jignesh h. patel, pharmd, b.sc. clinical pharmacy specialist, trauma/burn surgery
TRANSCRIPT
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UPDATES IN THE PHARMACOLOGIC TREATMENT OF
TRAUMATIC BRAIN INJURY
Jignesh H. Patel, PharmD, B.Sc.
Clinical Pharmacy Specialist, Trauma/Burn Surgery
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Conflicts of Interest
NONE
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Objectives
Critically appraise aspects of Brain Trauma Foundation (BTF) Guidelines
Classify elevated intracranial pressure and intracranial hypertension
Differentiate techniques to measure intracranial pressure (ICP)
Identify treatment strategies of intracranial hypertension
Evaluate the current literature comparing use of mannitol vs. hypertonic saline to lower ICP
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Epidemiology ~80,000 disabling head injuries/year ~$60 billion financial burden Almost all acute and catastrophic brain
injuries increase ICPTBIintracerebral and extracerebral hematomacerebral infarction with brain swellinggeneralized brain swelling of acute liver failure
Risk of death~18.4% for ICP < 20~55.6% for ICP > 40
Cooper DJ et al., N Engl J Med 2011; 364:1493-1502.
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BTF Guidelines ICP Management
Indication/use of ICP monitoring technology Hyperosmolar therapyAnesthesia, Analgesia, Sedation
Blood pressure managementBrain oxygenation/Cerebral Perfusion (CPP)
Seizure Prophylaxis
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BTF Guidelines
DVT Prophylaxis Others
Infection PreventionNutritionSteroids
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BTF Recommendations: Hyperosmolar Therapy
J Neurotrauma 07; 24(1): S1-106.
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BTF Recommendations: Blood Pressure and Oxygenation J Neurotrauma 07; 24(1): S1-106.
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BTF Recommendations: Seizure Prophylaxis J Neurotrauma 07; 24(1): S1-106.
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BTF Recommendations: Sedation and Analgesia
J Neurotrauma 07; 24(1): S1-106.
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BTF Recommendations: VTE Prophylaxis J Neurotrauma 07; 24(1): S1-106.
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BTF Recommendations: Infection Prophylaxis J Neurotrauma 07; 24(1): S1-106.
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BTF Recommendations: Steroid Prophylaxis
J Neurotrauma 07; 24(1): S1-106.
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Ropper AH, N Engl J Med 12 367(8): 746-752
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AANN Clinical Practice Guidelines, 2007
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Introduction to Intracranial Pressure:Monro – Kellie Doctrine Intracranial compartment incompressible Fixed volume 1400-1700 mL
Brain parenchyma – 80%Cerebrospinal fluid (CSF) – 10%Blood – 10%
↑ in 1 component at expense of the other 2 Normal range ICP in adults is 5-15 mmHg Intracranial HTN = ICP 20-30 mmHg
Rangel-Castillo R et al. Neurol Clin 2008;26:521-541
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Ropper AH, N Engl J Med 12 367(8): 746-752
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Cerebral Dynamics
Cerebral blood flow (CBF) determines volume of blood in intracranial space
CBF is maintained relatively constant when: CPP: 50 -70 mmHg
Cerebral perfusion pressure (CPP) CPP = MAP - ICP
Pressure autoregulation Maintain normal CBF with CPP 50-150 Vasodilation → ↓ CPP, CBF unchanged, but ICP ↑Vasoconstriction → ↑ CPP and ↓ ICP
Hypercapnia and hypoxia ↑ CBF Rapid and severe brain swelling
Rangel-Castillo R et al. Neurol Clin 2008;26:521-541
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Causes of Increased ICP
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Causes of Increased Intracranial Pressure
Intracranial mass lesions Cerebral edema
cerebral infarction, severe traumatic brain injury (TBI) Increased CSF production Decreased CSF absorption Obstructive hydrocephalus Obstruction of venous outflow
venous thrombosis, jugular vein compression, neck surgery Idiopathic intracranial hypertension
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Clinical Manifestations: S/Sx Headache Cranial nerve VI palsies Papilledema
Reliance post-trauma? Spontaneous periorbital bruising Cushing's Triad
BradycardiaHypertensionRespiratory depression
* Most reliable method of diagnosis = ICP monitoring *
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ICP Monitoring
CT ScanShow mass lesions, midline shiftNormal CT still have 10-15% chance of having elevated ICP
Sites for monitoring Intraventricular IntraparaenchymalSubarachnoidEpidural
Eisenberg HM et al. J Neurosurg. 1990;73(5):688.
