management of acute intracranial hypertension neurologist 2009

REVIEW ARTICLE

Management of Acute Intracranial HypertensionA Review

Julius Gene S. Latorre, MD,* and David M. Greer, MD†

Background: Patients with acute brain injury from various etiologies com-monly develop increased intracranial pressure. Acute intracranial hyperten-sion resulting from elevation of intracranial pressure is a medical emergencyrequiring prompt diagnosis and management. Appropriate and timely man-agement strategies result in better patient outcome in an otherwise severelydebilitating or fatal disease process.Review Summary: The clinical manifestation and principles of managementof acute intracranial hypertension are discussed and reviewed. Acute treat-ment protocols are presented in an algorithm-based format aimed at utilizingthe current available management strategies and suggested therapeutic goals.Individualization of specific therapeutic modalities is emphasized to opti-mize the clinical outcome.Conclusions: Clinicians treating patients with acute brain injury should befamiliar with the principles of management of increased intracranial pres-sure. Since acute intracranial hypertension is a potentially reversible condi-tion, high index of suspicion, and low threshold for diagnostic and thera-peutic strategies will improve patient care.

Key Words: intracranial pressure, intracranial hypertension, acute braininjury, neurocritical care

(The Neurologist 2009;15: 193–207)

MANAGEMENT OVERVIEW

Acute intracranial hypertension (AIH) is a clinical condi-tion defined as the persistent elevation of intracranial pressure(ICP) above 20 mm Hg1 for greater than 5 minutes in a patientwho is not being stimulated.2 AIH occurs commonly in acutebrain injury related to trauma,3,4 ischemia,5 or hemorrhage,6 andis associated with poor outcome regardless of cause.7 It is aneurologic emergency that requires prompt diagnosis and treat-ment. Aggressive treatment of AIH is effective in reducingmortality and improving outcome.8 –10 Because of potential sideeffects of therapy and intensive ICP monitoring,11 identifyingpatients at risk for developing AIH (Table 1) is crucial inpreventing pathologic changes that may result in poor outcomeand increased mortality. The creation of standardized manage-ment protocols has reduced variations in ICP, decreased durationof AIH,12 and improved outcome,9 and is the basis of this review.

Clinical signs and symptoms of AIH (Table 2) are highlyvariable and depend on the nature of the primary brain injury(ischemic, traumatic, or hemorrhagic), the extent of compartmental-ization, the presence and location of a mass lesion, and the rate ofincrease in ICP. The most common symptom of AIH is progressivedecline in mental status, eventually leading to a comatose state.27

Focal neurologic findings occur invariably, but are most commonlydue to horizontal tissue shifts28 that may not be associated withincreased ICP.29,30

All patients at risk for AIH should have a head CT onadmission and repeat imaging within the first 24 hours, or moreemergently if new symptoms or signs appear.31 Emergent brainimaging is critically important to evaluate the cause of the patient’schange in examination. A noncontrast head CT is the preferredimaging technique. When time permits, MRI may be useful tofurther define the brain pathology. If a mass lesion is identified,neurosurgical consultation should be done emergently for possibleevacuation or decompression.

ICP monitoring is advocated for patients at high risk for AIH,especially for those with a worsening examination due to the poorreliability of clinical signs and symptoms of AIH and the need forprompt recognition and timely intervention.32–34 ICP monitoringmakes AIH management straightforward with clear goals of therapy,enabling early identification of refractory cases for more aggressiveinterventions. In addition, neurosurgical consultation is facilitatedand appropriate surgical intervention may be planned if specificmedical endpoints (eg, poor response or lack of response to osmotictherapy, metabolic suppression, hypertonic saline, hypothermia, etc)are met. Although no randomized trial has been done, retrospectivestudies and reviews on aggressive management of AIH with ICPmonitoring have shown improved outcome in traumatic brain injury(TBI)11,13,35–40 and intracranial hemorrhage (ICH).41 The role ofICP monitoring in malignant ischemic infarction and diffuse cere-bral edema due to metabolic encephalopathies, such as acute liverfailure and central nervous system infection is not well defined.45 Anexternal ventricular drain (EVD) is the preferred monitoring tech-nique, as it also permits therapeutic cerebrospinal fluid (CSF)drainage for relief of increased ICP.46 When the ventricles are small,EVD placement may be more difficult, and an intraparenchymalmonitor may be used. The nondominant hemisphere is the preferredsite of ICP monitor placement, unless the primary pathology affectsthe nondominant hemisphere extensively, in which case the domi-nant side is used. The current intraparenchymal monitor systemshave added capabilities to monitor brain tissue oxygenation, tem-perature, and compliance and may be preferred in selected cases.The monitor is usually positioned in the perilesional area or ipsilat-eral to the most damaged hemisphere.47

The management of AIH primarily revolves around reduc-tion in volume of 1 of the 3 intracranial compartments: brain,blood, and CSF. Treatment response is highly dependent on

From the *Department of Neurology, SUNY Upstate Medical University, Syra-cuse, New York; and †Department of Neurology, Harvard Medical School,Massachusetts General Hospital, Boston, Massachusetts.

Reprint: Julius Gene S. Latorre, MD, 7134UH, Department of Neurology, SUNYUpstate Medical University, 750 East Adams Street, Syracuse, NY 13210.E-mail: [email protected].

Copyright © 2009 by Lippincott Williams & WilkinsISSN: 1074-7931/09/1504-0193DOI: 10.1097/NRL.0b013e31819f956a

ICP monitoring is advocated for patients at high risk

for AIH, especially for those with a worsening

examination.

