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Cardiovascular Protection Conservative Effects of Esketamine Versus µ-opioid Receptor Agonists in General Anesthesia

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ClinicalTrials.gov Identifier: NCT04553536
Recruitment Status : Recruiting
First Posted : September 17, 2020
Last Update Posted : March 17, 2021
Sponsor:
Information provided by (Responsible Party):
Zheng Guo, Second Hospital of Shanxi Medical University

Brief Summary:

Pain has two sides. The 'bad pain' refers to the adverse impact of pain on humans, which disturbs daily life of the sufferers. Evidence indicates that in the transduction and transmission of the painful signals some molecules may retrogradely moving to the tissues where the pain was initiated, to provide protection to the cells and the organ being insulted by the nociceptive stimulation. Transient receptor potential vanilloid 1 (TRPV1), as a nociceptor, promotes the release of calcitonin gene-related peptide (CGRP) and substance P (SP) in the small diameter primary sensory neurons, mediating the pain signals from nociceptor to the spinal dorsal horn, sending the pain signals to the central nervous system. In the same time, the neuropeptides are released from the peripheral nerve terminals of the innervating neurons, where the harmful stimulation occurred, including the heart and vasculature. CGRP and SP play important roles in cardio-protection and homeostasis of systemic hemodynamics via the neurogenic mechanism. All the beneficial effects initiated by pain is mentioned as 'good pain' by physiologists.

Surgery-related pain is mostly so severe and disturbing that must be medically treated. Unfortunately, the beneficial aspect of pain is commonly ignored in daily clinical practice. Does it matter to the patients' outcomes? We don't know yet! What we have been seeing is the shocking outcomes of patients underwent surgery, which shows about 0.8% and 7% of mortalities in the period of 48 hours and 30 days after surgery, respectively (https://www.rcplondon.ac.uk/projects/outputs/national-hip-fracture-database-annual-report-2016; Injury. 2017; 48(10): 2180-2183). What causes the disaster? Piles of evidence demonstrate that deep anesthesia or deep sedation is related to the high mortality of the patients (Anesthesiology. 2012; 116:1195-1203; Crit Care. 2014; 18(4):R156 ). What about the effect of analgesia, especially the over-analgesia, on the patients' outcome in and after surgery? Opioids are the most commonly used drugs in the treatment of moderate and sever pain including intra- and postoperative pain. The µ-opioid receptor agonists induce analgesic effect via inhibition of the transduction and the transmission of pain signals, by suppression of the release of CGRP and SP from the nerve terminals. The protective effects on cardiovascular system mediated by CGRP and SP can be inhibited, if the same effect is produced by the action of opioids in the peripheral nerve terminals innervating the heart and the vasculature. Our previous research shows that intrathecal administration of morphine or epidural administration of ropivacaine (1%, in 20 μL) significantly attenuates the increases of CGRP and its coding mRNA in ventricular myocardium and the innervating dorsal root ganglion neurons following occlusion of coronary artery in experimental animals. Based on the evidence, we hypothesize that over-analgesia using opioids significantly suppresses the activity of TRPV1/CGRP、SP mechanism and reduces the amount of CGRP and SP released, which results in an effective de-protection of the cardiovascular system. The severer myocardial damage under some insulting circumstances and eventful systemic hemodynamics is likely occurring upon some surgical/pathological/pharmacological insults in the intra- and postoperative periods.

This parallel, randomized controlled trial will be conducted in eleven centers in Shanxi province, China, which is designed to investigate the perioperative incidence of adverse cardiovascular events and alteration of cardiac troponin I (cTnI) in the patients (one thousand patients, ASA Physical Status 1-II, older than 16 years, regardless of the gender) undergoing surgery under total intravenous general anesthesia with conventional µ-opioid agonists or Esketamine, as the major analgesic. Clinically appropriate anesthesia depth or BIS readings will be used for judgement of anesthetic depth. Conventional monitoring parameters, including blood pressures, heart rate, SpO2 and ECG, will be recorded and analyzed. Blood samples will be collected at 30 min before induction of anesthesia, at the end of surgery and 24 h after the surgery. The association of the perioperative adverse cardiovascular events and the alterations of the levels of serum TRPV1, CGRP, SP and cTnI in the patients underwent general anesthesia using different analgesics (µ-opioid agonists vs Esketamine) will be evaluated. Postoperative outcome, including the functions of the brain and cardiovascular system, is also going to be traced for 1 year postoperatively.


Condition or disease Intervention/treatment Phase
Opioid Analgesic Adverse Reaction Drug: Esketamine, Sulfentanil or/and Remifentanil Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Prevention
Official Title: Perioperative Cardiovascular Protection Conservative Effects of Esketamine Versus µ-opioid Receptor Agonists in Total Intravenous General Anesthesia: Study Protocol for a Randomized Controlled Pilot Trial
Actual Study Start Date : November 2, 2020
Estimated Primary Completion Date : November 1, 2021
Estimated Study Completion Date : November 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Esketamine

Arm Intervention/treatment
Active Comparator: Opioid analgesics
Mu-opioid receptor agonists (remifentanil, sulfentanil) will be used as the only analgesic(s) in the surgery.
Drug: Esketamine, Sulfentanil or/and Remifentanil
The esketamine or the opioids will be intravenously injected or infused to the patients with propofol and one of the muscle relaxants to induce and maitain general anesthesia.
Other Name: Propofol, Atracurium Besilate or Cisatracurium besylate or Rocuronium Bromide

Experimental: Ketamine
Esketamine will be used as the only anagesic in the surgey.
Drug: Esketamine, Sulfentanil or/and Remifentanil
The esketamine or the opioids will be intravenously injected or infused to the patients with propofol and one of the muscle relaxants to induce and maitain general anesthesia.
Other Name: Propofol, Atracurium Besilate or Cisatracurium besylate or Rocuronium Bromide




Primary Outcome Measures :
  1. Perioperative adverse cardiac events [ Time Frame: 72 hours ]
    It includes intra- and post-operative adverse cardiac events.

  2. Cardiac protection related molecules, including transient receptor potential vanilloid 1 (TRPV1), calcitonin gene-related peptide (CGRP) and substance P. [ Time Frame: 24 hours ]
    The molecules exist in myocardium participating in carioprotection.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients undergoing general anesthesia

Exclusion Criteria:

  • Patients with diabetes and neuropathy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04553536


Locations
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China, Shanxi
Zheng Guo Recruiting
Taiyuan, Shanxi, China, 030001
Contact: Zheng Guo, MB,PhD    +863513365790    guozheng713@yahoo.com   
Contact: Weijun Liang, MSc    +863513365790    weijun_liang@126.com   
Principal Investigator: Zheng Guo, MB, PhD         
Sponsors and Collaborators
Second Hospital of Shanxi Medical University
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Responsible Party: Zheng Guo, Professor, Second Hospital of Shanxi Medical University
ClinicalTrials.gov Identifier: NCT04553536    
Other Study ID Numbers: ZGuo20200826
First Posted: September 17, 2020    Key Record Dates
Last Update Posted: March 17, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sufentanil
Remifentanil
Dsuvia
Bromides
Propofol
Esketamine
Rocuronium
Cisatracurium
Atracurium
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Analgesics, Opioid
Narcotics
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anticonvulsants
Neuromuscular Nondepolarizing Agents
Neuromuscular Blocking Agents
Neuromuscular Agents
Antidepressive Agents
Psychotropic Drugs
Nicotinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents