a b s t r a c t

Background: The anesthesia literature has reported that pre-intubation fentanyl use is associated with post-intu- bation hypotension which is a risk factor of poor post-emergency department (ED) prognosis. However, little is known about the relations between fentanyl use for intubation and Post-intubation hypotension in the ED. We aimed to determine whether pretreatment with fentanyl was associated with a higher risk of post-intubation hy- potension in the ED. Methods: We conducted a secondary analysis of data of ED airway management collected from a multicenter pro- spective study of 14 Japanese EDs from February 2012 through November 2016. We included all adult non-car- diac-arrest patients who underwent rapid sequence intubation for medical indication. Patients were divided into fentanyl and non-fentanyl groups. The primary outcome was post-intubation hypotension (systolic blood pres- sure <=90 mm Hg) in the ED. Results: Of 1263 eligible patients, 466 (37%) patients underwent pretreatment with fentanyl. The fentanyl group had a higher risk of post-intubation hypotension (17% vs. 6%; unadjusted OR, 1.73; 95%CI, 1.01-2.97; P = 0.048) compared to the non-fentanyl group. In the multivariable analysis adjusting for age, sex, weight, principal indi- cation, sedatives, intubator’s specialty, number of intubation attempts, and patient clustering within EDs, the fen- tanyl group had a higher risk of post-intubation hypotension (adjusted OR, 1.87; 95%CI, 1.05-3.34; P = 0.03) compared to the non-fentanyl group. In the sensitivity analysis using propensity score matching, this association remained significant (OR, 3.17; 95%CI, 1.96-5.14; P b 0.01).

Conclusion: In this prospective multicenter study of ED airway management, pretreatment with fentanyl in rapid sequence intubation was associated with higher risks of post-intubation hypotension.

(C) 2018

Introduction

Rapid Sequence Intubation is a standard tracheal intubation approach in the emergency department (ED) [1-3]. In the U.S., approx- imately 70% of ED intubations are performed with rapid sequence intu- bation (RSI) [3]. In RSI, ultrashort-acting opioids, such as fentanyl, have

Abbreviations: JEAN-2, second Japanese Emergency Airway Network; JEMNet, Japanese Emergency Medicine Network.

* Corresponding author.

E-mail address: [email protected]. (J. Takahashi).

been used as a pretreatment medication to mitigate the Catecholamine release related to laryngoscopy and intubation in patients with cardio- vascular diseases and those with Elevated intracranial pressure [4-6].

However, in the operating room setting, the anesthesia literature has reported that the use of fentanyl as pretreatment medication is associ- ated with an increased risk of adverse events during intubation, such as post-intubation hypotension [7,8]. Post-intubation hypotension is known to be a risk factor for higher in-hospital mortality and longer in- tensive care length-of-stay [9-11]. Despite the direct relevance to ED airway management practice, there is a dearth of research that exam- ines the relation between fentanyl use as a pretreatment agent for intu- bation and post-intubation hypotension in the ED.

https://doi.org/10.1016/j.ajem.2018.03.026

0735-6757/(C) 2018

To address the knowledge gap in the literature, by using the multi- center prospective study data of Emergency airway management, we tested the hypothesis whether a pretreatment with fentanyl is associ- ated with a higher risk of post-intubation hypotension in the ED.

Materials and methods

Study design and setting

We conducted a secondary analysis of multicenter prospective ob- servational study of ED patients who underwent emergency airway management — the second Japanese Emergency Airway Network (JEAN-2) study. The study design, setting, methods of measurement, and measured variables have been reported previously [12-15]. In brief, the JEAN-2 study started in February 2012 as a consortium of 14 academic and community EDs from different Geographic regions across Japan. The participating EDs consisted of 11 level I and three level II equivalent trauma centers. These EDs had a median ED census of 28,000 patient visits per year (range, 14,000-66,000). All EDs were affil- iated with emergency medicine residency training programs and staffed by Attending emergency physicians. Transitional-year residents (post- graduate years 1 and 2) also rotated through all of the EDs and partici- pated in airway management. Each hospital maintained individual protocols about the policy and procedures for ED airway management. Intubations were performed by attending physicians or resident physi- cians at the discretion of the attending physician. The institutional re- view board of each participating hospital approved the protocol with waiver of informed consent.

