1. Navaz Karanjia, MD Medical Director, Neurocritical Care Program and Neuro-ICU Assistant Professor of Neurosciences University of California-San Diego Health System

2. Navaz Karanjia, MD FINANCIAL DISCLOSURE: none UNLABELED/UNAPPROVED USE DISCLOSURE: hypertonic saline / propofol use for ICP control

3.  Severe TBI pathophysiology  Severe TBI management

5.  Closed/Blunt  Motor Vehicle Accidents  Sports Injuries  Penetrating  Gunshot wounds  Stab wounds  Blast  Bomb blasts  Battlefield Injuries

6.  Mild  no LOC or amnesia  brief amnesia or LOC, or impaired alertness, memory  postconcussive syndrome  GCS 13-15  Moderate  LOC > 5 min, or focal neurologic deficit  GCS 9-12  Severe  GCS < 8

7.  Primary Injury  Epidural  Subdural  Subarachnoid  Contusion/ICH  DAI  Secondary Injury  Cerebral edema / elevated ICP  Ischemia  Excitotoxicity  Inflammation

9. Cerebral Oxygenation  PaO2 (normooxic)  Hemoglobin (>8) Cerebral Metabolism  Sedation  Seizure screening/rx  Thermoregulatory mgmt Cerebral Perfusion  Blood pressure (SBP >90)  Cardiac output  Volume status (euvolemic)  ICP / CPP (ICP 60)  PaCO2 (normocarbic)

10. “Guidelines for the management of severe traumatic brain injury, 3 rd Edition (2007)” Brain Trauma Foundation and The American Association of Neurological Surgeons Congress of Neurological Surgeons J Neurotrauma 24 Suppl 1: p. S1-106 (2007) Download available: www.braintrauma.org

11.  Elevate and maintain head of bed > 30 0, keep neck straight  Provide sedation and analgesia  Resuscitate with isotonic to hypertonic fluids (NS)  Maintain normoxia with PaO2 target of >60 (not hyperoxic) mmHg  Maintain Hgb at least >8 or higher if intracerebral monitoring indicates  Avoid hypotension (SBP 60mmHg (and <70mmHg)  Maintain ICP < 20mmHg  Maintain normocapnia with PaCO2 35-45 mmHg  Maintain normothermia with temperature goal of 36.5-37.5 0  Antiepileptic therapy x 7 days, continue only if seizing  NO steroids  Early nutritional optimization  Normoglycemia

12. Cerebral Oxygenation  PaO2 (normooxic)  Hemoglobin (>8) Cerebral Metabolism  Sedation  Seizure screening/rx  Thermoregulatory mgmt Cerebral Perfusion  Blood pressure (SBP >90)  Cardiac output  Volume status (euvolemic)  ICP / CPP (ICP 60)  PaCO2 (normocarbic)

13. BTF/AANS GUIDELINE  Oxygenation is to be monitored  Hypoxia (O2 sat <90% and pO2<60) is to be avoided (Level 3)

14.  Oxygenation  Hypoxia is bad  ICP by CBF  Aerobic anaerobic metabolism energy failure, dying in 4 min

15.  Oxygenation  Hyperoxia is probably bad for TBI patients

16.  Oxygenation  Hyperoxia is probably bad for TBI patients Hyperoxia (Pa02>300) 63% mortality Hypoxia (Pa02<60) 57% mortality Normooxia 43% mortality OR for death w/ hyperoxia = 1.8

17.  Oxygenation  Normooxia is just right

18. Role of hemoglobin in neurovascular injury  Cerebral ischemia is caused by impaired CBF and cerebral oxygen delivery (DO2)  DO2= CBF x arterial oxygen content  Arterial oxygen content = linearly related to Hb  In normal brain, compensatory vasodilation occurs at Hb <10, brain hypoxia at Hb <6

19. Oddo M et al. Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage. Stroke 2009 Apr; 40(4): 1275-81 Percentage of episodes of brain tissue hypoxia (PbtO2 40) according to different Hgb ranges. *P<0.05 for Hgb <9 g/dl  In aneurysmal subarachnoid hemorrhage, ICH, and stroke, microdialysis and brain tissue oxygen monitoring associate Hb <9-10 with brain tissue hypoxia and metabolic distress