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multiple factors, including the nature of primary brain injury, theextent of tissue shift, cerebral edema, mass effect, obstruction ofCSF flow, and the status of the cerebrovascular autoregulatoryreserve.48 –52

Based on outcome studies, treatment thresholds (Table 3)have been established to minimize poor outcome and therapeuticcomplications while improving mortality and good outcome. Inan ICP-based management, the primary goal is reduction of ICPto �20 mm Hg using a number of therapeutic modalities asoutlined in the latter part of this review. On the other hand,proponents of cerebral perfusion pressure (CPP)-based therapyrecommend withholding AIH treatment for ICP �20 if CPP canbe maintained �80.53 This is based on the fact that brainmetabolism may be maintained in relatively normal state at CPPabove 80 mm Hg and become abnormal below 60 mm Hg. Todate, no study has shown any advantage over ICP-based orCPP-based management.54 Adjuncts to ICP or CPP monitoringinclude assessment of global (jugular venous O2 saturation�SjvO2�) and regional (brain tissue O2 saturation �PbtO2�) oxy-genation, enabling individualized CPP and ICP thresholds,55–59

although this has not yet been shown consistently to improveoutcome.60

TABLE 2. Overt Sign of AIH—The Herniation Syndromes42

Syndrome Mechanism Imaging Findings43 Clinical Manifestation44

Transtentorial—DescendingUnilateral (Uncal)

Medial temporal lobe pushes downwardinto the posterior fossa through theincisura

Contralateral temporal hornwidening

Ipsilateral ambient cistern wideningIpsilateral prepontine cistern

wideningUncus extending into the suprasellar

cistern

Ipsilateral pupil dilatation: earliest signExternal ophthalmoplegiaContralateral hemiparesisDecerebrate posturingVariable impairment in consciousness

Transtentorial-DescendingBilateral (Central)

Downward displacement of the cerebralhemispheres and the basal nucleicompressing and displacing thediencephalon and the midbrainrostrocaudally through the tentorialnotch

Effacement of sulciObliteration of the suprasellar

cisternCompression and posterior

displacement of the quadrigeminalcistern

Medium sized, fixed pupilsEarly comaDecorticate posturingCheyne-Stokes respirationDiabetes insipidus

Transtentorial-Ascending Infratentorial mass effect protrudingupward compressing the midbrain

Spinning top appearance of midbrainNarrowing of bilateral ambient

cisternsFilling of quadrigeminal cisterns

Nausea/vomitingProgressive stupor

Subfalcine-Cingulate Brain tissue extending under the falx inthe supratentorial cerebrum

Attenuation of ipsilateral aspect offrontal horn

Asymmetric anterior falxObliteration of ipsilateral atrium of

lateral ventricleSeptum pellucidum shift

Small reactive pupilsHeadacheContralateral leg paralysis

Tonsillar Cerebellar tonsils protruding below theforamen magnum compressing themedulla and upper cervical cord

Cerebellar tonsils at the level of thedens on axial images

Cerebellar tonsils on sagittal images5 mm below foramen magnum (7mm in children)

Hypertension-bradycardia-bradypneaComaRespiratory arrestBilateral arm dysesthesia

In an ICP-based management, the primary goal is

reduction of ICP to �20 mm Hg.

TABLE 1. Patients at Risk For Developing AIH Who MayBenefit From ICP Monitoring

Traumatic brain injury (TBI): Up to 72% develop AIH with 92%mortality vs. 18% without AIH13

Severe TBI (Glasgow Coma Scale �9)14

Mild to moderate TBI with abnormal admission head CT scan15

Mild to moderate TBI with normal admission head CT scan and 2 ofthe following:

Age �40, SBP �90 mm Hg, Motor posturing16

Hemorrhage:

Subarachnoid Hemorrhage (SAH): up to 20% develop AIH, with 40%mortality17

High grade (Hunt and Hess grade �2) SAH with radiologic evidenceof hydrocephalus6

Patients with SAH requiring endovascular treatment for vasospasm

Intraparenchymal hemorrhage (IPH):

Supratentorial IPH �50 mL with mass effect18

Cerebellar Hemorrhage18 �30 mm diameter

Subdural or Epidural hematoma with associated midline shift19,20

Ischemia:

Hemispheric Infarction �50% middle cerebral artery (MCA) territory21

Others: Refractory hypertensive encephalopathy22,23

Herpes virus or other viral encephalitides with stupor

Acute hepatic encephalopathy,24 Hepatic encephalopathy Grade III orIV, or hepatic failure with arterial ammonia �150 micromol/L25

Diabetic Ketoacidosis Encephalopathy26

Other Metabolic/Toxic Encephalopathy with radiologic evidence ofcerebral edema or hydrocephalus

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The general neurologist taking care of patient has the responsi-bility of determining the risk of developing AIH (Table 1). Once thepatient is identified as high risk for AIH, general measures as outlinedbelow should be instituted as soon as possible. The patient should bemonitored and evaluated serially for presence of signs and symptoms ofAIH (Table 2). This is ideally done in the intensive care unit. The patientshould be referred to an intensivist and/or neurosurgeon for further evalu-ation and management. Table 4 outlines the appropriate therapeutic mea-sures for patients with overt sign of intracranial hypertension.

GENERAL MEASURESMeticulous multidisciplinary management of critically ill pa-

tients is paramount to the success of any intensive care unit. In patientswho are at high risk for AIH but do not have overt signs of herniation,the basic tenets of acute resuscitation should be kept in mind. Theairway should be secured early and immediately. Indications for endo-tracheal intubation are outlined in Table 5. Intubation should be donewith full anesthesia support to avoid a sudden surge in ICP.

Once the airway has been secured, ventilator settings shouldbe adjusted to the optimal setting required to maintain an O2saturation above 90%, a PaO2 between 80 to 120 mm Hg and aPaCO2 within 35 to 40 mm Hg range.65–67 The mode of ventilationshould be selected based on patient response and comfort. Prophy-lactic hyperventilation is not advocated.67

Maintenance of euvolemia is important for hemodynamic sta-bility. Central venous pressure (CVP, normal: 4 to 8 mm Hg, withadditional 2 to 4 mm Hg during positive pressure ventilation68) roughlyestimates intravascular volume. In hypovolemic patients, the goal of resus-citation includes CVP � 8 to 12 mm Hg or pulmonary capillary wedgepressure � 10 to 15 mm Hg.18,54 Colloids are not recommended in acutebrain injury due to its adverse effect on survival69 except in acute ischemicstroke.70,71 Normal saline is the preferred solution for fluid bolus/mainte-nance in the neurocritical care unit.72,73 Hypertonic saline (3%–7.5%) maybe used to augment volume in the prehospital setting74 and in the ICU,75

especially for patients who are sensitive to volume overload, as long asserum sodium is maintained below 160 to 165 mEq/L and the patient isnot in renal failure. Prophylactic use of osmotic agents are not advo-cated due to their volume-depleting effect and questionable benefit.67

