ARISE to a New Day in Septic Shock Care

October 1, 2014

Controversy surrounding early goal-directed therapy in septic shock has heightened with the publication of the ARISE trial.

Evidence-based and guideline-directed medicine is the standard operating practice of most health care professionals today. Critical illnesses have seen data produced, collected, appraised, and transformed into consumable and applicable guidelines.

In the case of septic shock, we have the Surviving Sepsis Campaign guidelines to help deliver care to these patients in a protocolized fashion referred to as early goal-directed therapy (EGDT).1,2 In recent years, elements of EGDT have been questioned, and some have even been removed from the market with subsequent changes made to the guideline recommendations.2

In May 2014, the Protocol-Based Care for Early Septic Shock (ProCESS) trial added fuel to the fire when it showed no survival benefit to EDGT compared with patients who received “standard” or “usual” therapy, specifically with respect to invasive monitoring and additional therapies such as blood transfusions.3 But, before doing away with EGDT for the less-costly standard or usual care approaches, the emergency medicine and critical care communities collectively held their breath for the results of the Australasian Resuscitation in Sepsis Evaluation (ARISE) and Protocolised Management in Sepsis (ProMISE) trials of similar design.4

On October 1, 2014, the results of the ARISE trial comparing EGDT to usual care in patients with septic shock were published online.5 This was a randomized, prospective, parallel-group study of patients aged 18 years or older in the emergency department who, within 6 hours of presentation with suspected or confirmed infection, 2 or more systemic inflammatory response syndrome (SIRS) criteria, and evidence of refractory hypotension or hypoperfusion, were randomized to receive either EGDT or usual care for 6 hours.

Patients randomized to the usual care group had their treatment directed by the treating clinician, but invasive central venous oxygen saturation monitoring was not permitted during the 6-hour intervention period. As for patients randomized to EGDT, a trained study team followed the EGDT protocol, including placing arterial and central venous catheters within 1 hour after randomization. The primary outcome was death from any cause within 90 days of randomization, and the investigators also had a series of secondary and tertiary outcomes, including elements of care such as vasopressor use, renal replacement therapy, and adverse events.

Consistent with the prior ProCESS study, there was no difference in the primary outcome of death from any cause 90 days after randomization between EGDT patients (147 of 792, 18.6%) and those who received usual care (150 of 796, 18.8%) with a p value of 0.90.3,5 It should be pointed out, however, that the overall mortality rates in each group in this study were remarkably reduced compared to historical mortality rates prior to the Surviving Sepsis Campaign.2 The authors noted that “in-hospital mortality for patients who are admitted to ICUs with severe sepsis and septic shock has been reduced by 1 percentage point per year during the past 2 decades.”5 Additionally, the patients in this study may have had a lower risk of death, since few had chronic comorbidities or resided in a long-term care facility.5

There are secondary outcomes related to pharmacotherapy of EGDT to note. The time to first dose of antimicrobial therapy was similar between groups; however, the use of vasopressors was significantly higher among EGDT patients (76.3% vs. 65.8%; p<0.001) and dobutamine (15.4% vs 2.6%%; p<0.001).5 Similarly, the use of vasopressors and dobutamine continued between 6 and 72 hours more often in the EGDT group.5 While there were no differences in the rates of adverse events between groups, the supplementary appendix available online indicates there were numerically more patients with reported "arrhythmias," which would surprise some, given the lower utilization of vasopressors.5

The ARISE study adds to the results of the ProCESS trial and may provide clinicians and pharmacists practicing in resource-limited institutions evidence to support delivering usual care without costly and invasive central venous and arterial monitoring, all while preserving a patient's chance of survival.3,5 Although the attention of the emergency medicine and critical care communities has now turned to the results of the ProMISE trial, the results of ARISE and ProCESS must also be mulled over, dissected, and critically appraised by experts and local professionals to determine whether their local practices should change.


1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-77.

2. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.

3. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014; 370:1683-93.

4. Huang DT, Angus DC, Barnato A, et al. Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe. Intensive Care Med. 2013;39:1760-75.

5. Peake SL, Delaney A, Bailey M, et al. Goal directed resucitaiton for patients with early septic shock. N Engl J Med. 2014; Epub ahead of print on October 1, 2014. DOI: 10.1056/NEJMoa1404380