Obvious major regurgitation of gastric contents in the perioperative period is a relatively uncommon event. When it occurs however, it leads to pulmonary aspiration in up to 50% of cases.1 In addition, aspiration was the leading cause of anesthesia-related morbidity in the British NAP4 registry.2 Even though obvious major aspiration is uncommon,3,4 lesser degrees of passive regurgitation can occur at any time during the perioperative period and may cause silent aspiration and subsequent postoperative complications.2,4,5 Preservation of esophagogastric junction (EGJ) function, acting as a barrier between the stomach and pharynx, is crucial to prevent passive regurgitation of gastric contents.6,7 However, several induction agents and opioids used during general anesthesia have been shown to reduce the barrier function of the EGJ, thereby increasing the risk for regurgitation of gastric content.6,8 A typical example is the opioid remifentanil, as previously showed by our group.8,9
The ultrashort-acting β-1-adrenoreceptor antagonist esmolol,10 originally an antihypertensive drug,11 has been shown to possess properties that make the drug useful during general anesthesia. It can attenuate the sympathetic response to tracheal intubation12 and reduce the perioperative need for anesthetic agents.13 Furthermore, esmolol may also reduce the perioperative need for opioids.14 Based on in vitro studies, esmolol should not relax the EGJ. In contrast, it could theoretically increase the barrier pressure,15,16 which would be advantageous in a clinical context when the maintenance of the EGJ barrier pressure is of great importance. To our knowledge, no clinical study on the effect of esmolol on EGJ barrier function has been made. With this background, the aim of the present study was to evaluate and compare the effects of esmolol and remifentanil on EGJ pressures, and to test the hypothesis that esmolol in contrast to remifentanil does not affect the inspiratory EGJ augmentation, when administered as single drugs in healthy volunteers.
CONSORT flow chart is shown in Figure 1.
Fourteen volunteers were assigned to this double-blind, randomized, crossover study. The trial was conducted at the Department of Anesthesiology and Intensive Care at the Örebro University Hospital, Sweden, between January and March 2015. The study protocol, European Clinical Trials Database (EudraCT no. 2014-003714-90, https://eudract.ema.europa.eu), was approved by the Regional Ethics Committee in Uppsala, Sweden (D-no. 2014/372, approval date 2014-12-03). The volunteers were fully informed of the details of the study protocol and written informed consent was obtained. Financial remuneration was provided.
The subjects were healthy males (n = 8) and females (n = 6) with body mass index <30 and age 18–40 years (Table 1).
Exclusion criteria were: symptoms of gastroesophageal reflux disease, ongoing treatment with benzodiazepines or cardiovascular medication, allergy to drugs used in the trial, pregnancy and breastfeeding, abnormal electrocardiogram (atrioventricular block II–III, long Q-T syndrome), diabetes, and ongoing participation in another medical trial. Recruitment was achieved using an announcement on university noticeboards.
The interventions, which were administered sequentially in randomized order, consisted of: (a) esmolol (Brevibloc; Baxter Health care Ltd, Thetford, Great Britain) administered as a bolus dose of 1 mg/kg over 1 minute followed by an infusion of 10 μg·kg−1·minute−1 over 15 minutes (Alaris CC syringe pump; Alaris Medical Nordic AB, Solna, Sweden) and (b) remifentanil (Remifentanil Teva; TEVA Pharmaceuticals Works Private Limited Company, Gödöllö, Hungary) with a targeted effect site concentration of 4 ng/mL using a target-controlled infusion (TCI Minto Model, Alaris PK syringe pump; Alaris Medical Nordic AB, Solna, Sweden).17
The volunteers and the assessor of the manometry recordings were blinded to the order of drug administration. Esmolol and remifentanil were administered from syringes prepared by study personnel not taking part in the analysis of data. During the experiments, the syringe pumps were covered by a black opaque plastic sheet and positioned out of the volunteer’s field of view.
