This NIHR funded randomised controlled trial found that early goal-directed therapy for people with septic shock offered no benefit over usual resuscitation care. About three in ten people died in both groups. Early goal-directed therapy differed from routine care in that it involved rigorous monitoring with use of a central venous “oximetry” catheter to manage blood pressure and blood oxygen during the first six hours of care. It was consequently more expensive than usual care, on average by about £1,000.
This is the final of a trio of international co-ordinated trials looking at early goal-directed therapy. All three individual trials, in USA, Australasia and England, found that it offered no benefit over usual care. Pooling of the individual data will allow further analysis to see whether the therapy is helpful for certain populations or settings.
Why was this study needed?
Septic shock is when blood pressure drops to a dangerously low level as a result of infection that has got into the bloodstream. It is life-threatening – mortality rates vary between 40 to 60%. It is estimated that there are between about 50 and 100 cases of severe sepsis or septic shock per 100,000 people per year.
Early goal-directed therapy (EGDT) is a resuscitation protocol where the person’s arterial and venous blood pressures and oxygen levels are continuously monitored during the first few hours of septic shock, which guides treatment approach (e.g. intravenous fluids or drugs to increase blood pressure). EGDT is recommended by the Surviving Sepsis Campaign for patients presenting with early septic shock. However, adoption has been limited as uncertainty remains over its clinical and cost effectiveness. The NIHR funded this trial to compare patient outcomes of early goal-directed therapy with usual resuscitation care.
What did this study do?
This was a randomised controlled trial of 1,243 adult patients with septic shock in emergency departments across 56 NHS hospitals in England. Patients were randomised to receive either EGDT or usual care. All patients received their first dose of antimicrobial therapy before randomisation.
The early resuscitation protocol lasted for six hours. Blood pressures in the arteries and veins and central blood oxygen levels were monitored continuously. Treatment was then targeted to meet strict goals for these measures. Intubation - the placement of a flexible plastic tube into the windpipe - and mechanical ventilation was used as needed. For usual care, all monitoring and treatment was determined by the treating clinician. Although blood oxygen levels could be measured intermittently, continuous monitoring was not permitted.
This was a large and pragmatic trial set across a mixed sample of about one-quarter of NHS hospitals in England. The results should be reliable and applicable to NHS emergency settings.
What did it find?
- There was no difference in mortality after 90 days. A total 184 patients (29.5%) died in the EGDT group compared to 181 patients (29.2%) receiving usual care.
- There were no significant differences for any other outcomes, including health-related quality of life, or adverse events.
- Patients in the EGDT group received more intensive treatment, with an increased amount of intravenous fluids, vasoactive drugs (to help control blood pressure) and red blood cell transfusions.
- Cost effectiveness was similar for both EGDT and usual care at one year. The probability that EGDT was more cost-effective was below 30%.
What does current guidance say on this issue?
Resuscitation guidance in the 2012 guideline from the Surviving Sepsis Campaign, a joint collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, is largely based on the six hour protocol of early goal-directed therapy. It sets out targets for blood pressure, central venous pressure and blood oxygen levels during the first six hours of care.
NICE are in the process of developing guidance in this area. The expected publication date is July 2016. The scope document states that the NICE guidance will not replicate the existing Surviving Sepsis Campaign guidelines.
What are the implications?
EGDT is not used universally in the UK for resuscitation in septic shock. This study found that it did not reduce mortality and was more costly compared to resuscitation determined by clinical assessment.
This trial completes the planned trio of evaluations of EGDT. The three research teams collaborated to conduct trials in the USA (Protocolized Care for Early Septic Shock: ProCESS), Australasia (Australasian Resuscitation In Sepsis Evaluation: ARISE) and England (Protocolised Management In Sepsis: ProMISe) – the current trial. Both ProCESS and ARISE have published their results, in March 2014 and October 2014, respectively, and reported no benefit of EGDT. The three trials used similar methods and it is planned that the data will be pooled for all patients from the trials. This pooling of results will allow researchers to investigate if early goal-directed therapy is useful for certain populations or in certain settings.
The rate of death at 90 days in England was slightly lower than in the USA but higher than in Australasia. It is likely that this difference will be further analysed and that guideline panels will need to consider this new evidence in updates to their recommendations, if any.
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.
This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 07/37/47).
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.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
NICE. Sepsis: the recognition, diagnosis and management of severe sepsis. Final scope. London: National Institute for Health and Care Excellence, 2014.
Pike F, Yealy DM, Kellum JA, et al. Protocolized Care for Early Septic Shock (ProCESS) statistical analysis plan. Crit Care Resusc. 2013;15(4):301-10.
Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-77.
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