|Year : 2017 | Volume
| Issue : 6 | Page : 10-13
TAME cardiac arrest: A phase III multicenter randomized trial of targeted therapeutic mild hypercapnia after resuscitated cardiac arrest
Glenn M Eastwood1, Alistair Nichol2, Rinaldo Bellomo1, Yaseen Arabi3
1 Austin Hospital; Australia and New Zealand Intensive Care Research Centre, Monash University, Victoria, Melbourne, Australia
2 Australia and New Zealand Intensive Care Research Centre, Monash University, Victoria; Alfred Hospital, Melbourne, Australia; Irish Critical Care-Clinical Research Network, University College Dublin/St Vincent's University Hospital, Dublin, Ireland
3 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdualaziz Medical City, Riyadh, Saudi Arabia
|Date of Web Publication||23-Nov-2017|
Glenn M Eastwood
Department of Intensive Care, 145 Studley Road, Heidelberg, Victoria 3084
Source of Support: None, Conflict of Interest: None
Cardiac arrest (CA) is a catastrophic world-wide health problem with substantial human and financial costs. Ongoing cerebral vasoconstriction and cerebral hypoxia during the early post-resuscitation period may contribute to the often poor neurological outcome in CA survivors. Arterial carbon dioxide (PaCO2) is the major determinant of cerebral blood flow and an increased PaCO2 (hypercapnia) markedly increases cerebral blood flow and oxygenation. This paper reports on the background and method of The TAME Cardiac Arrest trial (Clinicaltrials.gov (NCT03114033) which is a phase III multi-center, randomized, parallel-group, controlled trial. The trial will determine if targeted therapeutic mild hypercapnia (TTMH) (PaCO250-55mmHg) during mechanical ventilation improves neurological outcome at 6 months compared to targeted normocapnia (TN) (PaCO235-45 mmHg) in resuscitated CA patients. The intervention is cost-free and will be applied over the first 24-hours of ICU care. A total of 1700 adult resuscitated CA patients from ICUs around the world will be enrolled. When completed the TAME Cardiac Arrest trial will provide unprecedented insights that will transform the care of resuscitated CA patients admitted to the intensive care unit (ICU) around the world. Moreover, this therapy is cost free and, if shown to be effective, will improve thousands of lives, transform clinical practice, and yield major financial savings.
Keywords: Cardiac arrest, hypercapnia, intensive care medicine, mechanical ventilation, resuscitation
|How to cite this article:|
Eastwood GM, Nichol A, Bellomo R, Arabi Y. TAME cardiac arrest: A phase III multicenter randomized trial of targeted therapeutic mild hypercapnia after resuscitated cardiac arrest. Saudi Crit Care J 2017;1, Suppl S2:10-3
|How to cite this URL:|
Eastwood GM, Nichol A, Bellomo R, Arabi Y. TAME cardiac arrest: A phase III multicenter randomized trial of targeted therapeutic mild hypercapnia after resuscitated cardiac arrest. Saudi Crit Care J [serial online] 2017 [cited 2018 Mar 17];1, Suppl S2:10-3. Available from: http://www.sccj-sa.org/text.asp?2017/1/6/10/219129
| Introduction|| |
This report focuses our attention on the personal and societal impacts of cardiac arrest (CA), on the neurological injury cascade resulting from a CA that leads to neurological injury, and on the potential role that early targeted carbon dioxide management may play in improving neurological outcomes in resuscitated CA survivors. In particular, this report describes the potential therapeutic benefits associated with targeting and sustaining mild hypercapnia during the early postresuscitation period. Specifically, the aim, outcomes, intervention, and processes associated with the TAME CA trial are presented. Completion of the TAME CA trial will provide unprecedented insights that will transform the care of resuscitated CA patients admitted to the Intensive Care Unit (ICU) around the world.
| Cardiac Arrest is a Major Health Problem|| |
CA is a major health problem with ~350,000 cases in Europe , and ~25,000 cases in Australia  each year, with mortality rates varying between 87% and 94%. For resuscitated out-of-hospital CA (OHCA) patients who are admitted to an ICU, survival remains unacceptably low at around 40%., For those who die in the ICU, the dominant reason for death or withdrawal of life support is devastating neurological injury. With a majority of individuals being of working age, the personal, financial, and societal costs associated with the initial care and rehabilitation of CA patients remain substantial., Efforts to attenuate the impact of neurological injury during the early postresuscitation period appear the logical target and desperately needed. Emerging evidence is beginning to support targeted interventions for both oxygenation and ventilation for resuscitated CA patients.
