The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes

Seelhammer, Troy G.; DeGraff, Eric M.; Behrens, Travis J.; Robinson, Justin C.; Selleck, Kristen L.; Schroeder, Darrell R.; Sprung, Juraj; Weingarten, Toby N.

doi:10.1016/j.bjane.2017.12.008

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Scientific Articles • Rev. Bras. Anestesiol. 68 (4) • Jul-Aug 2018 • https://doi.org/10.1016/j.bjane.2017.12.008 copy

The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background and objectives

The primary aim was to determine risk factors for flumazenil administration during postanesthesia recovery. A secondary aim was to describe outcomes among patients who received flumazenil.

Methods

Patients admitted to the postanesthesia recovery room at a large, academic, tertiary care facility after surgery under general anesthesia from January 1, 2010, to April 30, 2015, were identified and matched to 2 controls each, by age, sex, and surgical procedure. Flumazenil was administered in the recovery phase immediately after general anesthesia, according to the clinical judgment of the anesthesiologist. Demographic, procedural, and outcome data were extracted from the electronic health record. Conditional logistic regression, accounting for the 1:2 matched-set case-control study designs, was used to assess characteristics associated with flumazenil use.

Results

The incidence of flumazenil administration in the postanesthesia care unit was 9.9 per 10,000 (95% CI, 8.4-11.6) general anesthetics. History of obstructive sleep apnea (Odds Ratio [OR] = 2.27; 95% CI 1.02-5.09), longer anesthesia (OR = 1.13; 95% CI 1.03-1.24 per 30 minutes), use of total intravenous anesthesia (OR = 6.09; 95% CI 2.60-14.25), and use of benzodiazepines (OR = 8.17; 95% CI 3.71-17.99) were associated with risk for flumazenil administration. Among patients who received midazolam, cases treated with flumazenil received a higher median (interquartile range) dose than controls: 3.5 mg (2.0-4.0 mg) vs. 2.0 mg (2.0-2.0 mg), respectively (p < 0.001). Flumazenil use was correlated with a higher rate of unanticipated noninvasive positive pressure ventilation, longer postanesthesia care unit stay, and increased rate of intensive care unit admissions.

Conclusions

Patients who required flumazenil postoperatively had received a higher dosage of benzodiazepines and utilized more postoperative health care resources. More conservative perioperative use of benzodiazepines may improve postoperative recovery and use of health care resources.

KEYWORDS
Flumazenil; Benzodiazepine; Postanesthesia care unit; Postoperative complications

Variable	Cases (n = 131)	Controls (n = 262)
Age, y	57.7 (13.3)	57.9 (12.6)
Males	53 (40.5)	106 (40.5)
Surgical specialty
Cardiac	3 (2.3)	6 (2.3)
General	19 (14.5)	38 (14.5)
Head and neck	13 (9.9)	26 (9.9)
Neurosurgical	16 (12.2)	32 (12.2)
Ophthalmologic	2 (1.5)	4 (1.5)
Orthopedic	11 (8.4)	22 (8.4)
Plastic	7 (5.3)	14 (5.3)
Thoracic	25 (19.1)	50 (19.1)
Urologic and gynecologic	33 (25.2)	66 (25.2)
Vascular	1 (0.8)	2 (0.8)
Interventional pain	1 (0.8)	2 (0.8)

