NIHR Signal An emergency department protocol to restore circulation doesn’t improve outcomes in septic shock

Published on 4 July 2017

A protocol called early goal-directed therapy (EGDT) begun in the emergency department, did not reduce mortality compared with usual care for people with septic shock. The six hour treatment protocol aims to restore circulation for people with septic shock based on treatments that progress in a structured sequence before admission to intensive care. The protocol requires early placement of a central venous catheter.

The study pooled data from 3,723 patients included in three international trials comparing the early protocol with usual care. Duration of stay intensive care was increased. The protocol was also more expensive to deliver than usual care, and was not found to be cost effective.

Separate analysis also showed it was no more effective for people with more severe shock, or in treatment centres with lower intensity usual care. 

Survival from sepsis has improved over the years since the first trial of EGDT in 2001 and international guidelines still recommend it as a universal approach. This may need to be revised in light of these findings and specific interventions d their timing unbundled so that each is tailored to the individual’s needs with current care pathways in sepsis taken into account.

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Why was this study needed?

When a severe infection (sepsis) damages the body’s own tissues, this can cause septic shock. This is where cell damage, acting through multiple pathways, causes blood pressure to drop dangerously low, potentially leading to multiple organ failure and death. In the UK there are around 200,000 cases of sepsis every year, and 20-50% of these people will die.

Most international guidelines recommend treating sepsis and septic shock in a structured way to reach key “goals”, such as blood pressure and blood oxygen targets. An early US trial in 2001 found that EGDT provided before admission to the intensive care unit reduced mortality compared with usual care.

Three subsequent large trials have had conflicting findings. This meta-analysis aimed to combine information from each individual patient in these studies to get a clearer indication of an effect and to look better for any differential effects between subgroups.  

What did this study do?

This meta-analysis combined data from 3,723 patients included in three large, randomised controlled trials – ARISE, ProCESS and ProMISe. The trials were carried out across 138 hospitals in Australia, Finland, Hong Kong, Ireland, New Zealand, US and England.

Patients with sepsis were randomised to receive either EGDT or usual care. EGDT is a six-hour resuscitation protocol where people were given intravenous fluids, vasopressors and inotropes (drugs to support and maintain circulation) and red blood cell transfusions to reach set targets for central venous pressure, blood pressure, central venous oxygen and haemoglobin level.

Outcomes were analysed by subgroup, such as severity of sepsis, other illnesses and time from hospital presentation to randomisation. However, despite pooling the three trials some patient groups were small which may limit the reliability of findings in the sub-analyses.    

What did it find?

  • EGDT had no effect on the main outcome of mortality after 90 days (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.82 to 1.14). In the EGDT group, 24.9% died (462/1,852) compared with 25.4% in the usual care group (475/1,871).
  • There was also no difference in the chance of people surviving to one year (hazard ratio [HR] 0.98, 95% CI 0.86 to 1.11), the number of people dying before hospital discharge or after 28 days.
  • People receiving EGDT stayed in intensive care for longer (mean 5.3 days vs. 4.9 days) and more people needed cardiovascular support and received this for longer (mean 1.9 vs. 1.6 days).
  • There was no difference in other outcomes including length of hospital stay, need for mechanical ventilation or treatment of kidney failure.
  • In subgroup analyses, only two of 16 patient factors had an influence: EGDT was associated with higher mortality in patients with chronic liver disease, and lower mortality in those with chronic respiratory disease. Severity of septic shock or differences in usual care practices between centres had no effect.
  • The cost of EGDT was higher than usual care. As there was no benefit in outcome, EGDT would not be a cost-effective use of NHS resources.

What does current guidance say on this issue?

The Surviving Sepsis Campaign’s international guidelines for management of sepsis and septic shock (2016) recommend use of early goal-directed therapy. Their recommendations cover fluid resuscitation within the first three hours and use of vasopressors where indicated to reach targets for blood pressure and normalise blood lactate (a marker of low tissue perfusion). These recommendations incorporate evidence where available, but are mainly based on expert consensus.

NICE 2016 guidelines on sepsis cover recognition, diagnosis and early management, and do not focus on management of septic shock.

What are the implications?

