criteria and for whom informed consent was obtained were randomized before surgical intervention. The final inclusion criteria were determined based on systolic blood pressure (SBP) after aortic crossclamp release. Preliminary exclusion criteria included any of the following: (1) an awake resting heart rate of less than 120 beats/min for a neonate (≤28 days), less than 90 beats/min for an infant (>28 days to 28 d to <1 y14 (39%)13 (30%)18 (47%)45 (38%) ≥1 y to 6 y13 (36%)19 (43%)15 (39%)47 (40%)SD, Standard deviation.∗ Safety dataset: all patients receiving study esmolol. Open table in a new tab SD, Standard deviation. There was a significant decrease in SBP at 5 minutes in all dose groups compared with baseline values (Table 2). No statistical difference was found between dose groups. There was no difference between dose groups in the change (P = .24) from baseline in SBP. In the intent-to-treat subset, 63 (54%) of the subjects met the criteria for rescue medication after 5 minutes of blinded esmolol. Two analyses were performed on these data: an exact χ2 test to verify that the proportions of patients who met the criteria for and who were given rescue medications were the same and a Cochran–Armitage linear trend test to determine whether a trend existed across the dose groups. There were no statistical differences found (Table 2). Thirty-nine (62%) of the patients who met the criteria actually received rescue medication at 5 minutes after the start of esmolol. The types of rescue medications included increased isoflurane, nitroprusside, fentanyl, and propofol. Some patients received more than 1 agent.Table 2Primary end point evaluation (intent-to-treat subset)ParameterStatistic/categoryLow doseMedium doseHigh doseOverallP valueChange from baseline in systolic blood pressure within 5 min after esmolol start N364337116 Change from baseline (mm Hg)Mean (SD)−6.0 ± 12.6−12.2 ± 16.8−10.2 ± 18.7−9.6 ± 16.3.24 Tests for change from baseline equal to 0T (P value)−2.9 (<.01)−4.8 (<.001)−3.3 (<.01)−6.3 (<.001)Rescue medication at 5 min after blinded esmolol start Met rescue criterion22 (61%)21 (49%)20 (54%)63 (54%).54†Exact χ2 test..56‡Cochran–Armitage linear trend test. Rescue medication at 5 min∗Subjects might have received more than 1 rescue medication.12 (33%)12 (28%)15 (41%)39 (34%).48†Exact χ2 test..54‡Cochran–Armitage linear trend test. Type of rescue medication; Increased isoflurane9 (75%)12 (100%)13 (87%)34 (87%) Nitroprusside3 (25%)1 (8%)1 (7%)5 (13%) Fentanyl0 (0%)1 (8%)1 (7%)2 (5%) Propofol1 (8%)0 (0%)0 (0%)1 (3%)SD, Standard deviation.∗ Subjects might have received more than 1 rescue medication.† Exact χ2 test.‡ Cochran–Armitage linear trend test. Open table in a new tab SD, Standard deviation. There was no statistical difference in SBP response between age groups (neonate, infant, and child; P = .32). There were no statistical differences between dose groups for change from baseline in diastolic blood pressure or mean arterial pressure at 5 minutes after esmolol administration. There was a statistical difference seen in change from baseline in mean heart rate 5 minutes after esmolol administration for the per-protocol efficacy analyses and a trend toward significance in the intent-to-treat analyses (Table 3). There was no relationship between percentage decrease in SBP at 5 minutes and the simultaneous arterial plasma esmolol concentration. Subjects' heart rate decreased at 5 minutes with increasing arterial plasma esmolol concentration (r = 0.41).Table 3Change from baseline in heart rate at 5 minutes after the start of esmololParameterStatistic/categoryLow doseMedium doseHigh doseP valuePer-protocolN334135Change from baseline (beats/min)Mean (SD)−6.8 ± 9.9−14.2 ± 8.5−13.2 ± 12.7.00795% CL−10.4 to −3.3−17.4 to −11.0−16.7 to −9.7Intent to treatN363175Change from baseline (beats/min)Mean (SD)−7.4 ± 9.7−13.2 ± 10.7−12.3 ± 12.9.0695% CL−11.1 to −3.7−16.6 to −9.8−15.3 to −8.6SD, Standard deviation; CL, confidence limit. Open table in a new tab SD, Standard deviation; CL, confidence