The Safar Center for Resuscitation Research: Searching for Breakthroughs in the New Millennium

This review, written on the occasion of the 70 th anniversary of the Institute for General Reanimatology of the Russian Academy of Medical Sciences, provides an update of recent research in the field of resuscitation medicine carried out at the Safar Center for Resuscitation Research at the University of Pittsburgh School of Medicine. Current and recent studies describing bench to bedside investigation in the areas of traumatic brain injury (TBI), cardiopulmonary arrest, hemorrhagic shock, and ultranovel approaches to resuscitation are discussed. Investigation in TBI across a variety of topics by many investigators including mechanism of neuronal death, oxidative and nitrative stress, proteomics, adenosine, serotonin, novel magnetic resonance imaging application, inflicted childhood neurotrauma, and TBI rehabilitation is addressed. Research discussed in the program of  cardiopulmonary  arrest  includes  optimization  of  the  use  of  mild  hypothermia  and  novel  investigation  in  experimental asphyxial cardiac arrest. In the program on hemorrhagic shock, our recent work on the application of mild hypothermia to prolong the «golden hour» is presented. Finally, a brief overview of our studies of a novel approach to the resuscitation of exsanguination  cardiac  arrest  using  emergency  preservation  for  resuscitation  (EPR)  is  provided. 

1. Safar P. From Vienna to Pittsburgh for anesthesiology and acute medicine. Careers in Anesthesiology. Autobiographical Memoirs. American Society of Anesthesiologists, Wood Library-Museum; 2000.

2. Negovsky V. A., Gurvitch A. M., Zolotokrylina E. S. Postresuscitation disease. Elsevier, Amsterdam; 1983

3. Negovsky V. A. Resuscitation and artificial hypothermia. M.: Medgiz; 1960.

4. Negovsky V. A. Essays on Reanimatology. M.: Mir Publishers; 1989.

5. Kochanek P. M., Grenvik A. A Tribute to Peter J. Safar, MD. Crit. Care Med. 2003; 31: 2571—2573.

6. Dixon C. E., Clifton G. L., Lighthall J. W. et al. A controlled cortical impact model of traumatic brain injury in the rat. J. Neurosci. Methods 1991; 39: 253—262.

7. Clark R. S. B., Kochanek P. M., Dixon C. E. et al. Early neuropathologic effects of mild or moderate hypoxemia after controlled cortical impact injury in rats. J. Neurotrauma 1997; 14: 179—189.

8. Kotapka M. J., Graham D. I., Adams J. H. et al. Hippocampal pathology in fatal human head injury without high intracranial pressure. J. Neurotrauma 1994; 11: 317—324.

9. Kochanek P. M., Clark R. S. B., Ruppel R. A. et al. Biochemical, cellular and molecular mechanisms in the evolution of secondary damage after severe traumatic brain injury in infants and children: Lessons learned from the bedside. Pediatr. Crit. Care Med. 2000; 1: 4—19.

10. Clark R. S. B., Kochanek P. M., Chen M. et al. Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB. J. 1999; 13: 813—821.

11. Zhang X., Graham S. H., Kochanek P. M. et al. Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J. express article 10. 1096 / fj. 02-1067 fje. Published online May 8, 2003; 17(10): 1367—1369.

12. Zhang X., Chen Y., Ikonomovic M. D. et al. Increased phosphorylation of protein kinase B and its substrates after traumatic brain injury in humans and rats. J. Cereb. Blood Flow Metab. 2005 [Epub ahead of print].

13. Clark R. S. B., Kochanek P. M., Watkins S. C. et al. Caspase-3 mediated neuronal death after traumatic brain injury in rats. J. Neurochem. 2000; 74: 740—753.

14. Zhang X., Chen J., Graham S. H. et al. Mitochondrial to nuclear translocation of apoptosis-inducing factor and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J. Neurochem. 2002; 82: 181—191.

15. Zhao H., Shimohata T., Qang J. Q. et al. Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J. Neurosci. 2005; 25: 9794—9806.