Avoidance of hypotension is paramount in early management ofacute brain injury.76 Systolic blood pressure (SBP) must be kept above90 mm Hg and/or mean arterial blood pressure (MAP) above 70 mmHg77 (target SBP �120 mm Hg and MAP �90 mm Hg for severeTBI).77,78 When ICP monitoring is available, SBP and MAP should bemaintained to keep CPP �60 mm Hg.77,79 Norepinephrine is thevasopressor of choice due to its favorable cerebral hemodynamiceffects.80–82 It may cause reflex bradycardia. Combined inotropes orvasopressors such as dopamine, phenylephrine, or norepinephrine maybe used especially in patients with marginal or poor cardiac status.These agents may cause arrhythmia and telemetry monitoring is nec-essary. Higher goals (CVP: 8–12 mm Hg, SBP: 160–200 mm Hg) maybe necessary if there is an evidence of regional ischemia, such as inpatients with vasospasm due to subarachnoid hemorrhage, acute isch-emic stroke with large perfusion mismatch, or acute brain injury withperilesional ischemia. In these conditions, the use of albumin (5%) 250to 500 mL IV bolus Q6 to 8 hours PRN to achieve the CVP goal mayaugment volume expansion.

TABLE 3. Goals of Therapy For AIH

Parameter Normal Value Treatment ThresholdTherapeutic

Target

ICP 0–15 mm Hg �20 mm Hg for �5min61,62

�20 mm Hg

CPP 60–150 mm Hg �50–60 mm Hg63 �60 mm Hg

PBtO2 20–40 mm Hg 10–15 mm Hg55,64 �20 mm Hg

TABLE 4. Emergent Management of Patients With OvertSign of AIH: No ICP Monitoring in Place

Perform ABC’s while preparing patient for emergent non-contrast headCT

A–Airway: Secure airway, call Anesthesia stat to do rapid sequenceintubation, maintain/induce sedation with propofol and/or fentanyl

B–Breathing: Perform hyperventilation using ambu-bag while waitingfor Anesthesia/intubation, maintain PaCO2 26–30 mm Hg

C–Circulation: Assess for euvolemia, give 1L NS bolus if CVP �5 orSBP �100 or MAP �70 prior to instituting osmotic therapy

Once euvolemia is established, airway is secured, patient is sedated, HOBelevated to 30 degrees, hyperventilation on-going, institute osmotictherapy on the way to CT scanner

Serum Na, K, BUN, Glu, Osmolality stat, and Q4–6 h thereafter

Mannitol 1–2 g/kg IV bolus stat then 1 g/kg Q4–6 h

Hold mannitol dose for Osm Gap �10 or Change in Osm Gap �10

23.4% NaCl 0.5–1 mL/kg IV bolus over 15–30 min if no significantICP reduction within 1 hr of Mannitol administration, or if unable togive Mannitol due to high baseline serum Osmolality, repeat inbetween Mannitol doses if ICP �20

Once CT scan results are available, call neurosurgery stat as indicated,while continuing above maneuvers

Focal mass lesion with midline shift–refer for emergent decompressivecraniectomy

Diffuse brain edema/swelling–refer for intraparenchymal bolt placement

Hydrocephalus–refer for emergent EVD insertion and CSF drainage

Note: Gradually wean hyperventilation with ETCO2/PaCO2 guidance tono more than 1 mm Hg/h to avoid rebound ICP surge, post-operatively

Once ICP monitoring becomes available, switch mannitol dosing to 1g/kg IV bolus Q4–6 h as needed for ICP �20 for �5 min, otherwisecontinue with repeated dosing and follow-up clinical exam and serialimaging

TABLE 5. Indication for Endotracheal Intubation in theNeurocritical Care Unit

GCS �9 with one or more risk factors for AIH

Patients with signs of respiratory distress:

Declining O2 saturation

Increasing O2 requirement

Labored breathing

Patients unable to protect airway due to respiratory/oropharyngeal weakness

Adjuncts to ICP or CPP monitoring include

assessment of global and regional oxygenation,

enabling individualized CPP and ICP thresholds.

When ICP monitoring is available, SBP and MAP

should be maintained to keep CPP �60 mm Hg.

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Strict glucose control is essential to the management ofacutely injured brain, as hyperglycemia has been correlated withpoor outcome.83–86 Intensive insulin therapy to keep the bloodglucose level between 80 and 110 mg/dL is shown to improveoutcome and reduce mortality in medical and surgical intensive careunits.87–89 However, several experimental90 and clinical studies91

have shown that intensive systemic glucose lowering reduces brainglucose concentration, a risk factor for poor outcome. In a recentstudy on subarachnoid hemorrhage, intensive insulin therapyshowed no significant effect on neurologic outcome and mortality.92

Currently, a less aggressive glucose target of 80 to 140 mg/dL isrecommended for patients with acute brain injury. A continuousinsulin infusion should be started if 2 subsequent random bloodglucoses within 6 hours show values above 140 mg/dL, as this levelhas been found to discriminate between good and bad outcome inneurocritically ill patients;85 otherwise a regular insulin sliding scaleregimen may suffice.

Maintenance of normothermia at 36°C to 37°C augments ICPmanagement93 and may be done using antipyretics and coolingblankets. Care should be taken when giving paracetamol, as it maycause hypotension in selected individual, which may compromisecerebral perfusion.94 Special surface cooling devices and endovas-cular cooling catheters may be used for refractory hyperthermia.95,96

The use of sedation and analgesia is an important manage-ment strategy, especially in patients with AIH. Propofol is thepreferred agent for short-term sedation due to its short half-life,making frequent clinical examination possible. It also has a favor-able effect on cerebral hemodynamics, reducing ICP.97,98 A ceilingdose of 5 mg/kg/h is advocated to prevent complications related toprolonged propofol infusion.99 Fentanyl infusion may be added inseverely agitated patients who are not controlled adequately by highdose propofol. Narcotic analgesics are routinely used as needed forcomplimentary pain management. Short-acting benzodiazepinessuch as lorazepam or midazolam may be used for anxiety andrestlessness.100

Head of bed elevation to 30 degrees has been shown toreduce ICP while maintaining an adequate CPP in brain-injuredpatients,101–104 except in patients with large ischemic stroke when itmay compromise flow through a stenosed proximal cerebral ves-sel.105 Maintenance of straight head position prevents kinking of thejugular venous system and facilitates venous drainage.106

A significant number of patients with acute brain injury are atrisk for early seizures (Table 6). Seizures acutely increase the ICPand amplify metabolic demand. Because of this, patients at risk forAIH should be given seizure prophylaxis with phenytoin107 (loadingdose of 20 mg/kg IV over 1 hour and maintenance of 100 mg Q8Hdaily) or levetiracetam108 (500 mg Q12H daily). The duration oftherapy remains controversial. However for TBI, 7 days after trauma109

and 1 month after ICH18 is recommended, unless patients haveexperienced spontaneous seizures.