limit. Esmolol was discontinued when it was no longer believed to be needed because of hemodynamic stability (n = 75 [68%]), inadequate blood pressure control (n = 6 [6%]), AEs (n = 7 [6%]), or "other" (n = 22 [20%]). A total of 107 patients had pharmacokinetic data further analyzed: 22 newborns, 42 infants, and 43 children. The 15-minute arterial plasma esmolol concentration was significantly higher in children compared with that seen in newborns (P < .0001) and infants (P = .001); no difference was detected between newborns and infants. Plasma esmolol concentrations appeared to increase in proportion to dose (Figure 2). The time to steady state did not differ significantly as a function of age, and patients were approaching steady state by 15 minutes. The elimination rate constant (± standard error) determined across dose levels was 0.146 ± 0.04 (r2 = 0.67). The time to steady state for the population was 21 minutes, with a half-life of accumulation (equivalent to the half-life of elimination for a drug administered by means of continuous intravenous infusion) of 4.8 minutes. For children, the CSS values (± standard error) for the 125, 250, and 500 μg/kg dose levels were 992 ± 143, 1983 ± 287, and 3967 ± 573 ng/mL, and for the newborn/infants, the CSS values (± standard error) for the 125, 250 and 500 μg · kg−1 · min−1 dose levels were 444 ± 60, 888 ± 120, and 1777 ± 240 ng/mL, respectively. Esmolol clearance was greater in the newborn/infant group (281 mL · kg−1 · min−1; 95% confidence limit [CL], 267–296 mL · kg−1 · min−1) compared with that for children (126 mL · kg−1 · min−1; 95% CL, 83–169 mL · kg−1 · min−1). Because of the high degree of interpatient variability, individual drug clearances could not be calculated, and thus correlation between age and clearance could not be performed. There were no deaths and no serious AEs. Most of the complications were typical of patients recovering from surgical CoA repair. All 3 dose groups showed similar incidences of AEs. The most frequent AEs were postoperative pain (n = 90 [76%]), postoperative agitation (n = 24 [20%]), postoperative anemia (n = 22 [19%]), hypokalemia (n = 32 [27%]), and metabolic acidosis (n = 33 [28%]; Table 4). Specific to this patient population were bleeding that required transfusion (n = 35 [30%]), pneumothorax (n = 17 [14%]), and sequelae associated with the esmolol intravenous infusion site (n = 1 [1%]).Table 4Adverse events (%) occurring with an incidence of 10 or greater in the safety dataset∗If a subject had the same adverse event 2 or more times, the adverse event was only counted once.System organ class/adverse eventLow dose (n = 36)Medium dose (n = 44)High dose (n = 38)Overall (n = 118)Cardiac disorders Tachycardia NOS3 (8)5 (11)3 (8)11 (9)Gastrointestinal disorders Constipation3 (8)2 (5)10 (26)15 (13)General disorders Pyrexia3 (8)8 (18)4 (11)15 (13)Injury, poisoning, and procedural complications Agitation postoperative6 (17)10 (23)8 (21)24 (20) Anemia postoperative6 (17)8 (18)8 (21)22 (19) Pain postoperative27 (75)35 (80)28 (74)90 (76) Vomiting postoperative3 (8)4 (9)5 (13)12 (10)Metabolism and nutritional disorders Hypocalcemia3 (8)6 (14)3 (8)12 (10) Fluid overload2 (6)2 (5)6 (16)10 (8) Hypokalemia10 (28)10 (23)12 (32)32 (27) Metabolic acidosis9 (25)12 (27)12 (32)33 (28)Renal and urinary disorders Oliguria13 (36)13 (30)8 (21)32 (27)Skin and subcutaneous tissue disorders Subcutaneous emphysema1 (3)5 (11)6 (16)12 (10)Vascular disorders Hypotension NOS3 (8)3 (7)4 (11)10 (8)Respiratory, thoracic, and mediastinal disorders Atelectasis3 (8)13 (30)11 (28)27 (23) Pleural effusion2 (6)2 (5)6 (16)10 (8) Pneumothorax4 (11)7 (16)6 (16)17 (14) Respiratory acidosis2 (6)5 (11)4 (11)11 (9)∗ If a subject had the same adverse event 2 or more times, the adverse event was only counted once. Open table in a new tab There were 17 AEs that are known therapeutic end points or previously described side effects of esmolol: hypotension (n = 10 [8%]), bradycardia (n = 1 [1%]), wheezing (n = 3 [3%]), and reaction