The Effect of Low Pressure Pneumoperitoneum During Laparoscopic Colorectal Surgery on Innate Immune Homeostasis. (RECOVER-PLUS)

The Effectiveness of Low Pressure Pneumoperitoneum During Laparoscopic Colorectal Surgery in Preserving Innate Immune Homeostasis by Reducing Peritoneal Mesothelial Cell Injury.

Substudy of the RECOVER trial (a randomised controlled trial comparing the effect of low pressure pneumoperitoneum with deep neuromuscular block versus normal pressure pneumoperitoneum with moderate neuromuscular block during laparoscopic colorectal surgery on early quality of recovery) investigating innate immune homeostasis after laparoscopic colorectal surgery.

Study Overview

• Status: Completed
• Conditions: Pneumoperitoneum; Surgery; Neuromuscular Blockade; Immune Suppression
• Intervention / Treatment: Procedure: Low pressure pneumoperitoneum; Drug: Rocuronium bromide

Detailed Description

Rationale: increased intra-abdominal pressure can cause peritoneal mesothelial cell injury either directly or by compression of the capillary vessels, causing a variable degree of ischemia reperfusion injury. The immune system can identify damage to host cells by recognising Danger-Associated Molecular Patterns (DAMPs) that are released upon cell death in an uncontrolled fashion, such as during surgical trauma. DAMPs elicit an immune response similar to the response to invading pathogens and induce an anti-inflammatory immune response strongly related to postoperative recovery, infectious complications and mortality. Low pressure PNP is associated with lower levels of serum pro- and anti-inflammatory cytokines and better preservation of innate immune function.

Objective: to establish the relationship between the use of low pressure pneumoperitoneum with deep neuromuscular blockade and innate immune function after laparoscopic colorectal surgery.

Study design: a multi-center, blinded, randomized controlled clinical trial.

Study population: adult individuals scheduled for laparoscopic colorectal surgery with a primary colonic anastomosis.

Intervention: participants will be randomly assigned in a 1:1 fashion to either the experimental group (group A): low pressure PNP (8 mmHg) with deep NMB (PTC 1-2) or the control group (group B): normal pressure PNP (12 mmHg) with moderate NMB (TOF count 1-2).

Primary endpoint: mononuclear cell responsiveness ex-vivo as reflected by TNFα release upon LPS stimulation.

Secondary endpoints: mononuclear cell responsiveness ex-vivo as reflected by IL-6, IL-10 and IL-1beta release upon LPS stimulation. Peritoneal mesothelial hypoxia as reflected by peritoneal HIF1α mRNA expression, histological peritoneal mesothelial cell injury and plasma levels of DAMPs and cytokines.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6532SZ
      • Canisius Wilhelmina Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Scheduled for laparoscopic colorectal surgery with a primary anastomosis
• Obtained informed consent
• Age over 18 years

Exclusion Criteria:

• Insufficient control of the Dutch language to read the patient information and to fill out the questionnaires
• Primary colostomy
• Neo-adjuvant chemotherapy
• Chronic use of analgesics or psychotropic drugs
• Use of NSAIDs shorter than 5 days before surgery
• Known or suspected allergy to rocuronium of sugammadex
• Neuromuscular disease
• Indication for rapid sequence induction
• Severe liver- or renal disease (creatinine clearance <30ml/min)
• BMI >35 kg/m²
• Deficiency of vitamin K dependent clotting factors or coagulopathy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low pressure PNP, deep NMB; Low pressure pneumoperitoneum of 8 mmHg with deep neuromuscular block (post tetanic count of 1-2) reached by titration with continuous infusion of Rocuronium bromide.	Procedure: Low pressure pneumoperitoneum; Lowering intra-abdominal pressure during laparoscopic surgery; Other Names: Low intra-abdominal pressure; Drug: Rocuronium bromide; Deep (PTC 1-2) versus moderate (TOF count 1-2) neuromuscular block; Other Names: Deep muscle relaxation
Active Comparator: Normal pressure PNP, moderate NMB; Normal pressure pneumoperitoneum of 12 mmHg with moderate neuromuscular block (TOF count of 1-2) reached by titration with bolus or continuous infusion of a low dose of Rocuronium bromide.	Drug: Rocuronium bromide; Deep (PTC 1-2) versus moderate (TOF count 1-2) neuromuscular block; Other Names: Deep muscle relaxation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mononuclear cell responsiveness ex vivo	TNFalpha release upon LPS stimulation	Before surgery, 24 and 72 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mononuclear cell responsiveness ex-vivo	IL-6, IL-10 and IL-1beta release upon LPS stimulation	Before surgery, 24 and 72 hours after surgery
Serum DAMPs and cytokines	Danger associated molecular patterns, TNFalpha, IL-6 and IL-10	Before surgery, at the end of surgery and 24 hours after surgery
HLA-DR mRNA expression	MHC-II antigen presenting immune receptor	Before surgery, 24 and 72 hours after surgery
Peritoneal histology and HIF1alpha expression	Histology and HIF1alpha mRNA expression of a peritoneal biopsy	At the start and end of surgery

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Michiel C Warlé, MD, PhD, Radboud University Medical Center; Principal Investigator: Kim I Albers, MD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2018
• Primary Completion (Actual): August 31, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: June 18, 2018
• First Submitted That Met QC Criteria: June 18, 2018
• First Posted (Actual): June 28, 2018

Study Record Updates

• Last Update Posted (Actual): November 3, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Laparoscopic surgery; Low pressure pneumoperitoneum; Deep neuromuscular block; Postoperative immune suppression
• Additional Relevant MeSH Terms: Digestive System Diseases; Peritoneal Diseases; Pneumoperitoneum; Physiological Effects of Drugs; Peripheral Nervous System Agents; Anticonvulsants; Neuromuscular Agents; Neuromuscular Nondepolarizing Agents; Neuromuscular Blocking Agents; Bromides; Rocuronium
• Other Study ID Numbers: NL65290.091.18 substudy

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No