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General Concepts
General Concepts
Monro-Kellie Doctrine
Since the intracranial volume is fixed and as the contents are essentially non-compressible,
then any increase in one volume mandates and equal volume reduction in other compartments
OpenPediatrics Quick Concept Video on the Monro Kellie Doctrine
Intracranial contents composed of three compartments:
1) brain / interstitial fluid (~80%)
2) intravascular blood (~10%)
3) CSF – ventricles & subarachnoid space (~10%)
Figure 1: ICP as a function of volume Figure 2: Cerebral Blood flow as a function of Perfusion Presure (PP)
Physiologic Principles
CSF functions
Absorbs shock to CNS
Cushions CNS from bony surroundings
Helps circulate nutrients / waste
Cerebral vasculature: Blood Brain Barrier and Autoregulation
Starling equation: Q = K [ (Pmv - Pis) - σ (πmv - πis) ]
Transcapillary fluid exchange determined by transcapillary hydrostatic & osmotic pressures & reflection coefficient
Brain (intact Blood Brain Barrier and functional autoregulation)
High osmotic pressure due to low permeability to crystalloids and proteins – (osmolality of CSF/ECF > plasma)
Tightly autoregulated cerebral intracapillary hydrostatic pressure (CPP not critical if BBB/autoregulation intact)
Most tissues (and Brain if BBB disrupted and autoregulation impaired)
Low osmotic pressure due to high permeability to crystalloids (still low permeability to large proteins)
Hydrostatic pressure varies with MAP (CPP critical)
Autoregulation outstripped at adult CPP levels < 50 mm Hg (ischemia) or > 160 mmHg (cerebral edema)
Mechanisms may be directly impaired by disease processes (and may be heterogeneous in dysfunction)
Endothelial function contributes to autoregulation
States of endothelial dysfunction (sepsis, MODS) can impair autoregulation
Elevated ICP
Normal ICP: 7-20 cm H2O (5-15 mm Hg) [Ratio is about 2/3]
Harmful in 2 ways:
Brain ischemia: Cerebral Perfusion Pressure (CPP) = MAP – ICP (or the CVP if it is > ICP)
Herniation syndromes
Differential Diagnosis
Signs/Symptoms of Intracranial Hypertension
Common
Headache / Irritability
Vomiting (with or without nausea)
Visual obscurations, visual loss, photopsias
Papilledema
Diplopia
Pain on eye movement
Lethargy and increased sleep
Psychomotor retardation
Tinnitus
Less Common
Hearing distortion or loss
Vertigo
Facial weakness
Shoulder or arm pain
Neck pain or rigidity
Ataxia
Paresthesias of extremities
Anosmia
Trigeminal neuralgia
“Cushing’s Triad” = Hypertension, Bradycardia, Irregular Respirations – somewhat specific but insensitive
Intracranial HYPO-tension
Caused by low CSF volume
LP / EVD drainage
CSF leak following trauma, neurosurgery, or thoracotomy (CSF-pleural fistula)
Dural tear
Symptoms result from the loss of buoyancy of the brain as it floats within the CSF
Stretch of the dura & cortical veins (pain-sensitive structures)
Headache
Compensatory vasodilation, tachycardia (opposite of Cushing’s triad)
ICP/CPP Monitoring
ICP/CPP Monitoring
Figure 2: ICP Monitoring Devices
Rationale:
Clinical signs of severely elevated ICP
may never occur
usually a late finding (herniation)
Monitoring improves neurological outcomes
Methods:
Numerous (see diagram)
Variable advantage/disadvantages to each
Purpose:
Early detection of decompensation
Preserve cerebral perfusion
Prevent herniation
Customize/modulate therapies to control ICP
Indications:
Some controversy
GCS 3-8 (ICP>20 in >80% of TBI with GCS<8)
Clinical signs (posturing, cushings triad, etc)
Imaging consistent (slit vents, small cisterns, etc)
Obscured neuro exam and at risk
Risk of elevated ICP
Herniation Syndromes
Herniation Syndromes
Figure 3: Various Herniation Syndromes
Subfalcine Herniation
Cingulate gyrus & related structures herniate laterally under the falx cerebri
Usually from unilateral mass lesions
Usually no classic stigmata
Central Herniation
