Anesthesiology

Methohexital for procedural sedation of cardioversions in the emergency department

a b s t r a c t

Background: Procedural sedation for electrical cardioversion is a common practice in the emergency department (ED). Ideal sedative properties for this procedure are a short half-life and minimal hemodynamic effects. There is limited literature examining methohexital for this use.

Objective: To compare the use of methohexital to propofol and etomidate for procedural sedation for electrical cardioversions in the ED.

Methods: This was a single-center, retrospective study of adult patients who underwent procedural sedation for electrical cardioversion in the ED between February 1, 2015 and July 31, 2020. Included patients received methohexital, propofol, or etomidate as an initial Sedative agent in the ED. The primary outcome was time from initial dose of sedative to goal Aldrete score. The main secondary outcome was time from sedative agent to ED discharge. The safety outcome was the occurrence of a critical hemodynamic change requiring interven- tion. Outcomes were assessed using a single-factor ANOVA analysis.

Results: One-hundred and fifty cardioversion encounters were included with 50 encounters per cohort. The me- dian (IQR) time (minutes) to goal Aldrete score was 10.5 (7-18.5) for methohexital, 12.0 (9-16.8) for propofol, and 11.0 (8-15) for etomidate (p = 0.863). Mean (SD) time (minutes) to discharge from the ED (n = 105) was

90.4 +- 40.4 for methohexital, 89.0 +- 57.4 for propofol, and 94.0 +- 42.5 for etomidate (p = 0.897). No difference was seen between the groups regarding hemodynamic changes requiring intervention. Conclusion: Methohexital was found to have a similar efficacy and safety profile when compared to propofol and etomidate when used as procedural sedation for cardioversions in the ED.

Introduction
1. Background

Cardioversion of the heart during a dysrhythmic state is a common practice in the emergency department (ED) and can be performed with chemical or electrical cardioversion [1]. In stable patients, chemical cardioversion is typically attempted prior to electrical cardioversion for patient safety; however, Bellone and colleagues showed that electrical cardioversions have a higher success rate when studied in comparison [2-5]. Prior to electrical cardioversion, if time and patient stability al- lows, procedural sedation should be used to reduce anxiety, pain, and discomfort from the Electrical shock [2]. Common agents used for proce- dural sedation for electrical cardioversions are methohexital, propofol, etomidate, and midazolam. Currently, no single agent or combination of sedative agents is recommended over another for use as procedural

* Corresponding author.

E-mail address: epavich@iuhealth.org (E. Pavich).

sedation prior to electrical cardioversion [4]. Optimal characteristics of a sedative agent for electrical cardioversion include a pharmacokinetic property of a short half-life as well as a pharmacodynamic property of minimal effects on cardiopulmonary processes or hemodynamic func- tion [6]. Published literature exists on the use of propofol and etomidate for procedural sedation for electrical cardioversion in both emergent and elective situations; however, limited research has been published regarding the use of methohexital [7,8].

Methohexital is a barbiturate agent that depresses the sensory cor- tex in the brain leading to drowsiness and sedation [9]. It has a favorable pharmacokinetic profile, including an immediate onset of action and a quick time to recovery of five to fifteen minutes [9-11]. These pharma- cological properties make methohexital an intriguing agent for use as procedural sedation for electrical cardioversions. Commonly used agents for electrical cardioversion include propofol and etomidate. These agents have comparable pharmacologic properties, although etomidate causes less hemodynamic instability compared to propofol [12,13]. A study by Gale and colleagues found that patients who re- ceived methohexital prior to electrical cardioversions spent less time

https://doi.org/10.1016/j.ajem.2022.05.036

sedated and had less adverse events compared to midazolam; however, there were no significant differences compared to propofol [14]. There have been no clinical trials comparing the efficacy of methohexital to etomidate. The use of methohexital in clinical practice is likely limited due to the lack of available literature. The objective of this study was to analyze the time to clinical recovery and Time to discharge from the emergency department for patients who underwent procedural seda- tion prior to electrical cardioversion with methohexital compared to propofol and etomidate.