Reserved for the following:GCS < 8Suspected to be at riskNormal CT and ≥ 2 of following
Age >40 y/o Motor posturing
decerebrate or decorticate SBP < 90 mmHg
Rangel-Castillo R et al. Neurol Clin 2008;26:521-541
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Indications for ICP Monitoring
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Sites for ICP Monitoring
http://www.uptodate.com/contents/image?imageKey=PULM/78630&topicKey=NEURO%2F1659&source=outline_link&search=intracranial+hypertension&utdPopup=true
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Optimal Sites for ICP Monitoring Ventricular pressure measurement is the reference
standard for ICP monitoring. Parenchymal gauge pressure transduction is
similar to ventricular ICP. Parenchymal and subdural monitoring did not
always correlate well with ventricular ICP Fluid coupled epidural devices or subarachnoid
bolts and pneumatic epidural devices are less accurate than ventricular ICP monitors. Significant differences in readings have been demonstrated between ICP devices placed in the parenchyma versus the subdural space.
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Goals of ICP Monitoring and Treatment
1. Maintain ICP at less than 20 to 25 mm Hg.
2. Maintain CPP at greater than 60 mm Hg by maintaining adequate MAP.
3. Avoid factors that aggravate or precipitate elevated ICP.
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Algorithm for the
Treatment and
Management of ICH
Rangel-Castillo R et al. Neurol Clin 2008;26:521-541
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NEJM 14;370:2121-30.
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MANNITOLvs.
HYPERTONIC SALINE
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Mannitol and Hypertonic Saline:Mechanism of Action
Osmotic concentration gradient across BBB
Free water moves fromIS space → IV compartment
↓ Brain volume
↓ ICP
Forsyth LL et al. Pharmacotherapy 2008;28(4):469-484
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Mannitol and Hypertonic Saline:Mechanism of Action
Optimization of blood viscosity
Improved CBF, ↑ O2 delivery
Compensatory vasoconstriction
↓ cerebral blood volume
↓ ICP
Forsyth LL et al. Pharmacotherapy 2008;28(4):469-484
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Mannitol and Hypertonic Saline:Mechanism of ActionOsmotic concentration gradient across BBB
Free water moves fromIS space → IV compartment
↓ Brain volume
↓ ICP
Rebound ↑ ICPMannitol accumulates → ↑ intracellular brain volume
Forsyth LL et al. Pharmacotherapy 2008;28(4):469-484DiPiro JT et al. 7th Ed. McGraw Hill; 2008.