16. Satchell M. A., Lai Y., Kochanek P. M. et al. Cytochrome C, a biomarker of apoptosis, is increased in cerebrospinal fluid from infants with inflicted brain injury from child abuse. J. Cereb. Blood Flow Metab. 2005; 25: 919—927.

17. Bayir H., Kagan V. E., Tyurina Y. Y. et al. Assessment of antioxidant reserve and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr. Res. 2002; 51: 571—578.

18. Bayir H., Kochanek P. M., Liu S. X. et al. Increased S-nitrosothiols and S-nitrosoalbumin in cerebrospinal fluid after severe traumatic brain injury in infants and children: Indirect association with intracranial pressure. J. Cereb. Blood Flow Metab. 2003; 23: 51—61.

19. Varma S., Janesko K. L., Wisniewski S. R. et al. F 2 -isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children. J. Neurotrauma 2003; 20: 781—786.

20. Bayir H., Marion D. W., Puccio A. M. et al. Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients. J. Neurotrauma 2004; 21: 1-8.

21. Bayir H., Kagan V. E., Borisenko G. et al. Enhanced oxidative stress in iNOS-deficient mice after traumatic brain injury: Support for a neuroprotective role of iNOS. J. Cereb. Blood Flow Metab. 2005; 25: 673—684.

22. Bayir H., Adelson P. D., Kagan V. E. et al. Therapeutic hypothermia attenuates oxidative stress after traumatic brain injury in infants and children. 32nd SCCM Critical Care Congress, January 2003. Crit. Care Med. 2002; 30: A7.

23. Bayir H., Kagan V. E., Clark R. S. et al. Nitration and inactivation of MNSOD in brain after experimental and clinical traumatic brain injury. J. Neurotrauma. Abstr. 2005; 22: 1234.

24. Bayir H., Kagan V. E., Clark R. S. B. et al. Mechanisms of tyrosine nitration of MnSOD after traumatic brain injury. Crit. Care Med. 2005; 33: A16.

25. Gopinath S. P., Robertson C. S., Contant C. F. et al. Jugular venous dsaturation and outcome after head injury. J. Neurol. Neurosurg. Psychiatry 1994; 57: 717—723.

26. Jenkins L. W., Peters G. W., Dixon C. E. et al. Conventional and functional proteomics using large format two-dimensional gel electrophoresis 24 hours after controlled cortical impact in postnatal day 17 rats. J. Neurotrauma 2002; 19: 715—740.

27. Kochanek A. R., Kline A. E., Gao W. M. et al. Gel-based proteomic analysis of rodent hippocampus 2 weeks following traumatic brain injury of immature rats using controlled cortical impact. Develop. Neurosci. (in press).

28. Gao W., Chadha M. S., Berger R. P. et al. A gel-based proteomic comparison of human cerebrospinal fluid between inflicted and non-inflicted pediatric traumatic brain injury. J. Neurotrauma (in press).

29. Clark R. S. B., Carcillo J. A., Kochanek P. M. et al. Cerebrospinal fluid adenosine concentration and uncoupling of cerebral blood flow and oxidative metabolism after severe head injury in humans. Neurosurgery 1997; 41: 1284—1293.

30. Robertson C. L., Bell M. J., Kochanek P. M. Increased adenosine in cerebrospinal fluid after severe traumatic brain injury in infants and children: Association with severity of injury and excitotoxicity. Crit. Care Med. 2001; 29: 2287—2293.

31. Bell M. J., Robertson C. S., Kochanek P. M. et al. Interstitial brain adenosine and xanthine increase during jugular venous oxygen desaturations in humans after traumatic brain injury. Crit. Care Med. 2001; 29: 399—404.

32. Bell M. J., Kochanek P. M., Carcillo J. A. et al. Interstitial adenosine, inosine, and hypoxanthine, are increased after experimental traumatic brain injury in the rat. J. Neurotrauma 1998; 15: 163—170.

