J Neurocrit Care.  2020 Jun;13(1):19-31. 10.18700/jnc.190090.

Central fever: a challenging clinical entity in neurocritical care

• Goyal K
• Garg N
• Bithal P

• KMID: 2503382
• DOI: http://doi.org/10.18700/jnc.190090

Abstract

Fever is probably the most frequent symptom observed in neurointensive care by healthcare providers. It is seen in almost 70% of neurocritically ill patients. Fever of central origin was first described in the journal Brain by Erickson in 1939. A significant number of patients develop this fever due to a noninfectious cause, butare often treated as having an infectious fever. Unjustified use of antibiotics adds to the increased cost of treatment and the emergence of resistant strains, contributing to additional morbidity. Since fever has a detrimental impact on the recovery of the acutely injured brain and contributes to an increased stay in the neurointensive care unit (NICU), timely and accurate diagnosis of the cause of fever in the NICU is imperative. Here, we try to understand the underlying mechanism, risk factors, clinical characteristics, diagnosis and management options of the central fever. We also make an attempt to differentiate two noninfectious causes of fever in the NICU: paroxysmal sympathetic hyperactivity and central fever.

Keyword

Humans; Fever

Reference

1. Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Neurol Clin. 2008; 26:585–603.

2. Laupland KB. Fever in the critically ill medical patient. Crit Care Med. 2009; 37(7 Suppl):S273–8.

3. Grunau BE, Wiens MO, Brubacher JR. Dantrolene in the treatment of MDMA-related hyperpyrexia: a systematic review. CJEM. 2010; 12:435–42.

4. Sharma HS. Neurobiology of hyperthermia. Amsterdam: Elsevier;2007. p. 175–7. p. 485

5. Albrecht RF 2nd, Wass CT, Lanier WL. Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury. Mayo Clin Proc. 1998; 73:629–35.

6. Kilpatrick MM, Lowry DW, Firlik AD, Yonas H, Marion DW. Hyperthermia in the neurosurgical intensive care unit. Neurosurgery. 2000; 47:850–6.

7. Commichau C, Scarmeas N, Mayer SA. Risk factors for fever in the neurologic intensive care unit. Neurology. 2003; 60:837–41.

8. 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; 32:1489–95.

9. Stocchetti N, Rossi S, Zanier ER, Colombo A, Beretta L, Citerio G. Pyrexia in head-injured patients admitted to intensive care. Intensive Care Med. 2002; 28:1555–62.

10. Laws C, Jallo J. Fever and infection in the neurosurgical intensive care unit. JHN J. 2010; 5:5.

11. Erickson TC. Neurogenic hyperthermia: a clinical syndrome and its treatment. Brain. 1939; 62:172–90.

12. Oliveira-Filho J, Ezzeddine MA, Segal AZ, Buonanno FS, Chang Y, Ogilvy CS, et al. Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology. 2001; 56:1299–304.

13. Rossi S, Zanier ER, Mauri I, Columbo A, Stocchetti N. Brain temperature, body core temperature, and intracerebral pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry. 2001; 71:448–54.

14. Schwarz S, Häfner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology. 2000; 54:354–61.

15. Thompson HJ, Tkacs NC, Saatman KE, Raghupathi R, McIntosh TK. Hyperthermia following traumatic brain injury: a critical evaluation. Neurobiol Dis. 2003; 12:163–73.

16. Dimopoulos G, Falagas ME. Approach to the febrile patient in the ICU. Infect Dis Clin North Am. 2009; 23:471–84.

17. Otawara Y, Ogasawara K, Kubo Y, Tomitsuka N, Ogawa A, Suzuki M. Brain and systemic temperature in patients with severe subarachnoid hemorrhage. Surg Neurol. 2003; 60:159–64.

18. Honig A, Michael S, Eliahou R, Leker RR. Central fever in patients with spontaneous intracerebral hemorrhage: predicting factors and impact on outcome. BMC Neurol. 2015; 15:6.

19. Zawadzka M, Szmuda M, Mazurkiewicz-Bełdzińska M. Thermoregulation disorders of central origin: how to diagnose and treat. Anaesthesiol Intensive Ther. 2017; 49:227–34.

20. Ntaios G, Dziedzic T, Michel P, Papavasileiou V, Petersson J, Staykov D, et al. European Stroke Organisation (ESO) guidelines for the management of temperature in patients with acute ischemic stroke. Int J Stroke. 2015; 10:941–9.

