NIHR DC Discover

NIHR Signal Specialist drugs used for “shock” did not lead to either fewer or extra deaths in some critical care patients

Published on 15 January 2016

doi: 10.3310/signal-000179

Two types of specialist drug used to treat shock neither increased or reduced deaths of critical care patients. Inotropes and vasopressors are two types of drug that are used to increase and maintain blood flow in patients who are severely ill with critically low blood pressure - a condition known as shock.

The drugs are accepted care for severe shock but there has been concern that they may also increase mortality in some situations and their use in less severe shock has been debated. The findings provide general reassurance about current critical care practice, in that these commonly used drugs do not cause extra deaths. Their use, however, does carry a cost in terms of the drug itself and additional monitoring to adjust dosage.

This review studied adult patients across a range of critical care settings, and included a large number of trials. However, more specific research is needed to look at the beneficial effects of individual drug treatments and their use in treatment of different classes or severity of shock.

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Why was this study needed?

Critical care is expensive and also subject to audit (for example, the National Cardiac Arrest Audit) to ensure the best outcomes are achieved for patients and the best use is made of NHS resources. This systematic review collated the findings of trials on two types of drugs, inotropes and vasopressors, which are used in critical care to improve and maintain the circulation in the short term in people with life-threatening conditions (see Definitions). Previous research has suggested that they may be associated with adverse outcomes, in particular an increased risk of mortality. Individual trials on these drugs have involved relatively few deaths, so a review was needed to aggregate these outcomes.

What did this study do?

This large systematic review included 177 randomised controlled trials of variable size in which a total 28,280 people were randomly assigned to receive either one of these drugs, or alternatively placebo or best available treatment. Each trial compared survival between the two groups. Fifteen different vasopressor and inotropic drugs were used across the trials and the conditions leading to shock varied, including heart failure, sepsis and complications of major surgery. The length of time over which mortality outcomes were assessed ranged from in-hospital, to up to one month, to up to one year. The review was carried out to a high standard and drew on findings from a large number of moderate quality trials. The settings and underlying conditions treated in these trials varied as did the drugs (which had different mechanisms of action). A wide range of exploratory sub-analyses were conducted to look at these subgroups in detail but no clear signal was found to allow researchers  to apply the findings or draw particular conclusions for specific circumstances.

What did it find?

  • Overall there was no significant difference in the death rate for patients who received a vasopressor or inotropic drug (30.3%) compared with patients who did not (30%), (risk ratio [RR] 0.98, 95% confidence interval [CI] 0.96 to 1.01).
  • Levosimendan was the only individual drug that had a significant effect on mortality. Across 48 trials, fewer people who took this drug died (11%) compared with people in the same trials who did not (12.4%) (RR 0.80, 95% CI 0.68 to 0.94). This drug was used in 28% of all trials but is not available for use in the UK.
  • Looking at trials with different follow-up times, inotropes or vasopressors appeared to have a significant effect on mortality assessed one month after treatment. In 35 trials one-month mortality was reduced in the treatment groups (20.2%) compared with the control groups (26.1%) (RR 0.75, 95% CI 0.57 to 0.98). It is not clear if this outcome was specified by the researchers before starting the trial.

What does current guidance say on this issue?

There is no guidance focussing on the broad topic of using vasopressors and inotropes in critical care. However some guidelines do address aspects of the topic, such as Intensive Care Society standards on treatment after cardiac arrest (2008) or upcoming NICE guidance on treatment of sepsis and septic shock due to be published in July 2016.

What are the implications?

Inotropic and vasopressor drugs are in widespread use for patients in critical care. The findings of this review may reassure practitioners that there is no evidence that their use is associated with increased mortality risk as has been previously suspected, but neither was any substantial reduction in mortality shown.

The trials had some limitations which may reduce the applicability of the findings. They encompassed a wide range of drugs and clinical settings. The review did not find that inotropes or vasopressors differentially affected mortality across the different groups of people examined, such as those with heart failure, cardiac arrest or having major surgery. However, this does not remove the possibility that there may be some difference in effectiveness or safety depending on the drug used or the shock condition.

Some clinicians may consider these drugs essential for treating very ill patients with circulatory failure. As such the trial participants may predominantly represent those where the condition wasn’t thought immediately life threatening and where the treatment approach wasn’t clear. This may limit the applicability of the findings to all people with shock.

