Low-dose S-ketamine and Dexmedetomidine in Combination With Opioids for Postoperative Analgesia

Low-dose S-ketamine and Dexmedetomidine in Combination With Opioids for Patient-controlled Analgesia After Scoliosis Correction Surgery: a Randomized, Double-blind, Placebo-controlled Trial

Scoliosis correction surgery is followed with severe pain. Patients after scoliosis correction surgery usually require high dose opioids and long duration analgesia, which may increase side effects and even drug tolerance. S-ketamine is the pure dextrorotatory enantiomer of ketamine with stronger analgesic effect and less side effects, but mental side effects is a major concern. Dexmedetomidine can be used as an analgesic supplement; it also improves sleep quality in postoperative patients. We hypothesize that low-dose ketamine and dexmedetomidine in combination with opioids may have synergistic effect in analgesia and reduce drug-related side effects. This study aims to explore the effect of low-dose of S-ketamine and dexmedetomidine in combination with opioids for postoperative patient-controlled intravenous analgesia in patients following scoliosis correction surgery.

Scoliosis correction surgery is followed with severe pain. The reported median pain score on the first day after surgery is median 7 (IQR 4, 8); with an incidence of persistent postoperative pain from 5% to 75%. Most patients undergoing this surgery are young and adolescents; they are sensitive to pain and usually require higher dose analgesics and a long duration analgesia. The total dose of opioids required for postoperative analgesia is about 2-4 times higher than that after other surgeries. But even with high dose opioids, the analgesic effect remains unsatisfied. Furthermore, high dose opioids may cause side effects such as respiratory depression, drowsiness, nausea, vomiting, skin itching, and even drug tolerance. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist (NMDA) with analgesic and anti-hyperalgesia effects. It is widely used for anesthesia induction in critically ill patients, pediatric anesthesia and postoperative analgesia. The advantages of ketamine include mild influence on respiratory and circulatory function, and good analgesic effect. Recent guidelines recommends the use of low-dose ketamine infusion for postoperative analgesia in patients with moderate to severe pain, in order to reduce the consumption of opioids. S-ketamine is the pure dextrorotatory enantiomer of ketamine with stronger analgesic effect and lower incidence of adverse reactions. Dexmedetomidine is a highly selective α2 receptor agonist with effects of antianxiety, sedation and analgesia. When used as a supplement, it improves analgesic effect, and reduces opioid consumption and opioid related adverse reactions. In the same time, dexmedetomidine activates the endogenous sleep pathway and improves sleep quality by prolonging total sleep time, increasing sleep efficiency, and promoting subjective sleep quality. It is worthy to note that ketamine can produce adverse reactions such as agitation, delirium and anxiety, and increase the incidence of hallucinations and nightmares when the given dose is slightly higher; whereas the sedative effect of dexmedetomidine may help to reduce the adverse effects of ketamine. We hypothesize that low-dose ketamine and dexmedetomidine in combination with opioids may have synergistic effects in postoperative analgesia and reduce drug-related adverse reactions. This study aims to explore the effect of low-dose of S-ketamine and dexmedetomidine in combination with opioids for postoperative patient-controlled intravenous analgesia in patients following scoliosis correction surgery.

Patient-controlled analgesia is established with S-ketamine 50 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lock-out interval of 8 minutes and a background infusion rate at 1 ml/h.

Patient-controlled analgesia is established with sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lock-out interval of 8 minutes and a background infusion rate at 1 ml/h.

Sufentanil 4 microgram/kg (maximum 250 microgram) is included in the mixture for patient-controlled analgesia.

Pain severity is evaluated with the Numeric Rating Scale (NRS, an 11-point scale where 0 = no pain and 10 = the worst pain) twice daily (8:00-10:00 and 18:00-20:00) at rest and with movement. Moderate to severe pain is defined as any NRS pain score of 4 or higher.

Pain severity is evaluated with the Numeric Rating Scale (NRS, an 11-point scale where 0 = no pain and 10 = the worst pain) twice daily (8:00-10:00 and 18:00-20:00) at rest and with movement. Moderate to severe pain is defined as any NRS pain score of 4 or higher.

Agitation and sedation score is evaluated with the Richmond Agitation and Sedation Scale (RASS, with scores ranging from -5 [unarousable] to +4 [combative] and 0 indicates alert and calm) twice daily (8:00-10:00 and 18:00-20:00).

Delirium is assessed with the Three-dimensional Confusion Assessment Method (3D CAM) twice daily (8:00-10:00 and 18:00-20:00).

Subjective sleep quality is evaluated with the Numeric Rating Scale (NRS, an 11-point scale where 0 = the best sleep and 10 = no sleep at all) once daily (8:00-10:00)

Postoperative complications are defined as new-onset medical conditions that were deemed harmful and required therapeutic intervention (i.e., grade II or higher on the Clavien-Dindo classification)

Inclusion Criteria: Age ≥ 18 years old, body weight ≥ 40 kg; Scheduled to undergo scoliosis correction with pedicle screw fixation; Planned to use patient-controlled intravenous analgesia after surgery. Exclusion Criteria: Refused to participate in the study; Preoperative sick sinus syndrome, severe sinus bradycardia (heart rate < 50 beats/min), atrioventricular block grade II or above without pacemaker; or comorbid with congenital heart disease, arrhythmia, or other serious cardiovascular diseases with a cardiac function grade ≥ III; Patients with obstructive sleep apnea syndrome, or a STOP-Bang score ≥ 3 in combination with a serum HCO3- level ≥ 28 mmol/L; History of hyperthyroidism and pheochromocytoma; History of schizophrenia, epilepsy, myasthenia gravis, or delirium; Severe liver dysfunction (child Pugh grade C), severe renal dysfunction (preoperative dialysis), or American Society of Anesthesiologists grade ≥ IV; Barrier in communication; Other conditions that are considered unsuitable for study participation.

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