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Abstract & Commentary
By Richard R. Watkins, MD, MS, FACP
Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH.
Dr. Watkins reports no financial relationships in this field of study.
This article originally appeared in the July 2014 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.
SYNOPSIS: A large, multicenter clinical trial that compared protocol-based care to usual care for patients presenting to emergency departments with early sepsis and septic shock found no differences in clinical outcomes. However, early recognition and therapy was beneficial and should be the standard of care.
SOURCE: The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370(18):1683-93.
Despite recent improvement, the short-term mortality in patients presenting to emergency departments with early sepsis and septic shock remains unacceptably high, i.e. approximately 20% in the USA. Researchers have tried a variety of interventions to improve outcomes in sepsis and septic shock, one of which is early goal-directed therapy (EGDT). First described in 2001, this paradigm involves a set protocol by which central venous catheterization is used to guide volume resuscitation and vasopressor titration.1 Because of changes that have occurred in management of septic shock such as the less frequent use of central catheters (due to data showing no improvement in outcomes), the ProCESS investigators sought to determine whether protocol-based resuscitation was better than usual care and whether protocol-based resuscitation with central catheter monitoring was superior to a simpler protocol that did not include central catheter monitoring.
The study was a multicenter, randomized clinical trial conducted at 31 hospitals in the United States between March 2008 and May 2013. Subjects were those who presented to an emergency department at a participating site with a suspected diagnosis of sepsis, were at least 18 years of age, had two or more criteria for systemic inflammatory response syndrome (SIRS), and had refractory hypotension or a serum lactate ≥ 4 mmol per liter. Overall, 1,341 patients were enrolled and assigned in a 1:1:1 ratio to the following groups: protocol-based EGDT wherein a central venous catheter was used to monitor pressure and fluids (439 patients); protocol-based standard therapy that used a team approach with a set of 6-hour resuscitation instructions (446 patients); and usual care in which bedside physicians directed all medical therapy (456 patients). The primary outcome of the study was the rate of in-hospital death from any cause at 60 days. Secondary outcomes included mortality at 90 days and 1 year, duration of the need for vasopressors, duration of acute respiratory failure (defined as time spent on a ventilator), duration of acute renal failure (defined as the duration of dialysis), duration of stay in the intensive care unit and hospital, and disposition at hospital discharge.
The use of IV fluids, vasopressors, dobutamine and blood transfusions between 6 and 72 hours did not differ significantly between the groups. By 6 hours the target mean arterial pressure of 65 mm Hg or greater had been achieved in more patients in the two protocol-based groups compared to the usual care group (P = 0.02). The 60-day in-hospital death rate did not differ significantly between any of the three groups (P values between 0.31 and 0.89) and there were no significant differences in 90-day mortality or time to death up to 90 days and 1 year. The incidence of acute renal failure was higher in the protocol-based standard therapy group compared to the other two (6.0% in the protocol-based standard therapy group vs. 3.1% in the EGDT group vs. 2.8% in the usual-care group, P = 0.04). There were no significant differences between the groups in the length of stay in the ICU, incidence and duration of cardiovascular or respiratory failure, length of hospital stay or discharge disposition. Even when the investigators restricted the analysis to the sickest third of the patients (those with the highest APACHE II scores and serum lactate), no benefit was seen in the two protocol-based groups.
Finally, serious adverse events were rare during the study and did not differ between the treatment groups.
No improvement in outcomes, including mortality and length of stay in the ICU and hospital, was seen in patients who received protocol-based care. However, there are some aspects of the study that limit the generalizability of its findings to other settings. The patients were enrolled as soon as they were recognized to be in septic shock, so the observed benefits might not be as significant when septic shock is recognized later. Also, the care patients received before randomization may have had an impact on their subsequent clinical course. Finally, decisions to withdraw care in patients on life support are variable and their impact on in-hospital mortality during the study is unclear.
There are several interesting findings from the trial that can impact clinical practice. The rate of antibiotic administration in the first 6 hours after randomization was 97%, an exceptionally high and impressive figure. Data from multiple studies strongly supports the dictum that early recognition and antibiotic treatment are the keys to surviving sepsis. Patients in the two protocol-based treatment groups overall received more intravenous fluids, vasoactive agents and blood transfusions yet these interventions did not lead to improved outcomes. When analyzing these results, it is important to remember that all 3 of the study groups were treated according to the Surviving Sepsis Campaign guidelines2 including early recognition of sepsis and septic shock, early antimicrobial treatment and conservative transfusion thresholds as well as moderate glycemic control, low tidal-volume ventilation and serial monitoring of serum lactate levels. Indeed, this latter intervention has been shown to be equivalent to the use of invasive central catheters for monitoring physiological parameters. Thus, this study provides clinicians with strong evidence that central hemodynamic monitoring should not be a priority in the management of septic shock. Instead, the focus should be on early recognition via serum lactate, prompt antibiotic administration and volume resuscitation with care taken to ascertain the adequacy of circulation. The ProCESS trial is likely to become an important milestone for the evidence-based management of septic shock.