Search tips
Search criteria 


Logo of neurotherwww.springer.comThis journalToc AlertsSubmit OnlineOpen Choice
Neurotherapeutics. 2010 January; 7(1): 43–50.
PMCID: PMC2819078

The evidence for hypothermia as a neuroprotectant in traumatic brain injury


This article reviews published experimental and clinical evidence for the benefits of modest hypothermia in the treatment of traumatic brain injury (TBI). Therapeutic hypothermia has been reported to improve outcome in several animal models of CNS injury and has been successfully translated to specific patient populations. A PubMed search for hypothermia and TBI was conducted, and important papers were selected for review. The research summarized was conducted at major academic institutions throughout the world. Experimental studies have emphasized that hypothermia can affect multiple pathophysiological mechanisms thought to participate in the detrimental consequences of TBI. Published data from several relevant clinical trials on the use of hypothermia in severely injured TBI patients are also reviewed. The consequences of mild to moderate levels of hypothermia introduced by different strategies to the head-injured patient for variable periods of time are discussed. Both experimental and clinical data support the beneficial effects of modest hypothermia following TBI in specific patient populations. Following on such single-institution studies, positive findings from multicenter TBI trials will be required before this experimental treatment can be considered standard of care.

Key Words: Head trauma, hypothermia, hyperthermia, sex, pathomechanisms, pediatrics, rewarming phase, clinical trials


1. Bramlett HM, Green EJ, Dietrich WD, Busto R, Globus MY, Ginsberg MD. Posttraumatic brain hypothermia provides protection from sensorimotor and cognitive behavioral deficits. J Neurotrauma. 1995;12:289–298. doi: 10.1089/neu.1995.12.289. [PubMed] [Cross Ref]
2. Clark RS, Kochanek PM, Marion DW, et al. Mild posttraumatic hypothermia reduces mortality after severe controlled cortical impact in rats. J Cereb Blood Flow Metab. 1996;16:253–261. doi: 10.1097/00004647-199603000-00010. [PubMed] [Cross Ref]
3. Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL. Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab. 1991;11:114–121. doi: 10.1038/jcbfm.1991.13. [PubMed] [Cross Ref]
4. Dietrich WD, Alonso O, Busto R, Globus MY, Ginsberg MD. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol. 1994;87:250–258. doi: 10.1007/BF00296740. [PubMed] [Cross Ref]
5. Dixon CE, Markgraf CG, Angileri F, et al. Protective effects of moderate hypothermia on behavioral deficits but not necrotic cavitation following cortical impact injury in the rat. J Neurotrauma. 1998;15:95–103. doi: 10.1089/neu.1998.15.95. [PubMed] [Cross Ref]
6. Koizumi H, Povlishock JT. Posttraumatic hypothermia in the treatment of axonal damage in an animal model of traumatic axonal injury. J Neurosurg. 1998;89:303–309. doi: 10.3171/jns.1998.89.2.0303. [PubMed] [Cross Ref]
7. Lyeth BG, Jiang JY, Liu S. Behavioral protection by moderate hypothermia initiated after experimental traumatic brain injury. J Neurotrauma. 1993;10:57–64. doi: 10.1089/neu.1993.10.57. [PubMed] [Cross Ref]
8. Markgraf CG, Clifton GL, Moody MR. Treatment window for hypothermia in brain injury. J Neurosurg. 2001;95:979–983. doi: 10.3171/jns.2001.95.6.0979. [PubMed] [Cross Ref]
9. Yamamoto M, Marmarou CR, Stiefel MF, Beaumont A, Marmarou A. Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension. J Neurotrauma. 1999;16:487–500. doi: 10.1089/neu.1999.16.487. [PubMed] [Cross Ref]
