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

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 ischemia reperfusion injury simultaneously.


Table 1. Proposed neuroprotective mechanisms of therapeutic hypothermia.

Therapeutic Hypothermia in Cardiac Arrest Survivors 75

Analyses of the registries confirmed the results of clinical studies (Oksanen et al., 2007; Arrich, 2007). Several meta-analyses have however produced inconsistent results (table 3). While Holzer et al calculated that six patients have to be treated by TH to save one more life (95% CI 4–13, *p* < 0,05), Nielsens meta-analysis pointed out to some gaps in the evidence (Nielsen et al., 2010). Anyway, we have still quite firm evidence compared to other

> **DISCHARGE NEUROLOGICAL OUTCOME**

> > RR 1.68, 95%CI 1.29–2.07 favouring TH\*

RR 0.78, 95% CI 0.64-0.95 favouring TH\*

Therapeutic hypothermia is indicated in successfully resuscitated cardiac arrest patients, persistence of coma and requirement of mechanical ventilation. While there is good evidence supporting cooling of out-of-hospital adult cardiac arrest patients presenting with ventricular fibrillation, induction in other groups of in-hospital cardiac arrest patients, such as those with non-defibrillating initial rhythm and pediatric patients is supported by lower degrees of evidence (Holzer et al., 2006; Storm et al., 2008; Don et al., 2009; Polderman et al., 2003; Biarent et al., 2010; Testori et al., 2011). Nevertheless, clinical, experimental and patophysiological data suggest that hypothermia may also have protective effects in patients other than those with ventricular fibrillation OHCA. Therefore, it may be considered

Experimental data suggest that TH should be started as soon as possible after ROSC. Thus, in OHCA patients, pre-hospital initiation of cooling appears to be a method of choice and this is discussed further. On the contrary, there is weak evidence of what is an acceptable delay from ROSC to start chilling. It is generally considered that it should not be delayed

There is not any general agreement on contraindications to TH and there are differences

among the guidelines. However, Table 4 lists all conditions we should keep in mind.

<sup>2007</sup>registry 1555 - - TH: 44,6%

**6 MONTHS NEUROLOGICAL OUTCOME** 

NO TH: 32% - TH: 57%\*

RR 1.44, 95% CI 1.11–1.76 favouring TH\*

**HOSPITAL MORTALITY** 

NO TH: 32%


RR 0.84, 95%CI 0.70- 1.01 favouring TH

commonly used procedures in intensive care medicine.

Arrich, 2008 registry 650 TH: 45%\*

**NUMBER OF THE PATIENTS**

TH…therapeutic hypothermia, RR…relative risk, CI…confidence interval, \*…p<0.05 Table 3. The results of the analyses of the registries and metaanalyses.

**TYPE OF THE ANALYSIS**

<sup>2006</sup>metaanalysis 385

<sup>2010</sup>metaanalysis 478

**5. Indications and contraindications** 

reasonable to also use TH in these groups.

more than 6 hours.

**AUTHOR** 

Oksanen et al.,

Holzer et al.,

Nielsen et al.,

Hypothermia reduces cerebral metabolism by 7 % for each degree Celsius reduction in Body Temperature (BT) and reduces whole-body energy demand (Erecinska et al., 2003). Other mechanisms which play a role in hypothermia-induced neuroprotection are listed in table 1 (Ostadal, 2009; Polderman, 2009; Liu & Yenari, 2007; Busto et al., 2007; Kataoka & Yanase, 1998; Globus et al., 1995; Lei et al., 1994; Xu et al., 2002; Huang et al., 1999; Fischer et al., 1999).
