Safety and efficacy of combined sedation with dexmedetomidine and midazolam for endoscopic retrograde cholangiopancreatography in patients over 80 years of age

Abstract

Background: This study aimed to evaluate the safety and efficacy of using a combination of dexmedetomidine (DEX) and midazolam (MDZ) for sedation in patients over 80 years of age during endoscopic retrograde cholangiopancreatography (ERCP).

Methods: Thirty-two patients over 80 years of age who were scheduled to undergo ERCP from June 2020 to February 2021 at the International University of Health and Welfare Atami Hospital were included. Seventeen patients who received DEX + MDZ for sedation during ERCP were compared with a historical control group (patients who received MDZ alone). In addition, the safety and efficacy of sedation were evaluated using between-group comparisons.

Results: The MDZ dose required in the DEX + MDZ group was significantly lower than in the historical control group (8.5 mg vs. 18 mg, p<0.001). There was no significant difference in respiratory depression between the two groups (0% vs. 6.9%, p=0.585). During and after the examination, the minimum systolic blood pressure and minimum heart rate were significantly lower in the DEX + MDZ group than in the historical control group. However, serious complications were not observed.

Conclusions: The results indicate that the DEX + MDZ combination is potentially safe and effective in sedating the elderly and does not cause serious complications.

Background

Owing to the improved survival rates and performance indicators, the use of endoscopic retrograde cholangiopancreatography (ERCP) in elderly patients with pancreaticobiliary diseases is increasing. The successful and safe performance of ERCP requires careful achievement of conscious sedation, particularly in patients over 80 years of age, after assessing the need for the procedure. Various complications (e.g., respiratory depression, hypoxemia, bradycardia, and increase or decrease in blood pressure) can occur in elderly patients, and one of the most important factors in avoiding these complications is the choice of sedatives [1]. The effects of benzodiazepines and propofol tend to be excessive in these patients [2-4], leading to an increased rate of dose-dependent respiratory depression, resulting in fatal complications. The guidelines of the American Society of Gastrointestinal Endoscopy recommend lower doses of sedatives in elderly versus younger patients to reduce the incidence of complications [5]. However, information on the specific use of sedatives for ERCP in elderly patients is limited.

Dexmedetomidine (DEX), a highly selective α2-adrenoceptor agonist with sedative activity and minimal respiratory effects, has been widely used in intensive care unit patients in recent years [6,7]. However, its use for endoscopic procedures in elderly patients is unknown. The use of DEX during gastrointestinal endoscopy has attracted considerable attention although, unlike many other sedatives (e.g., benzodiazepines and propofol), it does not cause respiratory depression due to its limited affinity for γ-aminobutyric acid receptors. Although sedation using DEX has been pronounced to be beneficial in endoscopic procedures such as upper and lower endoscopy for screening and endoscopic submucosal dissection. Lee et al reported that the addition of DEX to the midazolam-meperidine regimen provided better sedative efficacy and a superior safety profile during ERCP compared with a midazolam-meperidine regimen [8]. However, the age of the participants of this study was, limited to 80 years or less, therefore, the regimen’s effectiveness in the elderly is controversial. Inatomi et al. reported that DEX could decrease the incidence of respiratory complications and the total dose of other sedative agents and could be used as an alternative to conventional methods with midazolam for adequate sedation during ERCP in patients over 80 years of age [9]; however, it was a retrospective study. Some studies have suggested that DEX alone is insufficient for sedation during ERCP [10,11]. Furthermore, other studies have reported fewer side effects with synergistic sedatives when used together with sedatives with different mechanisms of action than with monotherapy [12,13].

In this study, we prospectively investigated the safety and efficacy of the combination of DEX and midazolam (MDZ) for sedation in patients over 80 years of age during ERCP.

