intracranial hypertension therapy

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6

Prevention and treatment of intracranial

hypertension

Jan-Peter A.H. Jantzen* MD, PhD, DEAADr med habil, Professor at Johannes Gutenberg University Medical School at Mainz,

Professor at University of Texas, Southwestern Medical School at Dallas, and HeadDepartment of Anaesthesiology, Intensive Care and Pain Management., Academic Teaching Hospital Hannover

Nordstadt, Haltenhoffstrasse 41, D-30167 Hannover, Germany

Intracranial pressure (ICP) is the pressure exerted by cranial contents on the dural envelope. Itcomprises the partial pressures of brain, blood and cerebrospinal fluid (CSF). Normal intracranialpressure is somewhere below 10 mmHg; it may increase as a result of traumatic brain injury,stroke, neoplasm, Reyes syndrome, hepatic coma, or other pathologies. When ICP increasesabove 20 mmHg it may damage neurons and jeopardize cerebral perfusion. If such a condition

persists, treatment is indicated. Control of ICP requires measurement, which can only be per-formed invasively. Standard techniques include direct ventricular manometry or measurementin the parenchyma with electronic or fiberoptic devices. Displaying the time course of pressure(high-resolution ICP tonoscopy) allows assessment of the validity of the signal and identificationof specific pathological findings, such as A-, B- and C-waves. When ICP is pathologically elevated at or above 2025 mmHg it needs to be lowered. A range of treatment modalities is availableand should be applied with consideration of the underlying cause. When intracranial hypertensionis caused by hematoma, contusion, tumor, hygroma, hydrocephalus or pneumatocephalus, surgi-cal treatment is indicated. In the absence of a surgically treatable condition, ICP may be controlledby correcting the patients position, temperature, ventilation or hemodynamics. If intracranialhypertension persists, drainage of CSF via external drainage is most effective. Other first-tier

options include induced hypocapnea (hyperventilation; paCO2< 35 mmHg), hyperosmolartherapy (mannitol, hypertonic saline) and induced arterial hypertension (CPP concept). When au-toregulation of cerebral blood flow is compromised, hyperoncotic treatment aimed at reducingvasogenic edema and intracranial blood volume may be applied. When intracranial hypertensionpersists, second-tier treatments may be indicated. These include forced hyperventilation(paCO2< 25 mmHg), barbiturate coma or experimental protocols such as tris buffer, indometh-acin or induced hypothermia. The last resort is emergent bilateral decompressive craniectomy;once taken into consideration, it should be performed without undue delay.

* Tel.: 49 511 9701580; Fax: 49 511 9701012.

E-mail address: [email protected]

1521-6896/$ - see front matter 2007 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical AnaesthesiologyVol. 21, No. 4, pp. 517538, 2007

doi:10.1016/j.bpa.2007.09.001

available online at http://www.sciencedirect.com
mailto:[email protected]://www.sciencedirect.com/http://www.sciencedirect.com/mailto:[email protected]


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Key words: intracranial pressure; ICP; intracranial hypertension; hydrocephalus; ICP treatment;intracranial hypertension; ICP measurement; ICP monitoring; ICP etiology; ICP treatment; intra-cranial hypertension; Lund; CPP; intracranial osmolarity; cerebral edema; vasogenic cerebraledema; cerebral edema treatment; cerebrum; cerebrum blood flow; cerebrum blood volume;cerebral blood flow; cerebral circulation; cerebral vessels; CO2 reactivity.

The human brain is embedded in rigid structures dura mater and skull which protectit against traumatic injury. This protection may, however, become counterproductivewhen trauma is severe or following neurological surgery. Due to minimal compliance,space-occupying processes in the head cannot increase volume, as in abdominal emer-gencies, but will increase pressure. For the same reason the skull functions as a Starlingresistor, limiting cerebral perfusion pressure whenever pressure within the cranium ex-ceeds central venous pressure. Monitoring intracranial pressure (ICP) is of utmost valuefor early detection of such processes, and is almost exclusively used in patients receivingneurosurgical intensive care treatment. In the early postoperative period, when the pa-

tient is on the ventilator, comatose or sedated, ICP monitoring helps to detect postop-erative or posttraumatic complications such as pneumocephalus, rebleeding,hydrocephalus/hygroma or edema if undetected, could result in herniation and death.

PHYSIOLOGY OF INTRACRANIAL PRESSURE

Global ICP is the pressure exerted on the dura mater by the contents of the cranialvault. Pressure is built up entirely by arterial influx, hence ICP decreases to centralvenous pressure (CVP) level when arterial perfusion ceases. Under controlled venti-lation, the ICP curve looks quite similar to the CVP curve ( Figure 1). ICP reflects

the sum of three partial pressures:ICP pcerebrum pblood pCSF

This sum depends on posture and may increase significantly e.g. during coughing orsneezing. Such an increase is, however, transient and not considered to be intracranialhypertension. Beyond that, ICP remains rather constant. When one partial pressureincreases for example pcerebrum with the development of cerebral edema the otherpartial pressures (notably pCSF) will change in the opposite direction, keeping ICP con-stant. This interactivity considering volumes, not partial pressures was describedby Burrows in 1846 and is referred to as the MonroKellie-hypothesis. Once reserve

spaces are exhausted i.e. when most of CSF is displaced into the extracranial com-partment any further increase of intracranial content will raise ICP. The pressurevolume curve, following an exponential course, reflects that relation. The skullscapability to accommodate mass challenges is termed elastance (DP/DV; reciprocalof compliance). Elastance is highest in children and lowest in older patients due tocerebral atrophy.

