A high-pressure situation: decompressing the evidence regarding management of traumatic brain injury

Transcription

1 A high-pressure situation: decompressing the evidence regarding management of traumatic brain injury May 2 nd, 2017 Taylor Roberson, PharmD Dan James, PharmD Daniel Dybdahl, PharmD OhioHealth Grant Medical Center

2 Learning Objectives Define the pathophysiology of traumatic brain injury (TBI) in relation to its resulting complications. Evaluate common agents used for appropriately managing severe TBI in adults. Discuss the current evidence regarding treatment modalities surrounding severe TBI. Review the TBI pharmacotherapy recommendations as outlined in the 2016 Brain Trauma Foundation guidelines and 2015 ACS TQIP guidelines. 2

3 Content Outline Background Types and categorization Pathophysiology Complications Guidelines introduction Acute management Intracranial hypertension management Post-acute management Prophylaxis considerations Neuropsychiatric rehabilitation 3

4 Background Taylor A. Roberson, PharmD PGY2 Emergency Medicine Pharmacy Resident OhioHealth Grant Medical Center 4

5 Traumatic Brain Injury Definition Disruption in the normal function of the brain that can be caused by a bump, blow, or jolt to the head, or penetrating head injury. 5 Traumatic Brain Injury & Concussion;

6 Traumatic Brain Injury Open Closed Focal Focal Diffuse Diffuse 6 Kazim et al. J Emerg Trauma Shock Werner et al. Br J Anaesth

7 Traumatic Brain Injury Primary mechanical damage Occurs at moment of impact Direct trauma Acceleration/deceleration & rotational forces Secondary insult Delayed, non-mechanical damage Cerebral ischemia, intracranial hypertension 7 Greve et al. Mt Sinai J Med Werner et al. Br J Anaesth

8 Direct tissue damage Systemic insults Transient neuronal depolarization Intracranial lesion Cerebral ischemia NT release & neuronal excitation Impaired autoregulation & altered CBF Metabolic failure Cell energy failure & membrane disruption Cellular edema & microanatomic disruption Cerebral edema Brain swelling 8 Greve et al. Mt Sinai J Med Heegaard et al. Emerg Med Clin N Am Werner et al. Br J Anaesth

9 Cerebral Autoregulation 9 Wykes et al. Surgery Crown Copyright 2015 Published by Elsevier Ltd. All rights reserved.

10 Monro-Kellie Hypothesis 10 Ropper AH. N Engl J Med Wykes et al. Surgery Crown Copyright 2015 Published by Elsevier Ltd. All rights reserved.

11 Cerebral Perfusion Pressure 60 mmhg MAP ICP CPP 11 ACS TQIP

12 Goals of Treatment Pulse Oximetry 95% ICP mmhg ICP mmhg Serum sodium meq/l Serum sodium meq/l PaO mmhg PbtO 2 15 mmhg INR 1.4 CPP 60 mmhg * PaCO mmhg CPP 60 mmhg * Platelets 75 x 10 3 / mm 3 SBP 100 mmhg SBP 100 mmhg Temperature C Hemoglobin 7 g/dl ph Glucose mg/dl 12 ACS TQIP

13 Devices for Monitoring ICP Intraparenchymal bolt Diagnostic Monitoring capabilities include temperature and PbtO 2 External ventricular drain (EVD) Diagnostic Therapeutic 13 ACS TQIP

14 14 Meyerson et al. U.S. Application No. 2001/ A

15 Management Guidelines Brain Trauma Foundation: Guidelines for the Management of Severe Traumatic Brain Injury, 4 th Edition Class 1,2,3 studies Level of recommendations ACS TQIP: Best Practices in the Management of Traumatic Brain Injury 15 ACS TQIP Carney et al. Neurosurgery