21. Cerebral Oxygenation  PaO2 (normooxic)  Hemoglobin (>8) Cerebral Metabolism  Sedation  Seizure screening/rx  Thermoregulatory mgmt Cerebral Perfusion  Blood pressure (SBP >90)  Cardiac output  Volume status (euvolemic)  ICP / CPP (ICP 60)  PaCO2 (normocarbic)

22. BTF/AANS GUIDELINE  Blood pressure should be monitored  SBP < 90mmHg is to avoided (Level 2) Resuscitate patients to SBP>90 using isotonic to hypertonic, non-glucose containing fluids; use pressors if necessary

23. BTF/AANS GUIDELINE  Aggressive attempts to maintain CPP > 70mmHg with fluids and pressors should be avoided because of the risk of ARDS (Level 2)  Avoid CPP < 50mmHg (Level 3) Keep CPP >60; target CPP 60-70 if using pressors

24. 80% 12% 8%8% 92% 4%4% 4%4% 79%20% Monroe Kellie Doctrine  Skull is a rigid container (1600 cc)  Cranial contents (brain, blood, CSF) are incompressible  Additional volume (pathologic or expansile) will lead to displacement of normal cranial contents Normal ICP = 5-20 cm H20 CSF Blood Brain Blood Tumor Brain Normal Cerebral edema Tumor Saunders NR, Habgood MD, Dziegielewska KM (1999). "Barrier mechanisms in the brain, I. Adult brain". Clin. Exp. Pharmacol. Physiol. 26 (1): 11–9.

25. HV, mannitol, 23% Brain Volume No blood = BAD FOR BRAIN CPP = MAP - ICP Rosner M J, Rosner S D & Johnson A H. "Cerebral perfusion: management protocol and clinical results." J.Neurosurgery 1985; 83: 949-962.

26. CPP = MAP - ICP CBF = CPP/CVR CD02 = CBF x Ca02

27. Aerobic anaerobic metabolism energy failure, dying in 4 min

28. Rosner M J, Rosner S D & Johnson A H. "Cerebral perfusion: management protocol and clinical results." J.Neurosurgery 1985; 83: 949-962. Bratton SL et al. J Neurotrauma 24 (S1): S59-S64, 2007 Narotam P, Morrison J et al. Brain tissue oxygen monitoring in traumatic brain injury and major trauma: outcome analysis of a brain tissue oxygen-directed therapy. JNS (2009) 111 (4): 672-682 TBI: -1 episode of prehospital SBP<90 = 2x mortality -If CPP < 60 over 33% of the time, mortality ~100% -ICP 60 = mortality reduction by > 50% -HOWEVER, CPP>70 = increased mortality Healthy human subjects: normal CPP = 50-70 -CPP<50 = ischemia/decreased EEG amplitude TARGET CPP>60, ICP 90

29. Autoregulation

30. BTF/AANS GUIDELINE  ICP should monitored in all severe TBI patients (GCS <8) with abnormal CT (Level 2)  ICP should be monitored in all severe TBI patients (GCS 2 of the following (age > 40, posturing, SBP < 90mmHg) (Level 3)  Treatment should be initiated with ICP threshold > 20mmHg (Level 2)  A combination of ICP value, clinical and CT findings should be used to determine the need for treatment (Level 3)

31. Subfalcine Herniation  Cerebral cortex under falx  Leg weakness   mental status Central/Upward Herniation  Brainstem down/up through tentorium   mental status  Dilated pupil, eye “down and out” (CN3)  Weakness/posturing  Basilar stroke Tonsillar Herniation  Cerebellar tonsils in foramen magnum  Awake, pharynx weakness, quadriparesis  Arrhythmia/cardiac arrest  Respiratory arrest Uncal Herniation  Uncus over tentorial notch   mental status  Dilated pupil, eye “down and out” (CN3)  Weakness/posturing

