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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.
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
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.
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