Cardiac & Resuscitation, Exclusives, Heart of America, Top Story

Preventing Reperfusion Injury During Cardiac Arrest

Reperfusion injury is linked with several pathophysiological pathways leading to cell apoptosis. The metabolic processes associated with reperfusion injury are well described in the setting of a myocardial infarction and CVA and more recently in the setting of cardiac arrest. These processes include pro-apoptotic signaling and inflammatory response.

The mitochondria plays a critical role and mitochondrial transition pore (MTP) opening and calcium release are important determinant in the apoptosis signaling.1,2 Increased no-flow and low-flow duration as well as poor quality of CPR are associated with more severe reperfusion injury.3

Return of spontaneous circulation is achieved in 20–40% of out-of-hospital cardiac arrests (OHCA) with resuscitation attempted.3 For these patients, reperfusion injury is responsible for increased in-hospital mortality, and consequently 40–50% of them will survive to be discharged from hosptial.3,4 Moreover, survivors frequently have persistent subtle cognitive impairment and some have severe neurological deficit.5,6 In addition, some have persistent heart failure.

Therapeutic strategies developed to improve cardiac arrest survival (e.g., epinephrine use, extracorporeal CPR, etc.) may be successful in terms of increased survival but are often limited by the increase rate of reperfusion injury associated with prolonged CPR.7

Several strategies targeting different pathways have been developed in an effort to limit these lesions. First, optimizing CPR quality is a key component in order to limit reperfusion injury.8 Second, post-resuscitation care that targets normal oxygenation (avoiding hyper or hyopoxia), normocapnia, and normal blood pressure post ROSC seem to be of major importance.4

Recently, new research has focused on specific therapeutic options to try to limit these injuries. Targeted temperature management is one of the most studied. Its effects are multifactorial and target different pathways, providing an overall decrease in global metabolism proportional with core temperature.9,10

Several inhaled gases have also been studied (e.g., xenon, argon, sevoflurane, nitrous oxide), with promising results in preclinical and clinical studies.11–13

Sodium nitroprusside, a potent vasodilator, has also been associated with improvement in survival and a decrease in reperfusion injuries in animal studies.14–16

Ischemic post conditioning—using a series of 3–4 short (20–30 seconds) controlled pauses at the very start of CPR is associated with a decrease in myocardial infarction size and increased survival in animal models.17,18 The use of a bundle of care to prevent reperfusion injury is associated with survival with an extremely long no-flow duration (17 minutes) in an animal model.13

Reperfusion injury protection remains one of the most important challenges in cardiac arrest research. It’s unlikely that one drug or therapy will be able to succeed alone in preventing reperfusion injury. Use of a bundled approach to CPR and post-resuscitation care that includes one or more interventions known to reduce reperfusion injury is essential. At present, therapeutic hypothermia is the most widely used means to reduce perfusion injury and use of this modality should be broadly encouraged.


1. Bartos JA, Debaty G, Matsuura T, et al. Post-conditioning to improve cardiopulmonary resuscitation. Curr Opin Crit Care. 2014;20(3):242–249.

2. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121–35.

3. Gräsner JT, Lefering R, Koster RW, 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;105:188–195.

4. Nolan JP, Soar J, Cariou A, et al. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015. Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation. 2015;95:202–22.

5. Wilder Schaaf KP, Artman LK, Peberdy MA, et al. Anxiety, depression, and PTSD following cardiac arrest: A systematic review of the literature. Resuscitation. 2013;84(7):873–877.

6. Sulzgruber P, Kliegel A, Wandaller C, et al. Survivors of cardiac arrest with good neurological outcome show considerable impairments of memory functioning. Resuscitation. 2015;88:120–125.

7. Perkins GD, Ji C, Deakin CD, et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest. N Engl J Med. 2018;379(8):711–721.

8. Lurie KG, Nemergut EC, Yannopoulos D, et al. The physiology of cardiopulmonary resuscitation. Anesth Analg. 2016;122(3):767–783.

9. Holzer M. Targeted temperature management for comatose survivors of cardiac arrest. N Engl J Med. 2010;363(13):1256–1264.

10. Hassager C, Nagao K, Hildick-Smith D. Out-of-hospital cardiac arrest: In-hospital intervention strategies. Lancet. 2018;391(10124):989–998.

11. Laitio R, Hynninen M, Arola O, et al. Effect of inhaled xenon on cerebral white matter damage in comatose survivors of out-of-hospital cardiac arrest: A randomized clinical trial.. JAMA. 2016;315(11):1120–1128.

12. Zuercher P, Springe D, Grandgirard D, et al. A randomized trial of the effects of the noble gases helium and argon on neuroprotection in a rodent cardiac arrest model. BMC Neurol. 2016;16:43.

13. Bartos JA, Matsuura TR, Sarraf M, et al. Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest. Resuscitation. 2015;87:7–13.

14. Yannopoulos D, Matsuura T, Schultz J, et al. Sodium nitroprusside enhanced cardiopulmonary resuscitation improves survival with good neurological function in a porcine model of prolonged cardiac arrest. Crit Care Med. 2011;39(6):1269–1274.

15. Debaty G, Matsuura TR, Bartos JA, et al. Sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra-arrest therapeutic hypothermia in a porcine model of prolonged ventricular fibrillation. Crit Care Med. 2015;43(4):849–855.

16. Yannopoulos D, Bartos JA, George SA, et al. Sodium nitroprusside enhanced cardiopulmonary resuscitation improves short term survival in a porcine model of ischemic refractory ventricular fibrillation. Resuscitation. 2017;110:6–11.

17. Debaty G, Lurie K, Metzger A, et al. Reperfusion injury protection during Basic Life Support improves circulation and survival outcomes in a porcine model of prolonged cardiac arrest. Resuscitation. 2016;105:29–35.

18. Moore JC, Bartos JA, Matsuura TR, et al. The future is now: Neuroprotection during cardiopulmonary resuscitation. Curr Opin Crit Care. 2017;23(3):215–222.