, neurosurgical anesthesia

Preface

Neurosurgical anesthesia

P.H. Petrozza

Guest Editor

Not long ago, discussions about neurosurgical anesthesia were dominated by

prerequisites of hyperventilation, a proscription concerning the use of inhaled

anesthetics, surgery guided by crude CT examinations and cerebral arteriography,

and patients placed in unusual positions. In reviewing many superb articles

submitted for this issue of the Anesthesiology Clinics of North America, I was

impressed by the great progress that has been made in both neurosurgery and the

anesthetic management of patients who require complex and technically difficult

procedures. As editor of this issue, my aim is to provide readers with practical

discussions of issues that are clearly relevant to the daily practice of neuro-

anesthesia. I solicited manuscripts from recognized leaders in the field who are

excellent lecturers and clinicians, and who have conducted much of their research

within their own laboratories.

Many topics are covered in this issue. Innovative monitoring technology

allows insight into the basics of cerebral blood flow and the effects of anesthetics

on the brain, while monitors of cerebral oxygenation allow characterization of the

physiologic milieu of cerebral tissue in individual patients during complex

anesthetics. Important issues in anesthetic practice are emphasized in discussions

on fluids, brain protection, and pediatric neurosurgery. The increasing scope of

neurosurgery is explored in articles on interventional neuroradiology, minimally

invasive neurosurgery, and spine surgery. Finally, vitally important elements of

perioperative critical care are explored in the articles on traumatic brain injury

and neurointensive care.

0889-8537/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.

PII: S0889 -8537 (02 )00002 -0

Anesthesiology Clin N Am

20 (2002) xi–xii

I believe that readers of this issue of the Anesthesiology Clinics of North

America will not only be greatly enriched by the thoughtful discussions in this

issue, but will also become excited about recent developments within a field that

offers highly gratifying experiences to anesthesiologists, surgeons, and patients.

P.H. Petrozza

Department of Anesthesiology

Wake Forest University School of Medicine

Medical Center Boulevard

Winston-Salem, NC 27157-1009, USA

E-mail address: [email protected]

Preface / Anesthesiology Clin N Am 20 (2002) xi–xiixii

Cerebral blood flow and vascular physiology

Monica S. Vavilala, MD, Lorri A. Lee, MD,Arthur M. Lam, MD, FRCPC*

Department of Anesthesiology, Harborview Medical Center, Box 359724,

325 Ninth Avenue, Seattle, WA 98104, USA

Cerebrovascular anatomy

Arterial supply

The two common carotid arteries (anterior circulation) and the two vertebral

arteries (posterior circulation) supply blood to the anterior and posterior parts of

the brain respectively. In general (65–70% of patients), the common carotid

arteries originate from the innominate artery on the right side and from the aorta on

the left side. In adults, bifurcation of the common carotid artery into the internal

and external carotid arteries occurs usually at C4,5 compared to children in whom

bifurcation occurs one to two cervical levels rostral [1]. The internal carotid artery

(ICA) supplies the brain and the ipsilateral eye. There are four segments of the

ICA: cervical, petrous, cavernous, and supraclinoid, describing its course as it

enters the cranium. In general, the size of the area supplied by the artery

determines the diameter of the cerebral artery [2]. The ophthalmic, posterior

communicating, anterior choroidal, anterior cerebral, middle cerebral, and anterior

perforating arteries are all branches of the ICA, and provide most of the blood

supply to the cerebrum. All areas of the brain supplied by the main branches of the

ICA have good collateral circulation except the area supplied by the middle

cerebral artery (MCA). As a result, the MCA territory is prone to ischemia.

The two vertebral arteries and the basilar artery comprise the posterior

circulation. The vertebral arteries are the largest branches of the subclavian

artery, and before merging to form the basilar artery, the verterbral arteries give

rise to the anterior spinal and posterior inferior cerebellar arteries. Each anterior

spinal ramus originating from the vertebral artery merges with the opposite spinal

ramus to form the anterior spinal artery. The posterior inferior cerebellar artery is

the largest branch of the vertebral artery, and supplies the cerebellum and lower


PII: S0889 -8537 (01 )00012 -8

* Corresponding author.

E-mail address: [email protected] (A.M. Lam).


