Introduction: Survival after cardiac arrest and prolonged conventional cardiopulmonary resuscitation remains poor, with out-of-hospital survival rates of only 2%–10%. Conventional veno-arterial extracorporeal membrane oxygenation or extracorporeal cardiopulmonary resuscitation can restore circulation but provides uncontrolled reperfusion, fails to prevent ischemia–reperfusion injury and offers limited physiological monitoring, resulting in inconsistent neurological outcomes. Experimental evidence indicates that tissue viability after prolonged ischemia depends not only on its duration but critically on how reperfusion is performed. Methods: Controlled reperfusion strategies, such as controlled automated reperfusion of the whole body, achieve superior preservation of neurological and multi-organ function. Building on prior single-organ reperfusion research, controlled automated reperfusion of the whole body was developed as a next-generation, portable extracorporeal membrane oxygenation-based platform for multi-organ recovery after cardiac arrest and prolonged conventional cardiopulmonary resuscitation. Results: It integrates (1) advanced extracorporeal circulation with high pressure, high flow, pulsatility and rapid hypothermia; (2) a cytoprotective regimen targeting ischemia and reperfusion injury; (3) real-time hemodynamic, metabolic and temperature monitoring; and (4) a mobile design for rapid deployment. In experimental studies, controlled automated reperfusion of the whole body achieved up to 90% survival with intact neurological function after 20 min of cardiac arrest in porcine models. First clinical applications (since 2017) demonstrated favorable outcomes even after 120 min of conventional cardiopulmonary resuscitation. A recent multicenter European study (n = 69) reported 42% overall survival, with 79% of survivors achieving favorable neurological recovery (Cerebral Performance Category 1–2) at 90 days, particularly in in-hospital cardiac arrest and pre-hospital cannulation subgroups. Conclusion: Controlled automated reperfusion of the whole body thus represents a major advance in resuscitation science, enabling controlled multi-organ recovery after prolonged whole-body ischemia.
ClarkeGMaoJHannA, et al.A reproducible extended ex-vivo normothermic machine liver perfusion protocol utilizing improved nutrition and targeted vascular flows. Comm Med2024; 4: 14.
2.
RojasSVAvsarMIusF, et al.Ex-vivo preservation with the organ care system in high risk heart transplantation. Life2022; 12: 47.
3.
DumbillRKnightSHunterJ, et al.Prolonged normothermic perfusion of the kidney prior to transplantation: a historically controlled, phase 1 cohort study. Nat Comm2025; 16: 4584.
4.
WilliamsAMTrahanasJMBommarediS, et al.Rapid recovery of donor hearts for transplantation after circulatory death. N Engl J Med2025; 393: 267–274.
5.
KuceraJAOverbeyDMTurekJW: On-Table reanimation of a pediatric heart from donation after circulatory death. New Engl J Med2025; 393: 275–280.
DowningMSakarcanEQuinnK. The history of cardiopulmonary resuscitation and where we are today. Heart2025; 6: 8.
8.
McKenzieNBallSBaileyP, et al.Neurological outcome in adult out-of-hospital cardiac arrest – not all doom and gloom!Resuscitation2021; 167: 227–232.
9.
FischerMWnentJGräsnerJT, et al.Öffentlicher Jahresbericht 2024 des Deutschen Reanimationsregisters: Außerklinische Reanimation 2024. www.reanimationsregister.de/berichte.html.
10.
MitchellOJShiXAbellaBS, et al.Mechanical cardiopulmonary resuscitation during in-hospital cardiac arrest. J. Am. Heart Assoc2023; 12: e027726.
11.
RichardsonASCSchmidtMBaileyM, et al.ECMO cardio-pulmonary resuscitation (ECPR), trends in survival from an international multicentre cohort study over 12-years. Resuscitation2017; 112: 34–40.
12.
BelohlavekJSmalcovaJRobD, et al.Effect of intra-arrest transport, extracorporeal cardiopulmonary resuscitation, and immediate invasive assessment and treatment on functional neurologic outcome in refractory out-of-hospital cardiac arrest: a randomized clinical trial. JAMA2022; 327: 737–747.
13.
SuvereinMMDelnoijTSRLorussoR, et al.: Early extracorporeal CPR for refractory out-of-hospital cardiac arrest. New Engl J Med2023; 388: 299–309.