The signal obtained with an ICP monitor is more complex. The ICP wave form ismade up of at least three independent components: pulse wave, ventilatory wave andvasogenic wave(s). As a resultant of arterial perfusion, ICP fluctuates with the hemody-namic cycle; in ventilated patients this is superimposed on the pressure cycle produced

by the ventilator. The ICP number displayed by monitoring devices, is the mean pres-sure, calculated (depending on the software used) over one or more hemodynamicand ventilatory cycles. It is the mean value of a complex, cyclic wave form. The relation-ship between the arterial pressure input signal and the ICP output signal, the intracranial

518 J.-P. A. H. Jantzen


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transfer function, defines the frequency response for the cranial cavity. This response re-flects the physical properties of cranial contents. The derived variable ICP is the aver-

age of all oscillations, derived from the intracranial contents. The frequency of theseoscillations reflects the fundamental frequencyof cranial contents or their modificationby physiological or pathological impact. This impact changes the intracranial transfer func-tion and thus the ICP wave-form response to arterial input (Figure 2).

PATHOLOGY

In the supine position ICP should be somewhere below 10 mmHg. Any persistent (i.e.lasting more than 5 minutes) increase to !20 mmHg is considered intracranial hyperten-sion. Intracranial hypertension may be mild(2029 mmHg), moderate (3040 mmHg) or

severe (>40 mmHg). While transient intracranial hypertension even as high as100 mmHg! is tolerated well by the healthy brain, a persistently high ICP is detrimen-tal in itself, exerting pressure on neurons and shearing forces on the brain. Beyondthat, as one determinant of cerebral perfusion pressure (CPP), which equals mean

Figure 1. Intracranial pressure (ICP) versus time. ICP fluctuates in concert with ventilation (capnogram,

end-tidal carbon dioxide pressure, etpCO2) and pulse rate (arterial blood pressure, AP) (pig model). 17

The lack of increase in the cardiogenic ICP amplitude during inspiration (positive pressure ventilation) indi-

cates physiological intracranial elastance, or sufficient compensatory reserve. PAP, pulmonary artery pres-

sure; IOP, intraocular pressure; CVP, central venous pressure.

Prevention and treatment of intracranial hypertension 519


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arterial pressure (MAP) minus ICP, ICP may limit cerebral blood flow (CBF CPP: ce-rebrovascular resistance, CVR) once MAP has fallen below the lower limit of autore-gulation. Extended phases of very high ICP, known as Lundberg A-waves, are ominoussigns of intracranial pathology, heralding poor outcome. Lundberg B- and C-waves areless well defined and less indicative of poor prognosis.

Under pathological conditions, ICP is not necessarily homogeneous within the cra-nium owing to anatomical compartmentalization.1 The falx cerebri and the tentoriumcerebelli resist an even distribution of pressure exerted by mass lesions. The ensuing

pressure gradients may be as high as 30 mmHg and produce damaging shearing forcesand subsequent herniation. Associated mass movements may block CSF circulationwith a subsequent further increase in ICP.

To identify the cause of intracranial hypertension, analysis of the time course ishelpful. An ICP increase within seconds is frequently a stress response, elicited bycoughing, fighting the ventilator, endotracheal suctioning, or simply inadequate posi-tioning of the head (Figure 3). An increase within minutes may be caused by intracra-nial bleeding (arterial rebleeding at the site of surgery, ruptured aneurysm, epiduralhematoma) or other vascular accidents (e.g. acute occlusion of the sagittal sinus).Cerebral swelling early posttraumatic intracranial hyperemia due to vasoparalysis

may also develop rapidly. Its significance (or existence), however, is unclear. Intra-cranial hypertension subsequent to capillary or venous bleeding at the site of surgery,pneumocephalus, CSF outflow obstruction hygroma or hydrocephalus or cerebraledema may take hours or days to develop. Some space-occupying intracranial pathol-ogies, e.g. focal contusions or low-pressure-hydrocephalus, may not increase ICP atall, notably in elderly patients.

The adverse effects of intracranial hypertension mandate early intervention. Pre-requisite to lowering an increased ICP is measuring it; all ICP-monitoring techniquesare, however, invasive and require a clear indication.

INDICATIONS FOR MONITORING

In general terms, ICP should be measured whenever manifest or impending intracra-nial hypertension is assumed, but must be limited to patients that may benefit from

Cranium

Transfer function

Arterial pressure wave Intracranial pressure wave

Mechanical properties of

cranial content

Mechanical

properties of

arterial vessel walls

Mechanical

properties of

venous vessel walls

Cerebral vasculature

Figure 2. The relationship between the arterial pressure input signal and the intracranial pressure (ICP)

output signal.26



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ICP management. This excludes, for example, patients with infaust prognosis. For pa-tients with severe head trauma, indications are proposed by the Brain Trauma Foun-dation (BTF).2 According to current (2007) recommendations, there is level-IIevidence to support ICP monitoring in comatose patients Glasgow Coma score(GCS) 8 with pathological findings in the cranial computed tomography (CT)

scan.Level II evidence suggests that intracranial pressure (ICP) should be monitored in

all salvageable patients with a severe traumatic brain injury (TBI; GCS score of 38after resuscitation) and an abnormal CT scan. An abnormal CT scan of the head isone that reveals haematoma, contusion, swelling, herniation, or compressed basalcisterns.

Level III evidence suggests that ICP monitoring is indicated in patients with severeTBI with a normal CT scan if two or more of the following features are noted at ad-mission: age over 40 years, unilateral or bilateral motor posturing, or systolic bloodpressure (BP) 90 mmHg.

Beyond these recommendations concerning TBI, indications are less well defined,and there is ongoing debate as to the effect of ICP monitoring on outcome. Followingintracranial surgery, the most common complications are pneumocephalus and surgi-cal bleeding. Pneumocephalus is present in almost every patient having undergone cra-niotomy and may persist for up to 2 weeks.3 Bleeding occurs usually at the site of theoperation and is facilitated by poor hemostasis. Both conditions are readily detected inawake patients displaying clinical signs of intracranial hypertension, but not in patientsrequiring postoperative ventilatory support.