Nutrition is an important part of management of acutebrain injury patients. Feeding may be done enterally (jenunalpreferred over gastric) or if not possible due to concomitant

abdominal issues, parenterally and should be started as soon aspossible within 72 hours after injury. Patients with non-TBIshould be fed with 100% resting metabolic expenditure adjustedfor age, sex, and body surface area. Patients with TBI should begiven 140% resting metabolic expenditure with 15% protein.119

A summary of general measures outlined above is presented inTable 7.

EMERGENT MANAGEMENT OF PATIENTSWITH OVERT SIGN OF AIH: NO ICP MONITORING

IN PLACEPatients with overt signs of AIH need special attention and

require synchronized evaluation of the primary etiology of AIH andcontrol of elevated ICP (Table 4). Patients should have a noncontrasthead CT emergently. Hyperventilation must be instituted immedi-ately and PaCO2 should be maintained to 26 to 30 mm Hg.32

Although not effective and harmful for prolonged use,65,66,120

hyperventilation for acutely symptomatic patients may be lifesav-ing.121 Severe hypocapnea to PaCO2 less than 25 is not advocatedas the risk of brain ischemia significantly increases with no furtherreduction in ICP.122,123 Patient must be intubated if the airway hasnot yet been secured with full anesthesia support using rapid se-quence intubation to avoid further increases in ICP. Propofol with orwithout fentanyl IV infusion should be started to maintain adequatesedation. Head of bed elevation to 30 degrees above horizontal mayreduce ICP without compromising CPP. Euvolemia must be estab-lished prior to instituting osmotic therapy to avoid further reductionin cerebral perfusion. Mannitol in 20% or 25% concentration shouldbe given by IV bolus at 1 to 2 g/kg. Repeat doses may be done every4 to 6 hours (as necessary if ICP monitoring has been started) untilclinical response or stabilization of mass effect by serial imaging isachieved. Calculated (1.86 (Na�K) � Glu/18 � BUN/2.8 �10)124,125 and measured serum osmolality (normal value � 270–290 mOsm/L) and osmolar gap (measured–calculated osmolality:

Propofol is the preferred agent for short-term

sedation due to its short half-life, making frequent

clinical examination possible.

TABLE 6. Acute Brain Injury and Risk of Seizure

Pathology High Risk Condition Seizure Risk

Any acute brain injury Comatose 10%–34%110

TBI Moderate to severe TBI 4%–14%107,111,112

Abnormal CT scan

Subdural hematoma

Penetrating injury

Depressed skull fracture

Ischemic stroke Large corticalinvolvement

3%–6%113,114

Primary IntracerebralHemorrhage (ICH)

Lobar location(temporoparietal)

6%–28%113-115

Subcortical with corticalextension

SAH Unprotected aneurysm(pre-treatment)

16%–20%116,117

Fisher group 3

Post-operative Cerebral abscess Up to 14%118

Traumatic intracerebralhematomas

SAH (MCA) clipping

AVM

Glioma

Parasaggitalmeningioma




normal value � 0–5) should be done at baseline and prior to eachmannitol dosing to avoid mannitol-induced renal insufficiency. Ameasured serum osmolality �320 mOsm/L126 especially in patientswith history of hypertension and diabetes, osmolal gap �10 orchange in osmolal gap from baseline �10 correlate with poormannitol clearance,125 and increased risk of renal toxicity. Neuro-surgery consultation should be done at the onset of patient deterio-ration in anticipation for emergent surgical management based onimaging results.

EMERGENT MANAGEMENT OF PATIENTS WITHOVERT SIGN OF AIH: ICP MONITORING IN PLACE

Patients in whom ICP is being monitored usually do notsuddenly show overt signs of AIH without corresponding changes inICP. However, in the event that sudden deterioration occurs, asimilar management response as in an unmonitored patient (Table 4)should be initiated. If EVD is in place, CSF drainage of 5 to 10 mLmay be done for persistently elevated ICP. Osmotic therapy remainsthe cornerstone of management (Table 8). The decision to considersecond or third tier therapy for AIH (Table 9) must be individualizeddepending on the patient’s primary condition and with full partici-pation of the family members/designated patient’s decision makers.

SPECIFIC MEASURES FOR MANAGEMENT OF AIHThe goal of AIH management is to identify and prevent

secondary ischemic brain injury brought about by an excessivelyincreased ICP with a compromised CPP, thereby maintaining cere-bral perfusion adequate for a given metabolic demand and conse-quently improving outcome and reducing mortality. Available ther-apeutic options are outlined in Table 10.

OsmotherapyTwo osmotic agents are currently in use in most neurocritical

care units: mannitol and hypertonic saline. Both are highly effectivein reducing acutely elevated ICP in various clinical conditions, withalmost immediate effect lasting for several hours. Mannitol is thepreferred osmotic agent due to its availability and physician’sfamiliarity of use. It has several mechanisms of action. An imme-diate effect from bolus administration results from plasma expansionwith reduction of blood viscosity,127 improvement in microvascular

TABLE 7. General Management of Neurocritical CarePatients With AIH

Airway. Secure early in the following patients:

GCS �9 at high risk for AIH

Patient with signs of respiratory distress

Declining O2 saturation (�90%)

Increasing O2 requirement (FiO2 �50%)

