Abstract
BACKGROUND
Etomidate and ketamine are commonly used to facilitate prehospital rapid sequence intubation.
OBJECTIVE
We aimed to estimate the association between sedative agent and outcomes in this patient population.
METHODS
We evaluated all adult (≥18 years) patients in the ESO Data Collaborative research dataset during 2023 and 2024 who received ketamine or etomidate and a paralytic followed by an intubation attempt for inclusion. Our primary outcome was post-sedative cardiovascular collapse (SBP<65 mmHg, vasopressor administration, or cardiac arrest) and secondary outcomes included intubation success and survival to hospital discharge. To compare sedatives, we used multilevel mixed-effects logistic regression with EMS agency as a random intercept adjusted for age, sex, pre-sedative airway suction, route (IV vs. IO) patient type (trauma vs. medical), paralytic used, pre-sedative vital signs (minimum SBP, maximum HR, minimum SpO2), pre-sedative minimum Glasgow Coma Scale, first-attempt video laryngoscopy use, first-attempt bougie use, and treatment year.
RESULTS
We analyzed 10,727 patients treated by 703 EMS agencies, of whom 5,505 (51.3%) received ketamine as a sedative prior to the first endotracheal intubation attempt. Etomidate administration was associated with decreased odds of cardiovascular collapse in comparison to ketamine administration (aOR: 0.56 [0.48, 0.65], n=10,703). Sedative agent was not associated with the odds of first attempt intubation success (aOR: 1.11 [0.97, 1.27], n=10,703), overall intubation success (aOR: 1.19 [0.98, 1.43], n=10,703), or mortality (aOR: 0.99 [0.80. 1.21], n=3,074).
CONCLUSIONS
The use of etomidate as a sedative was associated with lower odds of hemodynamic instability following attempted rapid sequence intubation in comparison to ketamine.
Keywords: ketamine, etomidate, drug assisted airway management, rapid sequence intubation
INTRODUCTION
Etomidate and ketamine are the two most commonly used sedatives during rapid sequence intubation in hospital [1,2] and prehospital [3,4] settings. The choice of sedative may be important due to differing effects on patient physiology with implications for airway management success, subsequent hemodynamic perturbations, and mortality. Etomidate binds to gamma aminobutyric acid (GABA) receptors and increases their affinity for GABA. This medication is fast acting, has a short half-life, and has been reported to have minimal effects on patient hemodynamics, which has led to the widespread use of this medication for emergency intubation. However, etomidate also causes adrenal suppression via inhibition of 11-beta-hydroxylase, [5] which may lead to adrenal insufficiency and impair the recovery of critically ill patients [1,6]. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is also widely used for anesthesia induction prior to airway management in the emergency department. Despite possessing sympathomimetic properties, the use of ketamine has been associated with peri-intubation hypotension in multiple observational [2,3] and randomized studies [7,8].
Limited data exist comparing the effects of sedative agents on outcomes following attempted prehospital rapid sequence intubation. However, multiple randomized clinical trials have compared these two medications, primarily in the context of in-hospital emergency airway management by physicians. A recent meta-analysis of 7 trials that enrolled 2,384 (1,184 [49.7%] ketamine) patients suggested that, in comparison to single-dose etomidate, single-dose ketamine use led to a higher prevalence of post-induction hemodynamic instability, a lower prevalence of continuous vasopressor infusion during hospitalization, less vasopressor-dependent days, and a lower prevalence of adrenal suppression. No difference was detected for the outcomes of first attempt intubation success or mortality [7]. There are several limitations to these previous trials. Only one trial enrolled patients in the prehospital setting, which may limit generalizability. [9] The single prehospital trial was conducted in a physician-led system dissimilar from the majority of EMS systems worldwide and excluded patients who died prior to hospital arrival, which may have minimized the influence of early post-intubation cardiovascular collapse. In addition, prior trials were focused on long-term outcomes including organ dysfunction during hospitalization and survival to hospital discharge instead of mechanistic outcomes proximal to the intervention. For example, only three trials reported the outcome of intubation success. In the context of this evidence gap and observed variability in the prehospital use of induction agents, it is important to examine the outcomes of patients receiving etomidate and ketamine in the prehospital setting for rapid sequence endotracheal intubation.