Methods
1. Study design and setting

This was a retrospective study of adult patients who underwent pro- cedural sedation for electrical cardioversion from February 1, 2015 to July 31, 2020 in a community hospital ED with 29 beds, 20 additional flexible treatment spaces, and an annual ED volume of 47,000 visits per year. Patients were identified by an electronic medical record (EMR) database search of all ED encounters with ICD-10 billing codes of atrial fibrillation, atrial flutter, ventricular tachycardia, or supraven- tricular tachycardia from an ED physician or other practitioner. Patients were included for analysis if they were 18 years and older and received one of the three study medications (methohexital, propofol, or etomidate) as the initial sedative agent for electrical cardioversion in the ED. All patients were then separated into three cohorts based on which study medication they received. Patients were then randomized within the cohort by assigning numbers to each patient and using a ran- dom number generator for patient selection. Patients were excluded if they received an alternative sedative agent prior to study medication

(s) (patients were allowed to receive an alternative study agent after

initial study agent was given without being excluded) or if procedural sedation documentation was missing from the EMR. After randomiza- tion, the first 100 patients in each cohort that did not meet exclusion criteria were included for analysis. A formal sample size calculation was not performed due to a presumed low utilization of methohexital. A pre-determined mid-point analysis was set at 50 patients per cohort. If no difference was seen at the midpoint analysis, data collection was to be terminated early. This study was approved by the institutional re- view board. All data was collected by the primary author and a data sheet with dictionary was utilized for data organization and standardi- zation of data collection.

1. Methods of measurement and data collection

Demographic characteristics collected included age, weight, sex, type of dysrhythmia, ASA classification, and Mallampati score. Patient vital signs (heart rate, systolic blood pressure, respiratory rate, and oxy- gen saturation) immediately before and immediately after the proce- dure were collected. Other data collected from the procedural sedation flowsheet included dose of sedative agent and time of admin- istration, time and total number of electrical shocks, time of discharge from the ED or hospital admission, time of goal Aldrete score, if an opi- oid was administered prior to cardioversion, and success of the cardio- version. This procedural sedation flowsheet document was utilized by nursing staff and the attending physician to analyze ASA classification and Mallampati score prior to sedation, document medication adminis- tration during the procedure, and track Aldrete score and discharge criteria. The Aldrete score is a composite scoring system of breathing, blood pressure stability, level of consciousness, oxygen saturation, and extremity mobility [15]. The scoring system is a scale of zero to ten, and at the study institution, a patient requires a score of nine prior to being moved from the ED to an Inpatient unit and a score of ten prior to being discharged from the ED.

1. Outcome measures

The primary outcome was the time to clinical recovery from first dose of study sedative agent. Secondary outcomes included time from first dose of sedative agent to discharge from the ED, time from first dose of sedative agent to electrical cardioversion, success of electrical cardioversion, receipt of additional dose(s) of study sedative agent, re- quirement of additional sedative agent, change in systolic blood pres- sure, and occurrence of hospital admission. Cardioversion success was determined based on physician note documentation prior to discharge or admission. The safety endpoint was the occurrence of a critical hemo- dynamic change requiring intervention. A critical hemodynamic change was defined as a systolic blood pressure reading below 90 mmHg or an oxygen saturation below 90%. Patients who had baseline vitals below these levels were excluded from the safety analysis. An intervention could consist of intravenous fluids, vasopressor therapy, or mechanical ventilation.

1. Statistical analysis

All analyses were stratified by the study medication received (methohexital, propofol, or etomidate). Categorical data was described as raw data [n(%)]. Continuous data that was normally distributed was reported as mean (+-SD) and median (IQR) was reported for data that was not normally distributed, with a p-value <=0.05 indicating statistical significance. The primary outcome was assessed using a single-factor ANOVA analysis to determine significance. A pre-determined midpoint analysis was performed based on previous studies showing no differ- ence between methohexital and propofol [14]. The decision to perform a mid-point analysis was made to conserve efforts based on our hypoth- esis that no significant difference would be found. The pre-planned mid- point analysis took place after data from 50 patients in each cohort was collected (Fig. 1).

Results

The EMR database search for the ICD-10 codes noted in the study de- sign yielded a large number of encounters. These encounters were ran- domized and subsequently screened for inclusion and exclusion until 100 encounters were identified for each study medication cohort. Screening of the data bank for patients in each cohort was terminated after the goal inclusion for each cohort was reached. This resulted in 361 screened charts with 61 exclusions (Fig. 1). Three hundred patients were eligible for analysis: 100 methohexital patients, 100 propofol pa- tients, and 100 etomidate patients. At the midpoint analysis, there were 50 patients from each cohort analyzed when data collection was terminated early due to no significant difference being detected (Fig. 1). In total, 150 patients were included, 50 patients from each cohort.

