9/10/2017 NIHR DC | Signal - Noradrenaline conrmed as rst-choice vasopressor for septic shock

Noradrenaline conrmed as rst-choice

NIHR Signal
vasopressor for septic shock
Published on 17 December 2015

This review supports current guidance that noradrenaline should be used as the rst-choice
vasopressor for adults with septic shock. Noradrenaline reduced mortality (Death.) 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%.

Signal Published Abstract Denitions Comments

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 (Death.) rates vary between 40 to 60%. The number of cases of severe
sepsis, where the immune system overreacts to an infection, leading to widespread inammation,
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 ow of blood. They are used to treat patients with septic shock, helping to restore blood ow
to the vital organs and the rest of the body.

No single study had previously demonstrated survival benet of one vasopressor over another.
Therefore this reviews objective was to assess the overall evidence for the efciency and safety of all
vasopressors for septic shock.

What did this study do?

This was a systematic review (This is a synthesis of the medical research on a particular subject. It
uses tho...) of 32 randomised controlled trials that compared a vasopressor with either a different
vasopressor, a combination of vasopressors, inactive placebo (A dummy treatment that resembles a
medical treatment but is intended to have n...) 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 (This is a synthesis of the medical research on a particular subject. It uses
tho...) methods were used. Many of the trials were very small, just ve 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.

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9/10/2017 NIHR DC | Signal - Noradrenaline conrmed as rst-choice vasopressor for septic shock

What did it nd?

Compared to dopamine, noradrenaline reduced deaths from any cause at 28 days by 11%
(Relative Risk (Relative risk compares a risk in two different groups of people. All sorts of gr...)
[RR] 0.89, 95% Condence Interval (A condence interval (CI) expresses the precision of an
estimate and is often p...) [CI] 0.81 to 0.98). Forty-ve percent of people treated with
noradrenaline died, compared with 52% treated with dopamine. This result came from a meta-
analysis (This is a mathematical technique that combines the results of individual studies...) 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
(This is a mathematical technique that combines the results of individual studies...) of just three
trials. Meta-analysis (This is a mathematical technique that combines the results of individual
studies...) 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 (Death.) or major adverse effects was demonstrated for
noradrenaline compared to adrenaline, phenylephrine, vasopressin or terlipressin as any
difference in mortality (Death.) were not statistically signicant.
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
rst-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 rst-choice vasopressor
for septic shock. It reduces mortality (Death.) 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 uid resuscitation and steroids) and report not only all-
cause mortality (Death.) 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 (This is
a synthesis of the medical research on a particular subject. It uses tho...) and meta-analysis (This is a
mathematical technique that combines the results of individual studies...)
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523170/). PLoS One. 2015; 10(8): e0129305.

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9/10/2017 NIHR DC | Signal - Noradrenaline conrmed as rst-choice vasopressor for septic shock

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 (http://www.sccm.org/Documents/SSC-Guidelines.pdf). Crit Care Med.
2013; 41(2): 580-637.

Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488423/). Expert Rev Anti Infect Ther. 2012;10(6):701-
6

NICE. Sepsis: the recognition, diagnosis and management of severe sepsis. Final scope
(https://www.nice.org.uk/guidance/gid-cgwave0686/resources/sepsis-the-recognition-diagnosis-and-
management-of-severe-sepsis-nal-scope2). London: National Institute for Health and Care
Excellence, 2014.

UptoDate. Use of vasopressors and inotropes (http://www.uptodate.com/contents/use-of-vasopressors-

and-inotropes). Alphen aan den Rijn (Holland): Wolters Kluwer; 2014.

Expert commentary

The important nding 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

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