Downward displacement of brainstem
Any mass almost anywhere with high ICP (including hydrocephalus / diffuse edema)
Mild à traction on the abducens nerve (lateral rectus palsy)
Severe à herniation into foramen magnum (tonsilar herniation) à medulla injury à respiratory arrest, BP instability
Transtentorial/Uncal Herniation
Medial temporal lobe (i.e., the uncus) herniates inferiorly through tentorial notch
Causes clinical triad of “blown” pupil, hemiplegia, and coma
Compression of oculomotor nerve ipsilateral (85% of cases)
Initially: dilated & unresponsive pupil
Later: impairment of eye movement
Hemiplegia is often contralateral (compression of ipsilateral corticospinal tract in the midbrain or motor cortex)
Midbrain distortion leads to decreased level of consciousness and coma
Brain Injury: Multiple Mechanisms of Hypoxic-Ischemic Neuronal Cell Death
Necrosis (overt and acute energy failure with cytotoxic edema; direct disruptive trauma)
Apoptosis (programmed cell death)
Excitotoxicity (toxic glutamate receptor activation)
Management
Management
Management: Different Models
Opinions differ widely on optimal intracranial hypertension therapy based on
sustained versus acute increase in intracranial pressure
mechanism of injury (trauma vs. metabolic vs. infectious)
determination of cerebral vascular state (hypoperfusion vs. hyperemia vs. vasospasm)
controversial evidence (e.g., hyperventilation, hypothermia, animal versus human models, etc.)
how to tailor in setting of specific comorbidities (e.g., ventilation in ARDS, pressors in sepsis, etc.)
Numerous “Schools” of thought:
ICP Targeted: keep the ICP <15-20 mm Hg
CPP Targeted: keep the CPP >50-70 mm Hg
“Lund Concept”: (see below)
Figures 4 & 5: ICP increases after various interventions
Management: Applying Broad Goals in Specific Instances
ICP < 15-20 mm Hg
Perhaps lower <10-15 if large skull fractures/defects (avoid herniation)
Perhaps higher <25-30 if global/metabolic process and other maximized therapies potentially harmful
CPP > 50-70 mm Hg
Set an upper limit (excessive CPP can promote cerebral edema where autoregulation is impaired)
Attention to relative positions of monitoring devices (MAP at heart level, ICP at ear level, Auto-CPP calculations)
Age-Apropriate targets:
Infant 45-55 mm Hg
Child 55-65 mm Hg
Adult 60-75 mm Hg
CI > 2.5-3
Maintain intravascular euvolemia or mild hypervolemia (keep left ventricle full)
Optimize filling pressures to maximize starling curve of the heart without overly impeding venous return
Attention to cerebral vascular state: hypoperfusion vs. hyperemia vs. vasospasm
Careful selection of vasoactive substances from armamentarium
Epinephrine: probably ideal for most patients, especially if low CO, low BP
Dobutamine: may be optimal for global/metabolic processes, especially if normo/hypertensive
β-blockers (labetolol/metoprolol) +/- α2-agonists (clonidine): may be optimal antihypertensives
without causing significant cerebral vasodilatation that can lead to elevated ICP
Nimodipine: may have role in vasospasm
Figure 6: From Stochetti et al, NEJM 2014
Intracranial Volume Targeted (“Lund Concept”)
Ways it’s been described:
Antihypertensive and intracranial volume-targeted therapy
Physiological volume regulation of the intracranial compartments
Central premise:
Impaired autoregulation and blood brain barrier occur in the injured brain
This makes MAP and cerebral capillary hydrostatic pressure driving force behind cerebral edema, and therefore ICP
Furthermore, supporting the CPP with pressors can promote more cerebral edema
Therefore, a good CO with normotension and mild vasoconstriction of precapillary cerebral vessels decreases ICP
The volume-targeted “Lund Strategy” has several components
Reduction of stress response and cerebral energy metabolism (low dose pentothal, sedation)
Reduction of capillary hydrostatic pressure with systemic antihypertensives (metoprolol and clonidine)
