Impact of Dexmedetomidine Supplemented Analgesia on Sleep Quality in Elderly Patients After Major Surgery: A Randomized, Double-blind, and Placebo-controlled Pilot Study

Sleep disturbances usually develop in elderly patients after major surgery, which are manifested as prolonged sleep latencies, shortened sleep duration, frequent wake-up, disordered circadian rhythm, abnormally increased stages 1 and 2 non-rapid eye movement (N1 and N2) sleep, and decreased or absent slow wave sleep (SWS) and rapid eye movement (REM) sleep. Occurrence of sleep disturbances is harmful for the recovery of both physiological and mental functions after surgery, and may even lead to the development of postoperative complications. For example, study showed that postoperative sleep disturbances were associated with increase risks of delirium, cardiovascular events and infections, prolonged durations of stay in ICU and hospital, increased medical expenses and high mortality rate. However, methods that may effectively improve the quality of postoperative sleep are still lacking.

Multiple factors are responsible for the development of sleep disturbances after surgery. These include (1) environmental factors, such as noises, lights, medical and nursing activities, etc.; (2) comorbid diseases, such as cardiovascular disease, inflammatory reaction, infections, etc.; (3) stress response and pain stimulation provoked by surgery, especially major surgery; (4) mechanical ventilation. Studies found significantly disordered circadian rhythms, fragmented sleep and absent REM sleep in mechanically ventilated patients; and (5) multiple medications, such as benzodiazepines, opioids, non-steroidal anti-inflammatory drugs, and glucocorticoids,.

Dexmedetomidine is a high selective alpha 2 adrenoceptor agonist which produces hypnosis and sedation by activating the alpha 2 adrenoceptor in the locus coeruleus of the brain; it is well known that the locus coeruleus is the key part to adjust sleep and awakening. The study of Nelson et al. showed that dexmedetomidine induces the expression of c-Fos in the locus coeruleus nucleus and ventral lateral nucleus in rats' brain, which is similar to the expression of c-Fos during non-rapid eye movement sleep. They presumed that dexmedetomidine activates the endogenous sleep-promoting pathway to produce sedative effects, which is totally different from benzodiazepines and opiates on the mechanism.

A recent study of the investigators showed that, in elderly patients who were admitted to the ICU after surgery and did not require mechanical ventilation, low-dose dexmedetomidine infusion (at a rate of 0.1 ug/kg/h, for 15 hours) prolonged the total sleep time, increased the percentage of N2 sleep (and reduced the percentage of N1 sleep), increased the efficiency of sleep and improved the subjective sleep quality. Another study of the investigators showed that low-dose dexmedetomidine infusion in elderly patients who were admitted to the ICU after non-cardiac surgery improved the subjective sleep quality and reduced the daily prevalences of delirium during the first 3 days after surgery. We hypothesize that dexmedetomidine supplemented analgesia can improve the structure and circadian rhythm of sleep, and reduce the incidence of delirium in elderly patients after major non-cardiac surgery.

Simple randomization was performed. Random numbers were generated in a 1:1 ratio with a block size of 4 using the SAS 9.2 software (SAS Institute, USA). Study drugs (either 200 μg/2 ml dexmedetomidine hydrochloride or 2 ml 0.9% saline) were provided as clear aqueous solution in the same type of 3 ml volume ampules (manufactured by Jiangsu Hengrui Medicine Co, Ltd, China) and encoded according to the randomization results before the study by a pharmacist who did not participate in the rest of the study. The results of randomization were sealed in sequentially numbered envelopes until the end of the study.