ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12612000690853

Ethics application status

Approved

Date submitted

27/06/2012

Date registered

27/06/2012

Date last updated

14/12/2018

Date data sharing statement initially provided

14/12/2018

Date results provided

14/12/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Therapeutic hypercapnia after cardiac arrest: a pilot feasibility and safety randomized controlled trial

Scientific title

Therapeutic hypercapnia after cardiac arrest: a pilot feasibility and safety randomized controlled trial

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cardiac arrest

Condition category

Condition code

Cardiovascular

Coronary heart disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Immediately after randomization, the minute ventilation (as defined by the respiratory rate and tidal volume) will be set on the ventilator to aim for target PaCO2 between 50 and 55 mmHg for patients allocated to the intervention (“High PaCO2”) group and between 35 and 45 mmHg for patients allocated to the control (“normal PaCO2” group). To ensure that PaCO2 is and remains within the desired range, PaCO2 will be measured hourly on arterial blood gases and continuous end tidal CO2 (ETCO2) monitoring will be performed. ETCO2 is a measure of the highest alveolar concentration of CO2 at the end of expiration. It is assumed to represent CO2 partial pressure in alveolar gas, which, in normal lungs, closely parallels arterial levels of CO2. Hence, ETCO2, provides a convenient continuous approximation of PaCO2.

At the end of the 24 hours study period, the target PaCO2 will be set to normal (35-45 mmHg) for patients in both groups for the remainder of time that patients receive mechanical ventilation.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Normal group - Target normal arterial carbon dioxide tension (PaCO2) to 35-45 mmHg for the first 24 hours after cardiac arrest.

Control group

Dose comparison

Outcomes

Primary outcome [1]

Differences in neuron specific enolase and S-100 protein serum concentration between patients allocated to high PaCO2 50-55 mmHg and Normal PaCO2 35-45 mmHg targets in the first 24 hours after intensive care admission for cardiac arrest.

Timepoint [1]

neuron specific enolase (NSE) and S-100 protein serum concentration at baseline, 24, 48 and 72 hours.

Secondary outcome [1]

Safety outcomes:
- averse changes in NSE and S100b (at 24 h, 48 h and 72 h)
- averse acid-base balance
- averse changes in oxygenation (mean PaO2, FiO2, alveoloar-arterial gradient, positve end expiratory pressure requirement)
- cardiac arrhythmias: incidence and type
- averse findings of cardiac echocardiography or cerebral computerised tomography
- Renal: incidence and severity of acute kidney injury as estimated by urinary output, serum creatinine concentration (RIFLE score) and need for renal replacement therapy
- Liver: liver function tests including coagulation tests
- occurence of cerebral oxdema or right ventricular failure

Timepoint [1]

Baseline, 24, 48 and 72 hours. 6 month follow-up of neurological recovery via interview.

Secondary outcome [2]

Feasibility outcomes will be assess via medical record audit and tabulation of the site screening/patient assessment log. The feasibility outcomes for this study are: - Separation in PaCO2 between two groups - Distribution of values for primary and secondary outcome - Randomized / Screened patients ratio - Consent rate - Data completion rate - Loss to follow-up rate - Recruitment duration and Protocol adherence.

Timepoint [2]

From randomisation through to 6 month completion

Secondary outcome [3]

General outcomes will be assessed via medical record audit at the completion of the study and a patient/next-of-kin interview to assess recovery at 6 months via the Glascow outcome score-extended (GOSE):
- Total duration of mechanical ventilation
- Intensive care length of stay
- Hospital length of stay (date of discharge)
- Discharge vital status (alive vs dead)
- Discharge destination (home, other acute hospital, rehabilitation hospital, aged care)
- Glasgow outcome score-extended (6 Mo after admission)

Timepoint [3]

From randomisation to 6 month completion

Eligibility

Key inclusion criteria

- Non-traumatic, in- or out-of-hospital cardiac arrest with successful resuscitation (return of spontaneous circulation)
- Mechanical ventilation

Minimum age

18 Years

Maximum age

100 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Spontaenous ventilation
- Death considered immiment
- Clinical or Computerized Tomography suspicion of raised intra-cranial pressure
- Cardiac arrest secondary to intracranial bleed
- Pregnancy
- Age <18 years
- Severe chronic airflow limitation
- Severe metabolic acidosis (base deficit > 6 mEq/L)
- Severe acidemia (pH<7.1)
- Transfered from another healthcare facility
- Participation declined by the treating clinician

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Randomization will be by means of sealed envelopes with permuted blocks of variable size.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permute block randomisation will be used in this study to allocated patients to treatment groups.

Each envelope will contain a study arm allocation with the PaCO2 target as well as a copy of a simplified version of the study protocol.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Immediate randomisation of patient to target group on arrival to the intensive care unit.

