Antibiotics should be administered as soon as there is a concern for sepsis.

A large retrospective analysis using the Surviving Sepsis Campaign (SSC) database was conducted in 2014 to determine the risk of mortality for delay in antibiotics in patients with severe sepsis and septic shock.¹ Authors reviewed charts of all patients from January 2005 to February 2010 at 165 ICUs in Europe, the United States, and South America. After excluding those without documented antibiotics or antibiotic timing as well as those already receiving antibiotics prior to presentation, the authors included 17,990 patients. A regression model was used to analyze the relationship between time to antibiotic administration and in-hospital mortality. The model controlled for ICU admission source, geographic location, and sepsis severity score.

The authors found that the adjusted mortality OR linearly increased each hour from 0 to 6 hours for time to antibiotic administration (using 0-1 hour as the referent group, P < .05 from 2 hours onward). A sample computation that used the ED as the admission source, the United States as the geographic location, and a sepsis severity score of 52 (median score for all observations) showed that the probability of mortality increased from 24.6% to 33.1% from a time of 0 hours to >6 hours. Caveats of this study include its retrospective nature as well as the lack of information about appropriateness of initial antibiotics.

As a protocolized approach to sepsis management, EGDT does not reduce mortality compared to usual resuscitation.

EGDT is a protocolized approach for sepsis management utilizing arterial pressures, venous pressures, and ScvO₂ to guide administration
of IVF, vasoactive agents, and blood transfusions.² In the original single-center randomized controlled trial, EGDT decreased short-term mortality compared to nonprotocolized management. This trial led to a major shift in practice whereby early and aggressive fluid resuscitation became the standard of care for sepsis. However, several subsequent large, high-quality trials comparing EGDT protocols to this new aggressive “usual care” have not shown the same benefit, bringing the utility of EGDT into question.

A 2015 systematic review and meta-analysis sought to more formally answer this question and compared EGDT to usual care in patients with septic shock who presented to the ED.³ The authors performed a comprehensive literature review without language restrictions from 2000 to 2015 identifying randomized controlled trials of EGDT in septic shock. The primary outcome of interest was mortality; secondary outcomes were ICU admission rate, length of stay, and use of organ-supporting devices and medications. Eleven trials comprising 5407 patients were eventually included in the study.

EGDT did not decrease mortality in comparison to usual care (23.2% vs. 22.4%, pooled OR 1.01, 95% CI 0.88-1.16; P = .90). Patients receiving EGDT were more likely to receive vasopressors (pooled OR 1.25, 95% CI 1.10-1.41; P < .001) and be admitted to the ICU (pooled OR 2.19, 95% CI 1.82-2.65; P < .001). There was no difference in ICU length of stay (weighted mean difference −0.02 days, 95% CI −0.47 to 0.43; P = .93) or hospital length of stay (weighted mean difference −0.28 days, 95% CI −1.18 to 0.62; P = .55).

Overall, this meta-analysis concluded there was no evidence that EGDT improved outcomes. As a result, the 2016 SSC guidelines no longer recommend EGDT for resuscitation in sepsis.⁴ Instead, the SSC recommends aggressive initial resuscitation with 30 mL/kg of IVF for the average patient with septic shock (based on the mean volume of IVF given pre-randomization in EGDT trials; strong recommendation, low quality of evidence).

Norepinephrine is the initial vasoactive medication of choice for septic shock.

A systematic review and meta-analysis examined 32 randomized controlled trials that compared norepinephrine with either dopamine, epinephrine, vasopressin/terlipressin, or phenylephrine in adults with septic shock.⁵ The primary outcome was 28-day mortality, and secondary outcomes included ICU length of stay and adverse events (myocardial infarction, arrhythmias, cerebrovascular accident, skin necrosis, and internal organ ischemic damage).