NIHR DC Discover

NIHR Signal Corticosteroids could help reduce deaths due to blood poisoning

Published on 23 March 2016

doi: 10.3310/signal-000214

Treatment with low dose corticosteroids given over three or more days reduces the death rate from blood poisoning by 13%, saving about 43 lives per 1000 treated at one month. Blood sugar and sodium levels rose slightly but there was no increased risk of gastrointestinal bleeding or additional infection.

Current international guidance from 2012 only recommends using corticosteroids as an add-on therapy for people with blood poisoning whose circulation has not been restored by adequate fluid replacement and vasopressors. This review lends some weight to the case for using corticosteroids more widely for sepsis, but is not definitive. This uncertainty is due to inconsistency in results, with some trials finding no difference in mortality. There were also variations in the study populations and comparative treatments given in the included trials, which means it is not yet completely clear who should be offered steroids.

The results of this updated Cochrane review and other trials in progress will help inform new national guidance from NICE which is due to be published in July 2016.

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Why was this study needed?

Blood poisoning, known as sepsis, can strike young, previously healthy people as well as sick and older people. In the UK, more than 100,000 people are admitted to hospital with sepsis each year, of whom over a third die from the condition. At an approximate cost of £25,000 per admission, the total direct costs of these periods of hospital treatment has been estimated at £2.5 billion.  UK audits show that deaths from sepsis have reduced in some hospitals, but more remains to be done on a national scale.

Corticosteroid drugs have been used for decades to help treat sepsis. However, more evidence was needed on the indications to start corticosteroids and the most effective dose and treatment duration to adopt.

What did this study do?

This study updated a 2010 Cochrane review with an additional nine trials. This brought the number of trials in the review to 33 (of which three were in children), including 4,268 participants.

The review studied the impact of corticosteroid treatment on sepsis death rate at one month, and side effects of corticosteroids compared with placebo treatment or supportive care (such as receiving fluids via a drip). The review also compared the results of trials using different doses and duration of corticosteroid drugs.

This systematic review was rigorously carried out using the same approach as the Cochrane review it aimed to update. Though the majority of the underlying trials had low risk of bias, the body of evidence was judged to be of low to moderate quality due to variation in the treatments used, and in the trials’ design and their findings. This limits our confidence in the findings and the ability to apply them. The interventions and setting of the research were relevant to UK practice.

What did it find?

When compared with placebo or supportive care only:

  • Overall, there was evidence that corticosteroid use reduced mortality from 318 per 1000 in the control group to 275 per 1000 in the treatment arm, saving about 43 lives. This translates into a reduction in deaths of 13% at 28 days (risk ratio [RR] 0.87, 95% confidence interval [CI] 0.76 to 1.00, pooled from 27 trials).
  • Treatment using less than 400mg hydrocortisone per day, and lasting at least three days (called ‘low dose’ and ‘long course’ in this review) reduced mortality by 13% according to moderate levels of evidence (RR 0.87, 95% CI 0.78 to 0.97, pooled from 22 trials). In contrast, treatment with higher doses for shorter durations did not reduce mortality rate.
  • Corticosteroid use did not increase the risk of gastrointestinal bleeding (RR 1.24, 95% CI 0.92 to 1.67, pooled from 19 trials) or superinfection (RR 1.02, 95% CI 0.87 to 1.20, pooled from 19 trials).
  • Use of corticosteroid increased the risk of raised blood sugar by 26% (RR 1.26, 95% CI 1.16 to 1.37, pooled from 13 trials) and high sodium levels by 64% (RR 1.64, 95% CI 1.28 to 2.09, pooled from three trials).

What does current guidance say on this issue?

International ‘Surviving Sepsis’ guidance from 2012 recommends corticosteroids as an additional treatment option for people whose circulation has not improved with vasopressor drugs. The suggested dose is 200mg hydrocortisone per day, which is within the range of optimal dosage in this review. The guidance advises against giving corticosteroids to other adult patients with sepsis. This guidance is under review for possible update in 2016.

