NIHR Signal Giving immediate antibiotics reduces deaths from sepsis

Published on 18 April 2017

Giving immediate antibiotics (defined as within one hour) when people present to emergency departments with suspected sepsis reduces their risk of dying by a third compared with later administration.

This meta-analysis of observational data from 23,596 people in emergency department settings confirmed that giving antibiotics within one hour was linked to a lower risk of in-hospital mortality compared with giving antibiotics later.

This adds weight to recommendations from NICE and other organisations that antibiotics should be administered straight away in people with suspected sepsis. However, in practice up to a third of people in the UK do not receive antibiotics within the hour.

NHS England and the UK Sepsis Trust have recently launched a campaign to encourage all healthcare professionals to act quickly when they recognise sepsis.  

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Why was this study needed?

Sepsis is a life-threatening complication of infection involving response of the body's inflammatory and coagulation systems. Sepsis can lead to shock, with low blood pressure, multiple organ failure and death.

In the UK, an estimated 37,000 people die from sepsis each year. However, three-quarters of people with sepsis will survive if it is recognised and treated promptly.

Guidelines recommend giving antibiotics within the first hour of sepsis diagnosis, based on observational evidence that each hour’s delay increases mortality risk.

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reports that only two-thirds of people with sepsis in the UK receive antibiotics within one hour, which is thought to affect the outcome in 44% of people.

This systematic review of mainly observational studies aimed to gather the evidence to see if a delay in receiving antibiotics was associated with an increase in deaths.

What did this study do?

The systematic review identified 10 studies including 23,596 people admitted to emergency departments with sepsis. Studies compared in-hospital mortality when antibiotics were administered within one hour compared with after one hour.

One study was a randomised controlled trial, the others were observational. Five studies were conducted in the US, one in Europe, and the others in The Netherlands, Australia, Iran and Korea. They were rated mostly moderate to high quality on a score developed by the NHMRC, an Australian research funder. The results of most observational studies were adjusted for confounders, such as age, that could also have influenced the results. 

Studies varied in how they defined the starting point from which time to administration of antibiotics was measured (for example, some used arrival in the emergency department, others used detection of sepsis). How they diagnosed sepsis and assessed suitability of antibiotics also differed. Nevertheless the studies were sufficiently similar for their data to be pooled.

What did it find?

  • The 10 studies reported in-hospital mortality of between 4% and 34% for people who received antibiotics within one hour compared with 19 to 43% for people administered antibiotics later (ranging from above one to above six hours).
  • When the studies were pooled, giving antibiotics within one hour reduced mortality risk by 33% compared with giving antibiotics later (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.59 to 0.75).
  • Two studies contributed 74% of the data in the pooled analysis, but the results didn’t change when these two studies were removed (OR 0.70, 95% CI 0.57 to 0.87).
  • When the studies were considered individually, five of the 10 did not show a significant effect of the timing of antibiotic administration on in-hospital mortality.
  • The authors raised the possibility of publication bias, favouring studies with positive outcomes from earlier treatment, though this is unlikely to explain the benefit.

What does current guidance say on this issue?

The 2016 NICE guideline on sepsis recommends that adults in acute hospital settings who have suspected sepsis and one or more high risk criteria (for example, systolic blood pressure 90 mmHg or less, heart rate above 130 beats per minute) should be treated with a broad-spectrum antimicrobial at the maximum recommended dose without delay (within one hour).

The Surviving Sepsis Campaign’s international guidelines for management of severe sepsis and septic shock (2016) recommend that intravenous administration of antimicrobials should be initiated as soon as possible after recognition and within one hour. Empiric broad-spectrum therapy with one or more antimicrobials should be used.

What are the implications?

Many people with sepsis do not receive antibiotics within one hour. This analysis adds weight to guideline recommendations that broad-spectrum antimicrobials should be given immediately, because delay could compromise survival.

Various factors could influence time to antibiotics, such as diagnostic uncertainty, whether pre-hospital treatment is given, and in-hospital delays between prescription and delivery of antibiotics.

NHS England and the UK Sepsis Trust have recently launched a campaign to encourage all healthcare professionals to act quickly when they recognise sepsis. New technologies, such as rapid bed-side tests, could help to ensure that the antibiotics given are appropriately for the infection. Emergency departments may need to review their triage systems that prioritise patients suspected of sepsis.

Citation and Funding

Johnston AN, Park J, Doi SA, et al. Effect of immediate administration of antibiotics in patients with sepsis in tertiary care: a systematic review and meta-analysis. Clin Ther 2017;39(1):190-202.e6.

No funding information was provided for this study.

Bibliography

NCEPOD. Just say sepsis! A review of the process of care received by patients with sepsis. London: National Confidential Enquiry into Patient Outcome and Death; 2005.

NHS Choices. Sepsis. London: Department of Health; 2016.

NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; 2016.

Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock. Crit Care Med. 2016. [Epub ahead of print].

Why was this study needed?

Sepsis is a life-threatening complication of infection involving response of the body's inflammatory and coagulation systems. Sepsis can lead to shock, with low blood pressure, multiple organ failure and death.

In the UK, an estimated 37,000 people die from sepsis each year. However, three-quarters of people with sepsis will survive if it is recognised and treated promptly.

Guidelines recommend giving antibiotics within the first hour of sepsis diagnosis, based on observational evidence that each hour’s delay increases mortality risk.

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reports that only two-thirds of people with sepsis in the UK receive antibiotics within one hour, which is thought to affect the outcome in 44% of people.

This systematic review of mainly observational studies aimed to gather the evidence to see if a delay in receiving antibiotics was associated with an increase in deaths.

What did this study do?

