Preoperative High-dose Dexamethasone and Emergency Laparotomy

The Effects of Preoperative High-dose Dexamethasone on Inflammatory Response and Recovery After Emergency Laparotomy, a Randomized, Double-blind, Placebo-controlled Clinical Trial - AHA STEROID TRIAL

The aim of this trial is to evaluate the effect of high-dose glucocorticoid on inflammatory response and recovery after emergency laparotomy in participants with intestinal obstruction and perforated viscus.

Primary outcome is the reduction of C-reactive protein on postoperative day 1. Secondary outcomes are organ specific complications in the post anaesthesia phase, endothel and inflammatory markers, fluid status, preload dependency, pain, lung function, nausea and mobilization during the first 5 days after surgery, .

The investigators hypothesize, that a preoperative single high dose of glucocorticoid reduces systemic inflammatory response after emergency laparotomy.

Study Overview

• Status: Completed
• Conditions: Sepsis; Inflammatory Response; Pathophysiology; Intestinal Obstruction and Ileus; Perforated Viscus
• Intervention / Treatment: Drug: Dexamethasone 1 mg/kg; Drug: Physiologic saline

Detailed Description

Surgical trauma and accompanying inflammation results in increased capillary permeability leading to tissue edema. Since the vascular endothelium contributes to homeostasis, endothelial damage may increase the risk of cardiovascular and hemodynamic complications.

Pre-operative high-dose glucocorticoids provide reduction in the inflammatory response after surgery, effective pain relief in several major surgical procedures, as well as reducing fatigue, impairing endothelial dysfunction, potentially amend fluid extravasation, edema and dyscoagulation and vasodilation.

However, glucocorticoids have not been assessed in patients with peritonitis or intestinal obstruction, specifically, the impact on pain, fluid dynamics, respiratory as well as endothelial function and mobilization in both obstruction and perforation.

In this study, patients will be randomized to either high dose dexamethason (1 mg /kg) or placebo (0,9% NaCl), administered as a single dose preoperatively. The investigatoris hypothesize that a preoperative single high dose of glucocorticoid reduces systemic inflammatory response after emergency laparotomy.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Hvidovre, Denmark, 2650
    • Mirjana Cihoric

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults (18 years or over) undergoing emergency laparotomy (laparotomy or laparoscopy) for following abdominal pathology:

   1. Primary perforated viscus (perforated ulcer, small intestine or colon)
   2. Primary intestinal obstruction ( small intestine or colon)
2. Provided verbal and written informed consent
3. Must speak and understand the Danish language

Exclusion Criteria:

1. Appendectomies, cholecystectomies, negative diagnostic laparoscopies/laparotomies, herniotomies without bowel resections, sub-acute internal hernias after gastric bypass surgery, sub-acute surgery for inflammatory bowel diseases.
2. Emergency re-operations after elective surgery owing to paralytic/obstructive ileus, perforated viscus, anastomotic leakage
3. Reoperation owing to fascial separation with no other abdominal pathology identified and sub-acute colorectal cancer-surgery will be excluded from the cohort. Sub-acute surgery is defined as surgery planned within 48 hours.
4. Intestinal Ischemia
5. intraabdominal bleeding
6. Traumas, gynecological, urogenital and other vascular pathology, pregnant participants.
7. Dementia and/or cognitive dysfunction (diagnosed).
8. Participants not oriented in time, place and person
9. Insuline treatment for diabetes mellitus type I and II
10. Current treatment with systemic glucocorticoids or immune suppressive treatment ( apart from inhalation steroids)

