In spontaneously breathing patients under deep sedation during colonoscopy, remimazolam, compared with propofol, 1) reduces the need for airway intervention and the possibility of hypoxia, 2) provides improved respiration, 3) reduces the incidence of adverse events.
Remimazolam is new sedative. It acts on the GABAa receptors as propofol does. However, it produces the desired sedation and has the following potential advantages compared with propofol, including lower incidence of dose-associated hypoxemia and/or hypotension, antagonistic characteristics and improved controllability with flumazenil, better tolerability concerning injection pain[6, 7]. Nevertheless, whether it produce less respiratory suppression than propofol does at comparable sedation level remains unknown. Our study demonstrated that remimazolam produce the comparable sedation level with our protocol and comparable condition for colonoscopy, with lower depression of spontaneous breathing and incidence of adverse events compared with propofol.
Our primary outcome is the time from anesthesia induction to first airway intervention, which indirectly reflect oxygen and respiration. In the comparable sedation level, remimazolam prolong elapse time for first intervention. The first airway intervention time was 11 min for remimazolam, and 5 min for propofol. For a single patient, the 6-min extension of airway intervention may only be statistically significant without clinically significant. However, there is a need for more anesthesiologists, with the increasing number of colonoscopy patients[13, 14]. As a result, each anesthesiologist may have to manage multiple anesthetized patients simultaneously. The more patients need deep sedation, the more difficult it is to manage, especially in cases where there are high-risk patients with respiratory tract obstruction, such as the American Society of Anesthesiologists (ASA) III or above, the elderly, and obesity[15–17]. Even if there is bedside supervision of a nurse anesthetist, the extended time of 6 min airway intervention could reduce the difficulty of anesthesia management for the anesthesiologist who manages multiple patients simultaneously, and the overall safety of patients could also be improved.
There was no difference in the incidence of hypoxia between the two group, and both were 0%. This is because the care team promptly intervene when the patient had shallow, slow breathing or apnea. 62% of patients in the propofol group and 22% in the remimazolam group needed airway intervention. It indicates that remimazolam could reduce the risk of hypoxia.
Hypoxia in our observation is different from the previous study, in which the SpO2 in 22% of patients was less than 90%, and even in 3% of patients was less than 80% [12]. The reasons may be as follows. First, no obese patient was included, and the patients included in this study have no serious cardiovascular and pulmonary diseases. Second, before anesthesia induction, the patients can take oxygen for more than 2 min with an oxygen flow rate of 6 l/min, and it could maintain the oxygen saturation above 90% for about 5–6 min[18] Third, for the safety of the patients, the anesthesia provider had taken airway interventions before the decrease of SpO2 when they found that the patients had shallow, slow breathing or apnea.
However, we found MV decreased in both groups after deep sedation, with more decrease in propofol group. Another interesting findings were that remimazolam almost did not inhibit the RR of patients, with obvious inhibition of RR in the propofol group. According to MV = TV × RR, the decrease in MV was mainly caused by the TV decrease using remimazolam, the inhibition of propofol on patients' respiration was manifested in the reduction of TV and RR. It can also be inferred that propofol has a more significant inhibition on RR than remimazolam from the increase in the average number of apnoeic episodes and total duration of apnoea.
Respiratory nerve cells are widely distributed at all levels of the central nervous system, including the spinal cord, medulla oblongata, pons, diencephalon, and cerebral cortex, regulating respiratory rhythm and respiratory movement. The role of nerve cells of respiratory centers at all levels in the generation of respiratory rhythm and the regulation of respiratory movement is different, but they all complete the normal respiratory movement of the body through mutual coordination and mutual restriction among the centers at all levels. The autonomic respiratory rhythm is regulated above the spinal cord level, while the motor neurons innervating the respiratory muscle are located in the spinal cord and regulated by the high-level central system[19, 20]. Remimazolam had almost no inhibition on RR, but obvious inhibition on TV, propofol had obvious inhibition on TV and RR. We hypothesized that the respiratory nerve cells of remimazolam action might be mainly below the level of medulla oblongata plane, while propofol might have extensive inhibition on respiratory nerve cells. We are currently conducting further animal study to test this hypothesis. If the hypothesis holds, it might benefit difficult intubation patients who need to preserve spontaneous breathing during intubation.