Citation

Belletti A, Castro ML, Silvetti S, et al. The effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br J Anaesth. 2015;115(5):656-75.

Bibliography

Avni T, Lador A, Lev S, et al. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One. 2015; 10(8): e0129305.

Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

Grocott MPW, Dushianthan A, Hamilton MA, et al. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. Cochrane Database of Syst Rev. 2012;(11):CD004082.

Havel C, Arrich J, Losert H, et al. Vasopressors for hypotensive shock. Cochrane Database of Syst Rev. 2011;(5):CD003709.

ICNARC. The Intensive Care National Audit and Research Centre [internet]. London: ICNARC; 2015.

Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10(6):701-6.

NICE. Sepsis: the recognition, diagnosis and management of severe sepsis. Final scope. London: National Institute for Health and Care Excellence, 2014.

The Intensive Care Society. Standards for the management of patients after cardiac arrest. London: The Intensive Care Society; 2008.

UptoDate. Use of vasopressors and inotropes. Alphen aan den Rijn (Holland): Wolters Kluwer; 2014.

Why was this study needed?

Critical care is expensive and also subject to audit (for example, the National Cardiac Arrest Audit) to ensure the best outcomes are achieved for patients and the best use is made of NHS resources. This systematic review collated the findings of trials on two types of drugs, inotropes and vasopressors, which are used in critical care to improve and maintain the circulation in the short term in people with life-threatening conditions (see Definitions). Previous research has suggested that they may be associated with adverse outcomes, in particular an increased risk of mortality. Individual trials on these drugs have involved relatively few deaths, so a review was needed to aggregate these outcomes.

What did this study do?

This large systematic review included 177 randomised controlled trials of variable size in which a total 28,280 people were randomly assigned to receive either one of these drugs, or alternatively placebo or best available treatment. Each trial compared survival between the two groups. Fifteen different vasopressor and inotropic drugs were used across the trials and the conditions leading to shock varied, including heart failure, sepsis and complications of major surgery. The length of time over which mortality outcomes were assessed ranged from in-hospital, to up to one month, to up to one year. The review was carried out to a high standard and drew on findings from a large number of moderate quality trials. The settings and underlying conditions treated in these trials varied as did the drugs (which had different mechanisms of action). A wide range of exploratory sub-analyses were conducted to look at these subgroups in detail but no clear signal was found to allow researchers  to apply the findings or draw particular conclusions for specific circumstances.

What did it find?

  • Overall there was no significant difference in the death rate for patients who received a vasopressor or inotropic drug (30.3%) compared with patients who did not (30%), (risk ratio [RR] 0.98, 95% confidence interval [CI] 0.96 to 1.01).
  • Levosimendan was the only individual drug that had a significant effect on mortality. Across 48 trials, fewer people who took this drug died (11%) compared with people in the same trials who did not (12.4%) (RR 0.80, 95% CI 0.68 to 0.94). This drug was used in 28% of all trials but is not available for use in the UK.
  • Looking at trials with different follow-up times, inotropes or vasopressors appeared to have a significant effect on mortality assessed one month after treatment. In 35 trials one-month mortality was reduced in the treatment groups (20.2%) compared with the control groups (26.1%) (RR 0.75, 95% CI 0.57 to 0.98). It is not clear if this outcome was specified by the researchers before starting the trial.

What does current guidance say on this issue?

There is no guidance focussing on the broad topic of using vasopressors and inotropes in critical care. However some guidelines do address aspects of the topic, such as Intensive Care Society standards on treatment after cardiac arrest (2008) or upcoming NICE guidance on treatment of sepsis and septic shock due to be published in July 2016.

What are the implications?

Inotropic and vasopressor drugs are in widespread use for patients in critical care. The findings of this review may reassure practitioners that there is no evidence that their use is associated with increased mortality risk as has been previously suspected, but neither was any substantial reduction in mortality shown.

The trials had some limitations which may reduce the applicability of the findings. They encompassed a wide range of drugs and clinical settings. The review did not find that inotropes or vasopressors differentially affected mortality across the different groups of people examined, such as those with heart failure, cardiac arrest or having major surgery. However, this does not remove the possibility that there may be some difference in effectiveness or safety depending on the drug used or the shock condition.

Some clinicians may consider these drugs essential for treating very ill patients with circulatory failure. As such the trial participants may predominantly represent those where the condition wasn’t thought immediately life threatening and where the treatment approach wasn’t clear. This may limit the applicability of the findings to all people with shock.