10. Gal R, Cundrle I, Zimova I, Smrcka M. Mild hypothermia therapy for patients with severe brain injury. Clin Neurol Neurosurg. 2002;104:318–321. doi: 10.1016/S0303-8467(02)00023-9. [PubMed] [Cross Ref]
11. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet. 2008;371:1955–1969. doi: 10.1016/S0140-6736(08)60837-5. [PubMed] [Cross Ref]
12. Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM. The use of moderate therapeutic hypothermia for patients with severe head injuries: a preliminary report. J Neurosurg. 1993;79:354–362. doi: 10.3171/jns.1993.79.3.0354. [PubMed] [Cross Ref]
13. Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336:540–546. doi: 10.1056/NEJM199702203360803. [PubMed] [Cross Ref]
14. Polderman KH, Tjong Tjin Joe R, Peerdeman SM, Vandertop WP, Girbes AR. Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Med. 2002;28:1563–1573. doi: 10.1007/s00134-002-1511-3. [PubMed] [Cross Ref]
15. Qiu W, Zhang Y, Sheng H, et al. Effects of therapeutic mild hypothermia on patients with severe traumatic brain injury after craniotomy. J Crit Care. 2007;22:229–235. doi: 10.1016/j.jcrc.2006.06.011. [PubMed] [Cross Ref]
16. Qiu WS, Liu WG, Shen H, et al. Therapeutic effect of mild hypothermia on severe traumatic head injury. Chin J Traumatol. 2005;8:27–32. [PubMed]
17. Shiozaki T, Nakajima Y, Taneda M, et al. Efficacy of moderate hypothermia in patients with severe head injury and intracranial hypertension refractory to mild hypothermia. J Neurosurg. 2003;99:47–51. doi: 10.3171/jns.2003.99.1.0047. [PubMed] [Cross Ref]
18. Jiang JY, Xu W, Li WP, et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006;26:771–776. doi: 10.1038/sj.jcbfm.9600253. [PubMed] [Cross Ref]
19. Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol. 2003;59:381–385. doi: 10.1016/S0090-3019(03)00148-4. [PubMed] [Cross Ref]
20. Clifton GL, Allen S, Barrodale P, et al. A phase II study of moderate hypothermia in severe brain injury. J Neurotrauma. 1993;10:263–271. doi: 10.1089/neu.1993.10.263. [PubMed] [Cross Ref]
21. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556–563. doi: 10.1056/NEJM200102223440803. [PubMed] [Cross Ref]
22. Busto R, Dietrich WD, Globus MY, Valdés I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987;7:729–738. doi: 10.1038/jcbfm.1987.127. [PubMed] [Cross Ref]
23. Chatzipanteli K, Alonso OF, Kraydieh S, Dietrich WD. Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies. J Cereb Blood Flow Metab. 2000;20:531–542. doi: 10.1097/00004647-200003000-00012. [PubMed] [Cross Ref]
24. Büki A, Koizumi H, Povlishock JT. Moderate posttraumatic hypothermia decreases early calpain-mediated proteolysis and concomitant cytoskeletal compromise in traumatic axonal injury. Exp Neurol. 1999;159:319–328. doi: 10.1006/exnr.1999.7139. [PubMed] [Cross Ref]
25. Atkins CM, Oliva AA, Alonso OF, et al. Hypothermia treatment potentiates ERK1/2 activation after traumatic brain injury. Eur J Neurosci. 2007;26:810–819. doi: 10.1111/j.1460-9568.2007.05720.x. [PubMed] [Cross Ref]
26. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem. 1995;65:1704–1711. doi: 10.1046/j.1471-4159.1995.65041704.x. [PubMed] [Cross Ref]
27. Goss JR, Styren SD, Miller PD, et al. Hypothermia attenuates the normal increase in interleukin 1β RNA and nerve growth factor following traumatic brain injury in the rat. J Neurotrauma. 1995;12:159–167. doi: 10.1089/neu.1995.12.159. [PubMed] [Cross Ref]
28. Kinoshita K, Chatzipanteli K, Vitarbo E, Truettner JS, Alonso OF, Dietrich WD. Interleukin-1β messenger ribonucleic acid and protein levels after fluid-percussion brain injury in rats: importance of injury severity and brain temperature. Neurosurgery. 2002;51:195–203. doi: 10.1097/00006123-200207000-00027. [PubMed] [Cross Ref]