11. Allergies to trial medicine

    -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intestinal obstruction, Dexamethasone 1 mg/kg; Dexamethasone 1 mg/kg administered preoperatively as an i.v. infusion over 10-15 minutes	Drug: Dexamethasone 1 mg/kg; Dexamethasone 1 mg/kg administered as a single preoperative i.v. infusion over 10-15 min prior to general anaesthesia; Other Names: Dexa-ratiopharm
Placebo Comparator: Intestinal obstruction, PLACEBO; Physiologic saline, administered preoperatively as an i.v. infusion over 10-15 minutes	Drug: Physiologic saline; 100 mL Physiologic saline administered as a single preoperative i.v., infusion over 10-15 min prior to general anaesthesia
Active Comparator: Perforated viscus, Dexamethasone 1 mg/kg; Dexamethasone 1 mg/kg administered preoperatively as an i.v. infusion over 10-15 minutes	Drug: Dexamethasone 1 mg/kg; Dexamethasone 1 mg/kg administered as a single preoperative i.v. infusion over 10-15 min prior to general anaesthesia; Other Names: Dexa-ratiopharm
Placebo Comparator: Perforated viscus, PLACEBO; Physiologic saline, administered preoperatively as an i.v. infusion over 10-15 minutes	Drug: Physiologic saline; 100 mL Physiologic saline administered as a single preoperative i.v., infusion over 10-15 min prior to general anaesthesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
plasma C-reactive protein	24* hours (*+/- 6 hours) after surgery.

Secondary Outcome Measures

Outcome Measure	Time Frame
changes in plasma C-reactive protein	Preoperatively, 6 hours postoperatively, as well as postoperative day 3 and 5

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes in postoperative inflammatory responses (IL-6, TNF alfa)		Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
Change in plasma Syndecain-1sE-Selectin (CD62E)		Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
Change in plasma soluble thrombomodulin (sTM)(CD141)		Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
Change in plasma sE-Selectin (CD62E)		Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
Change in vascular endothelial growth factor (VEGF)	0 to 1 point: Not high risk; 2 to 3 points: High risk	Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
quick Sequential Organ Failure Assessment score, qSOFA		Assessed once preoperatively and 4 times daily during the first 5 postoperative days
Preload dependency via stroke volume(SV) guided resuscitation		Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
Fluid distribution, full body water via bioelectrical impedance vector analysis		Preoperatively, 6 hours postoperatively, as well as postoperative day 1,3 and 5
Peak flow measurements		Once a day on postoperative day 1,3 and 5
Postoperative need for antiemetic and analgesic beyond standard course		Once a day during the the first 5 postoperative days
Mobilization, The Cumulated Ambulation Score (CAS)	The CAS describes the patient's independence with regard to three activities (getting in and out of bed, sit-to-stand-to-sit from a chair, and walking). Each activity is assessed on a three-point ordinal scale from 0-2 (0 = Not able to, despite human assistance and verbal cueing, 1 = Able to, with human assistance and/or verbal cueing from one or more persons, 2 = Able to safely, without human assistance or verbal cueing, use of a walking aid allowed) resulting in a total daily CAS score ranging from zero to six	Once a day on postoperative day 1,3 and 5
Postoperative delirium via Confusion Assessment method scale	1.a: Acute onset 1b: Fluctuating course, 2: inattention 3: disorganized thinking 4: altered level of conciosness At least one criterion must be met for a positive result	Once a day during the the first 5 postoperative days
Postoperative resting pain measured according to Numeric Rating Scale (NRS)	0-10 where 0 is no pain and 10 is the worst pain imaginable	6 hours after surgery as well as once a day one postoperative day 1,3 and 5
Postoperative pain during mobilization, measured according to Numeric Rating Scale (NRS)	0-10 where 0 is no pain and 10 is the worst pain imaginable	6 hours after surgery as well as once one postoperative day 1,3 and 5
30-day postoperative mortality		30 days
90-day postoperative mortality		90 days
30-day postoperative complications		30 days
Length of ICU stay		30 days
Overall hospital stay		30 days
Plasma NO-bioavailability (L-arginine, asymmetric dimethylarginine)		preoperatively, 6 hours after surgery as well as once one postoperative day 1,3 and 5

Collaborators and Investigators

• Sponsor: Mirjana Cihoric
• Investigators: Study Director: Nicolai Bang Foss, Professor, Dept. of Anaesthesiology and Intensive Care

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): October 9, 2022
• Study Completion (Actual): December 9, 2022

Study Registration Dates

• First Submitted: March 3, 2021
• First Submitted That Met QC Criteria: March 8, 2021
• First Posted (Actual): March 10, 2021

Study Record Updates

• Last Update Posted (Estimate): December 14, 2022
• Last Update Submitted That Met QC Criteria: December 13, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease Attributes; Gastrointestinal Diseases; Intestinal Diseases; Emergencies; Intestinal Obstruction; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: H-20038432

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No