Changes in hemodynamic parameters with the use of etomidate versus ketamine induction in the emergency department

1. Introduction

Rapid sequence intubation (RSI) is the cornerstone of emergency airway management [1]. The administration of a sedative agent immediately followed by a neuromuscular blocking agent to produce rapid unconsciousness and paralysis provides optimum intubation conditions while minimizing aspiration [2, 3]. Nevertheless, selecting an appropriate sedative agent is a critical decision in emergency medicine. The ideal sedative agent is rapid acting, has a short duration of action, allows optimum intubation conditions, and is reliably effective and safe [4]. Hemodynamic control is also crucial for critically ill patients requiring RSI in the emergency department. Therefore, emergency physicians must be aware of the hemodynamic effects produced by the medications used during intubation.

Etomidate is a sedative agent popular among emergency physicians. It is a sedative-hypnotic with a very stable hemodynamic profile and a reliably rapid onset of action (10-15 s) and duration of action (4-10 min) when administered intravenously at a dose of 0.3 mg/kg. It inhibits excitatory stimuli by enhancing the effect of gamma-aminobutyric acid [4, 5]. A prospective observational study published in 2000 by Smith et al. investigated the hemodynamic effects of etomidate after RSI and found no significant change in blood pressure or heart rate in their patients [6]. Another prospective observational study published in 2006 by Zed et al. evaluated the hemodynamic effects of etomidate during RSI and found that the mean baseline systolic blood pressure, diastolic blood pressure, and heart rate were 132 $\pm$ 35.4 mmHg, 69 $\pm$ 21.2 mmHg, and 96 $\pm$ 26.2 beats per minute, respectively. They reported an overall elevation of 1.5 mmHg in systolic blood pressure (P = 0.0254) and 0.5 mmHg in diastolic blood pressure (P = 0.2213) at 10 min after intubation [7]. In contrast, a randomized controlled trial conducted in the operating room on patients scheduled for elective surgery showed a decrease in the mean systolic blood pressure from 133 $\pm$ 14 mmHg to 117 $\pm$ 9 mmHg and mean diastolic blood pressure from 78 $\pm$ 11 mmHg to 72 $\pm$ 10 mmHg [8].

Ketamine has also been gaining popularity among emergency physicians because of its catecholamine-mediated maintenance of blood pressure. Nonetheless, the rapid surge in the use of ketamine has revealed unpredictable hemodynamic effects during RSI. Early research in critically ill patients found ketamine to be occasionally associated with a reduction in the mean arterial pressure and cardiac output [9, 10, 11]. Recent clinical studies on RSI with ketamine reported hypotension rates of 3.6% to 24%, which may be harmful, especially in patients with an initial systolic blood pressure less than 100 mmHg [12]. A prospective observational study conducted on critically ill patients in the pre-hospital stage undergoing RSI with ketamine showed a blunted hypertensive response and more frequent hypotension in patients with a high shock index ($>$ 0.9) [12].

Studies comparing patient-centered outcomes between etomidate and ketamine show no difference in morbidity and mortality [13, 14]. However, few studies have directly compared the hemodynamic responses to etomidate and ketamine. The clinical question of whether ketamine should be used routinely for RSI deserves investigation. We believe such a study would provide significant insights on the hemodynamic response to ketamine induction. Therefore, the primary objective of this study was to compare the change in hemodynamic parameters between two commonly available induction agents, namely etomidate and ketamine. The secondary objective was to compare the rate of acute reduction in hemodynamic parameters between etomidate and ketamine. We hypothesized that ketamine would demonstrate a percent elevation in hemodynamic parameters when compared to that of etomidate.

2. Methods

Ethics approval for the study was obtained from the unit of biomedical ethics (reference 692-18). A waiver of consent was granted because of the observational and emergency nature of the study.

3. Results

During the 13-month study period, 119 patients in the emergency department were screened. Among them, 70 patients were excluded. Among the remaining 49 patients, 38 received etomidate for induction, while 11 received ketamine. The mean age of the patients was 56.64 $\pm$ 17.89 (SD) years, and 49.00% were male. The mean etomidate dose was 22.55 $\pm$ 4.79 (SD) mg, whereas the mean ketamine dose was 90.00 $\pm$ 7.26 (SD) mg. The primary indications for intubation included airway protection (44.8%), hypoxic respiratory failure (22.4%), hypercapnic respiratory failure (8.2%), and anticipated clinical course (4.1%) (Table 1).