16 16 Acute Management

17 Glasgow Coma Score 17 Best eye response Best verbal response Best motor response None 1 To pressure 2 To sound 3 Spontaneous 4 Untestable Reason: None 1 Sounds 2 Words 3 Confused 4 Oriented 5 Untestable Reason: None 1 Extension 2 Abnormal flexion 3 Normal flexion 4 Localizing 5 Obey commands 6 Untestable Reason: ACS TQIP ; Teasdale et al. Lancet

18 Glasgow Coma Scale 13 Mild brain injury 9-12 Moderate brain injury 8 Severe brain injury 18 ACS TQIP Teasdale et al. Lancet

19 Rapid Sequence Intubation (RSI) Endotracheal intubation for severe TBI Airway protection Intubation can transiently increase ICP RSI with medications including paralysis can ameliorate ICP rise Many clinical controversies on which medications should be used for RSI in TBI 19 Kuzak et al. Can J Emerg Med Patanwala et al. Pharmacotherapy Robinson et al. Emerg Med J

20 Fluid Resuscitation Avoid hypotension 0.9% sodium chloride preferred Avoid hypotonic & hypoosmolar solutions D5W 0.45% or 0.225% NaCl D5/0.45% NaCl or D5/0.225% NaCl Lactated Ringer s Colloids associated with higher mortality vs NS 20 Ertmer et al. Crit Care Haddad SH et al. Scand J Trauma Resusc Emerg Med The SAFE Study Investigators. N Engl J Med

21 Steroids Brain Trauma Foundation The use of steroids is not recommended for improving outcome or reducing ICP In patients with severe TBI, high-dose methylprednisolone Brain Trauma Foundation was associated with increased mortality and is contraindicated Level I recommendation 21 Carney et al. Neurosurgery Edwards et al. Lancet

22 Intracranial Hypertension Dan James, PharmD PGY1 Pharmacy Practice Resident OhioHealth Grant Medical Center 22

23 Approach to Management Tier Three Tier One Head of bed Sedation & analgesia Ventricular drainage Tier Two Hyperosmolar therapy Hyperventilation Neuromuscular paralysis Barbiturate coma Craniectomy Hypothermia If ICP remains mmhg proceed to next tier 23 ACS TQIP

24 Pros Sedation & Analgesia Tier 1 Prevention of agitation Treatment of pain Facilitation of ventilation Induction of anxiolysis Arterial hypotension Interference with neurological exam Propofol-related infusion syndrome Minimization of seizures Potential neuroprotective effects of propofol Cons 24 Roberts et al. Crit Care Med

25 Sedation & Analgesia Tier 1 Kelly et al, 1999 Double blind RCT, propofol vs morphine Daily ICP & CPP similar, ICP lower on day 3 in propofol group (p<0.05), no difference in mortality or overall GOS No convincing evidence that one sedative is more efficacious than another for improvement of patient outcomes Additional trials are Class III or not included in guidelines Most trials demonstrate improved ICP and CPP with varying sedative agents vs baseline High doses of opioids have potentially deleterious effects on ICP and CPP 25 Roberts et al. Crit Care Med Kelly et al. J Neurosurg

26 Sedation & Analgesia Tier 1 Brain Trauma Foundation Propofol is recommended for the control of ICP Not recommended for improvement in long-term outcomes Level IIB recommendation ACS TQIP Use short-acting agents (e.g. propofol, fentanyl, midazolam) 26 Carney et al. Neurosurgery ACS TQIP

27 Ventricular Drainage Tier 1 Option One Closed drain Continuous ICP measurements with intermittent drainage Option Two Open drain Continuous drainage with intermittent ICP measurements Option Three Drain + Monitor Continuous drainage with EVD and ICP measurements with additional monitor 27 Carney et al. Neurosurgery

28 Hyperosmolar Therapy - Mechanism Tier 2 1. Osmotic Gradient Increased osmotic gradient Water extraction from brain tissue Reduction in brain volume 2. Rheological Effect Reduction in blood viscosity Increased initial cerebral blood flow and oxygen Reflex cerebral vasoconstriction Reduction in cerebral blood volume 28 Moritz et al. N Engl J Med Diringer et al. Curr Opin Crit Care