32. 80% 12% 8%8% 92% 4%4% 4%4% 79%20% Monroe Kellie Doctrine  Skull is a rigid container (1600 cc)  Cranial contents (brain, blood, CSF) are incompressible  Additional volume (pathologic or expansile) will lead to displacement of normal cranial contents Normal ICP = 5-20 cm H20 CSF Blood Brain Blood Tumor Brain Normal Cerebral edema Tumor Saunders NR, Habgood MD, Dziegielewska KM (1999). "Barrier mechanisms in the brain, I. Adult brain". Clin. Exp. Pharmacol. Physiol. 26 (1): 11–9. CPP = MAP - ICP

33. UCSD Brain Code Guideline

34. Venous blood  HOB up 60 deg  Neck straight  No IJ lines, do not lay flat for lines  Do no use venodilating BP agents CSF  Place EVD  Change popoff Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) Lesion  Blood, tumor, pus -> surgery  Air-> 100% NRB, surgery Arterial blood  Normoventilate  Avoid hyperemia: CPP 50- 70  Avoid Hypoxia: Pa02>60  Decrease metabolism: sedation, cooling

35. Arterial blood  Normoventilat e target Pac02 35-45  Avoid hyperemia: CPP 50-70  Avoid hypoxia: Pa02>60  Decrease metabolism: propofol IVP, propofol/pentob arb gtt, hypothermia 32- 34 C Kramer A, Zygun D. Anemia and red cell transfusion in neurocritical care. Critical Care 2009 13:R89 35 60150 25 20 50

36. BTF/AANS GUIDELINE  Prophylactic hyperventilation of PaCO2 < 25mmHg is not recommended (Level 2)  HV should be avoided during the first 24 hours after injury (Level 3)  If HV is used, jugular bulb monitoring or brain tissue oxygen tension measurement is recommended to monitor oxygen delivery (Level 3)  Hyperventilation (HV) is recommended as a temporizing measure for reduction of elevated ICP (Level 3)

37. BTF/AANS GUIDELINE  Prophylactic administration of barbiturate to induce EEG burst suppression is not recommended (Level 2)  High dose barbiturate is recommended to control elevated ICP refractory to medical and surgical management; hemodynamic stability is critical before and during treatment (Level 2)  Propofol is recommended for ICP control but not for improving mortality or 6-month outcome; High dose propofol can produce significant increased morbidity (Level 2) Sedate patients to reduce cerebral metabolism; titrate to comfort and ICP control.

38. Venous blood  HOB up 60 deg  Neck straight  No IJ lines, do not lay flat for lines  Do no use venodilating BP agents CSF  Place EVD  Change popoff Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) Lesion  Blood, tumor, pus -> surgery  Air-> 100% NRB, surgery Arterial blood  Normoventilate  Avoid hyperemia: CPP 50- 70  Avoid Hypoxia: Pa02>60  Decrease metabolism: sedation, cooling

39. Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) CytotoxicVasogenic Stroke Tumor Abscess

40. Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) Sodium=1.0 Mannitol=0.9 Glycerol=0.5Sodium=0.6 Sodium=0.97 Mannitol=0.9 Glycerol=0.5Urea=0.6 Reflection Coefficient

41. Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC)  Increased vascular volume-> improves CBF up to 23%  Dehydration of erythrocytes increases deformability through small capillaries  Reduces inflammatory response by reducing PMN adhesion to microvasculature (unclear clinical significance) Pascual J et al. Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil rolling and adherence to endothelium and reduces in vivo vascular leakage. Ann Surg. 2000 Nov; 236 (5): 634-642 Tseng M, Pippa G et al. Effect of hypertonic saline on cerebral blood flow in poor grade patients with subarachnoid hemorrhage. Stroke 2003;34:1389-1396

42. Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) Sodium=1.0 Mannitol=0.9 Glycerol=0.5Sodium=0.6

43. Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) Sodium=1.0 Mannitol=0.9 Glycerol=0.5Sodium=0.6 Create a GRADIENT, DON’T dehydrate your patient!