Etomidate was the most used induction agent in 77.55% of the patients, while ketamine was used in only 22.44% of the patients. The overall first-pass success rate in this sample was 77.55%. First-pass success rate was 76.31% in the etomidate group and 72.72% in the ketamine group. Overall, good glottic views were observed in 71.43% of the patients, including 78.94% in the etomidate group but only 45.45% in the ketamine group (P = 0.76). Fentanyl was used in 71.05% of the patients in the etomidate group and 81.81% in the ketamine group. Succinylcholine was used in 89.47% of the patients in the etomidate group and 81.81% in the ketamine group (Table 2).

3.1 Hemodynamic response

The primary outcome of percent reduction in hemodynamic parameters was not statistically different between the etomidate and ketamine groups (Table 3). Patients receiving etomidate showed a negative reduction in all hemodynamic parameters: -15.02% in systolic blood pressure, -20.25% in diastolic blood pressure, -19.33% in mean arterial pressure, and -2.24% in heart rate. Similarly, patients receiving ketamine showed a negative reduction in all hemodynamic parameters: -13.14% in systolic blood pressure, -10.40% in diastolic blood pressure, -10.15% in mean arterial pressure, and -1.12% in heart rate (Table 4).

Table 3.Mean hemodynamic parameters 10-minutes pre-induction and 10-minutes post-induction with percent changes.

Etomidate	Percent change (%)
Pre-SBP (mmHg $\pm$ SD)	137.68 $\pm$ 25.31	Post-SBP (mmHg $\pm$ SD)	128.63 $\pm$ 37.67	-15.02%
Pre-DBP (mmHg $\pm$ SD)	81 $\pm$ 16.03	Post-DBP (mmHg $\pm$ SD)	73.34 $\pm$ 22.42	-20.45%
Pre-MAP (mmHg $\pm$ SD)	101.67 $\pm$ 21.50	Post-MAP (mmHg $\pm$ SD)	91.78 $\pm$ 26.73	-19.33%
Pre-HR (bpm $\pm$ SD)	111.13 $\pm$ 26.93	Post-HR (bpm $\pm$ SD)	109.76 $\pm$ 23.05	-2.24%
Ketamine	Percent change (%)
Pre-SBP (mmHg $\pm$ SD)	148.72 $\pm$ 56.06	Post-SBP (mmHg $\pm$ SD)	131.72 $\pm$ 36.59	-13.14%
Pre-DBP (mmHg $\pm$ SD)	79.27 $\pm$ 20.37	Post-DBP (mmHg $\pm$ SD)	72.18 $\pm$ 13.62	-10.40%
Pre-MAP (mmHg $\pm$ SD)	102.36 $\pm$ 31.04	Post-MAP (mmHg $\pm$ SD)	93.20 $\pm$ 19.48	-10.15%
Pre-HR (bpm $\pm$ SD)	118.63 $\pm$ 29.55	Post-HR (bpm $\pm$ SD)	124.27 $\pm$ 45.31	-1.12%
SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial pressure, HR: heart rate.

Table 4.Comparison of mean percent reduction in hemodynamic parameters between etomidate and ketamine.

	Etomidate	Ketamine	p-value
SBP	-15.02%	-13.14%	0.866
DBP	-20.45%	-10.40%	0.340
MAP	-19.33%	-10.15%	0.398
HR	-2.24%	-1.12%	0.875
SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial pressure, HR: heart rate.

The rate of $\ge$ 20% reduction in hemodynamic parameters was statistically similar between the two groups (Table 5). The rates in the etomidate versus those in the ketamine group were as follows: 26.32% vs. 27.27% (odds ratio [OR] = 1.05; 95% confidence interval [CI] = 0.32-4.74) for systolic blood pressure, 31.58% vs. 18.18% (OR = 0.48; 95% CI = 0.11-2.57) for diastolic blood pressure, 28.94% vs. 18.18% (OR = 0.45; 95% CI = 0.12-2.94) for mean arterial pressure, and 7.89% vs. 27.27% (OR = 4.37; 95% CI = 0.87-25.81) for heart rate.

