Pre-Hospital Antibiotics in Sepsis?

Background: Sepsis remains one of the leading causes of morbidity and mortality. It is well-established that earlier recognition and treatment can lead to better outcome for these patients .  Time to antibiotic therapy (from triage, not from onset of infection) has become a quality metric to improve the time to administration of these medications. In an effort to administer antibiotics earlier, many studies have attempted to give antibiotics in the prehospital setting but the benefit of this intervention is unclear.

Paper: Varney J et al. Prehospital Administration of Broad-Spectrum Antibiotics for Sepsis Patients: A Systematic Review and Meta-Analysis. Health Sci Rep 2022. PMID: 35387313

Clinical Question: Do prehospital antibiotics impact 28 day mortality, length of stay in the hospital and ICU length of stay for patients triggering sepsis compared to usual care (No prehospital antibiotics)?

What They Did:

• Systematic review and meta-analysis
  • P: Sepsis patients
  • I: Prehospital antibiotics
  • C: No prehospital antibiotics
  • O: 28d mortality, hospital length of stay, and ICU length of stay
• Searched PubMed, Scopus, Web of Science, and Embase as well as references of relevant articles
• Risk of bias assessment was done with Cochrane and Newcastle Ottawa scale tools for trials and observational studies respectively

Outcomes: 28 day mortality, Hospital LOS, ICU LOS.

Inclusion:

• Original studies, cross-sectional, case-control, and case series reporting prehospital administration of antibiotics for suspected sepsis patients

Exclusion:

• Overlapping datasets, books, conferences, case reports, editorials, letters, author responses
• Non-English studies
• Studies with non-available full text
• Animal and lab studies

Results:

• 1811 studies found
  • 19 studies were eligible for systematic review (Years of Publication: 2008 to 2021)
  • 4 studies were eligible for meta-analysis (Years of Publication: 2009 to 2020)
    • Receiving Prehospital Abx: 1779 patients
    • Not Receiving Prehospital Abx: 1744 patients
  • 28d Mortality
    • 3523 patients
    • Prehospital Abx: 190/1779 (10.7%)
    • No Prehospital Abx: 292/1744 (16.7%)
    • Pooled RR: 0.81; 95% CI 0.68 to 0.97; p = 0.02
  • Length of ICU Stay
    • 906 patients
    • Prehospital Abx: 300 pts
    • No Prehospital Abx: 606 pts
    • Pooled Mean Difference 0.11; 95% CI -1.85 to 2.07; p = 0.91
    • NOT STATISTICALLY SIGNIFICANT
  • Length of Hospital Stay
    • 3325 patients
    • Prehospital Abx: 1680 pts
    • No Prehospital Abx: 1645 pts
    • Pooled Mean Difference: 4.50; 95% CI -3.34 to 12.33; p = 0.26
    • NOT STATISTICALLY SIGNIFICANT

Strengths:

• Asks a clinically important question
• Broad search strategy using multiple databases
• Low heterogeneity for the primary outcome investigated (28d mortality)
• Cochrane risk of bias tool used to assess bias and study quality for inclusion
• Multiple authors extracted data with primary author acting to resolve disagreements 

Limitations:

• 2 of the 4 studies included in the meta-analysis were at high risk of bias. The two studies at high risk of bias were weighted 72.4% of the meta-analysis making conclusions at high risk of bias.
• Three outcomes were evaluated, with none being deemed the primary outcome. Any of the outcomes could be statistically significant by chance alone as mortality was not the primary outcome in all the included studies
• Too few studies included in the meta-analysis (4 trials total) to draw any definitive conclusions. 3 of the trials were observational and only one randomized clinical trial
• High statistical heterogeneity for hospital and ICU LOS raises doubts about whether this data could reasonably be used for a meta-analysis

Discussion:

• Of the 4 included trials for the meta-analysis only one was an RCT (The PHANTASi Trial):
  • Alam N et al Lancet Respr Med 2018: 2698 patients with sepsis enrolled into this RCT; Abx used 2g ceftriaxone; Time difference was 26min vs 70min with no difference in survival, regardless of illness severity
• There are many disease entities that will trigger sepsis and therefore the overuse of antibiotics can lead to antimicrobial resistance and should be considered with an earlier strategy
• Additionally blindly giving antibiotics prehospital without drawing blood cultures also decreases the ability to de-escalate antibiotics (12% absolute difference – The FABLED Trial – SEE BELOW Under More Thoughts on This Topic)
• Time to antibiotics is a measure that still needs a large multicenter RCT to confirm that this is best practice in all comers meeting SIRS criteria.  Until that time, the best evidence indicates that in the sickest patients (i.e. septic shock) earlier antibiotics most likely makes a difference in morbidity and mortality, however earlier antibiotics in all patients who meet SIRS criteria may not be a good thing and potentially cause more harms than good.

Author Conclusion: “This meta-analysis reveals that receiving prehospital antibiotics can significantly lower mortality in sepsis patients compared to patients who do not receive prehospital antibiotics. However, more clinical trials and multicenter prospective studies with high sample sizes are needed to get strong evidence supporting our findings.”

Clinical Take Home Point: Cutting corners to speed up time is not always a good thing in medicine.  Treatment is only as good as the diagnosis.  There are just as many potential harms as there are benefits in giving antibiotics in the prehospital setting.  More evidence is needed before this becomes mainstream practice.

References:

1. Varney J et al. Prehospital Administration of Broad-Spectrum Antibiotics for Sepsis Patients: A Systematic Review and Meta-Analysis. Health Sci Rep 2022. PMID: 35387313

For More Thoughts on This Topic Checkout:

• REBEL Cast Ep70: Time to Abx in Sepsis
• The FABLED Trial: Blood Cultures 1^st, Then Antibiotics in Sepsis

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter/X: @EMSwami)