Evaluation of low-dose esketamine on sleep quality in elderly patients undergoing painless gastroscopy

Purpose: To investigate the effect of low-dose esketamine on sleep quality in elderly patients undergoing painless gastroscopy. Methods: A total of 84 patients (ASA grade II - III, > 65 years old) who were to undergo painless gastroscopy in Guanggu District, Wuhan Third Hospital from June to July 2021 were enrolled. The diagnosis of sleep disorder was performed using Pittsburgh Sleep Quality Index (PSQI) before surgery. Patients with PSQI ≥ 5 were diagnosed with a sleep disorder (group E, n = 42), while those with PSQI < 5 were normal (group C, n = 42). Patients in both groups were given a single intravenous injection of esketamine 0.2 mg/kg 3 min before anesthesia induction, followed by an intravenous loading dose of propofol 1.5 mg/kg. Maintenance of anesthesia was achieved by intravenous pumping with propofol at 4 mg/kg per hour. Results: Sleep quality of patients in both groups improved after surgery, but the PSQI scores decreased more than that of group E (p < 0.05), especially on the night after surgery. Compared with group C, anesthesia induction time was longer and the number of propofol supplementation was increased in group E (p < 0.05). Groups C and E manifested no significant differences in postoperative satisfaction and occurrence of adverse reactions (p > 0.05). Conclusion: Low-dose esketamine improves the sleep quality of elderly patients with painless gastroscopy without increasing the risk of circulating breathing during surgery. However, multi-center large-scale studies will be required in further investigations in order to validate the findings of this study.


INTRODUCTION
Sleep disorders are important factors that affect the recovery of patients after surgery.In severe cases, it may lead to postoperative delirium [1,2], cognitive dysfunction, and other mental diseases [3], and even lead to increased mortality.For older patients, total sleep time and deep sleep time decrease, and sleep latency and non-REM sleep increase [4,5].Therefore, sleep quality may have some impact on elderly patients undergoing painless gastroscopy.Esketamine is D-ketamine that is sedative and analgesic, and its sympathomimetic activity may resist circulatory respiratory depression with propofol, making the anesthesia more stable for patients [6,7].

General information
This trial adopted a single-center, controlled, randomized, and double-blind design.A total of 84 patients (> 65 years old) who underwent elective painless gastroscopy in the outpatient clinic of Guanggu District, Wuhan Third Hospital from June to July 2021 were enrolled.
The study excluded patients with uncontrolled hypertension, heart disease, and mental illness, hyperthyroidism, high intracranial and intraocular pressure, difficulty in respiratory tract management (modified Markov score level IV), drug allergies, and intermittent or long-term use of opioids or sedatives within 2 months prior to admission.All patients were diagnosed with a sleep disorder by the Pittsburgh Sleep Quality Index (PSQI) before surgery.Patients with PSQI ≥ 5 were diagnosed with a sleep disorder (group E, n = 42), while those with PSQI < 5 were normal (group C, n = 42).

Ethical considerations
According to the Declaration of Helsinki and STROBE guidelines [9], this study was approved by the Ethical Committee of Guanggu District, Wuhan Third Hospital (approval no.KY2021-013).Written informed consent was obtained from all patients.

Preoperative preparation
All patients fasted for 8 h and water for 4 h before examination.Endoscopic diagnosis and treatment operations were performed by one of the three senior physicians in gastroenterology in the Guanggu District, Wuhan Third Hospital.Anesthesia was performed by a senior anesthesiologist, and an anesthesia resident was responsible for collecting relevant clinical data.

Anesthesia process
Electrocardiograms, pulse oxygen saturation, and non-invasive blood pressure were routinely monitored after admission.Patients were intravenously injected with a balanced salt solution at a due 4 mL/kg per hour and inhaled with oxygen at 10 L/min in the right lateral decubitus position.Two groups of patients received a single intravenous injection of esketamine at 0.2 mg/kg 3 mins before anesthesia induction, followed by an intravenous injection of a loading dose of propofol at 1.5 mg/kg, anesthesia maintenance: intravenous infusion of propofol 4 mg/kg per hour.Patients underwent gastroscopy when the eyelash reflex completely disappeared.Propofol 25 mg was supplemented when body dynamic responses occurred during the surgery.If the patient suffers from respiratory distress, the mask is pressurized to give oxygen to assist breathing.After 5 min of observation, the surgery should be continued depending on the patient's condition.For patients with hypotension (blood pressure decline ≥ 30 %) during surgery, the fluid infusion rate is accelerated and ephedrine 5 mg is concurrently administered intravenously.In patients with bradycardia (HR < 50 beats/min), atropine was administered intravenously at 5 µg/kg.