Selection of participants

In this analysis, we included all adult patients (aged >=18 years) who underwent RSI for non-cardiac-arrest medical indications during a 58- month period (from February 2012 through November 2016). We ex- cluded 1) patients with pre-intubation systolic blood pressure (SBP) of b90 mm Hg, 2) those who received pretreatment medications other than fentanyl (e.g., lidocaine, morphine, nicardipine, and pentazocine),

3) those who received sedatives other than ketamine, midazolam, or propofol, which were rarely used in this study (i.e., diazepam and thio- pental that consisted of 7% of RSI) [16], 4) those who received two or more types of sedatives, 5) those who received paralytics other than rocuronium, succinylcholine, or vecuronium, which were also rarely used in this study (i.e., pancuronium that was used in b1% of RSI), and

6) those with missing data on age, weight, pre-intubation SBP, sedative, Intubation device, or specialty of intubator.

Data collection and processing

Immediately after each intubation, the intubator completed a stan- dardized data collection form that included the patient demographics (age, sex, estimated height, and weight), primary indication for intuba- tion, methods of intubation, all medications and devises used to facili- tate intubation, level of training, specialty of the intubator, number of attempts, success or failure, intubation-related adverse events, and vital signs (blood pressure, heart rate, Arterial oxygen saturation) mea- sured immediately before, immediately after, and 30 min after the intu- bation. The JEMNet (Japanese Emergency Medicine Network) coordinating center and site investigator at each ED reviewed the data forms. If the form had any missing data, it was returned to the intubator for completion. If information on the form contained inconsistencies, the investigator interviewed the intubator for clarification. We moni- tored compliance continuously by reviewing professional billing codes and cross-referencing our findings with the intubation data forms. If an intubation was identified without a data form, the investigator interviewed the intubator within two weeks to maximize the capture rate. An intubation “attempt” was defined as a single insertion of the

laryngoscope (or other device) past the teeth. An attempt was success- ful if it resulted in a tracheal tube being placed through the vocal cords with confirmation by a quantitative or colorimetric end-tidal carbon di- oxide monitor.

Outcome measure

The outcome measure of interest was post-intubation hypotension, defined by post-intubation hypotension as any recorded SBP of

<=90 mm Hg during the 30-minute period following intubation in the

ED [3,17,18].

Statistical analysis

In this analysis, the patients were dichotomized into the fentanyl group and non-fentanyl group. To investigate the association between fentanyl use and risks of post-intubation hypotension, we constructed an unadjusted and adjusted two-level hierarchical models with bino- mial response using random intercepts for the EDs to account for pa- tient clustering within the EDs. The multivariable models adjusted for age, sex, weight, principal indication for intubation, sedatives (midazo- lam, ketamine, or propofol), specialty of the intubator, and number of intubation attempts. These covariates were selected based on the clini- cal plausibility and a priori knowledge [7,17-19]. Age and weight were dealt with as continuous variables [17]. Indication for intubation was classified into three categories, respiratory failure, shock, and others (airway obstruction, altered mental status, other medical indications) [19]. Specialty of the intubator was dichotomized into transitional- year resident and others including emergency medicine resident, emer- gency physician, and other specialties. The number of intubation at- tempts was dichotomized into two groups — <=2 and >=3 attempts [18,20].