33. Kochanek P. M., Hendrich K. S., Robertson C. L. et al. Assessment of the effect of 2-chloroadenosine on cerebral blood flow in normal rats using arterial spin labeled MRI. Magn. Reson. Med. 2001; 45: 924—929.

34. Varma M. R., Dixon C. E., Jackson E. K. et al. Administration of adenosine receptor agonists or antagonists after controlled cortical impact in mice: Effects on function and histopathology. Brain Res. 2002; 951: 191—201.

35. Kochanek P. M., Hendrich K. S., Jackson E. K. et al. Characterization of the effects of adenosine receptor agonists on cerebral blood flow in uninjured and traumatically injured rat brain using continuous arterial spin-labeled magnetic resonance imaging. J. Cereb. Blood Flow Metab. 2005; 25: 1596—1612.

36. Kochanek P. M., Vagni V. A., Janesko K. L. et al. Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury. J. Cereb. Blood Flow Metab. 2006; 26: 565—575.

37. Miller L. P., Hsu C. Therapeutic potential for adenosine receptor activation in ischemic brain injury. J. Neurotrauma 1992; 9: S563—S577.

38. Fredholm B. B. Adenosine receptors as targets for drug development. Drug News Perspect. 2003; 16: 283—289.

39. Hendrich K., Schiding J., Kochanek P. et al. Early perfusion after controlled cortical impact in rats: Quantification by arterial spin-labeled MRI and the influence of spin-lattice relaxation time heterogeneity. Magn. Reson. Med. 1999; 42: 673—681.

40. Marion D. W., Darby J., Yonas H. Acute regional cerebral blood flow changes caused by severe head injuries. J. Neurosurg. 1991; 74: 407—414.

41. Kline A. E., Yu J., Horvath E. et al. The selective 5-HT(1A) receptor agonist repinotan HC1 attenuates histopathology and spatial learning deficits following traumatic brain injury in rats. Neurosci. 2001; 106: 547—555.

42. Kline A. E., Yu J., Massucci J. L. et al. Protective effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin against traumatic brain injury-induced cognitive deficits and neuropathology in adult male rats. Neurosci. Letters 2002; 333: 179—182.

43. Kline A. E., Massucci J. L., Dixon C. E. et al. The therapeutic efficacy conferred by the 5-HT(1A) receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after experimental traumatic brain injury is not mediated by concomitant hypothermia. J. Neurotrauma 2004; 21: 175—185.

44. Forbes M. L., Hendrich K. S., Kochanek P. M. et al. Assessment of cerebral blood flow and CO2 reactivity after controlled cortical impact by perfusion magnetic resonance imaging using arterial spin labeling in rats. J. Cereb. Blood Flow Metab. 1997; 17: 865—874.

45. Hendrich K. S., Kochanek P. M., Melick J. A. et al. Cerebral perfusion during anesthesia with fentanyl isoflurane or pentobarbital in normal rats studied by arterial spin-labeled MRI. Magn. Reson. Med. 2001; 46: 202—206.

46. Hendrich K., Schiding J., Kochanek P. et al. Sequential MRI assessment of cerebral blood flow and blood-brain barrier permeability early after traumatic brain injury in rats. J. Cereb. Blood Flow Metab. 1997; 17: S76.

47. Kochanek P. M., Hendrich K. S., Dixon C. E. et al. Cerebral blood flow at one year after controlled cortical impact in rats: Assessment by magnetic resonance imaging. J. Neurotrauma 2002; 19: 1029—1037.

48. Foley L. M., Hitchens T. K., Kochanek P. M. et al. Murine orthostaticresponse during prolonged vertical studies: Effect on cerebral blood flow measured by arterial spin-labeled MRI. Magn. Reson. Med. 2005; 54: 798—806.

49. Berger R. P., Janesko K. L., Wisniewski S. R. et al. Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics 2002; 109(2), URL: http: //www. pediatrics. org/cgi/content/full/109/2/e31.

50. Lai Y. C., Stange C., Wisniewski S. R. et al. Mitochondrial heat shock protein 60 is increased in cerebrospinal fluid following pediatric traumatic brain injury. Dev. Neurosci. (in press).