44. MA Koenig, M Bryan, JL Lewin, III, MA Mirski, RG Geocadin and RD Stevens Neurology 2008;70;1023-1029; originally published online Feb 13, 2008  253 cases transtentorial herniation  30cc 23.4% saline bolus reversed clinical signs of TTH in 75%  Transient hypotension in 17%, no CPM on MRI at 17 days  Up to 50% reduction of ICP  65% of patients below 20mmHg ICP

45. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions Qureshi,,Geocadin,Suarez, Ulatowski, CRITICAL CARE MEDICINE 2000;28:1556-1564  11/28 (40%) survived to discharge  7/11 (59%) survivors functionally independent

46. BTF/AANS GUIDELINE  Mannitol is effective for control of raised ICP at doses of 0.25 g/kg to 1 g/kg. Arterial hypotension (SBP <90 mm Hg) should be avoided (Level 2)  Restrict mannitol use prior to ICP monitoring to those patients who are herniating or are neurologically deteriorating (not attributable to extracranial cause) (Level 3)

47. BTF/AANS GUIDELINE  The use of steroids is not recommended for improving outcome or reducing ICP. (Level 1)  High dose methylprednisolone in moderate-severe TBI patients is associated with increased mortality and is contraindicated. (Level 1)

48.  Mixed results in Blunt Trauma  Many case series show ICP reduction and mortality benefit  About 30% of patients have favorable long term outcomes Howard et al, J Trauma. 2008 Aug;65(2):380-5

49.  155 severe, diffuse TBI patients randomized  Early bifrontotemporal decompressive hemicraniectomy v. standard care  In adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and the length of stay in the ICU but was associated with more unfavorable outcomes Cooper DJ et. al. N Engl J Med 2011; 364:1493-1502

50.  Surgical intervention for moderate to severe penetrating and blast TBI in the theater  Early hemicraniectomy as blast brain becomes hyperemic and edematous very quickly (few hours)  Life saving  May allow for overseas transport Ling et al, J Neurotrauma (2009) Bell et al, Neurosurg Focus. 2010 May;28(5):E1.

51. Venous blood  HOB up 60 deg  Neck straight  No IJ lines, do not lay flat for lines  Do no use venodilating BP agents CSF  Place EVD  Change popoff Brain parenchyma  Osmotherapy (mannitol, hypertonic saline)  Steroids only if appropriate (tumor, HACE, some infections)  Surgery (hemicrani, SOC) Lesion  Blood, tumor, pus -> surgery  Air-> 100% NRB, surgery Arterial blood  Normoventilate  Avoid hyperemia: CPP 50- 70  Avoid Hypoxia: Pa02>60  Decrease metabolism: sedation, cooling

52. Cerebral Oxygenation  PaO2 (normooxic)  Hemoglobin (>8) Cerebral Metabolism  Sedation  Seizure screening/rx  Thermoregulatory mgmt Cerebral Perfusion  Blood pressure (SBP >90)  Cardiac output  Volume status (euvolemic)  ICP / CPP (ICP 60)  PaCO2 (normocarbic)

53.  Fever increases cerebral metabolic rate by 5-7% with each degree change in temp  Fever accelerates the secondary injury cascade, causing neuronal death,  infarct volume, cerebral edema,  ICP, midline shift, morbidity, mortality   in temp by 1°C increases OR of death by 2.2 in ischemic patients Henker, Brown, Marion; Neurosurgery 42:1071, 1998 Andrews, et al., J Neurosurg 97:326, 2002

54.  Normothermia is a class I AHA recommendation for ischemic stroke, ICH, and SAH patients  Hypothermia is a class I AHA recommendation for comatose post-cardiac arrest patients (improves good neurologic outcome in survivors from ~30% to ~50% (OR 5, NNT 6)  Techniques: acetaminophen, cooling blankets, advanced thermoregulatory devices (cooling catheter, conductive surface cooling devices)

55. Normothermia in TBI:  Fever is associated with significantly worse outcomes Li, J et al. J Neurotrauma. 2012 January 1; 29(1): 96–100

56. Hypothermia in TBI:  No clear evidence yet to support its use for neuroprotection (it IS effective for refractory ICP management)  National Acute Brain Injury Study: Hypothermia II (neuroprotection study) terminated early for futility GL Clifton, A Valadka, D Zygun et al. Lancet Neurol, 10 (2011), pp. 131–139 Sadaka F et al. Brain Inj. 2012;26(7-8):899-908.

