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Protease Activated Receptor-2 and Gastrointestinal Dysfunction in Critical Illness

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ClinicalTrials.gov Identifier: NCT03011151
Recruitment Status : Recruiting
First Posted : January 5, 2017
Last Update Posted : March 14, 2022
Sponsor:
Information provided by (Responsible Party):
Enid Martinez, Boston Children's Hospital

Brief 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.

Condition or disease
Gastroparesis Gastrointestinal Disorder, Functional Critical Illness

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.

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Study Type : Observational
Estimated Enrollment : 80 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Examining the Role of Protease-activated Receptor 2 Agonists in Gastrointestinal Dysfunction in Pediatric Surgical Critical Illness
Actual Study Start Date : August 1, 2017
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. PAR2 agonist activity- serum zonulin [ Time Frame: Immediately pre-operative versus post-operative day 1 ]
    PAR2 agonist activity will be measured by serum zonulin levels (ng/mL)

  2. PAR2 agonist activity- fecal protease activity [ Time Frame: Immediately pre-operative versus post-operative day 1 ]
    PAR2 agonist activity will be measured by fecal serine protease activity (trypsin units/gm protein)


Secondary Outcome Measures :
  1. Gastric motility by the acetaminophen absorption test- AUC [ Time Frame: Immediately pre-operative versus post-operative day 1 ]
    Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the concentration of acetaminophen at 60 minutes (mcg/mL).

  2. Gastric motility by the acetaminophen absorption test- Tmax [ Time Frame: Immediately pre-operative versus post-operative day 1 ]
    Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the time to maximum concentration of acetaminophen (minutes).

  3. Gastric motility by the acetaminophen absorption test- Cmax [ Time Frame: Immediately pre-operative versus post-operative day 1 ]
    Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including area under the curve at 60 minutes (mcg*min/mL).

  4. Epithelial barrier integrity by serum biomarkers [ Time Frame: Immediately pre-operative versus post-operative day 1 ]
    Epithelial barrier integrity by serum biomarkers, specifically serum zonulin (ng/mL) and lipopolysaccharide binding protein levels (ng/mL).


Biospecimen Retention:   Samples Without DNA
Blood, Stool


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Ages Eligible for Study:   2 Years to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children undergoing posterior spinal fusion and admitted to the pediatric intensive care unit
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03011151


Contacts
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Contact: Enid Martinez, MD 6173557327 enid.martinez@childrens.harvard.edu

Locations
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United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Enid Martinez, MD    617-355-7327    enid.martinez@childrens.harvard.edu   
Contact: Brooke Sens, RN    6173556185    brooke.sens@childrens.harvard.edu   
Sponsors and Collaborators
Boston Children's Hospital
Investigators
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Principal Investigator: Enid Martinez, MD Boston Children's Hospital
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Responsible Party: Enid Martinez, Assistant in Critical Care Medicine, Boston Children's Hospital
ClinicalTrials.gov Identifier: NCT03011151    
Other Study ID Numbers: IRB-P00024070
First Posted: January 5, 2017    Key Record Dates
Last Update Posted: March 14, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Enid Martinez, Boston Children's Hospital:
pediatric
critical illness
surgery
gastrointestinal dysfunction
gastric emptying
epithelial barrier
nutrition
Additional relevant MeSH terms:
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Gastroparesis
Gastrointestinal Diseases
Digestive System Diseases
Critical Illness
Disease Attributes
Pathologic Processes
Stomach Diseases
Paralysis
Neurologic Manifestations