NIHR DC Discover

NIHR Signal A focus on treating fever does not improve survival in sepsis

Published on 27 June 2017

doi: 10.3310/signal-000432

Specifically treating fever in adults with sepsis did not reduce the number of people dying within 28 days. It also had no effect on the frequency of hospital-acquired infections, reversing septic shock, lowering heart rate or improving breathing. Sepsis is a rare complication of an infection. Among the 123,000 people a year in England who develop sepsis around 30% will die from it, so improving our understanding of how to treat sepsis is clearly important.

Early treatment of sepsis is important for a number of reasons, but the findings of this review imply that it is not necessary to specifically treat fever. We don’t know whether there might be benefits for people with very high temperatures.

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Why was this study needed?

Sepsis is a complication of an infection, it is rare but is serious and can lead to organ failure and even death if it is not identified and treated promptly. Around 123,000 people a year develop sepsis in England, but it is often diagnosed late and can progress very swiftly. Many require treatment in hospital, often in intensive care, and around 37,000 people die from sepsis every year.

Both high body temperature (fever) and low body temperature may be signs of sepsis. The fever associated with sepsis is sometimes treated using drugs or other treatments such as physical cooling.

The role of fever in sepsis is poorly understood and it is unclear whether fever is beneficial or harmful. Therefore there is uncertainty about whether or not to treat fever.

What did this study do?

This systematic review and meta-analysis included eight randomised controlled trials of 1,507 adults and eight observational studies of 17,432 adults.  Most studies were from the US, none from the UK.

Treatments for fever were paracetamol, nonsteroidal anti-inflammatory drugs such as ibuprofen, and physical cooling. It was not clear what doses of the drugs were given, the precise physical cooling methods used or the duration of treatment.

The randomised trials were mostly at low risk of bias, though most were small studies apart from the HEAT trial from New Zealand.  Almost all (99%) of the data for the meta-analysis of observational data on 14 day mortality came from a single large case-control study which may have had selection bias meaning that it is less reliable.

What did it find?

  • Treating fever did not reduce the number of people dying within 28 days according to the randomised controlled trials (relative risk [RR] 0.93, 95% confidence interval [CI] 0.77 to 1.13) or the observational studies (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.54 to 1.51).
  • Findings for death within 14 days in the intensive care unit (ICU) were mixed, with randomised trials showing a significant reduction (RR 0.68, 95% CI 0.49 to 0.92), but observational studies suggesting a significant increase (OR 1.35, 95% CI 1.15 to 1.59). The observational data were from 2 studies, one a large case-control study with significant differences in age and severity scores, suggesting these are less reliable data.
  • Body temperature was significantly reduced following fever treatment (RR ‑0.38, 95% CI ‑0.63 to ‑0.13) based on randomised trials.
  • Treating fever did not reduce the frequency of hospital-acquired infections, orimprove the number of people who recovered from septic shock.
  • Fever treatment had no effect on heart rate or a measure of lung function and breathing rate called minute ventilation.

What does current guidance say on this issue?

NICE guidance from 2016 does not make any recommendations about whether or not to reduce fever during sepsis. They do say that sepsis should not be ruled in or out based on fever or hypothermia alone.

What are the implications?

The evidence for early death within 14 days was mixed, with randomised controlled trials indicating a reduced risk and observational studies suggesting an increased risk. The largest observational study was at risk of bias and the researchers say that this early outcome is of questionable importance and should not influence clinical practice.

A recent survey of 139 Intensive Care Units in 23 countries found that most controlled fever with paracetamol. This review suggests that contrary to current practice, it is not necessary to specifically treat fever in people with sepsis.

It is not known if people with higher temperatures might benefit from treatment of fever. The randomised trials used a cut-off of between 38.0°C to 38.4°C while the observational studies ranged between 37.3°C to 39.5°C.

Citation and Funding

Drewry AM, Ablordeppey EA, Murray ET, et al. Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2017;45(5):806-13.

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; 2015.

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.

Niven DJ, Laupland KB, Tabah A, et al. Diagnosis and management of temperature abnormality in ICUs: a EUROBACT investigators’ survey. Critical Care. 2013.17:R289.

Why was this study needed?

Sepsis is a complication of an infection, it is rare but is serious and can lead to organ failure and even death if it is not identified and treated promptly. Around 123,000 people a year develop sepsis in England, but it is often diagnosed late and can progress very swiftly. Many require treatment in hospital, often in intensive care, and around 37,000 people die from sepsis every year.