Reduction of capillary hydrostatic pressure with precapillary vasoconstrictors (low-dose pentathol & ergotamine)
Maintenance of colloid osmotic pressure and control of fluid balance
Reduction of cerebral blood volume
What it looks like
Euvolemia to Hypervolemia
Normotension using beta-blockers (metoprolol) and alpha-agonists (clonidine)
Low dose pentothal and dihydroergotamine
CPP typically near traditional limits, but lower CPP tolerated in preference of antihypertensive therapy
ICP effectively kept <20 mm Hg most of the time
Outcomes
Efficacy of the protocol has been evaluated in experimental and clinical studies
Surrogate physiological/biochemical improvements (lactate/pyruvate ratio in the penumbra zone by microdialysis)
Non-randomized/non-controlled studies suggest significant mortality benefit
Subjective clinical experiences favorable
ICP Management: General & Monitoring
Time is of the essence – the brain tolerates ischemia more poorly than other tissues & injury begets injury
Multi-pronged approach tailored to primary cause and comorbidities of patient
Serial neurologic assessments and physical examination with a short feed-back loop is critical
Continuous cardio-respiratory, ICP, and CPP monitoring
+/- role cerebral metabolism monitoring adjuncts (micro-dialysis, jugular venous saturation, NIRS)
ICP Management: Decrease intracranial pressure
Evacuate mass occupying lesions (e.g., hemorrhage, tumor, abscess, etc)
Patient Positioning
What: Head up 30 degrees and midline, neck position neutral and non-compressed (e.g., by cervical collar)
Why: Enhance cerebral venous outflow and maximize CPP
Pro: Simple, quick, well tolerated
Con: Confounding injuries, comorbidities requiring movement (e.g., proning)
CSF drainage
What: Removal of CSF ideally through ventriculostomy (alternately an LP)
Why: Decreases “volume” in the compliance equation
Pro: Effective, titratable, doubles as monitor, interpretable waveform
Con: Invasive, bleeding complications, infectious complications
Mannitol
What: 0.5 - 2 g/kg up to Osm of 320
Why: Increases intravascular oncotic pressure, rheological benefits, anti-oxidant effects
Pro: Rapid onset, titratable, predictable
Con: Intermittent, hypotension, hypovolemia, hypokalemia, duration hours or days, tolerance/rebound (reflection coefficient ~0.9)
Hypertonic Saline: Hypertonic Saline Myths Dispelled (AJRCCM 2012)
What: 5-10 ml/kg 3% NaCl up to [Na] of 145-180 meq/L – may bolus 5-10 ml/kg and start a sliding scale gtt @ 0.5-2 ml/kg/hr
Why: Increases intravascular oncotic pressure, volume expander
Pro: Rapid onset, titratable, continuous rx, predictable, high coefficient of reflection (reflection coefficient ~0.95), numerous others
Con: Can obfuscate DI/CSW, potential renal function impairment, some concerns for effects on immune function
HTS vs Mannitol: From Kamel et al, CCM 2011
Craniectomy
What: Resect large flap of skull
Why: Changes the “volume” part of the compliance equation
Pro: Large sustained ICP reduction
Con: Timing critical, surgical risk, tissue herniation through wound, catastrophic Hail Mary
ICP Management: Decrease Cerebral Metabolic Demand
Sedation & Analgesia
What: Benzos, narcs, barbiturates, Lido pETT/IV; possibly premedicate before stimulation; cluster nursing activity; calm environment
Why: Decrease CNS metabolic demand, dampen intrinsic catechols
Pro: Easy, quick, reversible
Con: Loss of neuro exam, depresses hemodynamics
Seizure Control
What: Agressively treat and consider prophylaxing, numerous choices of ACD (phenobarb, pentothal, dilantin)
Why: Decrease CNS metabolic demand
Barbiturates
What: Pentothol 1-5 mg/kg to a level of 10-60
Why: Decreased CNS metabolic demand, decreased cerebral blood flow
Pro: Blunts BP and respiratory fluctuations, anticonvulsant, titratable
Con: Hypotension, abnormal papillary responses, duration days
Antipyresis