21. Tam AK, Ilodigwe D, Mocco J, Mayer S, Kassell N, Ruefenacht D, et al. Impact of systemic inflammatory response syndrome on vasospasm, cerebral infarction, and outcome after subarachnoid hemorrhage: exploratory analysis of CONSCIOUS-1 database. Neurocrit Care. 2010; 13:182–9.

22. Rabinstein AA, Sandhu K. Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J Neurol Neurosurg Psychiatry. 2007; 78:1278–80.

23. Mackowiak PA. Concepts of fever. Arch Intern Med. 1998; 158:1870–81.

24. Saper CB, Breder CD. The neurologic basis of fever. N Engl J Med. 1994; 330:1880–6.

25. Dinarello CA, Cannon JG, Mier JW, Bernheim HA, LoPreste G, Lynn DL, et al. Multiple biological activities of human recombinant interleukin 1. J Clin Invest. 1986; 77:1734–9.

26. Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med. 1984; 311:1413–8.

27. Fontana A, Weber E, Dayer JM. Synthesis of interleukin 1/endogenous pyrogen in the brain of endotoxin-treated mice: a step in fever induction? J Immunol. 1984; 133:1696–8.

28. Gourine AV, Rudolph K, Tesfaigzi J, Kluger MJ. Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats. Am J Physiol. 1998; 275:R754–61.

29. Kluger MJ, Kozak W, Leon LR, Conn CA. The use of knockout mice to understand the role of cytokines in fever. Clin Exp Pharmacol Physiol. 1998; 25:141–4.

30. Klir JJ, McClellan JL, Kluger MJ. Interleukin-1 beta causes the increase in anterior hypothalamic interleukin-6 during LPS-induced fever in rats. Am J Physiol. 1994; 266(6 Pt 2):R1845–8.

31. Klir JJ, Roth J, Szelényi Z, McClellan JL, Kluger MJ. Role of hypothalamic interleukin-6 and tumor necrosis factor-alpha in LPS fever in rat. Am J Physiol. 1993; 265(3 Pt 2):R512–7.

32. Dinarello CA, Cannon JG, Mancilla J, Bishai I, Lees J, Coceani F. Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Res. 1991; 562:199–206.

33. Dinarello CA, Wolff SM. The role of interleukin-1 in disease. N Engl J Med. 1993; 328:106–13.

34. Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol. 1998; 275:R269–77.

35. Ganong WF. Central regulation of visceral function. In : Ganong WF, editor. Review of medical physiology. 17th ed. Norwalk: Appleton & Lange;1995. p. 210–32.

36. Kupfermann I. Hypothalamus and limbic system: motivation. In : Kandel ER, Schwartz JH, Jessell TM, editors. Principles of neural science. 3rd ed. New York: Elsevier;1991. p. 750–60.

37. Brazis PW, Masden JC, Biller J. Localization in clinical neurology. 3rd ed. Boston: Little Brown;1996. p. 381–400.

38. Alshahrani AM, Al-Said YA, Mamoun IA, Streletz LJ. Central fever due to hypothalamic lesion in a patient with tuberculous meningitis. Neurosciences (Riyadh). 2002; 7:301–3.

39. Shibata M. Hyperthermia in brain hemorrhage. Med Hypotheses. 1998; 50:185–90.

40. Rango M, Arighi A, Airaghi L, Bresolin N. Central hyperthermia, brain hyperthermia and low hypothalamus temperature. Clin Auton Res. 2012; 22:299–301.

41. Boulant JA. Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin Infect Dis. 2000; 31 Suppl 5:S157–61.

42. Won SJ, Lin MT. 5-Hydroxytryptamine receptors in the hypothalamus mediate thermoregulatory responses in rabbits. Naunyn Schmiedebergs Arch Pharmacol. 1988; 338:256–61.

43. Mayer SA, Lin J, Homma S, Solomon RA, Lennihan L, Sherman D, et al. Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke. 1999; 30:780–6.

44. Soffer D. Brain tumors simulating purulent meningitis. Eur Neurol. 1976; 14:192–7.

45. Tanriverdi F, Senyurek H, Unluhizarci K, Selcuklu A, Casanueva FF, Kelestimur F. High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma. J Clin Endocrinol Metab. 2006; 91:2105–11.

46. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah Growth Study: growth standards and the prevalence of growth hormone deficiency. J Pediatr. 1994; 125:29–35.