A high-resolution solid-state manometric assembly was used to measure EGJ pressures (ManoScan 360 A-100; Sierra Scientific Instruments, Inc, Los Angeles, CA). The manometric catheter has 36 circumferential sensors spaced at 1-cm intervals (outer diameter 4.2 mm). Each sensor consists of 12 radially dispersed sensing segments, detecting pressures over a length of 2.5 mm. Sector pressures are averaged within each sensor, making it circumferentially sensitive. The closely spaced sensors make it possible to obtain continuous measurements from the pharynx to the stomach, regardless of the catheter position relative to the moving anatomical structures. The data acquired by manometry are presented in real time as “topographic” plots (Figure 2), each plot displaying pressure encoded in color (high pressure orange and red, low pressure green and blue). The sensor position of the catheter is displayed on the vertical axis and time on the horizontal axis.8,18 Before and immediately after the examination the catheter was calibrated outside the body using calibration options present in the software.18
After a brief physical examination and interview, where exclusion criteria were ruled out, volunteers were randomized to 1 of the 2 intervention sequences. The randomization was performed using sealed opaque envelopes prepared by departmental staff that otherwise had no part in the study. A note informing which of the 2 possible intervention sequences (esmolol–remifentanil or remifentanil–esmolol) was to be administered, was placed in each envelope in a 1:1 ratio. The envelopes were then sealed, shuffled, and marked with numbers from 1 to 14 corresponding to the number of subjects enrolled in the study. The envelopes were then used consecutively.
Subjects were monitored by means of electrocardiography, pulse oximetry, and noninvasive blood pressure measurement. An IV line used for fluid and drug administration was established and the high-resolution solid-state manometric catheter introduced via the nose after the application of a topical anesthetic (Lidocaine 100 mg/mL, AstraZeneca, Södertälje, Sweden). Correct positioning was verified through the visualization of pressure landmarks between the pharynx and the stomach (Figure 2). The protocol included an initial 5-minute period to assess the baseline EGJ pressure. Registrations were performed with the volunteer in the supine position and after a 6-hour fasting period.
In 7 of the 14 volunteers the intervention sequence began with the administration of an IV bolus of esmolol (1 mg/kg) over 1 minute followed by an infusion of 10 μg·kg−1·minute−1 over a 15-minute period. The dose administered was based on total body weight. After a 20-minute washout period, an IV bolus dose of normal saline was administered over 1 minute to resemble the bolus dose of esmolol. Thereafter, a target-controlled IV infusion of remifentanil was started (Minto model programmed after ideal weight),17 with a targeted effect site concentration of 4 ng/mL, and continued for 15 minutes. For the other 7 volunteers, the intervention sequence was the reverse but otherwise identical (Figure 3).
Recordings of EGJ pressures were performed continuously throughout the study session and analyzed at baseline (T0), after 2 minutes (T2), and after 15 minutes of infusion of esmolol or remifentanil (T15). The interventions were terminated immediately after completion of data-requisition.
Inspiratory EGJ pressure was defined as the highest pressure during a normal respiratory cycle, whereas the expiratory pressure was defined as the EGJ pressure at the midpoint between 2 adjacent inspiratory pressures in a normal respiratory cycle.18 A mean of 2 values was derived when calculating inspiratory and expiratory EGJ pressures. Inspiratory EGJ augmentation was defined as the difference between inspiratory and expiratory EGJ pressures, and represents the increase in EGJ tone during inspiration.19 EGJ pressures are related to intragastric pressures, implying that the inspiratory and expiratory EGJ pressures reflect the actual barrier function of the EGJ.
The primary outcome was inspiratory EGJ augmentation. Secondary outcomes were inspiratory EGJ pressure and expiratory EGJ pressure.
Since different dosing strategies were chosen for esmolol and remifentanil, primarily due to the risk for respiratory depression when remifentanil is administered as a large bolus dose,20,21 primary comparisons were performed between esmolol at T2 and remifentanil at T15, and secondary comparisons between the 2 drugs at T15. T2 reflects the expected peak effect of esmolol,22 whereas T15 reflects the steady-state level of both esmolol and remifentanil.10,17
The effects of esmolol on EGJ metrics at point T2 and T15 were independently compared to remifentanil at T15 using a linear mixed model. The linear mixed model included the fixed factors: period (1, 2); sequence (1: esmolol first/remifentanil second and 2: remifentanil first/esmolol second); and group (esmolol, remifentanil); with baseline EGJ (T0) as covariate. Period was a repeated factor with compound symmetry as covariance structure, which showed the best model fit from Akaike information criteria. The Shapiro-Wilk test was used to verify the normality assumption for the residuals of the mixed model. No violation was found. To evaluate any possible carry-over effect of either intervention, the mixed model analyses were stratified according to intervention sequence (sequence 1: esmolol first/remifentanil second, sequence 2: remifentanil first/esmolol second). Correction for multiple comparisons was performed among the 2 secondary hypotheses using the Bonferroni-Holm method.23 Corrected P values <.05 were considered statistically significant. Mean differences with 95% confidence intervals were used as association measures. Statistical analyses were performed using SPSS version 22.0 (IBM Corp, Armonk, NY).