To determine the robustness of our inference, we performed a series of sensitivity analyses. First, to address the potential effects of a regular use medication that potentially affect the blood pressure (e.g., antihy- pertensive), we repeated the analysis limiting to the patients aged 18- 54 years, who had a low possibility of using antihypertensive medica- tions [21]. Second, we conducted an additional analysis to examine the dose-response on the risk of post-intubation hypotension using the fentanyl dose/body weight (ug/kg) as a continuous variable. We also modeled the fentanyl dose as a categorical variable (tertile) because it has an advantage that the model does not impose a linear relationship between the exposure and outcome. Third, to address the selection bias for fentanyl use, we performed following stratified analyses by indica- tion for altered mental status or seizure [22], pre-intubation SBP (90- 119 mm Hg, 120-139 mm Hg, and >=140 mm Hg), and sedative (midazo- lam, ketamine, or propofol). Lastly, we conducted propensity score (PS) matching analyses to further investigate the association of interest. First, we computed the PS using the logistic regression model in which fenta- nyl use was the dependent variable on the basis of the covariates in the primary models except for the number of intubation attempts. The number of attempts was not used for computing the PS as this variable was not measured at baseline. Next, we performed one-to-one matching of patients between the fentanyl and non-fentanyl groups with the closest estimated PS within a caliper (<=0.20 of the pooled stan- dard deviation of estimated logits) using the nearest neighbor method without replacement [23]. We examined the standard differences to evaluate the matching of the baseline characteristics between the groups. A standard difference of N10% was regarded as imbalanced. Lastly, we performed logistic regression analysis to examine the associ- ation between fentanyl use and risks of post-intubation hypotension in the PS-matched patients. The threshold for significance was P b 0.05. Analyses were performed with the use of STATA 14.1 (StataCorp, Col- lege Station, TX) and JMP 12.2.0 (SAS Institute, Inc., Cary, NC).

Results

During the 58-month period, the JEAN-2 study recorded a total of 7570 patients with emergency airway management in the 14 EDs (capture rate, 97%). Of these 1263 patients were eligible for the cur- rent analysis (Fig. 1). Overall, the median age was 68 years (Inter- quartile range (IQR), 54-78 years) and 67% were male. Fentanyl was used as a pretreatment medication of RSI in 466 patients (37%). The baseline characteristics of the fentanyl and non-fentanyl groups are summarized in Table 1. The patients who received fenta- nyl were less likely to be intubated for respiratory failure and more likely to be intubated with rocuronium as paralytics and by a video laryngoscope, compared to those who did not receive fentanyl (all P b 0.05). In addition, the fentanyl group was more likely to be intubated by emergency medicine resident and had a higher intuba- tion success rate at the first attempt when compared to the non-fen- tanyl group (81% vs. 72%; P b 0.05).

The heart rate and SBP of the fentanyl and non-fentanyl groups are summarized in Supplemental Figs. 1 and 2 In the fentanyl group, the median SBP was 132 mm Hg (IQR, 111-156 mm Hg) at pre-intubation, 127 mm Hg (IQR, 102-160 mm Hg) at immediate after intubation, and 126 mm Hg (IQR, 107-150 mm Hg) at 30 min after intubation. In the non-fentanyl group, the median SBP was 140 mm Hg (IQR, 119- 170 mm Hg) at pre-intubation, 139 mm Hg (IQR, 110-168 mm Hg) at

immediate after intubation, and 130 mm Hg (IQR, 110-152 mm Hg) at 30 min after intubation (Supplemental Fig. 2).

Overall, 125 patients (10%) experienced post-intubation hypoten- sion (i.e., SBP of <=90 mm Hg) during their ED course. Patients who re- ceived fentanyl had a higher risk of post-intubation hypotension compared to those who did not receive fentanyl (17% vs. 6%). The use of fentanyl was associated with a significantly higher risk of post-intu- bation hypotension in both univariate model (odds ratio [OR], 1.73; 95% CI, 1.01-2.97; P = 0.048; Table 2) and multivariable model adjusting for seven potential confounders and patient clustering within the EDs (adjusted OR, 1.87; 95% CI, 1.05-3.34; P = 0.03).

In the sensitivity analysis, in patients aged 18-54 years, while the statistical power is limited, the association of fentanyl use with post-in- tubation hypotension remained significant (1.6% vs. 4.2%; unadjusted OR = 1.73 [95%CI 1.01-2.97] P = 0.048; adjusted OR = 6.33 [95%CI

1.15-34.99] P = 0.03). In the additional analysis that examines the dose-response on the risk of post-intubation hypotension, while there was no significant linear dose-response relationship, the association remained significant with the use of tertiles (Supplemental Table 1). In the sensitivity analyses with stratification by indication, pre-SBP, and sedative, the associations between fentanyl use and post-intubation hypotension were consistent across all strata (Supplemental Table 3). Finally, in the analysis using one-to-one PS matching, the baseline char- acteristics of 402 matched pairs were successfully balanced between the

7,804 patients who underwent emergency tracheal intubation

Fig. 1. Patients receiving emergency airway management in the emergency department. During study period, the JEAN-2 study recorded a total of 7570 patients who underwent emergency airway management at one of the 14 emergency departments (capture rate, 97%). Of these, 1263 patients were eligible for the current study.

