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Date: February 14th, 2018

Reference: Alam N et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. The Lancet Nov 2017.

Guest Skeptics: Jay Loosley is the Superintendent of Education at Middlesex-London Paramedic Service. Jenn Doyle is a paramedic educator at Middlesex-London Paramedic Service.

Case: EMS is dispatched to a retirement home. They have a 73-year-old man who complains of weakness and a cough for the last 48 hours. You arrive and find the man lying in bed looking ill. He has a history of hypertension, benign prostatic hypertrophy and osteoarthritis. His medications include ramapril, hydrochlorothiazide and tamsulosin. On examination, he has a temperature of 38.7C, heart rate of 105 beats per minute, respiratory rate of 26, oxygen saturation of 88%. and a blood pressure of 88/50 mmHg. You load him on the stretcher, start an intravenous of normal saline and provide some supplemental oxygen via face mask. Clearly something infectious is going on and you wonder if starting antibiotics on route to the hospital would help?

Background: We have covered sepsis many times on the SGEM over the years (SGEM# 69, 90, 92, 113, and 168). It is a serious condition associated with high morbidity and mortality.

Jennifer Doyle

Jennifer Doyle

Other serious time-dependent conditions such as myocardial infarction and trauma have been improved significantly with emergency medical services (EMS). It has been reported that over half of patients with sepsis arrive to the emergency department via ambulance [1]. However, it is not clear if patients with suspected sepsis can have improved survival rates if antibiotics are provided in the pre-hospital setting.

There are studies showing that early recognition and prehospital administration of antibiotics are associated with increased survival rates [2-4]. Delay in antibiotics has been associated with an average decrease in survival of 7.6% per hour (Kumar et al).

We need to be skeptical of these retrospective studies, especially when prospective, observational studies have failed to show any association between early antibiotics and a reduction in mortality [5-7].

Now we have better evidence with the publication of the first prospective, randomized study investigating the effects of early antibiotic administration in patients with suspected sepsis.

Clinical Question: Can patients with varying degrees of sepsis benefit from early recognition and prehospital administration of IV antibiotics in the ambulance?

Reference:  Alam N et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. The Lancet Nov 2017.

  • Population: Adult patients (18 years and older) with a diagnosis of suspected infection, temperature >38C or <36C and at least one other SIRS (systemic inflammatory response syndrome) criteria (HR>90bpm, RR>20bpm, or both)
    • Exclusions: Allergy to ceftriaxone, other beta-lactams, know pregnancy or suspected prosthetic joint infection.
  • Intervention: Ceftriaxone 2g IV
  • Control: Usual care (fluid resuscitation and supplementary oxygen)
  • Outcome:
    • Primary: All-cause mortality at 28 days
    • Secondary: “Number of misdiagnoses of patients enrolled in the study by EMS, mortality during hospital stay and within 90 days, length of hospital stay, ICU admission, length of stay in ICU, TTA to the emergency department for usual care group, and TTA before hospital arrival for intervention group microbiological data, adverse events, and quality of life 1 month after discharge as measured with the SF-36 questionnaire”

Authors’ Conclusions: “In patients with varying severity of sepsis, EMS personnel training improved early recognition and care in the whole acute care chain. However, giving antibiotics in the ambulance did not lead to improved survival, regardless of illness severity.”

checklistQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes/No
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They enrolled 2,698 patients into the study with a mean age of 73 years with 42% female. They stratified patients into non-severe sepsis, severe sepsis, septic shock [8] and other diagnoses. The vast majority of patients (95%) had non-severe sepsis or severe sepsis and one in five patients were already on antibiotics before randomisation.

No difference in mortality at 28 days

  • Primary Outcome: Mortality at 28 days
    • 120/1,535 (8%) in the intervention group vs. 93/1,137 (8%) in the control
    • Relative risk 0·95 (95% CI 0·74–1·24)
  • Secondary Outcomes (Intervention vs. Usual Care):
    • Misdiagnoses: No difference (1% vs. 2%)
    • Mortality within 90 Days: No difference (12% vs. 12%)
    • Hospital Length of Stay: No difference (6 days vs. 6 days)
    • ICU Admission: No difference (10% vs. 9%)
    • ICU Length of Stay: No difference (4 days vs. 3 days)
    • Quality of Life: No difference
    • Time to Antibiotics Intervention Group: Before hospital arrival (26 minutes). This led to a time gain of 96 minutes.
    • Time to Antibiotics Usual Group: After arriving to the ED (70 minutes). This was 23 minutes faster than the baseline measure before they did the training for the study.
  • Adverse Events: No anaphylactic shock in the intervention group. There were seven mild allergic reactions that none could be attributed to the ceftriaxone.
  • Subgroup Analysis: This is hypothesis generating. However, there was no difference in the primary outcome (mortality at 28 days) for any of the subgroups including severity of sepsis.

