Emerg Delayed Antibiotics Sepsis

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Leisman D. et al. "Delayed Second Dose Antibiotics for Patients Admitted From the Emergency Department With Sepsis: Prevalence, Risk Factors, and Outcomes.". Crit Care Med. 2017. 45(6):956-965.
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Clinical Question

In adult patients with sepsis admitted in the emergency department, does the a delay in the second dosing of antimicrobial therapy affect patient outcomes.

Bottom Line

For patients that have a delay in second doses of antibiotics show an increase in mortality and mechanical ventilation, with a trend towards longer hospitalization and admission to critical care.

Major Points

Following the work of the Rivers Trial and the work done by Kumar et al [1], rapid antimicrobial therapy following recognition of sepsis/shock has become the standard of care. The Surviving Sepsis campaign recommends administration of antimicrobials within one hour[2] and a quality measure of American hospitals is a three-hour window for administration. Some newer evidence has suggested that this three hour window may not be as key.[3]

Not being well explored with other quality improvement systems,[4] the delivery of the second dose of antimicrobials was explored with this trial. Overall a major delay (defined as >25% of the dosing interval) in the second dose was seen in about 30% of cases. Of those with a major delay they had a odds of mortality (OR 1.61) and requiring mechanical ventilation (OR 2.44). These major delays were seen more commonly where therapy had a shorter dosing interval (6h) as compared to longer intervals but still occurred with 12h and 24h interval antimicrobials. The delay was also more commonly seen in patients that were boarded in the ED after being admitted and a paradoxical relationship that those that met the 3h Sepsis quality benchmarks had more delays in the second dose. These may suggest an issue with the care delivery / workflow.

This trial was done at a single centre and may lack some external validity but this may be occurring in other centres. Further study is required to further quantify the issue.


Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[5]

  • Begin treatment and resuscitation immediately (best practice statement [BPS] are ungraded, strong recommendations)
  • For sepsis-induced hypoperfusion, give ≥30 mL/kg IV crystalloid fluid in the first 3 hours (strong recommendation, low quality evidence)
  • After initial resuscitation, given additional fluids guided by frequent reassessment of status of hemodynamics like HR, BP, PaO2, RR, temp, UOP, noninvasive, and/or invasive monitoring (BPS)
  • Target MAP of 65 mm Hg in patients requiring vasopressors (strong recommendation, moderate quality of evidence
    • Norepinephrine as first line vasopressor (strong recommendation, moderate quality of evidence)
      • Add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to raise MAP to target
      • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, moderate quality of evidence)
  • Suggested guiding resuscitation to normalize lactate in those with lactate elevations (weak recommendation, low quality of evidence)
  • Recommend administration of IV antimicrobials as soon as possible, preferably within 1 hour of recognition (strong recommendation, moderate quality of evidence)


  • Single centre, retrospective, chart review
  • N=828
    • Major delay: 272
    • No Major Delay: 556
  • Setting: suburban, tertiary, academic medical centre in the United States
  • Enrollment: February to December, 2015
  • Mean follow-up: 3.5 years
  • Analysis: Intention-to-treat
  • Primary outcome: Determine frequency and magnitude of delays in second antimicrobial administration


Inclusion Criteria

  • Patients captured in a Sepsis Quality Improvement Database
  • suspected or confrmed infection (determined by provider’s clinical judgment)
  • ≥ 2 systemic inflammatory response syndrome (SIRS) criteria [6]
  • ≥ 1 organ dysfunction or hypoperfusion criterion

Exclusion Criteria

  • Excluded from the sepsis database:
    • < 18 years old
    • declined interventions
    • advance directives precluding bundle application
    • admitted directly to hospice or palliative care
  • Excluded from this trial
    • not receiving initial antibiotics in the ED
    • expiring or admitted to hospice before second antibiotic dose
    • antibacterial therapy discontinued after first dose

