Glycocalyx Levels in Patients Undergoing Pancreatectomy

Pancreatic Cancer Clinical Trial

Official title:

Glycocalyx Levels in Patients Undergoing Pancreatectomy With Human Albumin 5% vs. Gelofusine

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04058236
• Other study ID #: U1111-1237-9121
• Status: Recruiting
• Phase: Phase 4
• Start date: August 15, 2019
• Est. completion date: July 31, 2021

Study information

• Verified date: April 2020
• Source: University of Malaya
• Contact: Pui San Loh, MBBS, MMed
• Phone: 012-2268285
• Email: lohps[@]ummc.edu.my
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

On the surface of every healthy cellular membrane resides a layer known as the glycocalyx. This structure consists of extracellular domains of receptor, adhesion and transmembrane molecules such as syndecan-1 covalently bound to highly negatively charged glycosaminoglycans, heparan sulfates. It has a principal role to maintain wall integrity, avoid inflammation and tissue oedema in vessels but in contrast, glycocalyx is robust and elevated on cancer cells. This study examines whether the endothelial glycocalyx layer is preserved in patients undergoing pancreatectomy with human albumin 5% vs. gelofusine in a restrictive goal directed fluid regime perioperatively for the first 24hours. Degradation of glycocalyx will be investigated by analyzing basic levels of the core protein syndecan-1 and heparan sulfates with post-operative samples.

Description:

This is a prospective study that will be conducted in the Main Operating theatres of UMMC on patients with pancreatic cancer undergoing elective pancreatectomy (includes all forms of pancreatectomy such as Whipple's procedure, total or distal pancreatectomy).

This study aim to determine the association of glycocalyx degradation by measuring levels of syndecan-1 and heparan sulfate with type of colloidal fluid given, human albumin 5% versus gelofusine in a restrictive goal directed fluid therapy in pancreatectomy.

Institutional ethics approval and registration in Clinical Trial Registry will be obtained before recruiting the first case.

Recruited patients will be randomly allocated to either the group receiving human albumin 5% or gelofusine.

Sample size:

There is no previously published literature related exactly to the pathology and methods of this proposed study. Therefore, a preliminary sample size calculation will be based on the closest study on fluids with a two-sided confidence interval of 0.95 and a desired power of 0.80 to yield a result that investigators need nine patients in each group. After adjusting for drop out rate of 10%, investigators will recruit ten in each group for human albumin 5% and gelofusine respectively within the study period of 2 years.

Data collection:

1. Intraoperative phase All preoperative preparation including fasting will be done in accordance to UMMC protocol. Intraoperative monitoring includes standard routine monitoring as per American Society of Anaesthesiologist Guidelines, invasive haemodynamic monitoring with arterial blood pressure incorporating FloTrac, BIS and neuromuscular monitoring. All patients will be under general anesthesia.

Fluid management for both groups are in accordance to goal directed therapy and guided by stroke volume variation of approximately 12-15%. If SVV is > 15%, 250ml of fluid replacement according to patient group will be given over 30 min within 24 hours intra and post operatively in the Intensive Care Unit (ICU). In both groups, all clinical parameters and fluids including blood that will be given will be recorded.

2. Post-operative phase:

The allocated colloid fluid will be continued.

Patients will be assessed for pancreatic fistula leak. The grading of pancreatic fistula will be defined according to the guideline of Revised 2016 International Study Group on Pancreatic Fistula (ISGPF).

Reviews will be done on post op days 1, 3, 5 and 30. Amylase levels from drain tube post-op Day 3, 5 and 7 will be measured. The total duration of stay in intensive care, hospital and rate of mortality/ morbidity (re-laparotomy/ re-admission to ICU/ sepsis) within 30 days after surgery will be assessed and recorded.

3. Laboratory phase Blood samples are collected at 5 time points, a) preoperative, b) immediate postoperative and c) 24 hours postoperative d) Day 3 and e) Day 7 postoperative from both groups. The serum fraction will be frozen and stored at −80°C until assayed. Syndecan 1 concentrations and heparan sulfate concentrations are quantified using special enzyme-linked immunosorbent assay kit as previously reported. Inflammatory markers Interleukin-1 and CRP and any blood investigations as per hospital sepsis protocol will be determined as well.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: July 31, 2021
• Est. primary completion date: July 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• ASA 1-3

• patients aged between 18-75 years old with written informed consent

Exclusion Criteria:

• Patients who refuse to participate,

• Have severe congestive heart failure (NYHA class III/IV) or severe respiratory disease (PaO2/FiO2 < 200),

• Suffer significant renal or hepatic dysfunction (creatinine raised >50 % or liver enzymes >50 % of normal values),

• Pregnant

• Allergic to gelofusine and human albumin

Related Conditions & MeSH terms

• Endothelial Degeneration
• Fistula
• Pancreatectomy
• Pancreatic Cancer
• Pancreatic Fistula
• Postoperative Pancreatic Fistula