This is the most informative guidance at present. Corticosteroid treatment for people with sepsis is not mentioned in the 2013 standards for emergency care published by the College of Emergency Medicine. A NICE guideline on sepsis is due to be published in July 2016.

What are the implications?

Corticosteroid treatment is relatively cheap, so could help reduce death rates from sepsis at modest cost. At the moment, national guidance offers it as an option for treating selected patients only – when treatment with adequate fluid replacement and vasopressor drugs has not restored blood circulation.

The review’s findings were consistent with an earlier Cochrane systematic review, but strengthened the evidence by including nine additional trials.  However, evidence is still lacking on the best approach to providing corticosteroid treatment (e.g. continuous infusion versus interrupted treatment, the best dose to use and duration) and whether the treatment is helpful for children, or in people who have sepsis but not shock. Therefore the expert views available in a guideline development panel will be required to make strong recommendations and standardise practice. A large multicentre trial currently underway in Australia should provide further answers in the next few years.

Citation and Funding

Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis. Cochrane Database Syst Rev. 2015;(12):CD002243.

Sources of support for this study:
Internal sources: Hopital Raymond Poincaré, Garches, France.
External sources: Department for International Development, UK.

Bibliography

The College of Emergency Medicine. Standards for severe sepsis and septic shock management in adults (revised 2012) The College of Emergency Medicine; 2013.

Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013; 39(2):165-228.

Extract: Surviving Sepsis Campaign. Haemodyndamic support table. Surviving Sepsis Campaign; 2012.

ICNARC. Sepsis: our national analyses [internet]. London: Intensive Care National Audit and Research Centre; 2014.

NHS Choices. Sepsis [internet]. Leeds: NHS Choices; 2014.

NICE. Sepsis (clinical guideline in development). National Institute for Health and Care Excellence; due to publish in July 2016.

Richards, M. Sepsis management as an NHS clinical priority. Briefing. Sutton Coldfield: The Sepsis Trust; 2013.

The Sepsis Trust. www.sepsistrust.org [internet]. Sutton Coldfield: The Sepsis Trust; 2015.

Venkatesh B, Myburgh J, Finfer S, et al. The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock. Crit Care Resusc. 2013;15(2):83-8.

Why was this study needed?

Blood poisoning, known as sepsis, can strike young, previously healthy people as well as sick and older people. In the UK, more than 100,000 people are admitted to hospital with sepsis each year, of whom over a third die from the condition. At an approximate cost of £25,000 per admission, the total direct costs of these periods of hospital treatment has been estimated at £2.5 billion.  UK audits show that deaths from sepsis have reduced in some hospitals, but more remains to be done on a national scale.

Corticosteroid drugs have been used for decades to help treat sepsis. However, more evidence was needed on the indications to start corticosteroids and the most effective dose and treatment duration to adopt.

What did this study do?

This study updated a 2010 Cochrane review with an additional nine trials. This brought the number of trials in the review to 33 (of which three were in children), including 4,268 participants.

The review studied the impact of corticosteroid treatment on sepsis death rate at one month, and side effects of corticosteroids compared with placebo treatment or supportive care (such as receiving fluids via a drip). The review also compared the results of trials using different doses and duration of corticosteroid drugs.

This systematic review was rigorously carried out using the same approach as the Cochrane review it aimed to update. Though the majority of the underlying trials had low risk of bias, the body of evidence was judged to be of low to moderate quality due to variation in the treatments used, and in the trials’ design and their findings. This limits our confidence in the findings and the ability to apply them. The interventions and setting of the research were relevant to UK practice.

What did it find?