1,263 patients included in the current analysis

7,570 recorded in the JEAN-2 study

6,307 patients excluded

3,153 cardiac arrests

2,257 non-rapid sequence intubation

378 trauma

59 pediatric patients

249 pre-intubation systolic blood pressure ? 90mmHg

47 other pretreatment used 59 other sedative used

22 multiple sedatives used 1 other paralytics used

82 missing data

466 (37%) patients with the use of fentanyl

797 (63%) patients without the use of fentanyl

Table 1 Baseline characteristics, airway management characteristics, success rate, number of intu- bation attempts, and post-intubation hypotension of patients who underwent rapid se- quence intubation, according to fentanyl use.

	Fentanyl group (n	Non-fentanyl group	P-valueh
	= 466, 37%)	(n = 797, 63%)
Patient characteristics
Age, median (IQR), years	67 (53-76)	69 (54-78)	0.21
Male sex	301 (65)	547 (69)	0.14
Weight, median (IQR), kg Primary indicationa	60 (50-70)	60 (50-70)	0.21

Respiratory failure	141 (30)	411 (52)	b0.01
Shock	101 (22)	92 (12)	b0.01
Othersb	224 (24)	294 (37)	b0.01

Airway management characteristics Sedatives^a

Table 2 Unadjusted and adjusted associations of fentanyl use as a pretreatment for intubation with post-intubation hypotension in the emergency department.

Model and variable	Odds ratio (95%CI)	P-value
Unadjusted model Fentanyl use (vs no fentanyl use)	1.73 (1.01-2.97)	0.048
Adjusted model Fentanyl use (vs no fentanyl use)	1.87 (1.05-3.34)	0.03
Covariates

Age (per each incremental year)	1.04 (1.02-1.06)	b0.01
Female sex	0.88 (0.56-1.38)	0.56
Weight (per each incremental kg)	0.99 (0.97-1.01)	0.30
Primary indication

Respiratory failure	Reference
Shock	0.92 (0.53-1.61)	0.79
Othersa	0.37 (0.22-0.64)	b0.01

Midazolam	284 (61)	493 (62)	0.75	Sedative
Propofol	105 (23)	190 (24)	0.60	Ketamine	Reference
Ketamine	77 (17)	114 (14)	0.29	Midazolam	1.38 (0.74-2.55)	0.31
Paralyticsc				Propofol	1.76 (0.82-3.78)	0.15
Rocuronium	433 (93)	676 (85)	b0.01	Specialty of intubator
Succinylcholine	22 (5)	89 (11)	b0.01	Othersb	Reference
Vecuronium	18 (4)	33 (4)	0.81	Transitional year resident	1.02 (0.61-1.72)	0.93
Devicesa				Multiple intubation attempts	1.32 (0.60-2.93)	0.49

^a Defined as airway obstruction, altered mental status, and other medical indications.

direct laryngoscope	85 (18)	655 (82)	b0.01
Video laryngoscope	380 (82)	127 (16)	b0.01
Othersd	1 (b1)	15 (2)	0.01
Specialty of intubator
Transitional-year residente	69 (15)	431 (54)	b0.01
Emergency medicine	272 (58)	184 (23)	b0.01
resident
Emergency physician	85 (18)	78 (10)	b0.01
Others specialtiesf	40 (9)	104 (13)	0.02
Success rate at first	376 (81)	575 (72)	b0.01
attempt
Number of intubation	1 (1-1)	1 (1-2)	b0.01
attempts, median (IQR)
>=3 intubation attempts 25 (5)		73 (9)	0.02

^b Defined as emergency medicine resident, emergency physician, surgeon, anesthesi- ologist, pediatrician, and others.

