Early goal-directed therapy for septic shock – a patient-level meta-analysis

  • The PRISM Investigators: Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, Canter RR, et al.
  • N Engl J Med. 2017 Jun 8;376(23):2223-2234.

This meta-analysis pooled data from three large randomised controlled trials to determine whether early goal-directed therapy (EGDT) was an effective intervention for managing septic shock. The data were collected prospectively through collaboration between the investigators of the ProCESS, ARISE and ProMISe trials. The final analysis studied 3,723 patients across seven countries and multiple centres; it did not demonstrate a mortality benefit for EGDT in this setting, and suggested that it was not a cost-effective intervention. Subgroup analysis showed a mortality benefit for the patient group with severe chronic lung disease, and a negative effect on the survival of patients with chronic liver disease.

The initial report on EGDT in septic shock was published in 2001 by Rivers et al. EGDT is a 6-hour resuscitation protocol that focusses on the administration of intravenous fluids, vasopressors, ionotropes and packed red cells to meet defined ‘optimal’ physiological targets for arterial pressure, central venous pressure, central venous oxygen saturation and haemoglobin levels. The initial randomised control trial showed a reduced mortality, dropping from 46.5% to 30.5% with EGDT. This promising result provoked further investigation, and three large, multicentre trials were conducted: ProCESS, ARISE and ProMISe. These studies failed to show improved mortality with EGDT, and this meta-analysis was planned to increase the statistical power of those three trials by pooling data to establish whether a subtler effect could be elicited.

The three trials all investigated the same EGDT protocol, and the design for a meta-analysis was published prior to unblinding the data, allowing for a prospective analysis. In the both the usual treatment group and the EGDT group, early recognition of sepsis and prompt delivery of IV antibiotics and fluids were emphasised. The data were analysed on an intent-to-treat basis, with subgroups prespecified to explore the impact of EGDT on certain subgroups – such as those with more severe disease, or certain pre-existing conditions. Other subgroups were created to account for demographic differences.

After exclusions, 3,723 patients were included in the final analysis (1,852 in the EGDT group, 1,871 in the usual care group), and included data from 138 hospitals across the USA, Australia, New Zealand, Finland, Hong Kong, Ireland and the UK. Mortality within 90 days did not vary significantly (24.9% in the EGDT group versus 25.4% in the usual management group; adjusted odds ratio (OR) 0.97 [95% CI: 0.82–1.14] p=0.68). Secondary outcomes showed that 1-year mortality also did not vary significantly, while EGDT patients experienced a longer ITU/ICU stay and more frequent and longer duration cardiovascular support. Subgroup analysis also failed to show a mortality benefit in even those with the most severe disease. There was a mortality benefit from EGDT in the 370 patients with severe chronic lung disease (OR 0.54 [95% CI: 0.34–0.85] p=0.01), and higher mortality in patients receiving EGDT with severe chronic liver disease (n=117; OR 2.51 [95% CI: 1.12–5.63] p=0.01). The cost analysis demonstrated a higher cost up to 90 days with EGDT than with usual care; quality of life and quality-adjusted life year outcomes were similar, leading the analysis to suggest that the probability that EGDT is cost effective is 0.25 for realistic thresholds.

In their discussion, the authors highlight that there was no evidence to suggest EGDT resulted in improved mortality – an effect that persisted across a variety of healthcare systems. There was no evidence from the analysis that patients who were more unwell benefit, and the authors do not believe that the difference in disease severity is sufficient to explain the different outcomes found by Rivers et al. and this study. They concede that the intervention may have increased the standard of usual care, but subgroup analyses sought to establish whether there was inter-departmental variation, and did not find it to be so; highlighting that even those departments with the least aggressive usual care protocols did not demonstrate an EGDT benefit. Most of the evidence supporting EGDT thus far has been observational, and this study has potentially avoided some of the biases that may persist through an observational design. The authors point to the early harmonisation of research methodologies and alignment of key objectives as an example of how richer data can be generated – potentially leading to better practice.

The limitations to the study include: the relatively small size of some potentially important subgroups, the fact that the underlying trials were unblinded, and that the results may not be suitable for extrapolation to lower-income healthcare systems.

This study goes a long way towards demonstrating that a blanket approach to septic shock using EGDT is neither beneficial in terms of mortality nor cost-effective. It does however leave the door open for utilisation of some of the aspects of EGDT in clinically-relevant situations.

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