Gastric Microperfusion in Patients Undergoing Gastroesophageal Resections

NCT ID: NCT02077673

Last Updated: 2015-05-05

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 50 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2015-04-30

Brief Summary

Gastroesophageal resection because of gastroesophageal junction (GEJ) adenocarcinoma is a massive surgical intervention. Currently, gastroesophageal cancer surgery is performed with upper laparotomy followed by thoracotomy at the Department of Surgical Gastroenterology, Rigshospitalet, Denmark. However, minimal invasive techniques (MIT), e.g. robotic assisted laparoscopy, is in the progress of being implemented in this field as they are hypothesized to be more beneficial for the patients, and in some aspects better than conventional laparoscopic surgery.

The operative procedure is often complicated by low blood pressure (systolic blood pressure less than 90 mm Hg is experienced in more than 30 % of the patients) and is probably accompanied by a reduced splanchnic microcirculatory flow, leading to increased morbidity. Hypotension may be due to several factors, among them are epidural analgesia, mesentery traction reflex, and inflammatory and vasoactive hormones.

Aim of the project

The aim of the project is, through a series of sub-projects, to validate or invalidate the relationship between changes in the microcirculatory blood flow in the stomach and the systemic hemodynamic changes. Furthermore, the aim is to assess the changes in the microcirculatory blood flow as a consequence of the thoracic epidural anesthesia. In addition, the aim is to assess the hypothesis that the mesenteric traction reflex and changes in the PGI2 levels may influence systemic hemodynamic changes, and that robotic assisted MIT will attenuate the mesenteric traction reflex and changes in PGI2 compared to open surgery.

Detailed Description

Background:

Gastroesophageal resection because of gastroesophageal junction (GEJ) adenocarcinoma is a massive surgical intervention. Nevertheless, surgery is the only treatment with significant long-term survival. Currently, gastroesophageal cancer surgery is performed with upper laparotomy followed by thoracotomy at the Department of Surgical Gastroenterology, Rigshospitalet, Denmark. However, minimal invasive techniques (MIT), e.g. robotic assisted laparoscopy, is in the progress of being implemented in this field as they are hypothesized to be more beneficial for the patients, and in some aspects better than conventional laparoscopic surgery [1]. The benefits of MIT are believed to be due to several factors, a smaller surgical stress response [2] and less pain [3] resulting in earlier mobilization, to mention a few.

When reconstructing the gastrointestinal continuity, a gastric tube is prepared from the upper part of the remaining stomach. It is challenging to visualize, if the remaining stomach has adequate blood supply. Earlier studies have shown an up to 70 % reduction in blood flow, to the upper part of the remnant stomach [4-6], and ischemia is one of the most significant causes of anastomotic leakage [7, 8]. Anastomotic leakage occurs in up to 10 % of the patients and is fatal in up to 50 %. Furthermore, a recent study originated from the investigators department demonstrated, that patients experiencing anastomotic leakage after gastroesophageal cancer resection, have a significantly reduced long-term survival, even when early death and other postoperative complications were accounted for [9]. The overall 5-year survival rates in patients with and without anastomotic leakage were 20 and 35 %, respectively. Therefore, sufficient blood flow to the area of anastomosis is of paramount concern. Different techniques have been used in the attempt to assess the microcirculation during gastroesophageal resection [5, 10-13]. However, none of these techniques has proven to be practical, reliable, and time-efficient, and therefore not being routinely implemented in the clinical settings.

During open gastroesophageal resection, hypotension is common (systolic blood pressure less than 90 mm Hg is experienced in more than 30 % of the patients) and is probably accompanied by a reduced gastric microcirculatory flow. The hypotension may be due to several factors;

• Sympathic nerve system blockage due to thoracic epidural neuraxial anesthesia: Several studies have found reduced splanchnic flow after epidural anesthesia, which was associated with a decrease in systemic resistance and mean arterial pressure [14, 15]. The impact of the time-point for activation of epidural analgesia, on complications in the postoperative period is unknown. An unpublished study (Nielsen T: "Increased cardiac output after Whipple's procedure for pancreatic cancer") suggests that early activation during operation leads to significantly longer stay in the recovery ward after the surgery.
• The initial manipulation of viscera, results in a mesenteric traction reflex (also called eventration syndrome) with vasodilatation and secondary hypotension [16, 17]. The reason for mesenteric traction reflex is unknown, but is believed to be elicited by traction on the mesenterial blood vessels, resulting in a local release of prostacyclin (PGI2) from the endothelium. This reflex has mainly been shown to occur during pancreatic, gastric and aortic surgery, where manipulation of the mesenteric root is inevitable [18-21]. PGI2 is a potent vasodilatator, with inhibitory effect on platelet aggression and on vascular smooth cell proliferation [22-24].