Another interesting finding is that airway interventions were easier in the Group Rem than in the Group Pro. We know that chin lift and jaw thrust are easier than manually assisted ventilation, chin lift are easier than jaw thrust, supraglottic airway device and endotracheal intubation need more preparation. No patients received the supraglottic airway device or endotracheal intubation in both groups. All patients needed only chin lift and jaw thrust to improve respiration in the remimazolam group, but 21% of patients needed manually assisted ventilation in the propofol group. Furthermore, a chin lift could improve spontaneous ventilation in 83% of patients in the remimazolam group vs. 47% in the propofol group. More patients (54% vs. 20% ) needed jaw thrust to open the upper airway in the propofol group. We know that both sedatives meet the need for colonoscopy procedures. However, the easier the airway intervention, the greater the significance of clinical promotion, especially in the medical situations of fewer anesthetists and more endoscopic patients.
Although there is no statistical difference in the procedure success rate between the two groups, there is still a clinical difference. In the remimazolam group, 5 in 208 patients had body movement after 3–5 times of rescue during colonoscopy and finally used propofol to complete the colonoscopy. These 4 patients had anxiety, sleep disorder, or had taken psychotropic drugs history, and may be resistant to benzodiazepines[21]. One patient received 4 rescue doses after induction with remimazolam and 200 mg of propofol and remained awake without complaining of discomfort, with stable respiration and circulation. The reason is unclear and needs further study. The injection pain of remimazolam was significantly lower than that of propofol (0% vs. 28.37%), which was consistent with other research results[5, 22]. It may be related to remimazolam being a nonlipid solvent, and the local vascular irritation is less[23]. Hiccups in colonoscopy may be related to operation stimulation. However, 14 patients in the remimazolam group had a hiccup with no one in the propofol group. The same results were found in previous studies[5, 6, 9]. It was not completely ruled out that it was related to the remimazolam drug itself, but there was no study on the correlation and mechanism between remimazolam and hiccups.
We also found that patients sedated with remimazolam recovered slower than propofol. The time to full alert using remimazolam was 9.14 min vs. 6.83 min using propofol. The slower recovery of remimazolam was through the following principles. First, the clearance rate of remimazolam in vivo (0.88–1.37 l/min) was slower than that of propofol (1.5-2 l/min). Secondly, the onset time of remimazolam is 1–3 min, and the full awake time is 8–40 min, which is slower than that of propofol[24]. Third, patients in the remimazolam group received more rescue sedatives than the propofol group (23.08% vs. 14.42%), which prolonged the sedation time. However, remimazolam has a specific reversal agent, flumazenil, which makes its sedative effect more controllable. We found that MOAA/S increased to 5 points in 1 min after intravenous injection of flumazenil 0.2 mg in the 3 delayed recovery patients, without re-sedation or discomfort. Kilpatrick GJ et al confirmed that the sedative effect of remimazolam is easily reversed by flumazenil, and the risk of re-sedation is small, as the elimination half-time of remimazolam was approximately 48 min—and this did not depend upon bolus doses of up to 0.5 mg/kg—which was similar to that for flumazenil[5–7].
There are several potential limitations to this study. First, No BIS. But sedation level was determined with clicnal assessment, and this study was randomized and the sample size was large. We assume that the difference in the sedation levels between the two arms is NS and does not affect our conclusion. Second, No blind. The sedatives could not be blinded to the clinician or research staff, considering the safety of the patients. However, all parameters analyzed were automatically recorded except for the elapsed time from induction first airway intervention and the number and length of airway interventions. Third, sedation level at initiation of procedure was not protocalized. The gastroenterologists might start procedure before the target sedation level was achieved, but the occurance was few. We assume that it does not affect our conclusion. Fourth, Majority of the patients were non-obese. Therefore, our observation may not generalizable to obese population.