47. Kokshoorn NE, Wassenaar MJ, Biermasz NR, Roelfsema F, Smit JW, Romijn JA, et al. Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values. Eur J Endocrinol. 2010; 162:11–8.

48. Juul A, Behrenscheer A, Tims T, Nielsen B, Halkjaer-Kristensen J, Skakkebaek NE. Impaired thermoregulation in adults with growth hormone deficiency during heat exposure and exercise. Clin Endocrinol (Oxf). 1993; 38:237–44.

49. Agha A, Thompson CJ. Anterior pituitary dysfunction following traumatic brain injury (TBI). Clin Endocrinol (Oxf). 2006; 64:481–8.

50. Crompton MR. Hypothalamic lesions following closed head injury. Brain. 1971; 94:165–72.

51. 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; 25:163–76.

52. Clar HE. Clinical and morphological studies of pituitary and diencephalic space-occupying lesions before and after operation, with special reference to temperature regulation. Acta Neurochir (Wien). 1979; 50:153–99.

53. De Almeida AN, Marino R Jr. The early years of hemispherectomy. Pediatr Neurosurg. 2005; 41:137–40.

54. Kossoff EH, Vining EP, Pyzik PL, Kriegler S, Min KS, Carson BS, et al. The postoperative course and management of 106 hemidecortications. Pediatr Neurosurg. 2002; 37:298–303.

55. Savage KE, Oleson CV, Schroeder GD, Sidhu GS, Vaccaro AR. Neurogenic fever after acute traumatic spinal cord injury: a qualitative systematic review. Global Spine J. 2016; 6:607–14.

56. Huang YS, Hsiao MC, Lee M, Huang YC, Lee JD. Baclofen successfully abolished prolonged central hyperthermia in a patient with basilar artery occlusion. Acta Neurol Taiwan. 2009; 18:118–22.

57. Hocker SE, Tian L, Li G, Steckelberg JM, Mandrekar JN, Rabinstein AA. Indicators of central fever in the neurologic intensive care unit. JAMA Neurol. 2013; 70:1499–504.

58. Fernandez A, Schmidt JM, Claassen J, Pavlicova M, Huddleston D, Kreiter KT, et al. Fever after subarachnoid hemorrhage: risk factors and impact on outcome. Neurology. 2007; 68:1013–9.

59. Deogaonkar A, de Georgia M, Bae C, Abou-Chebl A, Andrefsky J. Fever is associated with third ventricular shift after intracerebral hemorrhage: pathophysiologic implications. Neurol India. 2005; 53:202–7.

60. Thompson HJ, Pinto-Martin J, Bullock MR. Neurogenic fever after traumatic brain injury: an epidemiological study. J Neurol Neurosurg Psychiatry. 2003; 74:614–9.

61. Young AB, Ott LG, Beard D, Dempsey RJ, Tibbs PA, McClain CJ. The acute-phase response of the brain-injured patient. J Neurosurg. 1988; 69:375–80.

62. Childers MK, Rupright J, Smith DW. Post-traumatic hyperthermia in acute brain injury rehabilitation. Brain Inj. 1994; 8:335–43.

63. Karaszewski B, Wardlaw JM, Marshall I, Cvoro V, Wartolowska K, Haga K, et al. Measurement of brain temperature with magnetic resonance spectroscopy in acute ischemic stroke. Ann Neurol. 2006; 60:438–46.

64. Sazbon L, Groswasser Z. Outcome in 134 patients with prolonged posttraumatic unawareness: part 1: parameters determining late recovery of consciousness. J Neurosurg. 1990; 72:75–80.

65. Cunha BA, Tu RP. Fever in the neurosurgical patient. Heart Lung. 1988; 17(6 Pt 1):608–11.

66. Segatore M. Fever after traumatic brain injury. J Neurosci Nurs. 1992; 24:104–9.

67. Powers JH, Scheld WM. Fever in neurologic diseases. Infect Dis Clin North Am. 1996; 10:45–66.

68. Cunha BA. Fever in the critical care unit. Crit Care Clin. 1998; 14:1–14.

69. Cunha BA. The clinical significance of fever patterns. Infect Dis Clin North Am. 1996; 10:33–44.

70. Cunha BA. Clinical approach to fever in critical care. In : Cunha BA, editor. Infectious diseases in critical care medicine. 3rd ed. New York: Informa;2010. p. 1–18.

71. Cunha BA. Clinical approach to fever in the neurosurgical intensive care unit: focus on drug fever. Surg Neurol Int. 2013; 4(Suppl 5):S318–22.