Microcirculatory measurements:

Laser Speckle Contrast Imaging (LSCI) is a relatively new technique for microcirculatory monitoring. When laser light encounters a surface of an object, a random interference effect generates, called laser speckle contrast. The speckle pattern changes depending on the velocity of the object, and it is possible to get information regarding the object's movements, by the fluctuations in the speckle pattern. By measuring the concentration and velocity of blood cells, tissue perfusion may be assessed by LSCI technique. A real-time and non-touch measurement can be made on a large field (0.5 cm x 0.7 cm up to 15 cm x 20 cm). The camera is placed at a distance of 20-30 cm and measures the relative flow (flux) in the regions of interest. The measurement is at a depth of 1-2 mm by infrared light reflected from circulating erythrocytes in the micro-vessels.

Hypothesis and aim:

Robot-assisted laparoscopic surgery alters the hemodynamics and microcirculation in the splanchnic system by reduced release of vasoactive substances, such as PGI2, compared to open surgery. With this study, the investigators wish to evaluate hemodynamic fluctuations and gastric microcirculation, and correlate these to serum levels of PGI2 at different stages of surgery in robotic assisted laparoscopic surgery and open surgery, respectively.

Methods:

2 × 25 consecutive patients selected for robotic assisted laparoscopic or open surgery. Hemodynamic assessments are according to standardized methods. Blood samples will be drawn at: 1) after induction of anesthesia, 2) when the peritoneum is first entered, 3) after 15 min. of surgery, 4) after liberation of stomach, 5) after abdominal skin closure, 6) after extraction of the gastric conduit into the thorax, 7) after formation of the anastomosis, 8) after thoracic skin closure, 9) 18 hours after surgery. LSCI will be used to measure the microcirculation at two locations (3 cm from the pylorus and just below the site of the anastomosis (the body)) on the stomach five times during open surgery, and twice during the thoracic part of robotic assisted laparoscopic surgery.

Statistics:

Statistical power-calculation is carried out on an expected difference of the occurrence of mesenteric traction reflex between patients operated with open vs. MIT. By using sample size of 50 comparing percentages where group one is 55 % and group two is 12 % [17], a requirement of 18 patients in each group is calculated in order to obtain a statistical power greater than 0.80 with a α-level of <0.05.

Conditions

Gastroesophageal Junction Adenocarcinoma; Surgery

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

open surgery

25 patients undergoing open gastroesophageal resection

No interventions assigned to this group

robotic-assissted surgery

25 patients under-going robotic-assisted gastroesophageal surgery

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Patients diagnosed with adenocarcinoma in the gastroesophageal junction
• Patients assumed to be resectable

Exclusion Criteria

• lack of consent
• non-adenocarcinomas

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Rikard Ambrus

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lars Bo Svendsen, prof., MD

Role: STUDY_DIRECTOR

Rigshospitalet, Denmark

Michael P Achiam, MD, PhD

Role: STUDY_CHAIR

Rigshospitalet, Denmark

Locations

Department of Surgical Gastroenterology, Rigshospitalet

Copenhagen Ø, , Denmark

Countries

Denmark

References

Daouadi M, Zureikat AH, Zenati MS, Choudry H, Tsung A, Bartlett DL, Hughes SJ, Lee KK, Moser AJ, Zeh HJ. Robot-assisted minimally invasive distal pancreatectomy is superior to the laparoscopic technique. Ann Surg. 2013 Jan;257(1):128-32. doi: 10.1097/SLA.0b013e31825fff08.

Reference Type: BACKGROUND

PMID: 22868357 (View on PubMed)

Braga M, Vignali A, Zuliani W, Radaelli G, Gianotti L, Martani C, Toussoun G, Di Carlo V. Metabolic and functional results after laparoscopic colorectal surgery: a randomized, controlled trial. Dis Colon Rectum. 2002 Aug;45(8):1070-7. doi: 10.1007/s10350-004-6362-2.

Reference Type: BACKGROUND

PMID: 12195192 (View on PubMed)

Gramigni E, Bracco D, Carli F. Epidural analgesia and postoperative orthostatic haemodynamic changes: observational study. Eur J Anaesthesiol. 2013 Jul;30(7):398-404. doi: 10.1097/EJA.0b013e32835b162c.

