NIHR Signal Protocol-led therapy for septic shock did not reduce mortality compared to usual resuscitation care

Published on 21 December 2015

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.

Protocol-led therapy for septic shock did not reduce mortality compared to usual resuscitation care

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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.

Citation

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).

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.

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.

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.

Citation

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).

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.

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.

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

Published on 26 November 2015

Mouncey, P. R.,Osborn, T. M.,Power, G. S.,Harrison, D. A.,Sadique, M. Z.,Grieve, R. D.,Jahan, R.,Tan, J. C.,Harvey, S. E.,Bell, D.,Bion, J. F.,Coats, T. J.,Singer, M.,Young, J. D.,Rowan, K. M.

Health Technol Assess Volume 19 , 2015

BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at pound20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at - pound725 (95% CI - pound3000 to pound1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.

Expert commentary

The ProMISe study is an excellent example of how important questions related to everyday NHS care of emergency patients with life threatening diseases – in this case septic shock – can be subjected to careful scientific scrutiny. Protocolised early haemodynamic resuscitation for the sickest patients with an infection is recommended by international consensus sepsis guidelines based on limited evidence. This complex interventional study was funded and delivered by the NIHR in partnership with a leading UK Clinical Trials Unit, resulting in the participation of 56 NHS hospitals. The results of the ProMISe trial have contributed to a reappraisal of international sepsis care guidance and serve to highlight how high quality research in emergency and critical care has become established within the modern NHS.

Dr Paul Dark, NIHR CRN Research Theme Lead in Critical Care, Kings College London

Expert commentary

This is an important randomised controlled trial for UK clinical practice. Sepsis is a major healthcare problem and recent international guidelines have recommended early-goal directed therapy for all cases of septic shock, largely based on a relatively small single centre trial in the USA. This much larger multi-centre trial has demonstrated no benefit from protocolised early-goal directed therapy for all patients compared to standard clinical care in the NHS. The protocolised care did, however, result in more resource use.

However, early adequate resuscitation still remains a vital part of sepsis management and should be tailored to individual patient requirements. Hopefully a planned individual patient data meta-analysis including similar American and Australasian trials will provide more information about the individual components of optimal resuscitation.

Dr Anthony Gordon, Consultant of Critical Care Medicine, Imperial College London