29. Lotocki G, de Rivero Vaccari JP, Perez ER, et al. Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. Eur J Neurosci. 2006;24:2283–2290. doi: 10.1111/j.1460-9568.2006.05123.x. [PubMed] [Cross Ref]
30. Jia F, Mao Q, Liang YM, Jiang JY. Effect of post-traumatic mild hypothermia on hippocampal cell death after traumatic brain injury in rats. J Neurotrauma. 2009;26:243–252. doi: 10.1089/neu.2008.0670. [PubMed] [Cross Ref]
31. Whalen MJ, Carlos TM, Clark RS, et al. The effect of brain temperature on acute inflammation after traumatic brain injury in rats. J Neurotrauma. 1997;14:561–572. doi: 10.1089/neu.1997.14.561. [PubMed] [Cross Ref]
32. Dietrich WD, Alonso O, Halley M, Busto R. Delayed posttraumatic brain hyperthermia worsens outcome after fluid percussion brain injury: a light and electron microscopic study in rats. Neurosurgery. 1996;38:533–541. doi: 10.1097/00006123-199603000-00023. [PubMed] [Cross Ref]
33. Verlooy J, Heytens L, Veeckmans G, Selosse P. Intracerebral temperature monitoring in severely head injured patients. Acta Neurochir (Wien) 1995;134:76–78. doi: 10.1007/BF01428508. [PubMed] [Cross Ref]
34. Cairns CJ, Andrews PJ. Management of hyperthermia in traumatic brain injury. Curr Opin Crit Care. 2002;8:106–110. doi: 10.1097/00075198-200204000-00003. [PubMed] [Cross Ref]
35. Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004;32:1489–1495. doi: 10.1097/01.CCM.0000129484.61912.84. [PubMed] [Cross Ref]
36. Oliveira-Filho J, Ezzeddine MA, Segal AZ, et al. Fever in sub-arachnoid hemorrhage: relationship to vasospasm and outcome. Neurology. 2001;56:1299–1304. [PubMed]
37. Thompson HJ, Hoover RC, Tkacs NC, Saatman KE, McIntosh TK. Development of posttraumatic hyperthermia after traumatic brain injury in rats is associated with increased periventricular inflammation. J Cereb Blood Flow Metab. 2005;25:163–176. doi: 10.1038/sj.jcbfm.9600008. [PubMed] [Cross Ref]
38. Fernandez A, Schmidt JM, Claassen J, et al. Fever after subarachnoid hemorrhage: risk factors and impact on outcome. Neurology. 2007;68:1013–1019. doi: 10.1212/01.wnl.0000258543.45879.f5. [PubMed] [Cross Ref]
39. Kilpatrick MM, Lowry DW, Firlik AD, Yonas H, Marion DW. Hyperthermia in the neurosurgical intensive care unit. Neurosurgery. 2000;47:850–855. doi: 10.1097/00006123-200010000-00011. [PubMed] [Cross Ref]
40. Dietrich WD, Bramlett HM. Hyperthermia and central nervous system injury. Prog Brain Res. 2007;162:201–217. doi: 10.1016/S0079-6123(06)62011-6. [PubMed] [Cross Ref]
41. Marklund N, Bakshi A, Castelbuono DJ, Conte V, McIntosh TK. Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr Pharm Des. 2006;12:1645–1680. doi: 10.2174/138161206776843340. [PubMed] [Cross Ref]
42. Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–557. doi: 10.1089/089771502753754037. [PMC free article] [PubMed] [Cross Ref]
43. Marion DW, White MJ. Treatment of experimental brain injury with moderate hypothermia and 21-aminosteroids. J Neurotrauma. 1996;13:139–147. doi: 10.1089/neu.1996.13.139. [PubMed] [Cross Ref]
44. Maxwell WL, Donnelly S, Sun X, Fenton T, Puri N, Graham DI. Axonal cytoskeletal responses to nondisruptive axonal injury and the short-term effects of posttraumatic hypothermia. J Neurotrauma. 1999;16:1225–1234. doi: 10.1089/neu.1999.16.1225. [PubMed] [Cross Ref]
45. Taft WC, Yang K, Dixon CE, et al. Hypothermia attenuates the loss of hippocampal microtubule-associated protein 2 (MAP2) following traumatic brain injury. J Cereb Blood Flow Metab. 1993;13:796–802. doi: 10.1038/jcbfm.1993.101. [PubMed] [Cross Ref]
46. Povlishock JT. Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol. 1992;2:1–12. [PubMed]