We used a nationwide prehospital dataset to provide real-world evidence comparing these sedatives across EMS systems in the United States. We aimed to determine whether the sedative administered during attempted rapid sequence endotracheal intubation was associated with post-sedative cardiovascular collapse. We also estimated the association between sedative agent and secondary outcomes including first attempt intubation success, overall intubation success, and survival to hospital discharge.
METHODS
Study design and data source
We performed a retrospective, observational cohort study using the ESO Data Collaborative [10] research datasets. These datasets contain de-identified prehospital electronic health record (EHR) data. During or following patient care, EMS clinicians document patient demographics, assessment findings, and interventions, including the dose, timing, and route of medication administration. Data elements are compliant with the National Emergency Medical Services Information System (NEMSIS) v3 standard [11]. Approximately 20% of transported patients have associated hospital disposition data obtained from a bi-directional health data exchange. Use of this de-identified dataset was approved by the relevant institutional review board (#2202524583).
Inclusion criteria
We included all adult (≥18 years of age) patients in the ESO Data Collaborative research dataset encountered during 2023 and 2024 who received intravenous or intraosseous (IV or IO) ketamine or etomidate and a paralytic drug (rocuronium, succinylcholine, or vecuronium) followed by at least one endotracheal intubation attempt. We excluded patients with an outcome event prior to sedative administration and patients who were encountered during an interfacility transfer. If a patient received both ketamine and etomidate (e.g. a patient received etomidate and then later received ketamine for post-procedural sedation), we allocated them to treatment group based on the first sedative administered.
Variables and outcome measures
We derived demographic variables (age, sex), patient type (trauma vs medical), and treatment year from existing data elements. Vital sign assessments and procedure attempts (e.g. suction, vascular access, endotracheal intubation) were included in the EHR with associated times. Each attempt at endotracheal intubation was associated with data describing whether the attempt was successful and what assisting device(s) were used (e.g., video laryngoscope, bougie).
Our primary outcome was the proportion of patients who experienced post-sedative cardiovascular collapse defined using a modified version of the Vanderbilt Definition of post-induction cardiovascular collapse (systolic blood pressure [SBP] < 65 mmHg or vasopressor administration [norepinephrine, push dose epinephrine, epinephrine infusion, dopamine, phenylephrine], or cardiac arrest) [12,13]. The Vanderbilt Definition has specific time thresholds for each component of the composite outcome: cardiac arrest has to occur within 60 minutes of induction, and an SBP < 65 or vasopressor administration has to occur between the time of induction and 2 minutes after intubation. Because very few patients in our cohort had a follow-up time (induction to hospital arrival) of >60 minutes, and a minority of patients had a blood pressure documented between induction and 2 minutes following intubation, we classified any patient meeting any of the criteria at any time following induction in the prehospital setting as experiencing cardiovascular collapse.
Our secondary outcomes included first pass ETI success and overall ETI success, which we determined based on EMS documentation of procedure success. We also assessed intubation attempt success on the first attempt without hypotension or hypoxia (DASH-1A), an outcome that has been proposed as a quality metric for airway management in the prehospital setting [14]. This outcome captures both procedural success and the avoidance of physiologic abnormalities associated with adverse outcomes following airway management. We calculated the proportion of patients who had DASH-1A in our cohort among the subgroup of patients who had at least one SBP and one SpO2 documented in the first 10 minutes following sedative administration time. For this analysis, we defined hypotension as an SBP < 90 mmHg, and hypoxia as an SpO2 <90%.
We assessed the outcome of survival to hospital discharge within the subgroup of patients with hospital disposition data. We classified patients who were discharged to home, a skilled nursing or rehabilitation facility, a long-term acute care facility, law enforcement, or a psychiatric facility as surviving to hospital discharge. We classified patients as dying prior to discharge if they were deceased at discharge or were discharged to hospice/palliative care.
Statistical analysis
We reported continuous variables as medians with interquartile ranges and categorical variables as percentages and frequencies. For binary outcomes, we reported between group differences as adjusted odds ratios with associated 95% confidence intervals.