In the authors institution, indications are rather liberal in comatose patients oncontrolled ventilation. Besides neurotrauma, ICP monitoring is considered in patients

with malignant media infarction, in higher Hunt-and-Hess grade (IIIIV) subarachnoidhemorrhage, intraventricular and intraparenchymal hematoma, or in Reye syndrome.ICP monitoring following major craniotomy is less frequently indicated, mainly owingto advancements in microneurosurgical techniques.

Head flexion bilateral

mmHg

70

60

50

40

30

20

10

Head rotation

left

Head rotation

right

Jugular venous

right

compression

left

Figure 3. Effect of head position and jugular compression on intracranial pressure (ICP). Hulme A, Cooper R.

In: Beks J, Bosch DA, Brock M (eds): Intracranial pressure III. Springer, Berlin Heidelberg New York, 1976.



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MEASUREMENT TECHNIQUES

ICP monitoring was introduced by Jenny and Guilleaume in 1951 and propagated asa useful clinical tool by Nils Lundberg in the 1960s. In general, ICP may be measuredanywhere within the skull or subarachnoid compartment. A variety of measuringsites have been used and abandoned over the last four decades, probes being placedin epidural, subdural, subarachnoidal or intraparenchymal spaces. Under physiologicalconditions (i.e. with unobstructed CSF circulation), and the patient in the supineposition, zero-point at the tragus, accurate measurement of ICP may be obtainedin the lumbar subarachnoid space, a technique pioneered by Heinrich Quincke in1905. Today, according to many guidelines, the gold standard for monitoring ICPis direct measurement in a lateral ventricle. This is also a standard technique in ex-perimental research.4 Cannulation of a ventricle and connecting a communicatingtube to an external metering device is a most versatile approach. It allows for con-tinuous and drift-free monitoring of ICP, ICP control by drainage of CSF, assessmentof elastance, and analysis of CSF for markers of glial damage (S-100, NSE), excitotox-icity (glutamate) or infection. However, this approach is invasive and carries the riskof complications (Figure 4). Positioning the catheter requires a burr hole of 8 mmand penetration of brain tissue to a depth of5 cm (Figures 5 and 6); up to threeattempts to a maximum depth of 5 cm are considered acceptable, which definitely isnot atraumatic. With severely increased ICP the ventricles may be compressed, mak-ing cannulation difficult or even impossible. Intraventricular placement of the cathe-ter fails in about 5% of cases.

External ventricular drainage

The technique of external ventricular drainage (EVD) was pioneered by Carl Wernickeat the end of the 19th century. In our institution, CSF drainage is frequently used inpatients with aneurysmal subarachnoid hemorrhage (SAH) and traumatic brain injury,especially when TBI is complicated by traumatic subarachnoid hemorrhage (tSAH). Inthese patients, circulation of CSF between the intra- and extracranial compartments

Figure 4. Complications associated with ventricular catheter placement. From Chesnut RM, Marshall LF:

Intracranial pressure monitoring and cerebrospinal fluid drainage. In: Benumof JL (ed) 1992, Clinical Proce-

dures in Anesthesia and Intensive Care, Philadelphia, Lippincott with permission.



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may be blocked; drainage of CSF is the most effective means of controlling ICP. Of pa-

tients with SAH and ventricular blood, 66% show neurological improvement whentreated with EVD.5

The ventricular catheter is connected to a drainage bag via a three-way stopcock.The position of the collecting bag or the highest point of the line in relation to thetragus determines the set value of ICP. When this is reached, CSF spills over, main-taining the set ICP. It must be kept in mind that height of the collecting bag relative tothe tragus reflects cmH2O, while ICP is measured as mmHg. Accordingly, if 15 mmHg isthe intended spillover pressure, the collecting bag must be positioned about 20 cmabove the tragus. Great caution must be exercised to adapt the setting wheneverthe patient is repositioned. Otherwise inadvertent (iatrogenic) intracranial hyperten-

sion or ventricular collapse may ensue, both complications being equally dangerous.Whenever an exact reading of ICP is required the direction of the stopcock is changedsuch that the ventricular catheter is connected to the pressure transducer.

The most frequently observed complications of EVD are malfunction and infection.Other complications include disconnection, CSF leakage or malpositioning of the cath-eter tip. Malfunction must always be suspected when cardiogenic or ventilatory oscil-lations of the ICP curve are diminished or lost. This happens in 25% of patients withventricular blood, and in 15% of other patients.5 The catheter may be cleared by injec-tion of 0.1 mL saline. If that fails twice, no more attempts should be made because ofincreased risk of infection; the catheter then needs to be removed. In 3% of EVD cases

surgical repositioning is required. The rate of infection is time-dependent, being ratherlow for up to 4 days and increasing significantly after day 5; overall, the average rate ofventriculitis is 10%. In neurotrauma with open skull fractures the rate may be as high as40%. Neither routine ventricular catheter exchange nor prophylactic antibiotic use forventricular catheter placement is recommended to reduce infection.6 When antimicro-bial treatment is indicated, combined intravenous and intrathecal administration ismost effective (cephalosporin and aminoglycoside, according to the antibiogram).

Naturally, EVD should be removed as early as possible. Factors to be consideredbefore removal include the following:

clinical condition (comatose versus awake); CSF volume per 24 h; ICP; CCT.

Figure 5. Contemporary techniques of intracranial pressure (ICP) monitoring. Parenchymal probe (left),

ventricular catheter (right). From Schweitzer JS, Bergsneider M, Becker DP: Intracranial pressure monitoring.

In: Cottrell JE, Smith DS (eds) 1994, Anesthesia in Neurosurgery, 3rd ed, St. Louis Mosby with permission.



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When ICP is below 20 mmHg for 24 h without treatment, CSF drainage is


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compensatory reserve and autoregulatory competence,8 but though promising, anyimpact of this derived information on patient outcome still needs to be demonstrated.