EGDT is more resource-intensive than usual care, and the combined data from these three large trials give evidence that the early standardised approach offers no clinical advantage over “usual care”. Usual care may include some of the interventions in the protocol but be more tailored to an individual’s need and responses and started before ITU admission. So it is still possible that a standardised protocol for sub groups might offer benefits.

International guidelines do recommend the early goal-directed therapy protocol.  It is likely that some aspects of EGDT are beneficial (and should be part of usual care) but it is unclear on the basis of current evidence which interventions to choose.

The authors suggest that there is still a lot to learn about how best to manage sepsis, but their findings suggest that the protocol as currently outlined may not offer clinical or economic value beyond current best practice.

Citation and Funding

PRISM Investigators, Rowan KM, Angus DC, et al. Early Goal-Directed Therapy for Septic Shock: A Patient-Level Meta-Analysis. N Engl J Med. 2017;376(23):2223-34.

This project was funded by the National Institute of General Medical Sciences, National Institutes of Health (P50 GM076659) (ProCESS trial); the National Health and Medical Research Council of Australia (491075 and 1021165), the Intensive Care Foundation, and the Alfred Foundation (ARISE trial); and the United Kingdom National Institute for Health Research Health Technology Assessment Programme (07/37/47) (ProMISe trial).

Bibliography

ARISE Investigators; ANZICS Clinical Trials Group, Peake SL et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-506.

Mouncey PR, Osborn TM, Power GS et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015;19(97):1-150.

Mouncey PR, Osborn TM, Power GS et al. Trial of early, goal-directed resuscitation for septic shock. New England Journal of Medicine. 2015 Apr 2;372(14):1301-11.

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. Septic shock. London: Department of Health; 2017.

NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; 2014.

ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;2014(370):1683-93.

Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.

Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Eng J Med. 2001;345(19): 1368-77.

Why was this study needed?

When a severe infection (sepsis) damages the body’s own tissues, this can cause septic shock. This is where cell damage, acting through multiple pathways, causes blood pressure to drop dangerously low, potentially leading to multiple organ failure and death. In the UK there are around 200,000 cases of sepsis every year, and 20-50% of these people will die.

Most international guidelines recommend treating sepsis and septic shock in a structured way to reach key “goals”, such as blood pressure and blood oxygen targets. An early US trial in 2001 found that EGDT provided before admission to the intensive care unit reduced mortality compared with usual care.

Three subsequent large trials have had conflicting findings. This meta-analysis aimed to combine information from each individual patient in these studies to get a clearer indication of an effect and to look better for any differential effects between subgroups.  

What did this study do?

This meta-analysis combined data from 3,723 patients included in three large, randomised controlled trials – ARISE, ProCESS and ProMISe. The trials were carried out across 138 hospitals in Australia, Finland, Hong Kong, Ireland, New Zealand, US and England.

Patients with sepsis were randomised to receive either EGDT or usual care. EGDT is a six-hour resuscitation protocol where people were given intravenous fluids, vasopressors and inotropes (drugs to support and maintain circulation) and red blood cell transfusions to reach set targets for central venous pressure, blood pressure, central venous oxygen and haemoglobin level.

Outcomes were analysed by subgroup, such as severity of sepsis, other illnesses and time from hospital presentation to randomisation. However, despite pooling the three trials some patient groups were small which may limit the reliability of findings in the sub-analyses.    

What did it find?

  • EGDT had no effect on the main outcome of mortality after 90 days (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.82 to 1.14). In the EGDT group, 24.9% died (462/1,852) compared with 25.4% in the usual care group (475/1,871).
  • There was also no difference in the chance of people surviving to one year (hazard ratio [HR] 0.98, 95% CI 0.86 to 1.11), the number of people dying before hospital discharge or after 28 days.
  • People receiving EGDT stayed in intensive care for longer (mean 5.3 days vs. 4.9 days) and more people needed cardiovascular support and received this for longer (mean 1.9 vs. 1.6 days).
  • There was no difference in other outcomes including length of hospital stay, need for mechanical ventilation or treatment of kidney failure.
  • In subgroup analyses, only two of 16 patient factors had an influence: EGDT was associated with higher mortality in patients with chronic liver disease, and lower mortality in those with chronic respiratory disease. Severity of septic shock or differences in usual care practices between centres had no effect.
  • The cost of EGDT was higher than usual care. As there was no benefit in outcome, EGDT would not be a cost-effective use of NHS resources.

