**Therapeutic Hypothermia in Cardiac Arrest Survivors**

Roman Škulec

*Emergency Medical Service of the Central Bohemian Region, Department of Anesthesiology and Intensive Care, Charles University in Prague, Faculty of Medicine in Hradec Kralove, University Hospital Hradec Kralove Czech Republic* 

#### **1. Introduction**

70 Coronary Interventions

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In Europe, cardiac arrest is the leading cause of death. Summary data indicate that the annual incidence of out-of-hospital cardiac arrest (OHCA) treated by Emergency medical systems is 38 per 100,000 population (Atwood et al., 2005). Survival is an estimated 10 % for all initial rhythms. Return of spontaneous circulation (ROSC) is followed by the development of post-cardiac arrest syndrome (PCAS), including post-cardiac arrest brain injury. This has been identified as the main cause of death and the condition limiting a long term quality of life (Edgren et al., 1994). Therapeutic hypothermia (TH) has became a cornerstone of early post-resuscitation care in cardiac arrest survivors (Nolan et al., 2008). So far, it has been the only known post-cardiac arrest intervention which can reduce the risk of unfavourable neurological outcome and decrease mortality. After an advisory statement of the International Liaison Committee on Resuscitation endorsed the use of TH in 2003, it was recommended as a standard therapeutic procedure in cardiac arres patients in the 2005 and 2010 guidelines for resuscitation and emergency cardiac care of the European Resuscitation Council and the American Heart Association (Nolan et al., 2005; Deakin et al., 2011). Accurate and safe management during the procedure of TH is a prerequisite for achieving the optimal neuroprotective effect. Moreover, the combination of TH along with other procedures (urgent myocardial revascularization, goal-directed haemodynamic support, control of blood glucose, ventilation and seizures) improves the goal of reaching a good neurological outcome (Sunde et al., 2007). This chapter summarizes patophysiological aspects of PCAS, the evidence supporting TH and significant aspects of its practice.

#### **2. Pathophysiology of post-cardiac arrest syndrome**

The return of spontaneous circulation after severe complete whole-body ischemia is an unnatural pathophysiological state created by successful cardiopulmonary resuscitation. It is followed by a number of undesirable processes leading to the development of PCAS. The following four key clinical components of PCAS have been identified: a) post-cardiac arrest brain injury, b) post-cardiac arrest myocardial dysfunction, c) systemic ischemia/reperfusion response, and d) persistent precipitating pathology (Nolan et al., 2008). While some of the processes develop very early during cardiac arrest, others follow

Therapeutic Hypothermia in Cardiac Arrest Survivors 73

adrenaline during CPR (Tang et al., 1995). On the other hand, post-cardiac arrest myocardial stunnig is a reversible condition and can be reversed by catecholamines (Vasquez et al., 2004). Critical whole-body ischemia during cardiac arrest, even if followed by successful reperfusion, is a very potent trigger for the whole-body immune system response. It is termed the systemic inflammatory response syndrome (SIRS) and represents a serious condition related to systemic inflammation and organ dysfunction. The underlying mechanism for development of SIRS is induced cytokine storm accompanied by activation of leucocytes and platelets, endothelial dysfunction and coagulopathy. Relative acute

Cardiac arrest does not develop on it's own but it is a complication of other underlying diseases. Persistent precipitating pathology may have a negative impact on further outcome, especially when it is a critical disease like extensive acute myocardial infarction, massive

Hundreds of substances have been studied to find some with clinically signifiant neuroprotective effect. However, promising pilot experimental results were always followed by further experimental or clinical failure. It is generally considered that the main reason for failure is the complexity of ischemia-reperfusion injury which can not be attenuated or reversed by a substance affecting only one specific metabolic pathway. On the other side, hypothermia is a robust non-specific intervention having an impact on all processes of

reduction of vascular permeability decrease of intracelullar calcium blood-brain barrier stabilizing effect supression of nitric oxide production

cell membrane stabilizing effect supress neutrophil and microglia

prevention of mitochondrial dysfunction • supression of cerebral metabolism

• antiapoptotic effect inhibition of glutamate excessive

inhibition of caspase activation decrease of oxygen and glucose

prevention of cytochrome c release attenuation of thermo-pooling

Table 1. Proposed neuroprotective mechanisms of therapeutic hypothermia.

supression of oxygen free radical

reduces production of matrix

formation

production

activation

release

consumption

phenomenon

metalloproteinases

adrenal insufficiency may worsen the course of the disease (Hékimian et al., 2004).

**3. Underlying mechanisms of protection by therapeutic hypothermia** 

• antiedematic effect • anti-inflammatory effect

• cellular protection supression of interleukin 6

pulmonary embolism, etc.

ischemia reperfusion injury simultaneously.

adjustment of cerebral blood flow to

dna preservation from oxygen free radical-

metabolic demand

mediated damage

later on after the return of spontaneous circulation, thus allowing potential space for therapeutic intervention.

Post-cardiac arrest brain injury is the most serious condition limiting long term quality of life of cardiac arrest survivors. Figure 1 summarizes the mechanisms leading to this condition (Škulec R et al., 2009).