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Comparison of Mannitol and HS
Mannitol Hypertonic Saline (HS)Addt’l MOA • ↓ CSF production up to 50% • Modulation of inflammatory response
Advantages over the other
• ↓ CSF production leads to prolonged ↓ ICP
• Min effects on serum Na levels• Well studied
• Superior brain oxygenation and quicker onset
• Less permeability across BBB = more effective osmotic drug
• Lack of diuretic effect ↓ risk of nephrotoxicity, dehydration, hypotension
• ↑ BV, MAP, CPP
Adverse Effects
• Rebound ↑ ICP• Acute renal dysfunction • Hyperkalemia, hypernatremia• Diuresis causes…
• Hypovolemia, dehydration• Hypotension
• Acute exacerbation of CHF
• Rebound ↑ ICP• Hypokalemia, rebound hyponatremia• Hyperchloremic metabolic acidosis • Myelinosis/osmotic demyelination syndrome• Infection • Hematologic: ↓ platelet aggregation and
prolonged coagulation times, phlebitis • Acute renal failure or chronic heart failure
Administration• 0.25-1 g/kg IV Q4H• Onset: lowers ICP in minutes• Duration: 1.5-6 hrs
• No standard dosing• Concentrations vary, (most common = 7.5%) • Given via central line
Forsyth LL et al. Pharmacotherapy 2008;28(4):469-484
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Comparison of Commonly Administered Sodium Chloride Mixtures
Sodium Chloride Concentration (%)
Sodium Concentration (mmol/L)
Osmolality (mosm/kg)
0.9% 154 308
Lactated Ringers 130 275
1.7% 291 582
Mannitol ------- 1098
3.0% 513 1026
7.5% 1283 2566
10% 1712 3424
23.4% 4004 8008
Hayden W et al. Anesth Analg 2006;102:1836-46
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Study Overview
Background:Randomized trials suggest hypertonic saline (HS) is
superior to mannitol to treat elevated ICPLimited impact on clinical practice
Objective:Better understand efficacy of mannitol and hypertonic saline
for treatment of elevated ICP
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Inclusion/Exclusion Criteria
Inclusion Criteria: Human subjects undergoing quantitative ICP monitoringEvidence of ↑ ICPEquimolar doses of hypertonic sodium and mannitol Randomized treatment but unblinded or crossover design
Exclusion Criteria:Studies with varying doses or varying infusion time
*Patient population: TBI, stroke, ICH, SAHKamel H et al. Crit Care Med 2011;39(3):554-9
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Study Characteristics
StudyCharacteristic Afifi et al
Battison et al
Francony et al Ichai et al
Schwarz et al
Study Year 2003 2005 2008 2009 1998
Subjects (n) 40 9 20 34 9
Age (yrs) 36 N/A 40 36 57
Cause of ICHTumor (n=40) TBI (n = 6),
subarachnoid hemm. (n=3)
TBI (n=17) ICH (n=2),
stroke (n=1)
TBI (n=34) Stroke (n=8), ICH (n=1)
Mannitol Conc 20% 20% 20% 20% 20%
Sodium Formulation
3% NaCl 7.5% NaCl + 6% dextran-70
7.5% NaCl Sodium lactate
7.5% NaCl + hydroxyethyl
starch (60 g/L)
Mannitol Dose 5.49 mosm/kg 249 mosm 255mosm 1.74 mosm/kg 220 mosm
Sodium Dose 5.49 mosm/kg 250 msosm 255 mosm 1.65 mosm/kg 257 mosm
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Comparison of Study Methodology
Battison et al Francony et al Ichai et al Schwarz et al
Inclusion and Exclusion
≥16 y/o, intubated, propofol,
midazolam, alfentanil or atracurium, nimodipine,
noradrenaline or dobutamine
I: ≥18y/o, mech vent, stable x 2h b4 study
E: brain surgery, unstable, RF,
Hgb<100 g/L, Serum osm >320, use of agent w/in past 6h
I: GCS <8
E: <18 or >65 y/o, polytrauma, dil. Pupils. Prolonged hypoxia or hypotension, Na>155,
prehospital barb, steroids, osm
Intubated, 30° upright, vent >90 PaO2, not
hyperthermic, electrolytes WNL
Monitor Unsure Parenchymal Unsure Epidural, parenchymal
IndicationICP >20 mmHg for
at least 5 minICP >20 mmHg for at
least 10 minICP >25 mmHg for at
least 5 minICP >20 mmHg for at ≥5 min or newly obs pupillary abnormality
Man 200 mL 20% 231 mL of 20% 1.5 mL/kg of 20% 200 mL of 20%
HS 100 mL of 7.5% saline 6% dextran
100 mL 7.45% NaCl 1.5 mL/kg Sodium Lactate (1160 mOsm)
100 mL of 7.5% saline HES (60g/L)
Admin Over 5 min x 4 tx 20 min infusion 15 min infusion 15 min infusion
Supp Tx4x q4h but given sooner if required
None. 6% HES if MAP ↓ >10%
Crossover if 1st tx failed. Mannitol only if
2nd failed
Crossover if 1st tx failed
Battison C et al. Crit Care Med 2005;33(1):196-202Francony G et al. Crit Care Med 2008;36:795-800
Ichai C et al. Intensive Care Med 2009;35:471-479Schwarz S et al. Stroke 1998;29:1550–5.