The rate of any reduction in hemodynamic parameters was also statistically similar between the two groups (Table 5). The rates of reduction in the etomidate versus those in the ketamine group were as follows: 57.89% vs. 63.63% (OR = 1.27; 95% CI = 0.47-5.09) for systolic blood pressure, 57.89% vs. 45.45% (OR = 0.60; 95% CI = 0.23-2.33) for diastolic blood pressure, 57.89% vs. 54.54% (OR = 0.87; 95% CI = 0.34-3.36) for mean arterial pressure, and 44.74% vs. 36.36% (OR = 0.70; 95% CI = 0.26-2.81) for heart rate.

Table 5.Incidence of acute reduction in hemodynamic parameter between etomidate and ketamine.

Acute reduction in hemodynamic parameters ($\ge$ 20% reduction)
	Etomidate	Ketamine	Odds ratio [95% CI]
SBP	26.32%	27.27%	1.05 [0.32-4.75]
DBP	31.58%	18.18%	0.48 [0.11-2.57]
MAP	28.94%	18.18%	0.45 [0.12-2.94]
HR	7.89%	27.27%	4.37 [0.87-25.81]
Acute reduction in hemodynamic parameters (any reduction)
	Etomidate	Ketamine	Odds ratio [95% CI]
SBP	57.89%	63.63%	1.27 [0.47-5.09]
DBP	57.89%	45.45%	0.60 [0.23-2.33]
MAP	57.89%	54.54%	0.87 [0.34-3.36]
HR	44.74%	36.36%	0.70 [0.26-2.81]
SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial pressure, HR: heart rate.

Fig. 1,2,3,4 show graphical illustrations of the absolute changes in the mean hemodynamic parameters between the etomidate and ketamine groups.

Fig. 1.Mean systolic blood pressure 10-minutes before and after induction.

Fig. 2.Mean diastolic blood pressure 10-minutes before and after induction.

Fig. 3.Mean arterial pressure 10-minutes before and after induction.

Fig. 4.Mean heart rate 10-minutes before and after induction.

4. Discussion

Previous studies directly comparing the hemodynamic effects of ketamine with those of etomidate for RSI in the emergency department setting are scant. The pharmacologic and safety profiles of etomidate offer many advantages for RSI in the emergency department setting [4, 7]. While etomidate remains the gold standard for induction in RSI, ketamine has unpredictable effects on hemodynamic parameters based on the patient’s catecholamine stores [7]. A dose-related increase in hemodynamics is seen in patients who are not catecholamine depleted. However, patients who are catecholamine depleted and lack autonomic control experience direct myocardial depressant effects, leading to dose-dependent negative ionotropic and chronotropic effects [7]. Nevertheless, our study revealed a statistically similar percent reduction in all hemodynamic parameters when comparing etomidate with ketamine. Importantly, ketamine showed a greater mean percent reduction in all hemodynamic parameters. This is supported by a study by Waxman et al. [11], who investigated 12 critically ill patients by comparing hemodynamic variables pre-ketamine and 5 min post-ketamine-only induction. In that study, one patient developed severe bradycardia, four demonstrated decreased cardiac output and mean arterial pressure, and six had decreased ventricular contractility. Lipmann et al. [15] repeated these measurements at 2-min intervals up to 15 min after induction in 22 critically ill patients. They reported that although myocardial performance was improved in the majority of patients, the response was not uniform, and patients with hypovolemia or those with prolonged operative stress were at most risk of reduced cardiac output. In vitro, ketamine is negatively ionotropic when applied directly to the cardiac muscle [16]. In vivo, however, it acts by releasing centrally mediated catecholamines and inhibiting their reuptake. This mechanism accounts for the hemodynamic stability of ketamine [17, 18]. Alternatively, post-intubation hypotension may not necessarily be an effect of pharmacology but may result from an interaction between the hypovolemic state of the patient, onset of positive-pressure ventilation, and a subsequent reduction in venous return [19, 20].

