By: Amanda Bernarde, PharmD; PGY-1 Pharmacy Resident
University of Missouri Health Care
Abbreviations: RSI = rapid sequence intubation; KPA = ketamine propofol admixture; ED= emergency department; SBP= systolic blood pressure; OR= odds ratio; CI= confidence interval; NEAR= National Emergency Airway Registry; TBI= traumatic brain injury; MAP = mean arterial pressure
Rapid sequence intubation (RSI) is a mainstay in critical care and emergency medicine to secure a patient’s airway.1,2 Endotracheal intubation may be indicated if the patient: 1) cannot protect his/her airway, 2) has a risk of aspiration, 3) fails to adequately ventilate or oxygenate, or 4) has anticipated further or rapid decompensation leading to any of the other indications. To facilitate endotracheal tube placement, RSI requires use of sedatives and paralytics to minimize consciousness and to blunt the pathophysiologic response of airway manipulation, respectively. Ideal sedatives produce deep anesthesia with a rapid onset of 30 seconds or less.3 The paralytic agent should have a similar duration. Midazolam, propofol, ketamine, and etomidate are among some of the most common sedatives used in RSI. Though the goal of sedative medications is to augment easy manipulation of the airway, they are not without their own adverse effects, including peri-intubation hypotension.
Concerns for peri-intubation hypotension limit sedative options due to the potential increased risk of cardiac arrest, need for vasopressor support, and in-hospital and post-discharge mortality.3-5 Etomidate, the gold standard sedative, displays hemodynamic neutrality when administered at a dose of 0.2-0.3 mg/kg, whereas midazolam and propofol have known risks of hypotension. Etomidate has potential adverse effects of adrenal suppression and lowering the seizure threshold, which makes it a suboptimal choice during RSI induction in patients presenting with sepsis, epilepsy, or traumatic brain injury (TBI) patients. Increased interest in exploring other RSI sedation options, particularly ketamine only and ketamine-propofol admixture (KPA) regimens, have been analyzed for use in these patient populations.
Mechanistically, ketamine at doses of 0.5-1 mg/kg increase catecholamine release while prohibiting its reuptake in the synaptic cleft.3,6,7 In patients with sufficient circulating catecholamines, this leads to increased blood pressure. In contrast, patients with autonomic dysfunction, such as in sepsis, diabetic ketoacidosis, and myocardial infarction, exhibit decreased myocardial contraction and heart rate.8 Recent literature of ketamine use for sedation during RSI in hemodynamically unstable patients has shown mixed results (Table 1).
Table 1. Summary of hemodynamic effects of ketamine alone compared to other sedatives.
Ischimaru et al was the first study to establish ketamine’s potential hemodynamic neutrality during intubation of hemodynamically unstable patients.6 This prospective observational study from Japan found a statistically significant decrease in ketamine-induced hemodynamic derangement, defined as SBP ≤ 90 mmHg or ≥ 20% decrease in SBP, when compared with the combined comparator of either midazolam or propofol administration. Statistical significance held after adjustments for differences in demographics, primary indication (except in trauma patients), premedication use, and paralytic choice between the two study groups. From this analysis, authors concluded ketamine is superior to midazolam or propofol in maintaining stable hemodynamics during intubation. Of note, etomidate was not compared to ketamine in this study because it is not approved for use in Japan. Due to this difference, additional studies comparing ketamine to etomidate were required to potentially change practice in the United States.
A single large-scale, prospective, multicenter, observational cohort study was conducted by April et al comparing the incidence of peri-intubation hypotension of ketamine to etomidate for any indication.9 Using the NEAR study dataset, ketamine was found to have a statistically significant increase in peri-intubation hypotension incidence in comparison to etomidate. Doses chosen by the practitioner did not impact this outcome. This indicated that ketamine may not provide hemodynamic neutrality as the above study suggested. There were several challenges that limit this study’s generalizability to all populations, including the propensity to choose ketamine over etomidate for sepsis and traumatic brain injury (TBI) patients.
A subgroup analysis of NEAR study participants examined current use of etomidate compared to other sedatives and intubation-associated hypotension incidence of etomidate and ketamine.10 Etomidate was the most frequently used sedative in sepsis patients despite the concerns for its potential adrenal suppression. However, etomidate administration decreased and ketamine administration increased in sepsis patients when compared to nonsepsis patients. In this patient population, patients receiving ketamine did experience intubation-related hypotension more often than those administered etomidate. The hypotension was not sustained or significant as there was no statistical difference in need of vasopressor therapy or peri-intubation cardiac arrest between the two medications. The TBI patient cohort had similar findings that showed significant intubation-associated hemodynamic instability with ketamine when compared to other sedatives.11 Unfortunately, analysis of emergency department or in-hospital use of ketamine for RSI in TBI patients is limited. Overall, in the setting of sepsis or TBI, ketamine does not provide beneficial hemodynamic outcomes, with mixed translation to need for vasopressors and incidence of peri-intubation cardiac arrest.
A novel approach to RSI induction was explored by Smischney et al in the KEEP-PACE trial.12 Reduced dose etomidate (0.15 mg/kg) was compared to a ketamine-propofol admixture (KPA; 0.5 mg/kg of each component) for hemodynamic stability. Because of the novelty of this admixture, the purpose was to establish KPA’s superiority over reduced dose etomidate and reanalyze the mixture against the full etomidate dose if superiority was found. The primary endpoint, the change in mean arterial pressure (MAP) from baseline at 5 minutes post-induction, was not statistically significant (KPA vs etomidate: -3.3 mmHg vs -1.1 mmHg; p= 0.385). Additionally, there was no difference at 10 minutes, 15 minutes, or in average MAP area under the curve. Due to the lack of efficacy, KPA has not been compared to full-dose etomidate.
Despite the initial positive results suggesting ketamine as an alternative to etomidate for hemodynamically unstable patients during RSI, several multicenter, large-scale observational cohort studies have concluded otherwise. At present, etomidate remains the gold standard for induction, particularly in patients who are hemodynamically unstable or have RSI-indications that could quickly decompensate. Nevertheless, the need remains for a hemodynamically neutral induction agent that does not manipulate the adrenal system or lower the seizure threshold, which continues to be the main concerns with universal etomidate use.