SUDDEN CARDIAC ARREST
SUDDEN CARDIAC ARREST
Sudden cardiac arrest is the abrupt cessation of cardiac activity with complete interruption of blood flow and oxygen delivery to all organs of the body. It is a leading cause of death worldwide and affects predominantly adults in their sixties and to a lesser extent children and young adults.
In the USA, sudden cardiac arrest occurs at a disturbing rate of 1,000 cases every day.1 CPR is attempted in approximately 67% of the cases, yet survival with good neurological function is achieved in only 8.4%.1
- Virani SS et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 Mar 3;141(9):e139-e596.
Despite their vital role, resuscitation interventions often cause additional myocardial injury limiting the ability of the heart to reestablish a mechanically competent function needed for survival.
The return of oxygenated blood to an ischemic myocardium causes reperfusion injury. Repeated delivery of electrical shocks to a myocardium not energetically ready for successful resuscitation causes structural damage. Epinephrine given during CPR accentuates the myocardial energy deficit failing to promote a lasting survival benefit despite a threefold increase in the initial resuscitation rate.
At RTx, we have recognized opportunities to ameliorate resuscitation-induced myocardial injury by pharmacological targeting reperfusion injury, developing alternative vasopressor agents, and guiding the delivery of electrical shocks (and other interventions) by real-time analysis of the ventricular fibrillation waveform.
With the abrupt cessation of systemic blood flow and oxygen delivery after cardiac arrest, organs develop ischemia with severity proportional to their metabolic needs and duration of cardiac arrest.
The return of oxygenated blood during CPR causes what is known as reperfusion injury, attributed in part to the generation of reactive oxygen species and to sodium-driven cytosolic and mitochondrial calcium overload.1 Reperfusion injury affects predominantly mitochondria and hence the ability of cells to efficiently transfer energy from nutrients to molecules of ATP needed to sustain energy-requiring processes and therefore organ function.1
This process is disrupted by reperfusion injury in part by to opening of the so-called mitochondrial permeability transition pore (mPTP).1
In preclinical studies using a rat model of cardiac arrest, we have documented an inverse relationship between mPTP opening and post-resuscitation myocardial function.2 Mitochondrial injury is also accompanied by the release of cytochrome c proportional to myocardial injury.3
- Gazmuri RJ, Radhakrishnan J. Protecting mitochondrial bioenergetic function during resuscitation from cardiac arrest. Crit Care Clin. 2012 Apr;28(2):245-70.
- Ayoub IM, Radhakrishnan J, Gazmuri RJ. In vivo opening of the mitochondrial permeability transition pore in a rat model of ventricular fibrillation and closed-chest resuscitation. Am J Transl Res. 2017 Jul 15;9(7):3345-3359.
- Radhakrishnan J, Origenes R, Littlejohn G, Nikolich S, Choi E, Smite S, Lamoureux L, Baetiong A, Shah M, Gazmuri RJ. Plasma Cytochrome c Detection Using a Highly Sensitive Electrochemiluminescence Enzyme-Linked Immunosorbent Assay. Biomark Insights. 2017 Dec 13;12:1177271917746972.
We have investigated three promising pharmacological interventions which could attenuate reperfusion injury and protect mitochondria during resuscitation from cardiac arrest leading to improved outcomes.
The goal of CPR is to artificially generate blood flow when the heart is no longer beating. Yet, the blood flow generated is only a fraction of the normal cardiac output, and often fails to increase the aortic pressure and the corresponding coronary blood flow at the levels required to attenuate myocardial ischemia and help reestablish cardiac activity.
Studies at the Resuscitation Institute support strategies for more effective vasopressor therapy, including the use of NHE-1 inhibitors to attenuate the adverse myocardial effects of epinephrine3,4 and the use of alternative vasopressors agent without the adverse effect of epinephrine.5
- Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018 Aug 23;379(8):711-721.
- Gazmuri RJ, Aiello S. Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2019 Jan 24;380(4):394-5..
- Kolarova J, Yi Z, Ayoub IM, Gazmuri RJ. Cariporide potentiates the effects of epinephrine and vasopressin by nonvascular mechanisms during closed-chest resuscitation. Chest. 2005 Apr;127(4):1327-34.
- Ayoub IM, Kolarova J, Kantola RL, Sanders R, Gazmuri RJ. Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation. Crit Care Med. 2005 Nov;33(11):2599-605.
- Lamoureux L, Whitehouse K, Radhakrishnan J, Gazmuri RJ. Zoniporide combined with alpha-methylnorepinephrine promotes greater hemodynamic stability than either agent alone during chest compression in rats. Circulation 2014;130:A149 (Abstract).
We are studying more effective vasopressor therapies for CPR. Stay tuned…
With the AMSA-driven protocol, the burden of unsuccessful shocks is reduced leading to better post-resuscitation myocardial function and improved short-term survival.1 We have recently expanded our AMSA-driven protocol to also limit the administration of epinephrine to only when increasing myocardial perfusion is required for successful defibrillation and thereby reducing myocardial adrenergic burden and the consequent adverse post-resuscitation effects.2
Adjusting the depth of chest compression according to real-time assessment of forward blood flow generation is another example of multiple opportunities for a tailored resuscitation effort.3
- Aiello S, Perez M, Cogan C, Baetiong A, Miller SA, Radhakrishnan J, Kaufman CL, Gazmuri RJ. Real-Time Ventricular Fibrillation Amplitude-Spectral Area Analysis to Guide Timing of Shock Delivery Improves Defibrillation Efficacy During Cardiopulmonary Resuscitation in Swine. J Am Heart Assoc. 2017 Nov 4;6(11):e006749.
- Aiello S, Mendelson JB, Baeting A, Radhakrishnan J, Gazmuri RJ. Targeted delivery of electrical shocks and epinephrine, guided by ventricular fibrillation amplitude spectral area, reduces electrical and adrenergic myocardial burden, improving survival in swine. J Am Heart Assoc 2021;10:e023956. DOI: 10.1161/JAHA.121.023956
- Trivedi K, Borovnik-Lesjak V, Gazmuri RJ. LUCAS 2™ device, compression depth, and the 2010 cardiopulmonary resuscitation guidelines. Am J Emerg Med. 2013 Jul;31(7):1154.e1-2.