14.
YannopoulosDBartosJRaveendranG, et al.Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomized controlled trial. Lancet2020; 396: 1807–1816.
15.
TaunyaneICBenkCBeyersdorfF, et al.Preserved brain morphology after controlled automated reperfusion of the whole body following normothermic circulatory arrest time of up to 20 minutes. Eur J Cardiothorac Surg2016; 50: 1025–1034.
16.
AllenBSKoYBuckbergGD, et al.Studies of isolated global brain ischemia. II. Controlled reperfusion provides complete neurologic recovery following 30 min of warm ischemia – the importance of perfusion pressure. Eur J Cardiothorac Surg2012a; 41: 1147–1154.
17.
AllenBSKoYBuckbergGD, et al.Studies of isolated global brain ischemia. III. Influence of pulsatile flow during cerebral perfusion and its link to consistent full neurologic recovery with controlled reperfusion following 30 min of global brain ischemia. Eur J Cardiothorac Surg2012b; 41: 1155–1163.
18.
VrseljaZDanieleSGSilbereisJ, et al.Restoration of brain circulation and cellular functions hours post-mortem. Nature2019; 568: 336–343.
19.
HossmannKAZimmermannV. Resuscitation of the monkey brain after 1 h complete ischemia. I. Physiological and morphological observations. Brain Res1974; 81: 59–74.
20.
HossmannK-ASchmidt-KastnerRGrosse OphoffB. Recovery of integrative central nervous function after one hour global cerebro-circulatory arrest in normothermic cat. J Neurol Sci1987; 77: 305–320.
21.
AndrijevicDVrseljaZLysyyT, et al.Cellular recovery after prolonged warm ischaemia of the whole bod. Nature2022; 608: 405–412.
22.
SudaIKitoKAdachiC. Viability of long term frozen cat brain in vitro. Nature1966; 212: 268–270.
23.
AthanasuleasCLBuckbergGDAllenBS, et al.Sudden cardiac death. Directing the scope of resuscitation towards the heart and the brain. Resuscitation2006; 70: 44–51.
24.
FoersterKD’InkaMBeyersdorfF, et al.Prolonged cardiac arrest and resuscitation by extracorporeal life support: favourable outcome without preceding anticoagulation in an experimental setting. Perfusion2013; 28: 520–528.
25.
FoersterKBenkCBeyersdorfF, et al.Twenty minutes of normothermic cardiac arrest in a pig model: the role of short-term hypothermia for neurological outcome. Perfusion2018; 33: 270–277.
26.
KreibichMTrummerGBeyersdorfF, et al.Improved outcome in an animal model of prolonged cardiac arrest through pulsatile high pressure controlled automated reperfusion of the whole body: animal model of prolonged CA through pulsatile high pressure CARL. Artif Organs2018; 42: 992–1000.
27.
BuckbergGD. Studies of controlled reperfusion after ischemia. I. When is cardiac muscle damaged irreversibly?J Thorac Cardiovasc Surg1986; 92: 483–487.
28.
AllenBSOkamotoFBuckbergGD, et al.Studies of controlled reperfusion after ischemia. XV. Immediate functional recovery after six hours of regional ischemia by careful control of conditions of reperfusion and composition of reperfusate. J Thorac Cardiovasc Surg1986; 92: 621–635.
29.
BeyersdorfFMatheisGKrügerS, et al.Avoiding reperfusion injury after limb revascularization: experimental observations and recommendations for clinical application. J Vasc Surg1989; 9: 757–766.
30.
MartinJLutterGIhlingC, et al.Myocardial viability twenty-four hours after orthotopic heart transplantation from non-heart-beating donors. J Thorac Cardiovasc Surg2003; 125: 1217–1228.
31.
SchlensakCDoenstTPreißerS, et al.Cardiopulmonary bypass reduction of bronchial blood flow: a potential mechanism for lung injury in a neonatal pig model. J Thorac Cardiovasc Surg2002; 123: 1199–1205.
HallCNReynellCGessleinB, et al.Capillary pericytes regulate cerebral flow in health and disease. Nature2014; 508: 55–60.
34.
