Traumatic Brain InjuryTraumatic Brain Injury

Pediatric Intensive Care UnitPediatric Intensive Care Unit

Epidemiology of TBIEpidemiology of TBI

An estimated 5.3 million Americans - a little more than 2% of the U.S. population - currently live with disabilities resulting from brain injury

Each year, in the United States:– ~1 million people are treated for TBI and released

from hospital emergency rooms– 80,000 Americans experience the onset of long-term

disability– More than 50,000 people die

Vehicle crashes are the leading cause of brain injury

Risk of TBI is highest among adolescents, young adults and those older than 75

Berney, Child's Nerv Syst (1994) 10:509Berney, Child's Nerv Syst (1994) 10:509

Pediatric TBIPediatric TBI

At leastAt least 185 - 334 cases per 100,000 185 - 334 cases per 100,000 Precise causes and distributions vary Precise causes and distributions vary

by localeby locale Boys more often injured; girls more Boys more often injured; girls more

often injured fatally often injured fatally Head injury is more common in Head injury is more common in

younger children, but syounger children, but severeevere injury injury more common in the older childrenmore common in the older children

Suspicion of abuse raises likelihood of Suspicion of abuse raises likelihood of serious injuryserious injury

Pediatric TBI – cont.Pediatric TBI – cont. Kennard PrincipleKennard Principle

– ““The age of animals affect both the rate of The age of animals affect both the rate of recovery and degree of deficit. Young and recovery and degree of deficit. Young and immature animals recover more quickly immature animals recover more quickly and extensively than adults”and extensively than adults”

““Talk and Die”Talk and Die”– Head injured children often exhibit rapid Head injured children often exhibit rapid

neurologic deterioration and high mortality neurologic deterioration and high mortality after an initial lucid periodafter an initial lucid period

– Edema around a contusionEdema around a contusion

Glascow Coma Scale

Best Eye Response (4) – 4.      Spontaneous– 3.      To verbal command– 2.      To pain – 1.      No response

Best Verbal Response (5) – 5.      Orientated– 4.      Confused – 3.      Inappropriate words– 2.      Sounds– 1.      No response

Best Motor Response (6) – 6.      Obeys commands – 5.      Localizes pain– 4.      Withdraws to pain – 3.      Flexion to pain– 2.      Extension to pain– 1.      No response

Primary InjuryPrimary Injury

Direct Direct mechanical injurymechanical injury

Disruption of Disruption of vascular or vascular or neuronal neuronal elementselements

Initiation of Initiation of cytotoxic cytotoxic cascadescascades

Hemorrhage – Hemorrhage – Subdural or Epidural?Subdural or Epidural?

Systemic: Systemic: hypoxiahypoxia (Pa (PaO2O2 < 60), < 60), hypotension (SBP< 90), hypotension (SBP< 90), hyperthermia, hypoglycemia, hyperthermia, hypoglycemia, anemia, SIRSanemia, SIRS

Cerebral: edema, vasospasm, Cerebral: edema, vasospasm, seizures, infection, ischemiaseizures, infection, ischemia

Cellular: excitotoxicity, membrane Cellular: excitotoxicity, membrane transport failure, fluid shifts, free-transport failure, fluid shifts, free-radical oxidation injury, apoptosisradical oxidation injury, apoptosis

Secondary Brain InjurySecondary Brain Injury

Kochanek et al. Pediatric Critical Care Kochanek et al. Pediatric Critical Care Medicine. 1(1):4-19, July 2000Medicine. 1(1):4-19, July 2000

Secondary Damage Secondary Damage following TBIfollowing TBI

Cerebral MetabolismCerebral Metabolism

High metabolic demandsHigh metabolic demands Aerobic metabolismAerobic metabolism

– Glucose, oxygen used to generate ATPGlucose, oxygen used to generate ATP– Substrate delivery affected by acid/base Substrate delivery affected by acid/base

balance and temperaturebalance and temperature Matching of cerebral blood flow (CBF) Matching of cerebral blood flow (CBF)

with cerebral metabolic rate of oxygen with cerebral metabolic rate of oxygen (CMRO(CMRO22))– Under normal conditions, rate of oxygen Under normal conditions, rate of oxygen

consumption not limited by supplyconsumption not limited by supply– Uncoupling of CBF from CMRO2 can result in Uncoupling of CBF from CMRO2 can result in

either ischemia or hyperemiaeither ischemia or hyperemia

Cerebral Blood FlowCerebral Blood Flow

Normal CBF: 45 - 60ml/100g/minNormal CBF: 45 - 60ml/100g/min Reductions in CBF result in time-Reductions in CBF result in time-

dependent neuronal eventsdependent neuronal events– Loss of consciousness, EEG slowing Loss of consciousness, EEG slowing