Labored breathing

Rising pCO2 (�45 mm Hg) in patients without COPD

Patient unable to clear out secretions due to respiratory/oropharyngealweakness

Patients with severe agitation requiring sedation that may compromiseairway

Breathing. Maintain PaO2 between 80–120 mm Hg, PaCO2 35–40 mmHg, O2Sat �90%

Circulation

Maintain Euvolemia with goal CVP �5 mm Hg

0.9% NaCl at 1–3 mL/kg/h maintenance fluid

0.9% NaCl 0.5–1.0 L IV bolus prn

Maintain MAP �70 mm Hg and/or SBP �90 mm Hg

Phenylephrine infusion at 10–1000 mcg/min

Norepinephrine infusion at 2–100 mcg/min

Dopamine infusion at 10–1000 mcg/min

Epinephrine infusion at 1–12 mcg/min

Head Position. HOB elevation, keep head at 30° (except in large ischemicstroke)

Temperature: Keep Temp below 38°C

Acetaminophen 650 mg PO/PR Q4H

Cooling blanket

Surface cooling

Endovascular cooling

Glucose control: Keep Blood Glucose (BG) between 80–140 mg/dL

Regular Insulin sliding scale

Regular Insulin IV drip if BG �140 mg/dL � 2 taken 6 h apart

Sedation/Analgesia:

Propofol IV drip at 0.1–5 mg/kg/h

Fentanyl IV drip at 50–200 �g/h

Morphine 2–4 mg IVP Q 2–4 h as needed

Ativan 1–2 mg IVP Q4–6 h as needed

Seizure prophylaxis, for patients at high risk:

Phenytoin (or Fosphenytoin) 1 g LD IV then 100 mg Q8H � 7 d

Levetiracetam 500 mg PO BID � 7 d

Nutrition:

Enteral (jenunal preferred vs gastric) to be started within 72 h

Parenteral (if with contraindication to enteral, or unable to startenteral feeding within 72 h)

100% RME for non-traumatic and patients on paralyzing agents

140% RME with 15% protein for TBI patients

Hyperventilation for acutely symptomatic patients

may be lifesaving.

TABLE 8. Emergent Management of Patients With OvertSign of AIH: ICP Monitor in Place

Perform management maneuvers as in Table 7

If EVD in place, drain 5–10 mL CSF stat and Q30–60 min as needed forICP �20 mm Hg

Keep EVD at 10–15 cm above external auditory meatus and open

Note: Close EVD during patient transport to avoid overdrainage. In SAHpatients with unsecured aneurysm, CSF drainage is not advocated andEVD should be clamped to prevent rebleed

If ICP �20 mm Hg despite sedation, controlled hyperventilation,euvolemia, CSF drainage, institute osmotic therapy:

Mannitol 1–2 g/kg IV bolus stat, then Q4–6 h as needed for ICP �20mm Hg

23.4% NaCl given as 0.5–1 mL/kg IV over 15–30 min Q4–6 h asneeded for ICP �20 mm Hg may be used in the followingcircumstances:

1. In lieu of mannitol in patients with high baseline osmolar gap (�15),high baseline serum osmolality (�320 mOsm/L), or history ofchronic or acute renal insufficiency, diabetes and poorly controlledhypertension

2. In sequence with mannitol infusion, in patients with partial response(ie post mannitol reduction �25% of pretreatment ICP but absoluteICP value �20 mm Hg)




cerebral blood flow,128 cerebral oxygenation,129 and CPP130 withreduction in cerebral blood volume,130,131 and ultimately loweringof ICP. A slightly delayed effect, occurring within 15 to 30 minutesand lasting for up to 6 hours, results from a direct osmotic effect onneural cells with reduction in total brain water.132 Additional pos-sible mannitol effects include reduced CSF production,133 freeradical scavenging,134 and inhibition of apoptosis.135 Doses rangingfrom 0.2 to 2.0 g/kg as intermittent or continuous infusion have beenstudied but 1 to 2 g/kg136 given as IV bolus137 as needed138 isrecommended. Repeated doses of mannitol require ICP monitoringsince the effect diminishes over time and a rebound phenomenonhas been noted after prolonged use in experimental models139,140

although clinical studies have shown variable results.141–143 Theosmolar gap correlates better with the mannitol level and is thepreferred monitoring parameter to prevent mannitol-induced re-nal failure.144

Hypertonic saline use in neurocritical care is increasing due toits favorable effect on systemic hemodynamics,145–147 ease of use,and proven efficacy.144,148–151 In addition to its dehydrating effect,it promotes rapid CSF absorption,152 increases cardiac output, andexpands intravascular volume thereby augmenting the CPP with apositive inotropic effect,153 diminishing the inflammatory re-sponse,154 and inducing glutamate reuptake.153 A number of prep-arations have been studied clinically ranging from 1.5% to 30%NaCl with variable results. For continuous infusion, 3% NaCl ispreferred,155,156 whereas for bolus administration, 23.4% NaCl isused.149,150,157 Hypertonic saline has similar efficacy with mannitoland may be used interchangeably, especially in patients with a highosmolar gap.144

Prolonged increase in osmolality induces the cerebral ho-meostatic mechanism to produce idiogenic osmoles to reduce the

osmotic gradient.158,159 Because of this phenomenon, osmotictherapy must be tapered after 24 hours of continued use to avoidrebound AIH.160 Relative contraindications to osmotic therapyinclude chronic or acute renal failure and symptomatic conges-tive heart failure.144

Other osmotically active agents have been evaluated clini-cally and experimentally for AIH. Glycerol, sorbitol, and urea werefound to be inferior to mannitol and associated with more severerebound edema.141

Metabolic Suppression TherapyIn patients with preserved flow-metabolism coupling, barbi-

turate-induced cerebral metabolic suppression is an effective way ofreducing ICP refractory to osmotherapy.14,40,161–166 Barbituratesreduce cerebral metabolism with concomitant reduction in cerebralblood flow thereby decreasing ICP.132 In addition, barbiturates haveneuroprotective properties including free radical scavenger func-tion,167 apoptosis inhibition,168 and reduction in intracerebral pyru-vate, and lactate production.165 Thiopental is a short-acting barbi-turate with a short half-life in the range of 9 to 27 hours afterprolonged infusion169 and may be more effective than pentobarbitalin reducing ICP.170

Pentobarbital is given as IV infusion at a usual rate of 1 to 8mg/kg/h. A loading dose of 5 to 10 mg/kg repeated every 15 to 20minutes as needed may be necessary if ICP does not respond.40

Thiopental may be given with a loading dose of up to 4 g over 1 to5 hours (300–500 mg IV bolus every 30 minutes) until a positiveICP response appears, followed by continuous infusion of 1 to 6mg/kg/h.169 Frequent small loading doses are advocated to preventsudden hypotension and reduction of CPP. The duration of therapydepends on the ICP response. Continuous infusion is not advocatedif the loading dose does not show any ICP response. If the ICP drops�25% with a loading dose, continuous infusion may be institutedfor 24 to 180 hours or until ICP is well controlled.