at the injection site (n = 1 [1%]). Seven subjects discontinued the study because of AEs: hypotension (n = 5), bilateral wheezing (n = 1), and reaction at the injection site (n = 1). CoA can present critically in infancy when the ductus arteriosus closes or later during childhood. The current approach to isolated CoA is either surgical, usually through a thoracotomy,2Wood A.E. Javadpour H. Duff D. Oslizlok P. Walsh K. Is extended arch aortoplasty the operation of choice for infant coarctation? Results of 15 years' experience in 181 patients.Ann Thorac Surg. 2004; 77: 1353-1358Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 3Wright G.E. Nowak C.A. Goldberg C.S. Ohye R.G. Bove E.L. Rocchini A.P. Extended resection and end-to-end anastomosis for aortic coarctation in infants: results of a tailored surgical approach.Ann Thorac Surg. 2005; 80: 1453-1459Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar or through interventional catheterization with a balloon angioplasty or intravascular stent.13Cowley C.G. Orsmond G.S. Feola P. McQuillan L. Shaddy R.E. Long-term, randomized comparison of balloon angioplasty and surgery for native coarctation of the aorta in childhood.Circulation. 2005; 111: 3453-3456Crossref PubMed Scopus (155) Google Scholar, 14Walhout R.J. Lekkerkerker J.C. Oron G.H. Bennink G.B.W.E. Meijboom E.J. Comparison of surgical repair with balloon angioplasty for native coarctation in patients from 3 months to 16 years of age.Eur J Cardiothorac Surg. 2004; 25: 722-727Crossref PubMed Scopus (45) Google Scholar Hypertension occurs in more than 65% of subjects during the postoperative period after surgical coarctation repair.4Sealey W.C. Paradoxical hypertension after repair of coarctation of the aorta: a review of its causes.Ann Thorac Surg. 1990; 50: 323-329Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 5Rocchini A.P. Rosenthal A. Barger A.C. Castaneda A.R. Nadas A.S. Pathogenesis of paradoxical hypertension after coarctation resection.Circulation. 1976; 54: 382-387Crossref PubMed Scopus (88) Google Scholar, 6Gidding S.S. Rocchini A.P. Beekman R. Szpunar C.A. Moorehead C. Behrendt D. et al.Therapeutic effect of propranolol on paradoxical hypertension after repair of coarctation of the aorta.N Engl J Med. 1985; 312: 1224-1228Crossref PubMed Scopus (58) Google Scholar Theories about the cause of postoperative hypertension include activation of the sympathetic nervous system, the renin–angiotension system, or both. More recent studies implicate abnormalities in the elastic properties of the aorta15Vogt M. Kuhn A. Baumgartner D. Baumgartner C. Busch R. Kostolny M. et al.Impaired elastic properties of the ascending aorta in newborns before and early after successful coarctation repair. Proof of a systemic vascular disease of the prestenotic arteries.Circulation. 2005; 111: 3269-3273Crossref PubMed Scopus (132) Google Scholar and autonomic dysfunction16Polson J.W. McCallion N. Waki H. Thorne G. Tooley M.A. Paton J.F.R. et al.Evidence of cardiovascular autonomic dysfunction in neonates with coarctation of the aorta.Circulation. 2006; 113: 2844-2850Crossref PubMed Scopus (52) Google Scholar as causes for postoperative hypertension, particularly in newborns. The use of β-blockade (propranolol) in children during the perioperative period for coarctation repair has been shown to result in a significant decrease in SBP and diastolic blood pressure and in plasma renin activity.6Gidding S.S. Rocchini A.P. Beekman R. Szpunar C.A. Moorehead C. Behrendt D. et al.Therapeutic effect of propranolol on paradoxical hypertension after repair of coarctation of the aorta.N Engl J Med. 1985; 312: 1224-1228Crossref PubMed Scopus (58) Google Scholar Esmolol has several advantages over propranolol: rapid hydrolysis by red blood cell esterases17Reynolds R.D. Gorczynski R.J. Quon C.Y. Pharmacology and pharmacokinetics of esmolol.J Clin Pharmacol. 1986; 26A: A3-A14Crossref Scopus (69) Google Scholar and selective, competitive β1-blockade.7Angaran D.M. Schultz N.J. Tschida V.H. Esmolol hydrochloride: an ultrashort-acting, beta-adrenergic blocking agent.Clin Pharm. 