Intervention

Other:
• human albumin 5%
Human Albumin 5% will be given as fluid management for this group in accordance to goal directed therapy and guided by stroke volume variation of approximately 12-15%. This percentage of SVV has been validated as a threshold above which fluid administration increases stroke volume with an area under the receiver operating characteristics curve reported at 0.87. If the SVV remains more than 15% for more than 2 minutes, 250ml of fluid replacement according to patient group will be given. These boluses are given in aliquots over 30 min to avoid effects of rapid volume expansion. and the same fluid and technique will be carried out within 24 hours intra and post operatively in the Intensive Care Unit (ICU). All clinical parameters and fluids including blood that will be given will be recorded.
• gelofusine.
Gelofusine will be given as fluid management for this group in accordance to goal directed therapy and guided by stroke volume variation of approximately 12-15%. This percentage of SVV has been validated as a threshold above which fluid administration increases stroke volume with an area under the receiver operating characteristics curve reported at 0.87. If the SVV remains more than 15% for more than 2 minutes, 250ml of fluid replacement according to patient group will be given. These boluses are given in aliquots over 30 min to avoid effects of rapid volume expansion. and the same fluid and technique will be carried out within 24 hours intra and post operatively in the Intensive Care Unit (ICU). All clinical parameters and fluids including blood that will be given will be recorded.

Locations

Country	Name	City	State
Malaysia	Anaesthesia Department, Faculty of Medicine, University Malaya	Kuala Lumpur	Federal Territory

Sponsors (1)

Lead Sponsor	Collaborator
University of Malaya

Country where clinical trial is conducted

Malaysia, 

References & Publications (15)

Alphonsus CS, Rodseth RN. The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia. 2014 Jul;69(7):777-84. doi: 10.1111/anae.12661. Epub 2014 Apr 28. Review. — View Citation

Chappell D, Bruegger D, Potzel J, Jacob M, Brettner F, Vogeser M, Conzen P, Becker BF, Rehm M. Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx. Crit Care. 2014 Oct 13;18(5):538. doi: 10.1186/s13054-014-0538-5. — View Citation

Cooper DJ, Myburgh J, Heritier S, Finfer S, Bellomo R, Billot L, Murray L, Vallance S; SAFE-TBI Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality? J Neurotrauma. 2013 Apr 1;30(7):512-8. doi: 10.1089/neu.2012.2573. Epub 2013 Mar 21. — View Citation

Curry FE, Adamson RH. Endothelial glycocalyx: permeability barrier and mechanosensor. Ann Biomed Eng. 2012 Apr;40(4):828-39. doi: 10.1007/s10439-011-0429-8. Epub 2011 Oct 19. Review. — View Citation

Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247-56. — View Citation

Jacob M, Bruegger D, Rehm M, Stoeckelhuber M, Welsch U, Conzen P, Becker BF. The endothelial glycocalyx affords compatibility of Starling's principle and high cardiac interstitial albumin levels. Cardiovasc Res. 2007 Feb 1;73(3):575-86. Epub 2006 Nov 21. — View Citation

Kang H, Wu Q, Sun A, Liu X, Fan Y, Deng X. Cancer Cell Glycocalyx and Its Significance in Cancer Progression. Int J Mol Sci. 2018 Aug 22;19(9). pii: E2484. doi: 10.3390/ijms19092484. Review. — View Citation

Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet. 2002 May 25;359(9320):1812-8. — View Citation

Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901-11. doi: 10.1056/NEJMoa1209759. Epub 2012 Oct 17. Erratum in: N Engl J Med. 2016 Mar 31;374(13):1298. — View Citation

Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012 Jul 12;367(2):124-34. doi: 10.1056/NEJMoa1204242. Epub 2012 Jun 27. Erratum in: N Engl J Med. 2012 Aug 2;367(5):481. — View Citation

Pries AR, Kuebler WM. Normal endothelium. Handb Exp Pharmacol. 2006;(176 Pt 1):1-40. Review. — View Citation

Sulzer JK, Sastry AV, Meyer LM, Cochran A, Buhrman WC, Baker EH, Martinie JB, Iannitti DA, Vrochides D. The impact of intraoperative goal-directed fluid therapy on complications after pancreaticoduodenectomy. Ann Med Surg (Lond). 2018 Oct 16;36:23-28. doi: 10.1016/j.amsu.2018.10.018. eCollection 2018 Dec. — View Citation

Tarbell JM, Cancel LM. The glycocalyx and its significance in human medicine. J Intern Med. 2016 Jul;280(1):97-113. doi: 10.1111/joim.12465. Epub 2016 Jan 8. Review. — View Citation

Vincent JL, Russell JA, Jacob M, Martin G, Guidet B, Wernerman J, Ferrer R, McCluskey SA, Gattinoni L. Albumin administration in the acutely ill: what is new and where next? Crit Care. 2014 Jul 16;18(4):231. doi: 10.1186/cc13991. Review. Erratum in: Crit Care. 2014;18(6):630. Roca, Ricard Ferrer [corrected to Ferrer, Ricard]. — View Citation

Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012 Mar;108(3):384-94. doi: 10.1093/bja/aer515. Epub 2012 Jan 29. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurence of pancreatic fistula leak	Review will be done according to guideline of Revised 2016 International Study Group on Pancreatic Fistula (ISGPF)	Within post-op 30 days
Primary	Changes in serum syndecan 1 concentrations	Blood samples are collected to check for syndecan 1 concentrations in serum	Within post-op 7 days
Primary	Changes in serum heparan sulfate concentrations	Blood samples are collected to check for heparan sulfate concentrations in serum	Within post-op 7 days
Secondary	Changes in levels of Inflammatory markers Interleukin-1 and CRP	Blood samples are collected to check level of the Inflammatory markers Interleukin-1 and CRP	Within post-op 7 days