Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest

Out-Of-Hospital Cardiac Arrest Clinical Trial

— TAME  

Official title:

TAME Cardiac Arrest Trial: Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest: A Phase III Multi-Centre Randomised Controlled Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03114033
• Other study ID #: ANZIC-RC/SB001
• Status: Active, not recruiting
• Phase: N/A
• Start date: February 15, 2018
• Est. completion date: December 2022

Study information

• Verified date: April 2022
• Source: Australian and New Zealand Intensive Care Research Centre
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The TAME Cardiac Arrest trial will study the ability of higher arterial carbon dioxide (PaCO2) levels to reduce brain damage, comparing giving patients 'normal' to 'slightly higher than normal' blood PaCO2 levels and assessing their ability to return to normal life-tasks. It will be the largest trial ever conducted in heart attack patients in the intensive care unit. This therapy is cost free and, if shown to be effective, will improve thousands of lives, transform clinical practice, and yield major savings.

Description:

Cardiac arrest is a common and catastrophic event with substantial human and financial costs. It is well understood that cardiac arrest leads to brain injury. However, what is not widely appreciated is that, after circulation has been restored, cerebral hypoperfusion continues. Ongoing cerebral vasoconstriction and cerebral hypoxia has been demonstrated using technologies that include positron emission tomography, ultrasound, jugular bulb oxygen saturation and cerebral oximetry.

A likely mechanism responsible for sustained early cerebral hypoperfusion relates to impaired cerebrovascular auto-regulation. Such impaired cerebral auto-regulation may make even a normal arterial carbon dioxide tension (PaCO2) (the major physiological regulator of cerebral blood flow) insufficient to achieve and maintain adequate cerebral perfusion and, consequently, cerebral oxygenation. However, PaCO2 is the major determinant of cerebral blood flow and an increased PaCO2 (hypercapnia) markedly increases cerebral blood flow. Moreover, arterial carbon dioxide is modifiable and, as such, is a potential therapeutic target.

The TAME Cardiac Arrest Trial is a definitive phase III multi-centre randomised controlled trial in resuscitated cardiac arrest patients. This trial will determine whether targeted therapeutic mild hypercapnia (TTMH) applied during the first 24 hours of mechanical ventilation in the intensive care unit (ICU) improves neurological outcome at 6 months compared to standard care (targeted normocapnia (TN).

Supported by compelling preliminary data, significant improvements in patient outcomes are achievable with this proposed simple and cost free therapy. Recruiting 1,700 patients, for multiple sites in many countries, this will be the largest trial ever conducted involving resuscitated cardiac arrest patients admitted to the ICU. If the TAME Cardiac Arrest Trial confirms that TTMH is effective, its findings will improve the lives of many, transform clinical practice and yield major economic gains worldwide.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1700
• Est. completion date: December 2022
• Est. primary completion date: December 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult (age =18 years or older)

• Out-of-hospital cardiac arrest of a presumed cardiac or unknown cause

• Sustained ROSC - defined as 20 minutes with signs of circulation without the need for chest compressions

• Unconscious (FOUR-score motor response of <4, not able to obey verbal commands after sustained ROSC) (Appendix D)

• Eligible for intensive care without restrictions or limitations

• Within <180 minutes of ROSC

Exclusion Criteria:

• Unwitnessed cardiac arrest with an initial rhythm of asystole

• Temperature on admission <30oC

• On ECMO prior to ROSC

• Obvious or suspected pregnancy

• Intracranial bleeding

• Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy

Related Conditions & MeSH terms

• Heart Arrest
• Hypercapnia
• Out-Of-Hospital Cardiac Arrest

Intervention

Other:
• Targeted therapeutic mild hypercapnia
Patients allocated to the TTMH protocol will be sedated to achieve moderate to deep sedation (a target Richmond Agitation Scale Score of -4). Arterial blood gases and end- tidal carbon dioxide levels will be measured at baseline and then used to guide respiratory rate adjustments of minute ventilation to remain within the target PaCO2 range of 50-55 mmHg. Arterial blood gases will be repeated every 4 hours for 24 hours following randomisation or if end-tidal carbon dioxide values change >5 mmHg
• Targeted normocapnia (Standard care)
Patients allocated to the standard care (TN) protocol will be managed according to current practice and in accordance with ILCOR guidelines which recommend maintaining normocapnia in these patients. They will be sedated to achieve moderate to deep sedation (a target Richmond Agitation Scale Score of - 4). Arterial blood gases and end-tidal carbon dioxide levels will be measured at baseline and then used to guide respiratory rate adjustments of minute ventilation to remain within the target PaCO2 range of 35-45 mmHg. Arterial blood gases will be repeated every 4 hours for 24 hours following randomisation or if end-tidal carbon dioxide values change >5 mmHg.

