SGEM#44: Pause (Etomidate and Rapid Sequence Intubation in Sepsis)

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Date: September 15, 2013

Guest Skeptic: Dr. Suneel Upadhye, McMaster University. He is an Associate Clinical Professor of Emergency Medicine and Associate Member in the Department CEB at McMaster University. Sunned is also the Chair of the CAEP Guideline Committee.

Case Scenario: 70 year old man arrives by ambulance from home with complaining of being weak and dizzy. No specific complaints of chest pain, shortness of breath, abdominal pain or focal weakness. He has a history of hypertension, benign prostatic hypertrophy, dyslipidemia and osteoarthritis. His vital signs are blood pressure 76/48mmHg, heart rate 110bpm , oxygen sat 86% and temperature of 39.5C. He is difficult to rouse and you decide he needs rapid sequence intubation.

Question: Can you use Etomidate for RSI in septic patients?

Background: Sepsis has received more attention over the last 5 years or so. This includes the Surviving Sepsis Campaign and the Early Goal-Directed Therapy. Both ACEP and CAEP have guidelines that address optimal management of severe sepsis.

Definition of sepsis: “Sepsis is defined as the presence of both systemic inflammatory response syndrome and the suspicion of an infection. Sepsis is a syndrome, and can range from relatively mild (simple infection) to severe (septic shock and multiorgan dysfunction). Morbidity and mortality increase if a patient deteriorates from sepsis to severe sepsis to multiorgan dysfunction (CAEP)”.

Key Aspects Early Recognition (Grade of Recommendation):

Intravenous Fluids (Grade B)
Intubations (Grade D)
Central Venous Pressure Monitoring (Grade D)
Vasopressors (Grade B)
Inotropes (Grade D)
Lactate Levels (Grade B)
Cultures (Grade D)
Broad Spectrum Antibiotics (Grade C)
Steroids (Grade D)
Blood Transfusions (Grade B)
Activated Protein C (Grade D)
Glucose Control (Grade D)

ACEP Surviving Sepsis Campaign Bundles 2012:

To Be Completed within 3 hrs:
1) Measure lactate level
2) Obtain blood cultures prior to administration of antibiotics
3) Administer broad spectrum antibiotics
4) Administer 30 ml/kg crystalloid for hypotension or lactate ≥4mmol/L

To Be Completed within 6hrs:
5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg
6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL):
–Measure central venous pressure (CVP)*
–Measure central venous oxygen saturation (ScvO2)*
7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of ≥8 mm Hg; ScvO2 of ≥70%, and normalization of lactate.

Reference: Chan CM et al, Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis. Crit Care Med 2012; 40: 2945-2953

Population: Septic patients requiring mechanical ventilation (pediatrics excluded)
Intervention: Single dose etomidate for RSI
Comparison: Other various sedative agents
Outcome: Mortality (all-cause, RCT only, 28 days), adrenal insufficiency

Results:

Mortality Outcomes (5 studies, n=867 patients): INCREASED risk of all-cause death with etomidate (RR 1.20; 95%CI 1.02-1.42, I2 = 4.9%). No difference in subgroup analyses with RCT results only, or standardized mortality at 28days. The 95%CI intervals in the all-cause and subgroup mortality analyses are rather wide. Adrenal Insufficiency (7 studies, n=1303 patients): INCREASED risk of AI with etomidate (RR 1.33; 95%CI 1.22-1.46, I2=43.9%). No difference in sensitivity analysis with RCTs only.

Authors Conclusion: “Administration of etomidate for rapid sequence intubation is associated with higher rates of adrenal insufficiency and mortality in patients with sepsis.”

BEEM Comments: This new review raises concerns about the safety of etomidate in septic RSI, as it is the first review that focusses on mortality issues rather than prior studies looking at AI only. The conclusions for mortality risk must be qualified, however, since the biggest study driving the mortality outcome is a postive observational substudy of the CORTICUS RCT by Cuthbertson et al (499 patients) which contributes 37.66-55.84% of the patients to the pooled results in various subgroups. Inspection of the forest plot reveals that this is the only positive study suggesting harm, and the other included studies show no significant difference. It is clear that excluding the Cuthbertson data would render the results statistically insignificant, which raises doubt about the overall mortality conclusions. Furthermore, the Cuthbertson cohort of patients scored relatively high on the SAPS II score (mean 48; IQR 37-62) which confers a hospital mortality of almost 50%. Other trials had similar illness severity SAPS II scores, yet found insignificant differences in groups (smaller sample sizes). It is not clear why the Cuthbertson results are an outlier compared to other studies/RCTs, and the results of pooling would certainly not be robust if this one study were removed. The authors do not address why the Cuthbertson results seem to be so different from other included studies…A more conservative and methodologically sound MA by Hohl et al (Cdn researcher Vancouver, published Annals EM 2010), rightly excluded this large observational study from RCT SR/MA, and there was no result suggesting increased mortality from etomidate bolus use in RSI in septic shock patients. Specific critiques of the Cuthbertson can also be found in Int J Intens Care 2010 (Pallin and Walls), in CJEM 2011 (Green et al), and most recently in Annals EM 2013 (Syn Snap, Hunter & Kirschner, Indiana University Sch of Med).

BEEM Bottom Line: This review updates the controversy on using single-dose etomidate for RSI in septic patients, and raises more concerns about increased in-hospital mortality. However, this is based on a single large observational substudy of a failed RCT, and it is not clear why these trial results were so different from others. This is enough information to give PAUSE to routine use of etomidate in septic RSI, but not to abandon it completely.

Case Resolution: You initiate 1L normal saline bolus. Do a rapid sequence intubation using etomidate, draw laboratory tests including blood/urine cultures, start broad spectrum antibiotics and call the ICU for admission.

More Sepsis Information:

Walls and Murphy. Clinical Controversies: Etomidate as an Induction Agent for Endotracheal Intubation in Patients With Sepsis. Ann Emerg Med. 2008 Jul;52(1):13-4. doi: 10.1016/j.annemergmed.2008.01.344.
Hohl et al. The Effect of a Bolus Dose of Etomidate on Cortisol Levels, Mortality, and Health Services Utilization: A Systematic Review. doi:10.1016/j.annemergmed.2010.01.030
Hunter and Kirschner. In Patients With Severe Sepsis, Does a Single Dose of Etomidate to Facilitate Intubation Increase Mortality? Ann Emerg Med Vol 61, No. 5: May 3013
Green and Gorman. Safety of etomidate bolus administration in patients with septic shock. CJEM 2011;13(2):105-108
Cuthbertson et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med (2009) 35:1868–1876

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