Phase

Not Applicable

Type of endpoint/s

Safety

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/10/2012

Actual

23/11/2012

Date of last participant enrolment

Anticipated

31/12/2014

Actual

6/01/2017

Date of last data collection

Anticipated

30/06/2018

Actual

10/07/2017

Sample size

Target

380

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Hospital

Recruitment hospital [2]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

North Island

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health - Anaesthesia Intensive Care Trust Fund

Address [1]

Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Road
Heidelberg VIC 3084

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Professor Rinaldo Bellomoo

Address [1]

Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

145 Studley Road
Heidelberg VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

17/07/2012

Approval date [1]

06/10/2014

Ethics approval number [1]

H2012/04737

Ethics committee name [2]

Health and Disability Ethics Committees

Ethics committee address [2]

Ministry of Health
1 the Terrace
PO Box 5013
Wellington
6011

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

29/03/2013

Approval date [2]

21/05/2013

Ethics approval number [2]

13/NTA/54

Summary

Brief summary

Cardiac arrest is a relatively common and devastating event in Australia and New Zealand (ANZ). It is associated with extremely high mortality. A large proportion of those who survive are left with serious neurological disability. Such disability includes memory loss, paralysis and difficulty in thinking and speaking. These deficits often lead to a loss of independence and the need to be admitted to aged-care facilities.

Immediate cardio-pulmonary resuscitation and defibrillation by bystanders has only partly improved the outcome of these patients. For those who survive the immediate phase and are admitted to the intensive care unit, actively decreasing the body temperature to 33-34 degrees C has been shown to protect the brain. Although limited, these results suggest that some interventions after cardiac arrest can improve brain outcome. Perhaps other interventions could lead to similar results and further improve patient’s recovery and quality of life after cardiac arrest. 

In a recent observational study in 12,000 ANZ patients who were admitted in ICU after a cardiac arrest, we found that those who had an elevated partial pressure of carbon dioxide (PaCO2) in the 24 hours following the cardiac arrest had a higher chance of having a satisfactory neurological recovery. These patients were 20% more likely to be able to go back home at the end of their hospital stay as compared with those whose PaCO2 was either in the normal or low range. These findings are similar to those seen in previous animal studies. They also make physiological sense: a higher PaCO2 is known to trigger an increase in the amount of blood directed towards the brain. An increase in brain blood flow after a cardiac arrest (a state of no flow) should be logically associated with a higher chance of recovery. However, these findings need to be confirmed by prospective trials before they can be applied to all patients with a cardiac arrest. 

PaCO2 is normally controlled by the lungs and its arterial partial pressure is directly related to the rate and amplitude of the breathing process. After a cardiac arrest, patients typically are unconscious or heavily sedated by medication and their breathing process is almost entirely taken care of by a ventilator (breathing machine). In such circumstances, the PaCO2 is determined by the medical team. Currently, a “normal” value for PaCO2 (35-45 mmHg) is targeted by clinicians. However, changing this target value to 50-55 mmHg, would be technically easy to implement and carry no extra cost. 

Based on the findings of our retrospective study (Schneider et al, Resuscitation 2013), on animal studies and logic, we hypothesize that a higher PaCO2 in the first 24 hours after cardiac arrest will be associated with less neurological injury and be feasible and safe. To test this hypothesis, we plan to randomly allocate 75 patients admitted to ICU after cardiac arrest to either “High PaCO2” or “Control” group.  

The pan to enrol 75 participants is purposeful.  This approahc willl provide the means to obtain a complete set of brain biomarker samples (those being baseline, 24 hour, 36 hour and 72 hour) for a total of 50 participants.

The key outcomes of interest would be whether such trial can be done, whether this therapy appears safe and whether it decreases blood test-based markers of brain injury (brain proteins like neuron specific enolase and S100 protein), indicating that a biological benefit is taking place.

Trial website

Trial related presentations / publications

Public notes

Attachments [1]

/AnzctrAttachments/362691-20141006 LETTER - 04737 HREC13Austin166 OOS - Amendment SERP RH - ethics approval.pdf

Attachments [2]

/AnzctrAttachments/362691-20140825 - Protocol V4_Therapeutic hypercapnia after cardiac arrest - clean.docx

Attachments [3]

/AnzctrAttachments/362691-HREC13Austin166_Full Approval.pdf

Contacts

Principal investigator

Name

Prof Professor Rinaldo Bellomo

Address

Austin Hospital Department of Intensive Care 145 Studley Road Heidelberg VIC 3084

Country

Australia

Phone

+61 3 9496 5992

Fax

+61 3 9496 3932

rinaldo.bellomo@austin.org.au

Contact person for public queries

Name

Professor Rinaldo Bellomo

Address

Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61 3 9496 5992

Fax

+61 3 9496 3932

rinaldo.bellomo@austin.org.au

Contact person for scientific queries

Name

Professor Rinaldo Bellomo

Address

Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61 3 9496 5992

Fax

+61 3 9496 3932

rinaldo.bellomo@austin.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Current Study Results

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Plain language summary	No		In cardiac arrest patients admitted to the intenis... [More Details]

Update to Study Results

Doc. No.	Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
2910	Study results article	No	https://doi.org/10.1016/j.resuscitation.2016.03.023	Eastwood GM, Schneider AG, Suzuki S, Peck L, Young... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: Study protocol for a randomized controlled trial.	2015	https://dx.doi.org/10.1186/s13063-015-0676-3
Embase	Haemodynamic and ventilator management in patients following cardiac arrest.	2015	https://dx.doi.org/10.1097/MCC.0000000000000205

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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Documents added manually

Documents added automatically