29 Hyperosmolar Therapy - Agents Tier 2 Mannitol Osmotic diuretic Preparation: 25% 50 ml vial, 20% 500 ml bag Dose: g/kg IV bolus Administration: Peripheral or central, filter Main monitoring parameter: Serum osmolality Hypertonic Saline (HTS) Concentrated NaCl Preparation: 3%, 7.5%, 23.4% intravenous solution Dose: IV bolus 250 ml of 3% 75 ml of 7.5% 30 ml of 23.4% Administration: Central line Main monitoring parameter: Serum sodium 29 Moritz et al. N Engl J Med Gross et al. J Pharm Pract Carney et al. Neurosurgery

30 Mangat, 2014 Tier 2 Study Design Retrospective cohort HTS vs mannitol in patients with severe TBI N = 73 Outcomes 2-week mortality, ICP burden Results Mortality not different, Cumulative ICP burden 15 vs 36% (p=0.003), Daily ICP burden 0.3 vs 1.3 hours/day (p=0.001) Conclusion: HTS was more effective in lowering ICP burden but did not effect mortality 30 Mangat et al. J Neurosurg

31 Hyperosmolar Therapy Tier 2 Evidence comparing agents is low quality, has significant limitations, and is conflicting Most studies demonstrate a similar or greater reduction in ICP with hypertonic saline when compared to mannitol Continuous vs. intermittent bolus HTS 31 Mangat et al. J Neurosurg Diringer et al. Curr Opin Crit Care Boone et al. Surg Neurol Int

32 Hyperosmolar Therapy Practical Considerations Tier 2 Mannitol Hypertonic Saline Diuresis Crystallization Rebound intracranial hypertension Volume expansion Extravasation Hypernatremia 32 Moritz et al. N Engl J Med

33 Hyperosmolar Therapy - Overview Tier 2 Equimolar boluses of mannitol and HTS act in similar manners to reduce ICP Both appear to be effective for ICP reduction in severe TBI Mannitol is considered the gold standard due to historical use but with no demonstrative superiority Distinct agents may be preferred in different clinical contexts 33 Mangat et al. J Neurosurg Diringer et al. Curr Opin Crit Care Boone et al. Surg Neurol Int

34 Hyperosmolar Therapy Tier 2 Brain Trauma Foundation Mannitol is effective for control of elevated ICP Re-stated recommendations from the 3 rd edition which are not supported by evidence meeting current standards ACS TQIP Hyperosmolar therapy (mannitol or hypertonic saline) should be given intermittently as needed for ICP elevation and not on a routine schedule 34 Carney et al. Neurosurgery ACS TQIP

35 Neuromuscular Paralysis Tier 3 Facilitation of ventilation Prevention of shivering Reduction in ICP Limitation of cough/icp surges Theoretical benefits Limited evidence Decrease in energy expenditure 35 Sanfilippo et al. Neurocrit Care

36 Neuromuscular Blocking Agents (NMBA) Tier 3 Depolarizing Succinylcholine Potential ICP surge Non-Depolarizing Rocuronium, vecuronium, atracurium, cisatracurium, pancuronium Vecuronium used as testdose Atracurium or cisatracurium used if responder as continuous infusion 36 Sanfilippo et al. Neurocrit Care

37 Sanfilippo, 2015 Tier 3 Design Systematic review evaluating effects of neuromuscular paralysis on TBI and elevated ICPs Lack of evidence to support or reject the use of neuromuscular blockage in patients with TBI Results Succinylcholine: 2/3 studies showed an ICP increase Non-depolarizing NMBA: 1/9 studies found a decrease in ICP No ICP changes were observed in the other studies Nondepolarizing NMBAs could be safer than succinylcholine (short-term effects on the ICP) Conclusion Confirmed the lack of strong evidence about the effect of NMBAs on longterm outcome in patients with TBI 37 Sanfilippo et al. Neurocrit Care