| Cardiac Arrest, Neurological Injury, and Carbon Dioxide|| |
CA is the sudden loss of heart function, breathing, and consciousness. At the time of the CA there is immediate brain ischemia and resuscitation leads to reperfusion injury with acute neuronal damage. Many CA survivors experience significant ongoing social and cognitive difficulties., These difficulties may be related to cerebral hypoperfusion and cerebral hypoxia that are experienced during the early postresuscitation period.,,, Investigations, using positron emission tomography, middle cerebral artery blood flow assessment via Doppler ultrasound, jugular bulb oxygen saturation, and cerebral oximetry, have all consistently showed sustained hypoperfusion and cerebral hypoxia in the resuscitated CA patient. An impaired cerebrovascular autoregulation may be the likely pathophysiological mechanism responsible for sustained early cerebral hypoperfusion., Such impaired autoregulation may make a normal arterial carbon dioxide tension (PaCO2) insufficient to maintain adequate cerebral perfusion and cerebral oxygenation. However, PaCO2 is the major determinant of cerebral blood flow in humans , and under normal physiological conditions hypercapnia increases cerebral blood flow., Moreover, studies have demonstrated that elevated PaCO2 levels have anticonvulsive, anti-inflammatory, and anti-oxidant properties that may lessen the inflammatory component of reperfusion injury., Importantly, PaCO2 is an easily modifiable physiological variable and therefore a potential therapeutic target for optimizing cerebral perfusion and oxygenation in resuscitated OHCA patients.,
| Mild Hypercapnia after Cardiac Arrest|| |
Previously, Australian-based investigators performed a large, multicenter, retrospective observational study in which they evaluated the association of early PaCO2 values ( first 24 h) in 16,542 CA patients with clinical outcomes admitted to 125 ICUs in Australia and New Zealand between 2000 and 2011. These investigators found that the occurrence of hypocapnia (PaCO2 <35 mmHg) carried a higher mortality rate and a lower likelihood of discharge home for survivors compared with normocapnia (PaCO2 35–45 mmHg). In contrast, hypercapnia (PaCO2 >45 mmHg) was not associated with increased mortality but was independently associated with a 16% increase in the likelihood of being discharged, suggesting both safety and a potential neurological benefit. Other observational studies, also evaluating adult resuscitated CA patients admitted to ICU, indicate that in survivors hypercapnia is independently associated with improved neurological outcomes, while hypocapnia is associated with worse neurological outcomes., For example, Finnish investigators studied 409 OHCA patients admitted to ICU and studied the independent relationship between PaCO2 levels in ICU and neurological outcome as assessed by the cerebral performance category method at 12 months. These investigators found that hypercapnia was independently associated with improved neurological outcome. Collectively, the emerging evidence is indicating that targeting mild hypercapnia and avoiding hypocapnia may be of major importance to cerebral protection and recovery among resuscitated OHCA survivors who are admitted to ICU [Table 1].
|Table 1: Six key points associated with the cardiac arrest and the TAME trial|
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| The TAME Cardiac Arrest Trial|| |
The TAME Cardiac Arrest trial is a phase III multicenter, randomized, parallel group, controlled trial (Clinicaltrials.gov [NCT03114033]). The aim of this trial is to determine whether targeted therapeutic mild hypercapnia (TTMH) during mechanical ventilation improves neurological outcome at 6 months compared to targeted normocapnia (TN) in resuscitated CA patients.
The primary outcome is the proportion of patients with a favorable neurological outcome at 6 months as assessed using the Glasgow Outcome Scale Extended (GOSE). The GOSE uses an 8-level scale from death (1) to upper good recovery (8) and can be administered by proxy or direct patient interview. A GOSE outcome is deemed to be favorable if a patient scores ≥5 [Figure 1]. Secondary outcomes include mortality during ICU and hospital stay at 6 months, functional and cognitive recovery, safety, and a health economic.
|Figure 1: The primary outcome measure for the TAME Cardiac Arrest trial is the proportion of patients with a favorable neurological outcome at 6 months as assessed using the Glasgow Outcome Scale Extended. A Glasgow Outcome Scale Extended outcome is deemed to be favorable (green/solid arrow) if a patient scores ≥5|
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Sample size and setting
Participating centers will enroll a total of 1700 resuscitated adult OHCAs. ICUs from multiple countries and regions throughout the world such as Australia, New Zealand, Hong Kong, Singapore, Western Europe, Saudi Arabia, Scandinavia, Ireland, and the United Kingdom will participate in TAME.