Median patient age was 67 (58-74) years old and mean weight was

93.9 +- 22 kg. The majority of patients were male, 86 (57.3%) in total. The most prominent dysrhythmia was atrial fibrillation in 99 (66%) pa- tients, followed by atrial flutter in 26 (17.3%) patients, ventricular tachy- cardia in 16 (10.7%) patients, and supraventricular tachycardia in nine (6%) patients. Complete baseline characteristics are displayed in Table 1. Mean initial dose (mg) was 65.4 +- 39.2 for methohexital,

45.3 +- 15.9 for propofol, and 14.7 +- 12.4 for etomidate. Mean cumula- tive dose (mg) was 73.3 +- 29.7 for methohexital, 78.5 +- 15.4 for propofol, and 14.9 +- 6.8 for etomidate. Ten (20%) methohexital patients required additional dose(s) for adequate sedation compared to 33 (66%) propofol patients and only two (4%) etomidate patients (p = 0.03). Cardiology was consulted on 14 (9.3%) patients, and 13 of the 14 patients (93%) received methohexital. Complete intervention data is displayed in Table 2.

Patients not included in the midpoint analysis (n=150)

aProcedural sedation flowsheet utilized for data collection

Etomidate (n=50)

Propofol (n=50)

Methohexital (n=50)

Patients from midpoint analysis (n=150)

Patient available for analysis (n=300)

Excluded patients (n=61) Missing documentation^a (n=29) Received medication inpatient (n=20)

Sedated for alternative

procedure (n= 8)

Initial use of alternative agent (n=4)

Patients screened (n=361)

Fig. 1. Patient analysis.

1. Main results

The primary outcome of time from first dose of sedative agent to goal Aldrete score was 10.5 (7-18.5) minutes for methohexital, 12

Table 1

Baseline characteristics.

(9-16.8) minutes for propofol, and 11 (8-15) minutes for etomidate (p = 0.863). The main secondary outcome of time from first sedative agent to discharge from the ED was 90.3 +- 40.3 min for methohexital, 89 +- 57.4 min for propofol, and 94 +- 42.5 min for etomidate (p = 0.897). The mean change in systolic blood pressure (mmHg) was

-9.2 +- 25.5 for methohexital, -21.7 +- 25.1 for propofol, and +1.88

+- 20.9 for etomidate (p = 0.0001). There was no significant difference in the safety outcome of critical hemodynamic changes requiring inter-

Characteristic Methohexital (n = 50)

Propofol (n = 50)

Etomidate (n = 50)

vention (p = 0.51). All outcome results are found in Table 3.

Age (years), median (IQR) 66 (58.3-73) 68 (54.3-75.8) 67 (60-73.8)

Weight (kg), mean (SD) 96.4 (24.3) 92.3 (22) 92.9 (19.7)

Male, n (%) 33 (66) 27 (54) 26 (52)

Female, n (%) 17 (34) 23 (46) 24 (48)

Type of dysrhythmia, n (%)

Atrial fibrillation	34 (68)	30 (60)	35 (70)
Atrial flutter	7 (14)	10 (20)	9 (18)
Ventricular tachycardia	6 (12)	6 (12)	4 (8)
Supraventricular tachycardia	3 (6)	4 (8)	2 (4)

ASA classification, n (%)

ASA I	7 (14)	11(22)	9 (18)
ASA II	23 (46)	29 (58)	35 (70)
ASA III	16 (32)	10 (20)	6 (12)
ASA IV	4 (8)	0 (0)	0 (0)
ASA V	0 (0)	0 (0)	0 (0)
SBP (mmHg), mean (SD)	122.6 (22.9)	129.9 (25.5)	121.8 (24.7)
HR (bpm^a), mean (SD)	130.6 (28)	140.3 (24.1)	134.3 (29.1)
RR (bpm^b), mean (SD)	18.3 (2.5)	18.6 (3.2)	18.6 (3.3)
SpO₂ (%), median (IQR)	98 (97-100)	98 (97-99)	98 (96-99)
Opioid received prior to	7 (14)	4 (8)	4 (8)

cardioversion, n (%)

SBP = systolic blood pressure; HR = heart rate; RR = respiratory rate; SpO₂ = oxygen saturation.

^a Beats per minute.

^b Breaths per minute.