A minimum barbiturate dose required to control ICP �20 isadvocated with frequent dose adjustment every 2 to 4 hours. Therehave been no consistent predictable relationships between cerebralmetabolism and barbiturate blood levels, precluding its clinicaluse.171 Continuous EEG monitoring is recommended only to pre-vent overdosing as the maximum effect on metabolic suppression,CBF and ICP reduction is achieved with an EEG pattern showing 1to 2 bursts per minute;172,173 any further increase in barbiturate doseincreases the risk of cerebral ischemia due to further reduction ofsystemic blood pressure and cardiac output without a further decre-ment in cerebral blood blow and ICP. In patients with impairedcerebral autoregulation, concomitant monitoring of global (SjvO2)or regional (PbtO2) cerebral oxygenation may be used in com-bination with continuous EEG monitoring to maximize barbitu-rate-induced ICP reduction without inducing cerebral isch-emia.161 Gradual weaning after prolonged infusion (more than 24hours) is suggested due to potential development of barbituratewithdrawal seizures.

Despite its efficacy, barbiturate therapy has a variable effecton outcome163,174,175 and no benefit has been shown with prophy-lactic administration.176 Systemic hypotension almost always occurswith barbiturate therapy, often requiring vasopressor therapy andmeticulous fluid management. Barbiturate infusion should be dis-continued if significant hypotension occurs that compromises CPPdespite vasopressor and fluid management. Other side effects ofbarbiturate therapy include sepsis, electrolyte abnormalities, andhepatic and renal dysfunction.177 Because of significant potentialadverse effects with no clear effect on long-term outcome, high dosebarbiturate therapy is considered a second tier treatment strategy forAIH intractable to osmotic agents.

Two osmotic agents are currently in use in most

neurocritical care units: mannitol and hypertonic saline.

TABLE 9. Therapeutic Failure Criteria: AIH Treatment Tier

First Tier to Second Tier Criteria

Failure to reduce ICP �20 mm Hg within 2 h of sequential mannitol/hypertonic saline infusion. (Note: Return of ICP to pretreatmentvalue within 4 h before next dose of osmotic agent is a relativeindication for switching to next AIH treatment tier, unless CPP canbe maintained �60)

Development of adverse effect (renal failure, congestive heart failure,rebound phenomenon, severe hypernatremia, poor mannitol clearancebased on osmotic gap) barring continuation of osmotic agents

Second Tier to Third Tier Criteria

Failure to reduce ICP by 25% of pretreatment value

Persistent ICP elevation �20–25 mm Hg during metabolic suppressiontherapy despite burst suppression EEG pattern at 1–2 burst perminute for �2 h

Persistent ICP elevation �20–25 mm Hg during induced hypothermiawith target temperature of 32°–34° for �2 h

Development of adverse effect (marked hypotension requiring �1vasopressor to keep MAP �70 or CPP �60; coagulation abnormalitywith increased bleeding risk; presence or development of severeinfection/sepsis) barring use/continuation of hypometabolic agents




TABLE 10. Specific Therapy for AIH

MOA Dose/Administration Monitoring Adverse Effect

Emergent Tx

Transienthyperventilation

Reduction of CO2 causingcerebral vasoconstrictionand reduction of CBV

Ambubag/ventilator rate of 30–40breaths per minute to increaseminute ventilation by 15–20L/min, wean slowly over 12–24 hto prevent rebound AIH Effectiveonly for a few hours Avoidprolonged (�6 h) or prophylacticuse

PaCO2 to keep at 26–30 mm HgABG monitoring Q15 min to

avoid overshootSjvO2 and/or PbtO2 monitoring

suggested

Cerebral ischemiaRebound AIH if

stopped suddenly

Decompressivesurgery

Expansion of cranial vaultreleasing pressure andimprovement in CBF

Evacuation of mass effect

Wide craniectomy with duraplastyand evacuation of mass lesion,done as soon as possible

ICP monitoring recommendedBrain imaging as clinically

indicated

Death, ICH, Stroke,Bleeding, infection

External ventriculardrainage

Drainage of CSF improvingcerebral compliance andreducing ICP

Usually inserted in the nondominantfrontal area

EVD at 10–15 cm above externalauditory meatus and open

5–10 mL CSF drainage every 30–60min as needed for ICP �20 mm Hg

ICP monitoringBrain imaging as clinically

indicated

CNS infectionBleedingEVD malfunction

First Tier

Mannitol Reduces brain waterReduced RBC viscosityIncrease CBFFree radical scavengerReduces CBVReduced CSF production

1–2 g/kg IV bolus every 4–6 htaper dose if continued use for �24 hAlternate with 23.4% NaCl if with

partial response

Serum Na, K, BUN, Glu, Osm,Osm gap before each dose

Hold for Osmolar gap �5 (usingformula: 1.86 (Na�K) �BUN/2.8 � Glu/18 � 10)

If baseline Osm Gap �5, holdfor change in Osm Gap �5

Renal failureElectrolyte abnormalityCHFRebound effect

Hypertonic saline Reduces brain waterReduced RBC viscosityIncrease CBF, Improves

COIncreased CSF absorption

23.4% NaCl IV bolus over 15–30min at 0.5–1 mL/kg/dose givenevery 4–6 h alternate with or inbetween mannitol doses

Serum Na, OsmDo not exceed Na rise �0.5

mEq/L per hr if with historyof chronic hyponatremia

Renal failureCHFElectrolyte abnormalityRebound effect

Second Tier

Barbiturate Reduction of metabolicdemand reduces CBF andICP

Free radical scavengerAnti-apoptoticNeuroprotective

Thiopental 1–5 g IV LD as 500 mgIV bolus Q15–30 min over 1–5 huntil ICP response

If complete response (ICP �20),return to first tier agents, orrepeat bolus doses as necessary