No in vivo study on the impact of esmolol on the EGJ function has been performed. Therefore, the assumption of the possible esmolol effect was based on knowledge generated by in vitro studies.15,16 These studies showed no relaxation of EGJ muscle strips when exposed to a β-receptor antagonist.15,16 In contrast, the negative effect of remifentanil on the EGJ is known from several in vivo studies from our own research group that have demonstrated a reduction in inspiratory EGJ augmentation and expiratory EGJ pressure of approximately −10 mm Hg.8,9 The assumed difference of 10 mm Hg between interventions was considered both clinically interesting and valid for the sample size calculation of the primary and secondary end points.
With a standard deviation of 8 mm Hg, a sample size of 7 subjects should have been sufficient to demonstrate a difference of 10 mm Hg between interventions, given the power of 0.8 and a type 1 error probability of .05. Since the effect of esmolol compared to remifentanil was totally unknown, as many as 14 subjects were enrolled in the present study. Sample size calculation was made using the PS (Power and Sample Size Calculations, version 3.0.43).24
The manuscript adheres to the applicable EQUATOR guidelines.
All 14 volunteers completed the study protocol without complications.
The inspiratory EGJ augmentation, inspiratory EGJ pressures, and expiratory EGJ pressures at each time point (T0, T2, and T15), as well as mean differences between interventions are presented in Tables 2 and 3.
Comparison Between Esmolol 1 mg/kg (T2min) and Remifentanil 4 ng/mL (Target-Controlled Infusion) (T15min)
No statistically significant difference between interventions was demonstrated on inspiratory EGJ augmentation (−4.0 mm Hg [−9.7 to 1.7]; P= .15). Mean difference in inspiratory EGJ pressure was −12.2 (−18.6 to −5.7, P= .003), and expiratory EGJ pressure −8.0 (−13.3 to −2.8, P= .006), when comparing esmolol with remifentanil (Table 2).
Comparison Between Esmolol 10 μg·kg−1·minute−1 (T15min) and Remifentanil 4 ng/mL (T15min)
No statistically significant difference between interventions was demonstrated on inspiratory EGJ augmentation (−2.5 mm Hg [−8.7 to 3.8]; P= .40). Mean difference in inspiratory EGJ pressure was −15.2 mm Hg (−23.4 to −7.0, P= .002) and expiratory EGJ pressures was −12.3 mm Hg (−19.1 to −5.5, P= .002) comparing esmolol with remifentanil (Table 3).
The main result of this study was that no effect on the inspiratory EGJ augmentation was demonstrated. We were thus not able to prove the hypothesis of the primary outcome. Even though the inspiratory EGJ augmentation was unaffected, the results show that remifentanil significantly weakens the EGJ barrier function by affecting both inspiratory and expiratory EGJ pressure, when compared to esmolol (Tables 2 and 3). This requires an explanation. Inspiratory EGJ augmentation is defined as the difference between inspiratory and expiratory EGJ pressures, and translates in the enhancement of EGJ pressure by the contraction of the crural diaphragm during inspiration.25 The lack of effect on the inspiratory EGJ augmentation could either be explained by lack of effect on any of the input parameters (inspiratory and expiratory pressures), which was the case with esmolol, or because the 2 variables are affected to the same extent, which was the case with remifentanil.
As mentioned above, EGJ pressure varies during the respiratory cycle and is lowest at the end of expiration.25 Theoretically this is the point in the respiratory cycle when the risk for regurgitation is at its highest, and the reason why expiratory EGJ pressure has been the focus of numerous manometry studies.8,26 In 2007, Pandolfino et al19 demonstrated an association between diminished inspiratory EGJ augmentation and objectively confirmed gastroesophageal reflux disease (endoscopy or pH-positive). Furthermore, our group has previously demonstrated that remifentanil decreases inspiratory EGJ augmentation when administered to healthy volunteers,9 suggesting a more profound negative effect of remifentanil on the crural aspect of the EGJ than on the sphincteric (lower esophageal sphincter). To be consistent with results from previous studies, the inspiratory EGJ augmentation was chosen as our primary end point. However, we cannot explain why we were not able to reproduce these results.
The dose of esmolol used in the present study is worth discussion. The dose of esmolol depends on the reason for its use. When administered to attenuate the sympathetic stress reaction to tracheal intubation, several administration strategies have been proposed, with bolus doses from 1 mg/kg27 to 500 mg·kg−1·minute−1 over 4 minutes,28 followed by various continuous infusion doses. To reduce the requirements of anesthetic agents, doses of 0.5 mg/kg followed by 50 μg·kg−1·minute−1, and 1 mg/kg followed by 250 μg·kg−1·minute−1 have been described.13 Collard et al14 were able to demonstrate significant postoperative opioid sparing after laparoscopic cholecystectomy using a bolus dose of 1 mg/kg followed by 5–15 μg·kg−1·minute−1. This dose also provided acceptable hemodynamic stability during induction and maintenance of anesthesia.14 It has also been stated that perioperative doses should be chosen with caution to avoid unexpected hypotension.29 With this in mind, we chose 1 mg/kg esmolol, followed by 10 μg·kg−1·minute−1.