THRESHOLD FOR INTERVENTION

Persistent intracranial hypertension is associated with poor prognosis; in some clinicalconditions such as Reye syndrome it is the primary cause of death. Particularly

Figure 6. Placement of a ventricular catheter. From Chesnut RM, Marshall LF: Intracranial pressure moni-

toring and cerebrospinal fluid drainage. In: Benumof JL (ed) 1992, Clinical Procedures in Anesthesia and

Intensive Care, Philadelphia, Lippincott with permission.



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when associated with low blood pressure, high ICP may reduce CPP to an extent that jeopardizes cerebral perfusion. In order to avoid cerebral ischemia ICP needs to becontrolled so as to maintain CPP >50 mmHg (range 5070 mmHg). Since CPP canbe managed by manipulation of arterial pressure to a great extent, the risk of hernia-tion is what defines the ICP intervention threshold. The goal is to balance the risks ofherniation against the iatrogenic risks of over-treatment. For the patient with TBI the

recommended threshold for intervention is a mean ICP of >20 mmHg (level-IIevidence)9; for other patient populations with intracranial hypertension this thresholdis less clear. When ICP monitoring is performed subsequent to surgical removal ofa space-occupying mass, the threshold for intracranial hypertension is lower, e.g.20 mmHg. In addition, the presence or absence of pathological waveforms (e.g.Lundberg waves) must be taken into consideration. Certain limitations must be takeninto account. The ICP as displayed by the monitor depends on the technology used,and even more so on the site of the probe, i.e. proximity to the lesion. When CPPis of concern, the blood pressure transducer must be zeroed at the same level asthe ICP monitor such as to reflect mean arterial pressure in the circle of Willis not

in the aorta. Taking the accuracy of monitors (ICP and MAP) into account it becomesclear that a calculated CPP of 60 in reality is anywhere between 50 and 70 mmHg atbest! This should be considered when ICP-lowering strategies CPP concept versusLund concept (see below) are evaluated (or disputed).

Figure 7. Placement of a parenchymal probe (Integra Camino

). From Chesnut RM, Marshall LF: Intracranialpressure monitoring and cerebrospinal fluid drainage. In: Benumof JL (ed) 1992, Clinical Procedures in

Anesthesia and Intensive Care, Philadelphia, Lippincott with permission.



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It is important to be aware that thresholds such as those given above always referto the expected reaction of a majority of patients to a standardized perturbation of phys-iological processes. The clinicians decision, in contrast, must always be tailored to theneeds of his individual patient which are determined by individual physiology andpathology and beyond any standardizing efforts!

MEANS TO LOWER RAISED INTRACRANIAL PRESSURE

Treatment of the patient with intracranial hypertension must take the cause of the hy-pertension into account. In some cases the cause may be quite remote from the brain,such as with abdominal compartment syndrome. Conditions like that require surgicalcorrection and are beyond the scope of this review. Assessment starts with checkingthe patients position, ventilation and hemodynamic status, and clearing the airway;maintaining gas exchange and treating arterial hypotension is essential before anythingelse is considered. Meticulous attention must be paid to correct positioning. The pre-

vious dogma of head-up position was abandoned years ago, particularly in the US. Put-ting the patient in an anti-Trendelenburg position will lower both ICP and MAP. Themaximum CPP is probably achieved in most patients at an angle of 30. However,with respect to stability, nursing care, and other aspects, the optimum angle is about15, which is the standard in this authors institution. Even more important is the po-sition of the head and cranio-cervical axis: The axis must be straight, the head mustnot be rotated, and the neck must not be flexed (Figure 3).

Adequate ventilatory support implies that the patient does not fight the ventilator.This is achieved by adapted modes of assisted ventilation (e.g. biphasic positive airwaypressure) and analgesia and sedation. Because evidence-based medicine has not yet

identified perfect ventilation or perfect analgesia and sedation, both can only beadapted to the needs of the individual patient as considered appropriate by the treat-ing physician. When PEEP or recruitment is indicated to improve oxygenation, theeffects on ICP are generally negligible; negative inotropic effects of PEEP, however,need attention if MAP decreases. Another means to improve oxygenation, whichmay be indicated when TBI is associated with acute lung injury, is the prone position.In our experience, turning the patient prone is not detrimental to ICP or CPP. If(re)positioning is performed gently and judiciously, ICP does not increase significantly.The prone position may, however, unmask latent hypovolemia, which would adverselyaffect CPP. Accordingly, normovolemia is prerequisite to turning the patient prone.

Analgesia and sedation should be titrated to achieve tolerance of ventilation. At ourinstitution, sedation is provided with midazolam (24 mg/h), and analgesia with withsufentanil or (preferably) sufentanil plus S-ketamine. Prior to nursing procedures likelyto provoke a stress response such as a endotrachel suctioning any adversehemodynamic reaction should be preempted. We prefer to administer lidocaine ata dose of 1 mg/kg IV at approximately 3 min before the nursing intervention.

If the ICP is still pathologically elevated, although CPP is !60 mmHg, ventilation isnormocapnic, and patient position is correct, a surgically treatable cause (hematoma,hygroma, pneumocephalus, space-occupying contusion) must be excluded. This is usu-ally done by cranial CT scan. When the CCT scan is negative, the most likely cause of

intracranial hypertension is cerebral edema. Edema may be intracellular (cytotoxicedema) or extracellular (vasogenic edema); however, in most patients a combinationof both is present. A perifocal vasogenic edema in patients with neoplastic lesions is re-sponsive to corticosteroids; hyperosmolar agents are drugs of first choice in cytotoxic



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edema. Intracranial hypertension may also be treated symptomatically. This may includehemodynamic augmentation, induced hypocapnea (hyperventilation), hypothermia,barbiturate coma, tris buffer or decompressive craniectomy. First-tier treatment (e.g.mannitol, hyperventilation) is usually well tolerated, but second-tier approaches (e.g.forced hyperventilation, barbiturate coma, craniectomy) are associated with signifi-cant side-effects.