What: Tylenol, paralyzation, cooling measures, caution NSAIDS
Why: Metabolic demands increase 5-10% per 1OC
Hypothermia
What: Pre-existing or induced redection of temperature with paralysis and active cooling measures
Why: Hypothermia prior to cerebral ischemic insult protective; induced hypothermia after insult questionable
Pro: Relatively simple, reversible
Con: Risks of coagulopathy, arrhythmia, sepsis (usually < 33OC)
ICP Management: Supportive and Indirect
Ventilation: Normoventilate if able, +/- Hyperventilation temporarily if necessary
What: pCO2 35-40 ideally, but 25-35 mm Hg may achieve needed ICP control (best if transient and minimal)
Why: Decrease cerebral blood flow and therefore edema/ICP; hypercapnia blunts CBF autoregulation
Pro: Immediate onset, well tolerated acutely
Con: Brain ischemia, hypotension, requires intubation, barotrauma, duration usually hours or less
Optimize Hemodynamics
What: Cardiac Output >2.5-3 (e.g., inotropes, volume); CPP target; good venous return (e.g., vec, low Paw); avoid cardiac depressants
Why: generate adequate oxygen/nutrient delivery and waste removal
Optimize Oxygen Carrying Capacity
What: PRBC, Epogen to goal Hb 8-10
Why: Deliver adequate O2
Pro: Oxygenation / DO2
Con: Hb <7-8 can impair DO2; Hb >10-11 can increase viscosity; stored PRBC are less deformable than natural RBC’s
Glucose Control
What: Tight glucose control with prudent dextrose administration and insulin gtt if needed
Why: Hypo- and hyperglycemia in the setting of cerebral ischemia leads to enhanced anaerobic metabolism; stablize osmotic variable
Pro: Relatively simple, physiologic
Con: Some safety issues with inducing hypoglycemia
Loop diuretics & Acetazolamide
What: Furosemide, Torsemide
Why: Decrease CSF production and total fluid overload
Pro: quick, simple, reversible
Con: Risk of dehydration and impaired CO, electrolyte & acid-base derangements
Muscle Relaxants
What: Vecuronium
Why: Stabilize patient, decrease intrathoracic pressure (CVP)
Pro: Easy, quick, reversible
Con: Loss of neuro exam, weakness
Corticosteroids
What: Dexamethasone 1-2 mg/kg q6-24h
Why: Antiinflamitory that decreases some forms of edema
Pro: Effective on vasogenic edema (tumors, abscesses)
Con: Less effective on cytotoxic edema (stroke or hematoma), systemic/immune/gastric side effects
Other Neuroprotective Strategies to Consider
More widely accepted - Literature generally neutral or is optimistic/supportive
Magnesium: to levels of 2.5-3 meq/L as a calcium antagonis, vasodilator, anti-vasospasmodic
Calcium channel blockers (e.g., nimodipine in vasospasm)
Allopurinol: free-radical scavenger
Serotonin agonists (e.g., Repinotan)
Caspase inhibitors: as anti-apoptotic agents
Neural stem cells
Experimental - Literature highly conflicted or is generally pessimistic
Carnitine
Glutamate antagonists / Excitatory Amino Acid (EAA) antagonist
Anti-inflammatory agents (e.g., Ibuprofen)
Sodium channel blockers (e.g., dilantin)
Potassium channel activator
Sundry free-radical scavengers
GABA Antagonists
Opioid Antagonists
NOS Inhibitors
Gangliosides
Neurotrophic factors
Combination Therapy
“The whole is greater than the sum of its parts”
…and yet, one bad ingredient can ruin an otherwise good recipe
Brain Injury is not “All or None”
Neuronal drop-out is fractional: 0-100%
Neuron populations heterogeneous (resilience, metabolic demands, vascular supply, etc.)
Global insult classically leads to
widespread partial dropout / injury of vulnerable cell populations
relatively spared territories (e.g., brainstem)
Focal insult classically leads to
a “core” of hopeless necrosis
a “penumbra” of neurons of varying injure ranging from dead to salvageable to stunned, to unaffected
Think of brain injury as “irreversible” can be a self-fulfilling prophesy
References
References
1. Dr. Matthew Niedner's resident lecture: ICP
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