Discussion

This retrospective analysis found that time to clinical recovery was similar between methohexital, propofol, and etomidate when utilizing the agents for procedural sedation prior to cardioversion in the ED. While this was a small study, the information is valuable due to limited available literature regarding the use of methohexital. To our knowl- edge, there are no published studies comparing methohexital to propofol and etomidate as procedural sedation in the ED.

Although methohexital is a viable option for procedural sedation based on its pharmacokinetic properties, many clinicians do not utilize it based on the limited data available regarding safety and efficacy. Prior to this study, there was only one published study analyzing methohexital for procedural sedation of electrical cardioversions. Gale et al. performed a small (n = 30), prospective, randomized control trial analyzing methohexital, propofol, and midazolam for procedural sedation of elective cardioversions [14]. The results demonstrated a mean time to recovery of 9 +- 3 min for methohexital and 11 +- 4 min for propofol. Both studies showed similar time to clinical recovery, how- ever Gale et al. did not utilize Aldrete score. Both studies also had small sample sizes, increasing risk of type II error. While Gale et al. was unique in its evaluation of methohexital, the study was limited due to the fact

Table 2

Interventions.
Intervention	Methohexital (n = 50)	Propofol (n = 50)	Etomidate (n = 50)	p-value
First dose (mg/kg), mean (SD)	0.68 (0.41)	0.49 (0.21)	0.16 (0.13)	n/a^a
First dose (mg), mean (SD)	65.4 (39.2)	45.3 (15.9)	14.7 (12.4)	n/a^a
Cumulative dose (mg/kg), mean (SD)	0.76 (0.43)	0.85 (0.41)	0.16 (0.13)	n/a^a
Cumulative dose (mg), mean (SD)	73.3 (29.7)	78.5 (15.4)	14.9 (6.8)	n/a^a
Requirement of additional doses of sedative agent, n (%)	10 (20)	33 (66)	2 (4)	0.03
Receipt of additional sedative agent, n (%)	4 (8)	1 (2)	0 (0)	0.74

^a Comparative statistics not performed due to different dosing strategies between the medications.

that etomidate, a commonly utilized alternative, was not included in this study. The study was also limited by the definition of clinical recov- ery, which was defined as time to awakening. This definition does not provide the degree of objective data that the Aldrete score does. Gale et al. also utilized a preset infusion dosing strategy, which is not a rea- sonable or practical option in the ED and does not allow for individual- ized weight-based dosing. The infusions were methohexital 50 mg infused over one minute, propofol 100 mg over one minute, and mid- azolam 5 mg over one minute. Despite differences in study design, de- creases in systolic blood pressure were seen by both methohexital and propofol between the two studies, confirming the results from this study that propofol has a more profound reduction in blood pressure compared to methohexital [14].

Within this study, patients who received methohexital had a higher ASA classification at baseline. Higher ASA classifications indicate pa- tients in the methohexital cohort had more comorbidities and were more medically complex at baseline compared to the other two cohorts. This may have resulted in more cardiology consults to assist with the cardioversion procedure in the ED. Methohexital patients had a high ad- mission rate to the hospital with 17 (34%) patients admitted, which was similar to propofol at 18 (36%) patients but more than patients who re- ceived etomidate (10 (20%) patients). These rates of admission are higher than the 12.5% national average of patients admitted to the hos- pital through the ED for any indication [16]. A higher ASA classification score at baseline correlates to higher mortality rates in the hospital [17]. There is a possibility that cardiology consults on patients with higher ASA classifications could have led to more admissions for observation to prevent unforeseen complications following the procedure.

At this practice site, it was noted that physicians often use the same

sedative agent at set doses instead of weight-based doses for individ- uals. Previous studies have suggested that clinicians may not feel com- fortable dosing sedatives for procedural sedation [18,19]. Common reasons were patient instability, avoidance of deep sedation, and con- cern with using agents with off-label indications for use for procedural sedation [18,19]. This study reiterates this concern as methohexital ini- tial doses were generally under-dosed at 0.68 +- 0.41 mg/kg when com- pared to the recommended weight-based dose of methohexital is 0.75-1.0 mg/kg (6). After subsequent doses of methohexital, median doses were in the goal dosing range (0.76 +- 0.43 mg/kg). Methohexital patients also had the highest rate of adjunctive sedative agent

requirements. Midazolam was the only adjunctive sedative agent uti- lized in methohexital patients (8%, 4/50). No methohexital patients who received an initial weight-based dose within package insert dosing recommendation required an additional sedative agent. This informa- tion shows that utilizing a weight-based dosing strategy may limit the need for subsequent doses and need for additional sedative agents and may potentially decrease time to goal sedation level.