Methods

Patients

This single-arm trial included patients over 80 years of age who underwent therapeutic ERCP at the International University of Health and Welfare Atami Hospital. The exclusion criteria were as follows: informed consent not received, difficulty in mutual understanding because of dementia or consciousness disorder, history of intolerance to DEX or benzodiazepines, substance abuse of sedatives or narcotics, baseline percutaneous arterial blood oxygen saturation (SpO₂) <90%, baseline systolic blood pressure <60 mmHg, heart rate <40 beats/min, and history of bradyarrhythmia (sick sinus syndrome and atrioventricular block ≥second-degree high grade).

This study was conducted according to the principles stated in the Declaration of Helsinki and received approval from the ethics committee of the International University of Health and Welfare (approval no. FA-2-1902-003). Written informed consent was obtained from all the patients before the procedure.

Sedation procedure

ERCP was performed by four experienced gastroenterologists who were either accredited by the Japan Gastroenterological Endoscopy Society or had experience with more than 300 cases of ERCP. The sedative was administered to all the patients by a doctor (non-anesthesiologist) familiar with the use of sedatives. A TJF-260 or JF-260 V duodenoendoscope (Olympus Medical System, Tokyo, Japan) was used. Oxygen (2 L/min), using a nasal cannula, was administered from the commencement of the examination. Blood pressure, heart rate, and SpO₂ were continuously monitored during the examination, and electrocardiograms were continuously obtained.

DEX (Precedex, Pfizer, Tokyo, Japan) was initiated at a loading dose and subsequently administered at 3 µg/kg/h for 10 min, followed by continuous infusion of a reduced dose of 0.4 µg/kg/h until the end of the examination to the extent described in previous reports (Fig. 1) [14,15]. MDZ (2.5 mg; Astellas Pharma, Tokyo, Japan) was administered intravenously at the start of the examination, followed by a single intravenous injection of 2 mg to maintain the sedation level at 4 on the Ramsay sedation scale (RSS) (Table 1) [16]. Flumazenil (0.5 mg) was administered intravenously at the end of ERCP. Both groups received catecholamine when the systolic blood pressure was ≦60 mmHg, and atropine was administered when the heart rate was ≦40 beats/min for >10 s.

Endpoints and measurements

The primary endpoint for evaluating the effectiveness of the drug combination was the required dose of MDZ. In recent years, conventional sedatives, such as benzodiazepines and propofol, have been widely used for sedation during endoscopic procedures; their benefits include the power of sedation. However, they often cause side effects (most notably, respiratory depression) in a dose-dependent manner [17]. MDZ, a short-acting benzodiazepine, is commonly used as an adjunct to propofol for short-term procedures such as endoscopies. It has a faster onset of action, a shorter duration of action, and high amnestic properties. However, when used alone, higher doses are required to maintain the desired depth of sedation, resulting in decreased cardiopulmonary function and increased recovery time [18]. Paradoxical stimulation is a serious side effect seen in up to 10% to 15% of elderly patients [8,19]. From the above, we hypothesized that a decrease in the dose of MDZ would lead to a decrease in its associated complications. Therefore, we studied the required dose of MDZ in this study as the primary endpoint.

The secondary endpoints were the frequency of sedation-associated respiratory depression, frequency of acute respiratory failure and bradyarrhythmia, and increase or decrease in blood pressure and heart rate requiring administration of atropine and catecholamine. The blood pressure and heart rate were continuously monitored from the commencement of sedation until the end of the examination. In addition, the values before the study (when entering the examination room), the lowest value during the study, and the value after the study (10 min after the study) were analyzed. Respiratory depression at the time of the study was defined as SpO₂ <90%. ERCP time was defined as the time taken from the insertion of the endoscope to the completion of the endoscopic procedure.

The endpoints were compared between patients receiving DEX + MDZ (our study) and a historical control group, namely, the MDZ alone group (n=87) in a retrospective study by Inatomi et al [9]. In that study, DEX safely reduced the need for additional doses of MDZ for sedation of patients aged over 80 years during ERCP, and the median required dose of MDZ was 18 mg and 10 mg with and without DEX respectively.