1986; 5: 288-303PubMed Google Scholar Initial pharmacokinetic data examining the use of esmolol in children indicate a faster elimination than reported in adults.8Cuneo B.F. Zales V.R. Blahunka P.C. Benson D.W. Pharmacodynamics and pharmacokinetics of esmolol, a short-acting beta-blocking agent, in children.Pediatr Cardiol. 1994; 15: 296-301Crossref PubMed Scopus (36) Google Scholar, 9Wiest D.B. Garner S.S. Uber W.E. Sade R.M. Esmolol for the management of pediatric hypertension after cardiac operations.J Thorac Cardiovasc Surg. 1998; 115: 890-897Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 18Wiest D.B. Trippel D.L. Gillette P.C. Garner S.S. Pharmacokinetics of esmolol in children.Clin Pharmacol Ther. 1991; 49: 618-623Crossref PubMed Scopus (29) Google Scholar Esmolol has been shown to control hypertension in children after cardiac surgery9Wiest D.B. Garner S.S. Uber W.E. Sade R.M. Esmolol for the management of pediatric hypertension after cardiac operations.J Thorac Cardiovasc Surg. 1998; 115: 890-897Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar and specifically after CoA repair (in both case reports10Smerling A. Gersony W.M. Esmolol for severe hypertension following repair of aortic coarctation.Crit Care Med. 1990; 18: 1288-1290Crossref PubMed Scopus (25) Google Scholar and small series9Wiest D.B. Garner S.S. Uber W.E. Sade R.M. Esmolol for the management of pediatric hypertension after cardiac operations.J Thorac Cardiovasc Surg. 1998; 115: 890-897Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 11Vincent R.N. Click L.A. Willliams H.M. Plauth W.H. Williams W.H. Esmolol as an adjunct in the treatment of systemic hypertension after operative repair of coarctation of the aorta.Am J Cardiol. 1990; 65: 941-943Abstract Full Text PDF PubMed Scopus (19) Google Scholar). When used as a single antihypertensive agent, reports indicate that higher doses might be required after CoA repair (830 ± 153 μg · kg−1 · min−1) compared with other lesions10Smerling A. Gersony W.M. Esmolol for severe hypertension following repair of aortic coarctation.Crit Care Med. 1990; 18: 1288-1290Crossref PubMed Scopus (25) Google Scholar and higher doses than suggested in the product label (300 μg · kg−1 · min−1). This article reports the first dose-response and safety study of esmolol for the treatment of hypertension in infants and children after CoA repair. The primary aim was to determine the efficacy (n = 116) at 3 dose levels of controlling postoperative hypertension within 30 minutes of aortic crossclamp release and at 5 minutes after the initiation of esmolol. The secondary aims were (1) the pharmacokinetics (n = 107) of esmolol when administered as a bolus followed by an immediate infusion and (2) the safety (n = 118) of esmolol use in this population. We found a significant decrease in SBP at 5 minutes after initiation of esmolol compared with baseline values in all dose groups, with no significant difference between dose groups. When patients were divided into age groups, there was still no significant difference in the effect on SBP between dose groups. The chosen dosing range (125–500 μg · kg−1 · min−1) was considered by the advisory committee to be within the standard of care. A placebo control was not believed to provide clinical equipoise. Other studies have suggested that higher doses of esmolol might be necessary when used as a single antihypertensive agent.10Smerling A. Gersony W.M. Esmolol for severe hypertension following repair of aortic coarctation.Crit Care Med. 1990; 18: 1288-1290Crossref PubMed Scopus (25) Google Scholar Although some patients received higher doses of esmolol (either blinded or open label), it occurred outside the close blood pressure monitoring window of the study and in conjunction with other antihypertensive agents. Thus the effect of higher-dose esmolol could not be evaluated in this study population. It might also be that esmolol in this range is most effective