Effect of Mild Hypothermia on the Coagulation-Fibrinolysis System and Physiological Anticoagulants after Cardiopulmonary Resuscitation in a Porcine Model
The aim of this study was to evaluate the effect of mild hypothermia on the coagulation-fibrinolysis system and physiological anticoagulants after cardiopulmonary resuscitation (CPR). A total of 20 male Wuzhishan miniature pigs underwent 8 min of untreated ventricular fibrillation and CPR. Of these, 16 were successfully resuscitated and were randomized into the mild hypothermia group (MH, n = 8) or the control normothermia group (CN, n = 8). Mild hypothermia (33°C) was induced intravascularly, and this temperature was maintained for 12 h before pigs were actively rewarmed. The CN group received normothermic post-cardiac arrest (CA) care for 72 h. Four animals were in the sham operation group (SO). Blood samples were taken at baseline, and 0.5, 6, 12, 24, and 72 h after ROSC. Whole-body mild hypothermia impaired blood coagulation during cooling, but attenuated blood coagulation impairment at 72 h after ROSC. Mild hypothermia also increased serum levels of physiological anticoagulants, such as PRO C and AT-III during cooling and after rewarming, decreased EPCR and TFPI levels during cooling but not after rewarming, and inhibited fibrinolysis and platelet activation during cooling and after rewarming. Finally, mild hypothermia did not affect coagulation-fibrinolysis, physiological anticoagulants, or platelet activation during rewarming. Thus, our findings indicate that mild hypothermia exerted an anticoagulant effect during cooling, which may have inhibitory effects on microthrombus formation. Furthermore, mild hypothermia inhibited fibrinolysis and platelet activation during cooling and attenuated blood coagulation impairment after rewarming. Slow rewarming had no obvious adverse effects on blood coagulation.
References
[1]
Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V, et al. (2007) Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia 62: 1207–1216.
[2]
Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, et al. (2002) Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 106: 562–568.
[3]
Hekimian G, Baugnon T, Thuong M, Monchi M, Dabbane H, et al. (2004) Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation. Shock 22: 116–119.
[4]
Bottiger BW, Motsch J, Bohrer H, Boker T, Aulmann M, et al. (1995) Activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis. Circulation 92: 2572–2578.
[5]
Gando S, Kameue T, Nanzaki S, Nakanishi Y (1997) Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest. Thromb Haemost 77: 278–282.
[6]
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, et al. (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346: 557–563.
[7]
Hypothermia after Cardiac Arrest Study Group (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346: 549–556.
[8]
Schmied H, Kurz A, Sessler DI, Kozek S, Reiter A (1996) Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. Lancet 347: 289–292.
Schochl H, Cadamuro J, Seidl S, Franz A, Solomon C, et al. (2013) Hyperfibrinolysis is common in out-of-hospital cardiac arrest: Results from a prospective observational thromboelastometry study. Resuscitation 84: 454–459.
[11]
Gong P, Li CS, Hua R, Zhao H, Tang ZR, et al. (2012) Mild hypothermia attenuates mitochondrial oxidative stress by protecting respiratory enzymes and upregulating MnSOD in a pig model of cardiac arrest. PLoS One 7: e35313.
[12]
Bottiger BW, Martin E (2001) Thrombolytic therapy during cardiopulmonary resuscitation and the role of coagulation activation after cardiac arrest. Curr Opin Crit Care 7: 176–183.
[13]
Fischer M, Bottiger BW, Popov-Cenic S, Hossmann KA (1996) Thrombolysis using plasminogen activator and heparin reduces cerebral no-reflow after resuscitation from cardiac arrest: an experimental study in the cat. Intensive Care Med 22: 1214–1223.
[14]
Adrie C, Monchi M, Laurent I, Um S, Yan SB, et al. (2005) Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway. J Am Coll Cardiol 46: 21–28.
[15]
Zhao H, Li CS, Gong P, Tang ZR, Hua R, et al. (2012) Molecular mechanisms of therapeutic hypothermia on neurological function in a swine model of cardiopulmonary resuscitation. Resuscitation 83: 913–920.
[16]
Hua R, Li CS, Gong P, Tang ZR, Mei X, et al. (2012) Cerebrospinal fluid biochemistry reflects effects of therapeutic hypothermia after cardiac arrest in a porcine model. Am J Emerg Med 30: 1420–1428.
[17]
Tang ZR, Li CS, Zhao H, Gong P, Zhang MY, et al. (2013) Effects of Hypothermia Treatment on Brain Injury Assessed by MRI after Cardiopulmonary Resuscitation in the Pig. Am J Emerg Med 31: 86–93.