The systematic review identified 10 studies including 23,596 people admitted to emergency departments with sepsis. Studies compared in-hospital mortality when antibiotics were administered within one hour compared with after one hour.

One study was a randomised controlled trial, the others were observational. Five studies were conducted in the US, one in Europe, and the others in The Netherlands, Australia, Iran and Korea. They were rated mostly moderate to high quality on a score developed by the NHMRC, an Australian research funder. The results of most observational studies were adjusted for confounders, such as age, that could also have influenced the results. 

Studies varied in how they defined the starting point from which time to administration of antibiotics was measured (for example, some used arrival in the emergency department, others used detection of sepsis). How they diagnosed sepsis and assessed suitability of antibiotics also differed. Nevertheless the studies were sufficiently similar for their data to be pooled.

What did it find?

  • The 10 studies reported in-hospital mortality of between 4% and 34% for people who received antibiotics within one hour compared with 19 to 43% for people administered antibiotics later (ranging from above one to above six hours).
  • When the studies were pooled, giving antibiotics within one hour reduced mortality risk by 33% compared with giving antibiotics later (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.59 to 0.75).
  • Two studies contributed 74% of the data in the pooled analysis, but the results didn’t change when these two studies were removed (OR 0.70, 95% CI 0.57 to 0.87).
  • When the studies were considered individually, five of the 10 did not show a significant effect of the timing of antibiotic administration on in-hospital mortality.
  • The authors raised the possibility of publication bias, favouring studies with positive outcomes from earlier treatment, though this is unlikely to explain the benefit.

What does current guidance say on this issue?

The 2016 NICE guideline on sepsis recommends that adults in acute hospital settings who have suspected sepsis and one or more high risk criteria (for example, systolic blood pressure 90 mmHg or less, heart rate above 130 beats per minute) should be treated with a broad-spectrum antimicrobial at the maximum recommended dose without delay (within one hour).

The Surviving Sepsis Campaign’s international guidelines for management of severe sepsis and septic shock (2016) recommend that intravenous administration of antimicrobials should be initiated as soon as possible after recognition and within one hour. Empiric broad-spectrum therapy with one or more antimicrobials should be used.

What are the implications?

Many people with sepsis do not receive antibiotics within one hour. This analysis adds weight to guideline recommendations that broad-spectrum antimicrobials should be given immediately, because delay could compromise survival.

Various factors could influence time to antibiotics, such as diagnostic uncertainty, whether pre-hospital treatment is given, and in-hospital delays between prescription and delivery of antibiotics.

NHS England and the UK Sepsis Trust have recently launched a campaign to encourage all healthcare professionals to act quickly when they recognise sepsis. New technologies, such as rapid bed-side tests, could help to ensure that the antibiotics given are appropriately for the infection. Emergency departments may need to review their triage systems that prioritise patients suspected of sepsis.

Citation and Funding

Johnston AN, Park J, Doi SA, et al. Effect of immediate administration of antibiotics in patients with sepsis in tertiary care: a systematic review and meta-analysis. Clin Ther 2017;39(1):190-202.e6.

No funding information was provided for this study.

Bibliography

NCEPOD. Just say sepsis! A review of the process of care received by patients with sepsis. London: National Confidential Enquiry into Patient Outcome and Death; 2005.

NHS Choices. Sepsis. London: Department of Health; 2016.

NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; 2016.

Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock. Crit Care Med. 2016. [Epub ahead of print].

Effect of Immediate Administration of Antibiotics in Patients With Sepsis in Tertiary Care: A Systematic Review and Meta-analysis

Published on 8 January 2017

Johnston, A. N.,Park, J.,Doi, S. A.,Sharman, V.,Clark, J.,Robinson, J.,Crilly, J.

Clin Ther , 2017

PURPOSE: The goal of this review was to synthesize existing evidence regarding outcomes (mortality) for patients who present to the emergency department, are administered antibiotics immediately (within 1 hour) or later (>1 hour), and are diagnosed with sepsis. METHODS: A search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL, using the MeSH descriptors "sepsis," "systemic inflammatory response syndrome," "mortality," "emergency," and "antibiotics," was performed to identify studies reporting time to antibiotic administration and mortality outcome in patients with sepsis. The included studies (published in English between 1990 and 2016) listed patient mortality based on time to antibiotic administration. Studies were evaluated for methodologic quality, and data were extracted by using a data extraction form tailored to this study. From an initial pool of 582 potentially relevant studies, 11 studies met our inclusion criteria, 10 of which had quantitative data for meta-analysis. Three different models (a random effects model, a bias-adjusted quality-effects [synthetic bias] model, and an inverse variance heterogeneity model) were used to perform the meta-analysis. FINDINGS: The pooled results suggest a significant 33% reduction in mortality odds for immediate (within 1 hour) compared with later (>1 hour) antibiotic administration (OR, 0.67 [95% CI, 0.59-0.75]) in patients with sepsis. IMPLICATIONS: Immediate antibiotic administration (<1 hour) seemed to reduce patient mortality. There was some minor negative asymmetry suggesting that the evidence may be biased toward the direction of effect. Nevertheless, this study provides strong evidence for early, comprehensive, sepsis management in the emergency department.

Expert commentary

In patients who become severely ill with overwhelming infection it is important to prescribe antibiotics as part of the treatment package. When patients present with severe infections to the emergency department it is important to know which treatments to prioritise, to improve the chances of their survival. It is helpful to know that prioritising the administration of antibiotics within one hour of arriving at the emergency department in a patient with severe infection will lead to improved survival. However, we do not know if this will lead to risks associated with over-treating those patients who subsequently are not found to have severe infection?

Suzanne Mason, Professor of Emergency Medicine, University of Sheffield