Clinical trial NCT06003218: Dexmedetomidine-esketamine for Percutaneous Radiofrequency Liver Ablation
Official title: Dexmedetomidine-esketamine Combined With Oxycodone for Ultrasound-guided Percutaneous Radiofrequency Ablation in Patients With Liver Cancer: a Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Liver Cancer
Radiofrequency Ablation
Esketamine
Dexmedetomidine
Keywords: Liver cancer
Radiofrequency ablation
Esketamine
Dexmedetomidine
Lead sponsor: Peking University First Hospital
Sponsor class: OTHER
First posted: 2023-08-21
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Aged ≥18 years but ≤85 years.
2. Scheduled for elective ultrasound-guided percutaneous radiofrequency ablation for primary or metastatic liver cancer.

Exclusion Criteria:

1. Refused to participate.
2. Diagnosed schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis before surgery.
3. 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.
4. Diagnosed obstructive sleep apnea (OSA) or judged to be at high-risk of moderate-to-severe OSA before surgery.
5. 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.
6. Inability to communicate due to coma, severe dementia, or language barrier before surgery.
7. Allergy to any drug used during the study, or other conditions that are considered unsuitable for study participation.

Primary outcomes:
measure: Area under curve of Numerical Rating Scale of pain during and within 24 hours after surgery.
timeFrame: During and within 24 hours after surgery.
Secondary outcomes:
measure: The highest Numerical Rating Scale of pain during surgery.
timeFrame: During surgery.
measure: Number of intraoperative adjustment of study drug infusion rate.
timeFrame: During surgery.
measure: Number of additional oxycodone or other analgesics during and within 24 hours after surgery.
timeFrame: During and within 24 hours after surgery.
measure: Dose of analgesics during and within 24 hours after surgery.
timeFrame: During and within 24 hours after surgery.
measure: Pain intensity and opioid consumption (PIOC) index during and within 24 hours after surgery.
timeFrame: During and within 24 hours after surgery.
measure: Numeric Rating Scale of subjective sleep quality on the first and second nights after surgery.
timeFrame: On the first and second nights after surgery.
Other outcomes:
measure: Patients' evaluation on anesthesia.
timeFrame: Within 30 minutes after surgery.
measure: Surgeons' evaluation on anesthesia.
timeFrame: Within 30 minutes after surgery.
measure: Postoperative recovery time.
timeFrame: Up to 2 hours after surgery.
measure: Length of hospital stay after surgery.
timeFrame: Up to 30 days after surgery.
measure: Incidence of postoperative complications during hospital stay.
timeFrame: Up to 30 days after surgery.
Locations:
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
Study officials:
affiliation: Peking University First Hospital
name: Dong-Xin Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McGahan JP, Browning PD, Brock JM, Tesluk H. Hepatic ablation using radiofrequency electrocautery. Invest Radiol. 1990 Mar;25(3):267-70. doi: 10.1097/00004424-199003000-00011. No abstract available.
citation: European Association for Study of Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. Eur J Cancer. 2012 Mar;48(5):599-641. doi: 10.1016/j.ejca.2011.12.021. No abstract available.
citation: Higgins H, Berger DL. RFA for liver tumors: does it really work? Oncologist. 2006 Jul-Aug;11(7):801-8. doi: 10.1634/theoncologist.11-7-801.
citation: Olesen AE, Kristensen K, Staahl C, Kell S, Wong GY, Arendt-Nielsen L, Drewes AM. A population pharmacokinetic and pharmacodynamic study of a peripheral kappa-opioid receptor agonist CR665 and oxycodone. Clin Pharmacokinet. 2013 Feb;52(2):125-37. doi: 10.1007/s40262-012-0023-8.
citation: Riviere PJ. Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol. 2004 Apr;141(8):1331-4. doi: 10.1038/sj.bjp.0705763. Epub 2004 Mar 29.
citation: Wang J, Yuan X, Guo W, Xiang X, Wu Q, Fang M, Zhang W, Ding Z, Xie K, Fang J, Zhou H, Fu S. Sedation and Analgesia for Liver Cancer Percutaneous Radiofrequency Ablation: Fentanyl and Oxycodone Comparison. Int J Med Sci. 2020 Aug 12;17(14):2194-2199. doi: 10.7150/ijms.47067. eCollection 2020.
citation: Wu WT, Jia ZY, Chen Y, Chen QF, Zu QQ, Yang ZQ, Liu S, Shi HB. The Safety and Efficacy of Oxycodone Versus Fentanyl in Percutaneous Microwave Ablation of a Liver Tumour Abutting the Capsule. Cardiovasc Intervent Radiol. 2019 Jan;42(1):87-94. doi: 10.1007/s00270-018-1980-6. Epub 2018 May 8.
