Inotropic and vasodilator strategies in people with cardiogenic shock or low cardiac output

Review question

We reviewed existing evidence on the treatment with different agents, which act by either increasing the ability of the heart to contract (inotropic drugs) or by expansion of the blood vessels (vasodilating drugs), regarding their effects on mortality in patients with cardiogenic shock (CS; shock due to critical reduction of cardiac pumping capacity) or low cardiac output syndrome (LCOS; reduced heart performance).

Background

CS and LCOS represent life-threatening entities. Drug therapy of CS and LCOS is based on substances that stimulate contraction of the heart. The potent agents are frequently used for rescue in acute cardiac care. However, evidence for the treatment of patients suffering from unstable blood circulation is limited especially with regard to mortality.

Study characteristics

We included 19 studies with 2385 participants with CS or LCOS complicating myocardial infarction, heart failure or cardiac surgery. The follow-up periods of the studies varied between the length of the recovery period and a period of up to 12 months. Eight studies were funded by the manufacturer of the investigated drug. In one study, the relationship to the pharmaceutical industry was not determined.

Key results

We compared different strategies employing inotropic or vasodilating drugs (i.e. levosimendan, enoximone, piroximone, epinephrine, norepinephrine, dopexamine, milrinone, dopamine and dobutamine). Low-quality evidence reflects uncertainty regarding short- and long-term mortality in the comparison of levosimendan with dobutamine. Very low-quality evidence reflects uncertainty regarding long-term mortality in the comparison of levosimendan with placebo; no data were available for the short-term follow-up. Very low-quality evidence reflects uncertainty regarding short-term mortality in the comparison of levosimendan with enoximone, epinephrine with norepinephrine-dobutamine, dopexamine with dopamine, enoximone with dobutamine, and dopamine-milrinone with dopamine-dobutamine; no data were available for the long-term follow-up. Very low-quality evidence reflects uncertainty for all-cause mortality in the short and long term when comparing epinephrine with norepinephrine. No data on all-cause mortality were available in the comparison of milrinone with dobutamine, enoximone with piroximone and enoximone with epinephrine-nitroglycerine.

Quality of evidence

This evidence is current to October 2019. We have very little confidence in the results of the studies that we analysed (low- or very low-quality evidence) due to relevant study limitations (risk of bias), imprecision or indirectness.

Authors' conclusions: 

At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS.

Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS.

Read the full abstract...
Background: 

Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery. While there is solid evidence for the treatment of other cardiovascular diseases of acute onset, treatment strategies in haemodynamic instability due to CS and LCOS remains less robustly supported by the given scientific literature. Therefore, we have analysed the current body of evidence for the treatment of CS or LCOS with inotropic and/or vasodilating agents. This is the second update of a Cochrane review originally published in 2014.

Objectives: 

Assessment of efficacy and safety of cardiac care with positive inotropic agents and vasodilator agents in CS or LCOS due to AMI, HF or after cardiac surgery.

Search strategy: 

We conducted a search in CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in October 2019. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied.

Selection criteria: 

Randomised controlled trials (RCTs) enrolling patients with AMI, HF or cardiac surgery complicated by CS or LCOS.

Data collection and analysis: 

We used standard methodological procedures according to Cochrane standards.

Main results: 

We identified 19 eligible studies including 2385 individuals (mean or median age range 56 to 73 years) and three ongoing studies. We categorised studies into 11 comparisons, all against standard cardiac care and additional other drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo; enoximone versus dobutamine, piroximone or epinephrine-nitroglycerine; epinephrine versus norepinephrine or norepinephrine-dobutamine; dopexamine versus dopamine; milrinone versus dobutamine and dopamine-milrinone versus dopamine-dobutamine.

All trials were published in peer-reviewed journals, and analyses were done by the intention-to-treat (ITT) principle. Eighteen of 19 trials were small with only a few included participants. An acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements occurred in nine of 19 trials. In general, confidence in the results of analysed studies was reduced due to relevant study limitations (risk of bias), imprecision or indirectness. Domains of concern, which showed a high risk in more than 50% of included studies, encompassed performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events.

All comparisons revealed uncertainty on the effect of inotropic/vasodilating drugs on all-cause mortality with a low to very low quality of evidence. In detail, the findings were: levosimendan versus dobutamine (short-term mortality: RR 0.60, 95% CI 0.36 to 1.03; participants = 1701; low-quality evidence; long-term mortality: RR 0.84, 95% CI 0.63 to 1.13; participants = 1591; low-quality evidence); levosimendan versus placebo (short-term mortality: no data available; long-term mortality: RR 0.55, 95% CI 0.16 to 1.90; participants = 55; very low-quality evidence); levosimendan versus enoximone (short-term mortality: RR 0.50, 0.22 to 1.14; participants = 32; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine-dobutamine (short-term mortality: RR 1.25; 95% CI 0.41 to 3.77; participants = 30; very low-quality evidence; long-term mortality: no data available); dopexamine versus dopamine (short-term mortality: no deaths in either intervention arm; participants = 70; very low-quality evidence; long-term mortality: no data available); enoximone versus dobutamine (short-term mortality RR 0.21; 95% CI 0.01 to 4.11; participants = 27; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine (short-term mortality: RR 1.81, 0.89 to 3.68; participants = 57; very low-quality evidence; long-term mortality: no data available); and dopamine-milrinone versus dopamine-dobutamine (short-term mortality: RR 1.0, 95% CI 0.34 to 2.93; participants = 20; very low-quality evidence; long-term mortality: no data available). No information regarding all-cause mortality were available for the comparisons milrinone versus dobutamine, enoximone versus piroximone and enoximone versus epinephrine-nitroglycerine.

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