(20ml/100g/min)(20ml/100g/min)– Disruption of ionic homeostasis and conversion Disruption of ionic homeostasis and conversion

to anaerobic metabolism (18ml/100g/min)to anaerobic metabolism (18ml/100g/min)– Loss of membrane integrity, massive calcium Loss of membrane integrity, massive calcium

influx -> irreversible damage (10ml/100g/min)influx -> irreversible damage (10ml/100g/min)– Tissue infarction (5ml/100g/min)Tissue infarction (5ml/100g/min)

http://www.fac.org.ar/scvc/llave/stroke/http://www.fac.org.ar/scvc/llave/stroke/heiss/heissi.htmheiss/heissi.htm

Cerebral Blood Flow Cerebral Blood Flow and Ischemia/Infarctand Ischemia/Infarct

Cerebral Blood Flow in Cerebral Blood Flow in TBI PatientsTBI Patients CBF falls precipitously in first 24 hCBF falls precipitously in first 24 h

– < 20-30 mL/100g tissue/min< 20-30 mL/100g tissue/min In survivors, CBF then increases for three daysIn survivors, CBF then increases for three days No fundamental difference between children No fundamental difference between children

and adultsand adults– Previously thought that cerebral hyperemia occurs Previously thought that cerebral hyperemia occurs

in childrenin children

High ICP is associated with High ICP is associated with lowlow CBF CBF

CMROCMRO22 is highest initially, then falls is highest initially, then falls Systemic hypotension linked to poorer Systemic hypotension linked to poorer

outcomes in head-injured patientsoutcomes in head-injured patients

Adelson, et. al., Pediatr Neurosurg Adelson, et. al., Pediatr Neurosurg 1997;26:200-2071997;26:200-207

CBF and Outcome in CBF and Outcome in Head-Injured ChildrenHead-Injured Children

CBF measured by XeCT in 30 childrenCBF measured by XeCT in 30 children– 18 boys, 12 girls, mean age 2.2y range 18 boys, 12 girls, mean age 2.2y range

0.10-8.0y0.10-8.0y Early CBF = 25.1 Early CBF = 25.1 ± 7.7 cc/100g/min± 7.7 cc/100g/min ““Good” outcome mean 43.9 ± 11 (n=12)Good” outcome mean 43.9 ± 11 (n=12) ““Bad” outcome mean 9.9 ± 5.9 (n=18)Bad” outcome mean 9.9 ± 5.9 (n=18) CBF < 20 at any time = bad outcomeCBF < 20 at any time = bad outcome p = 0.0006, sensitivity 63%, specificity 100%, p = 0.0006, sensitivity 63%, specificity 100%,

positive predictive value 100%positive predictive value 100%

Cerebral Cerebral AutoregulationAutoregulation Consistent perfusion with MAP’s 60 – 150 mm HgConsistent perfusion with MAP’s 60 – 150 mm Hg Cerebral autoregulatory triggers include pressure, Cerebral autoregulatory triggers include pressure,

viscosity, O2 delivery, and CO2viscosity, O2 delivery, and CO2 Autoregulation is impaired in injuryAutoregulation is impaired in injury

Monroe-Kelly DoctrineMonroe-Kelly Doctrine

Vtotal = Vtissue + Vblood + Vcsf

Intracranial PressureIntracranial Pressure

Clinical Signs of Clinical Signs of Increased Intracranial Increased Intracranial PressurePressureEarlyEarly

vomitingvomiting

headacheheadache

mental status mental status

changeschanges

acute neurologic acute neurologic

deteriorationdeterioration

respiratory respiratory

irregularitiesirregularities

Late Cushing’s

Reflex III or IV palsy motor posturing pupillary

dilation papilledema

Pupils: Window on the Pupils: Window on the BrainstemBrainstem

If normally reactive, problems are If normally reactive, problems are in the hemispheresin the hemispheres

If not, problems are in the If not, problems are in the brainstembrainstem

Hypothalamus Hypothalamus small, reactive small, reactive

Dorsal midbrain Dorsal midbrain slightly large, non- slightly large, non-reactivereactive

Central midbrain Central midbrain fixed, midpoint fixed, midpoint

Pontine Pontine pinpoint pinpoint

Brain HerniationBrain Herniation

Herniation typesHerniation types– 1. Subfalcine1. Subfalcine– 2. Uncal2. Uncal– 3. Caudal3. Caudal– 4. Tonsillar4. Tonsillar

Risk of herniation Risk of herniation increases with increases with intracranial intracranial hypertensionhypertension

Cerebral EdemaCerebral Edema

VasogenicVasogenic– Accumulation of Accumulation of

water in interstitial water in interstitial CNS spaces due to CNS spaces due to increased vascular increased vascular permeabilitypermeability

