Protease Activated Receptor-2 and Gastrointestinal Dysfunction in Critical Illness

Examining the Role of Protease-activated Receptor 2 Agonists in Gastrointestinal Dysfunction in Pediatric Surgical Critical Illness

Gastrointestinal (GI) dysfunction affects up to 50% of medical and surgical critically ill children. GI dysfunction, specifically gastric dysmotility and loss of epithelial barrier integrity, is associated with significant morbidity in critical illness. The mechanisms underlying GI dysfunction in critical illness are not well understood. GI dysfunction in surgery and critical illness has been associated with inflammation. There is evidence to suggest the protease-activated receptor 2 (PAR2) is a link between inflammation and GI dysfunction. PAR2 is a G-coupled receptor present throughout the GI tract. PAR2 mediates GI motility and epithelial barrier integrity. PAR2 is activated by PAR2 agonists, specifically GI serine proteases and zonulin, released under conditions of inflammation. In this study the investigators will examine the relationship between inflammation and PAR2 activation by PAR2 agonists and subsequent GI dysfunction in pediatric critically ill surgical patients. The overall hypothesis of this study is that PAR2 activation by PAR2 agonists, GI serine proteases and zonulin, released due to inflammation results in gastric dysmotility and loss of epithelial barrier integrity. In this study, the investigators will examine whether PAR2 agonist expression is increased and correlates with GI dysfunction in critically ill surgical pediatric patients. This proposal fills a knowledge gap in the understanding of mechanisms for GI dysfunction in critical illness, and will be applicable to all surgical and medical critically ill children.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Gastroparesis; Gastrointestinal Disorder, Functional

Detailed Description

The investigators in this study aim to examine a plausible mechanism by which gastrointestinal dysfunction, gastric dysmotility and loss of epithelial barrier integrity, occur in critical illness. Specifically, the investigators will examine whether an increase in PAR2 agonist levels, zonulin and serine proteases, are associated with gastric dysmotility and loss of epithelial barrier integrity in critical surgical illness in children. The investigators will examine GI function, gastric motility and epithelial barrier integrity, and PAR2 agonist levels, zonulin and serine protease, in participants before surgery and after surgery. Specifically, children undergoing posterior spinal fusion, a known significant inflammatory trigger, and with planned admissions to the intensive care unit will be enrolled. Gastrointestinal function and PAR2 agonist levels will be tested non-invasively in blood and stool.

• Study Type: Observational
• Enrollment (Anticipated): 80

Contacts and Locations

• Study Contact: Name: Enid Martinez, MD; Phone Number: 6173557327; Email: enid.martinez@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Enid Martinez, MD; Phone Number: 617-355-7327; Email: enid.martinez@childrens.harvard.edu
      • Contact: Brooke Sens, RN; Phone Number: 6173556185; Email: brooke.sens@childrens.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Children undergoing posterior spinal fusion and admitted to the pediatric intensive care unit

Description

Inclusion Criteria:

• 2 years and older

Exclusion Criteria:

• Liver dysfunction
• Renal dysfunction
• Pre-diagnosed gastroparesis/ delayed gastric emptying
• Pre-diagnosed gastrointestinal malabsorption
• Contraindication to acetaminophen administration

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PAR2 agonist activity- serum zonulin	PAR2 agonist activity will be measured by serum zonulin levels (ng/mL)	Immediately pre-operative versus post-operative day 1
PAR2 agonist activity- fecal protease activity	PAR2 agonist activity will be measured by fecal serine protease activity (trypsin units/gm protein)	Immediately pre-operative versus post-operative day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastric motility by the acetaminophen absorption test- AUC	Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the concentration of acetaminophen at 60 minutes (mcg/mL).	Immediately pre-operative versus post-operative day 1
Gastric motility by the acetaminophen absorption test- Tmax	Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the time to maximum concentration of acetaminophen (minutes).	Immediately pre-operative versus post-operative day 1
Gastric motility by the acetaminophen absorption test- Cmax	Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including area under the curve at 60 minutes (mcg*min/mL).	Immediately pre-operative versus post-operative day 1
Epithelial barrier integrity by serum biomarkers	Epithelial barrier integrity by serum biomarkers, specifically serum zonulin (ng/mL) and lipopolysaccharide binding protein levels (ng/mL).	Immediately pre-operative versus post-operative day 1

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Principal Investigator: Enid Martinez, MD, Boston Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2017
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: January 2, 2017
• First Submitted That Met QC Criteria: January 3, 2017
• First Posted (Estimate): January 5, 2017

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: pediatric; surgery; nutrition; gastric emptying; critical illness; gastrointestinal dysfunction; epithelial barrier
• Additional Relevant MeSH Terms: Pathologic Processes; Neurologic Manifestations; Disease Attributes; Stomach Diseases; Paralysis; Gastrointestinal Diseases; Digestive System Diseases; Critical Illness; Gastroparesis
• Other Study ID Numbers: IRB-P00024070

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO