Ketamine-based versus fentanyl-based regimen for rapid-sequence endotracheal intubation in patients with septic shock: A randomised controlled trial

Hypotension is a common and life-threatening complication after endotracheal intubation, especially when intubation is performed in emergency settings [1, 2]. Mounting evidence suggests that the risk of serious sequelae of hypotension is present even with very short periods of low blood pressure [3, 4]. In the operating room, the early intraoperative period between induction of anaesthesia and surgical skin incision is the critical period at which nearly 30% of hazardous hypotension occurs [5, 6].

Patients with septic shock commonly require endotracheal intubation in emergency departments and intensive care units. Furthermore, patients with septic shock frequently undergo surgical procedures, for which general anaesthesia is the usual choice. Patients with septic shock are characterised by refractory hypotension [7]; therefore, they are at higher risk of deleterious hypotension after induction of anaesthesia. The ideal regimen for induction of anaesthesia and/or endotracheal intubation in hypotensive patients should provide adequate hypnosis without further decrease in blood pressure [8]. However, most of the intravenous hypnotic agents have negative cardiovascular effects [8, 9]. Therefore, induction of anaesthesia and/or endotracheal intubation in patients with circulatory failure presents a challenging problem for intensivists, anaesthesiologists, and emergency physicians.

Ketamine is an induction anaesthetic with unique sympathomimetic properties [8]; thus, its use is usually associated with increased arterial blood pressure and cardiac output in patients whose sympathetic nervous activity is intact [9]. However, the use of ketamine in patients with acute circulatory failure showed conflicting evidence. Fentanyl is an ultrashort-acting opioid receptor agonist which is commonly used for sedation and analgesia in the operating theatre as well as the intensive care unit [10]. Fentanyl is widely used in the operating theatre, especially in cardiac surgery. However, its use in rapid sequence intubation in patients with septic shock was not adequately investigated. We hypothesized that fentanyl in rapid sequence induction may give a better hemodynamic profile than ketamine.

In this study, we compared ketamine-based versus fentanyl-based regimens for rapid-sequence induction of anaesthesia in patients with septic shock.

Between September 2018 and September 2019, this randomised controlled trial was performed in the surgical theatre at the emergency department of Cairo University Hospital. The study was approved by the Research Ethics Board of Faculty of Medicine, Cairo University (N-12-2018) and registered at the clinicaltrials.gov registry system before enrolment of the first participant (identifier: NCT03251170; principal investigator: Ahmed Hasanin; date of registration: 12 August^, 2017). The study was conducted in a double-blinded design and the participants were randomised using a computer-generated sequence of codes which was performed by a statistician. The codes were inserted in opaque envelopes which contained the instructions for preparation of study drugs. The investigators acquired informed consents from the participants or their surrogates before inclusion in the study.

Inclusion and exclusion criteria: The study included patients who fulfilled the following criteria: age between 18 and 65 years; experiencing septic shock; scheduled for emergency surgery to control the source of sepsis. Septic shock was defined as hypotension which required infusion of norepinephrine to maintain mean arterial pressure (MAP) > 65 mmHg with elevated serum lactate level (above 2 mmol/L) despite adequate fluid resuscitation in addition to the presence of infection [7]. Exclusion criteria were burns, traumatic brain injury or history of any cerebrovascular disorders.

Before induction of anaesthesia, initial resuscitation and hemodynamic management were performed according to the surviving sepsis campaign guidelines [11]. Initially, a 30 mL/Kg bolus of Ringer’s lactate solution was administered. Subsequent infusion of fluids was guided by dynamic methods for fluid responsiveness [12] until the patient was non-respondent. Norepinephrine infusion was titrated to keep MAP > 65 mmHg.

The following monitors were applied to the patients during resuscitation and surgery: electrocardiograph (ECG), pulse oximetry, and non-invasive blood pressure monitor. Invasive blood pressure monitor was connected to a radial arterial catheter. Non-invasive cardiac output measurement was obtained through electrical cardiometry ICON^R monitor (Osyka Medical, Inc., La Jolla, California and Berlin, Germany) which was applied to the patients’ neck and upper trunk through ECG electrodes. Four sites were used for placement of the electrodes; all at the left side: (1) At the upper neck below the ear; (2) At the clavicle, one centimetre cephalad to the midpoint; (3) At the mid-axillary line at the level of the xiphoid process; (4) Two inches caudad from the third site. The validity of the measurements of the electrical cardiometry was confirmed through the quality of the indicator bar signals and the ECG waveform.

Before induction of anaesthesia, patients were allocated into one of the two study groups according to the randomisation code:

After reaching the endpoint for hypnosis, an endotracheal tube was inserted after administration of IV succinyl choline (1 mg/kg). The endpoint for adequate hypnosis was defined as loss of the ability to respond to simple verbal orders [13, 14]. Maintenance of hypnosis was achieved by isoflurane at concentration of 1%. After fading of succinyl choline activity, paralysis was secured using atracurium (initial bolus of 0.5 mg/kg followed by 10 mg increments). The ventilator settings were adjusted at a tidal volume of 6 mL/Kg and a respiratory rate was set at 12–15 per minute to achieve a target end-tidal CO2 at 30–35 mmHg.

