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.