38 Neuromuscular Paralysis Tier 3 ACS TQIP Neuromuscular paralysis using a bolus test dose should be considered if previous measures fail If there is a positive response, continuous infusion of a neuromuscular blocking agent should be employed (Tier 3) The infusion should be titrated to maintain a train of four of at least two twitches 38 ACS TQIP

39 Barbiturate Coma Tier 3 The only non-surgical strategy for refractory intracranial hypertension Decreased cerebral metabolism Decreased cerebral blood volume Lowered intracranial pressure 39 Carney et al. Neurosurgery Gross et al. J Pharm Pract

40 Eisenberg, 1988 Tier 3 Design To evaluate effect of pentobarbital on refractory ICP RCT, five centers Pentobarbital vs standard, crossover, N=73 Outcomes Mortality, ICP Results ICP control two-times greater with pentobarbital, Responders had higher likelihood of survival (92% vs 17%), 6-month mortality: 36% responders vs 90% non-responders Conclusion: High-dose pentobarbital is an effective adjunctive therapy 40 Eisenberg et al. J Neurosurg

41 Barbiturate Coma Tier 3 Pentobarbital infusion 10 mg/kg over 30 minutes 5 mg/kg every hour for 3 doses 1 mg/kg/hour Titrated to burst suppression Maximum reduction in cerebral metabolism with burst suppression of 3 6 bursts/min (10 20 sec suppression) 41 Cesullo et al. J Neurosci Nurs Wolfe et al. Curr Neurol Neurosci Rep Gross et al. J Pharm Pract

42 Barbiturate Coma Tier 3 Pentobarbital 42 Cesullo et al. J Neurosci Nurs

43 Barbiturate Coma Tier 3 Poor correlation between pentobarbital levels and benefit or complications Sedation: 1 5 ug/ml Coma: ug/ml Presence of pentobarbital in the blood precludes pronouncement of brain death <5 ug/ml T 1/2 = hours 43 Cesullo et al. J Neurosci Nurs Cormio et al.. J Neurotrauma

44 Barbiturate Coma Concerns Tier 3 Hypotension Autoinduction Drug interactions Feeding intolerance Constipation Infection 44 Cesullo et al. J Neurosci Nurs Wolfe et al. Curr Neurol Neurosci Rep Gross et al. J Pharm Pract

45 Barbiturate Coma Tier 3 Brain Trauma Foundation High-dose barbiturate is recommended for elevated ICP refractory to maximum standard medical and surgical treatment Level IIB recommendation ACS TQIP Barbiturate or propofol coma may be used for those who have failed aggressive measures It should only be used if a test dose results in a decrease in ICP, thereby identifying the patient as a responder 45 Carney et al. Neurosurgery ACS TQIP

46 Decompressive Craniectomy Tier 3 Surgical procedure in which a large section of the skull is removed and the underlying dura mater is opened 46 Carney et al. Neurosurgery ACS TQIP

47 Post-Acute Management Daniel Dybdahl, PharmD PGY1 Pharmacy Practice Resident OhioHealth Grant Medical Center 47

48 Post-Acute Complications Post-traumatic seizures (PTS) Venous thromboembolism (VTE) Infection Neuropsychiatric disturbances 48

49 Post-Traumatic Seizures Occurs in up to 12% of patients with severe TBI Definitions: Early: within 7 days of injury Late: after 7 days of injury Post-traumatic epilepsy: recurrent seizures more than 7 days following injury 49 Carney et al. Neurosurgery

50 Seizure Prophylaxis Utilized for the prevention of early PTS Potential benefits of preventing seizures: Limiting physiological disturbances Preventing the development of chronic epilepsy Preventing herniation and death Phenytoin is considered the gold standard Increasing use of levetiracetam due to side effect profile 50 Carney et al. Neurosurgery