Furthermore, the RSS score and hemodynamic/respiratory parameters were monitored upon awakening from ERCP from 0 to 60 min or at 15-min intervals. In our study, recovery was assessed every 15 min, using the modified Aldrete score [20].

Statistical analysis

The reported median dose of MDZ was 10 mg, with a standard deviation of approximately 7 mg with the addition of DEX, compared to the median dose of 18 mg in the historical control group [9]. From these data, we estimated our sample size with the anticipated median MDZ dose as 10 mg, standard deviation as 10 mg, conservatively, and the threshold MDZ dose as 18 mg in this examination. Under a power of 80% and a bilateral significance level of 5%, the required number of cases was calculated to be 15 by a sample t-test. However, assuming an approximate deviation rate of 20%, we planned to set the number of cases as 20. Data are presented as median and range (quartiles) for non-normally distributed variables (amount of drug used) and mean ± standard deviation for normally distributed variables (e.g., blood pressure, heart rate, and oxygen dose). Drug use was analyzed using the Mann-Whitney U test. Baseline characteristics and complication rates were analyzed using the chi-square test, and hemodynamics over time were analyzed using repeated measures of variance. A p-value of <0.05 indicated a significant difference.

Results

Patient characteristics

Thirty-two patients over 80 years of age were scheduled for ERCP from June 2020 to February 2021 at the International University of Health and Welfare Atami Hospital. Among them, 15 were excluded from this study owing to dementia (eight patients), baseline systolic blood pressure of <60 mmHg (one patient), a history of bradycardia (three patients), a leak in the intravenous feeding tube (two patients), and a mistake in the drug dose administered (one patient). Ultimately, 17 patients who received DEX + MDZ for sedation during ERCP were compared to patients in the historical control group (who received MDZ alone in a retrospective study by Inatomi et al. [9]) (Fig. 2).

Several differences were observed between the DEX + MDZ group and the historical control group regarding sex, body mass index, medical history, New York Heart Association classification, the reason for examination, procedure type, and mean ERCP time (Table 2).

Total required dose of MDZ

The median required dose of MDZ was significantly lower in the DEX + MDZ group (8.5 mg) than in the historical control group (18 mg) (p<0.001) (Fig. 3).

Frequency of respiratory depression

There was no difference in the frequency of respiratory depression between the two groups (Table 3).

Sedation-related complications during ERCP

Problems related to the dynamics of blood circulation, including heart failure, sick sinus syndrome, and progressive atrioventricular block, were not observed in either group. Two (12%) and no patients in the DEX + MDZ group and the historical control group received atropine (0.5 mg) intravenously for bradycardia, respectively (p=0.024). The number of patients who received dopamine (3 μg/kg/min) was one (5.9%) and zero, respectively (p=0.36) (Table 3). Three patients who received atropine or catecholamine recovered quickly and underwent complete ERCP. There were no serious respiratory or circulatory disturbances leading to clinical problems during ERCP.

Changes in circulatory dynamics over time

The mean lowest systolic blood pressure during ERCP was 99 mmHg in the DEX + MDZ group and 114.3 mmHg in the historical control group. Both values were significantly lower than the pre-examination values (p<0.001). After ERCP, blood pressure improved in the historical control group, but remained depressed in the DEX + MDZ group (Fig. 4).

In the DEX + MDZ group, the mean lowest heart rate during ERCP was 53 beats/min; this value was significantly lower than the pre-examination value (p<0.001). The mean heart rate was similar before and during (75 beats/min) ERCP in the historical control group. However, the heart rate significantly decreased during and after ERCP in the DEX + MDZ group (mean post-examination heart rate: 55 beats/min) but improved instantly after ERCP in the historical control group (mean heart rate: 79.9 beats/min) (Fig. 5).

Changes in RSS during each procedure in our study

On arriving at the major duodenal papilla and during bile duct intubation, endoscopic retrograde cholangiography, and endoscopic sphincterotomy (EST), the sedation level was found to be sufficient. On insertion of an endoscope in the esophagus and removal of biliary stones from the biliary duct, the RSS tended to decrease, often requiring the addition of MDZ (Table 4).

