TQL-block for Laparoscopic Hemicolectomy

Improving Perioperative Pain Management for Laparoscopic Surgery Due to Colon Cancer Using the Ultrasound-guided Transmuscular Quadratus Lumborum Block. A Double Blind, Randomized, Placebo Controlled Trial.

Every year 350 patients undergo surgery due to colorectal cancer at Zealand University Hospital, Roskilde. The majority of the surgeries are performed using a minimal invasive laparoscopic technique where the bowl anastomosis is either hand sown or stapled. The procedure is performed, while the patient is under general anaesthesia. An observational prospective survey from 2016-17 of sixty patients undergoing hemicolectomy at Zealand University Hospital, Roskilde has shown, that even though the patients are subjected to a multimodal analgesic regimen, a substantial amount of opioids are being administered during the first 24 hours post surgery; i.e. 51.91 mg ± 36.22 mg (Mean ± SD) of oral morphine equivalents. Sixty-five percent of the patients receive opioids at the PACU. Their maximum pain score at the PACU is registered, using a numerical rating scale of 0-10, as 3.28 ± 2.65 (Mean ± SD). So it is obvious that there is room for improvement and a reduction in the use of postoperative opioids. Thus, there is a clearly defined research problem to explore. Currently ultrasound-guided nerveblocks are not part of the multimodal analgesic regimen. The primary aim of this study is to investigate the efficacy of the ultrasound-guided bilateral transmuscular quadratus lumborum block on reducing postoperative opioid consumption.