HEMODYNAMIC MANAGEMENT OF INTRACRANIALHYPERTENSION

Cerebral perfusion pressure concept

Intracranial blood volume (CBV) relates to cerebral blood flow (CBF), which is con-trolled by autoregulation. Autoregulatory mechanisms respond to changes in MAP.Within the range of autoregulation (MAPz 50150 mmHg), an increase in MAP initi-ates arteriolar vasoconstriction, which reduces CBV and consecutively ICP. When ICPis increased, e.g. because of cerebral edema, CPP drops. In order to maintain CBF, au-toregulation lowers cerebrovascular resistance (CVR). This is achieved by vasodilationassociated with an increase in CBV. The latter raises ICP, initiating a vicious cycle (Fig-ure 8). The philosophy of the CPP concept is to reverse that cycle.10In case of intra-cranial hypertension, autoregulation is triggered by pharmacologically increasing MAP.Drugs of choice are norepinephrine (0.1 mg/kg/min) or dopamine (410 mg/kg/min).Subsequently, CBV is reduced by vasoconstriction and thus, ICP is lowered. In patientswith TBI, the early goal was to achieve a MAP level of>70 mmHg. CPP managementdepends on intact autoregulation, which, however, may be disturbed under global orregional pathological conditions. In fact, in patients with severe TBI, the autoregulationis dysfunctional in most cases. Accordingly, autoregulatory competence should betested before the CPP concept is initiated. This test is done with a small dose of epi-nephrine IV (0.1 mg/kg). When the induced increase in MAP is followed by a decrease inICP, global autoregulation may be considered intact. When ICP increases in parallel withMAP, it may be unwise to apply the CPP concept. In our department, this test is carriedout routinely. Patients showing autoregulatory deficits, are not treated according to theCPP concept, but are switched to therapeutic approaches with the Lund concept.

In patients with defective autoregulation after SAH with vasospasm, inducing arte-rial hypertension expectedly raises ICP. This increase is accompanied by an increase inCPP and brain-tissue oxygenation (pTIO2), justifying the concept of induced arterial

Figure 8. Vicious cycle of intracranial hypertension: high intracranial pressure (ICP) decreases cerebral per-

fusion pressure (CPP). This activates autoregulation. Cerebral vascular resistance (CVR) is lowered by vaso-

dilation. Increased vascular diameters increase cerebral blood volume (CBV), which contributes to a further

increase in ICP. This cycle can be reversed by increasing CPP through arterial blood pressure elevation.



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hypertension.11 In vasospastic patients, maintaining cerebral blood flow does have pri-ority over lowering ICP.

Hyperoncotic treatment

This treatment modality for patients with TBI has been pioneered in the Swedishuniversity town of Lund.12 It is widely used in Scandinavia, but is less popular in otherparts of Europe, and almost unknown in the US. There are no clinical studies com-paring the Lund with the CPP concept, and published reports are anecdotal or oflow evidence. The concept assumes a pivotal importance of vasogenic edema andcolloid-osmotic pressure. The latter gains importance when the bloodbrain barrier(BBB) is disrupted and fluid exchange cannot be effectively controlled by transcapillarycrystalloid osmotic pressure. In order to reduce transmural/hydrostatic pressure incerebral vessels, arterial pressure and cardiac output are decreased with b-receptorantagonists and a2-receptor agonists. In order to reduce capillary pressure, precapil-

lary arterioles are constricted with dihydroergotamine (DHE). In addition, DHE willconstrict cerebral veins, significantly reducing CBV (60% of CBV is represented bythe venous vascular bed!), and consequently ICP.13 The ICP-lowering effect of DHE(4 mg/kg intravenously) can be striking (Figure 9). With neurotrauma, it is importantto recognize that DHE, in contrast to other vasoconstrictors, does not reduce CBF.The importance of colloid-osmotic pressure (COP) with respect to cerebral edemais poorly defined. Improved outcome with higher COP has as yet been shown inanimal models, only.14

Our experience indicates that using the Lund concept may indeed lower ICP whenincreasing CPP and plasma osmolarity is not effective. Specific complications of DHE

like ergotism16

must, however, be kept in mind.

Figure 9. Management of intracranial hypertension according to the Lund concept. Intracranial pressure

(ICP) increases despite induced arterial hypertension (CPP concept), mannitol administration (Mannit),

and buffering (Tris). Then the ICP decreases rapidly to dihydroergotamine (DHE). MAP, mean arterial pres-

sure; CPP, cerebral perfusion pressure; SvjO2, jugular venous oxygen saturation.



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In cases that do not respond to hemodynamic management alone, ventilatory andpharmacological means are indicated for controlling ICP. These therapeutic modalitiesare classified as first- or second-tier treatment, depending on the balance of desiredversus undesired effects. Accordingly, second-tier treatment is effective, but invasiveand burdened with side-effects.

MANAGEMENT APPROACHES TO REFRACTORY INTRACRANIALHYPERTENSION

First-tier treatment

Hyperventilation

CO2 is a powerful cerebral vasodilator (Figure 10). The sensitivity of cerebral vessels tochanges in paCO2 (CO2 reactivity) is an important physiological control system. Bloodflow is directed away from temporarily less active regions towards regions with higher

metabolic activity. On the average, lowering paCO2 by 1 mmHg reduces CBF by 4%.Hyperventilation lowers paCO2, resulting in respiratory alkalosis and subsequent vaso-constriction; accordingly, that effect subsides when pH equilibrium is re-established.When vasoconstriction is pronounced, intracranial blood volume will decrease andlower ICP; however, the iatrogenically increased cerebrovascular resistance (CVR)may reduce cerebral blood flow, possibly below the ischemic threshold. This is partic-ularly important in known low-CBF conditions, such as severe TBI or vasospasm. Toavoid cerebral ischemia, ventilation should be adjusted to a paCO2 of not less than30 mmHg. If a lower partial pressure (2025 mmHg) is deemed necessary to controlICP, additional cerebro-metabolic monitoring is indicated. This may include sjvO2,

pTiO2, near-infrared spectroscopy (NIRS) or microdialysis. In the authors departmentsjvO2 was the standard until the mid-1990s, then it was largely replaced by pTiO2. NIRSis currently under investigation, microdialysis is limited to study protocols.

