Effects of mild hypothermia therapy on the levels of glutathione in rabbit blood and cerebrospinal fluid after cardiopulmonary resuscitation

Document Type : Original Article


Department of Intensive Care Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China


Objective(s): The aim of this study wasto investigate the effects of mild hypothermia therapy on oxidative stress injury of rabbit brain tissue after cardiopulmonary resuscitation (CPR).

Materials and Methods: Rabbit models of cardiac arrest were established. After the restoration of spontaneous circulation, 50 rabbits were randomly divided into normothermia and hypothermia groups. The following five time points were selected: before CPR, immediately after CPR, 2 hr after CPR (hypothermia group reached the target temperature), 14 hr after CPR (hypothermia group before rewarming), and 24 hr after CPR (hypothermia group recovered to normal temperature). Glutathione (GSH) concentrations in both the blood and cerebrospinal fluid of the normothermia and hypothermia groups were measured.

Results:At 2, 14, and 24 hr after CPR, the GSH concentrations in both the blood and cerebrospinal fluid were significantly higher in the hypothermia group than in the nomorthermia group.

Conclusion:Mild hypothermia therapy may increase GSH concentrations in rabbit blood and cerebrospinal fluid after CPR as well as promote the recovery of cerebral function.


1.Madl C, Kramer L, Domanovits H, Woolard RH, Gervais H, Gendo A, et al. Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment. Crit Care Med 2000; 28:721-726.
2.Zakaria MM, Hajipour B, Khodadadi A, Afshari F. Ameliorating effects of dexpanthenol in cerebral ischaemia reperfusion induced injury in rat brain. J Pak Med Assoc 2011; 61:889-892.
3.Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013; 369:2197-2206.
4.Zhang H, Zhang JJ, Mei YW, Sun SG, Tong ET. Effects of immediate and delayed mild hypothermia on endogenous antioxidant enzymes and energy metabolites following global cerebral ischemia. Chin Med J (Engl) 2011; 124:2764-2766.
5.Kern KB. Optimal treatment of patients surviving out-of-hospital cardiac arrest. JACC Cardiovasc Interv 2012; 5:597-605.
6.Polderman KH.Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence. Intensive Care Med 2004; 30:556-575.
7.He FM, Zhang YJ, Li LD, Liang ZR, Xu WC, Wei H, et al. Rabbit model of heart arrest by tracheal occlusion asphyxia. Chin J Exp Surg 2004; 21:375-376.
8.Yapca OE, Turan MI, Borekci B, Akcay F, Suleyman H. Bilateral ovarian ischemia/reperfusion injury and treatment options in rats with an induced model of diabetes. Iran J Basic Med Sci 2014; 17:294-302.
9.Najafi M. Effects of postconditioning, preconditioning and perfusion of L-carnitine during whole period of ischemia/ reperfusion on cardiac hemodynamic functions and myocardial infarction size in isolated rat heart. Iran J Basic Med Sci 2013; 16:648-655.
10.Comments on the 2010 guidelines on cardiopulmonary resuscitation of the European Resuscitation Council. Anaesthesist 2010; 59:1105-1123.
11.Scirica BM. Therapeutic Hypothermia after Cardiac Arrest. Circulation 2013; 127:244-250.
12.Rittenberger JC, Callaway CW. Temperature management and modern post-cardiac arrest care. N Engl J Med 2013; 369:2262-2263.
13.Movassaghi S, Nadia Sharifi Z, Soleimani M, Joghataii MT, Hashemi M, Shafaroodi H, et al. Effect of pentoxifylline on ischemia- induced brain dfamage and spatial memory impairment in rat. Iran J Basic Med Sci 2012; 15:1083-1090.
14.Schneider A, Böttiger BW, Popp E. Cerebral resuscitation after cardiocirculatory arrest. Anesth Analg 2009; 108:971-979.
15.Yi ZH, Zhi XZ, Wang YJ, Li JY, Huang JF, Guo QL,             et al. Effects of selective head mild hypothermia on endogenous neuroprotection in brain following global cerebral ischemia/reperfusion injury: experiment with dogs. Zhonghua Yi Xue Za Zhi 2007; 87:1318-1321.
