UPDATES IN THE PHARMACOLOGIC TREATMENT OF

TRAUMATIC BRAIN INJURY

Jignesh H. Patel, PharmD, B.Sc.

Clinical Pharmacy Specialist, Trauma/Burn Surgery

Conflicts of Interest

NONE

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

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.

BTF Guidelines ICP Management

Indication/use of ICP monitoring technology Hyperosmolar therapyAnesthesia, Analgesia, Sedation

Blood pressure managementBrain oxygenation/Cerebral Perfusion (CPP)

Seizure Prophylaxis

BTF Guidelines

DVT Prophylaxis Others

Infection PreventionNutritionSteroids

BTF Recommendations: Hyperosmolar Therapy

J Neurotrauma 07; 24(1): S1-106.

BTF Recommendations: Blood Pressure and Oxygenation J Neurotrauma 07; 24(1): S1-106.

BTF Recommendations: Seizure Prophylaxis J Neurotrauma 07; 24(1): S1-106.

BTF Recommendations: Sedation and Analgesia

J Neurotrauma 07; 24(1): S1-106.

BTF Recommendations: VTE Prophylaxis J Neurotrauma 07; 24(1): S1-106.

BTF Recommendations: Infection Prophylaxis J Neurotrauma 07; 24(1): S1-106.

BTF Recommendations: Steroid Prophylaxis

J Neurotrauma 07; 24(1): S1-106.

Ropper AH, N Engl J Med 12 367(8): 746-752

AANN Clinical Practice Guidelines, 2007

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

Ropper AH, N Engl J Med 12 367(8): 746-752

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

Causes of Increased ICP

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

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 *

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

Indications for ICP Monitoring

Sites for ICP Monitoring

http://www.uptodate.com/contents/image?imageKey=PULM/78630&topicKey=NEURO%2F1659&source=outline_link&search=intracranial+hypertension&utdPopup=true

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.

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.

Algorithm for the

Treatment and

Management of ICH

Rangel-Castillo R et al. Neurol Clin 2008;26:521-541

NEJM 14;370:2121-30.

MANNITOLvs.

HYPERTONIC SALINE

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

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

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.

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

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

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

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

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

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.

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

Mean Quantitative Reduction of ICP

Kamel H et al. Crit Care Med 2011;39(3):554-9

Successful Control of Elevated ICP

p = 0.046

Kamel H et al. Crit Care Med 2011;39(3):554-9

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

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

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

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

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

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

Study Results

Adapted from Vialet R et al. Crit Care Med 2003;31:1683–7

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

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