if used in combination with an antihypertensive agent with an alternative mode of action, such as nitroprusside. Finally, it is possible that the incremental difference between dose ranges was too small to result in a statistically significant difference in blood pressure. This is supported by the pharmacokinetic finding of significant interpatient variability within each dose group. Plasma esmolol concentration increased in proportion to dose over the 125 to 500 μg · kg−1 · min−1 dose range. In addition, there was a 4-fold increase in 5-, 10-, and 15-minute plasma drug concentrations, respectively. Although there was significant interpatient variability, the esmolol clearance in children of 126 mL · kg−1 · min−1 was similar to that reported in other recent pediatric studies,8Cuneo B.F. Zales V.R. Blahunka P.C. Benson D.W. Pharmacodynamics and pharmacokinetics of esmolol, a short-acting beta-blocking agent, in children.Pediatr Cardiol. 1994; 15: 296-301Crossref PubMed Scopus (36) Google Scholar, 9Wiest D.B. Garner S.S. Uber W.E. Sade R.M. Esmolol for the management of pediatric hypertension after cardiac operations.J Thorac Cardiovasc Surg. 1998; 115: 890-897Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 19Adamson P.C. Rhodes L.A. Saul J.P. Dick M. Epstein M.R. Moate P. et al.The pharmacokinetics of esmolol in pediatric subjects with supraventricular arrhythmias.Pediatr Cardiol. 2006; 27: 420-427Crossref PubMed Scopus (33) Google Scholar whereas clearance in newborns (281 mL · kg−1 · min−1) was considerably greater. There were no mortalities and no serious AEs. The most common AEs were expected after surgical coarctation repair (pain, agitation, and anemia). Despite the maximum esmolol concentration of 20 mg/mL, only 1 patient had irritation at the site of intravenous administration. Because metabolic acidosis (28%) and hypokalemia (27%) are common after cardiac surgery, in the absence of nonsurgical controls, it is beyond the limits of this study to determine whether esmolol played a role. There was no effect of dose range on the incidence of AEs. The results of this study demonstrate that esmolol decreases SBP immediately after repair of CoA in infants and children, with no significant untoward events. This study is unique in the fact that it is perioperative and multi-institutional (United States and Canada) and crosses age groups (newborn to 6 years) and disciplines (surgeons, anesthesiologists, and intensivists). The collaboration for this study helped to lay the foundation and infrastructure for current, ongoing, multi-institutional pediatric cardiac trials. Because of concern over the risk of early postoperative bleeding from the aortic suture line, the use of a placebo control was believed to be unsafe. The dose range was limited by current practice in this patient population. The wide age range was chosen to enable an adequate study population. The intraoperative time period within 30 minutes of aortic crossclamp release was chosen to achieve the most uniform patient condition. Thus most patients were still receiving inhaled anesthetic, the vasodilating properties of which might diminish the effect of esmolol. The combination of these factors is the most likely explanation for why the decrease in SBP with esmolol was not statistically significant between dose groups. Furthermore, pharmacokinetic data analyses found that steady-state esmolol blood levels were achieved 20 minutes after the bolus was administered; however, primary efficacy measures were determined only 5 minutes after the esmolol bolus, perhaps underestimating the optimal effect of esmolol on decreasing blood pressure. Esmolol safely and significantly decreases SBP immediately after surgical repair of CoA in infants and children. However, no difference was found between doses (125, 250, and 500 μg · kg−1 · min−1). This study lays the foundation for determining the effect of higher doses of esmolol on blood pressure from both an age-dependent and drug-combination (eg, nitroprusside) approach.