When compared with placebo or supportive care only:

  • Overall, there was evidence that corticosteroid use reduced mortality from 318 per 1000 in the control group to 275 per 1000 in the treatment arm, saving about 43 lives. This translates into a reduction in deaths of 13% at 28 days (risk ratio [RR] 0.87, 95% confidence interval [CI] 0.76 to 1.00, pooled from 27 trials).
  • Treatment using less than 400mg hydrocortisone per day, and lasting at least three days (called ‘low dose’ and ‘long course’ in this review) reduced mortality by 13% according to moderate levels of evidence (RR 0.87, 95% CI 0.78 to 0.97, pooled from 22 trials). In contrast, treatment with higher doses for shorter durations did not reduce mortality rate.
  • Corticosteroid use did not increase the risk of gastrointestinal bleeding (RR 1.24, 95% CI 0.92 to 1.67, pooled from 19 trials) or superinfection (RR 1.02, 95% CI 0.87 to 1.20, pooled from 19 trials).
  • Use of corticosteroid increased the risk of raised blood sugar by 26% (RR 1.26, 95% CI 1.16 to 1.37, pooled from 13 trials) and high sodium levels by 64% (RR 1.64, 95% CI 1.28 to 2.09, pooled from three trials).

What does current guidance say on this issue?

International ‘Surviving Sepsis’ guidance from 2012 recommends corticosteroids as an additional treatment option for people whose circulation has not improved with vasopressor drugs. The suggested dose is 200mg hydrocortisone per day, which is within the range of optimal dosage in this review. The guidance advises against giving corticosteroids to other adult patients with sepsis. This guidance is under review for possible update in 2016.

This is the most informative guidance at present. Corticosteroid treatment for people with sepsis is not mentioned in the 2013 standards for emergency care published by the College of Emergency Medicine. A NICE guideline on sepsis is due to be published in July 2016.

What are the implications?

Corticosteroid treatment is relatively cheap, so could help reduce death rates from sepsis at modest cost. At the moment, national guidance offers it as an option for treating selected patients only – when treatment with adequate fluid replacement and vasopressor drugs has not restored blood circulation.

The review’s findings were consistent with an earlier Cochrane systematic review, but strengthened the evidence by including nine additional trials.  However, evidence is still lacking on the best approach to providing corticosteroid treatment (e.g. continuous infusion versus interrupted treatment, the best dose to use and duration) and whether the treatment is helpful for children, or in people who have sepsis but not shock. Therefore the expert views available in a guideline development panel will be required to make strong recommendations and standardise practice. A large multicentre trial currently underway in Australia should provide further answers in the next few years.

Citation and Funding

Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis. Cochrane Database Syst Rev. 2015;(12):CD002243.

Sources of support for this study:
Internal sources: Hopital Raymond Poincaré, Garches, France.
External sources: Department for International Development, UK.

Bibliography

The College of Emergency Medicine. Standards for severe sepsis and septic shock management in adults (revised 2012) The College of Emergency Medicine; 2013.

Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013; 39(2):165-228.

Extract: Surviving Sepsis Campaign. Haemodyndamic support table. Surviving Sepsis Campaign; 2012.

ICNARC. Sepsis: our national analyses [internet]. London: Intensive Care National Audit and Research Centre; 2014.

NHS Choices. Sepsis [internet]. Leeds: NHS Choices; 2014.

NICE. Sepsis (clinical guideline in development). National Institute for Health and Care Excellence; due to publish in July 2016.

Richards, M. Sepsis management as an NHS clinical priority. Briefing. Sutton Coldfield: The Sepsis Trust; 2013.

The Sepsis Trust. www.sepsistrust.org [internet]. Sutton Coldfield: The Sepsis Trust; 2015.

Venkatesh B, Myburgh J, Finfer S, et al. The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock. Crit Care Resusc. 2013;15(2):83-8.

Corticosteroids for treating sepsis

Published on 4 December 2015

Annane, D.,Bellissant, E.,Bollaert, P. E.,Briegel, J.,Keh, D.,Kupfer, Y.