Both high body temperature (fever) and low body temperature may be signs of sepsis. The fever associated with sepsis is sometimes treated using drugs or other treatments such as physical cooling.

The role of fever in sepsis is poorly understood and it is unclear whether fever is beneficial or harmful. Therefore there is uncertainty about whether or not to treat fever.

What did this study do?

This systematic review and meta-analysis included eight randomised controlled trials of 1,507 adults and eight observational studies of 17,432 adults.  Most studies were from the US, none from the UK.

Treatments for fever were paracetamol, nonsteroidal anti-inflammatory drugs such as ibuprofen, and physical cooling. It was not clear what doses of the drugs were given, the precise physical cooling methods used or the duration of treatment.

The randomised trials were mostly at low risk of bias, though most were small studies apart from the HEAT trial from New Zealand.  Almost all (99%) of the data for the meta-analysis of observational data on 14 day mortality came from a single large case-control study which may have had selection bias meaning that it is less reliable.

What did it find?

  • Treating fever did not reduce the number of people dying within 28 days according to the randomised controlled trials (relative risk [RR] 0.93, 95% confidence interval [CI] 0.77 to 1.13) or the observational studies (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.54 to 1.51).
  • Findings for death within 14 days in the intensive care unit (ICU) were mixed, with randomised trials showing a significant reduction (RR 0.68, 95% CI 0.49 to 0.92), but observational studies suggesting a significant increase (OR 1.35, 95% CI 1.15 to 1.59). The observational data were from 2 studies, one a large case-control study with significant differences in age and severity scores, suggesting these are less reliable data.
  • Body temperature was significantly reduced following fever treatment (RR ‑0.38, 95% CI ‑0.63 to ‑0.13) based on randomised trials.
  • Treating fever did not reduce the frequency of hospital-acquired infections, orimprove the number of people who recovered from septic shock.
  • Fever treatment had no effect on heart rate or a measure of lung function and breathing rate called minute ventilation.

What does current guidance say on this issue?

NICE guidance from 2016 does not make any recommendations about whether or not to reduce fever during sepsis. They do say that sepsis should not be ruled in or out based on fever or hypothermia alone.

What are the implications?

The evidence for early death within 14 days was mixed, with randomised controlled trials indicating a reduced risk and observational studies suggesting an increased risk. The largest observational study was at risk of bias and the researchers say that this early outcome is of questionable importance and should not influence clinical practice.

A recent survey of 139 Intensive Care Units in 23 countries found that most controlled fever with paracetamol. This review suggests that contrary to current practice, it is not necessary to specifically treat fever in people with sepsis.

It is not known if people with higher temperatures might benefit from treatment of fever. The randomised trials used a cut-off of between 38.0°C to 38.4°C while the observational studies ranged between 37.3°C to 39.5°C.

Citation and Funding

Drewry AM, Ablordeppey EA, Murray ET, et al. Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2017;45(5):806-13.

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; 2015.

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.

Niven DJ, Laupland KB, Tabah A, et al. Diagnosis and management of temperature abnormality in ICUs: a EUROBACT investigators’ survey. Critical Care. 2013.17:R289.

Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis

Published on 22 February 2017

Drewry, A. M.,Ablordeppey, E. A.,Murray, E. T.,Stoll, C. R.,Izadi, S. R.,Dalton, C. M.,Hardi, A. C.,Fowler, S. A.,Fuller, B. M.,Colditz, G. A.

Crit Care Med , 2017

OBJECTIVE: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults. DATA SOURCES: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016. STUDY SELECTION: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers. DATA EXTRACTION: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately. DATA SYNTHESIS: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38 degrees C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation. CONCLUSIONS: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Expert commentary

Fever is common in critically ill patients with sepsis. Use of antipyretic medications to control fever in these patients are also common. However, as fever is body’s response to infection, there is uncertainty around should we control fever in sepsis and what benefit will patients get from fever control? The available evidence to date suggests that fever in sepsis patients does not increase the risk of adverse outcomes and controlling fever does not reduce the risk of adverse outcomes. Maybe, we are yet to select those sepsis patients who are likely to benefit the most from controlling fever.

Dr Manu Shankar-Hari, Consultant, Intensive Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust; Clinician Scientist, National Institute for Health Research