To compare sedative agents, we used multilevel mixed effects logistic regression adjusted for age, sex, pre-sedative airway suction, sedative route (IV vs. IO), patient type (trauma vs. medical), paralytic used (succinylcholine, rocuronium, or vecuronium), pre-sedative vital signs (minimum SBP, maximum HR, minimum SpO2), pre-sedative minimum Glasgow Coma Scale, video laryngoscopy use at the first ETI attempt, bougie use at the first ETI attempt, and treatment year. We chose these covariables using a directed acyclic graph (DAG) [15] [Supplemental Material, section 2.0]. The use of a DAG facilitates identification of relevant confounders and avoidance of inappropriate adjustment for variables that serve as mediators or colliders. We included a random intercept for EMS agency to address clustering.
We performed subgroup analyses using the same method within subgroups defined by indication for airway management (trauma vs. medical), paralytic, hemodynamic status, sedative administration route, transport mode, and laryngoscopy type. To address the positivity assumption, [16] we performed a subgroup analysis restricted to patients treated by EMS agencies that administered both sedatives during the study period. Some EMS agencies have adopted a practice known as ‘delayed sequence intubation’ that entails the use of ketamine to facilitate preoxygenation for at least 3 minutes [17,18] prior to paralytic administration. Because this practice could influence our estimates of effect size, we performed subgroup analyses stratified by whether the first intubation attempt was performed ≥ 3 or < 3 minutes after sedative administration.
We used StataMP 19.0 for all data management and statistical analyses.
Secondary analyses
Because the use of a dichotomous threshold to define hypotension may obscure clinically important blood pressure changes, we performed a secondary analysis of the association between sedative agent and the post-sedative change in blood pressure among the subgroup of patients with at least one blood pressure documented within 10 minutes of sedative administration. For this analysis, we defined the pre-sedative blood pressure as the last SBP documented prior to sedative administration, and the post-sedative blood pressure as the lowest blood pressure recorded in the 10 minutes following sedative administration. We used a linear regression model with the same covariables as our primary analysis to determine whether sedative agent was associated with post-sedative blood pressure.
RESULTS
Cohort characteristics
We analyzed 10,727 patients treated by 703 EMS agencies, of whom 5,505 (51.3%) received ketamine as a sedative agent prior to the first endotracheal intubation attempt [Figure 1]. The cohort was a median 62 [43, 74] years of age, 42.9% female, and 23.5% were intubated following an injury. The median dose of ketamine was 2.0 (1.3-2.1) milligrams per kilogram (mg/kg) and the median dose of etomidate was 0.3 (0.3, 0.3) mg/kg. Overall, 1,527 (14.2%) patients experienced post-sedative cardiovascular collapse, 8,944 (83.4%) had first-attempt ETI success, and 9,910 (92.4%) were successfully intubated. Of the 3,083 patients with associated hospital disposition data, 2,129 (69.1%) survived to hospital discharge. Baseline characteristics of the cohort stratified by sedative agent are displayed in Table 1.
Figure 1. Cohort derivation from ESO Data Collaborative research datasets.
ETI – endotracheal intubation, IV = intravenous, IO = intraosseous, SBP = systolic blood pressure, HR = heart rate, GCS = Glasgow Coma Scale. *Paralytic = rocuronium, succinylcholine, or vecuronium.
Table 1.
Baseline cohort characteristics, stratified by sedative.