CytotoxicCytotoxic– Accumulation of Accumulation of

water in injured water in injured cellscells

ECG changes seen in nearly all patientsECG changes seen in nearly all patients Cerebrally induced arrhythmias seen in Cerebrally induced arrhythmias seen in

~50% ~50% – Related to autonomic dysfunctionRelated to autonomic dysfunction– Rate, rhythm or repolarization aberrationRate, rhythm or repolarization aberration

Peaked P’s, shortened PR’s, inverted T’s, ST Peaked P’s, shortened PR’s, inverted T’s, ST changes, large U waves, prolonged QTc, deep Q’schanges, large U waves, prolonged QTc, deep Q’s

Asystole is rareAsystole is rare Abnormalities resolve in 10 days to 2 weeks (or Abnormalities resolve in 10 days to 2 weeks (or

with brain death)with brain death) No direct correlation between type of No direct correlation between type of

injury and specific changesinjury and specific changes

Sequelae of Neurologic Sequelae of Neurologic Injury: CardiacInjury: Cardiac

Sequelae of Neurologic Sequelae of Neurologic Injury: PulmonaryInjury: Pulmonary

Acute neurogenic pulmonary edemaAcute neurogenic pulmonary edema– Seen with large injury or acute ICP riseSeen with large injury or acute ICP rise– May be secondary to hypertensionMay be secondary to hypertension– Brainstem injury usually presentBrainstem injury usually present

Acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS)(ARDS)

Aspiration pneumonitisAspiration pneumonitis

““Cushing’s ulcer”Cushing’s ulcer”– Related to hyperacidity + ischemiaRelated to hyperacidity + ischemia– Seen most often with hypothalamic Seen most often with hypothalamic

injuryinjury– 40% of bleeds start in first 48 hours40% of bleeds start in first 48 hours

Steroid ulcerSteroid ulcer Stress gastritisStress gastritis

Sequelae of Neurologic Sequelae of Neurologic Injury: GIInjury: GI

Minor to moderate injury Minor to moderate injury SIADH SIADH– Urine scant and concentratedUrine scant and concentrated– Serum sodium lowSerum sodium low– SeizuresSeizures

Severe injurySevere injury Diabetes insipidus Diabetes insipidus– Urine copious and diluteUrine copious and dilute– Serum sodium high and risingSerum sodium high and rising

Unpredictable Unpredictable Cerebral salt Cerebral salt wastingwasting

Sequelae of Neurologic Sequelae of Neurologic Injury: Fluid & Injury: Fluid & ElectrolytesElectrolytes

HyperglycemiaHyperglycemia– Commonly seen in pediatric head injuryCommonly seen in pediatric head injury– Serum glucose correlates with severity of Serum glucose correlates with severity of

injuryinjury– Worse outcome with higher levelsWorse outcome with higher levels– May be marker or part of pathophysiologyMay be marker or part of pathophysiology

Temperature instabilityTemperature instability– Hyper- or hypo-thermiaHyper- or hypo-thermia– Associated with neuroendocrine failureAssociated with neuroendocrine failure

Sequelae of Neurologic Sequelae of Neurologic Injury: MetabolicInjury: Metabolic

AnemiaAnemia

ThrombocytopeniaThrombocytopenia

Disseminated Intravascular Disseminated Intravascular

CoagulationCoagulation

Sequelae of Neurologic Sequelae of Neurologic Injury: HematologicInjury: Hematologic

Management of TBIManagement of TBI

Minimize secondary damageMinimize secondary damage Beginning in the 1970’s, use of Beginning in the 1970’s, use of

intensive management protocols intensive management protocols resulted in significant reductions in resulted in significant reductions in morbidity and mortalitymorbidity and mortality– Mortality rate: 50% -> 36%Mortality rate: 50% -> 36%

Objective of intensive monitoring:Objective of intensive monitoring:– maintain cerebral perfusion/oxygenation maintain cerebral perfusion/oxygenation

and avoid medical/surgical complications and avoid medical/surgical complications while the brain recoverswhile the brain recovers

Early ManagementEarly Management

ABC’sABC’s– Secure the airway if GCS < 8Secure the airway if GCS < 8– Use of appropriate induction agentsUse of appropriate induction agents– Restore perfusion using isotonic fluids (NS) Restore perfusion using isotonic fluids (NS)

colloid, and pressorscolloid, and pressors Induction agentsInduction agents

– Etomidate, propofol, Etomidate, propofol, thiopentalthiopental– Ketamine?Ketamine?

Muscle relaxantMuscle relaxant RocuroniumRocuronium Succinylcholine?Succinylcholine?