51. Berger R. P., Adelson P. D., Richichi R. et al. Serum biomarkers after traumatic and hypoxemic brain injuries: Insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev. Neurosci. (in press).

52. Berger R. P., Dulani T., Adelson P. D. et al. Identification of brain injury in well-appearing infants using serum and cerebrospinal markers: A possible screening tool. Pediatrics 2006; 117: 325—332.

53. Berger R. P., Kochanek P. M., Pierce M. C. Biochemical markers of brain injury: Could they be used as diagnostic adjuncts in cases of inflicted traumatic brain injury? (Invited Review) Child Abuse and Neglect: Int. J. 2004; 28: 739—754.

54. Dixon C. E., Kochanek P. M., Yan H. Q. et al. A One-year study of spatial memory performance, brain morphology and cholinergic markers after moderate controlled cortical impact in rats. J. Neurotrauma 1999; 16: 109—122.

55. Wagner A. K., Kline A. E., Sokoloski J. et al. Intervention with environmental enrichment after experimental brain trauma enhances cognitive recovery in male but not female rats. Neurosci. Letters 2002; 334: 165—168.

56. Chen X., Li Y., Kline A. E. et al. Gender and environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury. Neuroscience 2005; 135: 11—17.

57. Wagner A. K., Chen X., Kline A. E. et al. Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury. Exp. Neurol. 2005; 195: 475—483.

58. Safar P. Community-wide cardiopulmonary resuscitation. J. Iowa Med. Soc. 1964; 629—635.

59. Busto R., Dietrich W. D., Globus M. Y. et al. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J. Cereb. Blood Flow Metab. 1987; 7: 729—738.

60. Bernard S. A., Gray T. W., Buist M. D. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 2002; 346: 557—563.

61. Hypothermia after cardiac arrest study group: mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med. 2002; 346: 549—556.

62. Shankaran S., Laptook A. R., Ehrenkranz R. A. et al. National institute of child health and human development neonatal research network: whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N. Engl. J. Med. 2006; 353: 1574—1584.

63. Safar P. J., Kochanek P. M. Resuscitative hypothermia after cardiac arrest. Invited editorial, N. Engl. J. Med. 2002; 346: 612—613.

64. Kochanek P. M., Safar P. J. Therapeutic hypothermia for severe traumatic brain injury. Invited editorial, J. Amer. Med. Assoc. 2003; 289: 3007—3009.

65. Kochanek P. M. Brain Trauma: Laboratory Studies. In: Tisherman S. A., Sterz F. (eds. ) Therapeutic hypothermia. Springer Science +Business Media, Inc. 2005. 63—86.

66. Nozari A., Safar P., Stezoski S. W. et al. Mild hypothermia during prolonged cardiopulmonary-cerebral resuscitation increases conscious survival in dogs. Crit. Care Med. 2004; 32: 2110—2116. (Accompanying editorial) 2004; 32: 2164—2165.

67. Nozari A., Safar P., Stezoski S. W. et al. Critical time window for the induction of mild hypothermia during cardiopulmonary resuscitation from prolonged circulatory arrest in dogs. Circulation (in press).

68. Bernard S., Buist M., Monteiro O., Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of outof-hospital cardiac arrest: a preliminary report. Resuscitation 2003; 56: 9—13.

69. Fink E. L., Alexander H., Marco C. D. et al. Experimental model of pediatric asphyxial cardiopulmonary arrest in rats. Pediatr. Crit. Care Med. 2004; 5: 139—144.

70. Fink E. L., Marco C. D., Donovan H. A. et al. Brief induced hypothermia improves outcome in a pediatric model of asphyxial cardiopulmonary arrest in rats. American stroke association; fellows' research day, Hilton hotel. Pittsburgh, PA, February 13, 2004.

