Perioperative Metabolic and Hormonal Aspects in Major Emergency Surgery (PHASE)

Emergency laparotomies, which most often is performed due to high risk disease (bowel obstruction, ischemia, perforation, etc.), make up 11 % of surgical procedures in emergency surgical departments, however, give rise to 80 % of all postoperative complications. The 30-day mortality rates in relation to these emergent procedures have been reported between 14-30 %, with even higher numbers for frail and older patients. The specific reasons for these outcomes are not yet known, however, a combination of preexisting comorbidities, acute illness, sepsis, and the surgical stress response that arise during- and after the surgical procedure due to the activation of the immunological and humoral system, is most likely to blame. The complex endocrinological response and consequences of this response to emergency surgery are sparsely reported in the literature.

The aim of this PHASE project is to evaluate and describe the temporal endocrine, endothelial and immunological changes after major emergency abdominal surgery, and to associate these changes with clinical postoperative outcomes.

Study Overview

• Status: Completed
• Conditions: Stress; Surgery--Complications; Gastrointestinal Disease; Acute Illness
• Intervention / Treatment: Procedure: Major emergency gastrointestinal surgery

• Study Type: Observational
• Enrollment (Actual): 98

Contacts and Locations

Study Locations

• Denmark
  • Køge, Denmark, 2300
    • Department of Surgery, Zealand University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients ≥ 18 years old undergoing acute major gastrointestinal surgery within 72 hours of their admission to the Department of Surgery or an acute reoperation.

Major gastrointestinal surgery are defined as procedures involving the stomach, small or large bowel, or rectum for conditions such as perforation, ischaemia, abdominal abscess, bleeding or obstruction.

Patients will be consecutively screened for inclusion.

Description

Inclusion Criteria:

• Surgery within 72 hours of an acute admission to the Department of Surgery or an acute reoperation.
• Major gastrointestinal surgery on the gastrointestinal tract (see intervention definition)

Exclusion Criteria:

• Not capable of giving informed consent after oral and written information
• Previously included in the trial
• Elective laparoscopy
• Diagnostic laparotomy/laparoscopy where no subsequent procedure is performed (NB, if no procedure is performed because of inoperable pathology, then include)
• Appendectomy +/- drainage or Cholecystectomy +/- drainage of localized collection unless the procedure is incidental to a non-elective procedure on the GI tract
• Non-elective hernia repair without bowel resection.
• Minor abdominal wound dehiscence unless this causes bowel complications requiring resection
• Ruptured ectopic pregnancy, or pelvic abscesses due to pelvic inflammatory disease
• Laparotomy/laparoscopy for pathology caused by blunt or penetrating trauma, esophageal pathology, pathology of the spleen, renal tract, kidneys, liver, gall bladder and biliary tree, pancreas or urinary tract

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of immunological biomarkers	Assessment of: plasma inflammatory interleukines incl. IL-1-alfa, IL-1beta, IL-6, IL-10; plasma TNF-alfa; plasma TGF-beta	Change from preoperative levels at postoperative day 5
Number of patients with stress induced hyperglycemia	Assessment of: Blood glucose, plasma c-peptide, HbA1C; plasma Glucagon-like peptide 1 (GLP-1)	Postoperative day 5
Changes of plasma thyroid hormones	Assessment of: Thyropin-releasing hormone (TRH); Thyroid-stimulating hormone (TSH); Thyroid hormones (fT3, fT4, rT3)	Change from preoperative levels at postoperative day 5
Changes of the central endocrine stress response	Assessment of plasma corticotropin releasing hormone (CRH)	Change from preoperative levels at postoperative day 5
Changes of sE-selectin	Assessment of plasma sE-selectine; sE-selectin; syndecan-1; thrombomodulin; sVE-cadherin	Change from preoperative levels at postoperative day 5
Changes of the endothelial function	Assessed with the non-invasive EndoPAT and expressed as the reactive hyperemia index	Change from postoperative day 1 at postoperative day 5
Changes of the periferal endocrine stress response	Assessment of plasma adrenocorticotropic hormone (ACTH)	Change from preoperative levels at postoperative day 5
Changes of cortisol	Assessment of plasma cortisol (free and bound)	Change from preoperative levels at postoperative day 5
Changes of neuropeptides	Assessment of plasma neuropeptides	Change from preoperative levels at postoperative day 5
Changes of syndecan-1	Assessment of plasma syndecan-1	Change from preoperative levels at postoperative day 5
Changes of thrombomodulin	Assessment of plasma thrombomodulin	Change from preoperative levels at postoperative day 5
Changes of sVE-cadherin	Assessment of plasma sVE-cadherin	Change from preoperative levels at postoperative day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with major adverse cardiovascular events	Defined as: Cardiovascular death; Myocardial injury within postoperative day 4 (definition: peak plasma cardiac troponin-I ≥ 45ng/L (99th percentile URL, 10% CV at 40ng/L)); Acute coronary syndrome (unstable angina pectoris, NSTEMI, STEMI); Congestive heart failure; Stroke; Nonfatal cardiac arrest; New clinically important cardiac arrhythmia; Coronary revascularization procedure (PCI or CABG); Sudden unexpected death	365 days after surgery
Number of patients with postoperative non-cardiovascular complications	Defined as: Non-cardiovascular death with other defined reason for death; Sepsis (sepsis - severe sepsis - septic shock); Pneumonia; Respiratory failure; Surgical complications (Clavien-Dindo stage 3); Any non-cardiovascular life-threatening complication (Clavien-Dindo stage 4); Readmission due to a non-cardiovascular complication	365 days after surgery