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Study Results
Study Characteristic Afifi et al
Battison et al
Francony et al
Ichai et alSchwarz
et al
Goal ICP < 20 mmHg <18 mmHg >20% below baseline
↓ > 5 or abs < 20 mmHg
>10% below baseline
Mean/Median Baseline ICP (mmHg)
Mannitol 31 (4) 24 (18.8,25.9) 31 (6) N/A 26.1 (1.5)
HS 31 (4) 22 (20.1-26.3) 27 (3) N/A 28.6 (4.8)
Patients at Goal ICP
Mannitol 16/20 (80%) 14/18 (78%) 10/10 (100%) 19/27 (70%) 10/14 (71%)
HS 19/20 (95%) 16/18 (89%) 9/10 (90%) 28/31 (90%) 16/16 (100%)
Mean/Median ICP Decrease
Mannitol 13 (5) 7.5 (5.8-11.8) 14 (8) 5 (2) 4.6 (4.7)
HS 12 (5) 13 (11.5-17.3) 10 (5) 8 (2) 11 (7.1)
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Mean Quantitative Reduction of ICP
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Successful Control of Elevated ICP
p = 0.046
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Results of Meta-Analysis
Mannitol effective 69/89 episodes (78%) HS effective in 88/95 episodes (93%)
Using fixed effects model comparing HS to mannitol Relative risk of ICP control favored HS
○ 1.2 (1.05 – 1.36, p = 0.007)Weighted mean difference ICP reduction favored HS
○ 2 mmHg (0.1 – 3.8, p = 0.036)
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Limitations
Small size of all studies included None had power to detect statistical difference Methodological differences Lack of ADE reporting Primary outcome doesn’t look at reoccurrence Look at single episode vs. overall treatment of patient Unique benefits of each therapy
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Conclusions
Hypertonic saline more effective in controlling ICP
Hypertonic saline had a greater ICP reduction
Larger study neededUniform hypertonic saline solutionSame methodologyLong-term neurological outcomes
Kamel H et al. Crit Care Med 2011;39(3):554-9
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Renaud Vialet, Jacques Albanèse, Lauren Thomachot et al.
Critical Care MedicineVolume: 31 Number: 6
June 31st, 2003
Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic
intracranial HTN: 2 mL/kg 7.5% saline is more effective than 2 mL/kg
20% mannitol
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Study Design and Methods
Design: prospective randomized study
Inclusion Criteria: Head trauma and persistent coma Failure of protocol, require osmotic agents to treat
intracranial HTN
Outcomes Daily number and duration of ICH episodesFailure rate
Vialet R et al. Crit Care Med 2003;31:1683–7
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Study Methodology
All pts follow standardized protocol to initially control ICP Refractory if ICP >25 mmHg for ≥5 mins → osmotherapy Randomized to 20 min infusion of 2 mL/kg of
20% mannitol (1,160 mOsm/kg/H20)
7.5% hypertonic saline solution (HSS) (2,400 mOsm/kg/H20)
If 1st infusion failed repeat within 10 min Treatment failure if unable ICP <35 mmHg after 2
infusions
Vialet R et al. Crit Care Med 2003;31:1683–7
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Study Results
Adapted from Vialet R et al. Crit Care Med 2003;31:1683–7
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Results and Conclusions
Results suggested superiority of HSS over mannitol Number and duration of ICH episodes were 2x lower
in HSS group Failure rate of HSS significantly lower Limitations: small sample size Increasing osmotic load better efficacy
Vialet R et al. Crit Care Med 2003;31:1683–7
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Application to Practice Hypertonic Saline over Mannitol
Renal diseaseHypovolemia Hypotensive or at riskPMH of CHF or pulmonary edemaRefractory intracranial hypertension
Mannitol over Hypertonic SalineHypernatremic or hypokalemicMetabolic acidosis
Duration of Therapy Serum osmolality >320 mOsm/L or up to 365 mOsm/L in HS Serum sodium >155 mEq/L
Hayden W et al. Anesth Analg 2006;102:1836-46