| Ketamine | Etomidate | Total | |
|---|---|---|---|
| N | 5,505 (51.3%) | 5,222 (48.7%) | 10,727 (100.0%) |
| Age (years) | 61.0 (41.0-73.0) | 63.0 (45.0-74.0) | 62.0 (43.0-74.0) |
| Weight (kg) | |||
| missing: 2,017 | 81.6 (70.0-99.8) | 81.6 (68.0-99.8) | 81.6 (69.9-99.8) |
| Dose (mg/kg) | |||
| missing: 1,994 | 2.0 (1.3-2.1) | 0.3 (0.3-0.3) | - |
| Sex | |||
| Male | 3,138 (57.0%) | 2,965 (56.8%) | 6,103 (56.9%) |
| Female | 2,364 (42.9%) | 2,236 (42.8%) | 4,600 (42.9%) |
| Missing | 3 (0.1%) | 21 (0.4%) | 24 (0.2%) |
| Pre-sedative SBP (mmHg) | 132.0 (108.0-155.0) | 138.0 (113.0-164.0) | 135.0 (111.0-159.0) |
| Pre-sedative HR (bpm) | 111.0 (92.0-131.0) | 112.0 (92.0-133.0) | 112.0 (92.0-132.0) |
| Pre-sedative SpO2 (%) | 88.0 (77.0-95.0) | 88.0 (77.0-95.0) | 88.0 (77.0-95.0) |
| Pre-sedative GCS | 5.0 (3.0-9.0) | 5.0 (3.0-9.0) | 5.0 (3.0-9.0) |
| Pre-sedative suction | |||
| No | 4,691 (85.2%) | 4,627 (88.6%) | 9,318 (86.9%) |
| Yes | 814 (14.8%) | 595 (11.4%) | 1,409 (13.1%) |
| Sedative route | |||
| IV | 4,924 (89.4%) | 4,746 (90.9%) | 9,670 (90.1%) |
| IO | 581 (10.6%) | 476 (9.1%) | 1,057 (9.9%) |
| Both sedatives administered | |||
| No | 5,478 (99.5%) | 4,803 (92.0%) | 10,281 (95.8%) |
| Yes | 27 (0.5%) | 419 (8.0%) | 446 (4.2%) |
| Paralytic | |||
| Rocuronium | 3,959 (71.9%) | 1,823 (34.9%) | 5,782 (53.9%) |
| Succinylcholine | 1,354 (24.6%) | 3,197 (61.2%) | 4,551 (42.4%) |
| Vecuronium | 192 (3.5%) | 202 (3.9%) | 394 (3.7%) |
| Mechanism | |||
| Medical | 3,791 (68.9%) | 3,707 (71.0%) | 7,498 (69.9%) |
| Trauma | 1,364 (24.8%) | 1,158 (22.2%) | 2,522 (23.5%) |
| Mixed/unspecified | 350 (6.4%) | 357 (6.8%) | 707 (6.6%) |
| Year | |||
| 2023 | 2,533 (46.0%) | 2,531 (48.5%) | 5,064 (47.2%) |
| 2024 | 2,972 (54.0%) | 2,691 (51.5%) | 5,663 (52.8%) |
| Transport mode | |||
| Ground | 4,740 (86.1%) | 4,399 (84.2%) | 9,139 (85.2%) |
| Air | 289 (5.2%) | 223 (4.3%) | 512 (4.8%) |
| Missing | 476 (8.6%) | 600 (11.5%) | 1,076 (10.0%) |
| Initial laryngoscopy type | |||
| Direct | 3,262 (59.3%) | 3,645 (69.8%) | 6,907 (64.4%) |
| Video | 2,243 (40.7%) | 1,577 (30.2%) | 3,820 (35.6%) |
| Initial bougie use | |||
| No | 3,862 (70.2%) | 3,814 (73.0%) | 7,676 (71.6%) |
| Yes | 1,643 (29.8%) | 1,408 (27.0%) | 3,051 (28.4%) |
| Post-sedative CPR | |||
| No | 5,168 (93.9%) | 5,017 (96.1%) | 10,185 (94.9%) |
| Yes | 337 (6.1%) | 205 (3.9%) | 542 (5.1%) |
| Post-sedative SBP < 65 | |||
| No | 5,067 (92.0%) | 5,023 (96.2%) | 10,090 (94.1%) |
| Yes | 438 (8.0%) | 199 (3.8%) | 637 (5.9%) |
| Post-sedative vasopressor | |||
| No | 4,717 (85.7%) | 4,872 (93.3%) | 9,589 (89.4%) |
| Yes | 788 (14.3%) | 350 (6.7%) | 1,138 (10.6%) |
| CVC (Vanderbilt) | |||
| No | 4,473 (81.3%) | 4,727 (90.5%) | 9,200 (85.8%) |
| Yes | 1,032 (18.7%) | 495 (9.5%) | 1,527 (14.2%) |
| First attempt ETI success | |||
| No | 984 (17.9%) | 799 (15.3%) | 1,783 (16.6%) |
| Yes | 4,521 (82.1%) | 4,423 (84.7%) | 8,944 (83.4%) |
| Any ETI success | |||
| No | 451 (8.2%) | 366 (7.0%) | 817 (7.6%) |
| Yes | 5,054 (91.8%) | 4,856 (93.0%) | 9,910 (92.4%) |
SBP = systolic blood pressure, HR = heart rate, GCS = Glasgow Coma Scale, IV = intravenous, IO = intraosseous, CPR = cardiopulmonary resuscitation, CVC (Vanderbilt) = cardiovascular collapse, Vanderbilt Definition, ETI = endotracheal intubation.
