Medicating the Melon: Adjunctive Therapy after Traumatic Brain Injury

Transcription

1 Medicating the Melon: Adjunctive Therapy after Traumatic Brain Injury Kirstin Kooda, Pharm.D., BCPS, BCCCP Critical Care Pharmacist Pharmacy Grand Rounds January 24 th, 2017

2 Disclosures No financial relationships pertinent to this session Off label use of medications will be discussed 2012 MFMER slide-2

3 Objectives Review the pathophysiology and clinical course of traumatic brain injury (TBI) Discuss the pharmacology of the current standard of care following TBI Identify potential novel pharmacotherapy that can impact outcomes

4 Background Major cause of morbidity and mortality ages Long-term consequences of injury Reduced ability to work and care for own needs Mood instability High societal cost Centers for Disease Control and Prevention. (2015). Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention. Atlanta, GA MFMER slide-4

5 Primary Injury Brain Brain

6 Secondary Injury Result of pathological processes started at time of injury Delayed clinical impact Stage 1 Stage 2 Ischemia Ca 2+ influx Lactic acidosis Failure of membrane ion pumps Terminal membrane depolarization Glutamate release NDMA activation Increased FFA and free radicals Neuron necrosis and apoptosis Werner C and Engelhard K. British Journal of Anaesthesia. 99(1);4-9: MFMER slide-6

7 Severity of Injury Criteria Mild Moderate Severe Structural Imaging Loss of consciousness Post traumatic amnesia (PTA) Glasgow Coma Scale Abbreviated Injury Scale: Head Normal < 30 minutes Normal or abnormal 30 minutes to 24 hrs Normal or abnormal > 24 hrs 0-1 day > 1 and < 7 days > 7 days Centers for Disease Control and Prevention. (2015). Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention. Atlanta, GA MFMER slide-7

8 Consequences? million in US affected by TBI disability Long term behavioral changes with mild or moderate injury Severe injury: Death Vegetative Disability Functional Jiang JY, et al. J Neurotrauma. 2002;19(7):869. Schuller JS, et al. Vital Health Stat. 2012;10(252) MFMER slide-8

9 Rating Scales and Defining Outcomes GCS Glasgow Outcome Scale (6 months) Disability Rating Scale Total: = death 0-29; higher worse Motor: = vegetative Consciousness Eye 1-4 Verbal = dependent for daily activities 4 = Some independence Cognitive ability Dependence on others 5 = Full independence Employability Carney N, et al. Neurosurgery MFMER slide-9

10 Can we use medication to minimize damage and alter these outcomes? 2012 MFMER slide-10

11 Acute Pharmacology Management immediately after injury Recall acute physiology Goal Minimize ICP elevation Manage ICH Optimize CPP Ameliorate cellular toxicity Mechanism Adequate Sedation Hyperosmotic Therapy Vasopressors Progesterone or NAC? ICP: intracranial pressure; ICH: intracranial hypertension; CPP: cerebral perfusion pressure; NAC: n- acetylcysteine Carney N, et al. Neurosurgery

12 Sedation Goal: minimize ICP elevation in acute phase post TBI Drug Propofol Evidence ICP No impact on mortality, 6 month outcomes Guideline recommended Barbituates Reserve for refractory cases Opioids Benzodiazepines High bolus doses ICP Pain control in multi-trauma important Fentanyl primary Generally avoided due to long duration of action Consider midazolam if CI to propofol CI: contraindications Carney N, et al. Neurosurgery MFMER slide-12

13 Dexmedetomidine? Design Single-center, prospective, observational Population Adults with TBI Need for mechanical ventilation > 24 hours Receiving continuous infusion sedation Intervention Dexmedetomidine Dexmedetomidine AND propofol Propofol Neither Primary Outcome Mean time in target RASS (-2 to 0) based on patient-days (1,028 for 198 patients) Secondary Outcomes Max ICP for each group Adverse events Pajoumand M, et al. J Trauma Acute Care Surg. 2016:81(2);

14 Results Time (h) Mean Time in Goal RASS % Patients SBP Hypotension MAP DEX PROP DEX + PROP Neither Pajoumand M, et al. J Trauma Acute Care Surg. 2016:81(2); MFMER slide-14