If incomplete response (ICP �20but reduction �25%), start IVinfusion at 1–8 mg/kg and adjustdose every 30–60 min to ICPgoal �20 or until burstsuppression EEG pattern at 1–2burst/min

Duration of treatment between 12–180 h with gradual weaning over24 h

Continuous EEGKeep CPP �60 using

vasopressors as necessarySjvO2 or PbtO2 recommendedBlood culture Q24–48 hSerum lytes, CBC, coags, LFTs

daily

Systemic hypotension,severe infection,respiratorycomplications, renaland hepaticdysfunction

Hypothermia Reduction of metabolicactivity reduces CBF andICP

Reduces release ofexcitatoryneurotransmitters

Target temperature of 32°C–34°Cwith surface or endovascularcooling method

Duration of treatment between 24–72 h, followed by passiverewarming over 12–24 h

Bladder temperatureSurveillance cultureRoutine coagulation studies

ShiveringSepsisHypotension and

electrolyteabnormality

Third Tier

Surgery Expansion of cranial vaultreleasing pressure andimprovement in CBF

Evacuation of mass effect

Most effective if done in patientswho failed medical AIHmanagement but does not haveovert herniation syndrome yet

ICP monitoring by EVD or boltSjvO2 or PbtO2 recommended

Death, ICH, Stroke,Bleeding, infection




Other metabolic suppressive agents have been evaluated forICP reduction but side effects have limited their use. Prolonged useof high dose propofol (more than 5 mg/kg/h) may cause “propofolinfusion syndrome” with rhabdomyolysis, pancreatitis, and meta-bolic acidosis.99,178,179 In addition, bolus administration of propofolcauses significant hypotension that may compromise CPP.180,181

Studies on etomidate have shown variable results,182–187 with anincreased incidence of adrenal suppression188 and renal failure.189

Relative contraindications to metabolic suppression therapy in-clude active septicemia, coagulopathy, and unstable hemodynamic status.

HypothermiaInduced hypothermia is effective in reducing ICP from mul-

tiple causes190–194 by suppressing all cerebral metabolic activities,thereby reducing CBF. It has been found to be cytoprotective inanimal models,195 reducing ischemia-induced release of gluta-mate.196 The use of hypothermia for patients at high risk for AIH butno overt sign of increased ICP have shown variable re-sults.191,192,197–203 The increased amount of resources associatedwith its use in addition to potential adverse effects make hypother-mia a second tier AIH therapy in refractory ICP.

Mild (34°C–36°C) to moderate (32°C–34°C) hypothermiamay be induced by surface cooling200 or endovascular coolingcatheter.95 Surface cooling with a body vest is the preferred methoddue to its noninvasive nature and relative efficacy in achieving thetemperature goal.204 The endovascular cooling catheter has theadvantage of faster time to target temperature but is associated withthe risk of infection, bleeding, and intravascular thrombosis.205

Other side effects206,207 common to all techniques of hypother-mia include bleeding diathesis, respiratory infection, shivering,and myocardial dysfunction especially with deep208 (less than31°C) hypothermia.209 Rebound cerebral edema occurs com-monly during rewarming.210

A target temperature between 32°C and 35°C achieved as fastas possible for maximum effect is advocated for ICP reductiontherapy. Cold saline infusion (30 mL/kg of 0.9% NS at 4°C as an IVbolus over 30 minutes) is safe and shortens the time to targettemperature.211 Patients require an aggressive antishivering regimenwith adequate sedation (mentioned in Table 11). Cooling is main-tained for 24–72 hours or longer depending on ICP response.212

Passive rewarming over 24 hours is critical due to development ofrebound cerebral edema, hypotension, and electrolyte abnormali-ties.192,213,214 In addition, meticulous attention should be devoted tomanagement of shivering (Table 12) to prevent a hypercatabolicstate and rebound hyperthermia. Relative contraindications to hypo-thermia include active septicemia, coagulopathy, and unstable he-modynamic status.

A significant number of issues215 remain unresolved, includ-ing the ideal target temperature (mild, moderate, or deep hypother-mia), patient selection,190,216,217 mode of administration of cooling(surface vs. endovascular), timing of intervention (prophylactic,early vs. delayed or only with AIH), duration of treatment (24 hours

vs. prolonged �72 hours),212 duration and rapidity of rewarming,and control of shivering.218

OthersA number of agents for AIH management have been used in

the past but have not gained wide acceptance because of variableclinical results and lack of solid evidence on efficacy. These agentsmay be used as a last resort while waiting for definitive managementsuch as surgical decompression or prior to switching to second tiertherapy in patients with relative contraindications to a specific agent.

Tris-hydroxymethyl-amino-methane or tromethamine is ef-fective in reducing refractory AIH,227–229 given as 0.3 M solution ata dose of 1 mmol/kg (121 mg/kg or 4 mL/kg) over 1 hour, repeatedevery 12 hours, or followed by continuous infusion of 1 mL/kg/h forup to 5 days. It acts as a cerebral buffer and induces metabolicalkalosis without increasing PCO2 and serum Na, resulting incerebral vasoconstriction, reduction in CBV and ICP. Patients needto be ventilated to avoid respiratory compensation. Side effectsinclude local tissue irritation and necrosis, respiratory depression,

Induced hypothermia is effective in reducing ICP

from multiple causes by suppressing all cerebral

metabolic activities, thereby reducing CBF.