51 Inaba, 2013 Class II Study Design Prospective observational study in blunt head trauma Levetiracetam 1000 mg IV Q12H vs. phenytoin 20 mg/kg IV loading dose then 5 mg/kg/day IV divided every 8 hours Outcomes Early PTS in patients on levetiracetam (n=406) vs. phenytoin (n=407) Results No difference in seizure rate (1.5% vs. 1.5%, p=0.997) No significant difference in adverse drug reactions (7.9% vs. 10.3%, p=0.227) No significant difference in mortality (5.4% vs. 3.7%, p=0.236) 51 Inaba et al. J Trauma Acute Care Surg

52 Seizure Prophylaxi s Brain Trauma Foundation Phenytoin is recommended to decrease incidence of early PTS when benefits outweigh risks Insufficient evidence to recommend levetiracetam over phenytoin Not recommended to prevent late PTS Level IIA recommendation 52 Carney et al. Neurosurgery

53 Venous Thromboembolism Patients with TBI have a high risk for VTE Up to 54% incidence of deep venous thrombosis (DVT) without prophylaxis 20-30% incidence of DVT with mechanical prophylaxis VTE risk increases with severity of TBI 53 Carney et al. Neurosurgery

54 VTE Risk Factors in TBI Trauma Elderly age Motor deficits Reduced mobility VTE Multisystem trauma 54 Carney et al. Neurosurgery

55 Modified Berne-Norwood Criteria Low risk Moderate risk High risk No moderate or high risk criteria Subdural or epidural hematoma > 8 mm Contusion or intraventricular hemorrhage > 2 cm Multiple contusions per lobe Subarachnoid hemorrhage with abnormal CT angiogram Evidence of progression at 24 hours ICP monitor placement Craniotomy Evidence of progression at 72 hours Initiate pharmacologic prophylaxis if CT stable at 24 hours Initiate pharmacologic prophylaxis if CT stable at 72 hours Consider placement of an IVC filter 55 ACS TQIP

56 VTE Prophylaxis Brain Trauma Foundation Low molecular weight heparin (LMWH) or low-dose unfractionated heparin may be used in combination with mechanical prophylaxis Increased risk for intracranial hemorrhage with pharmacologic therapy Level III recommendation ACS TQIP VTE prophylaxis should be considered within the first 72 hours following TBI in most patients Earlier initiation of pharmacologic prophylaxis (<72 hours) appears to be safe in patients who have a low risk for progression of intracranial bleeding and have a stable repeat head CT 56 ACS TQIP Carney et al. Neurosurgery

57 Infection TBI increases risk for ventilator-associated pneumonia and ventriculostomy-related infections Infection rates are as high as 27% in patients undergoing ICP monitoring Infection prophylaxis includes: Systemic antimicrobial prophylaxis Antimicrobial-impregnated catheters (AIC) 57 Carney et al. Neurosurgery

58 Systemic Antimicrobial Prophylaxis Correlation between length of time EVD is in place and infection risk Two approaches to systemic prophylaxis: Periprocedural Continue for duration EVD is in place Goal: reduce infection rates without increasing the risk for multidrug-resistant pathogens or adverse effects 58 Fried et al. Neurocrit Care

59 Murphy, 2015 Study Design Prospective performance analysis Periprocedural vs. extended use of antibiotics in patients with EVD Outcomes Rates of catheter-related ventriculitis and nosocomial infections over 4 years with periprocedural (n=135) vs. extended use of antibiotics (n=410) in patients with EVD Results No significant difference in rates of ventriculitis (1.1% vs. 0.4%, p=0.22) Significantly increased risk for nosocomial infections with extended antibiotic use (2.0% vs. 0.0%, p=0.026) Cost savings of $162,516 in periprocedural group 59 Murphy et al. J Neurosurg

60 Dellit, 2014 Study Design Retrospective review Cefazolin for duration EVD in place vs. periprocedural cefazolin Outcomes Rates of Clostridium difficile and positive cerebrospinal fluid cultures 12 months before and after protocol change Cefazolin 1 g IV Q8H while EVD in place (n=352) periprocedural cefazolin only (n=369) Results No significant difference in positive cerebrospinal fluid cultures (12.8% vs. 10.3%, p=0.29) Increased rate of C. difficile in patients with extended antibiotic use (19 cases vs. 9 cases, p=0.04) 60 Dellit et al. Infect Control Hosp Epidemiol