57. BTF/AANS GUIDELINE  Prophylactic hypothermia does not increase nor decrease mortality when compared to normothermic controls (Level 3)  When hypothermia is maintained for > 48 hours, there is decreased mortality risk (Level 3)  Prophylactic hypothermia is associated with higher GOS (4 and 5) than normothermic controls (Level 3) Maintain normothermia; hypothermia is not standard of care for neuroprotection but is useful for refractory ICP treatment

58. ▪ Proper sedation cuts resting cerebral metabolic rate in half ▪ No evidence that one sedative is better than another for TBI as long as ICP / CPP /SBP are controlled Crit Care Med. 2011 Dec;39(12):2743-51.

59. BTF/AANS GUIDELINE  Prophylactic administration of barbiturate to induce EEG burst suppression is not recommended (Level 2)  High dose barbiturate is recommended to control elevated ICP refractory to medical and surgical management; hemodynamic stability is critical before and during treatment (Level 2)  Propofol is recommended for ICP control but not for improving mortality or 6-month outcome; High dose propofol can produce significant increased morbidity (Level 2) Sedate patients to reduce cerebral metabolism; titrate to comfort and ICP control.

60.  Pentobarbital  Loading Dose ▪ 10 mg/kg i.v. over 30 minutes ▪ 5 mg/kg i.v. every hour X 3 doses  Maintenance Dose ▪ 1 mg/kg/hr, i.v. infusion  Propofol  Start: 50  g/kg/min  Maintenance: 100  g/kg/min (titrate prn) Helpful to use EEG/SEDLINE monitoring during sedation for ICP control, to ensure excessive doses not being used J Clin Neurophysiol. 2011 Oct;28(5):483-8. Eisenberg et al, J Neurosurg 69:15-23 (1988)

61. Are seizures common in TBI patients?  22% of all moderate to severe TBI patients; 50% NCSz only (Vespa)  20-50% of all altered hypoxic-ischemic injury patients; most NCSz (Wijdicks, Krumholz, Wright, Geocadin)  8-10% of MICU patients without known brain injury with unexplained AMS; 67-100% were NCSz only (Towne, Oddo)  21% of MICU patients with encephalopathy due to toxic-metabolic cause, sepsis, or renal failure; 98% were NCSz only (Classen)  48% of patients who present with status epilepticus with persistent AMS have NCSz when monitored for 24 hrs; 14% were in NCSE (DeLorenzo)  11% of all altered ischemic stroke patients; 80% were NCSz only (Claassen)  31-36% of ICH patients with AMS; 58% NCSz only (Claassen, Vespa)  19% of all altered SAH patients; 70% were in NCSE (Claassen)

62. Are seizures problematic?

63. Cerebral Increased blood flow Energy requirements are matched by increased lactate, increased glucose MetabolicHyperglycemia Lactic acidosis AutonomicHypertension Increased CO Increased CVP MassiveCatecholaminesTachycardiaArrythmiasHyperpyrexiaVomiting Physiologic Changes--compensated

64. Physiologic Changes--decompensatedCerebral Failure of autoregulation HypoxiaHypoglycemia Decreased lactate Increased ICP Cerebral edema MetabolicHypoglycemiaHyponatremiaHypo/HyperkalemiaAcidosis Hepatic/Renal dysfunction DICRhabdomyolysisSerum/CSFleukocytosisAutonomicHypoxia Decreased blood pressure Falling CO Pulmonary edema CHFArrythmiasHyperpyrexia