Reference Type: BACKGROUND

PMID: 23435278 (View on PubMed)

Briel JW, Tamhankar AP, Hagen JA, DeMeester SR, Johansson J, Choustoulakis E, Peters JH, Bremner CG, DeMeester TR. Prevalence and risk factors for ischemia, leak, and stricture of esophageal anastomosis: gastric pull-up versus colon interposition. J Am Coll Surg. 2004 Apr;198(4):536-41; discussion 541-2. doi: 10.1016/j.jamcollsurg.2003.11.026.

Reference Type: BACKGROUND

PMID: 15051003 (View on PubMed)

Gomes M, Ramacciotti E, Miranda F Jr, Henriques AC, Fagundes DJ. Vascular flow of the gastric fundus after arterial devascularization: an experimental study. J Surg Res. 2009 Mar;152(1):128-34. doi: 10.1016/j.jss.2008.04.016. Epub 2008 May 7.

Reference Type: BACKGROUND

PMID: 18805545 (View on PubMed)

Thomas DM, Langford RM, Russell RC, Le Quesne LP. The anatomical basis for gastric mobilization in total oesophagectomy. Br J Surg. 1979 Apr;66(4):230-3. doi: 10.1002/bjs.1800660404.

Reference Type: BACKGROUND

PMID: 454988 (View on PubMed)

Pacheco PE, Hill SM, Henriques SM, Paulsen JK, Anderson RC. The novel use of intraoperative laser-induced fluorescence of indocyanine green tissue angiography for evaluation of the gastric conduit in esophageal reconstructive surgery. Am J Surg. 2013 Mar;205(3):349-52; discussion 352-3. doi: 10.1016/j.amjsurg.2012.11.005.

Reference Type: BACKGROUND

PMID: 23414958 (View on PubMed)

Reavis KM. The esophageal anastomosis: how improving blood supply affects leak rate. J Gastrointest Surg. 2009 Sep;13(9):1558-60. doi: 10.1007/s11605-009-0906-7. Epub 2009 May 5. No abstract available.

Reference Type: BACKGROUND

PMID: 19415398 (View on PubMed)

Kofoed SC, Calatayud D, Jensen LS, Jensen MV, Svendsen LB. Intrathoracic anastomotic leakage after gastroesophageal cancer resection is associated with reduced long-term survival. World J Surg. 2014 Jan;38(1):114-9. doi: 10.1007/s00268-013-2245-9.

Reference Type: BACKGROUND

PMID: 24129798 (View on PubMed)

Boyle NH, Pearce A, Hunter D, Owen WJ, Mason RC. Scanning laser Doppler flowmetry and intraluminal recirculating gas tonometry in the assessment of gastric and jejunal perfusion during oesophageal resection. Br J Surg. 1998 Oct;85(10):1407-11. doi: 10.1046/j.1365-2168.1998.00943.x.

Reference Type: BACKGROUND

PMID: 9782026 (View on PubMed)

Murawa D, Hunerbein M, Spychala A, Nowaczyk P, Polom K, Murawa P. Indocyanine green angiography for evaluation of gastric conduit perfusion during esophagectomy--first experience. Acta Chir Belg. 2012 Jul-Aug;112(4):275-80.

Reference Type: BACKGROUND

PMID: 23008991 (View on PubMed)

Schilling MK, Redaelli C, Maurer C, Friess H, Buchler MW. Gastric microcirculatory changes during gastric tube formation: assessment with laser Doppler flowmetry. J Surg Res. 1996 Apr;62(1):125-9. doi: 10.1006/jsre.1996.0184.

Reference Type: BACKGROUND

PMID: 8606499 (View on PubMed)

Schroder W, Beckurts KT, Stahler D, Stutzer H, Fischer JH, Holscher AH. Microcirculatory changes associated with gastric tube formation in the pig. Eur Surg Res. 2002 Nov-Dec;34(6):411-7. doi: 10.1159/000065709.

Reference Type: BACKGROUND

PMID: 12403940 (View on PubMed)

Gould TH, Grace K, Thorne G, Thomas M. Effect of thoracic epidural anaesthesia on colonic blood flow. Br J Anaesth. 2002 Sep;89(3):446-51.

Reference Type: BACKGROUND

PMID: 12402724 (View on PubMed)

Lundberg J, Lundberg D, Norgren L, Ribbe E, Thorne J, Werner O. Intestinal hemodynamics during laparotomy: effects of thoracic epidural anesthesia and dopamine in humans. Anesth Analg. 1990 Jul;71(1):9-15. doi: 10.1213/00000539-199007000-00002.