Characteristic	Cases (n = 131)	Controls (n = 262)	Univariable analysis^b b Analyses were completed with conditional logistic regression factoring in the matched-set (1:2) study design. In addition to univariable analysis, all variables were included in the multivariable model. The odds ratio is presented for a 5 kg.m-2 increase in BMI, 30 min increase in anesthetic duration, and 5-ME increase in intraoperative systemic opioid.			Multivariable analysis^b b Analyses were completed with conditional logistic regression factoring in the matched-set (1:2) study design. In addition to univariable analysis, all variables were included in the multivariable model. The odds ratio is presented for a 5 kg.m-2 increase in BMI, 30 min increase in anesthetic duration, and 5-ME increase in intraoperative systemic opioid.
			OR	95% CI	p	OR	95% CI	p
Medical comorbidity or condition
BMI	28.3 (6.8)	29.0 (7.5)	0.93	0.80-1.08	0.37	0.96	0.92-1.01	0.09
Lung disease	10 (7.6)	27 (10.3)	0.73	0.35-1.53	0.40	0.77	0.31-1.92	0.57
Long-term use of opioid or benzodiazepine	40 (30.5)	81 (30.9)	0.98	0.60-1.61	0.93	0.78	0.41-1.48	0.44
OSA^c c Diagnosis from a documented history or a positive screen for OSA.	31 (23.7)	40 (15.3)	1.83	1.04-3.20	0.04	2.27	1.02-5.09	0.046
ASA PS score
I or II	67 (51.1)	153 (58.4)	1.00	-	-	-	-	-
≥III	64 (48.9)	109 (41.6)	1.48	0.90-2.41	0.12	1.28	0.68-2.41	0.44
Anesthetic agent
Volatile	63 (48.1)	195 (74.4)	1.00	-	<0.001	-	-	<0.001
TIVA^d d Secondary analysis for patients maintained with TIVA, compared to those who received inhalation agents, showed an increased frequency of receiving midazolam (number of instances), an increased median (SD) dose of midazolam (in milligrams), and a decreased median dose (interquartile range) of intraoperative systemic opioid (ME in milligrams): 110 (84.0%) vs. 169 (64.5%); 3.23 (0.24) vs. 1.65 (0.17); and 10 (5.0-15.3) vs. 25 (17.9-35.0), respectively (all p < 0.001).	68 (51.9)	67 (25.6)	5.72	3.07-10.66	-	6.09	2.60-14.25	-
Anesthetic duration, min^e e Multivariate analysis with 95% confidence in units of 30 minutes.	169 (104-296)	171 (92-268)	1.08	1.01-1.16	0.03	1.13	1.03-1.24	0.01
Preoperative medication
Gabapentin	21 (16.0)	26 (9.9)	2.67	1.11-6.42	0.03	1.63	0.47-5.64	0.44
Benzodiazepine^f f Among patients who received midazolam, index cases received a median dose (interquartile range) of 3.5 mg (2.0-4.0 mg), and controls received 2.0 mg (2.0-2.0 mg) (p < 0.001).	119 (90.8)	160 (61.1)	6.74	3.41-13.31	<0.001	8.17	3.71-17.99	<0.001
Sustained-release opioid	20 (15.3)	21 (8.0)	2.68	1.23-5.82	0.01	2.60	0.88-7.68	0.08
Intraoperative medication
Neuraxial opioid	4 (3.1)	13 (5.0)	0.45	0.11-1.87	0.27	0.26	0.04-1.80	0.17
Systemic opioid (ME), mg	19 (5-30)	23.3 (10-31.5)	0.89	0.82-0.98	0.02	0.94	0.81-1.08	0.38
Ketamine^g g Secondary analysis for patients who received ketamine showed no difference between the median perioperative dose (interquartile range) for index cases (20 mg [10-20 mg]) and controls (20 mg [10-20 mg]) (p = 0.88).	31 (23.7)	45 (17.2)	1.57	0.91-2.73	0.11	1.77	0.85-3.71	0.13
Nondepolarizing muscle relaxants	64 (48.9)	133 (50.8)	0.86	0.48-1.55	0.62	1.31	0.56-3.07	0.53

Outcome	Cases (n = 131)^a a Categorical data are summarized as number of patients (percentage of sample) and compared with the Fisher exact test; continuous data are summarized as median (interquartile range) and compared with the rank sum test.	Controls (n = 262)^a a Categorical data are summarized as number of patients (percentage of sample) and compared with the Fisher exact test; continuous data are summarized as median (interquartile range) and compared with the rank sum test.	p
Recovery room
Respiratory depressive events	10 (7.6)	14 (5.3)	0.38
Noninvasive positive pressure ventilation in those without OSA^b b Analysis was restricted to 100 cases and 222 controls who did not have a history of OSA.	5 (5.0)	1 (0.5)	0.01
Duration of stay, min^c c Analysis excluded 19 cases and 28 controls who bypassed phase 1 recovery in the postanesthesia care unit for various reasons, including direct transfer to ICU, to a general care ward, or to a subsequent procedural care area.	106 (65-155)	71 (43-106)	<0.001
ICU admission	25 (19.1)	20 (7.6)	0.001
Inpatient length of stay, days	3 (1-7)	2 (1-4)	0.15
Death	1 (0.8)	4 (1.5)	0.67

Sociedade Brasileira de Anestesiologia R. Professor Alfredo Gomes, 36, 22251-080 Botafogo RJ Brasil, Tel: +55 21 2537-8100, Fax: +55 21 2537-8188 - Campinas - SP - Brazil
E-mail: bjan@sbahq.org

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[1] * Corresponding author. E-mail:seelhammer.troy@mayo.edu (T.G. Seelhammer).