This is a prospective, single-center, randomized, double-blinded, and placebo-controlled clinical trial registered in the Chinese Clinical Trial Registry (ChiCTR2200063793). Our study obtained approval from the Ethics Committee of Jinan Central Hospital (2022-107-02) and all methods were performed in accordance with the relevant guidelines and regulations. The total sample size was one hundred and forty patients (seventy patients per each group). Patients were randomly scheduled by using Epicalc 2000 soft and divided into two groups in a 1:1 group allocation to receive either normal saline (Group S) or remimazolam (Group R). We included patients (ASA I–II, aged 18–65 years, BMI 18–28 kg/m2) who were to undergo procedural sedation during gastroscopy regardless of gender. We excluded patients with recent upper respiratory tract infection and asthma, benzodiazepines and propofol susceptibility, nervous system or cardiovascular diseases, suspected abuse of narcotic analgesics or sedatives, difficult airway, pregnant and lactation and men with family planning in recent 3 months. All selected patients were informed about the purpose of the trial and written consent was obtained.
Patients were fasted for 8 h and only clear liquids were allowed up to 2 h before the induction of anesthesia. After the patient entered the examination room, peripheral venous access was established in the upper extremity. The patient was placed in the left decubitus position, and oxygen was received through the nasal catheter with 4 l/min. Vital signs such as noninvasive blood pressure (BP), electrocardiogram, heart rate (HR), and peripheral capillary oxygen saturation (SpO2) were monitored. Patients were divided into two groups: Group S (n = 70), which was injected with normal saline 0.1 ml/kg in advance within 60 s; In group R (n = 70), remimazolam 0.1 mg/kg was injected intravenously also within 60 s. 30 s after the injection of normal saline or remimazolam, patients were received intravenously propofol at the rate of 0.5 ml/s until loss of consciousness. Drugs used in the study: Propofol injection (20 ml: 200 mg, Sichuan Guorui Pharmaceutical Co., Ltd., batch number: 2201233); Remimazolam, toluene sulfonate (36 mg, Jiangsu Heng Rui Pharmaceutical Co., Ltd., batch number: 200205AK); 0.9% sodium chloride injection (100 ml: 0.9 g, China Otsuka Pharmaceutical Co., Ltd., batch number: 5J80F2). The pre-treating drugs were prepared in a 10 ml syringe with either 10 ml of normal saline or remimazolam diluted with normal saline (1 mg/ml) to 10 ml. Sealed envelopes were selected for concealment of the study group allocation until the drug was prepared. The assistor who prepared all drugs did not participate in anesthesia induction. Both patients and investigators were blinded to the randomized grouping allocation and the drugs. All prepared drugs were stored at room temperature and used in 10 min.
The Ambesh four-point pain score method18 was used by investigators who were blinded to the group location to evaluate the severity of PIP. The patient was repeatedly asked about the intensity of PIP every 5 s during the induced anesthesia of propofol: grade 0, no pain (the patient complained of no pain at the injection site after repeated questioning); grade 1, mild pain (the patient complained of pain through the doctor’s initiative, but no physical movement); grade 2, moderate pain (voluntarily complaining of pain at the injection site to the doctor, or self-reported pain accompanied by physical activity when the anesthetist asked); grade 3, severe pain (facial pain, painful expression, accompanied by strong vocal response, arms retracted, or tears).
The primary endpoint variable in this study was the incidence of PIP. Secondary endpoints included the intensity of PIP, patient satisfaction of anesthesia, vital signs, characteristics of surgery and recovery, and adverse events, including hypotension (≤ 80% of basic blood pressure), hypoxemia (SpO2 < 90%), chin lifting (SpO2 < 90%), bradycardia (< 50 beats/min), physical movement, cough, nausea and vomiting. BP, HR, SpO2, and other vital signs were recorded at the following time points: before the pre-treatment with normal saline or remimazolam (T0), immediately after insertion of the gastroscope (T1), withdrawal of the gastroscope (T2), and the patient responds to the call for the first time (T3). The patient satisfaction of anesthesia was measured by a questionnaire19 about satisfaction (mild dizziness or none, mild nausea, vomiting or no) or dissatisfaction (dizziness, nausea, vomiting) by an assistor who did not participate in anesthesia induction. The questionnaire was collected before the patient leaving the Post-Anesthesia Care Unit. The definition of characteristics of surgery and recovery: the anesthesia time was defined as the time from the pre-treating drugs administrated to the end of gastroscopy; the surgery time was defined as the time from T1 to T2; the recovery time was defined as the time from the end of gastroscopy to T3.
The incidence of PIP in the previous studies was various from 28 to 90%, and our preliminary study found that about 50% in our department. We hypothesized a 50% reduction in the incidence of PIP based on an alpha of 0.05 and a power of 80%. 57 patients were included in each group to detect a significant difference under these assumptions. Considering 20% potential loss to follow-up, 70 patients were needed in each group.
All statistical analyses were analyzed with IBM SPSS 26.0 statistical software. All data are expressed as number (%) or mean ± SD. Continuous data of patients between the two groups were analyzed by independent sample t-test. Categorical data were compared by x2 test or Fisher’s test. p-values or corrected p-value of 0.05 were indicated as statistically significant.