TAME Cardiac Arrest – a randomised controlled trial

TAME Cardiac Arrest is a phase III, multi-centre, randomised, parallel-group, controlled trial to determine whether targeted therapeutic mild hypercapnia (TTMH) ;improves neurological outcome at 6 months compared to standard care (targeted normocapnia (TN)) in resuscitated cardiac arrest patients who are admitted to the intensive care unit.

Goal: The hypothesis being evaluated is that, in resuscitated cardiac arrest patients admitted to ICU, TTMH improves neurological outcome at 6 months as assessed by the Glasgow Outcomes Scale Extended (GOSE) method. Fully eligible patients enrolled into this trial will be allocated to a TTMH protocol (target PaCO2 range 50 - 55 mmHg) or the Standard Care protocol (target PaCO2 range 35 - 45 mmHg) for 24 hours following randomisation. Patients in each group will be sedated to achieve moderate to deep sedation (a target Richmond Agitation Sedation Scale of -4). Arterial blood gas (ABG) and end-tidal carbon dioxide (ETCO2) levels will be measured at baseline and then used to guide respiratory rate adjustments of minute ventilation to remain within their target PaCO2 range. Importantly, ventilation management for all patients will be guided by ABG data assessed after adjustment to 37oC (alpha-stat) and, to ensure safety, the treating ICU physician can modify patients management, including the use of sedative agents, muscle relaxants and paralysis, as clinically indicated throughout the 24-hour intervention period. After the 24-hour intervention period, for patients allocated to TTMH, it is recommended that restoration of normocapnia occur slowly over the subsequent 4-hours (study time period 24 - 28 hours) facilitated by the use of ABG samples and ETCO2 levels to guide respiratory rate adjustments.

Rationale: Cardiac arrest is a common and dramatic event with major human and financial consequences. It is well understood that cardiac arrest leads to brain injury from lack of blood flow to the brain. However, what is not widely appreciated is that, even after the heart has been restarted, poor blood flow to the brain continues and can cause more brain injury. This continued poor blood flow has been repeatedly shown to happen by many complex technologies (positron emission tomography, brain vessel ultrasound, jugular bulb oxygen saturation and cerebral oximetry).

A likely reason for this continued poor brain blood flow after the heart has been restarted is the loss of the normal ability of brain blood vessel to adjust blood flow to meet the needs of the brain, a function called "autoregulation". Such impaired brain vessel auto-regulation may make even a normal blood carbon dioxide tension (PaCO2) (the major factor that normally controls brain blood flow) unable to achieve and maintain best brain blood flow and best brain oxygen levels. However, an increased PaCO2 (hypercapnia) can still increase brain blood flow in these patients. In this way, arterial carbon dioxide can be increased above normal levels to hopefully deliver best brain blood flow in patients admitted to the intensive care unit after a cardiac arrest.

The TAME Cardiac Arrest Trial is a definitive trial in cardiac arrest patients whose heart has been restarted and who are on a breathing machine in the intensive care unit. This trial will determine whether increasing carbon dioxide to above normal levels [so-called targeted therapeutic mild hypercapnia (TTMH)] during the first 24 hours on a breathing machine in the intensive care unit improves brain recovery at 6 months compared to current standard care.

Supported by strong preliminary studies, significant improvements in patient outcomes are achievable with this simple and cost free therapy. TAME Cardiac Arrest has a recruitment target of 1,700 patients and will be conducted in multiple sites in many countries. If the TAME Cardiac Arrest Trial confirms that TTMH is effective, its findings will improve the lives of many and transform clinical practice.

Study Progress: The TAME Cardiac Arrest trial received NHMRC funding in November 2016 and Irish Health Research Board (Irish HRB) funding in March 2017. Patient recruitment is anticipated to begin in December 2017, with follow-up, data cleaning and data lock in June 2022.

Trial Registration: ClinicalTrials.gov NCT03114033, ANZCTR 12617000036314p

Contact: For further information about this study, please contact the ANZIC-RC Project Managers Bridget Ady (Mon, Tue, Thu) and Vanessa Singh (Wed); and Principal Investigator Glenn Eastwood by email.

Bridget Ady Vanessa Glen

Publications:

1. Schneider AG, Eastwood GM, Bellomo R, Bailey M, Lipcsey M, Pilcher D, Young P, Stow P, Santamaria J, Stachowski E, Suzuki S, Woinarski NC, Pilcher J. Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest. Resuscitation 2013;84:927-34.
2. Eastwood GM, Tanaka A, Bellomo. Cerebral oxygenation in mechanically ventilated early cardiac arrest survivors: The impact of hypercapnia. Resuscitation 2016;102:108-114.
3. Eastwood GM, Schneider AG, Suzuki S, Bailey M, Bellomo R; CCC trial investigators. A pilot feasibility, safety and biological efficacy study protocol for a randomised trial. Trials 2015;16:135.
4. 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, Archer JS, Bernard S, Stub D, Hart GK, Bellomo R. Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre ranodmised controlled trial (the CCC trial). Resuscitation 2016;104:83-90.