When induced hypocapnea is to be monitored by end-tidal capnometry, the arte-rialend-tidal pCO2 gradient must be taken into account. This gradient mainly reflectsventilatory dead space and is about 5 mmHg (Figure 11). In hemodynamically unstablepatients and those with multiple injuries a (much) higher gradient should be expected,measured, and taken into account. Once the arterialend-tidal gradient has stabilized,ventilatory control may be facilitated by a closed-loop feedback system.17

Figure 10. Effects of hypercapnea on intracranial pressure (ICP). ICP changes parallel fluctuations of end-

tidal carbon dioxide pressure (etpCO2) (pig model).17



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CO2 reactivity is prerequisite to hyperventilation therapy. Compared to autoregu-lation of CBF, CO2 reactivity is more stable and is maintained even in the traumatizedor otherwise injured brain. With major intracranial derangement, however, CO2 re-activity may be lost, and hyperventilation becomes ineffective. Such a condition usuallyheralds poor prognosis.

It must be kept in mind that controlled hyperventilation and forced hyperventila-tion in particular is more a rescue maneuver than a standard treatment.

Hyperosmolar therapy

When ICP is high despite adequate hemodynamic and ventilatory management, the ad-ministration of mannitol is indicated. Alternatively, glycerol (10%) or sorbitol (40%)may be used; however, mannitol 20% has become a standard. Although there is ongo-ing debate as to the mechanisms of mannitol-induced ICP control, increasing plasmaosmotic pressure, and thus the osmotic gradient between plasma and brain tissue,is one factor. Improved rheology subsequent to reduced viscosity and an increase inMAP may further contribute to the beneficial effect. The osmotic gradient is believedto drain fluid from the brain and make cells shrink. This mechanism implies that the

effect is time-limited. As soon as a new osmotic equilibrium is reached, fluid translo-cation will stop. It also becomes clear that this mechanism requires an intact bloodbrain barrier. If this barrier is damaged regionally or locally no osmotic gradient willbe established. On the contrary, the osmotic agent may cross the defective barrier,enter the cells and increase the pressure there. This rebound effect may draw plasmainto the cells, increasing edema. In this authors experience, that effect is overrated inthe literature and of minor clinical significance. However, mannitol should be adminis-tered judiciously. A single dose should not exceed 0.251.0 g/kg and should not be re-peated more than twice. Normotension and normovolemia must be maintained at alltimes. Plasma osmolarity should not increase beyond 320 mOsm/L, the threshold to

renal tubular necrosis. In the absence of ICP monitoring, mannitol should primarilybe considered a rescue medication.

Another way to increase plasma osmolarity is the administration of hypertonicsaline (HS). The use of HS for ICP control resulted from initial studies on small-volumeresuscitation. Hypertonic saline solutions were used in pre-hospital trauma care andimproved outcome most notably in patients with TBI. These findings stimulated re-search on the effects on increased ICP.18 Proposed beneficial effects of HS may arisefrom more than one mechanism. Like mannitol, HS produces an osmotic gradient, re-sulting in shrinkage of brain tissue and reduction in ICP. Furthermore, HS augments vol-ume resuscitation and increases circulating blood volume, MAP and CPP. Animal and

human studies suggest that HS is a potential therapeutic agent to assist with medicaltreatment of patients with TBI. It may have a place as osmotherapy to reduce brainsize, predominately of the uninjured brain, and has several potential advantages overmannitol; e.g. the osmotic threshold for renal tubular necrosis is 360 mOsm/L with

paCO2 > pACO2 >> petCO2

Diffusion Dead space

02 mmHg 5 mmHg

Figure 11. The arterialend-tidal pCO2 gradient. paCO2, arterial partial pressure of CO2; pACO2, alve-olar partial pressure of CO2; petCO2, end-tidal partial pressure of CO2.



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HS, increasing the margin of safety. HS may be considered a therapeutic adjunct to themedical management of cerebral edema or intracranial hypertension, awaiting definitiveevidence to support routine use.19 Beyond effects on ICP, HS may improve cerebralperfusion by reversing endothelial swelling of capillaries. This occurs within low-flowareas after TBI.

Second-tier treatment

When intracranial hypertension persists, a surgically treatable cause must be assessedby CT scan. If such a cause hematoma, hygroma, hydrocephalus, contusion is ex-cluded, other forms of treatment must be considered.

Forced hyperventilation

Hypoventilation down to a paCO2 of 2025 mmHg may be readily achieved, but theeffect may be short-lived and carries the risk of cerebral ischemia. It is mostly a mea-

sure to buy time for further diagnostic procedures or with impending herniation to survive the trip to the theater.