72. O’Grady NP, Barie PS, Bartlett JG, Bleck T, Garvey G, Jacobi J, et al. Practice guidelines for evaluating new fever in critically ill adult patients. Task Force of the Society of Critical Care Medicine and the Infectious Diseases Society of America. Clin Infect Dis. 1998; 26:1042–59.

73. Mukhtar U, Shoukat U, Athar MK, Rincon F. Utility of biomarkers in the evaluation of fever in the intensive care unit after brain injury. JHN J. 2017; 12:6.

74. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 1997; 92:739–50.

75. DeMaio J, Bartlett JG. Update on diagnosis of Clostridium difficile-associated diarrhea. Curr Clin Top Infect Dis. 1995; 15:97–114.

76. Stein M, Caplan ES. Nosocomial sinusitis: a unique subset of sinusitis. Curr Opin Infect Dis. 2005; 18:147–50.

77. Haley RW, Culver DH, White JW, Morgan WM, Emori TG, Munn VP, et al. The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol. 1985; 121:182–205.

78. Haley RW. Measuring the costs of nosocomial infections: methods for estimating economic burden on the hospital. Am J Med. 1991; 91(3B):32S–38S.

79. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am. 1996; 10:85–91.

80. Busto R, Globus MY, Dietrich WD, Martinez E, Valdés I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke. 1989; 20:904–10.

81. Kil HY, Zhang J, Piantadosi CA. Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab. 1996; 16:100–6.

82. Dietrich WD, Busto R, Halley M, Valdes I. The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol. 1990; 49:486–97.

83. Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intensive Care Med. 1999; 25:668–73.

84. Peres Bota D, Lopes Ferreira F, Mélot C, Vincent JL. Body temperature alterations in the critically ill. Intensive Care Med. 2004; 30:811–6.

85. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005; 6:369–75.

86. Holtzclaw BJ. The febrile response in critical care: state of the science. Heart Lung. 1992; 21:482–501.

87. 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; 7:729–38.

88. Wass CT, Lanier WL, Hofer RE, Scheithauer BW, Andrews AG. Temperature changes of > or = 1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology. 1995; 83:325–35.

89. 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; 38:533–41.

90. Minamisawa H, Smith ML, Siesjö BK. The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol. 1990; 28:26–33.

91. Jaber S, Chanques G, Altairac C, Sebbane M, Vergne C, Perrigault PF, et al. A prospective study of agitation in a medical-surgical ICU: incidence, risk factors, and outcomes. Chest. 2005; 128:2749–57.

92. Kiekkas P, Samios A, Skartsani C, Tsotas D, Baltopoulos GI. Fever and agitation in elderly ICU patients: a descriptive study. Intensive Crit Care Nurs. 2010; 26:169–74.

93. Aldemir M, Ozen S, Kara IH, Sir A, Baç B. Predisposing factors for delirium in the surgical intensive care unit. Crit Care. 2001; 5:265–70.

94. Huschak G, Hoell T, Wiegel M, Hohaus C, Stuttmann R, Meisel HJ, et al. Does brain temperature correlate with intracerebral pressure? J Neurosurg Anesthesiol. 2008; 20:105–9.

95. Bruder N, Raynal M, Pellissier D, Courtinat C, François G. Influence of body temperature, with or without sedation, on energy expenditure in severe head-injured patients. Crit Care Med. 1998; 26:568–72.

96. Hasday JD, Garrison A. Antipyretic therapy in patients with sepsis. Clin Infect Dis. 2000; 31 Suppl 5:S234–41.

97. Barie PS, Hydo LJ, Eachempati SR. Causes and consequences of fever complicating critical surgical illness. Surg Infect (Larchmt). 2004; 5:145–59.

98. Mackowiak PA, Boulant JA. Fever’s glass ceiling. Clin Infect Dis. 1996; 22:525–36.

99. Todd MM, Hindman BJ, Clarke WR, Torner JC, Weeks JB, Bayman EO, et al. Perioperative fever and outcome in surgical patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2009; 64:897–908.

100. Rousseaux P, Scherpereel B, Bernard MH, Graftieaux JP, Guyot JF. Fever and cerebral vasospasm in ruptured intracerebral aneurysms. Surg Neurol. 1980; 14:459–65.