Early Management – Early Management – cont.cont. ATLS evaluationATLS evaluation

– C-spine, associated injuriesC-spine, associated injuries Emergent non-contrast head CTEmergent non-contrast head CT Pursue surgical remediesPursue surgical remedies

– Decompressive craniectomyDecompressive craniectomy– Clot evacuationClot evacuation

Minimize ED and intra-hospital Minimize ED and intra-hospital

transport timetransport time

General ManagementGeneral Management

Maintain BP with balance of Maintain BP with balance of isotonic fluid (euvolemia) isotonic fluid (euvolemia) and pressorsand pressors

Maintain normal physiologic Maintain normal physiologic parametersparameters– PaOPaO22100, PCO100, PCO2 2 30-35, T 37, 30-35, T 37,

[glucose] 80-110, HCT 30[glucose] 80-110, HCT 30 Head of Bed 30Head of Bed 30°°, in midline, in midline Minimize noxious Minimize noxious

stimulationstimulation Sedation/analgesiaSedation/analgesia

Specific Therapies for Specific Therapies for TBITBI

ICP/CPP directed ICP/CPP directed therapytherapy

HyperventilationHyperventilation**

OsmotherapyOsmotherapy BarbituratesBarbiturates AnticonvulsantsAnticonvulsants Steroids Steroids ** Hypothermia Hypothermia **

ICP MonitoringICP Monitoring

Intracranial hypertension associated with poor Intracranial hypertension associated with poor neurologic outcomeneurologic outcome

ICP monitoring and aggressive treatment of ICP monitoring and aggressive treatment of intracranial hypertension associated with best intracranial hypertension associated with best reported clinical outcomesreported clinical outcomes

Ventricular pressure measurementVentricular pressure measurement– ““Gold standard”Gold standard”– Therapeutic CSF drainageTherapeutic CSF drainage

Parenchymal catheter tip pressure transducer devicesParenchymal catheter tip pressure transducer devices– Easy of placementEasy of placement– Cannot be recalibrated in-situCannot be recalibrated in-situ– Potential for driftPotential for drift

Clinically significant infections or hemorrhage are rareClinically significant infections or hemorrhage are rare

Types of ICP MonitorsTypes of ICP Monitors

Intraventricular Intraventricular devicesdevices

Parenchymal Parenchymal catheter tip catheter tip pressure pressure transducer devicestransducer devices

Subdural devicesSubdural devices Subarachnoid fluid Subarachnoid fluid

coupled device with coupled device with an external strain an external strain gaugegauge

Epidural devicesEpidural devices

Patients with GCS≤8 at highest risk Patients with GCS≤8 at highest risk for intracranial hypertensionfor intracranial hypertension

Marmarou et al. (1991) Analysis of Marmarou et al. (1991) Analysis of 428 severely head-injured patients 428 severely head-injured patients from Traumatic Coma Data Bank from Traumatic Coma Data Bank (TCDB)(TCDB)– Strongest predictor of outcome was Strongest predictor of outcome was

percentage of time ICP exceeded 20 percentage of time ICP exceeded 20 mmHgmmHg

– Class IIClass II

ICP Monitoring: ICP Monitoring: Assessment of Disease Assessment of Disease SeveritySeverity

Objectively guide:Objectively guide:– ICP-lowering interventionsICP-lowering interventions– CPP-driven treatment strategiesCPP-driven treatment strategies

Early detection of developing brain swelling or Early detection of developing brain swelling or mass lesions in the sedated/paralyzed patientmass lesions in the sedated/paralyzed patient

Deleterious side effects of ICP control therapiesDeleterious side effects of ICP control therapies– HyperventilationHyperventilation– MannitolMannitol– Sedation and paralysisSedation and paralysis– Decompressive craniotomyDecompressive craniotomy

Potential elimination of unnecessary Potential elimination of unnecessary interventionsinterventions

Outcome predictionOutcome prediction

How Does ICP How Does ICP Monitoring Change Monitoring Change Management?Management?

Evidence for ICP Evidence for ICP MonitoringMonitoring Eisenberg et al. (1988) Prospective Eisenberg et al. (1988) Prospective

study of 73 patients with severe head study of 73 patients with severe head injury and elevated ICP refractory to injury and elevated ICP refractory to standard measuresstandard measures– Patients Patients randomizedrandomized to receive high-dose to receive high-dose

pentobarbital or similar treatment without pentobarbital or similar treatment without pentobarbitalpentobarbital

– All decisions relative to therapy were All decisions relative to therapy were based on ICP databased on ICP data

– Patients whose ICP was controlled with Patients whose ICP was controlled with pentobarbital had much better outcomepentobarbital had much better outcome

– Class I evidenceClass I evidence

Cerebral Perfusion Cerebral Perfusion Pressure (CPP)Pressure (CPP) CPP = MAP – ICPCPP = MAP – ICP Low CPP (<40mmHg) and hypotension Low CPP (<40mmHg) and hypotension

have both been associated with have both been associated with worsened clinical outcomesworsened clinical outcomes

