Fentanyl versus placebo with ketamine and rocuronium for patients undergoing rapid sequence intubation in the emergency department: The FAKT study—A randomized clinical trial

Ferguson I Academic Emergency Medicine, 2021; DOI: 10.1111/acem.14446

Clinical Question

  • In patients requiring rapid sequence intubation (RSI) in the emergency department does the addition of fentanyl to ketamine and rocuronium reduce the frequency of patients having a systolic blood pressure (SBP) outside of a target range of 100-150mmHg?


  • The INTUBE study showed high rates (42%) of cardiovascular instability in patients undergoing tracheal intubation in ICU, ED and the wards
  • Ketamine has become a commonly used drug for RSI in both pre-hospital and emergency department settings, due to its’ perceived preferable haemodynamic profile
  • Fentanyl may prevent the pressor response to laryngoscopy and prevent episodes of hypertension which may be harmful in some patient groups
  • It is unclear whether the use of Fentanyl as a co-induction agent increases the risk of hypotension when compared with placebo


  • Multi-centre, double blind placebo-controlled randomised controlled trial
  • Randomised 1:1 to treatment or intervention
  • Active and placebo drug prepared by Baxter pharmaceutical and then labelled with study ID by unblinded pharmacist
  • Blinding maintained until manuscript written
  • Intention-to-treat analysis
  • Observations were recorded every 2 minutes by a nominated member of the clinical team for 10 minutes
  • Type of laryngoscope, airway grade, use of adjuncts, number of attempts and immediate complications (e.g. oesophageal intubation) were recorded contemporaneously
  • Study powered to detect a 20% decrease in the primary outcome (Systolic BP outside of the range 100-150) or a change of ≥ 10% if the (SBP) was already outside of this range at baseline
    • If SBP ≥ 151 mmHg then primary outcome met if postinduction SBP rose by ≥ 10% or fell outside the lower limit (i.e. 100 mmHg)
    • If SBP ≤ 99 mmHg then primary outcome met if postinduction SBP fell by ≥ 10% or rose above the upper limit (i.e. 150 mmHg)
  • Ethical approval gained and registered with Australian and New Zealand Clinical Trial Registry


  • 5 ED in New South Wales, Australia, mixture of tertiary and secondary hospitals.
  • August 2018-December 2020


  • Inclusion:
    • Adult patients requiring RSI in the emergency department
  • Exclusion:
    • Allergy to study drugs
    • Paralysis only or no drug intubation
    • Clinician believed another regimen to be necessary
    • Emergency department overwhelmed
    • No specialist trained in the protocol available
  • 476 patients assessed for eligibility
    • 174 excluded
      • Need for alternative induction regimen (n=82)
      • No staff trained in study protocol (n=54)
    • 302 randomised
      • 149 Fentanyl group –> 142 analysed
      • 153 Placebo group –> 148 analysed
  • Comparing baseline characteristics of fentanyl vs placebo group
    • Very similar between the two groups
    • Median age: 55 vs 54
    • Male: 65% vs 53%
    • Estimated Weight: 80kg vs 77.5kg
    • Baseline Vital Signs
      • Median SBP: 132 vs 135
      • Baseline SBP ≤ 99mmHg: 7% vs 7%
      • Baseline SBP ≥ 151 mmHg: 24% vs 30%
      • Median SpO2: 100% vs 100%
    • Co-morbidities
      • Hypertension: 29% vs 28%
    • Indication for Intubation
      • Medical: 90% vs 86%
        • Stroke/ICH: 12% vs 13%
      • Trauma: 10% vs 14%
    • Vasopressor use at time of intubation: 12% vs 12%
    • Median drug doses:
      • Ketamine: 1.4mg/kg vs 1.25 mg/kg
      • Rocuronium: 1.55mg/kg vs 1.55 mg/kg
      • Study Drug: 0.14mg/kg vs 0.13 mg/kg


  • Fentanyl
    • 10mcg/ml in a 20ml syringe administered in volume equal to dose of Ketamine 10mg/ml administered as induction drug (e.g. if administering 100mg Ketamine would administer 100mcg Fentanyl)


  • 0.9% Saline
    • In a 20ml syringe administered in volume equal to dose of Ketamine 10mg/ml administered as induction drug (e.g. if administering 100mg Ketamine would administer 10ml 0.9% Saline)