Citation

Belletti A, Castro ML, Silvetti S, et al. The effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br J Anaesth. 2015;115(5):656-75.

Bibliography

Avni T, Lador A, Lev S, et al. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One. 2015; 10(8): e0129305.

Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.

Grocott MPW, Dushianthan A, Hamilton MA, et al. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. Cochrane Database of Syst Rev. 2012;(11):CD004082.

Havel C, Arrich J, Losert H, et al. Vasopressors for hypotensive shock. Cochrane Database of Syst Rev. 2011;(5):CD003709.

ICNARC. The Intensive Care National Audit and Research Centre [internet]. London: ICNARC; 2015.

Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10(6):701-6.

NICE. Sepsis: the recognition, diagnosis and management of severe sepsis. Final scope. London: National Institute for Health and Care Excellence, 2014.

The Intensive Care Society. Standards for the management of patients after cardiac arrest. London: The Intensive Care Society; 2008.

UptoDate. Use of vasopressors and inotropes. Alphen aan den Rijn (Holland): Wolters Kluwer; 2014.

The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials

Published on 18 October 2015

Belletti, A.,Castro, M. L.,Silvetti, S.,Greco, T.,Biondi-Zoccai, G.,Pasin, L.,Zangrillo, A.,Landoni, G.

Br J Anaesth Volume 115 , 2015

BACKGROUND: Inotropes and vasopressors are frequently administered to critically ill patients in order to improve haemodynamic function and restore adequate organ perfusion. However, some studies have suggested a possible association between inotrope administration and increased mortality. We therefore performed a meta-analysis of randomized trials published in the last 20 yr to investigate the effect of these drugs on mortality. METHODS: BioMedCentral, PubMed, Embase and the Cochrane Central Register were searched (all updated April 8th, 2015). Inclusion criteria were: random allocation to treatment, at least one group receiving an inotropic or vasopressor drug compared with at least one group receiving a non-inotropic/vasopressor treatment, study published after 1st January 1994, and systemic drug administration. Exclusion criteria were overlapping populations, studies published as abstract only, crossover studies, paediatric studies and lack of data on mortality. RESULTS: A total of 28 280 patients from 177 trials were included. Overall, pooled estimates showed no difference in mortality between the group receiving inotropes/vasopressors and the control group [4255/14 036 (31.7%) vs 4277/14 244 (31.8%), risk ratio=0.98 (0.96-1.01), P for effect=0.23, P for heterogeneity=0.30, I(2)=6%]. A reduction in mortality was associated with inotrope/vasopressor therapy use in settings of vasoplegic syndromes, sepsis and cardiac surgery. Levosimendan was the only drug associated with improvement in survival. Subgroup analysis did not identify any groups with increased mortality associated with inotrope/vasopressor therapy. CONCLUSIONS: Our systematic review found that inotrope/vasopressor therapy is not associated with differences in mortality in the overall population and in the majority of subsettings.

“Shock” is a general term for failure of the body’s heart and circulation to supply enough oxygenated blood to meet the needs of the vital organs and the rest of the body.  It can have various causes such as infection (septic shock), bleeding (hypovolaemic shock) or problems with the heart (cardiogenic shock). The best treatment approach will depend on the cause. In shock the blood pressure is usually low: vasopressors and inotropes are both used to try to improve pressure and flow to vital organs.

Vasopressors are drugs that cause blood vessels to narrow, increasing blood pressure. Examples of vasopressors are adrenaline, noradrenaline and vasopressin.

Inotropes are drugs that make the heart beat more strongly, increasing the amount of blood pumped out with each heart beat, which also helps improve blood flow and oxygen delivery to the rest of the body. Examples of inotropic drugs are dobutamine, dopamine and also adrenaline.

Expert commentary

This paper is interesting because it highlights the long running uncertainty about inotropic agents within intensive care medicine. We regard these as life-saving drugs, and we use them routinely in many of our patients. So why the equivocal findings of this systematic review? It’s important to highlight that we can only randomise patients to inotrope versus placebo, when the patient does not require inotropic agents to survive. Consequently, these findings are only relevant to less sick patients where discretionary use may be considered. My interpretation? Only use inotropic drugs when you have to, and then only at the minimum dose and shortest period necessary.

Rupert Pearse, NIHR Research Professor & Consultant in Intensive Care Medicine, Queen Mary University of London