Intestinal Ischemia as a Stimulus for Systemic Inflammatory Response After Cardiac Arrest (TICA)

Out-of-hospital cardiac arrest (CA) is a leading public health problem causing nearly one third of a million deaths annually in the US, accounting for half of all cardiovascular deaths and surpassing deaths from stroke, heart failure, and breast and lung cancer combined. Twenty to fifty percent of CA patients (pts) can be resuscitated initially but many die before hospital discharge or suffer permanent neurologic damage. Therapeutic hypothermia (TH) improves survival and neurological outcomes. Despite aggressive, targeted post arrest management, including TH, approximately 50% of pts die before leaving the hospital due to global ischemia-reperfusion injury (IRI) known as the "post arrest syndrome", 1 which is a sepsis-like state characterized by elevated markers of cellular inflammation and injury. It is believed that TH works by decreasing the body's basal metabolic rate (BMR) and attenuating the systemic inflammatory response (SIR). However, specific triggers of the intense pro-inflammatory response are unclear. This "gap" in knowledge must be closed to identify targeted therapy to decrease IRI and improve outcomes.

Blood flow to the gut is decreased markedly and intestinal tissue becomes ischemic during CA and CPR, particularly when vasoconstrictor drugs such as epinephrine, are given. IRI of the intestine increases intestinal permeability leading to intestinal microbial translocation and endotoxin release that can stimulate and perpetuate systemic inflammation and cause subsequent multi-organ dysfunction. Endotoxin also increases body temperature and energy expenditure and may attenuate TH induced reductions in BMR and hence, decrease efficacy. The purpose of this novel pilot study is to detect systemic endotoxin release following CA in humans and determine association with cytokine activation, and BMR alterations during TH.

Study Overview

• Status: Completed
• Conditions: Reperfusion Injury; Cardiac Arrest

Detailed Description

Hypothesis 1 Intestinal ischemia during and following Caridac Arrest leads to increased gut permeability and endotoxin release that stimulates the Systemic Inflammatory Response that is responsible for subsequent death and disability after resuscitation.

Hypothesis 2: Different degrees of systemic endotoxin activity variably affect Basic Metabolic Rate during Therapeutic Hypothermia

Serial samples of blood, stool and expired gas will be measured at predetermined timepoints after ROSC from cardiac arrest.

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

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

All adult patients resuscitated from Cardiac Arrest successfully and undergoing therapeutic hypothermia will be evaluated for potential inclusion

Description

Inclusion Criteria:

Adult, Cardiac Arrest with ROSC receiving Therapeutic Hypothermia-

Exclusion Criteria:

• Age < 18
• Cardiac Arrest of traumatic etiology
• Known to be pregnant
• Prisoner

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Cardiac Arrest patients undergoing Therapeutic Hypothermia; Cardiac Arrest subjects with Return Of Spontaneous Circulation (ROSC) and undergoing treatment with Therapeutic Hypothermia will undergo sampling of blood, stool, and expired gas data at physiologically predetermined time points.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection of Endotoxin Activity	Endotoxin activity will be measured by the Endotoxin Activity Assay and values . of >0.4 EA units will be used as the "cut-off" for the presence of pathological endotoxin.	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection of sCD14	To demonstrate activation of endotoxin by the immune system and "upstream" physiologic changes necessary for systemic endotoxemia to occur	48 hours
Detection of stool lactoferrin and stool α1-antitrypsin	To demonstrate evidence of intestinal inflammation and permeability that can lead to endotoxemia and "downstream" cellular inflammatory responses responsible for end organ damage	48 hours
Detection and quantification of inflammatory cytokines	To demonstrate an association with the primary outcome	48 hours
BMR measurement elevation	To determine its association with endotoxemia and cytokine. BMR is being measured to determine if pts with higher levels of endotoxin and cytokines have higher BMR and therefore blunted therapeutic value of TH	48 hours

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Mary Ann Peberdy, M.D., Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): March 30, 2014
• Study Completion (Actual): March 30, 2014

Study Registration Dates

• First Submitted: September 12, 2013
• First Submitted That Met QC Criteria: September 12, 2013
• First Posted (Estimate): September 17, 2013

Study Record Updates

• Last Update Posted (Actual): October 6, 2017
• Last Update Submitted That Met QC Criteria: October 5, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Endotoxin; Cytokine; Metabolism
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Ischemia; Heart Arrest; Reperfusion Injury
• Other Study ID Numbers: HM15326