Baseline Characteristics

  • Male sex, n (%) 404
  • Age (yr), mean (sd) 75 (15)
    • Charlson Comorbidity Index, median (IQR) 5 (2–6)
    • Chronic renal failure, n (%)a 81 (9.8)
    • Congestive heart failure, n (%)a 136 (16.4)
    • Chronic obstructive pulmonary disease, n (%)a 87 (10.5)
    • Immune-modifying medications at presentation, n (%)a 150 (18.1)
    • Metastatic disease, n (%)a 59 (7.1)
  • Quick Sepsis-Related Organ Failure Assessment ≥ 2 in the ED, n (%) 243 (29.3)
  • Hypotension, n (%)b 293 (35.4)
  • Initial serum lactate (mmol/L), median (IQR) 2.6 (2.0–3.7)
  • Altered mental status, n (%) 216 (26.1)
  • Hypoxia, n (%)c 122 (14.7)
  • Acute kidney injury, n (%)d 178 (21.5)
  • Coagulopathy, n (%)e 165 (19.9)
  • Source of Infection:
    • Urinary 257 (31.0)
    • Respiratory 284 (34.2)
    • Gastrointestinal 81 (9.8)
    • Skin/soft tissue 57 (6.9)
    • Other or unknown source of infection 148 (17.8)


  • First-to-second antibiotic time and delay frequency
    • ≥ 25% of the recommended interval


Primary Outcomes

‘'Presented as % patients with ≥25% delay in dosing interval(CI), median time to second dose in minutes(IRQ)’'

Entire cohort (N=828)
Cohort with 6h(360min) dosing interval (n=157)
72%(64.5-75.4%), 573(424-729)
Cohort with 8h(480min) dosing interval (n=251)
46.6%(40.5-52.8%), 576(397-812)
Cohort with 12h(720min) dosing interval (n=124)
25.5%(18.2-33.3%), 635(460-881)
Cohort with 24h(1440min) dosing interval (n=295)
3.7% (2.1-6.6%), 1111(529-1415)

Secondary Outcomes

‘’'Risk factors for delay’

Antibiotic with 6h interval
OR 71.95 (CI 25.13-206) P<0.001
Antibiotic with 8h interval
OR 23.7 (CI 8.13-69.12) P<0.001
Antibiotic with 12h interval
OR 6,98 (CI 2.33-20.89) P=0.001
Boarding in the ED after admission
OR 2.67 (CI, 1.74–4.09) P < 0.001)
Initial 3-hour bundle compliance
OR 1.57 (CI 1.07–2.30) P = 0.020
Older age
OR 1.16 per 10 yr (CI 1.01–1.34) P = 0.045

(Exploratory) Patient Centered Outcomes’’' Presented as Major Delay vs. No Major Delay

unadjusted 21% vs. 15.3%
adjusted OR 1.61 (95% CI 1.01-2.57) P=0.046
Hospital Length of Stay, days
unadjusted 11.9 vs. 14.7
adjusted Inverse OR 1.16 (0.97-1.39) P=NS
Mechanical Ventilation after second antibiotic dose
unadjusted 11.5% vs. 4.6%
adjusted OR 2.44 (1.27-4.69) P=0.007
ICU Admission
unadjusted 26% vs. 18.3%
adjusted OR 1.49 (0.92-2.40) P=0.103


  • Data-base driven so information bias potential
    • Missing data on potential confounders such as renal dysfunction changing dosing recommendations
    • Missing details that may contribute to delay: unavailable vascular access, drug access, appropriateness of initial empiric therapy, and details and rationale for revision of initial empiric therapy selection
  • Retrospective design
  • Lower external validity due to single site


Not clearly stated

Further Reading

  1. Kumar A et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 2006. 34:1589-96.
  2. Rhodes A et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017. 43:304-377.
  3. Sterling SA et al. The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit. Care Med. 2015. 43:1907-15.
  4. Ferrer R et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit. Care Med. 2014. 42:1749-55.
  5. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  6. Kaukonen KM et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N. Engl. J. Med. 2015. 372:1629-38.