Fig. 1. Cellular and subcellular mechanisms of post-cardiac arrest brain injury. ATP … adenosine triphosphate, NMDA … N-methyl-D-aspartate receptor, AMPA … amino-3-hydroxy-5-metylisoxazole-4-propionate receptor, NO … nitric oxide, VMK … free fatty acids, ARCH … arachidonate, COX … cyclo-oxygenase, LOX … lipo-oxygenase, DNA … deoxyribonucleotic acid.

Triggering of the glutamate neuroexcitatory cascade plays a crucial role. Cardiac arrest leads to excessive glutamate release followed by an overflow of calcium to neurons via N-methyl-D-aspartate receptor stimulation. This is a potent trigger of the metabolic and inflammatory pathways causing neuronal necrosis and apoptosis. Increased intracellular calcium pool activates phosphatases and proteases, which causes neuronal damage, phospholipases responsible for oxygen free radical formation and nitric oxide synthase activation, which enhances proinflammatory nitric oxide production. Nitric oxide also opens the apoptotic pathway via activation of proapoptotic genes of the Bcl-2 family, causing mitochondrial damage, cytochrome C release, activation of caspases and endonucleases resulting in DNA fragmentation and programmed neuronal death. Glial cell activation potentiates an undesirable proinflammatory cascade. This very complex deleterious response to global cerebral ischemia is amplified by impaired cerebral perfusion due to failed blood flow autoregulation and by microthrombi formation in small vessels due to activated coagulation (Nolan et al., 2008).

Post-cardiac arrest systolic and diastolic myocardial dysfunction is a common phenomenon of multifactorial origin. It is supposed that decreased cardiac output may contribute to the unfavourable outcome (Laver et al., 2004). Myocardial stunning has been identified as the main underlying mechanism (Laurent et al., 2002; Checchia et al., 2003). Moreover, myocardial dysfunction may be worsened through the administration of high doses of

later on after the return of spontaneous circulation, thus allowing potential space for

Post-cardiac arrest brain injury is the most serious condition limiting long term quality of life of cardiac arrest survivors. Figure 1 summarizes the mechanisms leading to this

Fig. 1. Cellular and subcellular mechanisms of post-cardiac arrest brain injury. ATP … adenosine triphosphate, NMDA … N-methyl-D-aspartate receptor, AMPA … amino-3-hydroxy-5-metylisoxazole-4-propionate receptor, NO … nitric oxide, VMK … free fatty acids, ARCH … arachidonate, COX … cyclo-oxygenase, LOX … lipo-oxygenase, DNA

Triggering of the glutamate neuroexcitatory cascade plays a crucial role. Cardiac arrest leads to excessive glutamate release followed by an overflow of calcium to neurons via N-methyl-D-aspartate receptor stimulation. This is a potent trigger of the metabolic and inflammatory pathways causing neuronal necrosis and apoptosis. Increased intracellular calcium pool activates phosphatases and proteases, which causes neuronal damage, phospholipases responsible for oxygen free radical formation and nitric oxide synthase activation, which enhances proinflammatory nitric oxide production. Nitric oxide also opens the apoptotic pathway via activation of proapoptotic genes of the Bcl-2 family, causing mitochondrial damage, cytochrome C release, activation of caspases and endonucleases resulting in DNA fragmentation and programmed neuronal death. Glial cell activation potentiates an undesirable proinflammatory cascade. This very complex deleterious response to global cerebral ischemia is amplified by impaired cerebral perfusion due to failed blood flow autoregulation and by microthrombi formation in small vessels due to activated coagulation

Post-cardiac arrest systolic and diastolic myocardial dysfunction is a common phenomenon of multifactorial origin. It is supposed that decreased cardiac output may contribute to the unfavourable outcome (Laver et al., 2004). Myocardial stunning has been identified as the main underlying mechanism (Laurent et al., 2002; Checchia et al., 2003). Moreover, myocardial dysfunction may be worsened through the administration of high doses of

therapeutic intervention.

condition (Škulec R et al., 2009).

… deoxyribonucleotic acid.

(Nolan et al., 2008).

adrenaline during CPR (Tang et al., 1995). On the other hand, post-cardiac arrest myocardial stunnig is a reversible condition and can be reversed by catecholamines (Vasquez et al., 2004).

Critical whole-body ischemia during cardiac arrest, even if followed by successful reperfusion, is a very potent trigger for the whole-body immune system response. It is termed the systemic inflammatory response syndrome (SIRS) and represents a serious condition related to systemic inflammation and organ dysfunction. The underlying mechanism for development of SIRS is induced cytokine storm accompanied by activation of leucocytes and platelets, endothelial dysfunction and coagulopathy. Relative acute adrenal insufficiency may worsen the course of the disease (Hékimian et al., 2004).

Cardiac arrest does not develop on it's own but it is a complication of other underlying diseases. Persistent precipitating pathology may have a negative impact on further outcome, especially when it is a critical disease like extensive acute myocardial infarction, massive pulmonary embolism, etc.
