Hoffman 2003.

Study characteristics
Methods	Study design: randomised controlled trial, parallel arm Setting: multicentre (31 tertiary care children’s hospitals/hospitals providing paediatric congenital cardiac surgery in North America) Study start/end dates or study duration: first patient enrolled July 2000 and last patient enrolled February 2001 Funding sources: "supported by Sanofi‐Synthelabo, New York, NY, and conducted by Covance Periapproval Services, Inc, Radnor, Pa." Declarations of interest: not stated
Participants	Sample size: 242 Patient age: placebo group 8.3 ± 14.8 months, low‐dose milrinone group 5.9 ± 10.2 months, high‐dose milrinone group 8.6 ± 16.5 months Patient sex: 36 males and 39 females in the placebo group, 48 males and 31 females in the low‐dose milrinone group, 39 males and 34 females in the high‐dose milrinone group Diagnosis/severity: all with biventricular heart disease: tetralogy of fallot, atrioventricular septal defect, d‐transposition of the great arteries, ventricular septal defect, mitral valve surgery, double outlet right ventricle, total anomalous pulmonary venous return, truncus arteriosus, Ross procedure Inclusion criteria: children between gestational age 36 weeks and 6 years without preoperative LCOS who were undergoing biventricular repair of certain cardiac lesions involving cardiopulmonary bypass
Interventions	Intervention 1: placebo infusion at the same rate as the other study drugs. "The physicians were given the option to discontinue study drug between 24 and 36 hours for patients who appeared clinically well." Intervention 2: low‐dose milrinone bolus of 25 μg/kg over 1 hour, followed by infusion of 0.25 μg/kg/min for (23‐)35 hours, starting within 90 minutes after arrival at the ICU from the operating room. "The physicians were given the option to discontinue study drug between 24 and 36 hours for patients who appeared clinically well." Intervention 3: high‐dose milrinone bolus of 75 μg/kg over 1 hour, followed by infusion of 0.75 μg/kg/min for (23‐)35 hours, starting within 90 minutes after arrival at the ICU from the operating room. "The physicians were given the option to discontinue study drug between 24 and 36 hours for patients who appeared clinically well." Co‐interventions: "Baseline catecholamines were administered at the discretion of the physician" (inotrope score was calculated)
Outcomes	Primary outcome(s): composite primary endpoint: “death or development of LCOS which requires mechanical support, increased need for existing pharmacologic support (at least 100% over baseline) or administration of new, open‐label positive inotropic agents or other pharmacologic interventions” “or other interventions (eg, mechanical pacing)” to treat LCOS at 36 h after randomisation Definition of LCOS: “clinical signs or symptoms (eg, tachycardia, oliguria, poor perfusion, or cardiac arrest) with or without a widened arterial‐mixed venous oxygen saturation difference or metabolic acidosis” vs. “clinical signs and symptoms of the syndrome – such as tachycardia, oliguria, cold extremities, or cardiac arrest – with or without an at least 30% difference in arterial‐mixed venous oxygen saturation or metabolic acidosis (an increase in the base deficit of >4 or an increase in the lactate of >2 mg/dl) on 2 successive blood gas measurements”. Cut‐offs for outcome variables (tachycardia, oliguria, cold extremities) were determined by the principal investigator (not reported in detail). The composite endpoint was later reviewed by an adjudication committee. Secondary outcome(s) Primary composite endpoint “between 36h after initiation of study drug and the final visit up to 30 days after randomization” [Circulation 2003] versus “14 days after randomization” [AHJ 2002] “individual components of the primary composite end point 14 days after randomization” “total UOP (ml/kg/h) in the first 36h after initiation of study medication” “creatinine clearance at the end of study drug administration” (to be measured for 36 hours of urine collection postoperative) “length of hospital stay” “pharmacokinetic assessment of milrinone within 36h after initiation of study medication” (procedure well described) “duration of mechanical ventilation” Recording of haemodynamic parameters (heart rate, systolic and diastolic blood pressure, right atrial pressure, left atrial pressure, if available) and laboratory parameters (arterial and venous oximetry, lactate levels) at the start of study drug infusion and every 4 hours through 36 hours (analysing SBP and DBP as percent change from baseline)
Notes	Intention‐to‐treat analysis: no. Of 242 randomised patients, 238 received the study drug. 11 were excluded "because of major protocol violations". Of the remaining 227 "per‐protocol population" (placebo n = 75; LD n = 79; HD n = 73), 13 received open‐label milrinone after 36 hours and were not included in further analyses (figure 3, p 999), and 5 were lost to follow‐up, leaving 209 patients (placebo n = 71; LD n = 74; HD n = 64). Two patients (unknown group) died on the 5th and the 13th postoperative day, respectively, leaving 207 patients for 30‐day follow‐up. Trialists contacted: yes Unpublished information received: study dates, placebo infusion rate, duration of postoperative urine collection, numbers of patients reaching outcomes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Performed by commercial CRO, no additional information available
Allocation concealment (selection bias)	Unclear risk	Performed by commercial CRO, no additional information available
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Same infusion rate for all study drugs
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded clinical endpoint committee
Incomplete outcome data (attrition bias) All outcomes	High risk	Dropout of a total of 33 participants at different stages (treatment groups not always known), calculation of outcomes using different populations
Selective reporting (reporting bias)	High risk	Outcomes are only partially reported as absolute numbers or percentages. The review authors contacted the study authors and obtained additional information. However, due to the long time elapsed since the study had been conducted, many outcomes could not be comprehensively reconstructed.
Other bias	High risk	Study supported by a grant from the manufacturer (Sanofi Synthelabo) and reports co‐authored by manufacturer representatives