47. Suehiro E, Povlishock JT. Exacerbation of traumatically induced axonal injury by rapid posthypothermic rewarming and attenuation of axonal change by cyclosporin A. J Neurosurg. 2001;94:493–498. doi: 10.3171/jns.2001.94.3.0493. [PubMed] [Cross Ref]
48. Matsushita Y, Bramlett HM, Alonso O, Dietrich WD. Posttraumatic hypothermia is neuroprotective in a model of traumatic brain injury complicated by a secondary hypoxic insult. Crit Care Med. 2001;29:2060–2066. doi: 10.1097/00003246-200111000-00004. [PubMed] [Cross Ref]
49. Hum PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20:631–652. [PubMed]
50. Roof RL, Hall ED. Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats. J Neurotrauma. 2000;17:1155–1169. doi: 10.1089/neu.2000.17.1155. [PubMed] [Cross Ref]
51. Stein DG. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci. 2001;24:386–391. doi: 10.1016/S0166-2236(00)01821-X. [PubMed] [Cross Ref]
52. Bramlett HM, Dietrich WD. Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females. J Neurotrauma. 2001;18:891–900. doi: 10.1089/089771501750451811. [PubMed] [Cross Ref]
53. Suzuki T, Bramlett HM, Dietrich WD. The importance of gender on the beneficial effects of posttraumatic hypothermia. Exp Neurol. 2003;184:1017–1026. doi: 10.1016/S0014-4886(03)00389-3. [PubMed] [Cross Ref]
54. Suzuki T, Bramlett HM, Ruenes G, Dietrich WD. The effects of early post-traumatic hyperthermia in female and ovariectomized rats. J Neurotrauma. 2004;21:842–853. doi: 10.1089/0897715041526186. [PubMed] [Cross Ref]
55. Rosomoff HL. The effects of hypothermia on the physiology of the nervous system. Surgery. 1956;40:328–336. [PubMed]
56. Rosomoff HL. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol. 1954;179:85–88. [PubMed]
57. Dietrich WD. The importance of brain temperature in cerebral injury. J Neurotrauma. 1992;9(Suppl 2):S475–S485. [PubMed]
58. Jiang JY, Liang YM, Luo QZ, Zhu C. Effect of mild hypothermia on brain dialysate lactate after fluid percussion brain injury in rodents. Neurosurgery. 2004;54:713–717. doi: 10.1227/01.NEU.0000109535.58429.49. [PubMed] [Cross Ref]
59. Lyeth BG, Jiang JY, Robinson SE, Guo H, Jenkins LW. Hypothermia blunts acetylcholine increase in CSF of traumatically brain injured rats. Mol Chem Neuropathol. 1993;18:247–256. doi: 10.1007/BF03160117. [PubMed] [Cross Ref]
60. Koizumi H, Fujisawa H, Ito H, Maekawa T, Di X, Bullock R. Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat. Brain Res. 1997;747:304–312. doi: 10.1016/S0006-8993(96)01240-1. [PubMed] [Cross Ref]
61. Jiang JY, Lyeth BG, Kapasi MZ, Jenkins LW, Povlishock JT. Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol. 1992;84:495–500. doi: 10.1007/BF00304468. [PubMed] [Cross Ref]
62. Kinoshita K, Chatzipanteli K, Alonso OF, Howard M, Dietrich WD. The effect of brain temperature on hemoglobin extravasation after traumatic brain injury. J Neurosurg. 2002;97:945–953. doi: 10.3171/jns.2002.97.4.0945. [PubMed] [Cross Ref]
63. Arican N, Kaya M, Yorulmaz C, et al. Effect of hypothermia on blood-brain barrier permeability following traumatic brain injury in chronically ethanol-treated rats. Int J Neurosci. 2006;116:1249–1261. doi: 10.1080/00207450600550303. [PubMed] [Cross Ref]
64. Chatzipanteli K, Wada K, Busto R, Dietrich WD. Effects of moderate hypothermia on constitutive and inducible nitric oxide synthase activities after traumatic brain injury in the rat. J Neurochem. 1999;72:2047–2052. doi: 10.1046/j.1471-4159.1999.0722047.x. [PubMed] [Cross Ref]
65. Vitarbo EA, Chatzipanteli K, Kinoshita K, Truettner JS, Alonso OF, Dietrich WD. Tumor necrosis factor α expression and protein levels after fluid percussion injury in rats: the effect of injury severity and brain temperature. Neurosurgery. 2004;55:416–424. doi: 10.1227/01.NEU.0000130036.52521.2C. [PubMed] [Cross Ref]