Recovery time and complications after ERCP in our study

The mean recovery time (modified Aldrete score of ≧9) was 40 min. During recovery, two patients vomited, and one patient coughed. No serious complications (e.g., acute respiratory failure and bradyarrhythmia, and increase or decrease in the blood pressure and heart rate requiring administration of atropine and catecholamine) were noted during recovery (Table 5).

Discussion

In this study, the required dose of MDZ for sedation of patients aged over 80 years was significantly lower when DEX was co-administered. However, we did not observe any significant difference in the frequency of apnea between the DEX + MDZ group and the historical control group (patients who received MDZ alone). Although DEX lowered the blood pressure and heart rate during and after ERCP, complications related to serious circulatory hemodynamics did not occur.

We assumed the cohort from the retrospective study of Inatomi et al. [9] as the control group in this study. The use of a historical control group can lead to selection bias. Elderly patients tend to experience more effects in comparison to young patients [21]. Hence, any clinical study for the elderly should be carried out with careful attention to safety. Therefore, safety must first be confirmed with a single-arm design like in a phaseⅡtrial, and subsequently should be advanced to a randomized controlled trial. Sedation and analgesia enable patients to endure uncomfortable procedures by reducing anxiety, discomfort, and pain. Sedation in ERCP can be easily performed and avoids duodenal perforation, pancreatitis, and other complications that result from poor patient cooperation.

Various complications are usually associated with endoscopic treatment in the very elderly, and one of the most important preventive factors is the use of sedatives [1].Furthermore, respiratory depression usually occurs in ERCP. In a prospective study of MDZ and pethidine hydrochloride, the incidence of deep sedation with respiratory depression was 86% during ERCP versus 26% during upper gastrointestinal endoscopy [22].

DEX, an α2-adrenergic agonist has recently been used for conscious sedation. DEX has sedative as well as analgesic properties without causing significant respiratory depression. However, when used as the sole agent for conscious sedation, DEX has not been shown to be considerably effective. In particular, its effectiveness in ERCP is controversial. The greater invasiveness of ERCP compared with other endoscopic procedures may account for these discrepancies. In addition, ERCP involves injecting a contrast medium into the pancreatic and bile ducts or mechanical expansion of the papilla (e.g., endoscopic papillary balloon dilation) and is painful. In contrast, mucosal resection in endoscopic submucosal dissection is usually painless; therefore, a deep sedation level is required for ERCP [22]. In this study, although the RSS was sufficient, it tended to decrease probably during each procedure (including EST) when the biliary stones were removed, often requiring the addition of MDZ. Therefore, we believe that deepening the sedation level is necessary before performing procedures inducing substantial pain such as stone removal and bile duct expansion.

This study has several limitations: [1] the control group was a historical control and significant differences were found in the characteristics of patients in the DEX + MDZ and the control group [2], it was a single-arm study at a single center [3], the number of patients was relatively small.

Declarations

Ethics approval and consent to participate - This study was conducted according to the principles stated in the Declaration of Helsinki and received approval from the ethics committee of the International University of Health and Welfare (approval no. FA-2-1902-003). Written informed consent was obtained from all the patients before the procedure.

Consent for publication – Not applicable

Availability of data and materials – The datasets used during the current study available from the corresponding author on reasonable request.

Competing interests - The authors declare that they have no competing interests.

Funding - All authors disclose no financial relationships relevant to this study.

Authors' contributions

TT was involved in analyzing the results and writing the manuscript. YS, TK, and WT participated in the design of the study and performed the statistical analysis. HI helped procedure for ERCP. AN conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Acknowledgements - None

Authors' information

Takuya Takayanagi, Email：[email protected]

Yasunari Sakamoto, Email：[email protected]

Takayuki Kato, Email：[email protected]

Wataru Tomeno, Email：[email protected]

Hideki Itoh, Email：[email protected]

Atsushi Nakajima, Email：[email protected]

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