Management common to both groups

  • All patients received standardised dose of ketamine and rocuronium
    • Ketamine standard dose (1-2mg/kg)
    • Ketamine reduced dose (0.5-1mg/kg)
    • Rocuronium 1.5mg/kg
    • Drugs administered in the same order: study drug, then ketamine and then rocuronium
  • Preparation for intubation standardised including:
    • Monitoring NIBP every 2 minutes, ECG, SpO2 and ETCO2
    • Resuscitation with optimisation of preoxygenation and haemodynamic state
    • Position optimised
    • Airway checklist
    • All intubation performed by emergency physicians trained in study protocol
    • Laryngoscopy 60 seconds post rocuronium administration
  • Additional sedatives in the 10 minutes post induction discouraged


  • Primary outcome:
  • Proportion of patients with SBP outside 100 mmHg – 150 mmHg, (or > 10% change if outside this range) within 10 minutes of induction
  • Fentanyl: 66% vs Placebo: 65%
    • Difference 1% (95% CI – 10 – 12, p=0.86)
  • Secondary outcomes:
  • Comparing fentanyl vs placebo
  • Physiology within 10 minutes of induction:
    • Significantly greater in fentanyl group:
      • Hypotension (SBP < 100): 29% vs 16% Difference 13% (95% CI 3-23)
    • Significantly greater in placebo group:
      • Hypertension (SBP > 150): 55% vs 69% Difference 14% (95% CI 3-24)
      • Tachycardia (HR ≥ 120): 48% vs 61% Difference 13% (95% CI 2-25)
    • No significant difference in:
      • Hypoxia (SpO2 < 93): 19% vs 13% Difference 6% (95% CI -2 to 15)
      • Cardiac arrest: 1.4% vs 0.7% Difference 1% (95% CI -1 – 3)
  • Intubation Characteristics:
    • No significant difference in any of the below
    • Laryngoscopy view
      • Grade I: 61% vs 62%
      • Grade II: 29% vs 29%
    • First pass intubation success
      • 92% vs 92%
    • Use of supraglottic airway devices: 0% vs 1%
    • Need for surgical airway: 0% vs 0%
  • Clinical Outcomes: No difference in any of the below
    • Ventilator free days at day 30: 28 vs 28
    • Mortality at day 30: 19% vs 24%
  • Subgroup Analyses
    • Pre planned subgroup analysis of patients receiving reduced dose ketamine (<1mg/kg, 39% of fentanyl and 33% of placebo groups)
      • No difference in proportion of participants meeting primary end point

Authors’ Conclusions

  • In a mixed population of adults requiring RSI in the ED the addition of fentanyl to rocuronium and ED did not reduce the incidence of an SBP outside of a target range on 100-150
  • However there was an increased incidence of hypotension and reduced incidence of hypertension in the fentanyl group. Clinicians should consider postinduction haemodynamic targets before the decision to use fentanyl as a co-induction agent with ketamine


  • Well-designed double-blinded study performed in the emergency setting
  • Primary outcome data available for 96% of those randomised
    • Sensitivity analyses reveal no change in primary outcome if the missing data was imputed as either meeting or not meeting the primary outcome
  • Included hospitals of different sizes
  • Standardised pre-intubation optimisation
  • Good separation between groups in a manner that is biologically plausible


  • Non-patient centred outcome that was designed by the study authors
    • The authors allude to a lack of a consistent approach in the literature around a pragmatic primary outcome
  • The long term clinical significance of transient haemodynamic changes is not clear
  • Fixed ratio of fentanyl to ketamine may not reflect clinician’s practice
  • Additional sedation discouraged in the 10 minutes post induction – this may not be reflective of treating post-operative hypertension with further sedation doses
  • Large number of patients excluded due to clinician preference for alternate induction regimen which may suggest lack of equipoise
  • Inability to regularly recruit overnight may introduce a selection bias
  • Hospitals all from one region which may limit generalisability

The Bottom Line

  • Fentanyl, when given in a fixed ratio with ketamine, may increase the risk of peri-intubation hypotension
  • I will continue to individually select the doses of induction agents based on patient characteristics and the co-induction agent used

External Links


Summary author: Alastair Brown – @alastairbrown21
Summary date: 15th May 2022
Peer-review editor: George Walker

Picture by: Pexels / Karoline Grabowska

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