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.

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.

Cardiac Arrest, Intensive Care Unit, Therapeutic Mild Hypercapnia, Normocapnia, Mortality, Neurological function

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

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.

Proportion of patients with a favourable (score ≥5) neurological outcome as assessed using the Glasgow Outcomes Score Extended (GOSE) method.

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 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.

Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.

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 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 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.

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

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.