What is the best sedation method for high‐risk patients such as those with cirrhosis?

Gastrointestinal endoscopy is an essential diagnostic examination for gastrointestinal diseases. However, gastrointestinal endoscopy is invasive and painful; therefore, sedatives and analgesics are required. Moreover, these drugs are essential for endoscopic treatment. When using sedatives and analgesics during endoscopic treatment, especially for high-risk patients, attention must be paid not only to efficacy but also to safety. A balance between efficacy and safety is important. Chen et al.1 investigated the efficacy and safety of sedation during esophageal endoscopy in patients with liver cirrhosis. Patients with an esophageal procedure and/or with decreased liver function, such as cirrhosis, are at high risk of sedation complications. There are several types of sedatives used in endoscopic procedures. Benzodiazepines, such as midazolam, are commonly used as sedatives in Japan, although their disadvantages include their prolonged effects and half-life (approximately 3 h), which are inappropriate for short endoscopic procedures. Remimazolam, an ultrashort-acting benzodiazepine, was developed recently. Although remimazolam is metabolized in the liver, unlike other benzodiazepine drugs, it is not mediated by cytochrome P450 enzymes (CYP). Because CYP expression in the liver is suppressed in patients with liver cirrhosis, midazolam metabolism decreases when administered to patients with liver damage, resulting in delayed excretion and prolonged sedation.2 Therefore, sedation endoscopy with remimazolam may be beneficial for patients with cirrhosis. Remimazolam combines better safety with rapid recovery and early restoration of cognitive function. Recent reports also show its usefulness in the field of gastrointestinal endoscopy.3 Propofol is another fast-acting drug with a short recovery and ambulation time. However, it has a narrow sedation threshold and causes hypotension, bradycardia, and hypoxemia, requiring continuous monitoring with an anesthesiologist during endoscopy. In the treatment of esophageal disease, use of benzodiazepines such as midazolam may make it difficult to continue the procedure due to body movement; in contrast, propofol reduces body movement. Therefore, propofol may be better suited for esophageal procedures. The Japan Gastroenterological Endoscopy Society guidelines for endoscopic sedation consider elderly people, pregnant patients, and patients with chronic obstructive pulmonary disease, heart disease, chronic renal failure, or liver cirrhosis to be at high risk.4 Since many sedatives are metabolized in the liver, side-effects such as hypotension and hypoxemia are more likely to affect sedated patients with cirrhosis since they have impaired liver function. Patients with cirrhosis have impaired protein synthesis, altered drug metabolism pathways, and reduced blood flow. Benzodiazepine receptors may be increased in patients with cirrhosis, and midazolam has been reported to exacerbate hepatic encephalopathy compared with propofol. Therefore, propofol may be more useful for endoscopy in patients with cirrhosis than midazolam.5-7 From a safety point of view, there is a high risk of hypotension when propofol is used in patients with impaired liver cirrhosis. If the propofol dose can be reduced, the risk of hypotension is reduced. Concomitant analgesics may reduce the propofol dose. Recent studies on new analgesics such as sufentanil and esketamine in gastrointestinal endoscopy have been conducted mainly in China.1, 8, 9 However, it is not known which analgesics can be added to propofol to reduce adverse events, such as hypotension. In this issue of Digestive Endoscopy, Chen et al.1 investigated the efficacy and safety of propofol plus esketamine sedation compared with sufentanil during endoscopic variceal ligation (EVL) with or without injection sclerotherapy in patients with liver cirrhosis. In this study, 100 patients were divided into four groups (25 patients each). The first group received sedation with 1.5 mg/kg propofol in combination with 0.1 μg/kg sufentanil (group S), the second received propofol with 0.2 mg/kg esketamine (group E 0.2), the third received propofol with 0.3 mg/kg esketamine (group E 0.3), and the fourth received propofol with 0.4 mg/kg esketamine (group E 0.4). Then EVL was performed. Hypotension occurred in 36%, 20%, 24%, and 72% of the patients from groups E 0.2, E 0.3, E 0.4, and S, respectively. The incidence of hypotension was significantly reduced in the groups that received esketamine compared with group S. Furthermore, the frequency of hypoxemia was significantly lower in group E 0.4 (4%) than in group S (32%). Esketamine, a novel N-methyl-D-aspartate receptor antagonist, is less likely to cause hemodynamic instability and respiratory depression. It is used to treat depression in the United States and Europe, although no psychological side-effects have been observed. However, the addition of esketamine to propofol causes hypotension in about 20% of cases; while this is less than sufentanil, there is still room for improvement in terms of safety. Other reports have shown the usefulness of adding esketamine to propofol for sedation. Yang et al.8 reported that adding esketamine to propofol allowed for a decrease in the propofol dose. Consequently, the incidence of hypotension and recovery time were minimized. Regarding countries other than China, Eberl et al.9 discussed the significance of adding esketamine to propofol during endoscopic retrograde cholangiopancreatography in the Netherlands. In conclusion, sedation by adding esketamine to propofol may address difficult cases of sedation, like esophageal treatment of liver cirrhosis. Propofol use in patients with cirrhosis suppresses metabolism and delays excretion, making hemodynamic side-effects more likely to occur at higher doses. Esketamine is effective because it has fewer circulatory side-effects, can be used in combination with propofol, and can reduce the amount of propofol used. However, this combination would not apply to all countries and regions. It is necessary to administer appropriate sedatives and appropriate doses for each region and each patient. With the increasing demand for sedation during gastrointestinal endoscopy, sedatives have become essential to the procedure. The number of high-risk patients is increasing, and many sedatives and analgesics are being used during gastrointestinal endoscopy. It is necessary to improve the conditions for endoscopy under sedation, which include safety management through proper drug selection and administration. I thank Editage (www.editage.com) for English language editing. Author declares no conflict of interest for this article. None.