Early Goal-directed Therapy for Sepsis

Abstract & Commentary

By Saadia M. Akhtar, MD, MSc, Idaho Pulmonary Associates, Boise. Dr. Akhtar reports no financial relationship to this field of study. This article originally appeared in the January 2010 issue of Critical Care Alert. It was edited by David J. Pierson, MD and peer reviewed by William Thompson, MD. Dr. Pierson is Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, and Dr. Thompson is Staff Pulmonologist, VA Medical Center; Associate Professor of Medicine, University of Washington; they report no financial relationships relevant to this field of study.

Synopsis: One-year mortality post-severe sepsis and septic shock was significantly reduced after implementation of an early goal-directed therapy protocol for sepsis in a large urban emergency department.

Source: Puskarich MA, et al. One year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: A before and after study. Crit Care. 2009;13:R167; Epub ahead of print.

Early goal-directed therapy (EGDT) has been shown to reduce hospital mortality from severe sepsis and septic shock. Puskarich et al hypothesized that long-term outcome would also be improved. They performed a prospective, observational study of the one-year outcome of patients presenting to the emergency department (ED) with severe sepsis or septic shock in the year before ("pre") and the two years after ("post") implementation of an EGDT protocol. Their protocol was derived from that of Rivers et al,1 with minor differences; a lactate level was not required and the resuscitation was transferred to ICU physicians as soon as an ICU bed became available (rather than after six hours).

Eligible subjects were > 17 years old, met usual criteria for sepsis, and had persistent hypotension after fluid resuscitation (20 mL/kg isotonic fluid bolus) or lactate ≥ 4.0 mM with anticipated need for ICU stay. The pre-implementation phase was 13 months, and patient resuscitation and care were as per the discretion of the emergency medicine physician. The post-implementation phase was 24 months. Puskarich et al gathered data on usual demographics, severity of illness, ICU and hospital lengths of stay, and use of specific sepsis therapies such as activated protein C. At ≥ 15 months after enrollment, searches of a large, regional medical record database and Social Security death index were performed; if the patient's status was still unknown after these searches, the patient was assumed to be alive.

The study enrolled 293 patients; eight were eliminated post-hoc, as they died within six hours of enrollment, leaving 79 subjects in the pre-implementation and 206 subjects in the post-implementation group. The two groups were well matched, except for more end-stage renal disease in the pre-implementation group and slightly greater severity of illness and lower initial blood pressures in the post-implementation group. More subjects in the post-implementation group received corticosteroids for sepsis. In terms of outcomes, post-implementation patients had longer ICU lengths of stay and trended toward longer hospital stays, received more intravenous fluids and vasopressors, and were more likely to be intubated. One-year mortality was significantly less at 37% in the post-implementation group, compared to 49% in the pre-implementation group, which translates to an estimated number needed to treat of eight.

Commentary

In 2001, Rivers et al published a landmark study of the early management of patients with severe sepsis or septic shock.1 They randomized 263 patients presenting to their ED with severe sepsis or septic shock to standard therapy or six hours of a fairly simple but aggressive protocol targeting a specific central venous pressure, mean arterial pressure, and central venous oxygen saturation. They found that their early goal-directed therapy reduced organ dysfunction and severity of illness; most significantly, hospital mortality was 30.5% in the treatment group, compared to 46.5% in the control group.

This intervention is now recommended as standard of care for sepsis.2 Implementation, however, has lagged.3

The study by Puskarich et al is an interesting addition to the literature. The overall hospital mortality from severe sepsis and septic shock in this study is less than that observed by Rivers et al (27% in the pre-implementation group and 17% in the post-implementation group), although the relative reduction with EGDT is similar and this adds support to the efficacy of that intervention. The etiology of the difference is unknown but changes in overall ED and hospital care over time (timing and appropriateness of initial antibiotics, for instance) and differences in patient populations may be important contributing factors.

Puskarich et al's hypothesis that EGDT may improve long-term outcomes is intriguing, but it is difficult to associate intervention in the first few hours of a medically complicated septic patient's care with outcome at one year; a very robust analysis would be needed to truly support this association. They use multivariate regression models (it is unclear whether their variables were defined a priori) to attempt to adjust for some factors that could account for long-term mortality differences. However, the non-contemporaneous (and, thus, unmatched and non-randomized) small patient populations in this study and the very limited information about patient characteristics, their care, and course beyond the initial few hours of hospitalization are significant limiting factors. Thus, I believe the question of whether EGDT directly impacts long-term outcomes such as one-year mortality remains unanswered.

Perhaps, most importantly, this study serves as an excellent example of the feasibility of implementing EGDT protocols in any ED and will, hopefully, lead hospitals without such protocols in place to reconsider EGDT.

References

1. Rivers E, et al; for Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377.

2. Dellinger RP, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296-327.

3. Carlbom DJ, Rubenfeld GD. Barriers to implementing protocol-based sepsis resuscitation in the emergency department—results of a national survey. Crit Care Med 2007;35:2525-2532.