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Adelaide	South Australia
Australia	Ballarat Base Hospital	Ballarat	Victoria
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Prince Charles Hospital	Chermside	Queensland
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	The Northern Hospital	Epping	Victoria
Australia	University Hospital Geelong	Geelong	Victoria
Australia	Alfred Health	Melbourne	Victoria
Australia	Austin Health	Melbourne	Victoria
Australia	Footscray Hospital-Western Health	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Sunshine Hospital-Western Health	Melbourne	Victoria
Australia	Nepean Hospital	Penrith	New South Wales
Australia	Gold Coast University Hospital	Southport	Queensland
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Nambour Hospital	Sunshine Coast	Queensland
Australia	Sunshine Coast University Hospital	Sunshine Coast	Queensland
Australia	Royal Darwin Hospital	Tiwi	Northern Territory
Australia	Wollongong Hospital	Wollongong	New South Wales
Belgium	Cliniques Universitaires de Bruxelles Hospital Erasme	Bruxelles
Belgium	Ziekenhuis Oost-Limburg AV	Genk
Belgium	University Hospital Ghent	Gent
Denmark	Aarhus University Hospital	Aarhus
Finland	Helsinki University Central Hospital	Helsinki
France	CHRU Jean Minjoz Besancon	Besancon	Franche Comte
Ireland	Beaumont Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	St. Vincent's University Hospital	Dublin
Ireland	University Hospital Galway	Galway
Italy	Ospedale San Raffaele	Milan
Netherlands	Amsterdam University Medical Centre	Amsterdam
New Zealand	North Shore Hospital	Auckland
New Zealand	Auckland City Hospital CVICU	Grafton	Auckland
New Zealand	Auckland City Hospital DCCM	Grafton	Auckland
New Zealand	Wellington Regional Hospital	Newtown	Wellington
New Zealand	Middlemore Hospital	Otahuhu	Auckland
New Zealand	Christchurch Hospital	Riccarton	Christchurch
New Zealand	Rotorua Hospital	Rotorua
Norway	Oslo University Hospital - Ullevål	Oslo
Saudi Arabia	King Abdulaziz Medical City	Riyadh
Slovenia	University Medical Centre Maribor	Maribor
Sweden	Skane Region-Helsingborg	Helsingborg
Sweden	Skane Region Malmö	Malmö
United Kingdom	Royal Victoria Hospital Belfast	Belfast
United Kingdom	Birmingham University Hospital	Birmingham
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Bristol Royal Infirmary	Bristol
United Kingdom	University Hospital Wales	Cardiff
United Kingdom	Queen Alexandra Hospital Portsmouth	Cosham	Portsmouth
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	Royal Berkshire Hospital	Reading

Sponsors (3)

Lead Sponsor	Collaborator
Australian and New Zealand Intensive Care Research Centre	Health Research Board, Ireland, National Health and Medical Research Council, Australia

Countries where clinical trial is conducted

Australia,  Belgium,  Denmark,  Finland,  France,  Ireland,  Italy,  Netherlands,  New Zealand,  Norway,  Saudi Arabia,  Slovenia,  Sweden,  United Kingdom, 

References & Publications (1)

Eastwood GM, Schneider AG, Suzuki S, Peck L, Young H, Tanaka A, Mårtensson J, Warrillow S, McGuinness S, Parke R, Gilder E, Mccarthy L, Galt P, Taori G, Eliott S, Lamac T, Bailey M, Harley N, Barge D, Hodgson CL, Morganti-Kossmann MC, Pébay A, Conquest A, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality Adjust Life Years (QALYs)	Quality Adjust Life Years (QALYs)	6 months after randomisation
Other	Health economic evaluation	Evaluation of hospital and post-discharge estimates of costs at 6 months	6 months after randomisation
Other	Pneumonia	Pneumonia as defined by the presence of increased or purulent trachael secretions, new or progressive radiographic infiltrate and a decreased arterial oxygen tension fraction of inspired oxygen ratio of less than 240 mmHg or less than 32 kPa	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Other	Sepsis and septic shock	Sepsis and septic shock according to the third international consensus definitions for sepsis and septic shock as published in the journal JAMA 2016;315:801-810	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Other	Bradycardia	Bradycardia requiring pacing	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Other	Moderate or severe bleeding	Moderate or severe bleeding according to the GUSTO criteria as reported in the journal N Engl J Med 1993;329:673-82	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Other	Cooling device-related skin complications	Cooling device-related skin complications as defined as being blistering or skin necrosis in areas covered by surface device.	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Other	Arrhythmia	Arrhythmia that results in haemodynamic compromise (for example ventricular fibrillation and ventricular tachycardia).	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Primary	Neurological outcome	Proportion of patients with a favourable (score =5) neurological outcome as assessed using the Glasgow Outcomes Score Extended (GOSE) method.	6 months following enrolment
Secondary	Mortality at intensive care unit discharge	Mortality at intensive care unit discharge	6 months after randomisation
Secondary	Mortality at hospital discharge	Mortality at hospital discharge	6 months after randomisation
Secondary	Health-related Quality of Life (EQ-5D-5L)	Health-related Quality of Life (EQ-5D-5L) at 6 months	6 months after randomisation
Secondary	modified Rankin scale (mRS)	modified Rankin scale (mRS) with favourable score of equal to or less than 3	6 months after randomisation
Secondary	Montreal Cognitive Assessment (MoCA-blind)	Montreal Cognitive Assessment (MoCA-blind) at 6 months	6 months after randomisation
Secondary	Mortality at 6 months	Mortality at 6 months	6 months after randomisation
Secondary	Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE)	IQCODE	6 months after randomisation
Secondary	Symbol Digit Modality Test	SDMT at 6 months	6 months after randomisation