16.Krep H, Brinker G, Pillekamp F, Hossmann KA. Treatment with an endothelin type A receptor-antagonist after cardiac arrest and resuscitation improves cerebral hemodynamic and functional recovery in rats. Crit Care Med 2000; 28:2866-2872.
17.Li W, Busu C, Circu ML, Aw TY. Glutathione in cerebral microvascular endothelial biology and pathobiology: implications for brain homeostasis. Int J Cell Biol 2012; 2012:434971.
18.Wiklund L, Martijn C, Miclescu A, Semenas E, Rubertsson S, Sharma HS. Central nervous tissue damage after hypoxia and reperfusion in conjunction with cardiac arrest andcardiopulmonary resuscitation: mechanisms of action and possibilities for mitigation. Int Rev Neurobiol 2012; 102:173-187.
19.Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003; 4:399-415.
20.Dringen R, Hirrlinger J. Glutachione pathways in the brain. Biol Chem 2003; 384:505-516.
21.Vereczki V, Martin E, Rosenthal RE, Hof PR, Hoffman GE, Fiskum G. Normoxic resuscitation after cardiac arrest protects against hippocampalaxidatives stress, metabolic dysfunction, and neuronal death. J Cereb Blood Flow Metab 2006; 26:821-835.
22.Janata A, Holzer M. Hypothermia after cardiac arrest. Prog Cardiovasc Dis 2009; 52:168-179.
23.Gulati P, Muthuraman A, Jaggi AS, Singh N. Neuroprotective effect of gadolinium: a stretch-activated calcium channel blocker in mouse model of ischemia-reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 2013; 386:255-264.
24.Walson KH, Tang M, Glunac A, Alexander H, Manole MD, Ma L, et al. Normoxic versus hyperoxic resuscitation in pediatric asphxial cardiac arrest: Effecits on oxidative stress. Crit Care Med 2011; 39:335-343.
25.Smith TL, Bleck TP. Hypothermia and neurologic outcome in patients following cardiac arrest: Should we be hot to cool off our patients. Critical Care 2002; 6:377-380.
26.Meybohm P, Gruenewald M, Zacharowski KD, Albrecht M, Lucius R, Fösel N, et al. Mild hypothermia alone or in combination with anesthetic post-conditioning reduces expression of inflammatory cytokines in the cerebral cortex of pigs after cardiopulmonary resuscitation. Crit Care 2010; 14:R21.
27.Fairchild KD, Singh IS, Carter HC, Hester L, Hasday JD. Hypothermia enhances phosphorylation of IkB kinase and prolongs nuclear localization of NF-kB in lipoopolysaccharide-activated macrophages. Am J Physiol Cell Physiol 2005; 289:1114-1121.
28.Lishmanov YB, Naryzhnaya NV, Maslov LN, Prokudina ES, Gorbunov AS, Tsibulnikov SY. Functional state of myocardial mitochondria in ischemia reperfusion of the heart in rats adapted to hypoxia. Bull Exp Biol Med 2014; 156:645-648.
29.Fritz HG. Mild therapeutic hypothermia in cardiac arrest. Dtsch Med Wochenschr 2014; 139:141-146.
30.Alzaga AG, Cerdan M, Varon J. Therapeutic hypothermia. Resuscitation 2006; 70:369-380.
31.Nordmark J, Enblad P, Rubertsson S. Cerebral energy failure following experimental cardiac arrest hypothermia treatment reduces secondary lactate/pyruvate- ratio increase. Resuscitation 2009; 80:573-579.
32.Erb JL, Hravnak M, Rittenberger JC. Therapeutic hypothermia after cardiac arrest. Am J Nurs 2012; 112:38-45.
33.Pynnönen L, Falkenbach P, Kämäräinen A, Lönnrot K, Yli-Hankala A, Tenhunen J. Therapeutic hypothermia after cardiac arrest - cerebral perfusion and metabolism during upper and lower threshold normocapnia. Resuscitation 2011; 82:1174-1179.
34.FujitaY, YamamotoN, SobueK, Inagaki M, Ito H, Arima H, et al. Effect of mild hypothermia on the expression of aquaporin family in cultured rats astrocytes under hypoxic condition. Neurosci Res 2003; 47:437-444.
35.Kuo JR, Lo CJ, Chang CP, Lin MT, Chio CC. Attenuation of brain nitrostative and oxidative damage by brain cooling during experimental traumatic brain injury. J Biomed Biotechnol 2011; 2011:145214.
36.Eberspacher E, Wemer C, Engelhard K, Pape M, Laacke L, Winner D, et al. Long-term effects of hypothermia on neuronal cell death and the concentration of apoptotic proteins after incomplete cerebral ischemia and reperfusion in rates. Acta Anaesthesiol Scand 2005; 49:477-487.