Studies have shown that increasing Studies have shown that increasing blood pressure does not significantly blood pressure does not significantly increase ICPincrease ICP

Suggested critical adult threshold: 70 – Suggested critical adult threshold: 70 – 80 mmHg80 mmHg

Optimal pediatric threshold may be Optimal pediatric threshold may be lower (50 – 65 mmHg)lower (50 – 65 mmHg)

CPP-Directed TherapyCPP-Directed Therapy

M. Rosner, M. Rosner, Journal of TraumaJournal of Trauma, 1990, 1990 Autoregulation not defective, but Autoregulation not defective, but autoregulatory curve autoregulatory curve

shifted to the rightshifted to the right– CPP below lower limit of autoregulation -> decreased ICP, CPP below lower limit of autoregulation -> decreased ICP,

but risk for ischemiabut risk for ischemia– CPP exceeds lower limit of autoregulation -> decreased ICP CPP exceeds lower limit of autoregulation -> decreased ICP

via vasoconstriction-induced reduction in intracranial blood via vasoconstriction-induced reduction in intracranial blood volumevolume

Rosner et. al. J. Neurosurg 1995; 83:949-Rosner et. al. J. Neurosurg 1995; 83:949-6262

↓SBP

↓ CPP

Vasodilatation

↑ CBV

↑ ICP

↑ Edema↑ CSF

↓ CBF

hypovolemia, cardiogenic,loss of sympathetic tone

Vasodilatory CascadeVasodilatory Cascade

Rosner MJ. Introduction to Cerebral Rosner MJ. Introduction to Cerebral Perfusion Pressure Management. Perfusion Pressure Management.

Neurosurgery Clinics of North America Neurosurgery Clinics of North America 1995;6(4):761-7731995;6(4):761-773

Reversing the Reversing the Vasodilatory CascadeVasodilatory Cascade

CPP Monitoring – CPP Monitoring – Clinical OutcomesClinical Outcomes Rosner et al, 1990: Prospective study of 34 TBI Rosner et al, 1990: Prospective study of 34 TBI

patients managed by keeping CPP above 70 mm Hgpatients managed by keeping CPP above 70 mm Hg– Mortality rate 21%; good recovery rate 68%Mortality rate 21%; good recovery rate 68%

Robertson et al, 1998: Randomized clinical trial of 189 Robertson et al, 1998: Randomized clinical trial of 189 TBI patients comparing ICP with CBF-targeted therapyTBI patients comparing ICP with CBF-targeted therapy– No significant difference in outcomeNo significant difference in outcome– Increased rate of ARDS in CBF groupIncreased rate of ARDS in CBF group

No pediatric studies demonstrating that active No pediatric studies demonstrating that active maintenance of CPP above any threshold is maintenance of CPP above any threshold is responsible for improved morbidity or mortalityresponsible for improved morbidity or mortality

Potential hazardsPotential hazards– Intentional hypertension Intentional hypertension raised ICP via pressure or raised ICP via pressure or

leakleak

Eker et. al. Crit Care Med 1998; 26:1881-6Eker et. al. Crit Care Med 1998; 26:1881-6

↓ capillarypressure

↓ capillaryleak

↓ edema

↓ diffusion distances↓ capillary obstruction

Max ΔPoncotic

Min Phydrostatic

Lund ModelLund Model

ICP-directedICP-directed– No specified CPPNo specified CPP– Keep ICP < 20 mmHgKeep ICP < 20 mmHg– Keep BP normal, treat Keep BP normal, treat

hypertensionhypertension

CPP-directed (Rosner)CPP-directed (Rosner)– Maintain CPP > 70 mmHgMaintain CPP > 70 mmHg– Volume expansionVolume expansion– VasopressorsVasopressors

Lund therapyLund therapy– Maintain CPP > 50 mmHgMaintain CPP > 50 mmHg– Aggressively treat Aggressively treat

hypertensionhypertension– Maintain low venous Maintain low venous

pressurespressures

Coles, et. al., Crit Care Med 2002; Coles, et. al., Crit Care Med 2002; 30(9):1950-1959 30(9):1950-1959

HyperventilationHyperventilation

Decreased pCO2 -> cerebral Decreased pCO2 -> cerebral vasoconstriction -> decreased ICPvasoconstriction -> decreased ICP

Decreases regional cerebral blood flowDecreases regional cerebral blood flow

CT Baseline PET Hyperventilation PET

Hyperventilation in TBIHyperventilation in TBI

ICP decreased in only 15 of 31 head-injured ICP decreased in only 15 of 31 head-injured patientspatients– J Neurosurg 51:292, 1979J Neurosurg 51:292, 1979

ICP actually increased in 4/14 patientsICP actually increased in 4/14 patients– Br Med J 4:634, 1973Br Med J 4:634, 1973

