Trial Review

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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 information initially 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] 280743 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiac arrest 286792 0
Condition category
Condition code
Cardiovascular 287103 287103 0 0
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] 285169 0
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] 287424 0
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] 287424 0
neuron specific enolase (NSE) and S-100 protein serum concentration at baseline, 24, 48 and 72 hours.
Secondary outcome [1] 298113 0
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] 298113 0
Baseline, 24, 48 and 72 hours. 6 month follow-up of neurological recovery via interview.
Secondary outcome [2] 298118 0
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] 298118 0
From randomisation through to 6 month completion
Secondary outcome [3] 298119 0
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] 298119 0
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?
No
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
86
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1052 0
Austin Hospital
Recruitment hospital [2] 1639 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 1640 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 6912 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 5101 0
New Zealand
State/province [1] 5101 0
North Island

Funding & Sponsors
Funding source category [1] 285527 0
Hospital
Name [1] 285527 0
Austin Health - Anaesthesia Intensive Care Trust Fund
Country [1] 285527 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 284369 0
Individual
Name [1] 284369 0
Professor Rinaldo Bellomoo
Address [1] 284369 0
Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084
Country [1] 284369 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287548 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 287548 0
145 Studley Road
Heidelberg VIC 3084
Ethics committee country [1] 287548 0
Australia
Date submitted for ethics approval [1] 287548 0
17/07/2012
Approval date [1] 287548 0
06/10/2014
Ethics approval number [1] 287548 0
H2012/04737
Ethics committee name [2] 289319 0
Health and Disability Ethics Committees
Ethics committee address [2] 289319 0
Ministry of Health
1 the Terrace
PO Box 5013
Wellington
6011
Ethics committee country [2] 289319 0
New Zealand
Date submitted for ethics approval [2] 289319 0
29/03/2013
Approval date [2] 289319 0
21/05/2013
Ethics approval number [2] 289319 0
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] 201 201 0 0
/AnzctrAttachments/362691-20141006 LETTER - 04737 HREC13Austin166 OOS - Amendment SERP RH - ethics approval.pdf
Attachments [2] 202 202 0 0
/AnzctrAttachments/362691-20140825 - Protocol V4_Therapeutic hypercapnia after cardiac arrest - clean.docx
Attachments [3] 203 203 0 0
/AnzctrAttachments/362691-HREC13Austin166_Full Approval.pdf

Contacts
Principal investigator
Name 34369 0
Prof Professor Rinaldo Bellomo
Address 34369 0
Austin Hospital Department of Intensive Care 145 Studley Road Heidelberg VIC 3084
Country 34369 0
Australia
Phone 34369 0
+61 3 9496 5992
Fax 34369 0
+61 3 9496 3932
Email 34369 0
[email protected]
Contact person for public queries
Name 17616 0
Prof Professor Rinaldo Bellomo
Address 17616 0
Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084
Country 17616 0
Australia
Phone 17616 0
+61 3 9496 5992
Fax 17616 0
+61 3 9496 3932
Email 17616 0
[email protected]
Contact person for scientific queries
Name 8544 0
Prof Professor Rinaldo Bellomo
Address 8544 0
Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084
Country 8544 0
Australia
Phone 8544 0
+61 3 9496 5992
Fax 8544 0
+61 3 9496 3932
Email 8544 0
[email protected]

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
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo In cardiac arrest patients admitted to the intenis... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: Study protocol for a randomized controlled trial.2015https://dx.doi.org/10.1186/s13063-015-0676-3
EmbaseHaemodynamic and ventilator management in patients following cardiac arrest.2015https://dx.doi.org/10.1097/MCC.0000000000000205
N.B. These documents automatically identified may not have been verified by the study sponsor.