61 Infection Prophylaxis Neurocritical Care Society Suggest one dose of antimicrobials prior to EVD insertion Recommend against the use of antimicrobials for the duration of EVD placement Infectious Diseases Society of America Periprocedural prophylactic antimicrobial administration is recommended for patients undergoing EVD placement (strong, moderate) Prolonged antimicrobial prophylaxis for the duration of the EVD is of uncertain benefit and not recommended (strong, moderate) 61 Fried et al. Neurocrit Care Tunkel et al. Clin Infect Dis

62 Neuropsychiatric Disturbances Arousal Sympathetic storm Attention Agitation & aggression Memory Executive function 62

63 Adjunctive Therapy Attention Arousal Memory Executive function Agitation & aggression Neurostimulants Amantadine and other dopaminergics Donepezil Neurostimulants Amantadine and other dopaminergics Modafinil Neurostimulants Donepezil/Dopaminergics Dopaminergics Propranolol Amantadine Atypical antipsychotics Antidepressants Methylphenidate Carbamazepine/Valproate Lithium 63 Arciniegas et al. American Psychiatric Association

64 Summary Management of TBI remains a controversial topic High quality studies are limited Guideline recommendations are not all-inclusive Understanding the pathophysiology of TBI is key to properly manage its complications 64

65 References 1. American College of Surgeons Trauma Quality Improvement Program. Best practices in the management of traumatic brain injury. Jan Arciniegas DB, Zasler ND, Vanderploeg RD, et al. Management of adults with traumatic brain injury. In: Whyte J, Giacino J, eds. Disorders of Consciousness. Arlington, VA: American Psychiatric Association. 2013: Boone MD et al. Mannitol or hypertonic saline in the setting of traumatic brain injury: What have we learned? Surg Neurol Int. 2015; 6: Carney N, Totten AM, O Reilly C, et al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. 2017;81(1): Censullo JL, Sebastian S. Pentobarbital sodium coma for refractory intracranial hypertension. J Neurosci Nurs Oct;35(5): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Division of Unintentional Injury Prevention. Traumatic Brain Injury & Concussion; Accessed April 13, Cormio M, Gopinath SP, Valadka A, Robertson CS. Cerebral hemodynamic effects of pentobarbital coma in head-injured patients. J Neurotrauma Oct;16(10): Dellit TH, Chan JD, Fulton C, et al. Reduction in Clostridium difficile infections among neurosurgical patients associated with discontinuation of antimicrobial prophylaxis for the duration of external ventricular drain placement. Infect Control Hosp Epidemiol. 2014;35: Diringer MN. New trends in hyperosmolar therapy? Curr Opin Crit Care Apr;19(2): Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomized placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365: Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg. Jul 1988;69(1): Ertmer C, Van Aken H. Fluid therapy in patients with brain injury: what does physiology tell us? Crit Care. 2014;18: Fried HI, Nathan BR, Rowe AS, et al. The insertion and management of external ventricular drains: an evidence-based consensus statement. Neurocrit Care. 2016;24: Greve MW, Zink BJ. Pathophysiology of traumatic brain injury. Mt Sinai J Med. 2009;79: Gross AK, Norman J, Cook AM. Contemporary pharmacologic issues in the management of traumatic brain injury. J Pharm Pract Oct;23(5): Haddad SH, Arabi YM. Critical care management of severe traumatic brain injury in adults. Scand J Trauma Resusc Emerg Med. 2012;20: Heegaard W, Biros M. Traumatic brain injury. Emerg Med Clin N Am. 2007;25: Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. Mar 2013;74(3): Kazim SF, Shamim MS, Tahir MZ, Enam SA, Waheed S. Management of penetrating brain injury. J Emerg Trauma Shock. 2011;4(3):

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