65. Vespa et al Crit Care Med 2007 Higher Microdialysis Lactate/Pyruvate with seizures

66. Vespa et al Crit Care Med 2007 Increase in ICP in TBI patients

67. MRI after seizure

68. 2012 Neurocritical Care Society Guidelines for Treatment of Status Epilepticus: Indications for Continuous EEG Monitoring

69. TBI: Phenytoin or carbamazepine are effective in preventing early post-traumatic seizures They do not prevent onset of late post- traumatic seizures  Newer agents lack evidence to support their use (ex: leviteracetam Temkin et al, NEJM 323:497 (1990) Glotzner et al, Neurochir 26:66-79 (1983) Manaka et al, JpnJ Psych Neuro 46:311-315 (1992) Amer Acad Phys Med Rehab Arch Phys Med 79: 594 (1998)

70. BTF/AANS GUIDELINE  Anticonvulsant therapy is indicated to decrease the incidence of early post- traumatic seizures (< 7 days) (Level 2)  Phenytoin and valproate are not recommended for preventing late post- traumatic seizures (> 7 days) (Level 2) Give AED’s for 7 days, then stop unless pt is seizing or has had craniotomy

71.  PbO 2 measures interstitial brain tissue oxygenation (PbtO2) in mmHg and brain temperature (°C)  The goal is to prevent secondary injury by ensuring viable tissue is receiving adequate oxygen  Hypoxia strongly associated with a poorer outcome  Brain Tissue Oxygen Monitoring in Traumatic Brain Injury (BOOST 2) ongoing (closes 2014) Neurol. Res 20 Suppl 1, S71-75 (1998). J Neurosurg. 2009 Oct;111(4):672-82 J Neurosurg. 2009 Oct;111(4):644-9.

72. BTF/AANS GUIDELINE  Jugular venous saturations (< 50%) or brain tissue oxygenation tension (< 15mmHg) are treatment thresholds. (Level 3)

73.  Any episode of hyperglycemia >200 mg/dl associated with 3.6x risk of hospital mortality

74. BTF/AANS GUIDELINE  Patients should be fed to attain full caloric replacement by day 7 post-injury. (Level 2)  Normoglycemia is probably recommended

75. BTF/AANS GUIDELINE  Periprocedural antibiotics for intubation should be used to reduce the incidence of pneumonia but they do not change length of stay or mortality (Level 2)  Routine ventricular catheter exchanges or prophylactic antibiotic use for ventricular catheter placement is not recommended to reduce infection (Level 3)

76. BTF/AANS GUIDELINE  Early tracheostomy should be used to reduce the number of mechanical ventilation days; Does not reduce mortality or rate of nosocomial pneumonia (Level 2)

77. BTF/AANS GUIDELINE  Graduated compression stockings and intermittent pneumatic stockings should be used (Level 3)  Low molecular weight heparin or low dose unfractionated heparin should be used in combination with mechanical prophylaxis (Level 3)

78. AACP 2008 GUIDELINE  Use both Mechanical Compression Devices and heparin agents  Apply MCD as early as possible (typically upon admission)  Begin heparin agent at 36-48 hours  TBI without hemorrhage is not a contraindication to heparin agent  Active bleeding or intracranial hemorrhage is a contraindication  No evidence supporting the use of prophylactic inferior vena cava filters if heparin agent can be used American College of Chest Physicians (ACCP, 8th edition, 2008)

79.  Elevate and maintain head of bed > 30 0, keep neck straight  Provide sedation and analgesia  Resuscitate with isotonic to hypertonic fluids (NS)  Maintain normoxia with PaO2 target of >60 (not hyperoxic) mmHg  Maintain Hgb >8 or higher if intracerebral monitoring indicates  Avoid hypotension (SBP 60mmHg (and <70mmHg)  Maintain ICP < 20mmHg  Maintain normocapnia with PaCO2 35-45 mmHg  Maintain normothermia with temperature goal of 36.5-37.5 degrees Celsius  Antiepileptic therapy x 7 days, continue only if seizing  NO steroids  Early nutritional optimization  Normoglycemia

80. Josh Duckworth Holly Hinson Geoffrey Ling Romer Geocadin