Remote Ischemic Preconditioning in Patients Undergoing Acute Minor Abdominal Surgery

Overview

This study examines if remote ischemic preconditioning in patients undergoing minor acute abdominal surgery (laparoscopic cholecystitis due to acute cholecystitis) is associated with a modulation of endothelial dysfunction. half of the patients will receive remote ischemic preconditioning prior to surgery, the other half will serve as controls.

Full Title of Study: “Remote Ischemic Preconditioning in Patients Undergoing Acute Minor Abdominal Surgery: The PUMAS Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Single (Care Provider)
  • Study Primary Completion Date: February 28, 2020

Detailed Description

Remote ischemic preconditioning (RIPC) consists of cycles of forearm or leg ischemia and reperfusion by the inflation of a blood-pressure cuff over the systemic blood pressure for brief periods. The procedure is simple, safe and with no clear side effects. In clinical studies covering acute cardiology RIPC has effectively reduced myocardial injury, postoperative cardiovascular complications and cardiac mortality. Recently, the effect of RIPC on attenuating ischemia-reperfusion injury has been investigated in non-cardiac surgery as well. The organ specific ischemia-reperfusion injury, systemic oxidative stress and inflammatory response were attenuated due to the intervention but a complete understanding of the underlying protective mechanisms of RIPC is however still lacking.

Experimental and clinical studies have implicated that the stimulus of RIPC is transmitted from the preconditioned tissue to other tissues and organs by humoral, neural and systemic anti-inflammatory mediators. The humoral and neural pathway are thought to be dependent on endogen substances such as adenosine, bradykinin, nitrogen oxide (NO) and calcitonin-gene-related-peptide (CGRP).

Interventions

  • Procedure: Remote Ischemic Preconditioning (RIPC)
    • Cycles of forearm ischemia and reperfusion by the inflation of a blood-pressure cuff over the systemic blood pressure for brief periods

Arms, Groups and Cohorts

  • Experimental: Remote Ischemic Preconditioning
    • Remote ischemic preconditioning is carried out before the induction of general anesthesia. All four cycles will be completed before general anesthesia. The blood pressure cuff is placed on the upper limb. The cuff is inflated to 200 mmHg (if systolic blood pressures exceeds 185 mmHg, the cuff will be inflated to at least 15 mmHg above the systolic blood pressure) resulting in a total occlusion of the blood flow to the limb. After 5 minutes of ischemia, the cuff is deflated, and the limb is reperfused for 5 minutes. This cycle is repeated 4 times. Pulse oximetry is performed on the RIPC limb to make sure that the blood flow is completely interrupted during ischemia
  • No Intervention: Control
    • Will receive no intervention, but will go through same tests at the same time-points (endothelial function measured by reactive hyperemia index, blood samples, Heart rate variability and questionaires)

Clinical Trial Outcome Measures

Primary Measures

  • Changes in endothelial function measured by reactive hyperemia index (RHI)
    • Time Frame: 24 hours
    • Changes in endothelial function measured by reactive hyperemia index (RHI) at baseline, four hours and 24 hours after surgery (cholecystectomy due to acute cholecystitis)