TABLE 11. Indication for Surgery in Patients With AIH

Decompressive craniectomy, evacuation of mass lesion with or withoutduraplasty

Severe TBI, no mass lesion, refractory ICP

Any TBI, mass lesion causing significant tissue shift

Malignant MCA infarction

Infratentorial ICH �3 cm diameter with or without hydrocephalus

Patients with diffuse brain edema from a number of causes who arerefractory to medical AIH management

Minimally invasive surgery with or without thrombolysis

ICH with GCS 6–12 and deteriorating neurologic status

ICH with clot volume 20–80 mL causing midline shift and raised ICP

External ventricular DrainVentricular obstruction causing hydrocephalus

Intraventricular hemorrhage or extension distortion of 4th ventricle witheffacement of ambient cisterns

Need for ICP monitoring

TABLE 12. Antishivering Strategies forTherapeutic Hypothermia

Nonpharmacologic204

Boots and mittens heated to 46°C

Application of warming blanket

Neck and face air warming with humidified air (standard face tent with6–10 L/min of humidified air warmed to 32°C)

Pharmacologic:

For nonintubated patients

Tramadol219 100–200 mg PO Q4–6H

Clonidine220 0.1–0.2 mg PO Q12H

Meperidine221,222 25–75 mg IV/PO Q2–4H0.4 mg/kg/h IV infusion

Ondansetron222 8 mg IV/PO Q6–8 H

Buspirone204 30 mg PO Q8H

For intubated patients:

Dexmedetomidine223 0.05–0.7 mcg/kg/H IV infusion

*Propofol224 1–5 mg/kg/H IV infusion

*Alfentanyl225 50–75 mcg/kg IV LD then 0.5–3 mcg/kg/min IVinfusion

*Require paralytic agent: Cisatracurium226 0.1–0.2 mg/kg LD as IV bolus then0.01–0.15 mg/kg/h.




and hypoglycemia. Renal failure is a relative contraindication totromethamine use.

Indomethacin is a nonspecific cyclooxygenase inhibitor thathas been found to have a vasoconstrictive effect in cerebral vessels,predominantly affecting the small resistance vessels, causing reduc-tion in ICP by reducing CBV and CBF.230–232 It is usually given asa 50 mg IV bolus repeated every 6 to 8 hours or followed by 10 to30 mg/h continuous infusion � 24–48 hours.233 So far, its effect onlong-term outcome is unknown, and there is theoretical danger ofinducing cerebral ischemia from vasoconstriction. In addition, re-bound AIH has been noted with use of indomethacin after suddendiscontinuation.233–235

Ineffective or Harmful TherapyThere is ample evidence that corticosteroids do not improve

outcome in acute brain injury from trauma, ischemia, or hemorrhageand may actually be harmful due to increased adverse effects relatedto its use.123,236–241

Hyperventilation beyond 6 hours looses its efficacy inreducing ICP due to rapid cerebral compensation.121,242,243 Pro-found hypocapnea (reduction of PaCO2 below 25 mm Hg) mayinduce severe cerebral vasoconstriction causing global cerebral

ischemia, but mild to moderate hypocapnea may be enough tocause regional ischemia due to regional differences in cerebralautoregulatory dysfunction in the acutely injured brain (perile-sional area being most affected).65,244 Prophylactic hyperventi-lation has been shown to adversely affect outcome. For thesereasons, prophylactic, prolonged, and/or profound hyperventila-tion is highly discouraged.65– 67,245–247

Fluid limitation resulting in dehydration in acute brain injuryhas been advocated in the past in the hope of preventing cerebraledema but has been associated with an adverse outcome. Dehydra-tion causes inadequate systemic and cerebral perfusion, increasessusceptibility to renal and drug toxicity, reduces responsiveness toosmotic therapy, and adversely affects blood viscosity. The currentrecommendation is for fast and adequate fluid resuscitation tomaintain normovolemia and preserve CPP.67

SurgerySurgical decompression and early evacuation of a focal mass

lesion is effective in reducing ICP but the efficacy on improvingfunctional outcome and mortality depends largely on timing andselection of patients248 (Table 11).

FIGURE 1. Algorithm for the Management ofAcute Intracranial Hypertension.




Following initial resuscitation, early (�24 hour) decompres-sive craniectomy and evacuation of a focal mass lesion is the singlemost important treatment in TBI, resulting in improved outcome.249

Decompressive craniectomy after massive hemisphericstrokes in selected patients with clinical and radiographic evidenceof cerebral edema is effective in reducing ICP250 and improvingoutcome.251–253 Predictors of poor outcome after decompresivecraniectomy include age beyond 60,254 low preoperative GCS (�8),preoperative anisocoria, early (�72 hours from stroke onset) clinicaldeterioration, and multiple territory infarction.255

Despite several case series showing positive results, a largerandomized controlled trial of decompressive craniectomy for spon-taneous ICH failed to improve outcome compared with aggressivemedical management.256 However, minimally invasive surgicaltechniques employing stereotaxy with or without frame and endos-copy with or without clot thrombolysis consistently show benefitcompared with medical management alone.257–260 Surgery is cur-rently advocated in patients suffering from ICH with GCS 6 to 12,deteriorating neurologic examination, large ICH, lobar ICH, infrat-entorial ICH �3 cm diameter, ventricular obstruction, intraventric-ular extension, hydrocephalus, cerebellar ICH with vermian involve-ment, distortion of the fourth ventricle with effacement of ambientcisterns, superficial hemorrhage, clot volume 20 to 80 mL, worsen-ing neurologic status, relatively young patients, and hemorrhagecausing midline shift or raised ICP.18,261,262 Poor prognostic factorsinclude coma with loss of upper brainstem reflexes (pupillaryreflexes, corneals, and oculocephalics) and extensor posturing priorto surgery.263

Decompressive craniectomy may be lifesaving for patientswith refractory AIH.264,265 However, long-term functional outcomeis usually not very good.

SUMMARYAcute intracerebral hypertension is a complex condition re-

quiring integrated management of systemic and cerebral hemody-namic parameters that needs to be tailored to the individual patientand the primary etiologic mechanism. As one of the final commonprocesses in the evolution of acute brain injuries, an algorithmicapproach to management (Fig. 1) helps to put things into perspectiveso that all aspects of care are attended to. However, the importanceof tailoring the actual details of management to the individualpatient cannot be over emphasized and may be achieved with the useof new multimodality monitoring techniques such as the BtO2 orSjvO2. Multidisciplinary level care preferably led by a neurologistor neurosurgeon with special training in critical care is recom-mended to optimize patient outcome.

Hypertonic saline and therapeutic hypothermia are rela-tively new therapeutic strategies with promising utility in themanagement of refractory intracranial hypertension. Althoughlarge randomized controlled trials are yet to be done, it is likely

that future outcome studies may shed light in the efficacy of thesenew treatment options.

ACKNOWLEDGMENTSThe authors thank Guy Rordorf, MD, Jonathan Rosand, MD,

Raul Nogueira, MD, Mary Guanci, RN, and Lee Schwamm, MD fortheir critical review and appraisal of the manuscript.

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management of acute intracranial hypertension neurologist 2009

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