AnstadtMPTedderMHegdeSS, et al.Pulsatile versus non-pulsatile reperfusion improves cerebral blood flow after cardiac arrest. Ann Thorac Surg1993; 56: 453–461.
35.
BarsanWGLevyRC. Experimental design for study of cardiopulmonary resuscitation in dogs. Ann Emerg Med1981; 10: 135–137.
36.
YuHYWangCHChiNH, et al.Effect of interplay between age and low-flow duration on neurologic outcomes of extracorporeal cardiopulmonary resuscitation. Intensive Care Med2019; 45: 44–54.
37.
StubDBernardSDuffySJ, et al.Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation2011; 123: 1428–1435.
38.
LazzarinTTononCRMartinsD, et al.Post-cardiac arrest: mechanisms, management, and future perspectives. J Clin Med2023; 12: 259.
39.
TrummerGFoersterKBuckbergGD, et al.Successful resuscitation after prolonged periods of cardiac arrest: a new field in cardiac surgery. J Thorac Cardiovasc Surg2010; 139: 1325–1332.
40.
TrummerGFoersterKBuckbergG, et al.Superior neurologic recovery after 15 minutes of normothermic cardiac arrest using an extracorporeal life support system for optimized blood pressure and flow. Perfusion2014; 29: 130–138.
41.
TrummerGBenkCBeyersdorfF. Controlled automated reperfusion of the whole body after cardiac arrest. J Thorac Dis2019; 11: S1464–S1470.
42.
TrummerGBenkCPoothJS, et al.Treatment of refractory cardiac arrest by controlled reperfusion of the whole body: a multicenter, prospective observational study. J Clin Med2024; 13: 56.
43.
BeyersdorfFTrummerGBenkC, et al.Application of cardiac surgery techniques to improve the results of cardiopulmonary resuscitation after cardiac arrest: controlled automated reperfusion of the whole body. J Thorac Cardiovasc Surg2021; 8: 47–52.
44.
DanieleSGTrummerGHossmannKA, et al.Brain vulnerability and viability after ischaemia. Nat Rev Neurosci2021; 22: 553–572.
45.
LiakopoulosOJAllenBSBuckbergGD, et al.Resuscitation after prolonged cardiac arrest: role of cardiopulmonary bypass and systemic hyperkalemia. Ann Thorac Surg2010; 89: 1972–1980.
46.
NolanJPSandroniCBöttigerBW, et al.European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Resuscitation2021; 161: 220–269.
47.
KatzABrosnahanSBPapadopoulosJ, et al.Pharmacologic neuroprotection in ischemic brain injury after cardiac arrest. Ann N Y Acad Sci2022; 1507: 49–59.
48.
PollardKGonzalesARenY, et al.Abstract Sa1105: the effect of a combination of neuroprotective medications on post-cardiac arrest survival. Circulation2024; 150. DOI: 10.1161/circ.150.suppl_1.Sa1105.
49.
YinTBeckerLBChoudharyRC, et al.Hydrogen gas with extracorporeal cardiopulmonary resuscitation improves survival after prolonged cardiac arrest in rats. J Translat Med2021; 19: 62.
50.
PoothJSBrixiusSSörensenA, et al.Reversal of no-reflow phenomenon after prolonged cardiac arrest by controlled automated reperfusion of the whole body: preliminary results of an ongoing [150] water PET study. Thorac Cardiovasc Surg2021; 69: S57–S58.
51.
BrixiusSJPoothJSHaberstrohJ, et al.Beneficial effects of adjusted perfusion and defibrillation strategies on rhythm control within controlled automated reperfusion of the whole body (CARL) for refractory out-of-hospital cardiac arrest. J Clin Med2022; 11: 2111.
52.
PoothJSLiuYPetzoldR, et al.Effects of prolonged serum calcium suppression during extracorporeal cardiopulmonary resuscitation in pigs. Biomedicines2023; 11: 2612.
53.
TrummerGSupadyABeyersdorfF, et al.Controlled automated reperfusion of the whole body after 120 min of cardiopulmonary resuscitation: first clinical report. Scand J Trauma Resusc Emerg Med2017; 25: 66.
54.
PhilippAPoothJSBenkC, et al.Enabling the control of reperfusion parameters in out-of-hospital cardiac arrest: first applications of the CARL system. Perfusion2023; 38: 436–439.