Hyperventilation -> ischemiaHyperventilation -> ischemia– J Neurosurg 61:241, 1984J Neurosurg 61:241, 1984

Brain Trauma Foundation Recommendations:Brain Trauma Foundation Recommendations:– Avoid pCOAvoid pCO2 2 < 25 torr< 25 torr– Avoid entirely, if possible (esp. day 1)Avoid entirely, if possible (esp. day 1)– Use during acute deterioration or refractory ICP > 20Use during acute deterioration or refractory ICP > 20

OsmotherapyOsmotherapy

Osmotic Agents are solutions containing simple, Osmotic Agents are solutions containing simple, LMW solutes; hyperosmolar relative to plasmaLMW solutes; hyperosmolar relative to plasma

Examples: Examples: mannitolmannitol, glycerol, dextrose, , glycerol, dextrose, sorbitol, sucrose, sorbitol, sucrose, sodium chloridesodium chloride

A Few Important A Few Important ConceptsConcepts Molarity vs. TonicityMolarity vs. Tonicity

– Molarity is function of the number of Molarity is function of the number of osmotically active particles per unit volume of osmotically active particles per unit volume of solutionsolution

– Tonicity depends on membrane properties as Tonicity depends on membrane properties as well as respective molaritieswell as respective molarities

Uniqueness of Blood-Brain BarrierUniqueness of Blood-Brain Barrier– Impermeable to small particles such as Impermeable to small particles such as

mannitol, sodium ions, and chloridemannitol, sodium ions, and chloride– For any given change in plasma concentration For any given change in plasma concentration

of LMW impermeants, there is much greater of LMW impermeants, there is much greater osmotic force favoring movement of water out osmotic force favoring movement of water out of the brain in comparison with other tissuesof the brain in comparison with other tissues

MannitolMannitol

Hexahydric alcohol related to mannose; Hexahydric alcohol related to mannose; isomeric with sorbitolisomeric with sorbitol

C(6)H(14)O(6)C(6)H(14)O(6) Mannitol is not metabolized, but has a short Mannitol is not metabolized, but has a short

elimination half-life of 30-60 minutes elimination half-life of 30-60 minutes because of rapid renal clearancebecause of rapid renal clearance

In the presence of intact renal function, the In the presence of intact renal function, the accumulation of mannitol within tissues is accumulation of mannitol within tissues is unlikely – “autodilution effect”unlikely – “autodilution effect”

Dose: 0.25 – 1 gm/kg IV over 30 minutesDose: 0.25 – 1 gm/kg IV over 30 minutes Co-administration of FurosemideCo-administration of Furosemide

Qureshi et al., Crit Care Med, 2000Qureshi et al., Crit Care Med, 2000

Hypertonic SalineHypertonic Saline

Several concentrations used, including 3%, 7.5%, and Several concentrations used, including 3%, 7.5%, and 23%; no evidence that one more effective than others 23%; no evidence that one more effective than others in reducing brain water volumein reducing brain water volume

Effect of HS on the cardiovascular system is transient, Effect of HS on the cardiovascular system is transient, lasting between 15 – 75 minuteslasting between 15 – 75 minutes

Action augmented by addition of a colloid such as Action augmented by addition of a colloid such as hydroxyethyl starch or dextranhydroxyethyl starch or dextran

Osmotic EffectOsmotic Effect Hemodynamic alterationsHemodynamic alterations Alterations of Blood ViscosityAlterations of Blood Viscosity DiuresisDiuresis Atrial natriuretic peptide (ANP) releaseAtrial natriuretic peptide (ANP) release CSF dynamicsCSF dynamics Modification of inflammatory response Modification of inflammatory response Membrane potential restorationMembrane potential restoration Free radical scavengingFree radical scavenging

How do Osmotic Agents How do Osmotic Agents Lower Intracranial Lower Intracranial Pressure?Pressure?

Osmotic EffectOsmotic Effect

Theory: intravascular hyperosmolarity Theory: intravascular hyperosmolarity draws water from the interstitial & draws water from the interstitial & intracellular spaces of the brain into the intracellular spaces of the brain into the intravascular compartmentintravascular compartment

Animal studies: decreased cerebral water Animal studies: decreased cerebral water content in non-injured brain regions after content in non-injured brain regions after treatment with mannitol or HStreatment with mannitol or HS

Movement of water from injured brain: Movement of water from injured brain: controversial, may depend on the type of controversial, may depend on the type of injuryinjury

Hemodynamic Hemodynamic AlterationsAlterations Osmotic agents reduce blood Osmotic agents reduce blood

viscosity and increase cerebral viscosity and increase cerebral perfusion pressureperfusion pressure– Increased cerebral blood flow Increased cerebral blood flow

