Low Pressure Pneumoperitoneum and Deep Neuromuscular Block Versus Standard Laparoscopy During Robot Assisted Radical Prostatectomy to Improve the Quality of Recovery and Immune Homeostasis; Study Protocol for a Randomized Controlled Study.

Study Overview
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Brief Summary
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Intra-abdominal pressure (IAP) needed to create sufficient workspace during laparoscopic surgery affects the surrounding organs with ischemia-reperfusion injury and a systemic immune response. This effect is related to postoperative recovery, pain scores, opioid consumption, bowel function recovery, morbidity and possibly mortality. In clinical practice standard pressures of 12-16mmHg are applied instead of the lowest possible IAP, but accumulating evidence shows lower pressure pneumoperitoneum (PNP) (6-8mmHg) to be non-compromising for sufficient workspace, when combined with deep neuromuscular blockade (NMB) in a vast majority of patients. Therefore, low impact laparoscopy, meaning low pressure PNP facilitated by deep NMB, could be a valuable addition to Enhanced Recovery After Surgery (ERAS) Protocols. The use of low pressure PNP may also reduce hypoxic injury and the release of DAMPs and thereby contributing to a better preservation of innate immune function which may help to reduce the risk of infectious complications. The participants will be randomly assigned to one of the experimental groups with low impact laparoscopy or one of the control groups with standard laparoscopy.

Detailed Description
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Intra-abdominal pressure (IAP) needed to create sufficient workspace during laparoscopic surgery affects the surrounding organs with ischemia-reperfusion injury and a systemic immune response. This effect is related to postoperative recovery, pain scores, opioid consumption, bowel function recovery, morbidity and possibly mortality. Therefore, low impact laparoscopy, meaning low pressure PNP facilitated by deep NMB, could be a valuable addition to Enhanced Recovery After Surgery (ERAS) Protocols. The use of low pressure PNP may also reduce hypoxic injury and the release of DAMPs and thereby contributing to a better preservation of innate immune function which may help to reduce the risk of infectious complications. The participants will be randomly assigned to the experimental group 1: low impact laparoscopy (low pressure (8 mmHg) and deep NMB (PTC 1-2)); 8 mmHg IAP after trocar introduction for perfusion measurement or the experimental group 2: low impact laparoscopy (low pressure (8 mmHg) and deep NMB (PTC 1-2)); 12 mmHg IAP after trocar introduction for perfusion measurement, or control group 1: standard laparoscopy (standard pressure (12 mmHg) and moderate NMB (TOF 1-2)); 8 mmHg IAP after trocar introduction for perfusion measurement, or control group 2: standard laparoscopy (standard pressure (12 mmHg) and moderate NMB (TOF 1-2)); 12 mmHg IAP after trocar introduction for perfusion measurement. ICG injection will take place with starting pressure to quantify parietal peritoneum perfusion, and a parietal peritoneal biopsy will be taken. At the end of surgery, a second parietal peritoneum biopsy will be taken. NB: After introduction of the camera trocar, insufflation of carbon dioxide is titrated to an IAP of 8mmHg in group A and C, and 14 mmHg in group B and D. After placement of the last trocar the injection of ICG and video registration of peritoneum will take place, and a peritoneal biopsy will be taken. There after surgery will take place with an IAP of 14mmHg in the control groups (C and D), and an IAP of 8mmHg in the experimental groups (A and B). In the control groups (C and D) Pre- and postoperative a few questionnaires will be taken and blood withdrawals to evaluate the quality of recovery, and the immune response.