Parameters evaluated
The sleep status of the patients was investigated using PSQI and patients' satisfaction and willingness to undergo painless examination again was investigated by VAS score.Also, adverse reactions such as coughing, nausea, vomiting, hypotension, respiratory depression, etc. were recorded.The recovery of patients was investigated using a modified observer's assessment of alert/sedation (MOAA/S = 5: patients respond sensitively to calling in a normal tone of voice; MOAA/S = 1: patients respond to pain stimuli).

Statistical analysis
Statistical Package for the Social Sciences (SPSS) 22.0 was employed for statistical analysis.Measurement data were expressed as mean ± standard deviation (SD) and analyzed using independent samples t-test for normally distributed data or Bonferroni test for nonnormally distributed data.For categorical data, data analysis was done with χ 2 test or Fisher's exact test.P < 0.05 was considered statistically significant.

General patient profile
No significant difference existed in basic information such as age, gender, height, weight,  1).

PSQI scores
Esketamine had no significant effect on the postoperative PSQI scores of group C (P > 0.05), and PSQI scores increased at T1, which may be related to the hyperactivity of one patient, but there was no difference compared with preoperative status.At T2 and T3, patients' sleep returned to normal (P > 0.05).
However, the PSQI scores in group E decreased at T1 (P < 0.05).Although the PSQI scores at T2 and T3 were lower than those at T, the difference was not statistically significant (P > 0.05, Table 2).0.79 0.08 Note: T is before gastroscopy, T1 is the night after surgery, T2 is the first night after surgery, and T3 is the second night after surgery.*P < 0.05 compared to T at different time points

Patient satisfaction and willingness to receive gastroscopy again
Without considering the cost of anesthesia, no significant difference was presented between the two groups in terms of patient satisfaction and willingness to receive gastroscopy again (P > 0.05, Table 3).

Incidence of adverse events
During the sedation process, the anesthesia induction time and the number of propofol supplementation in group E were more than those in group C (P < 0.05).The recovery time and the number of patients with hypotension, nausea, and vomiting in group C had no statistical significance in group E (p > 0.05).

DISCUSSION
Sleep disorder is a common problem in the elderly, with more than half of old people suffering from sleep problems [10].The structure, duration, and quality of sleep change with age [11,12].In addition, elderly patients are prone to anxiety, resulting in difficulty in falling asleep and insomnia due to underlying diseases, lack of professional knowledge of the disease, and worry about the efficacy and prognosis.The use of anesthetics is also one of the causes of postoperative sleep disorder.
Esketamine, the D-isomer of ketamine, has a higher affinity for NMDA receptors and opioid μ receptors.Esketamine has a stronger sedative and analgesic efficacy and a lower incidence of side effects than ketamine [7,13,14].After ketamine treatment in patients with depressive disorder, sleep mode changes, mainly manifested as increased slow wave activity and increased amplitude in early sleep, but these changes appear in the first period after administration.During the second night's sleep, slow-wave sleep activity and amplitude decrease [8].Animal experiments have confirmed that ketamine increases delta sleep intensity (the characteristic wave of stage 3 sleep in non-REM sleep), and its mechanism may be through increasing synaptic plasticity and BDNF levels, thereby increasing sleep slow wave activity [8].Similar to ketamine, the rapid antidepressant effects of esketamine are associated with increased total sleep time, slow-wave sleep, slow-wave activity, and rapid eye movement sleep, decreased wakefulness, enhanced delta sleep intensity [15,16], and increased BDNF level.The study results showed that esketamine had no significant effect on postoperative sleep-in patients with normal sleep, but improved postoperative sleep in patients with sleep disorder.Some limitations present in the study, include the relatively small number of study cases, and a lack of long-term research, and further study on the mechanism will be necessary.

CONCLUSION
Combined low-dose esketamine/propofol intravenous anesthesia improves postoperative sleep quality in patients undergoing painless gastrointestinal endoscopy and has the advantages of less impact on breathing and circulation, rapid recovery time, and high patient satisfaction.However, multi-center large-scale studies will be required in further investigations in order to validate the findings of this study.

Table 2 :
PSQI scores at different time points

Table 3 :
Patient satisfaction and willingness to receive gastroscopy again