Secondary Measures

  • Heart rate variability
    • Time Frame: 24 hours
    • Changes in Heart rate variability measured with eMotion Faros from baseline and 24 hours consecutively.
  • Changes in p-L-arginine
    • Time Frame: 24 hours
    • Changes in p-L-arginine in μmol/L from baseline til 24h post-surgery
  • Changes in p-asymmetric dimethylarginine
    • Time Frame: 24 hours
    • Changes in p-asymmetric dimethylarginine in μmol/L from baseline til 24h post-surgery
  • Changes in p-biopterins
    • Time Frame: 24 hours
    • Changes in p-biopterins in ng/ml from baseline til 24h post-surgery
  • Changes in soluble endothelial (E-) selectin
    • Time Frame: 24 hours
    • Changes in soluble E-selectin in ng/ml from baseline til 24h post-surgery
  • Changes in soluble plasma (P-) selectin
    • Time Frame: 24 hours
    • Changes in soluble P-selectin in ng/ml from baseline til 24h post-surgery
  • Changes in Intercellular Adhesion Molecule 1 (ICAM-1)
    • Time Frame: 24 hours
    • Changes in soluble Intercellular Adhesion Molecule 1 (ICAM-1) in ng/ml from baseline til 24h post-surgery
  • Changes in syndecan-1
    • Time Frame: 24 hours
    • Changes in syndecan-1 in pg/ml from baseline til 24h post-surgery
  • Changes in thrombomodulin
    • Time Frame: 24 hours
    • Changes in thrombomodulin in pg/ml from baseline til 24h post-surgery
  • Changes in arginine vasopressin
    • Time Frame: 24 hours
    • Changes in arginine vasopressin in ng/ml from baseline til 24h post-surgery
  • Changes in adrenalin
    • Time Frame: 24 hours
    • Changes in adrenalin in ng/ml from baseline til 24h post-surgery
  • Changes in noradrenalin
    • Time Frame: 24 hours
    • Changes in noradrenalin in pg/ml from baseline til 24h post-surgery
  • Changes in ascorbic acid
    • Time Frame: 24 hours
    • Changes in ascorbic acid in ng/μL from baseline til 24h post-surgery
  • Changes in dehydroascorbic acid
    • Time Frame: 24 hours
    • Changes in dehydroascorbic acid in ng/μL from baseline til 24h post-surgery
  • Changes in angiotensin II
    • Time Frame: 24 hours
    • Changes in angiotensin II in pg/mL from baseline til 24h post-surgery
  • Changes in bradykinin
    • Time Frame: 24 hours
    • Changes in bradykinin in pg/mL from baseline til 24h post-surgery
  • Changes in calcitonin-gene related peptide
    • Time Frame: 24 hours
    • Changes in calcitonin-gene related peptide in pg/mL from baseline til 24h post-surgery
  • Changes in prostacyclin
    • Time Frame: 24 hours
    • Changes in prostacyclin in pg/mL from baseline til 24h post-surgery
  • Changes in serotonin
    • Time Frame: 24 hours
    • Changes in serotonin in ng/mL from baseline til 24h post-surgery
  • Changes in endothelin-1
    • Time Frame: 24 hours
    • Changes in endothelin-1 in pg/mL from baseline til 24h post-surgery
  • Changes in adrenomedullin
    • Time Frame: 24 hours
    • Changes in adrenomedullin in ng/mL from baseline til 24h post-surgery
  • Changes in platelets
    • Time Frame: 24 hours
    • Changes in platelets x 109/L from baseline til 24h post-surgery
  • Changes in adenosin
    • Time Frame: 24 hours
    • Changes in adenosin μmol/L from baseline til 24h post-surgery
  • Changes in interleukin-6(IL-6), interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta)
    • Time Frame: 24 hours
    • Changes in IL-6, IL-10, TNF-Alpha, TGF-beta in pg/mL from baseline til 24h post-surgery
  • Changes in gene expression metabolic pathway panel from NanoString
    • Time Frame: 4 hours
    • Changes in gene expression profiles in the metabolic pathway panel from NanoString from baseline until four hours post-surgery.
  • Differences in mesenterial vessel contractility between arms in the trial
    • Time Frame: 6 hours
    • Using wire myographs with isolated mesenterial vessels to measure contractility following drug administration of adrenalin and adrenomedullin in patients from both arms (intervention and controls)
  • Local complications to RIPC
    • Time Frame: 24 hours
    • Pain, changed sensibility or decreased function of the upper extremity where remote ischemic preconditioning were carried out preoperatively.
  • Differences in postoperative quality of recovery score 15 (QoR-15) between arms in the trial
    • Time Frame: 30 days
    • Questionnaire on Postoperative quality of recovery with 15 questions comparing scores from baseline, 24 hours and 30 days after surgery between study arms (intervention and controls)
  • Differences in Self reported pain on a 0-10 scale between arms in the trial
    • Time Frame: 24 hours
    • Self reported pain on a 0-10 scale at baseline and 24 hours after surgery between study arms (intervention and controls)

Participating in This Clinical Trial

Inclusion Criteria

  • Patients undergoing acute or subacute cholecystectomy due to acute cholecystitis with a maximum of 7 days of symptoms prior to surgery

Exclusion Criteria

  • Not capable of giving informed consent after oral and written information
  • Surgery within 30 days of study inclusion
  • Conditions that prevent the performance of remote ischemic preconditioning on the upper extremity, e.g. fractures, paresis, lymphedema
  • performance of concomitant endoscopic retrograde cholangiopancreatography (ERCP) during surgery
  • synchronous pancreatitis
  • synchronous cholangitis

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 120 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Zealand University Hospital
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Kirsten L Wahlstroem, MD, Principal Investigator, Center for Surgical Science, Zealand University Hospital,
  • Overall Contact(s)
    • Kirsten L Wahlstroem, MD, +45 20 24 62 86, kirstenwahlstroem@gmail.com

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