15 Cerebral Perfusion Pressure MAP ICP = CPP Normal CPP > 50 mmhg; TBI goal mmhg CBF CPP Vasodilate CBV ICP CPP Vasoconstrict CBV ICP CPP Carney N, et al. Neurosurgery MFMER slide-15

16 The place of vasopressors No specific commentary in 2016 guidelines CPP goal mmhg SBP goal 100mmHg in yo 110 mmhg in yo or 70 yo Vasopressors reasonable if hypotensive No specific data exists regarding selection Norepinephrine, phenylephrine, vasopressin? Carney N, et al. Neurosurgery MFMER slide-16

17 ICH = ICP > 20 mm Hg ICP Brain Brain CPP Blood Blood CSF

18 Mannitol and Hypertonic Saline Administer if ICP > 22 mmhg for prolonged period of time Unclear if either agent better for long-term outcomes Selection based on individual patient variables (sosm, renal function, Na level) Carney N, et al. Neurosurgery MFMER slide-18

19 Adjuncts Immediately After Injury Attempt to mitigate spread of cellular toxin mediated damage Progesterone neuroprotective via multiple mechanisms Early RCT revealed significant improvement in functional outcome and decrease in mortality HR 0.43 (95% CI ) Moderate TBI improved GOS-E and DRS Wright DW, et al. Ann Emerg Med. 2007:49(4); MFMER slide-19

20 Progesterone Unfulfilled Potential Design Multi-national, prospective, randomized Population 1195 adults with severe TBI (age 16-70, GCS 8) Intervention 597 patients: progesterone 0.71 mg/kg load, followed by 0.5 mg/kg/hr for 119 hours 598 patients: placebo No Difference in Any Measured Outcome Primary Outcome 6 month Glasgow Outcome Scale Secondary Outcomes 1 and 6 month mortality 3 month Glasgow Outcome Scale Safety and monitoring endpoints Skolnick BE, et al. N Engl J Med.371;26:

21 N-Acetylcysteine Neuroprotective in rodent studies of brain injury Antioxidant, anti-inflammatory, acts on glutamate receptors Some evidence to reduce hearing loss in humans Wells, et al. Critical Care 2012, 16:R193.

22 Promising Initial Results Design Prospective, randomized, double blind Population 81 adults with mild TBI after blast injury in Iraq Intervention 40 patients: NAC 4g load, then 2g BID x4 days, then 1.5g BID x 3 days 41 patients: placebo Primary Outcome % of subjects free from all mild TBI symptoms at 7 days Secondary Outcomes Balance dysfunction Absence of headache, confusion, memory problems, abnormal sleep % of subjects free from all mild TBI symptoms at 3 days Results OR 3.6, p = for symptom resolution with NAC Time of treatment and distance from blast also significant Potentially beneficial, further data needed Hoffer ME, et al. PLOS ONE. 2013;8(1):e54163.

23 Standard of Care and Novel Therapies in Progression of TBI

24 Paroxysmal Sympathetic Hyperactivity 8-30% severe TBI True incidence unknown, historically illdefined Sympathetic storm, dysregulation, dysautonomia (+31 other names) Increased morbidity, healthcare cost, longer hospitalization, poor outcomes Baguley IJ, et al. J Neurotrauma. 2014:31;

25 Key Criteria Intermittent episodes with resolution in between Continues for 3 days No resolution with differential diagnosis treatment Possible Mechanisms Excessive sympathetic response to stimuli Lack of inhibitory neurons Enhanced glutamate transmission 2012 MFMER slide-25

26 Translation of Protective Findings Multiple retrospective studies link βb pre-injury with improved survival Potentially related to decrease in PSH episodes Clonidine enhances central negative feedback mechanisms via α2 Dexmedetomidine theoretically carries same benefit Heffernan DS, et al. J Trauma. 2010;69(6): MFMER slide-26

27 DASH Published Protocol Design Prospective, randomized, double blind Population Planned in each group Intervention Propranolol 1 mg IV Q6H, clonidine 0.1 mg Q12H Primary Outcome Plasma norepinephrine level on day 8 Secondary Outcomes Other physiologic variables RASS, agitated behavior scale, need for additional medications Ventilator days, coma free days, ICU and hospital LOS Patel M, et al. Trials. 2012:13; MFMER slide-27

28 DASH Preliminary Results Interval change in primary endpoint to ventilator-free days Study halted for futility after 21 in treatment group and 26 controls Trend toward decreased mortality but nonsignificant (OR 0.71, 95% CI ) Further study and full results needed Value of Adrenergic Blockade in Acute Severe TBI Questioned. Medscape. Apr 28, 2016.

29 Other Potential Management Options Drug Mechanism Benefit Symptoms Gabapentin GABA agonist Prevent episodes Benzodiazepines Bromocriptine GABA agonist Dopamine agonist Prevent/abort episodes Prevent episodes HR, BP, agitation, posturing HR, BP, agitation, posturing Fever, posturing, dystonia Baclofen GABA agonist Prevent episodes Clonus, rigidity, pain Opiates µ-opioid receptor agonist Prevent/abort episodes HR, exaggerated pain response Dantrolene Decreased muscle contraction Prevent episodes Posturing, rigidity Choi HA, et al. Curr Neurol Neurosci Rep. 2013;13: MFMER slide-29

30 Delirium in TBI? Difficult to differentiate delirium from posttraumatic amnesia Agitation and behavioral dyscontrol frequent after TBI Antipsychotics? Rat data suggests harm Internal study no difference in duration of post-traumatic amnesia Kline AE, et al. Neuroscience Letters. 2008;448: Elovic EP, et al. J Head Trauma Rehabil. 2008;23(2): MFMER slide-30

31 Moving Out of the ICU 5-15% severe TBI persistent vegetative state Possibly related to altered dopaminergic and noradrenergic transmitters Amantadine antagonizes NMDA and agonizes dopamine Small initial studies suggest improved neurorecovery, but started at variable times after injury Meythaler JM, et al. J Head Trauma Rehabil. 2002;17(4): MFMER slide-31

32 Vegetative on Rehab Admission Design Prospective, randomized, double blind, multicenter Population 184 patients vegetative or minimally conscious 4-16 weeks after TBI with inpatient rehab Intervention 87 patients: amantadine for 4 weeks, escalating doses based on DRS 97 patients: placebo Primary Outcome Rate of improvement of DRS at 4 weeks Secondary Outcomes Rate DRS improvement in 2 week washout after treatment Adverse events Exposure to other psychoactive drugs Results Significant improvement of DRS with amantadine; effect lost when drug stopped 0.24 points per week (p = 0.007) Giacino JT, et al. N Eng J Med ;9: MFMER slide-32

33 The future of amantadine Current clinical practice varies with start time after injury More data needed Consider initiation at 4 weeks post injury if patients minimally conscious or vegetative Meythaler JM, et al. J Head Trauma Rehabil. 2002;17(4): Giacino JT, et al. N Eng J Med ;9: MFMER slide-33

34 Prevent other sequelae? Design Prospective, randomized, double blind Population 94 patients with TBI and PTA resolution in 4 weeks Intervention 48 patients: sertraline 100 mg QD x24 weeks 46 patients: placebo Primary Outcome Time to onset of depressive disorder Secondary Outcomes Adverse effects Memory and cognitive function at 24 weeks Results NNT = 5.9 to prevent 1 episode of depressive disorder Minimal adverse effects No changes in memory or cognitive function Jorge RE, et al. JAMA Psychiatry. 2016;73(10): MFMER slide-34

35 Other Ongoing Research Drug Memantine Growth hormone Statins Marijuana Enzogenol Proposed Mechanism Antagonizes NMDA Modifies behavioral dysfunction Reduce inflammatory cytokines Reduce glutamate, free radicals, inflammation Anti-oxidant, anti-inflammatory Gruenbaum SE, et al. CNS Drugs. 2016;30: MFMER slide-35

36 Conclusions No single agent impacting outcomes exists Complex disease state Multi-pronged approach needed Optimize early care by following guidelines Consider amantadine in persistent vegetative state Look for further studies related to NAC and PSH 2012 MFMER slide-36

37 Which is an example of secondary injury in acute TBI? 1. Traumatic hemorrhage 2. Penetrating injury 3. Diffuse axonal injury 4. Cellular mediated toxicity 2012 MFMER slide-37

38 Progesterone has an important role in current standard of care after TBI True False 2012 MFMER slide-38

39 What are potential options for paroxysmal sympathetic hyperactivity? A. Propanolol and clonidine B. Antipsychotics C. Gabapentin D. Mannitol E. A & C F. A & B 2012 MFMER slide-39

40 Questions and Discussion 2012 MFMER slide-40