101. Wartenberg KE, Schmidt JM, Claassen J, Temes RE, Frontera JA, Ostapkovich N, et al. Impact of medical complications on outcome after subarachnoid hemorrhage. Crit Care Med. 2006; 34:617–24.

102. Naidech AM, Bendok BR, Bernstein RA, Alberts MJ, Batjer HH, Watts CM, et al. Fever burden and functional recovery after subarachnoid hemorrhage. Neurosurgery. 2008; 63:212–8.

103. Saxena M, Young P, Pilcher D, Bailey M, Harrison D, Bellomo R, et al. Early temperature and mortality in critically ill patients with acute neurological diseases: trauma and stroke differ from infection. Intensive Care Med. 2015; 41:823–32.

104. Lausberg G. Significance of thermoregulatory disorders in the multi-injured with predominantly cranial lesion. Cah Anesthesiol. 1971; 19:315–24.

105. Ferguson A. Evaluation and treatment of fever in intensive care unit patients. Crit Care Nurs Q. 2007; 30:347–63.

106. Henker R, Rogers S, Kramer DJ, Kelso L, Kerr M, Sereika S. Comparison of fever treatments in the critically ill: a pilot study. Am J Crit Care. 2001; 10:276–80.

107. Steele RW, Tanaka PT, Lara RP, Bass JW. Evaluation of sponging and of oral antipyretic therapy to reduce fever. J Pediatr. 1970; 77:824–9.

108. Lenhardt R, Negishi C, Sessler DI, Vuong K, Bastanmehr H, Kim JS, et al. The effects of physical treatment on induced fever in humans. Am J Med. 1999; 106:550–5.

109. O’Donnell J, Axelrod P, Fisher C, Lorber B. Use and effectiveness of hypothermia blankets for febrile patients in the intensive care unit. Clin Infect Dis. 1997; 24:1208–13.

110. Mayer S, Commichau C, Scarmeas N, Presciutti M, Bates J, Copeland D. Clinical trial of an air-circulating cooling blanket for fever control in critically ill neurologic patients. Neurology. 2001; 56:292–8.

111. Diringer MN; Neurocritical Care Fever Reduction Trial Group. Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. Crit Care Med. 2004; 32:559–64.

112. Schmutzhard E, Engelhardt K, Beer R, Brössner G, Pfausler B, Spiss H, et al. Safety and efficacy of a novel intravascular cooling device to control body temperature in neurologic intensive care patients: a prospective pilot study. Crit Care Med. 2002; 30:2481–8.

113. Keller E, Imhof HG, Gasser S, Terzic A, Yonekawa Y. Endovascular cooling with heat exchange catheters: a new method to induce and maintain hypothermia. Intensive Care Med. 2003; 29:939–43.

114. Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001; 51:275–81.

115. Wang H, Olivero W, Lanzino G, Elkins W, Rose J, Honings D, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J Neurosurg. 2004; 100:272–7.

116. Liu WG, Qiu WS, Zhang Y, Wang WM, Lu F, Yang XF. Effects of selective brain cooling in patients with severe traumatic brain injury: a preliminary study. J Int Med Res. 2006; 34:58–64.

117. Toulmond S, Rothwell NJ. Interleukin-1 receptor antagonist inhibits neuronal damage caused by fluid percussion injury in the rat. Brain Res. 1995; 671:261–6.

118. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke. 1998; 29:529–34.

119. Mendieta Zerón H, Arriaga García Rendon JC. Remission of central fever with morphine post traumatic brain injury. J Med Liban. 2014; 62:57–61.

120. Shemano I, Nickerson M. Effect of ambient temperature on thermal responses to drugs. Can J Biochem Physiol. 1958; 36:1243–9.

121. Korepu P, Sriganesh K, Vinay B. Hyperpyrexia following hemispherotomy and role of unconventional therapy. J Neuroanaesth Crit Care. 2014; 1:210–1.

122. Natteru P, George P, Bell R, Nattanmai P, Newey CR. Central hyperthermia treated with bromocriptine. Case Rep Neurol Med. 2017; 2017:1712083.

123. Frenette AJ, Kanji S, Rees L, Williamson DR, Perreault MM, Turgeon AF, et al. Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. J Neurotrauma. 2012; 29:1–18.

124. Ünver Tuhan H, Anık A, Çatlı G, Abacı A, Öztürk T, Güleryüz H, et al. Recovery of central fever after gh therapy in a patient with GH deficiency secondary to posttraumatic brain injury. J Clin Res Pediatr Endocrinol. 2015; 7:77–9.