Prior to data collection, it was presumed there may be an evenly distributed rate of hemodynamic changes and adverse effects between the three cohorts due to similar pharmacokinetic properties. Adverse event rates were low amongst cohorts, which may be due to be docu- mentation inconsistencies or conservative dosing of sedative agents. Only two patients required intervention for persistent hypotension, both in the etomidate cohort. It is expected in clinical practice that methohexital and propofol can cause dose-dependent hypotension; however, it is expected that this hypotensive response typically has no lasting effect [19]. Methohexital had no hemodynamic differences when compared to propofol and etomidate as procedural sedation in this study. There was no statistically significant difference, although this study may be underpowered to detect these differences.

1. Limitations

While this study provided important additional data regarding the use of methohexital, there are several limitations. As this was a Retro- spective analysis, confounding variables such as co-administration of alternative sedatives, dosing of sedative agent, and patient’s clinical sta- tus were unable to be controlled throughout the study, which reduced the internal validity. There were also many documentation inconsis- tencies on the sedation flowsheet. During the procedure, Aldrete score documentation was to be completed every five minutes per institution policy, though 28 (18.7%) patients did not have consistent documenta- tion. This could have resulted in a longer time to goal Aldrete score cal- culation when documentation was not completed frequently enough. There was also selection bias as methohexital was used in the majority of cases where cardiology was consulted, which could have resulted in more hospital admissions for observation under cardiology care. The cardiologists often utilized midazolam as an additional sedative agent along with methohexital, which could have led to more hemodynamic changes as benzodiazepines are known to rapidly lower blood pressure

Table 3

Outcomes.

Outcome	Methohexital (n = 50)	Propofol (n = 50)	Etomidate (n = 50)	p-value
Time (min) from initial dose of sedative agent to goal Aldrete Score^a, median (IQR)	10.5 (7-18.5)	12.0 (9-16.8)	11.0 (8-15)	0.863
Time (min) from first dose of sedative to discharge from ED^b, mean (SD)	90.4 (40.4)	89.1 (57.4)	94.0 (42.5)	0.897
Time (min) from first dose of sedative to cardioversion, mean (SD)	3.6 (4.3)	2.4 (1.3)	2.1 (1.4)	0.01
Cardioversion success, n (%)	48 (96)	42 (84)	45 (90)	0.13
Admission to hospital, n (%)	17 (34)	18 (36)	10 (20)	0.19
Change in SBP (mmHg), mean (SD)	-9.2 (25.5)	-21.7 (25.1)	+1.9 (20.9)	0.0001
Occurrence of critical hemodynamic change requiring intervention^c, n (%)	0 (0)	0 (0)	2 (4)	0.51

SBP = systolic blood pressure.

ED = emergency department.

^a Goal Aldrete score for admission (9) and discharge (10).

^b Different sample sizes; methohexital (n = 33), propofol (n = 32), and etomidate (n = 40).

^c <90 mmHg and/or SpO₂ < 90%; interventions included fluid boluses and short-term vasopressor therapy for hypotension.

and can cause respiratory depression [20]. Discharge times were vari- able and could have been affected by other factors, such as department volume, acuity of the department, consultation with other services, and pending lab results. Lastly, due to the small sample size, documentation inconsistencies, and retrospective nature of this study, the safety out- come could have been negatively affected. It is known that adverse events are rare in patients undergoing procedural sedation. A larger sample size would be needed to detect any meaningful difference in all outcomes as this was a small-scale study and is at risk for type II error [21].

Conclusion

Methohexital, when used for procedural sedation for electrical cardioversions in the ED, was found to have a similar efficacy and safety profile when compared to propofol and etomidate. Due to the small sample size and risk for type II error; larger, prospective studies are necessary to show the place in therapy for methohexital when using as procedural sedation for electrical cardioversions.

Declarations of Competing Interest

None to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Credit authorship contribution statement

Jacob Bauer: Writing – review & editing, Writing – original draft, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. Lauren Beauchamp: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration. Emily Pavich: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration.

References

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findings. Itl J Evid Based Healthc. 2013;11(4):275-84.

AJEM

Methohexital for procedural sedation of cardioversions in the emergency department

a b s t r a c t

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