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How Ischemic Post-conditioning Can Help the Cardiac Arrest Patient

cerebral-recovery

A change is coming in cardiac arrest care. As return of spontaneous circulation (ROSC) rates improve in the prehospital setting, the focus is shifting toward improving neurologic outcomes: We need to save brains, not just hearts. (Even though saving the heart is the stepping-stone to successful brain resuscitation, at least for the present and near future.)

Ischemic post-conditioning (IPC) is a procedure that has been studied in both animals and humans as a way of protecting the heart and brain cells from reperfusion injury after prolonged ischemia.(1–3) IPC works at the cellular level to reduce reperfusion injury. The idea is to turn perfusion on and off, alternating short bursts of blood flow with short controlled pauses of flow that cause intermittent short ischemic episodes through a variety of methods. A small number of these quick on/off bursts are thought to trigger a cascade of cellular protection mechanisms that reduce myocardial injury in ischemic hearts (such as during myocardial infarctions), and improve brain function, such as post-cardiac arrest neurological recovery.(4–7)

The benefits of IPC in humans have been seen in the cardiac catheterization labs during angioplasty. Independent research in 2003 showed that two minutes of global ischemia (post-conditioning) after prolonged ventricular fibrillation (v fib) in isolated rat hearts led to a 100% ROSC rate where hearts that didn’t receive global ischemia had no return of spontaneous contraction.(8) Research has shown that stuttering reperfusion to the brain during treatment of acute strokes, as well as global ischemia, shows promise in decreasing neurologic injury.(3,9)

Cardiac Arrest Management
In “Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation,” published in the November 2012 issue of Resuscitation, the researchers explored the role IPC may play in prehospital cardiac arrest management. Eighteen swine were randomized into two groups of nine. All animals were sedated with ketamine and inhaled isoflurane gas, placed into v fib via electric current and left untreated for 15 minutes. After 15 minutes, a control group of nine animals received standard CPR, while the other nine received IPC followed by standard CPR.

The IPC group received four cycles of on/off CPR, with 20 seconds of “on the chest” CPR (performing compressions) followed by 20 seconds of hands off time. During that time ventilation was also stopped to avoid ventilation-induced blood flow via intrathoracic pressure mechanisms.(10) The animals then received uninterrupted standard CPR with defibrillation and epinephrine. All successfully resuscitated animals received 12 hours of post-arrest cooling.

In the standard CPR group, eight of nine swine achieved ROSC; however, after 48 hours, only one animal from the standard CPR group survived. It had severe neurological deficit and a cerebral performance category (CPC) score of 3 out of 5 (1 indicates normal neurological function, 4 indicates being in a deep coma and 5 brain dead). It’s interesting to note that no animals with a CPC score of 4 or 5 survived past 24 hours.(11)

In the IPC group, all nine animals achieved ROSC, with eight animals surviving to 48 hours. All animals in the IPC group had a positive neurological outcome (CPC score of 1–2).

In “Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation,” a 2013 follow-up study published in Resuscitation, researchers from the same group have found that, in the same type of animals, IPC decreases troponin and Creatine Kinase-MB (CK-MB) elevation at four and 24 hours post ROSC while significantly decreasing ischemic histological injury of the brain minimizing neuronal death. Those findings are complimentary to the clinical-based outcomes reported in the November study. They suggest that IPC offers cellular protection from reperfusion injury in a large mammalian model of cardiac arrest.

Although the 2013 study sample was small, this research has large implications. We know that prolonged pauses in CPR throughout the resuscitative effort lead to poor outcomes; however, study authors were looking at finessed, calculated pauses early in CPR, followed by standard, high quality ACLS care. With the addition of impedance threshold devices (ITDs), early defibrillation, high-quality CPR and post-arrest cooling, resuscitation rates could continue to climb. Previously reviewed research on ischemic post-conditioning with the use of sodium nitroprusside, a potent vasodilator, showed equally as promising results. There is a strong potential for synergy between flow optimizing CPR methods coupled with interventions to minimize reperfusion injury.

Looking Forward
This promising research paves the way for human trials to come. Trials of this magnitude will require extensive training with all levels of EMS providers because the first few minutes of many cardiac arrests are managed by the layperson or a first responder. Pre-arrival instructions by dispatchers could be tinkered to allow the layperson to perform IPC CPR before the first responding units even arrive. Mechanical CPR devices, could be reprogrammed for arrests where no bystander CPR has been performed. In that setting, they could be applied and provide IPC in a highly efficient and reproducible way. Look for exciting research to come.

References
1. Tsang A, Hausenloy DJ, Yellon DM. Myocardial postconditioning: Reperfusion injury revisited. Am J Physiol Heart Circ Physiol. 2005;289(1):H2–H7.
2.  Rohilla A, Rohilla S, Kushnoor A. Myocardial postconditioning: Next step to cardioprotection. Arch Pharm Res. 2011;34(9):1409–1415.
3.  Zhao H. Ischemic postconditioning as a novel avenue to protect against brain injury after stroke.
J Cereb Blood Flow Metab. 2009;29(5):873–885.
4.  Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation. 2005;112(14):2143–2148.
5.  Sun HY, Wang NP, Halkos M, et al. Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis. 2006;11(9):1583–1593.
6.  Mykytenko J, Reeves JG, Kin H, et al. Persistent beneficial effect of postconditioning against infarct size: Role of mitochondrial k(atp) channels during reperfusion. Basic Res Cardiol. 2008;103(5):472–484.
7.  Wang JK, Yu LN, Zhang FJ, et al. Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3k/Akt pathway. Brain Res. 2010;1357:142–151.
8.  Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: Comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285(2):H579–H588.
9. Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke. 2008;39(3):983–990.
10.  Chandra NC, Beyar R, Halperin HR. Vital organ perfusion during assisted circulation by manipulation of intrathoracic pressure. Circulation. 1991;84(1):279–286.
11.  Segal N, Matsuura T, Caldwell E, et al. Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation. Resuscitation. 2012;83(11):1397–1403.



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