Dexmedetomidine-esketamine for Percutaneous Radiofrequency Liver Ablation

Dexmedetomidine-esketamine Combined With Oxycodone for Ultrasound-guided Percutaneous Radiofrequency Ablation in Patients With Liver Cancer: a Randomized Controlled Study

Percutaneous radiofrequency ablation is a commonly treatment for patients with liver cancer that cannot be surgically resected. During the procedure, patients need to keep awake and cooperate with the procedure, including deep breath and hold breath. However, intolerable pain generated during puncture and radiofrequency heating may cause body movements and interfere the procedure. Oxycodone is frequently used for analgesia but still insufficient. A recent study showed that dexmedetomidine-esketamine combination improves analgesia without increasing adverse events. After stopping infusion, the analgesic/sleep-promoting effects of dexmedetomidine-esketamine seemed to last for up to 24 hours. The investigators hypothesize that dexmedetomidine-esketamine combination as a supplement to oxycodone will improve sedation and analgesia in patients undergoing radiofrequency liver ablation of the liver.

Ultrasound-guided percutaneous radiofrequency ablation is a new technique to treat liver cancer. Under ultrasound guidance, a radiofrequency electrode needle is inserted into the cancer through which local high temperature is generated to coagulate and necrose the cancer tissue. Percutaneous radiofrequency ablation is currently recognized as the best treatment for patients with liver cancer that cannot be surgically resected. During the procedure, patients need to keep awake and cooperate with the procedure, including deep breath and hold breath. However, intolerable pain generated during puncture and radiofrequency heating may cause body movements and interfere the procedure. Oxycodone is a widely used opioid. It activates the μ and κ receptors and relieves pain including visceral pain, which makes it suitable for analgesia during radiofrequency ablation. However, due to the strong stimulation of radiofrequency liver ablation, supplemental analgesics are often required to improve patient cooperation. As a commonly used supplement, remifentanil is also a μ receptor agonist that quickly reaches blood-brain balance in about 1 minute in and is rapidly hydrolyzed in tissues and blood. The problems with remifentanil are the ultra-short action and pain allergy after stopping infusion. The burning pain after percutaneous liver radiofrequency ablation may last for up to 24 hours. Dexmedetomidine is a highly selective α2-adrenergic receptor agonist that has sedative, anxiolytic, and analgesic effects. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that is widely used in pediatric anesthesia and postoperative analgesia. Recent studies found that low-dose ketamine also has antidepressant and sleep promoting effects. Esketamine is the S-enantiomer of racemic ketamine with a higher affinity for NMDA receptors and is approximately twice as potent as racemic ketamine in analgesia. A recent study showed that dexmedetomidine-esketamine combination improves analgesia without increasing adverse events. After stopping infusion, the analgesic and sleep-promoting effects of dexmedetomidine-esketamine seemed to last for up to 24 hours. The investigators hypothesize that dexmedetomidine-esketamine combination as a supplement to oxycodone will improve sedation and analgesia in patients undergoing radiofrequency liver ablation of the liver.

Dexmedetomidine-esketamine combination will be infused in addition to oxycodone; the target is to maintain a Richmond Agitation and Sedation Scale between -2 and -1 during surgery.

Remifentanil will be infused in addition to oxycodone; the target is to maintain a Richmond Agitation and Sedation Scale between -2 and -1 during surgery.

Dexmedetomidine-esketamine mixture will be infused with doses adjusted to maintain a Richmond Agitation-Sedation Scale between -2 to -1 during surgery.

Remifentanil will be infused with doses adjusted to maintain a Richmond Agitation-Sedation Scale between -2 to -1 during surgery.

Numerical Rating Scale (NRS, an 11-point scale where 0=no pain and 10=the worst pain) of pain will be assessed after percutaneous liver puncture, start of radiofrequency-ablation, every 2 minutes during radiofrequency-ablation, end of radiofrequency-ablation, and 10 minutes after needle removal during surgery, as well as at 0.5, 1, 6, 12, and 24 hours after surgery.

Numerical Rating Scale (NRS, an 11-point scale where 0=no pain and 10=the worst pain) of pain will be assessed after percutaneous liver puncture, start of radiofrequency-ablation, every 2 minutes during radiofrequency-ablation, end of radiofrequency-ablation, and 10 minutes after needle removal during surgery

Dose of opioids (excluding remifentanil administered as study drugs) will be converted to intravenous morphine equivalent.

Pain intensity will be calculated as area under curve (AUC) of Numerical Rating Scale (NRS, an 11-point scale where 0=no pain and 10=the worst pain) of pain during and within 24 hours after surgery. Opioid consumption (OC) during and within 24 hours after surgery will be calculated after excluding remifentanil administered as study drugs. Pain intensity and opioid consumption (PIOC) index will be calculated as: PIOC=[(AUCmean rank - AUCrank)/AUCmean rank] + [(OCmean rank - OCrank)/OCmean rank]. The range of the sum is -200% to +200%. Values above 0 indicate increased summed AUC and OC compared to the all patients.

Numerical Rating Scale (NRS, an 11-point scale where 0=the best sleep and 10=the worst sleep) of sleep quality on the first and second nights after surgery.

Patients' evaluation will be performed using the Likert five-point scale: 1=very dissatisfied, 2=dissatisfied, 3=neutral, 4=satisfied, and 5=very satisfied.

Surgeons' evaluation will be performed using the Likert five-point scale: 1=very dissatisfied, 2=dissatisfied, 3=neutral, 4=satisfied, and 5=very satisfied.

Postoperative complications are defined as new-onset conditions after surgery that have adverse effects on postoperative recovery and require therapeutic interventions.

Inclusion Criteria: Aged ≥18 years but ≤85 years. Scheduled for elective ultrasound-guided percutaneous radiofrequency ablation for primary or metastatic liver cancer. Exclusion Criteria: Refused to participate. Diagnosed schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis before surgery. Preoperative left ventricular ejection fraction (LVEF) <30%, or those with sick sinus syndrome, sinus bradycardia (heart rate <50 beats per minute), or atrioventricular block at grade II or above without pacemaker. Diagnosed obstructive sleep apnea (OSA) or judged to be at high-risk of moderate-to-severe OSA before surgery. Severe liver dysfunction (Child-Pugh grade C), severe renal dysfunction (dialysis before surgery), or classified as American Society of Anesthesiologists (ASA) grade >III before surgery. Inability to communicate due to coma, severe dementia, or language barrier before surgery. Allergy to any drug used during the study, or other conditions that are considered unsuitable for study participation.

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