Moreover, the incidence of acute reduction in all hemodynamic parameters was statistically similar. When comparing our study to previous ones that investigated similar hemodynamic parameters in the context of ketamine use in either a pre-hospital or emergency setting, we found similar results with some differences that may be explained by various factors, such as different sample sizes and definitions of endpoints. Price et al. [20] conducted a retrospective study that compared the hemodynamic effects of etomidate to those of ketamine in 100 patients undergoing endotracheal intubation (ETI) in a pre-hospital setting. Researchers assessed up to two sets of vital signs before ETI and up to five sets of vital signs after ETI. The median pre-ketamine heart rate was 99-100 beats per minute and the median post-ketamine heart rate was 92-101 beats per minute. The median pre-ketamine systolic blood pressure was 128-140 mmHg and the median post-ketamine systolic blood pressure was 123-137 mmHg. Furthermore, the rate of occurrence of bradycardia in their study was 9.3% and that of hypotension was 36.1% [20]. We observed a greater percent reduction in hemodynamic parameters, with a rate of $\ge$ 20% reduction in heart rate of 27.27% with ketamine and the rate of any reduction in heart rate of 63.63%. In contrast, the rates of $\ge$ 20% reduction in systolic blood pressure, diastolic blood pressure, and mean arterial pressure with ketamine were 27.27%, 18.18%, and 18.18%, respectively. The rates of any reduction in systolic blood pressure, diastolic blood pressure, and mean arterial pressure were 63.63%, 45.45%, and 54.54%, respectively. The different results reported in our study may be attributed to differences in the definition of events. Ballow et al. [21] compared the outcomes of 177 patients who received ketamine for RSI to those of 266 patients who received etomidate and reported hypotension in only 3.6% of the patients in the ketamine group compared to 6% in the etomidate group. Their study, despite the reasonable sample size, reported significantly lower hypotensive events than did our study. It appears that hemodynamic events after ketamine administration depend on many factors that include, but are not limited to, patient factors and perhaps ketamine doses.

In summary, we can clearly state that despite ketamine’s sympathomimetic effect, it may cause hemodynamic instability in select patients. Ketamine increases the central nervous system sympathetic outflow and decreases the reuptake of catecholamines, producing an elevation in hemodynamic parameters. On the other hand, it can also cause cardiac depression after induction. This effect is commonly overlooked in clinical practice. Therefore, patients who are apparently catecholamine depleted and lack autonomic control will experience direct myocardial depressant effects, leading to negative ionotropic and chronotropic effects [22, 23]. This may explain why we observed a reduction in all hemodynamic parameters comparable to those of etomidate.

This study also has some limitations. It was an observational study with a small convenience-based sample and lacked randomization. Additionally, we relied on noninvasive blood pressure monitoring, which may yield inaccurate results [21]. However, invasive blood pressure monitoring is not practical for every patient undergoing RSI. Moreover, many patients had incomplete data, and they could not be analyzed. Furthermore, we did not account for other factors affecting hemodynamic changes, including but not limited to pretreatment agent use, type of airway device used, volume/cardiac status prior to induction, and amount of positive-pressure ventilation.

5. Conclusions

The use of ketamine as an induction agent during RSI was associated with a reduction in all hemodynamic parameters when compared to those of etomidate. Therefore, we advise caution with the use of ketamine during RSI, especially for select patients in the emergency department. Ketamine may not necessarily improve hemodynamic parameters in critically ill catecholamine-depleted patients. A randomized clinical trial assessing these induction agents in hemodynamically compromised patients would undoubtedly help inform clinical practice.

Ethics approval and consent to participate

Ethics approval for the study was obtained from the unit of biomedical ethics (reference 692-18). A waiver of consent was granted because of the observational and emergency nature of the study.

Author contributions

Abdullah Bakhsh designed the study, collected data in real-time, assisted with statistical analysis and drafted the manuscript. Maryam Alnashri, Fatimah Alawami, Rafal Aseel, Maha Almaghthawi, Ghada Alrahaili, Anas Bifari, and Hassan Algethami assisted with data collection, performed statistical analysis, analyzed the results, and assisted with drafting the manuscript.

Acknowledgment

We would like to thank the emergency department staff at the King Abdulaziz University Hospital for their diligent work in providing care for critically ill patients. We also would like to thank the Research Summer School at the King Abdulaziz University for their continuous support during the project.

Funding

This research study received no financial support.

Conflict of interest

The authors of this study declare no conflicts of interest.

Data availability

Data to support findings are available from the corresponding author upon request.

Supplementary material

Supplementary material associated with this article can be found, in the online version, at https://oss.signavitae.com/mre-signavitae/article/1348925342553653248/attachment/Supplementary%20material.rar.