(Poiseuille’s Law)(Poiseuille’s Law)– Cerebral autoregulation leads to a Cerebral autoregulation leads to a

compensatory decrease in CBFcompensatory decrease in CBF via via vasoconstrictionvasoconstriction

Blood viscosity is reduced via Blood viscosity is reduced via hemodilution & decreased RBC hemodilution & decreased RBC adhesivenessadhesiveness (Burke et al., J Neurosurg, 1981) (Burke et al., J Neurosurg, 1981)

By expanding plasma volume By expanding plasma volume (preload) and via direct inotropic (preload) and via direct inotropic effects, cardiac output and MAP are effects, cardiac output and MAP are increased increased (Willerson et al., Circulation, 1975)(Willerson et al., Circulation, 1975)

Other EffectsOther Effects

Acute plasma hyperosmolarity may increase the Acute plasma hyperosmolarity may increase the absorption of CSFabsorption of CSF (Tagaki et al., No To Shinkei 1984)(Tagaki et al., No To Shinkei 1984)

Hypertonic saline and mannitol have been Hypertonic saline and mannitol have been shown experimentally to attenuate pulmonary shown experimentally to attenuate pulmonary edema following ischemic strokeedema following ischemic stroke (Toung et al., Crit Care (Toung et al., Crit Care Med, 2005)Med, 2005)

Hypertonic saline may increase regional Hypertonic saline may increase regional cerebral blood flow cerebral blood flow (Shackford et al., J Trauma, 1994)(Shackford et al., J Trauma, 1994)

Hypertonic saline has been shown to attenuate Hypertonic saline has been shown to attenuate the inflammatory response in brain injurythe inflammatory response in brain injury (Hartl et (Hartl et al., J Trauma, 1997)al., J Trauma, 1997)

HS may help restore normal membrane HS may help restore normal membrane potentialspotentials (Nakayama et al., J Surg Res, 1985)(Nakayama et al., J Surg Res, 1985)

Mannitol: scavenger of free radicals Mannitol: scavenger of free radicals (Suzuki et al., (Suzuki et al., Stroke, 1985)Stroke, 1985)

Adverse EffectsAdverse Effects

Hemodynamic instabilityHemodynamic instability– Acute hypotensionAcute hypotension– Congestive heart failureCongestive heart failure

Fluid & electrolyte disturbancesFluid & electrolyte disturbances– Mannitol: hyperosmolar dehydration, hypernatremia, Mannitol: hyperosmolar dehydration, hypernatremia,

Potassium/magnesium/phosphate lossPotassium/magnesium/phosphate loss– HS: diuresis & natriuresis, hypokalemic hyperchloremic HS: diuresis & natriuresis, hypokalemic hyperchloremic

metabolic acidosismetabolic acidosis Cerebral hyperemia & other intracranial alterationsCerebral hyperemia & other intracranial alterations

– Increased Cerebral blood volumeIncreased Cerebral blood volume– Midline shiftMidline shift– Central pontine myelinolysisCentral pontine myelinolysis

Rebound phenomenonRebound phenomenon

Mannitol – Adult Mannitol – Adult EvidenceEvidence 2003 Cochrane review of mannitol for acute traumatic 2003 Cochrane review of mannitol for acute traumatic

brain injurybrain injury– ““There is not enough evidence from trials to show how There is not enough evidence from trials to show how

best to use mannitol for people with head injury”best to use mannitol for people with head injury” 2 trials have compared high-dose & conventional dose 2 trials have compared high-dose & conventional dose

mannitol in the pre-operative care of patients with mannitol in the pre-operative care of patients with intracranial hemorrhages intracranial hemorrhages (Cruz et al., Neurosurgery, 2001, (Cruz et al., Neurosurgery, 2001, 2002)2002)– There was lower mortality and disability in the high-dose There was lower mortality and disability in the high-dose

mannitol groupsmannitol groups– The studies were faulted for not describing allocation The studies were faulted for not describing allocation

concealmentconcealment Randomized trial comparing mannitol to pentobarbital Randomized trial comparing mannitol to pentobarbital

in 59 patients with elevated ICP in 59 patients with elevated ICP (Schwartz et al., Can J (Schwartz et al., Can J Neurol Sci, 1984)Neurol Sci, 1984)– slight reduction in mortality and improved CPP in the slight reduction in mortality and improved CPP in the

mannitol-treated groupmannitol-treated group

Hypertonic Saline – Hypertonic Saline – Clinical EvidenceClinical Evidence Human studies on the use of HS in the Human studies on the use of HS in the

treatment of cerebral edema & elevated ICP treatment of cerebral edema & elevated ICP are limited to:are limited to:– Case reportsCase reports– Case seriesCase series– Small controlled groupsSmall controlled groups

Concentration of HS studied has not been Concentration of HS studied has not been uniform & dose-response curves are lackinguniform & dose-response curves are lacking