Primary analysis
Multi-level mixed effects logistic regression demonstrated that etomidate administration was associated with decreased odds of cardiovascular collapse in comparison to ketamine administration (aOR: 0.56 [0.48, 0.65], n=10,703). Sedative agent was not associated with first attempt endotracheal intubation success (aOR: 1.11 [0.97, 1.27], n=10,703), overall endotracheal intubation success (aOR: 1.19 [0.98, 1.43], n=10,703), or mortality (aOR: 0.99 [0.80. 1.21], n=3,074).
Secondary analyses
A blood pressure was documented within 10 minutes of sedative administration for 8,970 (83.6%) patients. After adjustment for pre-sedative systolic blood pressure and the other factors in our primary model, linear regression modeling demonstrated that ketamine use was associated with a 6 [4, 7] mmHg lower post induction minimum systolic blood pressure in comparison to etomidate use.
Overall, 8,693 (81.0%) patients had at least one SBP and SpO2 value documented within 10 minutes of sedative administration, and 4,828 (55.5%) achieved DASH-1A in this subgroup. Within this subgroup, etomidate administration was associated with increased odds of achieving DASH-1A in comparison to ketamine administration (aOR: 1.14 [1.02, 1.28]).
DISCUSSION
In this nationwide dataset, more than one in ten patients experienced cardiovascular collapse following rapid sequence intubation, underscoring the risk associated with this procedure in the prehospital setting. Although ketamine and etomidate were both widely used to facilitate prehospital airway management, our findings indicate that the risk is not evenly distributed between medications. Ketamine administration was associated with a higher prevalence of post-induction cardiovascular collapse in comparison to etomidate. Collectively, these results highlight that agent selection during induction may have meaningful implications for patient hemodynamic stability and subsequent resuscitation needs.
The results of our primary analysis align with the results of a systematic review and meta-analysis that compared single-dose ketamine to single-dose etomidate for rapid sequence intubation in emergency settings [7] and a recently published large, randomized clinical trial comparing these agents for emergency intubation in the emergency department and ICU. [8] However, direct comparison of our results are limited by variation in the definitions of peri-intubation hemodynamic instability used by trialists. While some of the included trials used the Vanderbilt Definition of post-induction cardiovascular collapse [8,13] or components of this definition such as vasopressor administration and cardiac arrest, others used less stringent criteria such as a SBP < 90 mmHg [19].
Ketamine administration causes the release of catecholamines, [20,21] which has been shown to increase blood pressure and heart rate. However, this drug has also been suggested to have negative inotropic effects on the myocardium [22] and has been associated with hypotension and cardiovascular collapse [2,7]. It is possible that these deleterious effects are most pronounced in patients with catecholamine depletion.
Our analysis suggested that, overall, etomidate administration was not associated with an increased prevalence of first pass intubation success and overall intubation success. These data align with randomized data suggesting that the use of ketamine and etomidate result in similar intubating conditions [9] and similar first attempt intubation success [7].
We classified patients into treatment groups using the first sedative administered and included patients who received both etomidate and ketamine in the prehospital setting. We made this choice because the need for additional sedation is on the causal path between initial sedative choice and cardiovascular collapse. For example, etomidate use may lead to an increased requirement for repeat sedation because of a shorter duration of effect in comparison to ketamine. If repeated sedative dosing increases the risk for hypotension and cardiovascular collapse, eliminating cases with repeated sedative administration would inappropriately bias our estimate of effect size. Less than 5% of the patients in this study received both drugs, and the majority of these cases were patients who initially received etomidate and later received ketamine, likely for post-procedure sedation and analgesia. A sensitivity analysis excluding patients who did not receive both medications resulted in estimates of effect size that were similar to our analyses of the overall cohort. [Table 2]
Table 2.