Cochrane Database Syst Rev Volume 12 , 2015

BACKGROUND: Sepsis occurs when an infection is complicated by organ failures as defined by a sequential organ failure assessment (SOFA) score of two or higher. Sepsis may be complicated by impaired corticosteroid metabolism. Giving corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and again in 2015. OBJECTIVES: To examine the effects of corticosteroids on death at one month in patients with sepsis, and to examine whether dose and duration of corticosteroids influence patient response to this treatment. SEARCH METHODS: We searched the Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (October 2014), EMBASE (October 2014), Latin American Caribbean Health Sciences Literature (LILACS; October 2014) and reference lists of articles, and we contacted trial authors. The original searches were performed in August 2003 and in October 2009. SELECTION CRITERIA: We included randomized controlled trials of corticosteroids versus placebo or supportive treatment in patients with sepsis. DATA COLLECTION AND ANALYSIS: All review authors agreed on the eligibility of trials. One review author extracted data, which were checked by the other review authors, and by the primary author of the paper when possible. We obtained some missing data from trial authors. We assessed the methodological quality of trials. MAIN RESULTS: We identified nine additional studies since the last update, for a total of 33 eligible trials (n = 4268 participants). Twenty-three of these 33 trials were at low risk of selection bias, 22 were at low risk of performance and detection bias, 27 were at low risk of attrition bias and 14 were at low risk of selective reporting.Corticosteroids reduced 28-day mortality (27 trials; n = 3176; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 1.00; P value = 0.05, random-effects model). The quality of evidence for this outcome was downgraded from high to low for imprecision (upper limit of 95% CI = 1) and for inconsistency (significant heterogeneity across trial results). Heterogeneity was related in part to the dosing strategy. Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (22 trials; RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01, fixed-effect model). The quality of evidence was downgraded from high to moderate for inconsistency (owing to non-significant effects shown by one large trial). Corticosteroids also reduced mortality rate in the intensive care unit (13 trials; RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04, random-effects model) and at the hospital (17 trials; RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03, random-effects model). Quality of the evidence for in-hospital mortality was downgraded from high to moderate for inconsistency and imprecision (upper limit of 95% CI for RR approaching 1). Corticosteroids increased the proportion of shock reversal by day seven (12 trials; RR 1.31, 95% CI 1.14 to 1.51; P value = 0.0001) and by day 28 (seven trials; n = 1013; RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) and reduced the SOFA score by day seven (eight trials; mean difference (MD) -1.53, 95% CI -2.04 to -1.03; P value < 0.00001, random-effects model) and survivors' length of stay in the intensive care unit (10 trials; MD -2.19, 95% CI -3.93 to -0.46; P value = 0.01, fixed-effect model) without inducing gastroduodenal bleeding (19 trials; RR 1.24, 95% CI 0. 92 to 1.67; P value = 0.15, fixed-effect model), superinfection (19 trials; RR 1.02, 95% CI 0.87 to 1.20; P value = 0.81, fixed-effect model) or neuromuscular weakness (three trials; RR 0.62, 95% CI 0.21 to 1.88; P value = 0.40, fixed-effect model). Corticosteroid increased the risk of hyperglycaemia (13 trials; RR 1.26, 95% CI 1.16 to 1.37; P value < 0.00001, fixed-effect model) and hypernatraemia (three trials; RR 1.64, 95% CI 1.28 to 2.09; P value < 0.0001, fixed-effect model). AUTHORS' CONCLUSIONS: Overall, low-quality evidence indicates that corticosteroids reduce mortality among patients with sepsis. Moderate-quality evidence suggests that a long course of low-dose corticosteroids reduced 28-day mortality without inducing major complications and led to an increase in metabolic disorders.

Sepsis is a potentially life-threatening condition which is triggered by infection. The body’s immune system response can cause widespread inflammation and loss of circulation.

“Septic shock” occurs when the heart and circulation fail to supply enough oxygenated blood to meet the needs of the vital organs and the rest of the body.

Expert commentary

The primary treatments for severe sepsis are antibiotics, intravenous fluids, vasopressor drugs and control of infection source. Second-line treatment with corticosteroids is very variable. They are sometimes used to improve the effect of vasopressor drugs. There is equipoise around whether corticosteroids improve short-term survival and whether any benefit is limited to patients with reduced adrenal function. The large Australian ADRENAL study will recruit as many patients as this review examines and will provide the definitive answer about effects on mortality

Duncan Young, Professor of Intensive Care Medicine, University of Oxford