Hoffman 2003.

Methods	Randomised, double‐blind, placebo‐controlled study with three parallel treatment groups.
Participants	242 paediatric patients undergoing cardiac surgery. Age: All gestational age 36 weeks or more up to 6 years of age: 8.3 (+/‐ 14.8) months in the placebo group, 5.9 (+/‐ 10.2) months in the low‐dose (LD) milrinone group, 8.6 (+/‐ 16.5) months in the high‐dose (HD) milrinone group. Male = 48% of placebo (36/75), 60.8% of LD milrinone (48/75), 53.4% of HD milrinone group (39/75). Female = 52% of placebo (39/75), 39.2% of LD milrinone (31/75), 46.6% of HD milrinone group (34/75). Of 242 randomised patients, 238 received the study drug. 11 were excluded "due to 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.
Interventions	Milrinone low‐dose: 79 = Bolus of 25 mcg/kg over 1 hour, followed by infusion of 0.25 μg/kg/min for (23‐)35 hours, starting within 90 minutes after arrival to the ICU from the operating room. Milrinone high‐dose: 73 = Bolus of 75 mcg/kg over 1 hour, followed by infusion of 0.75 μg/kg/min for (23‐)35 hours, starting within 90 minutes after arrival to the ICU from the operating room. Placebo: 75.
Outcomes	Mortality within 30 days: Not reported beyond hospital discharge. Mortality within 36 hours (during study drug infusion): none in any group. Two deaths after 36 hours ("deemed to be unrelated to study drug"), study group unknown. Time to death (censored after 3 months): not reported. LCOS within 30 days from surgery yes/no: a) Numbers given for 227 (per protocol population) within the first 36 hours = during study drug infusion: HD Milrinone (n = 73) n = 7 (9.6%); LD Milrinone (n = 79) n = 14 (17.7%); Placebo (n = 75) n = 20 (26.7%). Relative risk reduction: HD Milrinone vs. Placebo 55% (P = 0.023) in all treated patients vs. 64% (P = 0.007) in the per‐protocol population of 227 patients. LD Milrinone vs. Placebo 34% (P = 0.183). b) Numbers given for 209 patients for the entire follow‐up period (missing participants: 4 received no study medication, 11 with "major protocol violations", 13 participants who received open‐label milrinone after the study drug infusion, and 5 participants who were lost to follow‐up), as measured from figure 3, p. 999: HD Milrinone (n = 64) n = 10 (15.6%); LD Milrinone (n = 74) n = 16 (21.6%); Placebo (n = 71) n = 21 (29.6%). Duration of ICU stay: not reported. Duration of hospital stay: Geometric mean of duration of hospital stay: Placebo (n= 71) 10.2 days, LD Milr (n= 74) 8.6 d, HD Milr (n= 64) 9.3 days. (Numbers assuming population of n = 209 with complete follow‐up.) Duration of mechanical ventilation: Geometric mean duration of mechanical ventilation: Placebo (n = 71) 1.6 days, LD Milr (n = 74) 1.7 days, HD Milr (n = 64) 1.7 days. (Numbers assuming population of n = 209 with complete follow‐up.) Max. inotrope score: not reported, "no statistically significant differences among the 3 treatment groups with respect to [...] baseline inotropic support". Number of patients requiring MCS or HTX within 30 days from surgery: 2 patients received ECMO for LCOS (treatment group unknown), heart transplantation not reported. Number/proportion of adverse events: ‐ Arrhythmia: Ventricular arrhythmia (n = 1), SVT (n = 1), groups unknown; "no differences between the groups" ‐ Tachycardia: "HR was significantly higher (mean, 10 beats per minute) in the treatment arms at 1, 12, and 24 hours compared with placebo”. No patient numbers reported using a cutoff heart rate value. ‐ Hypotension: “In both milrinone treatment arms, systolic and diastolic blood pressures decreased between 5% and 9% immediately after the bolus and were not significantly different from placebo by 12h into the study infusion.” [Circulation 2003, p.999]. Hypotension occurred in 1 patient each in the placebo (1.2%) and LD (1.3%) arms and in 2 patients (2.6%) in the HD arm. No differences between the groups. ‐ LVEF < 28%: not reported ‐ Thrombocytopenia: not reported (“no statistical difference in platelet count over time (baseline, 36 hours, 72 hours, and discharge) by treatment arm”, “no difference in the incidence of thrombocytopenia (platelet count < 50 000) during the study infusion”) ‐ Elevated liver enzymes: "no differences between the groups" According to extended information about this trial by MHRA 2005: "Adverse events were reported in 79% of placebo treated patients, 78.8% of low dose milrinone patients and 71% of high dose milrinone patients. Those occurring at a frequency of >10% in any group are as follows:" (absolute numbers in the treatment groups calculated according to percentages, mostly adding up to the intention‐to‐treat population of n = 238) ‐ Fever: Placebo 14/81 (17.3%), LD 12/80 (15%), HD 10/77 (13%). ‐ Cardiac failure: Placebo 21/81 (25.9%), LD 18/80 (22.5%), HD 12/77 (15.6%). ‐ Hypotension: Placebo 10/81 (12.3%), LD 3/80 (3.8%), HD 10/77 (13%). ‐ Nodal arrhythmia: Placebo 2/81 (2.5%), LD 6/80 (7.5%), HD 8/77 (10.4%). ‐ Thrombocytopenia: Placebo 9/81 (11.1%), LD 8/80 (10%), HD 7/77 (9.1%). ‐ Pleural effusion: Placebo 10/81 (12.3%), LD 14/80 (17.5%), HD 19/70 (27.4%). ‐ Stridor: Placebo 10/81 (12.3%), LD 10/80 (12.5%), HD 10/77 (13%).
Notes	Cutoffs 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. Comparison of milrinone with placebo.
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 end point committee.
Incomplete outcome data (attrition bias) All outcomes	High risk	Drop out 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.