Reference Type: BACKGROUND

PMID: 2194404 (View on PubMed)

Brinkmann A, Seeling W, Wolf CF, Kneitinger E, Junger S, Rockemann M, Oettinger W, Georgieff M. [The effect of thoracic epidural anesthesia on the pathophysiology of the eventration syndrome]. Anaesthesist. 1994 Apr;43(4):235-44. doi: 10.1007/s001010050053. German.

Reference Type: BACKGROUND

PMID: 8179173 (View on PubMed)

Nomura Y, Funai Y, Fujimoto Y, Hori N, Hirakawa K, Hotta A, Nakamoto A, Yoshikawa N, Ohira N, Tatekawa S. Remifentanil increases the incidence of mesenteric traction syndrome: preliminary randomized controlled trial. J Anesth. 2010 Oct;24(5):669-74. doi: 10.1007/s00540-010-0998-y. Epub 2010 Aug 7.

Reference Type: BACKGROUND

PMID: 20694481 (View on PubMed)

Brinkmann A, Seeling W, Rockemann M, Junge JH, Radermacher P, Wiedeck H, Buchler MW, Georgieff M. Changes in gastric intramucosal pH following mesenteric traction in patients undergoing pancreas surgery. Dig Surg. 1999;16(2):117-24. doi: 10.1159/000018703.

Reference Type: BACKGROUND

PMID: 10207237 (View on PubMed)

Bucher M, Kees FK, Messmann B, Lunz D, Rath S, Zelenka M, Schlitt HJ, Hobbhahn J. Prostaglandin I2 release following mesenteric traction during abdominal surgery is mediated by cyclooxygenase-1. Eur J Pharmacol. 2006 May 1;536(3):296-300. doi: 10.1016/j.ejphar.2006.03.009. Epub 2006 Mar 13.

Reference Type: BACKGROUND

PMID: 16581062 (View on PubMed)

Gottlieb A, Skrinska VA, O'Hara P, Boutros AR, Melia M, Beck GJ. The role of prostacyclin in the mesenteric traction syndrome during anesthesia for abdominal aortic reconstructive surgery. Ann Surg. 1989 Mar;209(3):363-7. doi: 10.1097/00000658-198903000-00018.

Reference Type: BACKGROUND

PMID: 2647052 (View on PubMed)

Hudson JC, Wurm WH, O'Donnel TF Jr, Kane FR, Mackey WC, Su YF, Watkins WD. Ibuprofen pretreatment inhibits prostacyclin release during abdominal exploration in aortic surgery. Anesthesiology. 1990 Mar;72(3):443-9. doi: 10.1097/00000542-199003000-00009.

Reference Type: BACKGROUND

PMID: 2106806 (View on PubMed)

Kothapalli D, Stewart SA, Smyth EM, Azonobi I, Pure E, Assoian RK. Prostacylin receptor activation inhibits proliferation of aortic smooth muscle cells by regulating cAMP response element-binding protein- and pocket protein-dependent cyclin a gene expression. Mol Pharmacol. 2003 Aug;64(2):249-58. doi: 10.1124/mol.64.2.249.

Reference Type: BACKGROUND

PMID: 12869629 (View on PubMed)

Weksler BB, Marcus AJ, Jaffe EA. Synthesis of prostaglandin I2 (prostacyclin) by cultured human and bovine endothelial cells. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3922-6. doi: 10.1073/pnas.74.9.3922.

Reference Type: BACKGROUND

PMID: 333448 (View on PubMed)

Wharton J, Davie N, Upton PD, Yacoub MH, Polak JM, Morrell NW. Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells. Circulation. 2000 Dec 19;102(25):3130-6. doi: 10.1161/01.cir.102.25.3130.

Reference Type: BACKGROUND

PMID: 11120706 (View on PubMed)

Strandby RB, Ambrus R, Secher NH, Goetze JP, Achiam MP, Svendsen LB. Plasma pro-atrial natriuretic peptide to estimate fluid balance during open and robot-assisted esophagectomy: a prospective observational study. BMC Anesthesiol. 2017 Feb 3;17(1):20. doi: 10.1186/s12871-017-0314-6.

Reference Type: DERIVED

PMID: 28159014 (View on PubMed)

Other Identifiers

30-1152

Identifier Type: REGISTRY

Identifier Source: secondary_id

H-2-2013-101

Identifier Type: -

Identifier Source: org_study_id