66. Truettner JS, Alonso OF, Dietrich DW. Influence of therapeutic hypothermia on matrix metalloproteinase activity after traumatic brain injury in rats. J Cereb Blood Flow Metab. 2005;25:1505–1516. doi: 10.1038/sj.jcbfm.9600150. [PubMed] [Cross Ref]
67. Keane RW, Kraydieh S, Lotocki G, Alonso OF, Aldana P, Dietrich WD. Apoptotic and antiapoptotic mechanisms after traumatic brain injury. J Cereb Blood Flow Metab. 2001;21:1189–1198. doi: 10.1097/00004647-200110000-00007. [PubMed] [Cross Ref]
68. Truettner JS, Suzuki T, Dietrich WD. The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat. Brain Res Mol Brain Res. 2005;138:124–134. doi: 10.1016/j.molbrainres.2005.04.006. [PubMed] [Cross Ref]
69. Sedzimir CB. Therapeutic hypothermia in cases of head injury. J Neurosurg. 1959;16:407–414. doi: 10.3171/jns.1959.16.4.0407. [PubMed] [Cross Ref]
70. Metz C, Holzschuh M, Bein T, et al. Moderate hypothermia in patients with severe head injury: cerebral and extracerebral effects. J Neurosurg. 1996;85:533–541. doi: 10.3171/jns.1996.85.4.0533. [PubMed] [Cross Ref]
71. Tateishi A, Soejima Y, Taira Y, et al. Feasibility of the titration method of mild hypothermia in severely head-injured patients with intracranial hypertension. Neurosurgery. 1998;42:1065–1069. doi: 10.1097/00006123-199805000-00066. [PubMed] [Cross Ref]
72. Jiang J, Yu M, Zhu C. Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases. J Neurosurg. 2000;93:546–549. doi: 10.3171/jns.2000.93.4.0546. [PubMed] [Cross Ref]
73. Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD. Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab. 1993;13:541–549. doi: 10.1038/jcbfm.1993.71. [PubMed] [Cross Ref]
74. Colboume F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci. 1995;15:7250–7260. [PubMed]
75. Clifton GL, Choi SC, Miller ER, et al. Intercenter variance in clinical trials of head trauma—experience of the National Acute Brain Injury Study: Hypothermia. J Neurosurg. 2001;95:751–755. doi: 10.3171/jns.2001.95.5.0751. [PubMed] [Cross Ref]
76. Brain Trauma Foundation. American Association of Neurological Surgeons. Congress of Neurological Surgeons. Joint Section on Neurotrauma and Critical Care, AANS/CNS. Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. III. Prophylactic hypothermia. J Neurotrauma. 2007;24(Suppl 1):S21–S25. [PubMed]
77. Aibiki M, Maekawa S, Yokono S. Moderate hypothermia improves imbalances of thromboxane A2 and prostaglandin I2 production after traumatic brain injury in humans. Crit Care Med. 2000;28:3902–3906. doi: 10.1097/00003246-200012000-00029. [PubMed] [Cross Ref]
78. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–563. doi: 10.1056/NEJMoa003289. [PubMed] [Cross Ref]
79. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med. 2005;33:2744–2751. doi: 10.1097/01.CCM.0000190427.88735.19. [PubMed] [Cross Ref]
80. Mansfield RT, Schiding JK, Hamilton RL, Kochanek PM. Effects of hypothermia on traumatic brain injury in immature rats. J Cereb Blood Flow Metab. 1996;16:244–252. doi: 10.1097/00004647-199603000-00009. [PubMed] [Cross Ref]
81. Biswas AK, Bruce DA, Sklar FH, Bokovoy JL, Sommerauer JF. Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension. Crit Care Med. 2002;30:2742–2751. doi: 10.1097/00003246-200212000-00020. [PubMed] [Cross Ref]
82. Adelson PD, Ragheb J, Kanev P, et al. Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children. Neurosurgery. 2005;56:740–754. doi: 10.1227/01.NEU.0000156471.50726.26. [PubMed] [Cross Ref]
83. Hutchison JS, Ward RE, Lacroix J, Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008;358:2447–2456. doi: 10.1056/NEJMoa0706930. [PubMed] [Cross Ref]

Articles from Neurotherapeutics are provided here courtesy of Springer