Subgroup analyses.
| Subgroup etomidate vs. ketamine |
CV collapse aOR [95% CI] |
Mortality aOR [95% CI] |
|---|---|---|
|
Overall Total n: 10,727 Survival n: 3,083 |
0.56 [0.48, 0.65] | 0.99 [0.80, 1.21] |
|
Trauma Total n: 2,522 Survival n: 642 |
0.62 [0.44, 0.87] | 1.11 [0.65, 1.89] |
|
Medical Total n: 7,498 Survival n: 2,253 |
0.55 [0.47, 0.65] | 0.96 [0.75, 1.22] |
|
Rocuronium Total n: 5,782 Survival n: 1,695 |
0.56 [0.47, 0.68] | 1.13 [0.87, 1.46] |
|
Succinylcholine Total n: 4,551 Survival n: 1,341 |
0.53 [0.41, 0.67] | 0.71 [0.50, 1.00] |
|
Pre-sedative SBP<110 Total n: 2,493 Survival n: 760 |
0.59 [0.46, 0.75] | 1.07 [0.74, 1.55] |
|
IV sedative Total n: 9,670 Survival n: 2,820 |
0.57 [0.49, 0.67] | 0.99 [0.80, 1.23] |
|
IO sedative Total n: 1,057 Survival n: 263 |
0.45 [0.32, 0.64] | 0.93 [0.50, 1.70] |
|
Direct laryngoscopy Total n: 6,907 Survival n: 1,977 |
0.57 [0.48, 0.68] | 0.88 [0.68, 1.15] |
|
Video laryngoscopy Total n: 3,820 Survival n: 1,106 |
0.49 [0.39, 0.63] | 1.13 [0.83, 1.52] |
|
Treated by EMS agencies that administered both sedatives during the study period Total n: 7,890 Survival n: 2,432 |
0.60 [0.51, 0.71] | 1.02 [0.81, 1.29] |
|
Single sedative agent administered in prehospital setting Total n: 10,281 Survival n: 3,006 |
0.54 [0.46, 0.63] | 0.99 [0.80, 1.23] |
|
First ETI attempt < 3 minutes after sedative administration Total n: 5,344 Survival n: 1,657 |
0.57 [0.47, 0.70] | 0.97 [0.74, 1.28] |
|
First ETI attempt ≥ 3 minutes after sedative administration Total n: 5,383 Survival n: 1,476 |
0.51 [0.42, 0.63] | 1.00 [0.73, 1.35] |
|
Removal of paralytic agent, bougie use, and video laryngoscopy use from model Total n: 10,727 Survival n: 3,083 |
0.50 [0.44, 0.58] | 1.01 [0.83, 1.23] |
|
Patients with documented weight Total n: 8,710 Survival n: 2,057 |
0.58 [0.50, 0.68] | 0.99 [0.78, 1.26] |
|
Ground transport Total n: 9,139 Survival n: 2,726 |
0.58 [0.50, 0.68] | 1.00 [0.80, 1.24] |
|
Air transport Total n: 512 Survival n: 78 |
0.13 [0.04, 0.42] | 1.87 [0.41, 8.64] |
SBP = systolic blood pressure, IV = intravenous, IO = intraosseous, CV = cardiovascular, ETI = endotracheal intubation, aOR = adjusted odds ratio, CI = confidence interval.
We included paralytic agent and the use of a bougie or video laryngoscope during the first intubation attempt in our multivariable models despite the fact that paralytic administration and attempted intubation occur shortly after sedative administration during the rapid sequence intubation procedure. It is appropriate to include these ‘post-treatment’ variables in our models because they are not on the causal path between our exposure and primary outcome of interest. For example, there is no reason why a patient’s response to a sedative medication would influence a clinician’s subsequent choice of paralytic agent, as both paralytic drugs and sedatives are nearly universally drawn into syringes prior to sedative administration. A subgroup analysis removing these covariables from our multilevel mixed-effects regression model produced results that were similar to our primary estimate. [Table 2]
LIMITATIONS
Despite our efforts to minimize the influence of confounding variables on our estimates of effect size, our findings are still at risk of bias from unknown or unmeasured confounders and residual confounding. Confounding by indication may also bias our results, as clinicians may have selected a sedative based on their perception of the relative hemodynamic effects of ketamine or etomidate among patients with shock. However, the baseline characteristics of patients treated with each sedative were similar with respect to vital signs and mechanism of injury, which suggests that, in this overall cohort, clinicians may not have been preferentially selecting one sedative for more severely ill or injured patients.
