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?

Background

• 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

Design

• 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

Setting

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

Population

• 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

Intervention

• 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)

Control

• 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

Outcome

• 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

Strengths

• 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

Weaknesses

• 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

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

Metadata

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

Picture by: Pexels / Karoline Grabowska