NIHR Signal Noradrenaline confirmed as first-choice vasopressor for septic shock

Published on 17 December 2015

This review supports current guidance that noradrenaline should be used as the first-choice vasopressor for adults with septic shock. Noradrenaline reduced mortality by 11% and major adverse events by two-thirds compared to dopamine. However, evidence of its effectiveness compared to the other vasopressors remains limited. Septic shock accounts for nearly one in ten admissions to intensive care units, where it is the most common cause of death. The survival rate for septic shock is only about 50%.

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Why was this study needed?

Septic shock is when blood pressure drops to a dangerously low level after an infection. It is a life-threatening condition. Mortality rates vary between 40 to 60%. The number of cases of severe sepsis, where the immune system “overreacts” to an infection, leading to widespread inflammation, swelling, blood clotting and organ failure, are rising. It is currently estimated that severe sepsis affects between 50 and 100 cases per 100,000 people, and many of these cases may progress to septic shock.

Vasopressors are drugs that cause blood vessels to narrow, thereby increasing blood pressure and hence the flow of blood. They are used to treat patients with septic shock, helping to restore blood flow to the vital organs and the rest of the body.

No single study had previously demonstrated survival benefit of one vasopressor over another. Therefore this review’s objective was to assess the overall evidence for the efficiency and safety of all vasopressors for septic shock.

What did this study do?

This was a systematic review of 32 randomised controlled trials that compared a vasopressor with either a different vasopressor, a combination of vasopressors, inactive placebo or no vasopressor, for the treatment of adult patients with septic shock. A total of 3,544 patients were included.

The following vasopressors were included: dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine), phenylephrine, vasopressin and terlipressin. The most common comparisons were noradrenaline with dopamine (14 trials) and noradrenaline with adrenaline (7 trials).

Standard systematic review methods were used. Many of the trials were very small, just five trials included over a hundred patients. Trial quality was variable and differed with regard to dosages, timings and outcomes measure. However, the authors were careful to take into account the variety of trials in their analyses and so the results should be reliable.

What did it find?

  • Compared to dopamine, noradrenaline reduced deaths from any cause at 28 days by 11% (Relative Risk [RR] 0.89, 95% Confidence Interval [CI] 0.81 to 0.98). Forty-five percent of people treated with noradrenaline died, compared with 52% treated with dopamine. This result came from a meta-analysis of 11 trials.
  • Noradrenaline reduced the risk of major adverse effects, such as irregular heart-beat, heart attack, stroke or reduction in blood supply (ischaemia) to the heart or limbs, by about two-thirds compared with dopamine (RR 0.34, 95% CI 0.14 to 0.84). This result came from a meta-analysis of just three trials. Meta-analysis of four trials found that noradrenaline reduced the risk of irregular heart beat by about a half compared to dopamine (RR 0.48, 95% CI 0.40 to 0.58).
  • No reduction in all-cause mortality or major adverse effects was demonstrated for noradrenaline compared to adrenaline, phenylephrine, vasopressin or terlipressin as any difference in mortality were not statistically significant.
  • Other outcomes, including length of stay in intensive care, were similar between the different vasopressors. However, noradrenaline did improve some other measures indicating stability of blood pressure and circulation, such as urine output.

What does current guidance say on this issue?

The 2012 guideline from the Surviving Sepsis Campaign, a joint collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, recommend noradrenaline as the first-choice vasopressor. Adrenaline may be added to, and potentially substituted for, noradrenaline when an additional agent is needed. Dopamine is only recommended as an alternative to noradrenaline in highly selected patients.

NICE are in the process of developing guidance in this area. The expected publication date is July 2016. The scope document states that the NICE guidance will not replicate the existing Surviving Sepsis Campaign guidelines.

What are the implications?

The results support current guidance that noradrenaline should be used as the first-choice vasopressor for septic shock. It reduces mortality and adverse events compared to dopamine. There is little evidence available to judge other vasopressors.

More trials are needed. The authors recommend that future trials should use a common sepsis management protocol (including the use of fluid resuscitation and steroids) and report not only all-cause mortality but also length of hospital stay, length of ventilation, length of vasopressor support and adverse events.

Citation

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.

Bibliography

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.

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.

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

Why was this study needed?

Septic shock is when blood pressure drops to a dangerously low level after an infection. It is a life-threatening condition. Mortality rates vary between 40 to 60%. The number of cases of severe sepsis, where the immune system “overreacts” to an infection, leading to widespread inflammation, swelling, blood clotting and organ failure, are rising. It is currently estimated that severe sepsis affects between 50 and 100 cases per 100,000 people, and many of these cases may progress to septic shock.

Vasopressors are drugs that cause blood vessels to narrow, thereby increasing blood pressure and hence the flow of blood. They are used to treat patients with septic shock, helping to restore blood flow to the vital organs and the rest of the body.