If the patient developed postintubation hypotension, norepinephrine infusion rate was increased till reaching MAP > 65mmHg. Postintubation hypotension was considered if the MAP decreased to ≤ 80% from the pre-induction value. In cases of severe or persistent hypotension, the isoflurane concentration was decreased by 50% until the norepinephrine infusion achieved MAP > 65mmHg

The primary outcome was the mean arterial pressure at 1 min after induction of anaesthesia. Other outcomes included the incidence of postinduction hypotension (MAP ≤ 80% the baseline value during the period from induction of anaesthesia until 10 min). The mean arterial pressure, heart rate, and cardiac output were analysed at baseline value, 1, 2, 3, 4, 5, and 10 mins after the induction of anaesthesia. Serum lactate at baseline and 1 min after the induction of anaesthesia was also analysed.

Fifty patients were evaluated for eligibility for the study. Four patients were excluded for not meeting the inclusion criteria. Forty-six patients were randomized to receive one of the two interventions. Twenty-three patients in the ketamine group and 19 patients in the fentanyl group were available for final analysis (Figure 1). Demographic data and baseline characteristics were comparable between both study groups (Table 1).

Figure 1

The mean blood pressure was higher in the ketamine groupthan in the fentanyl group at 1, 2 and 5 minutes after the induction of anaesthesia. The mean blood pressure was maintained in relation to the baseline reading during the first 10 minutes after induction in the ketamine group. In the fentanyl group, the MAP decreased in relation to baseline reading at 1 minute after the induction of anaesthesia (Figure 2).

Figure 2

The number of patients with postinduction hypotension was lower in the ketamine group than in the fentanyl group (11 [47.8%] versus 16 [84.2%], P-value= 0.014) (Table 2). Other hypodynamic parameters, namely the heart rate (Figure 3) and cardiac output (Figure 4), were comparable between both groups; these were generally maintained in relation to the baseline reading in each group.

Figure 3

Figure 4

We compared two regimens for rapid-sequence intubation in patients with septic shock and found that the ketamine-based regimen was associated more stable cardiovascular profile compared to the fentanyl-based regimen.

In patients with normal arterial blood pressure, induction of hypnosis with ketamine was associated with the most stable hemodynamic profile among different hypnotic agents [9]. Ketamine is a sympathomimetic agent which increases the cardiac output by 40–50% [15, 16, 17]. However, the use of ketamine in patients with shock was not adequately explored. In vitro studies have shown that ketamine reduces contractility in failing myocardial muscle fibres [18, 19]. However, clinical studies favoured the use of ketamine in patients with shock. In an observational study, Ishimaru et al. had reported that ketamine is associated with a lower risk of post-intubation hypotension compared to midazolam and propofol when used in undifferentiated hemodynamically unstable patients, defined by high shock index, in the emergency department [20]. Another retrospective study favoured ketamine over midazolam in stable patients with ST elevation myocardial infarction [21]. Our study has the advantage of randomised controlled design. Furthermore, our comparison focused on one subgroup of patients, septic shock patients, and compared ketamine versus fentanyl in induction of anaesthesia. Finally, we included more critical patients who were on norepinephrine infusion at enrolment.

Fentanyl is widely used in patients with cardiac morbidities, especially those undergoing cardiac surgery [10]; however, its use in patients with shock was not adequately evaluated. Two recent observational studies had reported that pre-treatment with fentanyl before sedative agents increases the incidence of post-intubation hypotension in the emergency department [22, 23].

To the best of our knowledge, this is the first randomised controlled trial comparing ketamine-based versus opioid-based endotracheal intubation in patients with septic shock during emergency procedures. Our results support ketamine over fentanyl in this high-risk group of patients. Rapid-sequence endotracheal intubation in emergency patients is commonly associated with hypotension due to many factors such as cardiovascular depression by sedative agents, decreased venous return due to positive pressure ventilation [24] and increased pulmonary vascular resistance [25]. Post-intubation hypotension had been recently reported as a risk factor for peri-intubation cardiac arrest. In the special subgroup of patients with septic shock, refractory hypotension [7] is sometimes associated with myocardial dysfunction [26]. Hence, proper choice of the induction protocol would avoid further aggravation of hypotension during induction of anaesthesia.

Our study has the advantage of randomised controlled double-blinded design. Furthermore, the study focused on a special group with high shock index plus norepinephrine infusion. The study has some limitations: it is based on a single centre, the results cannot be extrapolated to patients with other types of shock, and our results might differ if other combinations of drugs were used. Also, special studies in the elderly and children should be performed.

In conclusion, the ketamine-based regimen provided a better hemodynamic profile compared to the fentanyl-based regimen for rapid-sequence intubation in patients with septic shock undergoing emergency surgery.