UMIN-CTR Clinical Trial

Public title

Investigation of the relationship between immune system and coagulation system in patient with cardiac arrest outside the hospital

Acronym

Investigation of the relationship between immune responses and coagulation responses in patient with cardiac arrest outside the hospital

Scientific Title

Investigation of the relationship between innate immune responses and coagulofibrinolytic responses in patients with out-of-hospital cardiac arrest

Scientific Title:Acronym

Investigation of the relationship between innate immune responses and coagulofibrinolytic responses in patients with out-of-hospital cardiac arrest

Region

Japan

Condition

Out-of-hospital cardiac arrest

Classification by specialty

Emergency medicine

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

Danger-associated molecular patterns (DAMPs) such as histones cause the endothelial cell injury and the activation of neutrophil.
DAMPs cause hypercoagulation, dysfunction of anticoagulation system and inhibition of fibrinolysis.
DAMPs produce immunothrombosis depending on activated neutrophils and systemic inflammation causes disseminated intravascular coagulation (DIC).
Cardiac arrest and resuscitation, namely systemic ischemia an reperfusion cause the release of DAMPs.
The development of DIC in patients after cardiac arrest and resuscitation cause organ dysfunction, leading to poor outcome.

Based on the above reports, the purpose of this study is to prove the hypothesis that thrombin, which is produced by histones released after cardiac arrest and resuscitation is associated with the development of DIC, leading organ dysfunction and poor outcome.

Basic objectives2

Others

Basic objectives -Others

Investigation of pathomechanism

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Severity of organ dysfunction, assessed by Sequential Organ Failure Assessment (SOFA) score

Key secondary outcomes

The levels of histone H3, interleukin-6, and various markers of coagulation and fibrinolysis
Outcome (organ dysfunction, 28-days mortality and hospital death)
Impact of DIC on outcome

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Patients who are 20 years of age or older at the time of obtaining consent
Patients who died without return of spontaneous circulation after out-of-hospital cardiac arrest
Patients who get return of spontaneous circulation
Investigators have to get informed consent from the patients or their legal authorized representatives after explaining the participation in this study to them and confirming their understanding.

Key exclusion criteria

Patients with cardiac arrest due to trauma, acute aortic dissection or ruptured aortic aneurysm
Patients who take anticoagulants
Patients with coagulofibrinolytic disorders as underlying diseases
Other patients who are judged inappropriate by the principal investigator

Target sample size

120

Name of lead principal investigator

1st name	Takeshi
Middle name
Last name	WADA

Organization

Hokkaido University Hospital

Division name

Department of Emergency Medicine

Zip code

060-8648

Address

Kita-ku, N14W15, Sapporo

TEL

011-706-7377

Email

twada1@med.hokudai.ac.jp

Name of contact person

1st name	Takeshi
Middle name
Last name	WADA

Organization

Hokkaido University Hospital

Division name

Department of Emergency Medicine

Zip code

060-8648

Address

Kita-ku, N14W15, Sapporo

TEL

011-706-7377

Homepage URL

Email

twada1@med.hokudai.ac.jp

Institute

Hokkaido University Hospital

Institute

Department

Personal name

Organization

Japan Society for the Promotion of Science

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

JP

Co-sponsor

Name of secondary funder(s)

Organization

Division of Clinical Research Administration, Hokkaido University Hospital

Address

Kita-ku, N14W5, Sapporo

Tel

0117067636

Email

crjimu@huhp.hokudai.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2020

Year

01

Month

23

Day

URL releasing protocol

N/A

Publication of results

Published

URL related to results and publications

https://www.frontiersin.org/articles/10.3389/fcvm.2022.885406/full

Number of participants that the trial has enrolled

62

Results

Patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period.Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation and PIC 3 h after arriving at the hospital. This correlation was prominent in the patient population with MODS.

Results date posted

2022

Year

07

Month

29

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

There were no significant differences in age, sex, or initial rhythm of the electrocardiogram between patients from the two groups. The frequencies of witnessing the onset of cardiac arrest and bystander CPR were comparable between groups. However, the non-MODS group had a significantly higher percentage of patients with cardiogenic cardiac arrests. The CPR duration was significantly longer in the MODS group
than in the non-MODS group. Patients in the MODS group exhibited a higher DIC score on day 1 and a higher APACHE II score than those in the non-MODS group. Furthermore, the hospital survival rate was significantly higher in the non-MODS group than in the MODS group.

Participant flow

Out of the 47 patients, 12 were excluded from the study. Among the excluded patients, 11 did not achieve return of spontaneous circulation. We also excluded one patient because the samples were not treated appropriately.
In the present study, we analyzed the final cohort of 35 patients.
The patients were divided into multiple organ dysfunction (MODS) (n = 15) and non-MODS (n=20) groups.

Adverse events

N/A

Outcome measures

N/A

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2018

Year

06

Month

04

Day

Date of IRB

2018

Year

06

Month

22

Day

Anticipated trial start date

2018

Year

09

Month

03

Day

Last follow-up date

2021

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Measurement items
Histone H3, IL6, activated protein C, soluble fibrin, plasmin antiplasmin complex, soluble thrombomodulin, tPA activity, PAI1 activity

Observation items and its implementation methods
Researchers investigate the following items in patient group and use the data for this study. These are all items which are performed in daily clinical practice, and their frequency is equivalent to that in daily clinical practice.

Basic information of the objectives in this study. age, gender, weight, height, body temperature, blood pressure, pulse rate, respiratory rate, urine volume, medical past history, underlying disease, surgery, treatment, and 28 days or hospital outcome
Hematology. Ht, white blood cell counts, platelet counts
Blood biochemical tests. total bilirubin, creatinine, Na, K
Coagulation and fibrinolysis test. PT, fibrinogen, FDP, D dimer
Blood gas test. pH, PaO2, PaCO2, BE, HCO3
Various scores. APACHEII, SOFA, SIRS, DIC

Registered date

2020

Year

01

Month

23

Day

Last modified on

2022

Year

07

Month

29

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000044738