71. Fink E. L., Bayir H., Lai Y. et al. Clark RS: γ-glutamylcysteine ethyl ester increases brain glutathione after asphyxial cardiac arrest in post-natal day 17 rats: 86. 34th SCCM Critical care congress, Crit. Care Med. 2004; 32(12 Suppl): A22.

72. Fink E. L., Marco C. D., Chen Y. et al. Protracted increase in hippocampal Poly-ADP-ribosylation after asphyxial cardiac arrest in juvenile rats. Pediatric academic societies' annual meeting; 2005; PAS 57: 51.

73. Kim S. H., Stezoski S. W., Safar P. et al. Hypothermia and minimal fluid resuscitation increase survival after uncontrolled hemorrhagic shock in rats. J. Trauma 1997; 42: 213—222.

74. Kim S. H., Stezoski S. W., Safar P. et al. Hypothermia, but not 100% oxygen breathing, prolongs survival time during lethal uncontrolled hemorrhagic shock in rats. J. Trauma 1998; 44: 485—491.

75. Takasu A., Carrillo P., Stezoski S. W. et al. Mild or moderate hypothermia but not increased oxygen breathing prolongs survival during lethal uncontrolled hemorrhagic shock in rats, with monitoring of visceral dysoxia. Crit. Care Med. 1999; 27: 1557—1564.

76. Wu X., Stezoski J., Safar P., Behringer W. et al. Systemic hypothermia, but not regional gut hypothermia, improves survival from prolonged hemorrhagic shock in rats. J. Trauma 2002; 53: 654—662.

77. Wu X., Stezoski J., Safar P. et al. Mild hypothermia during hemorrhagic shock in rats improves survival without significant effects on inflammatory responses. Crit. Care Med. 2003; 31: 195—202.

78. Wu X., Kochanek P., Cochran K. et al. Mild hypothermia improves survival after prolonged, traumatic hemorrhagic shock in pigs. J. Trauma 2005; 59: 291—299; discussion 299—301.

79. Mullie A., Lewi P., Van Hoeyweghen R. Pre-CPR conditions and the final outcome of CPR. The cerebral resuscitation study group. Resuscitation 1989; 17(Suppl): S11—S21.

80. Bellamy R., Safar P., Tisherman S. A. et al. Suspended animation for delayed resuscitation. Crit. Care Med. 1996; 24 (2 Suppl): S24—S47.

81. Behringer W., Prueckner S., Kentner R. et al. Rapid hypothermic aortic flush can achieve survival without brain damage after 30 minutes cardiac arrest in dogs. Anesthesiology 2000; 93: 1491—1499.

82. Behringer W., Safar P., Wu X. et al. Survival without brain damage after clinical death of 60—120 mins in dogs using suspended animation by profound hypothermia. Crit. Care Med. 2003; 31: 1523—1531.

83. Nozari A., Safar P., Wu X. et al. Suspended animation can allow survival without brain damage after traumatic exsanguination cardiac arrest of 60 minutes in dogs. J. Trauma 2004; 57: 1266—1275.

84. Wu X., Drabek T., Tisherman S. A. et al. Emergency preservation and resuscitation with energy substrates and hypothermia allow reliable neurological recovery after 3 h of cardiac arrest following rapid exsanguination in dogs. International Anesthesia Research Society Control No 1357, (in press).

85. Wu X., Kochanek P. M., Drabek T. et al. Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival from cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs. Circulation 2006; 113: 1974—1982.

86. Drabek T., Stezoski J., Wu X. et al. Establishment of a rat model of suspended animation with delayed resuscitation: A preliminary report: 211. Crit. Care Med. 2004; 32(12 Suppl): A56.

87. Janata A., Holzer M., Bayegan K. et al. Rapid induction of cerebral hypothermia by aortic flush during normovolemic cardiac arrest in pigs. Crit. Care Med. 2006; 34: 1769—1774.

88. DePalma R. G., Burris D. G., Champion H. R. et al. Blast injuries. N. Engl. J. Med. 2005; 352: 1335—1342.

89. Okie S. Traumatic brain injury in the war zone. N. Engl. J. Med. 2005; 352: 2043—2047.