What does current guidance say on this issue?

The Surviving Sepsis Campaign’s international guidelines for management of sepsis and septic shock (2016) recommend use of early goal-directed therapy. Their recommendations cover fluid resuscitation within the first three hours and use of vasopressors where indicated to reach targets for blood pressure and normalise blood lactate (a marker of low tissue perfusion). These recommendations incorporate evidence where available, but are mainly based on expert consensus.

NICE 2016 guidelines on sepsis cover recognition, diagnosis and early management, and do not focus on management of septic shock.

What are the implications?

EGDT is more resource-intensive than usual care, and the combined data from these three large trials give evidence that the early standardised approach offers no clinical advantage over “usual care”. Usual care may include some of the interventions in the protocol but be more tailored to an individual’s need and responses and started before ITU admission. So it is still possible that a standardised protocol for sub groups might offer benefits.

International guidelines do recommend the early goal-directed therapy protocol.  It is likely that some aspects of EGDT are beneficial (and should be part of usual care) but it is unclear on the basis of current evidence which interventions to choose.

The authors suggest that there is still a lot to learn about how best to manage sepsis, but their findings suggest that the protocol as currently outlined may not offer clinical or economic value beyond current best practice.

Citation and Funding

PRISM Investigators, Rowan KM, Angus DC, et al. Early Goal-Directed Therapy for Septic Shock: A Patient-Level Meta-Analysis. N Engl J Med. 2017;376(23):2223-34.

This project was funded by the National Institute of General Medical Sciences, National Institutes of Health (P50 GM076659) (ProCESS trial); the National Health and Medical Research Council of Australia (491075 and 1021165), the Intensive Care Foundation, and the Alfred Foundation (ARISE trial); and the United Kingdom National Institute for Health Research Health Technology Assessment Programme (07/37/47) (ProMISe trial).

Bibliography

ARISE Investigators; ANZICS Clinical Trials Group, Peake SL et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-506.

Mouncey PR, Osborn TM, Power GS et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015;19(97):1-150.

Mouncey PR, Osborn TM, Power GS et al. Trial of early, goal-directed resuscitation for septic shock. New England Journal of Medicine. 2015 Apr 2;372(14):1301-11.

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. Septic shock. London: Department of Health; 2017.

NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; 2014.

ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;2014(370):1683-93.

Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.

Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Eng J Med. 2001;345(19): 1368-77.

Early Goal-Directed Therapy for Septic Shock: A Patient-Level Meta-Analysis

Published on 21 March 2017

Rowan, R. Angus, D. Bailey, M. Barnato, A. Bellomo, R. Canter1, R. Coats, T. Delaney, A. Gimbel, E. Grieve, R. Harrison, D. Higgins, A. Howe, B. Huang, D. Kellum, J. Mouncey, P. Music, E. Peake, S. Pike, F. Reade, M. Sadique, Z. Singer, M. Yealy, D.

New England Journal of Medicine , 2017

BACKGROUND After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others

Early goal-directed therapy is a six-hour resuscitation protocol for the administration of:

  • intravenous fluids
  • vasopressors
  • inotropes and
  • red-cell transfusion

The protocol guides treatment to achieve pre-specified targets for arterial blood pressure, central venous pressure, central venous oxygen saturation, and haemoglobin level. Variations exist and are based on the original protocol described in a US based trial by Rivers in 2001.

Expert commentary

Pragmatic clinical trials seeking to establish the best evidence for interventions in patients with sepsis can be plagued with adequacy of sample size and heterogeneity leading to uncertainties about treatment effects. Organised international collaboration provides an opportunity to improve statistical power and explore heterogeneity.

The PRISM investigators provide an excellent example of how three different clinical trials in early goal-directed resuscitation for sepsis were planned in advance to allow individual patient data meta-analysis of treatment effects, including sub-groups relevant to evidence gaps in clinical practice.

The results show, with much greater confidence than any of the trials alone, that early goal-directed resuscitation for sepsis does not produce better outcomes and it is associated with higher costs. In addition, valuable lessons were learned about pre-trial collaboration, data sharing and data integration that are leading to closer international collaborations for future trials.

Professor Paul Dark, Chair of Critical Care Medicine, University Hospital of South Manchester

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