Adult resuscitated OHCA patients who have return of spontaneous circulation in 20 minutes or less and are admitted to a participating study site will be screened for enrollment. Full eligibility criteria are shown in [Table 2]. Each enrolled participant will be randomized to receive either the TTMH or TN protocol, briefly described below. The participant experience is summarized in [Figure 2].
|Table 2: Eligibility criteria for patients to be enrolled into the TAME cardiac arrest trial|
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|Figure 2: Participant flow for resuscitated out-of-hospital cardiac arrest patients enrolled into the TAME Cardiac Arrest trial in which the participants experience their cardiac arrest outside the hospital (marked as “x”), is screened, enrolled, and randomized; the intervention period of 24 h (applied between the “o” points) with follow-up time points being Intensive Care Unit discharge, hospital discharge at 6 months and 2 years. PaCO2; arterial carbon dioxide|
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Targeted therapeutic mild hypercapnia protocol
Patients allocated to the TTMH protocol will be sedated to achieve moderate-to-deep sedation (a target Richmond Agitation Scale Score of –3 to –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 h for 24 h following randomization or if end-tidal carbon dioxide values change >5 mmHg.
Targeted normocapnia protocol
Patients allocated to the standard care (TN) protocol will be managed according to the current practice and recent guidelines which recommend maintaining normocapnia in these patients. Patients will be sedated to achieve moderate-to-deep sedation (a target Richmond Agitation Scale Score of –3 to –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 h for 24 h following randomization or if end-tidal carbon dioxide values change >5 mmHg.
After the 24-h intervention period, the treating clinician will determine the target PaCO2 range with all other hospital care delivered in accordance with the local existing best practice protocols and international guideline recommendations. To evaluate the patient-centered outcomes, participants are followed up at 30 days, 6 months, and 2 years after enrollment into the study.
To help us better understand why people react differently following a CA, a biomarker substudy will also be conducted. The information drawn from this sub-study will collect blood tissue samples from participants (at baseline, 24, 48, and 72 h following randomization). This could be related to genetic factors or the extent of brain or heart injury or inflammation that occurs during the early postresuscitation period. The findings of this biomarker substudy may help us develop a test that will inform best practice decisions in the future.
| Summary|| |
CA represents a major health problem that affects thousands of individuals around the world annually. The financial and personal costs associated with CA are substantial. Undertaking studies to evaluate therapeutic interventions to improve the often devastating consequences of neurological injury following CA is desperately warranted. During the early postresuscitated period, the brain experiences ongoing and persistent cerebral hypoperfusion and cerebral hypoxia that may be attenuated by the targeted mild hypercapnia. In response, and supported by compelling preliminary data, to evaluate the potential therapeutic role of PaCO2, a multidisciplinary multinational team of investigators are conducting the TAME CA trial. If TTMH therapy, applied during the early postresuscitation period, is shown to be effective, the lives of countless CA survivors will be improved, clinical practice will be transformed, and major financial and human cost savings will be realized.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gräsner JT, Lefering R, Koster RW, Masterson S, Böttiger BW, Herlitz J, et al.
EuReCa ONE-27 nations, ONE Europe, ONE registry: A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe. Resuscitation 2016;105:188-95.
Böttiger BW, Gräsner JT, Castren M. Sudden cardiac death: Good perspectives with this major health care issue. Intensive Care Med 2014;40:907-9.
Victorian Cardiac Arrest Registry. VACAR Annual Report 2013-2014. Victoria: Victorian Cardiac Arrest Registry; 2014.
Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation 2010;81:1479-87.
Schneider AG, Eastwood GM, Bellomo R, Bailey M, Lipcsey M, Pilcher D, et al.
Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest. Resuscitation 2013;84:927-34.
Lemiale V, Dumas F, Mongardon N, Giovanetti O, Charpentier J, Chiche JD, et al.