There are some limitations of the present study that need to be addressed. No plasma drug concentrations were analyzed, which complicates the discussion of possible carry-over effects. The 20-minute washout period was decided to give time for remifentanil to be eliminated. This corresponds to more than 5 half-lives, which makes any carry-over effect of remifentanil unlikely.30 The elimination half-life of esmolol is somewhat longer, approximately 7–9 minutes depending,10 requiring a washout period of 35–45 minutes to completely rule out any possible carry-over effect. When planning the present study, we were influenced by the short duration of the clinical effect of esmolol demonstrated in a previous study, showing complete recovery from the β-blocking effect of esmolol 20 minutes after termination of a 300 μg·kg−1·minute−1 infusion.11 We therefore considered a 20-minute washout period to be long enough considering the much lower infusion dose that was to be used (10 μg·kg−1·minute−1). To evaluate the presence of any carry-over effect, stratification according to intervention sequence was performed. These stratified analyses showed that the effect of remifentanil compared to esmolol was consistently negative, independently of whether administered as first or second intervention. Since in vitro studies suggest that esmolol reinforces EGJ pressures,15,16 any residual effect of esmolol should have attenuated the negative effect of remifentanil on the EGJ, given that esmolol has a similar in vivo as in vitro effect. We found that remifentanil reduced both inspiratory and expiratory pressures to a greater extent when administrated after esmolol than when administered before esmolol, which suggests that there was no significant carry-over effect. Any residual effect of esmolol on basal EGJ pressures (T0) when administered before remifentanil should have been minute, if any.
When the stratified analyses are examined, it is noted that the baseline EGJ pressures differ between groups, and are consistently higher in the volunteers in sequence 1 (esmolol first/remifentanil second) compared to those in sequence 2 (remifentanil first/esmolol second). This difference in baseline data probably reflects differences in biological characteristics and should have been offset by the randomized allocation of subjects, but may be evident due to the small sample size.
Regurgitation with subsequent aspiration during anesthesia is a rare event, and thus difficult to study. There is no valid data relating regurgitation to a specified barrier pressure. However, in theory, a barrier pressure above 0 mm Hg should be sufficient to prevent passive regurgitation. In the present study, we observed relatively high EGJ pressures, well above 0 during both interventions (Tables 2 and 3). One can thus question if the reduction of the barrier pressure could have any clinical relevance. It should be noted however, that the measurements were performed in healthy volunteers, and the study drugs were administered separately without addition of any anesthetic agent. The conditions could be different in a clinical context in which multiple anesthetic agents are combined. For example, propofol has been shown to decrease the expiratory EGJ pressure in a dose dependent manner,31 and to amplify the negative effect of remifentanil.8 We therefore consider the demonstrated reduction of the barrier pressure of approximately 10 mm Hg to be a finding of clinical relevance. To investigate whether the addition of esmolol to balanced anesthesia may help maintain EGJ barrier pressure, further studies where esmolol is combined with remifentanil and an anesthetic agent are required.
Even though we found no difference in inspiratory EGJ augmentation between interventions, remifentanil, in contrast to esmolol, did affect the barrier pressure in the EGJ negatively. Since esmolol possesses properties suitable during anesthesia, its use might be beneficial in the perioperative setting in patients where the maintenance of the barrier function is of utmost importance.
Name: Fredrik Ander, MD.
Contribution: This author helped with conception and design; acquisition, analysis, and interpretation of data; drafting the article and giving final approval.
Name: Anders Magnuson, BSc.
Contribution: This author helped with analysis and interpretation of data; drafting and critically revising the article; and giving final approval.
Name: Lars Berggren, MD, PhD.
Contribution: This author helped with analysis and interpretation of data; critically revising the article; and giving final approval.
Name: Rebecca Ahlstrand, MD, PhD.
Contribution: This author helped with conception and design; acquisition, analysis, and interpretation of data; drafting and critically revising the article; and giving final approval.
Name: Alex de Leon, MD, PhD.
Contribution: This author helped with conception and design; acquisition, analysis, and interpretation of data; drafting and critically revising the article; and giving final approval.
This manuscript was handled by: Ken B. Johnson, MD.
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