citation: Wu J, Lu Y, Cao X. Different effects of oxycodone and remifentanil in patients undergoing ultrasound-guided percutaneous radiofrequency ablation of hepatic cancer: a randomized trial. Drug Des Devel Ther. 2019 Jan 18;13:365-372. doi: 10.2147/DDDT.S188728. eCollection 2019.
citation: Yu EH, Tran DH, Lam SW, Irwin MG. Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia. 2016 Nov;71(11):1347-1362. doi: 10.1111/anae.13602.
citation: Ongiem A, Siriussawakul A, Aungsumat Wangdee BNS W, Homsud S, Jaiyen T. Assessment of Pain Severity after Radiofrequency Ablation in Patients with Hepatocellular Carcinoma. J Med Assoc Thai. 2016 May;99(5):572-7.
citation: Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 2003 Feb;98(2):428-36. doi: 10.1097/00000542-200302000-00024.
citation: Xia ZQ, Chen SQ, Yao X, Xie CB, Wen SH, Liu KX. Clinical benefits of dexmedetomidine versus propofol in adult intensive care unit patients: a meta-analysis of randomized clinical trials. J Surg Res. 2013 Dec;185(2):833-43. doi: 10.1016/j.jss.2013.06.062. Epub 2013 Jul 24.
citation: Sun YM, Zhu SN, Zhang C, Li SL, Wang DX. Effect of low-dose dexmedetomidine on sleep quality in postoperative patients with mechanical ventilation in the intensive care unit: A pilot randomized trial. Front Med (Lausanne). 2022 Aug 31;9:931084. doi: 10.3389/fmed.2022.931084. eCollection 2022.
citation: Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versatile tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020 Oct;33(5):633-638. doi: 10.1097/ACO.0000000000000916.
citation: Kaur U, Pathak BK, Singh A, Chakrabarti SS. Esketamine: a glimmer of hope in treatment-resistant depression. Eur Arch Psychiatry Clin Neurosci. 2021 Apr;271(3):417-429. doi: 10.1007/s00406-019-01084-z. Epub 2019 Nov 19.
citation: Song B, Zhu J. A Novel Application of Ketamine for Improving Perioperative Sleep Disturbances. Nat Sci Sleep. 2021 Dec 25;13:2251-2266. doi: 10.2147/NSS.S341161. eCollection 2021.
citation: Bartova L, Papageorgiou K, Milenkovic I, Dold M, Weidenauer A, Willeit M, Winkler D, Kasper S. Rapid antidepressant effect of S-ketamine in schizophrenia. Eur Neuropsychopharmacol. 2018 Aug;28(8):980-982. doi: 10.1016/j.euroneuro.2018.05.007. Epub 2018 Jul 2.
citation: Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sanchez E, Gutierrez-Rojas L, Meana JJ. Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs. 2018 May;32(5):411-420. doi: 10.1007/s40263-018-0519-3.
citation: Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630. doi: 10.1176/appi.ajp.2018.17060720. Epub 2018 Apr 16.
citation: Segmiller F, Ruther T, Linhardt A, Padberg F, Berger M, Pogarell O, Moller HJ, Kohler C, Schule C. Repeated S-ketamine infusions in therapy resistant depression: a case series. J Clin Pharmacol. 2013 Sep;53(9):996-8. doi: 10.1002/jcph.122. Epub 2013 Jul 24. No abstract available.
citation: Persson J, Hasselstrom J, Maurset A, Oye I, Svensson JO, Almqvist O, Scheinin H, Gustafsson LL, Almqvist O. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol. 2002 Feb;57(12):869-75. doi: 10.1007/s002280100353.
citation: Bornemann-Cimenti H, Wejbora M, Michaeli K, Edler A, Sandner-Kiesling A. The effects of minimal-dose versus low-dose S-ketamine on opioid consumption, hyperalgesia, and postoperative delirium: a triple-blinded, randomized, active- and placebo-controlled clinical trial. Minerva Anestesiol. 2016 Oct;82(10):1069-1076. Epub 2016 Jun 21.
citation: Hu ZC, Xu G, Zhang XW, Ma K, Jin JJ, Li PS. [Meta-analysis of the effects of dexmedetomidine combined with ketamine during dressing changes in burn patients]. Zhonghua Shao Shang Za Zhi. 2020 Jun 20;36(6):458-464. doi: 10.3760/cma.j.cn501120-20190327-00145. Chinese.
citation: Lee KH, Lee SJ, Park JH, Kim SH, Lee H, Oh DS, Kim YH, Park YH, Kim H, Lee SE. Analgesia for spinal anesthesia positioning in elderly patients with proximal femoral fractures: Dexmedetomidine-ketamine versus dexmedetomidine-fentanyl. Medicine (Baltimore). 2020 May;99(20):e20001. doi: 10.1097/MD.0000000000020001.
citation: Nagappa M, Wong J, Singh M, Wong DT, Chung F. An update on the various practical applications of the STOP-Bang questionnaire in anesthesia, surgery, and perioperative medicine. Curr Opin Anaesthesiol. 2017 Feb;30(1):118-125. doi: 10.1097/ACO.0000000000000426.
citation: Andersen LPK, Gogenur I, Torup H, Rosenberg J, Werner MU. Assessment of Postoperative Analgesic Drug Efficacy: Method of Data Analysis Is Critical. Anesth Analg. 2017 Sep;125(3):1008-1013. doi: 10.1213/ANE.0000000000002007.