Key messages
- Using levosimendan as a prevention makes it less likely that children undergoing heart surgery will die. The risk for reduced heart function is largely decreased with levosimendan and likely also with milrinone, compared to placebo. Side effects are likely more common with levosimendan or dobutamine and may be more common with milrinone but less common with low-dose milrinone, compared to placebo.
- Our confidence in the evidence is limited because only a small number of patients received each medication, the patients' ages and diseases differed, and there was short follow-up or incomplete reporting of outcomes.
What is low cardiac output syndrome?
Children who undergo heart surgery are at risk of reduced heart function after surgery (low cardiac output syndrome, LCOS). This affects up to one-quarter of these children, and there is a risk of death. Reduced heart function causes children to stay longer on breathing machines and longer in the intensive care unit (ICU).
What did we want to find out?
We wanted to find out if any medications that increase the pumping force of the heart prevent reduced heart function or death in children following heart surgery, if there are associated harms, and if we could rank the treatments. These medications are used when LCOS is present, but sometimes also to prevent it. There have been a few studies comparing some of these drugs against each other, each with few patients. By conducting a network meta-analysis, where several different treatments can be compared to each other, we hoped to provide further information on how to prevent low heart function or death in children who undergo heart surgery.
What did we do?
We searched medical literature databases for planned, ongoing, and completed studies that compared any of these medications to each other, to standard care (measures commonly performed on the ICU after heart surgery), or to placebo (a solution that looks the same as the medication infusion, but has no active ingredient). Two review authors collected and reviewed the data independently. We then calculated how effective the drugs were when studies' results were combined, summarised the results, and rated our confidence in the evidence.
What did we find?
We found 13 studies comparing levosimendan, milrinone, dobutamine, dopamine, combinations of these with other drugs, or placebo, with 937 total participants. Two of the studies were conducted at multiple hospitals. Participants differed between the studies; for example, by age, from newborns less than one month of age to children aged 14 years old. All studies included children undergoing surgery for congenital heart defects by temporarily using a heart-lung machine. Some studies examined only children with two heart chambers, one only children with one heart chamber, and some both.
Five studies compared levosimendan versus milrinone, two levosimendan versus placebo, and two milrinone versus placebo. One study compared levosimendan versus dobutamine, another milrinone versus dobutamine, and two studies used combination treatments. Patients were watched mostly for the duration of their stay in the ICU or in the hospital. The study authors received funding from governments, hospitals, and non-profit organisations, but also from drug manufacturers; in some cases, we do not know how they were funded.
Key results
Levosimendan results in fewer patients dying after childhood heart surgery than placebo, milrinone likely does not change that risk, and for dobutamine, we do not know the risk (14 events, 557 participants, 9 studies).
The risk of reduced heart function was largely reduced with levosimendan and likely largely reduced with milrinone, and may be reduced with low-dose milrinone, compared to placebo (85 events, 513 participants, 5 studies).
The length of ICU stay may be no different with levosimendan and is likely no different with milrinone or with dobutamine, compared to placebo (9 studies, 577 participants).
The length of hospital stay is likely no different with levosimendan or with milrinone, but is likely reduced with dobutamine, compared to placebo (7 studies, 297 participants).
The time children need to be on a respirator after heart surgery is likely longer with levosimendan or milrinone and is likely no different with dobutamine, compared to placebo (9 studies, 577 participants).
Side effects in general are likely more common with levosimendan or dobutamine and may be more common with milrinone and less common with low-dose milrinone, compared to placebo (8 studies, 706 participants, 380 events).
What are the limitations of the evidence?
We found few studies with different trial designs where often not all of these effects were looked at. Our confidence in the evidence is limited due to the small number of included patients for each drug treatment, and because we were not always convinced that all patients in a study would have been treated in a completely comparable way, that they were followed up for long enough, or that all study results were completely reported. Therefore, all results of our network meta-analysis must be viewed cautiously.
How up-to-date is this evidence?
This evidence is up-to-date to December 2023.
Levosimendan likely results in a large reduction in mortality compared to placebo in paediatric patients undergoing surgery for congenital heart disease, whereas milrinone likely results in no difference, and the effect of dobutamine is unknown.
Low cardiac output syndrome (LCOS) is largely reduced with levosimendan, likely largely reduced with milrinone, and may be reduced with low-dose milrinone, compared to placebo.
The length of ICU stay may be no different with levosimendan and is likely no different with milrinone or with dobutamine, compared to placebo.
The length of hospital stay is likely no different with levosimendan or with milrinone, but is likely reduced with dobutamine, compared to placebo.
The duration of mechanical ventilation is likely increased with levosimendan or with milrinone and is likely no different with dobutamine, compared to placebo.
Adverse events are likely increased with levosimendan or dobutamine, and may be increased with milrinone and decreased with low-dose milrinone, compared to placebo.
The evidence is based on few, heterogeneous studies, with small numbers of patients and short follow-up periods. Future research should include large numbers of patients, consistently report all co-interventions, and ensure the longest possible follow-up.