Post-intubation hypotension^g

81 (17) 44 (6) b0.01

room settings [7,8]. For example, in a study of 2406 patients who underwent intubation in the operating room, the use of fentanyl was a significant predictor for hypotension 0-10 min after anesthetic induc- tion [7]. However, in the non-anesthesia settings, there has been no con- crete evidence of the relation of any intubation-related medications, let alone fentanyl, with post-intubation hypotension. For example, in the intensive care unit settings, Green et al. reported that no conclusions can be drawn regarding the relation of any intubation-related media- tions with the risk of post-intubation hypotension [24]. In contrast,

Abbreviation: IQR, interquartile range.

Data are shown as n (%) unless otherwise specified.

^a Percentages may not equal 100 due to rounding.

^b Defined as airway obstruction, altered mental status, other medical indications.

^c Percentage may not equal 100 because of the use of multiple paralytic use in eight cases.

^d Defined as flexible bronchoscope, a combination of a Gum elastic bougie with a direct laryngoscope or video laryngoscope.

^e Defined as post-graduate years 1 or 2.

^f Defined as surgeon, anesthesiologist, pediatrician, and others.

^g Any recorded systolic blood pressure of <=90 mm Hg during the 30-minute period following intubation in the emergency department.

^h t-test for continuous variables; chi-square test or Fisher’s exact test for categorical variables.

fentanyl and non-fentanyl groups (all standardized differences of b10, Supplemental Table 3). Similar to the primary analysis, the patients with fentanyl use had a significantly higher risk of post-intubation hy- potension (17% vs. 6%), with a corresponding OR of 3.17 (95% CI, 1.96- 5.14; P b 0.01).

Discussion

In this analysis of 1263 adult patients who underwent RSI in the ED, we found that the use of fentanyl as pretreatment medication was asso- ciated with a significantly higher risk of post-intubation hypotension. This association remained significant across the different statistical as- sumptions – in both multivariable hierarchical model and PS-matched model. To the best of our knowledge, this is the first study that has dem- onstrated the association between the use of fentanyl and post-intuba- tion hypotension in the ED population.

The anesthesia literature has shown that fentanyl administration is associated with the risk of post-intubation hypotension in the operating

the current analysis using the data from a large multicenter prospective

study with a high capture rate (97%) extends these prior studies by demonstrating the robust association between the use of fentanyl and the risk of post-intubation hypotension in the ED.

Fentanyl is an ultrashort acting opioid receptor agonist and is used to blunt the potential elevation of blood pressure and intracranial pressure [4-6] in the setting of RSI. However, its effectiveness has not been con- firmed in the ED population [25,26]. In addition, fentanyl also has an ef- fect of attenuating the sympathetic nervous system which may result in hypotension. Consequently, pretreatment with fentanyl is not viewed as a nonessential step of RSI [25]. Further, the lack of difference in the heart rate changes observed in the current study is also consistent with the previous literature which did not show the preventive effects of fentanyl on heart rate fluctuations following the use of fentanyl com- pared to the use of lidocaine or lidocaine with fentanyl [27]. Our findings lend further support to the concept that the use of fentanyl as pretreat- ment of RSI should not be used routinely in the ED. Clinicians should weigh the potential risks and benefits of fentanyl use judiciously, partic- ularly for patients at high risk for hemodynamic instability.

Potential limitations

This study has several potential limitations. First, we did not mea- sure the post-ED outcomes, such as hospital length of stay and in-hospi- tal mortality. While one may surmise that intubation-related hypotension is a transient adverse event, a body of evidence has indi- cated that intubation-related hypotension is associated with higher in- hospital mortality and longer hospital length-of-stay [9-11]. Second, surveillance data introduce the potential of self-reporting bias, which may lead to underestimation of the proportion of hypotension. How- ever, we used the previously applied self-reporting systems with a