Intensive care unit mortality after cardiac arrest: The relative contribution of shock and brain injury in a large cohort. Intensive Care Med 2013;39:1972-80.
Petrie J, Easton S, Naik V, Lockie C, Brett SJ, Stümpfle R, et al.
Hospital costs of out-of-hospital cardiac arrest patients treated in intensive care; a single centre evaluation using the national tariff-based system. BMJ Open 2015;5:e005797.
The Economic Cost of Spinal Cord Injury and Traumatic Brain Injury in Australia. Melbourne, Australia: Access Economics for Victorian Neurotrauma Initiative (TAC); 2009.
Wiklund L, Martijn C, Miclescu A, Semenas E, Rubertsson S, Sharma HS, et al.
Central nervous tissue damage after hypoxia and reperfusion in conjunction with cardiac arrest and cardiopulmonary resuscitation: Mechanisms of action and possibilities for mitigation. Int Rev Neurobiol 2012;102:173-87.
Polanowska KE, Sarzyńska-Długosz IM, Paprot AE, Sikorska S, Seniów JB, Karpiński G, et al.
Neuropsychological and neurological sequelae of out-of-hospital cardiac arrest and the estimated need for neurorehabilitation: A prospective pilot study. Kardiol Pol 2014;72:814-22.
Andrew E, Nehme Z, Wolfe R, Bernard S, Smith K. Long-term survival following out-of-hospital cardiac arrest. Heart 2017;103:1104-10.
Ahn A, Yang J, Inigo-Santiago L, Parnia S. A feasibility study of cerebral oximetry monitoring during the post-resuscitation period in comatose patients following cardiac arrest. Resuscitation 2014;85:522-6.
Buunk G, van der Hoeven JG, Meinders AE. Cerebral blood flow after cardiac arrest. Neth J Med 2000;57:106-12.
Koch KA, Jackson DL, Schmiedl M, Rosenblatt JI. Total cerebral ischemia: Effect of alterations in arterial PCO2 on cerebral microcirculation. J Cereb Blood Flow Metab 1984;4:343-9.
Sundgreen C, Larsen FS, Herzog TM, Knudsen GM, Boesgaard S, Aldershvile J, et al.
Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest. Stroke 2001;32:128-32.
Beckstead JE, Tweed WA, Lee J, MacKeen WL. Cerebral blood flow and metabolism in man following cardiac arrest. Stroke 1978;9:569-73.
Curley G, Laffey JG, Kavanagh BP. Bench-to-bedside review: Carbon dioxide. Crit Care 2010;14:220.
O'Croinin D, Ni Chonghaile M, Higgins B, Laffey JG. Bench-to-bedside review: Permissive hypercapnia. Crit Care 2005;9:51-9.
Meng L, Gelb AW. Regulation of cerebral autoregulation by carbon dioxide. Anesthesiology 2015;122:196-205.
Kavanagh BP, Laffey JG. Hypercapnia: Permissive and therapeutic. Minerva Anestesiol 2006;72:567-76.
Tolner EA, Hochman DW, Hassinen P, Otáhal J, Gaily E, Haglund MM, et al.
Five percent CO2
is a potent, fast-acting inhalation anticonvulsant. Epilepsia 2011;52:104-14.
Eastwood GM, Tanaka A, Bellomo R. Cerebral oxygenation in mechanically ventilated early cardiac arrest survivors: The impact of hypercapnia. Resuscitation 2016;102:11-6.
Eastwood GM, Schneider AG, Suzuki S, Peck L, Young H, Tanaka A, et al.
Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial). Resuscitation 2016;104:83-90.
Eastwood GM, Young PJ, Bellomo R. The impact of oxygen and carbon dioxide management on outcome after cardiac arrest. Curr Opin Crit Care 2014;20:266-72.
Vaahersalo J, Bendel S, Reinikainen M, Kurola J, Tiainen M, Raj R, et al.
Arterial blood gas tensions after resuscitation from out-of-hospital cardiac arrest: Associations with long-term neurologic outcome. Crit Care Med 2014;42:1463-70.
Smith K, Andrew E, Lijovic M, Nehme Z, Bernard S. Quality of life and functional outcomes 12 months after out-of-hospital cardiac arrest. Circulation 2015;131:174-81.
Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: Guidelines for their use. J Neurotrauma 1998;15:573-85.
[Figure 1], [Figure 2]
[Table 1], [Table 2]