The Effect of Low Pressure Pneumoperitoneum During Laparoscopic Colorectal Surgery on Innate Immune Homeostasis.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Surgery, Pneumoperitoneum, Neuromuscular Blockade, Immune Suppression

Intervention / Treatment
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* Procedure: Low pressure pneumoperitoneum
* Drug: Rocuronium bromide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low pressure PNP, deep NMB<br>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<br>* Lowering intra-abdominal pressure during laparoscopic surgery<br>* Other names: Low intra-abdominal pressure;Drug: Rocuronium bromide<br>* Deep (PTC 1-2) versus moderate (TOF count 1-2) neuromuscular block<br>* Other names: Deep muscle relaxation;|
| Active Comparator: Normal pressure PNP, moderate NMB<br>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<br>* Deep (PTC 1-2) versus moderate (TOF count 1-2) neuromuscular block<br>* Other names: Deep muscle relaxation;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Laparoscopic surgery, Deep neuromuscular block, Low pressure pneumoperitoneum, Postoperative immune suppression