Screen Shot 2015-04-25 at 3.11.12 PM

  1. Protocol Violations – During the first few months, EMS personnel were opening envelopes until they found one that read “intervention.” This led to a higher number of patients being enrolled in the intervention group and a decrease in the randomization of patients. However, even with the violation, there were no differences between the groups in terms of primary or secondary outcomes.
  2. Time to Antibiotics – This was not measured as time from onset of infection but rather time to antibiotics in the pre-hospital setting or in the emergency department. There was a huge net gain of patients getting antibiotics more than 96 minutes earlier in the intervention group. However, this did not lead to a mortality benefit and demonstrates the difference between statistical significance and clinical significance. Antibiotics given more than one and a half hours earlier seems to be inconsequential in the overall time from onset of illness to antibiotics.
  3. Confounders – In this study there was concurrent training on sepsis recognition. You can see the improvement in time to antibiotics for the usual care when compared to the baseline statistics. It went from 93 minutes down before they provided training to 70 minutes after the training. This decrease was not statistically significant, but it could decrease any potential benefit of giving antibiotics in the pre-hospital setting. In addition, the 20% of patients already on antibiotics before randomization may also have diluted any effect of the intervention.
  4. Short Response and Transport Times – They have a very good EMS system in the Netherlands with 93% of cases having a response time of <15min and an average of 40 minutes from dispatch to arrival to the emergency department. Would the results differ if done in a system that was not as robust or in rural remote areas that have longer response/transport times?
  5. Staffing of EMS – As stated previously, this study was conducted in the Netherlands. In their EMS system ambulances are staffed with nurses. It is possible that they have more experience or different skill set in treating septic than other EMS services.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: Pre-hospital antibiotics in the ambulance do not appear to have a mortality benefit in patients with varying degrees of sepsis in an optimized EMS system.

Case Resolution: After loading him up on the stretcher you make your way to the hospital. He receives about 500cc of normal saline on route to the hospital in addition to supplemental oxygen. He arrives no longer hypotensive or hypoxic. You sign over to the triage nurse and express your concerns about this patient having sepsis.

Jay Loosley

Jay Loosley

Clinical Application: This re-affirms that we should focus on things that provide benefit in the pre-hospital setting and not on those that do not. Until there is good evidence demonstrating a patient-oriented outcome, antibiotics will not be part of our EMS protocol. However, as the superintendent of education, I will be use this as an opportunity to remind staff about early recognition of sepsis and the use of personal protective equipment.

What Do I Tell My Patient? You are probably weak because of an infection.  We suspect a chest infection because you were coughing and your oxygen was low. We are going to start an intravenous line, give you some fluids on the way to the hospital and provide extra oxygen. They will do some tests in the emergency department and determine your diagnosis and give you the proper treatment.

 Keener Kontest: Last weeks’ winner was Matt Corey a PA from Phoenix. He knew foreign body aspiration should be considered in a pre-schooler with wheeze but without signs of an infection. Corey has won before, but I have got new cool skeptical prizes. So if you have won before, play again. 

Listen to the SGEM podcast on iTunes to hear this weeks’ question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive one of our cool new skeptical prizes.

FOAM logoOther FOAMed:

 

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments.
Crit Care Med 2007; 35: 1928–36.
  2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of e ective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34: 1589–96.
  3. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the rst hour: results from a guideline-based performance improvement program. Crit Care Med 2014; 42: 1749–55.
  4. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38: 1045–53.
  5. Ryoo SM, Kim WY, Sohn CH, et al. Prognostic value of timing of antibiotic administration in patients with septic shock treated with early quantitative resuscitation. Am J Med Sci 2015;
349: 328–33.
  6. de Groot B, Ansems A, Gerling DH, et al. The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multi-center study. Crit Care 2015; 19: 194.
  7. Puskarich MA, Trzeciak S, Shapiro NI, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol.
Crit Care Med 2011; 39: 2066–71.
  8. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ ATS/SIS International Sepsis De nitions Conference. Crit Care Med 2003; 31: 1250–56.