Official Title
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Low Pressure Pneumoperitoneum and Deep Neuromuscular Blockade Versus Standard Laparoscopy During RARP to Improve the Quality of Recovery and Immune Homeostasis; Study Protocol for a Randomized Controlled Study

Conditions
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Quality of Life, Postoperative Complications, Acute Pain, Immune System Tolerance

Intervention / Treatment
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* Other: Low intra-abdominal pressure
* Other: Deep neuromuscular blockade (NMB)
* Other: Standard intra-abdominal pressure
* Other: Moderate neuromuscular blockade (NMB)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Age ≥ 18 years Undergoing elective robot assisted radical prostatectomy (RARP) Obtained informed consent Exclusion Criteria: Laparoscopic radical prostatectomy without robot assistance Insufficient control of the Dutch language to read the patient information and to fill out de questionnaires Neo-adjuvant chemotherapy Chronic use of analgesics or psychotropic drugs Use of NSAID's shorter than 5 days before surgery Severe liver- or renal disease Neuromuscular disease Hyperthyroidism or thyroid adenomas Deficiency of vitamin K dependent clotting factors or coagulopathy Planned diagnostics or treatment with radioactive iodine < 1 week after surgery Indication for rapid sequence induction BMI >35kg/m2 Known of suspected hypersensitivity to ICG, sodium iodide, iodine, rocuronium or sugammadex Use of medication interfering with ICG absorption as listed in the summary of product characteristics (SPC); anticonvulsants, bisulphite compounds, haloperidol, heroin, meperidine, metamizol, methadone, morphium, nitrofurantoin, opium alkaloids, phenobarbital, phenylbutazone, cyclopropane, probencid

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: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Randomized
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group: Low Impact laparoscopy<br>low impact laparoscopy (low pressure (8 mmHg) and deep NMB (PTC 1-2) | Other: Low intra-abdominal pressure<br>* 8 mmHg<br>Other: Deep neuromuscular blockade (NMB)<br>* Deep NMB (PTC1-2)<br>|
| Active Comparator: Control group: Standard laparoscopy<br>standard laparoscopy (standard pressure (14 mmHg) and moderate NMB (TOF 1-2) | Other: Standard intra-abdominal pressure<br>* 14 mmHg<br>Other: Moderate neuromuscular blockade (NMB)<br>* Moderate NMB (TOF 1-2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of recovery - 40 items questionnaire score (QoR-40) | 40 points (minimum: extremely poor quality of recovery) to 200 points (maximum: excellent quality of recovery) | at postoperative day 1 | 
| Immune response represented by IL-6 | IL-6 response upon whole blood LPS stimulation | at postoperative day 1 | 
| Immune response represented by IL-10 | IL-10 response upon whole blood LPS stimulation | at postoperative day 1 | 
| Perfusion index of the parietal peritoneum | calculated from the slope of ICG fluorescence intensity, and time to maximal intensity in seconds. (extracted from video registration). | From ICG injection, up to 20 seconds | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of recovery - 40 items questionnaire score (QoR-40) | 40 points (minimum: extremely poor quality of recovery) to 200 points (maximum: excellent quality of recovery) | day 10 after surgery | 
| Health status with short form survey (SF-36) | The lower the score the more disability. The higher the score the less disability. | day 10 and 3 months after surgery | 
| Chronic pain with McGill pain questionnaire (MPQ) | range from 0 (no pain) to 78 (severe pain) | 3 months after surgery | 
| Pain score with VAS | pain scores with VAS 0 (no pain) to 10 (severe pain) | During hospital stay up to 3 days | 
| Analgesia use | non-cumulative and cumulative opioid use per day in morphine equivalent | During hospital stay up to 3 days | 
| PONV | With PONV impact scale score o (no PONV) to 6 (extreme PONV) | During hospital stay up to 3 days | 
| Hospital stay | length of hospital stay in days | from admission up to 3 days | 
| Postoperative recovery time | time to reach discharge criteria in days | From day of surgery up to 3 days | 
| Operating conditions | surgical conditions with L-SRS 0 (extremely poor work field) to 5 (excellent work field) | During operation for up to 8 hours | 
| Complications | postoperative complications scored by Clavien Dindo classification; grade 0 (no deviation from ideal) grade 5 (death of patient) | Day of surgery untill 30days after surgery |