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Investigators: Principal Investigator: Jakob Burcharth, MD, PhD, Zealand University Hospital

Publications and helpful links

General Publications

• Preiser JC, Ichai C, Orban JC, Groeneveld AB. Metabolic response to the stress of critical illness. Br J Anaesth. 2014 Dec;113(6):945-54. doi: 10.1093/bja/aeu187. Epub 2014 Jun 26.
• Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Kovacs EJ, Koenderman L, Kubes P, Lilford RJ. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014 Oct 18;384(9952):1455-65. doi: 10.1016/S0140-6736(14)60687-5. Epub 2014 Oct 17.
• Munzel T, Sinning C, Post F, Warnholtz A, Schulz E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med. 2008;40(3):180-96. doi: 10.1080/07853890701854702.
• McIlroy DR, Chan MT, Wallace SK, Symons JA, Koo EG, Chu LC, Myles PS. Automated preoperative assessment of endothelial dysfunction and risk stratification for perioperative myocardial injury in patients undergoing non-cardiac surgery. Br J Anaesth. 2014 Jan;112(1):47-56. doi: 10.1093/bja/aet354. Epub 2013 Oct 29.
• Huddart S, Peden CJ, Swart M, McCormick B, Dickinson M, Mohammed MA, Quiney N; ELPQuiC Collaborator Group; ELPQuiC Collaborator Group. Use of a pathway quality improvement care bundle to reduce mortality after emergency laparotomy. Br J Surg. 2015 Jan;102(1):57-66. doi: 10.1002/bjs.9658. Epub 2014 Nov 10.
• Marik PE, Bellomo R. Stress hyperglycemia: an essential survival response! Crit Care Med. 2013 Jun;41(6):e93-4. doi: 10.1097/CCM.0b013e318283d124. No abstract available.
• Hassan-Smith Z, Cooper MS. Overview of the endocrine response to critical illness: how to measure it and when to treat. Best Pract Res Clin Endocrinol Metab. 2011 Oct;25(5):705-17. doi: 10.1016/j.beem.2011.04.002.
• Gibbison B, Angelini GD, Lightman SL. Dynamic output and control of the hypothalamic-pituitary-adrenal axis in critical illness and major surgery. Br J Anaesth. 2013 Sep;111(3):347-60. doi: 10.1093/bja/aet077. Epub 2013 May 9.
• Ekeloef S, Larsen MH, Schou-Pedersen AM, Lykkesfeldt J, Rosenberg J, Gogenur I. Endothelial dysfunction in the early postoperative period after major colon cancer surgery. Br J Anaesth. 2017 Feb;118(2):200-206. doi: 10.1093/bja/aew410.

Helpful Links

• Center for Surgical Science

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2018
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): November 1, 2019

Study Registration Dates

• First Submitted: February 13, 2018
• First Submitted That Met QC Criteria: March 22, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Actual): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 21, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Inflammation; Hypothalamic-pituitary-adrenal axis; Thyroid hormones; Insulin-glucose homeostasis; Endothelial function and damage
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Emergencies; Gastrointestinal Diseases; Digestive System Diseases
• Other Study ID Numbers: PHASE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No