[18]
Wang S, Li CS, Ji XF, Yang L, Su ZY, et al. (2010) Effect of continuous compressions and 30:2 cardiopulmonary resuscitation on global ventilation/perfusion values during resuscitation in a porcine model. Crit Care Med 38: 2024–2030.
[19]
Ji XF, Shuo W, Yang L, Li CS (2012) Impaired beta-adrenergic receptor signalling in post-resuscitation myocardial dysfunction. Resuscitation 83: 640–644.
[20]
Ji XF, Li CS, Wang S, Yang L, Cong LH (2010) Comparison of the efficacy of nifekalant and amiodarone in a porcine model of cardiac arrest. Resuscitation 81: 1031–1036.
[21]
Ji XF, Yang L, Zhang MY, Li CS, Wang S, et al. (2011) Shen-fu injection attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest. Shock 35: 530–536.
[22]
Wu JY, Li CS, Liu ZX, Wu CJ, Zhang GC (2009) A comparison of 2 types of chest compressions in a porcine model of cardiac arrest. Am J Emerg Med 27: 823–829.
[23]
Su ZY, Li CS, Han Y, Yin X, Guo M (2011) Evaluation of cerebral metabolism by (1)H-magnetic resonance spectroscopy for 4 degrees C saline-induced therapeutic hypothermia in pig model of cardiac arrest. Am J Emerg Med 29: 913–921.
[24]
Hu CL, Wen J, Liao XX, Li X, Li YJ, et al. (2011) Effects of therapeutic hypothermia on coagulopathy and microcirculation after cardiopulmonary resuscitation in rabbits. Am J Emerg Med 29: 1103–1110.
[25]
Watts DD, Trask A, Soeken K, Perdue P, Dols S, et al. (1998) Hypothermic coagulopathy in trauma: effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma 44: 846–854.
[26]
Valeri CR, MacGregor H, Cassidy G, Tinney R, Pompei F (1995) Effects of temperature on bleeding time and clotting time in normal male and female volunteers. Crit Care Med 23: 698–704.
[27]
Polderman KH (2009) Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 37: S186–202.
[28]
Esmon CT (2008) Crosstalk between inflammation and thrombosis. Maturitas 61: 122–131.
[29]
Esmon CT (2003) Coagulation and inflammation. J Endotoxin Res 9: 192–198.
[30]
van der Spuy WJ, Pretorius E (2012) Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia. Rev Neurosci 23: 269–278.
[31]
Levi M, Keller TT, van Gorp E, ten Cate H (2003) Infection and inflammation and the coagulation system. Cardiovasc Res 60: 26–39.
[32]
Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, et al. (2004) Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care 10: 208–212.
[33]
Meybohm P, Gruenewald M, Albrecht M, Zacharowski KD, Lucius R, et al. (2009) Hypothermia and postconditioning after cardiopulmonary resuscitation reduce cardiac dysfunction by modulating inflammation, apoptosis and remodeling. PLoS One 4: e7588.
[34]
Meybohm P, Gruenewald M, Zacharowski KD, Albrecht M, Lucius R, et al. (2010) 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 14: R21.
[35]
Nozza S, Pogliaghi M, Chiappetta S, Spagnuolo V, Fontana G, et al. (2012) Levels of soluble endothelial protein C receptor are associated with CD4+ changes in Maraviroc-treated HIV-infected patients. PLoS One 7: e37032.
[36]
Kazanskaya GM, Volkov AM, Karas’kov AM, Lomivorotov VN, Shun’kin AV (1999) Experimental studies on the endothelium ultrastructure of heart capillaries under moderate (28–30 degrees) and deep (22–24 degrees) hypothermia without perfusion. Microvasc Res 58: 250–267.
[37]
Green D (2006) Coagulation cascade. Hemodial Int 10 Suppl 2S2–4.
[38]
Andre P (2004) P-selectin in haemostasis. Br J Haematol 126: 298–306.
[39]
Bottiger BW, Motsch J, Braun V, Martin E, Kirschfink M (2002) Marked activation of complement and leukocytes and an increase in the concentrations of soluble endothelial adhesion molecules during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans. Crit Care Med 30: 2473–2480.
[40]
Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, et al. (2008) Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 118: 2452–2483.
[41]
Staikou C, Paraskeva A, Drakos E, Anastassopoulou I, Papaioannou E, et al. (2011) Impact of graded hypothermia on coagulation and fibrinolysis. J Surg Res 167: 125–130.