No single study had previously demonstrated survival benefit of one vasopressor over another. Therefore this review’s objective was to assess the overall evidence for the efficiency and safety of all vasopressors for septic shock.

What did this study do?

This was a systematic review of 32 randomised controlled trials that compared a vasopressor with either a different vasopressor, a combination of vasopressors, inactive placebo or no vasopressor, for the treatment of adult patients with septic shock. A total of 3,544 patients were included.

The following vasopressors were included: dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine), phenylephrine, vasopressin and terlipressin. The most common comparisons were noradrenaline with dopamine (14 trials) and noradrenaline with adrenaline (7 trials).

Standard systematic review methods were used. Many of the trials were very small, just five trials included over a hundred patients. Trial quality was variable and differed with regard to dosages, timings and outcomes measure. However, the authors were careful to take into account the variety of trials in their analyses and so the results should be reliable.

What did it find?

  • Compared to dopamine, noradrenaline reduced deaths from any cause at 28 days by 11% (Relative Risk [RR] 0.89, 95% Confidence Interval [CI] 0.81 to 0.98). Forty-five percent of people treated with noradrenaline died, compared with 52% treated with dopamine. This result came from a meta-analysis of 11 trials.
  • Noradrenaline reduced the risk of major adverse effects, such as irregular heart-beat, heart attack, stroke or reduction in blood supply (ischaemia) to the heart or limbs, by about two-thirds compared with dopamine (RR 0.34, 95% CI 0.14 to 0.84). This result came from a meta-analysis of just three trials. Meta-analysis of four trials found that noradrenaline reduced the risk of irregular heart beat by about a half compared to dopamine (RR 0.48, 95% CI 0.40 to 0.58).
  • No reduction in all-cause mortality or major adverse effects was demonstrated for noradrenaline compared to adrenaline, phenylephrine, vasopressin or terlipressin as any difference in mortality were not statistically significant.
  • Other outcomes, including length of stay in intensive care, were similar between the different vasopressors. However, noradrenaline did improve some other measures indicating stability of blood pressure and circulation, such as urine output.

What does current guidance say on this issue?

The 2012 guideline from the Surviving Sepsis Campaign, a joint collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, recommend noradrenaline as the first-choice vasopressor. Adrenaline may be added to, and potentially substituted for, noradrenaline when an additional agent is needed. Dopamine is only recommended as an alternative to noradrenaline in highly selected patients.

NICE are in the process of developing guidance in this area. The expected publication date is July 2016. The scope document states that the NICE guidance will not replicate the existing Surviving Sepsis Campaign guidelines.

What are the implications?

The results support current guidance that noradrenaline should be used as the first-choice vasopressor for septic shock. It reduces mortality and adverse events compared to dopamine. There is little evidence available to judge other vasopressors.

More trials are needed. The authors recommend that future trials should use a common sepsis management protocol (including the use of fluid resuscitation and steroids) and report not only all-cause mortality but also length of hospital stay, length of ventilation, length of vasopressor support and adverse events.

Citation

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.

Bibliography

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.

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.

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

Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis

Published on 4 August 2015

Avni, T.,Lador, A.,Lev, S.,Leibovici, L.,Paul, M.,Grossman, A.

PLoS One Volume 10 , 2015

OBJECTIVE: International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock. METHODS: Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled. RESULTS: Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels. CONCLUSIONS: Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.

Vasopressors are drugs that can help increase blood pressure and have been used since the 1940s. However, despite their long history there have been relatively few trials directly comparing one vasopressor against another. Consequently, the choice of vasopressor has for a long time been based on expert opinion, data from animal studies and the use of surrogate outcomes for mortality and the severity of illness, such as tissue oxygenation.

Different vasopressors work by a variety of means. The adrenergic group of vasopressors work by stimulating the sympathetic nervous system. Drugs in this group include noradrenaline, adrenaline and phenylephrine which work by narrowing blood vessels and dopamine which stimulates the heart. Vasopressin and terlipressin are called non-adrenergic vasopressors. They do not act upon the heart or blood vessels, but increase blood pressure by reducing water loss through urination.

Expert commentary

The important finding of this study is that noradrenaline is superior to dopamine but non-superior to other therapeutic strategies including dual vasopressors. This supports what is already usual practice in the UK. It adds to the weight of evidence supporting noradrenaline as the vasopressor of choice in septic shock, which represents the biggest proportion of cases of severe sepsis. Evidence is currently being reviewed by NICE and this and other evidence will be considered by the Surviving Sepsis Campaign in their revised guidelines next year. It is hoped that this and similar works will help us to reach international consensus in a critical aspect of the management of these complex cases.

Dr Ron Daniels, CEO of UK Sepsis Trust and Global Sepsis Alliance, Clinical Adviser to NHS England