Some clinicians may decrease the dose of sedative administered in the context of hemodynamic instability. We did not adjust for the dose of sedative administered in our analysis because of a prior study that suggested dose was not associated with post-intubation hypotension [23] and significant missingness of patient weight in this dataset. Whether the hemodynamic effects of these drugs are dose dependent is an important area of future study.
We included paralytic agent in our model because of a randomized clinical trial that suggested succinylcholine use may result in increased post-induction hypotension and vasopressor use [24] in comparison to rocuronium. One hypothesis to explain this relationship is that the use of depolarizing, shorter acting paralytics may result in administration of higher doses of sedatives and analgesics, which may lead to hemodynamic compromise. Future work to investigate the influence of paralytic choice and dosing on hemodynamic compromise and endotracheal intubation success in the context of prehospital rapid sequence intubation may be warranted.
We excluded patients who experienced our primary outcome prior to sedative administration, and therefore hemodynamically unstable patients who received resuscitation with vasopressors prior to induction were not included in our cohort. Because the use of push dose vasopressors or a vasopressor infusion to treat or prevent peri-intubation hypotension is common practice, this may limit the generalizability of our results to patients with significant physiologic derangement at the time of induction.
To ensure appropriate temporality between our exposure and outcome of interest, we relied on the times documented by EMS clinicians. Because these times may be documented after the provision of patient care, inaccuracies may influence our analysis. However, based on the clinical experience of our team, which includes clinicians who regularly perform reviews of prehospital EHR and cardiac monitor biosignal data recorded during the treatment of patients who receive prehospital rapid sequence intubation, the relative timing of documented events (e.g. vasopressor administration prior to or after sedative administration) is likely accurate.
Significant heterogeneity exists in the approach to endotracheal intubation between EMS systems. While we attempted to address this by including variables such as initial video laryngoscopy and/or bougie use in our regression model, residual confounding from factors such as clinician experience or opportunities for training may have biased our results. Alternative observational study designs such as interrupted time series analyses evaluating outcomes within EMS systems after transition from one sedative medication to another [25] may be used to address this issue. However, to definitively test the hypothesis that ketamine administration results in increased cardiovascular collapse compared to etomidate administration in the context of prehospital rapid sequence intubation, a multicenter randomized clinical trial would be required.
Because hospital disposition data was not available for greater than 70% of this cohort, our survival analyses may be subject to selection bias. Some patients were transferred from the receiving facility to hospitals that did not participate in the bidirectional health data exchange, which prevented the ability to determine their final disposition. Because patients who were transferred may have had more severe injuries or a greater need for specialty care, this may impact the generalizability of our analysis. However, the baseline characteristics of patients with and without hospital disposition data were similar [Supplemental Table 1].
CONCLUSION
In this retrospective analysis of a nationwide dataset, the use of etomidate as a sedative was associated with lower odds of hemodynamic instability following rapid sequence endotracheal intubation in comparison to ketamine. Overall, cardiovascular collapse afflicted more than 1 in 10 patients and should be anticipated following sedative administration for airway management in the prehospital setting.
Supplementary Material
ACKNOWLEDGEMENTS:
We would like to thank the ESO Data Collaborative for the data required to make this study possible.
FUNDING SOURCES:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM104942-05. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
DECLARATION OF INTEREST STATEMENT
The authors report there are no competing interests to declare.
DECLARATION OF GENERATIVE AI IN SCIENTIFIC WRITING
The authors did not use a generative artificial intelligence (AI) tool or service to assist with preparation or editing of this work. The author(s) take full responsibility for the content of this publication.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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