Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Out-Of-Hospital Cardiac Arrest
• Intervention / Treatment: Other: Targeted therapeutic mild hypercapnia; Other: Targeted normocapnia (Standard care)

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 1700
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital Sydney
    • Penrith, New South Wales, Australia, 2750
      • Nepean Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Wollongong, New South Wales, Australia, 2500
      • Wollongong Hospital
  • Northern Territory
    • Tiwi, Northern Territory, Australia, 0810
      • Royal Darwin Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Chermside, Queensland, Australia, 4032
      • Prince Charles Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Sunshine Coast, Queensland, Australia, 4560
      • Nambour Hospital
    • Sunshine Coast, Queensland, Australia, 4575
      • Sunshine Coast University Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 3929
      • Flinders Medical Centre
  • Victoria
    • Ballarat, Victoria, Australia, 3350
      • Ballarat Base Hospital
    • Epping, Victoria, Australia, 3076
      • The Northern Hospital
    • Geelong, Victoria, Australia
      • University Hospital Geelong
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health
    • Melbourne, Victoria, Australia, 3011
      • Footscray Hospital-Western Health
    • Melbourne, Victoria, Australia, 3021
      • Sunshine Hospital-Western Health
• Belgium
  • Bruxelles, Belgium, 1070
    • Cliniques Universitaires de Bruxelles Hospital Erasme
  • Genk, Belgium, 3600
    • Ziekenhuis Oost-Limburg AV
  • Gent, Belgium, 9000
    • University Hospital Ghent
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital
• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Central Hospital
• France
  • Franche Comte
    • Besancon, Franche Comte, France, 25000
      • CHRU Jean Minjoz Besancon
• Ireland
  • Dublin, Ireland, Dublin 9
    • Beaumont Hospital
  • Dublin, Ireland, Dublin 4
    • St. Vincent's University Hospital
  • Dublin, Ireland, Dublin 8
    • St. James's Hospital
  • Galway, Ireland, H91 YR71
    • University Hospital Galway
• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele
• Netherlands
  • Amsterdam, Netherlands, 1105
    • Amsterdam University Medical Centre
• New Zealand
  • Auckland, New Zealand, 0622
    • North Shore Hospital
  • Rotorua, New Zealand, 3010
    • Rotorua Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital CVICU
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital DCCM
    • Otahuhu, Auckland, New Zealand, 2025
      • Middlemore Hospital
  • Christchurch
    • Riccarton, Christchurch, New Zealand, 8011
      • Christchurch Hospital
  • Wellington
    • Newtown, Wellington, New Zealand, 6021
      • Wellington Regional Hospital
• Norway
  • Oslo, Norway, 0450
    • Oslo University Hospital - Ulleval
• Saudi Arabia
  • Riyadh, Saudi Arabia, 14611
    • King Abdulaziz Medical City
• Slovenia
  • Maribor, Slovenia, 2000
    • University Medical Centre Maribor
• Sweden
  • Helsingborg, Sweden, 25437
    • Skane Region-Helsingborg
  • Malmö, Sweden, 21421
    • Skane Region Malmö
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Royal Victoria Hospital Belfast
  • Birmingham, United Kingdom, B15 2TH
    • Birmingham University Hospital
  • Bournemouth, United Kingdom, BH7 7DW
    • Royal Bournemouth Hospital
  • Bristol, United Kingdom, BS2 8HW
    • Bristol Royal Infirmary
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital Wales
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary
  • Reading, United Kingdom, RG1 5AN
    • Royal Berkshire Hospital
  • Portsmouth
    • Cosham, Portsmouth, United Kingdom, PO6 3LY
      • Queen Alexandra Hospital Portsmouth

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Targeted therapeutic mild hypercapnia; Target arterial carbon dioxide range of 50-55 mmHg for 24 hours following randomisation	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
Active Comparator: Targeted normocapnia (Standard care); Target arterial carbon dioxide range of 35-45 mmHg for 24 hours following randomisation	Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at intensive care unit discharge	Mortality at intensive care unit discharge	6 months after randomisation
Mortality at hospital discharge	Mortality at hospital discharge	6 months after randomisation
Health-related Quality of Life (EQ-5D-5L)	Health-related Quality of Life (EQ-5D-5L) at 6 months	6 months after randomisation
modified Rankin scale (mRS)	modified Rankin scale (mRS) with favourable score of equal to or less than 3	6 months after randomisation
Montreal Cognitive Assessment (MoCA-blind)	Montreal Cognitive Assessment (MoCA-blind) at 6 months	6 months after randomisation
Mortality at 6 months	Mortality at 6 months	6 months after randomisation
Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE)	IQCODE	6 months after randomisation
Symbol Digit Modality Test	SDMT at 6 months	6 months after randomisation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality Adjust Life Years (QALYs)	Quality Adjust Life Years (QALYs)	6 months after randomisation
Health economic evaluation	Evaluation of hospital and post-discharge estimates of costs at 6 months	6 months after randomisation
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.
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.
Bradycardia	Bradycardia requiring pacing	Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
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.
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.
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.

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborators: National Health and Medical Research Council, Australia; Health Research Board, Ireland
• Investigators: Principal Investigator: Glenn M Eastwood, RN, PhD, Monash University

Publications and helpful links

General Publications

• Eastwood GM, Schneider AG, Suzuki S, Peck L, Young H, Tanaka A, Martensson 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, Pebay A, Conquest A, Archer JS, Bernard S, Stub D, Hart GK, Bellomo R. Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial). Resuscitation. 2016 Jul;104:83-90. doi: 10.1016/j.resuscitation.2016.03.023. Epub 2016 Apr 7.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2018
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: April 11, 2017
• First Submitted That Met QC Criteria: April 11, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Intensive Care Unit; Mortality; Cardiac Arrest; Neurological function; Therapeutic Mild Hypercapnia; Normocapnia
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Signs and Symptoms, Respiratory; Heart Arrest; Out-of-Hospital Cardiac Arrest; Hypercapnia
• Other Study ID Numbers: ANZIC-RC/SB001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No