How Much does Timing Matter when Treating Sepsis?

Reem Gebrekidan, Mercer University College of Pharmacy

Sepsis is characterized as a systemic detrimental response to infection which could lead to tissue damage, organ failure, and death. Management of sepsis may include source control, fluid resuscitation, antibiotics, and vasopressors depending on hemodynamic stability after fluid resuscitation. [1] The Surviving Sepsis Campaign (SSC) recommends initiating antibiotics within the first hour of sepsis recognition and a treatment bundle which requires administration of 30 mL/kg crystalloid for hypotension or lactate level of less than 4 mmol/L within 3 hours from admission. [2] It was stated that administration within 3 hours of emergency department triage and/or within 1 hour of shock recognition was not associated with significant improvement in mortality and might not be feasible. [3]


Time to Treatment and Mortality during Mandated Emergency Care for Sepsis
Design Multicenter retrospective study; N= 49,331
Objective To examine the association between the timing of treatment and risk-adjusted mortality
Study Groups Group 1: 3-Hr Bundle completed (n= 40,696)

Group 2: Did not complete 3-Hr Bundle (n= 8,635)

Methods Patients who were older than 17 years of age, had community acquired severe sepsis or septic shock, and had sepsis protocol initiated within 6 hours were included. They were excluded if the 3-hour bundle was completed in more than 12 hours, enrolled in a separate clinical trial, had protocols initiated outside the emergency department, and were being treated in hospitals with fewer than 50 cases of sepsis.

The protocol included: a 3-hr bundle time during which blood cultures and serum lactate levels were obtained before administration of antibiotics; and, a 6-hr bundle time where 30 mL/kg intravenous fluid was administered in patients with systolic blood pressure less than 90 mmHg and serum lactate level less than 4 mmol/L or vasopressors is initiated for refractory hypotension.

Duration Data collection: 2014 to 2016
Primary Outcome Measure Time until completion of the 3-hour bundle and risk-adjusted in-hospital mortality
Baseline Characteristics
  Group 1 Group 2
*Median age 73 71
*Female, n (%) 19,175 (47.1) 4,477 (51.8)
*Race, n (%)
White 27,605 (67.8) 5,470 (63.3)
Black 6,487 (15.9) 1,782 (20.6)
Coexisting condition, n (%)
*Chronic respiratory failure 4,656 (11.4) 1,082 (12.5)
Congestive heart failure 8,311 (20.4) 1,781 (23.0)
*End-stage renal disease 4,109 (10.1) 1,098 (12.7)
*Positive blood cultures, n (%) 12,322 (30.3) 2,252 (26.1)
Median serum lactate, mmol/L 2.8 2.5
Septic shock, n (%) 18,393 (45.2) 3,943 (45.7)

*Difference between groups: p< 0.001

  Odds ratio of in-hospital mortality per hour 95% CI p-value
Until completion of 3-hour bundle per hour 1.04 1.02 to 1.05 <0.001
Until of  administration antibiotics 1.04 1.03 to 1.06 <0.001
Until fluid bolus was completed 1.01 0.99 to 1.02 0.21


Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions A longer time to 3-hour bundle completion of care and the administration of broad-spectrum antibiotics were associated with greater risk-adjusted in-hospital mortality among patients with severe sepsis and septic shock.

Confounding bias can not be ruled out due to lack of randomization but these results do complement the SSC treatment guidelines. Patients included in the study were limited to community acquired sepsis, which may not have generalizability in other patient populations. Appropriateness of the initial choice of an antibiotic agent has been associated with greatest risk-adjusted mortality; however, this data was not disclosed in the study. The lack of association between time to completion of the fluid bolus and in-hospital mortality should be interpreted with caution as it’s prone to confounding indications (e.g. severity of sepsis and comorbidities). Adherence to the protocol was 60 to 90% which could indicate its implementation feasibility.



[1] Sepsis. Centers for Disease Control and Prevention website Updated April 13, 2017. Accessed June 6, 2017.

[2] Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.

[3] Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit Care Med. 2015;43(9):1907-15.

[4] Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017;376(23):2235-2244.



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