HS has clearly been shown to lower ICP, but HS has clearly been shown to lower ICP, but its safety & efficacy need further evaluationits safety & efficacy need further evaluation

Low frequency of side effectsLow frequency of side effects

Khanna et al., Crit Care Med, 2000Khanna et al., Crit Care Med, 2000

Hypertonic Saline – Hypertonic Saline – Pediatric EvidencePediatric Evidence Non-controlled prospective study of sliding scale 3% Non-controlled prospective study of sliding scale 3%

saline to maintain ICP < 20 mmHg in 10 children with saline to maintain ICP < 20 mmHg in 10 children with raised ICP resistant to conventional therapyraised ICP resistant to conventional therapy– ICP, CPP, MAP, CVP, serum [Na+], serum osm, and serum ICP, CPP, MAP, CVP, serum [Na+], serum osm, and serum

creatinine were continuously monitoredcreatinine were continuously monitored– A significant reduction in ICP spikes & increase in CPP A significant reduction in ICP spikes & increase in CPP

was observed during treatment with 3% salinewas observed during treatment with 3% saline– The mean duration of treatment with 3% saline was 7.6 The mean duration of treatment with 3% saline was 7.6

daysdays– There was a steady increase in serum sodium & osmThere was a steady increase in serum sodium & osm– The mean highest serum sodium = 170.7 mEq/L, The mean highest serum sodium = 170.7 mEq/L,

osmolarity = 364.8 mosm/L, creatinine = 1.31 mg/dLosmolarity = 364.8 mosm/L, creatinine = 1.31 mg/dL– 2 patients developed 2 patients developed acute renal failureacute renal failure requiring CVVH requiring CVVH

in the setting of sepsis and MODS; both patients in the setting of sepsis and MODS; both patients recoveredrecovered

Khanna et al., Crit Care Khanna et al., Crit Care Med, 2000Med, 2000

BarbituratesBarbiturates

Barbiturates lower ICP Barbiturates lower ICP – Lancet 1:141, 1937Lancet 1:141, 1937

Sometimes even when other modalities Sometimes even when other modalities failfail– Shapiro, et. al.; J Neurosurg 40:90, 1974Shapiro, et. al.; J Neurosurg 40:90, 1974

When they work, outcome is better…but When they work, outcome is better…but hypotension is a problemhypotension is a problem– Eisenberg, et. al. J Neurosurg 69:15-23, 1988Eisenberg, et. al. J Neurosurg 69:15-23, 1988

RCT’s don’t support standard useRCT’s don’t support standard use– Brain Trauma Foundation Guidelines, 2000Brain Trauma Foundation Guidelines, 2000

AnticonvulsantsAnticonvulsants

Seizures elicit pathophysiologic responseSeizures elicit pathophysiologic response– Increased neurotransmitter release, glucose Increased neurotransmitter release, glucose

metabolism, intracranial pressuremetabolism, intracranial pressure Post-traumatic seizuresPost-traumatic seizures

– Early (<7d) = 4-25% vs late = 9-42% after traumaEarly (<7d) = 4-25% vs late = 9-42% after trauma– Risk factors: GCS < 10, cortical contusion, Risk factors: GCS < 10, cortical contusion,

depressed skull fracture, subdural/epidural depressed skull fracture, subdural/epidural hematoma, penetrating injury, seizure in first 24 hhematoma, penetrating injury, seizure in first 24 h

Majority of studies indicate that prophylactic Majority of studies indicate that prophylactic AED’s reduce incidence of early post-AED’s reduce incidence of early post-traumatic seizurestraumatic seizures

Fosphenytoin Fosphenytoin or Carbamazepineor Carbamazepine

Continuous EEGContinuous EEG

Majority of seizures are non-Majority of seizures are non-convulsiveconvulsive

Vespa et al (1999) Preliminary study:Vespa et al (1999) Preliminary study:– Improvement in clinical outcome using Improvement in clinical outcome using

cEEG as clinical guidecEEG as clinical guide Burst suppression in barbiturate Burst suppression in barbiturate

comacoma Bispectral Index (BIS) monitoringBispectral Index (BIS) monitoring

SteroidsSteroids Evidence indicates that steroids Evidence indicates that steroids

do not improve outcome or lower do not improve outcome or lower ICP in severely head-injuried ICP in severely head-injuried patientspatients

Routine use of steroids is not Routine use of steroids is not recommendedrecommended

HypothermiaHypothermia

Decreases CMRODecreases CMRO22

In animal models, hyperthermia In animal models, hyperthermia worsens injury and outcomeworsens injury and outcome

Profound hypothermia pre-injury Profound hypothermia pre-injury is clearly protective (ex. DHCA, is clearly protective (ex. DHCA, drowning)drowning)