Introduction
Methods
Eligibility criteria
Search strategy
Study selection and data extraction
Bias risk assessment
Error matrix approach
Statistical analysis
Trial sequential analysis (TSA)
GRADE approach
Results
Characteristics of the included trials
Trial | Patients | Clinical setting | Milrinone bolus and infusion rate | Comparator | Outcomes |
---|---|---|---|---|---|
Cardiac surgery setting | |||||
Doolan [46] | 30 | CHF, ONCAB and valve surgery | 50 µg/kg | Placebo (67 % received open label milrinone) | Primary: none Secondary: arrhythmia Other: none Surrogate: failure of weaning from CPB, haemodynamic and biochemical parameters |
0.5 µg/kg/min for minimum 4 h | |||||
Feneck [38] | 120 | AHF, cardiac surgery | 50 µg/kg | Dobutamine 10 up to 20 µg/kg/min if clinically indicated | Primary: none Secondary: MI, arrhythmias, hypotension Other: adverse events, severe low output state Surrogate: haemodynamic parameters |
0.5–0.75 µg/kg/min | |||||
Möllhoff [51] | 30 | CHF, cardiac surgery | No bolus | Nifedipine 0.2 µg/kg/min for at least 24 h (dobutamine or epinephrine added when needed; no data) | Primary: mortality (1 year) Secondary: arrhythmias Other: hospital stay, angina pectoris at 1 year, NYHA at 1 year Surrogate: haemodynamic and biochemical parameters |
0.375 µg/kg/min for at least 24 h (dobutamine or epinephrine added when needed; no data) | |||||
Al-Shawaf [41] | 30 | CHF, cardiac (valve) surgery | 50 µg/kg | Levosimendan bolus 12 µg/kg followed by 0.1–0.2 µg/kg/min for 24 h | Primary: mortality (48 h) Secondary: MI, arrhythmias, mechanical ventilation Other: renal replacement therapy Surrogate: haemodynamic parameters |
0.3–0.5 µg/kg/min for 24 h | |||||
Brackbill [43] | 40 | CHF, cardiac surgery | 50 µg/kg | Nesiritide bolus 2 µg/kg with infusion 0.01 µg/kg/min for approx. 24 h (30 % received epinephrine; 40 % dopamine) | Primary: mortality (30 days) Secondary: none Other: renal failure, length of ICU and hospital stay Surrogate: haemodynamic parameters |
0.375 µg/kg/min for approx. 24 h (20 % received epinephrine; 35 % dopamine) | |||||
De Hert [45] | 30 | CHF, cardiac surgery | No bolus | Levosimendan 0.1 µg/kg/min maximum 24 h (+dobutamine 5 µg/kg/min) | Primary: mortality (30 days) Secondary: MI, arrhythmias, mechanical ventilation Other: length of ICU and hospital stay Surrogate: biochemical and haemodynamic parameters |
0.5 µg/kg/min (+dobutamine 5 µg/kg/min) | |||||
Jebeli [48] | 70 | CHF, ONCAB | 50 µg/kg | Placebo (>90 % received dopamine) | Primary: mortality (until ICU discharge) Secondary: MI, arrhythmia, mechanical ventilation Other: myocardial ischemia, non-myocardial ischemic events, renal failure, duration of CPB, inotropic support and ICU stay Surrogate: biochemical parameters, need for IABP |
0.5 µg/kg/min for 24 h (>90 % received dopamine) | |||||
Hadadzadeh [47] | 80 | CHF, OPCAB | 50 µg/kg | Placebo (52.5 % received other ‘inotropic support’) | Primary: mortality (until ICU discharge) Secondary: MI, arrhythmia, mechanical ventilation Other: myocardial ischemia, ICU stay, inotropic support duration, renal failure, non-myocardial ischemic events Surrogate: need for IABP, biochemical parameters |
0.5 µg/kg/min for 24 h (47.5 % received other ‘inotropic support’) | |||||
Non-cardiac surgery setting | |||||
Biddle [42] | 79 | CHF | 50 or 75 µg/kg | Dobutamine 2.5 µg/kg/min, increased to max. 15.0 µg/kg/min | Primary: mortality (48 h) Secondary: arrhythmias Other: adverse reactions Surrogate: haemodynamic parameters |
0.5 up to 0.75 or 1.0 µg/kg/min | |||||
Karlsberg [49] | 30 | AHF post MI | 50 µg/kg | Dobutamine 2.5 µg/kg/min titrated to a max. of 15 µg/kg/min | Primary: mortality (24 h) Secondary: arrhythmias Other: adverse events Surrogate: echocardiographic and haemodynamic parameters |
First 3 h up titration from 0.5, 0.62 to 0.75 µg/kg/min and then 0.25–0.75 µg/kg/min | |||||
Siostrzonek [50] | 20 | CHF | No bolus | Conventional (+dobutamine) | Primary: mortality (24 h) Secondary: none Other: length of ICU stay Surrogate: days until complete weaning from catecholamine, haemodynamic and biochemical parameters |
0.5 µg/kg/min > 24 h (+dobutamine) | |||||
Cuffe [44] | 949 | AHF, CHF | No bolus | Placebo (9.3 % received dobutamine) | Primary: mortality (60 days) Secondary: SAE, MI, arrhythmias, hypotension Other: length of stay Surrogate: none |
0.5 µg/kg/min, titrated to 0.375–0.75 µg/kg/min and maintained for 48–72 h (11.5 % received dobutamine) | |||||
Aranda [40] | 36 | CHF, awaiting Htx | No bolus | Dobutamine 2.5 µg/kg/min titrated 2.5 µg/kg/min to a max. 10 µg/kg/min (18 % received dopamine) | Primary: mortality (until hospital discharge) Secondary: arrhythmias Other: Htx, inotrope (bridge to Htx), LVAD (bridge to Htx), IABP (bridge to Htx), length of stay Surrogate: switched to alternate drug, haemodynamic parameters, cost-effectiveness |
0.25 µg/kg/min, titrated 0.125 µg/kg/min to max. 0.75 µg/kg/min (32 % received dopamine) | |||||
Yang [36] | 120 | AHF post MI | No bolus | Control | Primary: mortality (7 days) Secondary: none Other: none Surrogate: echocardiographic, haemodynamic and biochemical parameters |
0.5 µg/kg/min for 5 h once a day for 7 days | |||||
Pang [35] | 50 | AHF post MI | 50 µg/kg | Placebo (+dobutamine) | Primary: mortality (5 days) Secondary: none Other: none Surrogate: gastrointestinal reaction, haemodynamic parameters |
0.5 µg/kg/min (+dobutamine) | |||||
Wang [52]a
| 60 | Sepsis | 30 µg/kg | Control | Primary: mortality (28 days) Secondary: none Other: adverse events, ICU/hospital stay Surrogate: haemodynamic and biochemical parameters |
0.375–0.5 µg/kg/min |
Bias risk assessment
Outcomes
Number of trials | Number of patients | Conventional meta-analysis | ||
---|---|---|---|---|
RR with 95 % CI | Test of interaction | |||
Mortality | ||||
Inactive control | 5 | 1267 | 0.99 (0.77–1.27) | |
Potentially active control | 9 | 344 | 0.76 (0.31–1.89) | |
Any control | 14 | 1611 | 0.96 (0.76–1.21) |
P = 0.59 |
MI | ||||
Inactive control | 3 | 1060 | 0.54 (0.11–2.69) | |
Potentially active control | 2 | 60 | 1.09 (0.36–3.29) | |
Any control | 5 | 1120 | 0.73 (0.25–2.09) |
P = 0.48 |
VT/VF | ||||
Inactive control | 4 | 1087 | 0.80 (0.40–1.61) | |
Potentially active control | 3 | 139 | 1.11 (0.58–2.15) | |
Any control | 7 | 1226 | 0.96 (0.65–1.41) |
P = 0.50 |
SVT | ||||
Inactive control | 2 | 988 | 1.43 (0.80–2.54) | |
Potentially active control | 2 | 150 | 0.60 (0.13–2.70) | |
Any control | 4 | 1138 | 0.89 (0.43–1.87) |
P = 0.29 |
MV durationa
| ||||
Inactive control | 2 | 150 | −2.85 (−5.00 to −0.69) | |
Potentially active control | 2 | 60 | 12.66 (−3.48 to 28.80) | |
Any control | 4 | 210 | 1.03 (−4.87 to 6.93) |
P = 0.06 |
Comparison 1: all critically ill patients with cardiac dysfunction
All-cause mortality
Myocardial infarction
Other outcomes
Comparison 2: patients with cardiac dysfunction after cardiac surgery
All-cause mortality
Myocardial infarction
Other outcomes
Comparison 3: patients with cardiac dysfunction not having cardiac surgery
All-cause mortality
Other outcomes
Error matrix approach
Small trial bias
GRADE approach
Quality assessment | No. of patients | Effect | Quality | Importance | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Milrinone | Any control | Relative (95 % CI) | Absolute (95 % CI) | ||
Serious adverse events—not reported | ||||||||||||
– | – | – | – | – | – | – | – | – | – | – | – | Critical |
Milrinone mortality at max FU comparator | ||||||||||||
14 | Randomised trials | Seriousa
| Not seriousb
| Seriousb,c,d
| Very seriouse
| Nonef
| 86/815 (10.6 %) | 86/796 (10.8 %) | RR 0.96 (0.76 to 1.21) | 4 fewer per 1000 (from 23 more to 26 fewer) | ⨁◯◯◯ Very low | Critical |
6.9 % | 3 fewer per 1000 (from 14 more to 17 fewer) | |||||||||||
Myocardial infarction | ||||||||||||
5 | Randomised trials | Seriousa
| Seriousg
| Seriousc,d
| Very serious5
| None | 19/568 (3.3 %) | 26/552 (4.7 %) | RR 0.73 (0.25 to 2.09) | 13 fewer per 1000 (from 35 fewer to 51 more) | ⨁◯◯◯ Very low | Important |
22.5 % | 61 fewer per 1000 (from 169 fewer to 245 more) | |||||||||||
Ventricular arrhythmias | ||||||||||||
7 | Randomised trials | Seriousa
| Not serioush
| Seriousc,d
| Very seriouse
| None | 41/622 (6.6 %) | 42/604 (7.0 %) | RR 0.96 (0.65 to 1.41) | 3 fewer per 1000 (from 24 fewer to 29 more) | ⨁◯◯◯ Very low | Important |
5.1 % | 2 fewer per 1000 (from 18 fewer to 21 more) | |||||||||||
Supraventricular arrhythmias | ||||||||||||
4 | Randomised trials | Seriousa
| Seriousg
| Seriousc,d
| Very seriouse
| None | 38/577 (6.6 %) | 36/561 (6.4 %) | RR 0.89 (0.43 to 1.87) | 7 fewer per 1000 (from 37 fewer to 56 more) | ⨁◯◯◯ Very low | Not important |
12.9 % | 14 fewer per 1000 (from 74 fewer to 112 more) | |||||||||||
Mechanical ventilation duration | ||||||||||||
4 | Randomised trials | Seriousa
| Seriousg
| Very seriousc,d
| Seriouse
| None | – | MD 1.03 higher (4.87 lower to 6.93 higher) | ⨁◯◯◯ Very low | Not important |