Every year 350 patients undergo surgery due to colorectal cancer at Zealand University Hospital, Roskilde. The vast majority of the patients has to have part of their colon removed, a so-called hemicolectomy. The majority of the surgeries are performed using a minimal invasive laparoscopic technique where the bowl anastomosis is either hand sown or stapled. The procedure is performed, while the patient is under general anaesthesia using a continuous intravenous (iv.) infusion of propofol and remifentanil to keep the patient asleep. As postoperative pain management the patients receive IV. paracetamol, IV. sufentanil (30 minutes prior to surgery) and local would infiltration. At the post anaesthesia care unit (PACU) the patients are offered paracetamol and morphine as pain management. An observational prospective survey from 2016-17 of sixty patients undergoing hemicolectomy at Zealand University Hospital, Roskilde has shown, that even though the patients are subjected to a multimodal analgesic regimen as described, a substantial amount of opioids are being administered during the first 24 hours post surgery; i.e. 51.91 mg ± 36.22 mg (Mean ± SD) of oral morphine equivalents. Sixty-five percent of the patients receive opioids at the PACU. Their maximum pain score at the PACU is registered, using a numerical rating scale of 0-10, as 3.28 ± 2.65 (Mean ± SD). So it is obvious that there is room for improvement and a reduction in the use of postoperative opioids. Thus, there is a clearly defined research problem to explore. Surgical technique: The procedure is performed as a standard 4 port laparoscopic or robot-assisted technique with a vessel first dissection approach. The principles of complete mesocolic excision with is the standard procedure. The extraction site is for the right side and transverse colon through an upper transverse incision and for the left side and rectum through a pfannenstiel incision. Anaesthesia and postoperative pain management: The laparoscopic hemicolectomy is performed with the patient under general anaesthesia. As the surgery ends the surgeon injects local would infiltration in the laparoscopic port entries. Around 30 minutes prior to emergence the anaesthetic nurse injects iv. sufentanil (synthetic morphine), often around 0.3 μg/kg and 1g of iv. paracetamol. At the PACU a nurse will administer iv. morphine or sufentanil or oral morphine, when needed. The postoperative pain management continues at the surgical ward, where morphine is administered when needed. Paracetamol 1 gram x 4 daily is administered until discharge. Side effects of current treatment: The use of morphine can cause severe side effects, including nausea and vomiting, bowl paralysis, urine retention, sleep disturbances and respiratory depression. These side effects can delay mobilisation after surgery, increase the risk of complications and worst of all be fatal. Recent research indicates a connection between immunologic and stress related reactions in relation to surgery and the development of cancer metastasis. It has already been shown, that a minimal invasive surgical technique, laparoscopic vs. open surgery, improves the postoperative immunologic response. A recent meta-analysis shows that perioperative regional anaesthesia/analgesia improves survival in cancer patients, which can be related to a reduction in metastasis due to a reduced surgical stress response. This indicates, that there are multiple advantages in offering an opioid sparing pain management, that also reduces the stress response related to surgery. The short term advantage being a reduction in postoperative opioid consumption, opioid-related side effects and postoperative pain score and possibly a long-term advantage of fewer cancer recurrences. Ultrasound-guided nerve blocks: With regards to the side effects related to the current treatment it has been of the upmost interest to develop new techniques to manage postoperative pain and a at the same time reduce surgical stress. Associate Professor and head of research at The Department of Anaesthesiology and Intensive Care, Jens Børglum, has in collaboration with other international peripheral nerve block experts developed several different abdominal nerve blocks that are described in both cadaveric and clinical randomized studies. Of specific interest to this study is the Transmuscular Quadratus Lumborum(TQL) block, an ultrasound-guided(USG) single-shot nerve block using local anaesthesia, designed to anaesthetize the entire abdominal wall and viscera and the retroperitoneal area. Using ultrasound as visual guidance provides extra safety and insurance of the correct placement of local anaesthetic. The TQL block is described in a recent cadaver study and in several peer review articles. There are two other clinical trials using the TQL-block for percutaneous nefro-lithotripsy and for caesarean section (Eudra-CT 2016-004594-41/2015-004770-16). Both of these trials have ended patient inclusion, and the preliminary data analysis have clearly showed a vast improvement in postoperative pain management and early mobilization with the active TQL blocks - without any adverse events recorded. The pain from laparoscopic abdominal surgery arises from several locations, both the surgical incisions, the inflation of the entire abdominal wall and parietal peritoneum and traction/stress on the colon. The innervation of the abdominal wall origins at the ventral rami of the spinal nerves from Th6-L1. The intercostal nerves (VII-XI) and the subcostal nerve all branch out in a lateral and anterior branch. The iliohypogastric and the ilioinguinal nerves innervate the lower part of the abdominal wall. The visceral pain arising from the intraperitoneal organs; i.e. colon, travel via different nerves to join in the thoracic sympathetic trunk before entering the central nervous system. The results from the cadaveric study show a very favourable spread of injectate with the TQL block. Not only does the injected dye in this study spread to colour the ventral rami of the thoracic spinal nerves up to T9 in the thoracic paravertebral space and the iliohypogastric and ilioinguinal nerve; the injectate also spread to colour the thoracic sympathetic trunk. Thus, this seem to indicate that the TQL block can be used to treat not only the pain from the incisions and tears superficially to the colon, but also the pain from the colon itself, and the adjacent intraperitoneal organs and structures, which is affected in patients undergoing laparoscopic hemicolectomy. The cadaveric study has also shown that the lumbar sympathetic trunk and lumbar plexus were not affected by the injected dye. These results seem to imply that there would be minimal or no affection of ambulation or lumbar sympathectomy; i.e. no hypotension or dysfunctional bladder as can often be observed with the epidural technique. Both findings that coincides with the clinical experiences from the investigators pilot studies, and indeed also from the aforementioned clinical trials that have just been finalized. Cancer progression and the peroperative immunologic stress response: Studies suggest that events in the perioperative period can induce metastasis formation and tumor growth. Tumor cells are released into the blood stream during surgery and the surgical stress may create a favorable environment for dissemination of tumor cells into distant tissue. This is done by a cascade of pro-cancerous catecholamines, prostaglandins and cytokines combined with an impaired anti-cancerous cell mediated immune response. Until recently, focus on the anesthetic management of cancer patients has been limited. Relatively small alterations in the perioperative anesthetic management may play a tremendous role in tumor progression. Optimizing anesthesia to reduce the surgical stress response could improve recurrence rates and long-term outcomes for cancer patients by inhibiting perioperative metastasis formation. Regional anesthesia and amide local anesthetics are suspected to calm the immunologic storm of prostaglandins, catecholamines and cytokines when used in the perioperative phase. Aim: The investigators want to help create an opioid sparing anaesthesia, thus reducing opioid related side effects. Therefore, the investigators wish to conduct a randomized, controlled and double blind study, comparing the effect of the TQL-block vs. placebo. The aim with this study is to investigate the efficacy of the TQL block vs. placebo in patients undergoing laparoscopic surgery due to colon cancer. The hypothesis is, that the bilateral TQL block will significantly reduce the opioid consumption during the first 24 postoperative hours and significantly reduce the Numerical Rating Scale (NRS) pain score (0-10) and opioid related side effects. The investigators will further obtain blood samples in the perioperative period in order to demonstrate effects on the immune system between the two groups. Blood samples and heart rate variability measurement results will be reported in separate peer-review publications.

Active bilateral ultrasound-guided transmuscular quadratus lumborum (TQL) block. 60 mL ropivacaine 0,375% single shot. Every six hours postoperative, all patients are administered 1 g of acetaminophen. In both arms morphine will be administered IV as part of a patient controlled analgesia (PCA)-pump regimen or additionally after contact with the nursing staff as it is the standard treatment. On the day of surgery, postop day 1+2 and day 10-14, all patients will have blood samples taken for immunological analysis. On the day of surgery, postop day 1+2 and day 10-14, all patients are asked to fill out a Quality of recovery-15 questionaire. Before surgery, and 3, 6 and 24 hours postop. All patients are tested for orthostatic hypotension.

Placebo bilateral ultrasound-guided transmuscular quadratus lumborum (TQL) block. 60 mL saline single shot. Every six hours postoperative, all patients are administered 1 g of acetaminophen. In both arms morphine will be administered IV as part of a patient controlled analgesia (PCA)-pump regimen or additionally after contact with the nursing staff as it is the standard treatment. On the day of surgery, postop day 1+2 and day 10-14, all patients will have blood samples taken for immunological analysis. On the day of surgery, postop day 1+2 and day 10-14, all patients are asked to fill out a Quality of recovery-15 questionaire. Before surgery, and 3, 6 and 24 hours postop. All patients are tested for orthostatic hypotension.