Paediatric patients undergoing surgery for congenital heart disease (CHD) are at risk for postoperative low cardiac output syndrome (LCOS) and mortality. LCOS affects up to 25% of children after heart surgery. It consists of reduced myocardial function and increases postoperative morbidity, prolongs mechanical ventilation, and lengthens the duration of intensive care unit (ICU) stay. Pharmacological prophylaxis involves inotropes, including catecholamines, phosphodiesterase III inhibitors, or calcium sensitisers, to enhance myocardial contractility. It is unclear whether they are effective in preventing LCOS or death in this vulnerable population.
1. To evaluate the relative benefits and harms of inotropes for the prevention of LCOS and mortality in paediatric patients undergoing surgery for CHD.
2. To generate a clinically useful ranking of prophylactic inotropes for the prevention of LCOS and mortality in paediatric patients undergoing surgery for CHD according to benefits and harms.
We searched CENTRAL, MEDLINE, Embase, Web of Science, and clinical trial registries, most recently in December 2023 and April 2024. We also checked reference lists from identified studies and review articles. We did not apply any language restrictions.
We included randomised controlled trials comparing inotropes from one drug class (catecholamines, phosphodiesterase type III inhibitors, calcium sensitisers) to another (either alone or in combination) or placebo, in paediatric patients (birth to 18 years of age) undergoing surgery for CHD.
Two review authors independently selected studies, extracted data, assessed risk of bias, and rated the certainty of evidence using the CINeMA framework. We performed random-effects network and pairwise meta-analyses comparing the relative effects of each possible pair of medications with each other or placebo. Where meta-analysis was not possible, we provided a narrative description of the results. We ranked the prophylactic medications according to their effects relative to each other. The primary outcomes were all-cause mortality within 30 days, time to death, and LCOS incidence; secondary outcomes were length of ICU stay, length of hospital stay, duration of mechanical ventilation, inotrope score, mechanical circulatory support, and adverse events.
We included 13 studies with 937 participants. All except two multicentre studies were conducted at single tertiary care hospitals. Participants comprised children from birth to 14 years of age undergoing surgery for different types of CHD on cardiopulmonary bypass. Five studies compared levosimendan versus milrinone; two compared levosimendan versus placebo; two compared milrinone versus placebo (one comparing two different doses); one compared levosimendan versus dobutamine, another milrinone versus dobutamine. Two studies used combinations of inotropes. Study duration was between less than one year and 5.3 years, with follow-up mostly during ICU or hospital stay. Funding sources included governmental bodies and hospital departments, but also drug manufacturers. We downgraded the certainty of evidence for high risk of bias at study level, or imprecision at comparison level.
Primary outcomes
Compared to placebo, levosimendan likely results in a large reduction in mortality (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.15 to 2.13) and milrinone likely results in no difference (RR 0.97, 95% CI 0.11 to 8.49), whereas for dobutamine, no effect was estimable; all moderate-certainty evidence (9 studies, 557 participants, 14 events).
LCOS was largely reduced with levosimendan (RR 0.45, 95% CI 0.24 to 0.83; high-certainty evidence), likely largely reduced with milrinone (RR 0.46, 95% CI 0.24 to 0.89; moderate-certainty evidence), and may be reduced with low-dose milrinone (RR 0.7, 95% CI 0.39 to 1.28; low-certainty evidence), compared with placebo (5 studies, 513 participants, 85 events).
Secondary outcomes
The length of ICU stay may be no different with levosimendan (ratio of means (ROM) 1.12, 95% CI 0.77 to 1.63; low-certainty evidence), and is likely no different with milrinone (ROM 1.13, 95% CI 0.75 to 1.69) or with dobutamine (ROM 1.11, 95% CI 0.66 to 1.86), compared with placebo (9 studies, 577 participants); both moderate-certainty evidence.
The length of hospital stay, compared with placebo, is likely no different with levosimendan (ROM 1.03, 95% CI 0.84 to 1.27) or with milrinone (ROM 1, 95% CI 0.78 to 1.3), but is likely reduced with dobutamine (ROM 0.68, 95% CI 0.37 to 1.26); all moderate-certainty evidence (7 studies, 297 participants).
The duration of mechanical ventilation, compared with placebo, is likely increased with levosimendan (ROM 1.17, 95% CI 0.65 to 2.12) or with milrinone (ROM 1.25, 5% CI 0.67 to 2.36) and is likely no different with dobutamine (ROM 1.04, 95% CI 0.45 to 2.38); all moderate-certainty evidence (9 studies, 577 participants).
There is moderate-certainty evidence that adverse events are likely increased with levosimendan (incidence rate ratio (IRR) 1.23, 95% CI 0.78 to 1.96) or dobutamine (IRR 1.24, 95% CI 0.75 to 2.03) and low-certainty evidence that they may be increased with milrinone (IRR 1.31, 95% CI 0.96 to 1.79) and decreased with low-dose milrinone (IRR 0.84, 95% CI 0.47 to 1.5), compared with placebo (8 studies, 706 participants, 380 events).