Protease Activated Receptor-2 and Gastrointestinal Dysfunction in Critical Illness

Critical Illness Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03011151
• Other study ID #: IRB-P00024070
• Status: Recruiting
• Start date: August 1, 2017
• Est. completion date: December 31, 2023

Study information

• Verified date: March 2023
• Source: Boston Children's Hospital
• Contact: Enid Martinez, MD
• Phone: 6173557327
• Email: enid.martinez[@]childrens.harvard.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness
• Digestive System Diseases
• Gastrointestinal Diseases
• Gastrointestinal Disorder, Functional
• Gastroparesis

Locations

Country	Name	City	State
United States	Boston Children's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Boston Children's Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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