Barbiturate coma

Barbiturates are known to suppress the cerebral metabolic rate for oxygen (CMRO2),terminate convulsions, scavenge free oxygen radicals, and obtund a cerebral hyperther-mic response to ischemia. Only when cerebrovascular CO2 reactivity is maintained, isinducing barbiturate coma an option. Another mandatory prerequisite is hemodynamicstability. Barbiturates have not been shown to improve outcome, but they do lower theICP. The treatment should be monitored by electroencephalogram (EEG), which issuperior to plasma-level-guided administration. The desired EEG rhythm is a burst-sup-pression pattern. Barbiturate dosages are 5 mg/kg thiopental over 30 min, followed byan infusion of 5 mg/kg/h. Less experience has been gained with hydroxybarbiturates(e.g. methohexital) in comparison to thiopental. However, they may be advantageouswith respect to accumulation, hemodynamic or immunological suppression. Alterna-tively, propofol may be used at a dosage not exceeding 5 mg/kg/h. Awareness of therare, but potentially lethal complication, the propofol infusion syndrome, is necessary.Some second tier options notably forced hyperventilation and barbiturate coma may be bypassed (See note 4 in the algorithm). This applies primarily to youngerpatients with limited primary injury and excessively high ICP when time is brain.

Decompressive craniectomy

In consideration of the physiology of ICP, eliminating the rigid envelope (craniectomy,duraplasty) should be a most effective way to reduce ICP. The procedure is invasive,however, and not all neurosurgeons are ready to perform such radical surgery of un-certain benefit. Most reports concerning intracranial hypertension subsequent to ma-lignant media infarction or TBI are anecdotal or case series. However, recent dataappear promising enough to justify prospective evaluation.20 Currently, a multicenterstudy is under way in Europe which is trying to identify the position of decompressive

craniectomy in TBI: RESCUEicp.21

In our institution bilateral craniectomy is performedwhen all less-invasive treatment modalities have failed and the patients condition al-lows for major surgery. This is particularly the case in younger patients with initiallyreactive pupils and no brain-stem injury. If surgical decompression is taken into



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consideration it should be performed without undue delay. Timing of the indication isnot a matter of hours or days, but is a consequence of the patients response to first-tier or other less-invasive treatments. When these treatments have failed and craniec-tomy is considered useful, it should be performed promptly. Delaying surgery forwait-and-see, may harm the patient and discredit the procedure.

Other second-tier treatment

Hypothermia. There is convincing evidence from preclinical studies that mild hypother-mia is associated with improved neurological outcome following regional cerebral is-chemia, TBI, or cardiac arrest. Such evidence was confirmed in patients with cardiacarrest; the situation is less clear with respect to aneurysm surgery or TBI. Mild hypo-thermia was, however, shown to lower ICP in patients with TBI. The underlying mech-anism is not fully understood. Hypothermia-induced reduction of CMRO2 may bea factor, such that under conditions of artificial ventilation with fixed minute volume

a decrease in CMRO2 will result in hypocapnea. This effect my go undetected whenthe blood-gas analyzer is not adjusted for in-vivo temperature. In the authors institu-tion mild hypothermia is induced in patients with TBI and SAH. Temperature is low-ered by convective cooling, aiming at a bladder temperature of 3536 C for 48 hfollowing trauma or hemorrhage. The major objective of this protocol is not necessar-ily to achieve hypothermia, but rather to avoid inadvertent hyperthermia.

Tris buffer. Acidosis is detrimental in patients with cerebral ischemia. One aspect isthat acidosis removes the Mg2 lock from the NMDA receptor, facilitating excitotox-icity. When the pH drops below 7.0, acid-sensitive ion channels a group of calcium-

permeable acid-sensing ion channels may be activated, allowing intracellular Ca2

toincrease further.22 In contrast, low pH protects energy-dependent glutamate portersystems and thus delays onset of excitotoxicity.

Tris buffer corrects intracellular acidosis and increases the buffering capacity of CSF.Accordingly, it has been used in combination with controlled hyperventilation. In ce-rebral ischemia it reduces tissue lactate concentration, edema and infarct size.

Tham (trishydroxymethylaminomethane) was shown to reduce ICP in patients withTBI.23 However, it was also shown that the decrease in ICP is accompanied by a de-crease in cerebral tissue oxygenation in some patients. Due to unpredictable effects onMAP15, the net effect on CPP and PTiO2 requires close observation. In our institution,

Tham (1 mg/kg intravenously) is given ex juvantibus to patients with intracranialhypertension who do not respond to first-tier treatment.

Steroids. Steroids have been in use for neurosurgical patients for decades. Drugs, dos-ages and indications have varied with time. After steroids were eliminated from theneurotraumatologists armamentarium following a negative recommendation by theBTF18 and the CRASH trial24, they sneaked back via the spinal-trauma discussion;10% of patients with TBI have an associated spinal trauma. With respect to intracranialhypertension following TBI, there is no indication for steroids. However, classical in-dications, such as perifocal edema surrounding intracranial tumors or edema associ-

ated with cerebral abscess, remain valid.

Indomethacin. The non-selective cyclo-oxygenase inhibitor indomethacin is known toreduce ICP following TBI or intracranial surgery. ICP is assumed to fall subsequent to



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Nordstadt ICP-Algorithm

GCS < 8

CCT

Surgical mass No surgical mass

Surgery

ICU ICU

ICP monitoring indicated1?

no yes

Observation / Standard

ICU care

ICP > 20-25 mmHg ?

no yes

Rev. Trendelenburg Pos.: 15+

Head and craniocervical axis

straight Ventilation: paCO

235-36 mmHg

saO2> 95%

Temperature < 36,5 MAP > 70 mmHg

ICP > 20-25 mmHg ?

no yes

Ext. ventr. drain

CSF drainage

ICP > 20-25 mmHg?

no yesClinical

assessment?

COP?Hyperventilation

paCO230 mmHg

ICP > 20-25 mmHg?

no yes

Hyperosmolar treatmentMannitol 0,25-1,0 g/kg; n < 3x

Intubation, ventilation,

art. line, cv line, normovolemia

hemodynamic stabilization

ICP > 20-25 mmHg?

no yes

Autoregulation-test

Norepinephrin 0,2 g IV

Parenchymal probe

Figure 12. Nordstadt intracranial pressure (ICP) algorithm for the management of intracranial hypertension.



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ICP > 25 mmHg ?

no yesClinical

assessment?