On the day of surgery, postop day 1+2 and day 10-14, all patients will have blood samples taken for immunological analysis

On the day of surgery, postop day 1+2 and day 10-14, all patients are asked to fill out a short questionaire.

Registered upon arrival at the postanaesthesia care unit (PACU) and again 30 min, 1, 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 hours postoperative.

Registered upon arrival at the PACU and again 30 min, 1, 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 hours postoperative.

This assessment is calculated using data from outcome 1 and 2. An individual rank for pain intensity using numerical rating scale (0-10/10), 0-24 hours postoperatively and for total opioid consumption 0-24 hours postoperatively will be combined and compared with a mean rank of all patients (active and placebo). The difference between the individual rank and the mean rank will be expressed as a percentage. As described by: Andersen LPK, Gögenur I, Torup H, Rosenberg J, Werner MU. Assessment of Postoperative Analgesic Drug Efficacy: Method of Data Analysis Is Critical. Anesth Analg. 2017 Sep;125(3):1008-13.

The degree of morphine-related side effects. Nausea or post anaesthesia nausea and vomiting (PONV) registered in the case report form, if any.

Orthostatic hypotension (yes/no) and orthostatic intolerance i.e. symptoms of orthostatic hypotension without a drop in blood pressure (yes/no).

The Quality of Recovery -15 questionnaire results in a score of 0-150. Very poor recovery = 0, excellent recovery = 150. These outcome measures will be correlated with changes in immunologic outcome measures in the perioperative period.

On 24 consecutive patients (3 randomization blocks of 4) data will be obtained on heart rate variability using electrocardiography from block administration and the first 24 hours postoperatively. Minimal changes in HRV characterizes differences in sympathetic stress response between the groups

An evaluation of gene expression fold changes compared to POD 0 using an Affymetrix gene expression array. The investigators will specifically measure relative changes in expression of the GZMB gene, which encodes Granzyme B. Granzyme B is expressed by cytotoxic t-cells and NK-cells. The regularized t-test limma will be used to calculate differences in gene expression between samples taken at different time sets, and the Benjamini Hochberg method using the false discovery rate (FDR) will be used to correct for multiple hypothesis testing.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to postoperative day (POD) 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of cytokine assays for alterations in inflammation and cancer related immune-function measured by commercial enzyme-linked immunosorbent assays (ELISAs) on a BEP2000 ELISA instrument. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Part of standard blood samples that will be obtained and analyzed immediately at each time point. Relative changes compared to POD 0.

Difference in cytokine levels (tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b), interleukin -2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-11 (IL-11), interleukin-15 (IL-15), interleukin-17a (IL-17a), interleukin-17f (IL-17f), interleukin-18 (IL-18), interleukin-22 (IL-22) and GM-CSF, all pg/ml) between postoperative and preoperative whole blood exposed to lipopolysaccharide measured with multiplex assay

Difference in cytokine levels (tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b), interleukin -2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-11 (IL-11), interleukin-15 (IL-15), interleukin-17a (IL-17a), interleukin-17f (IL-17f), interleukin-18 (IL-18), interleukin-22 (IL-22) and GM-CSF, all pg/ml)between postoperative and preoperative whole blood exposed to CD3 and CD28 with multiplex assay

Difference in cytokine levels (tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b), interleukin -2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-11 (IL-11), interleukin-15 (IL-15), interleukin-17a (IL-17a), interleukin-17f (IL-17f), interleukin-18 (IL-18), interleukin-22 (IL-22) and GM-CSF, all pg/ml)between postoperative and preoperative whole blood exposed to Polyinosinic:polycytidylic acid with multiplex assay

Difference in cytokine levels (tumor necrosis factor alpha (TNF-a), interleukin-1b (IL-1b), interleukin -2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-11 (IL-11), interleukin-15 (IL-15), interleukin-17a (IL-17a), interleukin-17f (IL-17f), interleukin-18 (IL-18), interleukin-22 (IL-22) and GM-CSF, all pg/ml)between postoperative and preoperative whole blood exposed to Resiquimod (R848) with multiplex assay

Inclusion Criteria: Age > 18 Scheduled for laparoscopic or robot assisted hemicolectomy or sigmoidectomy due to colon cancer Have received thorough information, oral and written, and signed the "Informed Consent" form on participation in the trial American Society of Anaesthesiologist physical status classification, class 1-3 Exclusion Criteria: Inability to cooperate Inability to speak and understand Danish Allergy to local anaesthetics or opioids Daily intake of opioids (evaluated by the investigators) Drug and/or substance abuse Local infection at the site of injection or systemic infection Difficulty visualisation of muscular and fascial structures in ultrasound visualisation necessary to the block administration Pregnant* or breastfeeding Daily use of oral or intravenous steroids Known immune deficiency (evaluated by the investigators) Other simultaneous or previous cancer diagnosis (except non-melanoma skin cancer) within the last five years (within the last five years added 28th nov 2019 after ethics committee approval).

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