standardized data form and high capture rate [12-18,28-31], and the in- cidence of post-intubation hypotension in our study was comparable to that was reported in a prior systematic review [32]. Third, as with any observational study, the observed association between fentanyl use and higher risk of post-intubation hypotension does not necessarily prove causality and might be confounded by unmeasured factors, such as physiological reserve of each patient, peri-intubation fluid resuscita- tion, past history and related medications (e.g., anti-hypertensives), and the use of vasopressors. Nevertheless, we excluded the patients with pre-intubation SBP of b90 mm Hg — the population who potentially re- quire these resuscitative measures. Furthermore, in the ED setting, there is often very little information available to the clinicians who must make rapid decisions on whether to use pretreatment (e.g., fentanyl) for intu- bation. Therefore, our data represent the best available data and clini- cally relevant in the real-world settings. Fourth, our observational study does not have the information on the methods for measuring blood pressure (e.g., non-invasive vs. invasive measurement), which may be a source of measurement bias [33]. However, non-invasive monitoring is well correlated with the invasive blood pressure [34] and widely used in clinical settings. Fifth, there was a possibility of selec- tion bias. Therefore, we conducted the main analysis with the variables (i.e., age, principal indication for intubation, sedatives, specialty of the intubator) which could be the rationales for selecting fentanyl. Addi- tionally, to address the rationale behind fentanyl use for intubation, we also conducted sensitivity analyses stratified by indication for intu- bation, pre-SBP, and sedatives. Although the part of the results was not statistically significant due to the limited number of events, the as- sociations between fentanyl use and post-intubation hypotension were also consistent with main analysis (Supplemental Table 2). Lastly, our study population consisted of patients in academic EDs in Japan. Al- though it is tempting to dismiss the broader generalizability, multiple studies – despite differing patient populations and settings (e.g., anes- thesia setting) – arrived at a similar conclusion.

Conclusion

Based on the data from a prospective multicenter study of ED airway management, we found that fentanyl administration for pretreatment of RSI was associated with a higher risk of post-intubation hypotension in the ED. The significant association persisted across different statistical assumptions. As post-intubation hypotension is related to worse post- ED outcomes [9,10], our observations offer a caution to the use of fenta- nyl as RSI pretreatment of ED. Furthermore, our data should facilitate further investigation into the development of optimal airway manage- ment in ED patients at high risk for hemodynamic instability and ele- vated intracranial pressure, which will, in turn, improve the patient outcomes.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2018.03.026.

Author contributions

J.T. takes responsibility for the paper as a whole. J.T., T.G., T.S., and K.

H. conceived the study. H.O., Y.H., H.W., and K.H. supervised the conduct of the study. T.G., H.O., T.S., and K.H. provided statistical advice. J.T. and T.

G. analyzed the data. J.T. drafted the manuscript, and all authors contrib- uted substantially to its revision.

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

This work was supported by grants from St. Luke’s Science Institute (Tokyo, Japan). The study sponsor has no involvement in the study

deign, in the collection, analysis and interpretation of data, in the writ- ing of the manuscript, and in the decision to submit the manuscript for publication.

Acknowledgment

The authors acknowledge the following research personnel at the study hospitals for their assistance with this project: Fukui University Hospital (Hiroshi Morita, MD; Takahisa Kawano, MD; Yohei Kamikawa, MD), Fukui Prefectural Hospital (Hideya Nagai, MD; Takashi Matsumoto, MD; Suguru Nonami, MD; Yusuke Miyoshi, MD), Kameda Medical Center (Sho Segawa, MD; Kitai Yuya, MD; Kenzo Tanaka, MD), Kishiwada Tokushukai Hospital (Hiromasa Yakushiji, MD), Kura- shiki Central Hospital (Hiroshi Okamoto, MD), Nagoya Ekisaikai Hospi- tal (Yukari Goto, MD), Nigata City General Hospital (Nobuhiro Sato, MD, MPH), Okinawa Chubu Prefectural Hospital (Koichiro Gibo, MD; Masashi Okubo, MD; Yukiko Nakayama, MD), Otowa Hospital (Nobuhiro Miyamae, MD), Shonankamakura General Hospital (Hirose Kaoru, MD; Taichi Imamura, MD; Azusa Uendan, MD), St. Marianna Uni- versity School of Medicine Hospital (Yasuaki Koyama, MD), Tokyo Bay Urayasu Ichikawa Medical Center (Hiroshi Kamura, MD; Nakashima Yoshiyuki, MD), University Hospital, Kyoto Prefectural University of Medicine (Jin Irie, MD), and Yokohama Rosai Hospital (Seiro Oya, MD), Hyogo emergency medical center (Akihiko Inoue, MD), and our many emergency physicians and residents for their perseverance in pursuing new knowledge about this vital resuscitative procedure.

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