CCT/TCD?

Osmolarity?

Forced hyperventilation

paCO2

20-25 mmHg

cerebral oximetry

ICP > 25 mmHg ?

no yes

Barbiturate coma

Thiopental 5 mg/kg

EEG: Burst suppression

ICP > 25 mmHg?

no yes

Thiopental

5 mg/kg*hTemp. 35C

Tris-buffer

1 mg/kg

DHE 4 g/kg

Indomethacin

0,5 mg/kg

ICP > 25 mmHg?

no yes

Case conference

Decompressive craniectomy

ICU / Rehabilitation

Terminate

treatment

Withdraw

treatment

Clinical

assessment?

CCT / TCD / MRI

Donor program

1: Primary injury must allow acceptable quality of life, contraindications be observed. GCS < 8

and pathological CCT (Hematoma, edema, contusion, midline shift). Or: GCS 8 and age > 40 /

SAP < 90 mmHg / motor posture (2 of 3).

80 mmHg. Norepinephrin 0,1 g/kg*min or dopamin 4-10 g/kg*min3: CPP > 50 / MAP > 70 mmHg. DHE 4 g/kg, albumin, metoprolol and clonidine as required.

4: Alternative pathway (see text for details)

ICP ?

no yes

CPP-Concept

2

Lund-Concept

3

Autoregulation-test

Norepinephrin 0,2 g IV

4

Figure 12. (Continued).



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a decrease in CBV caused by vasoconstriction of small resistance vessels. This may bedue to inhibition of vasodilator arachidonic-acid metabolites.25 Uncertainty persists asto whether or not the decrease in CBF may render the brain ischemic. However, ce-rebral ischemia has so far not been shown in clinical studies, and some authors ascribeneuroprotective properties to indomethacin. For the time being, the routine use ofindomethacin has to await further clinical studies.

Treatment algorithm

The sequence and use of first- and second-tier treatment as practised in this authorsinstitution is summarized in our management of intracranial hypertension algorithm(Figure 12).

Concluding remarks

Measurement of ICP is the essential component of most brain-monitoring systems.After almost 50 years it has stood the test of time. Despite enthusiastic attemptsto introduce potential alternatives, notably monitors to assess cerebral metabolism,intracranial tonometry has proved to be robust and reliable. It is only moderately in-vasive and may be performed in many hospitals, including those without neurosurgicalservices.

Practice points

intracranial pressure (ICP) is the pressure exerted on the dural envelope bycontents of the cranium

ICP is non-uniform because of hydrostatic gradients and compartmentalizationof the intracranial space

under pathological conditions, regional pressure differences may be!30 mmHg; the place of the ICP probe must therefore be taken into consid-eration when interpreting measured values

ICP may be regarded as the sum of three partial pressures, reflecting three par-tial volumes: brain tissue (80%), CSF (812%) and blood: ICP pcerebrum pCSF pblood

normal ICP is approximately 510 mmHg; values of 2030 mmHg/3040 mmHg indicate mild/moderately increased ICP, values above 40 mmHg se-verely increased ICP

under physiological conditions the ICP is kept constant within a narrow range;the increase of the partial pressure of one component (brain tissue, CSF) iscompensated by the contradirectional change of the intracranial blood volume(MonroKellie hypothesis)

the ICP is one determinant of cerebral perfusion pressure (CPP MAP ICP)and thus is an indirect determinant of cerebral blood flow (CBF CPP:CVR)

continuously increased ICP injures the brain, directly and indirectly (perfusion

damage); in patients with traumatic brain injury or aneurysmal subarachnoidhemorrhage, continuously raised ICP is an independent indicator of poorprognosis



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control of pathologically increased ICP presupposes its measurement; this canonly be accomplished invasively. Established sites for placement of ICP probesinclude the epidural, ventricular and intraparenchymal space. Measurementtechniques are based on the principle of the communicating tube (e.g. in thelateral ventricle), electronically or fiber-optically

direct ICP measurement with a catheter placed into the lateral ventricle (theofficial gold standard) allows for pressure control by CSF drainage, assess-ment of intracranial elastance (DP/DV) as well as microbiological and metabolicanalysis

placement of that catheter is traumatic (burr hole diameter 4.4 mm, depth ofbrain passage 4.5 cm) and may be complicated by bleeding (1.4%) and contam-ination/infection (3%)

ICP measurement with a fiber-optical or electronic sensor in brain parenchymais less traumatic (burr hole 2.8 mm, depth of brain passage 1.5 cm) and is as-sociated with fewer complications

not monitoring ICP while treating intracranial hypertension can be deleteriousand result in poor outcome

ICP measurement is indicated whenever intracranial hypertension is assumed;the result of ICP monitoring may prompt cranial CT scanning, but CCT is byno means a substitute for ICP monitoring

Research agenda

a randomized clinical trial of ICP monitoring to assess its impact upon outcomeis desirable, but probably unlikely to be performed

technical standard for ICP monitors should include in-vivo clinical ICP driftmeasurement; in-vitro testing of devices does not necessarily reflect clinicalperformance

the difference in pressure between ventricular and parenchymal ICP measure-ment needs to be elucidated; both positive and negative differences have been

reported in clinical studies the most suitable site for parenchymal monitoring needs to be identified: near

to or remote from a cerebral lesion? further improvement in ICP monitoring technology should focus on developing

multiparametric ICP devices, possibly combining ventricular CSF-drainage andparenchymal-ICP-monitoring options

ICP may closely relate to the risk of herniation; a method to estimate herni-ation pressure should be developed

ICP monitors that allow for high-resolution display (tonoscopy) are needed;tonoscopy must allow wave-form analysis and computer-based calculation of

derived variables, e.g., ratio of pulse-pressure amplitude to mean ICP. The rel-evance of derived variables for outcome assessment should be examined inprospective studies



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