20 (2002) 247–264

brainstem. The basilar artery ascends ventral to the pons and terminates in the

pontomesencephalic junction. It gives rise to the anterior inferior cerebellar,

superior cerebellar, and posterior cerebral arteries. The posterior communicating

arteries (Pcom) connect the basilar artery to the carotid circulation.

The Circle of Willis represents an anastomosis of the basal cerebral arteries

and the potential collateral circulation. (Fig. 1) This polygonal-shaped ring is

composed of the anterior communicating segments (Acom) of the anterior cere-

bral artery, and the ICA anteriorly. The posterior portion of the circle of Willis is

composed of the two Pcoms, and the two posterior cerebral arteries. However,

this classic pattern is found in less than 50% of the people; the Acom and Pcom

are frequently hypoplastic. While the main function of the Circle of Willis is to

provide collateral flow to the part of the brain with insufficient blood flow,

hypoplasia of the Acom or Pcom can be a limiting factor.

Venous drainage

The venous system of the brain consists of superficial and deep cerebral veins.

The superficial veins drain from the surface and the cortex of the cerebral

hemispheres, whereas the deep veins drain from the deep white matter, the basal

ganglia, the diencephalons, the cerebellum, and the brainstem. Large subepen-

dymal veins empty into the basal veins to form the great vein of Galen, which is

part of the deep venous system. Both superficial and deep veins including the

Fig. 1. The Circle of Willis showing the potential collaterals via the communicating arteries.

M.S. Vavilala et al / Anesthesiology Clin N Am 20 (2002) 247–264248

vein of Galen drain into the major dural venous sinuses, which, in addition to

receiving blood from the brain, also reabsorb cerebrospinal fluid from the

subarachnoid space. The walls of the cerebral veins are very thin while the walls

of the dural sinuses are fibrous. Both the veins and sinuses lack valves. The dural

sinuses eventually drain into one of the two internal jugular veins. In most

individuals one of the internal jugular veins is dominant, usually the right one

[3] (Fig. 2).

Dural venous sinuses

The major venous sinuses are the superior sagittal sinus, inferior sagittal sinus,

sigmoid sinus, transverse sinus, straight sinus and cavernous sinus.

Superior sagittal sinus—this sinus lies in the attached margin of the falx

cerebri and receives numerous superficial cerebral veins. Where the falx joins the

tentorium cerebelli, the sinus turns laterally to become one of the transverse

sinuses, usually the right one.

Inferior sagittal sinus—this lies in the free margin of the falx cerebri and runs

posteriorly to join the straight sinus in the midline of the tentorium cerebelli.

Straight sinus—this sinus receives blood from the inferior sagittal sinus and

great cerebral vein that drains from deep parts of the brain. The straight sinus

usually turns left to become the left transverse sinus.

Fig. 2. Venous angiogram demonstrating the drainage from sagittal sinus into the two transverse

sinuses, which became the sigmoid sinuses. The final drainage is into the two internal jugular veins.

The jugular bulb is situated at the junction between the internal jugular vein and the sigmoid sinus.

M.S. Vavilala et al / Anesthesiology Clin N Am 20 (2002) 247–264 249

Sigmoid sinuses—each sigmoid sinus lies in an S-shaped groove in the

petrous part of the temporal bone and in the occipital bone. The groove carries

the sinus downward to the posterior part of the jugular foramen, where it becomes

the internal jugular vein.

Cavernous sinuses—each cavernous sinus runs on either side of the sphenoid

bone between the dura of the middle cranial fossa and the periosteum covering

the bone. The two sinuses communicate with each other across the midline near

the pituitary where it is joined by the ophthalmic veins and the central retinal

veins. The superficial cerebral vein also drains into the roof of the sinus. Through

the foramen ovale, the sinuses communicate with the petrous sinuses. The

cavernous sinuses also communicate with the facial veins. Various nerves and

arteries also traverse through the cavernous sinus.

Basilar venous plexus—this plexus of veins lies on the clivus and provides

communication between the internal verterbral venous plexus and the veins and

venous sinuses in the cranial cavity.

Normal cerebral blood flow and metabolism

Normal cerebral blood flow (CBF) is approximately 50 mL/100 g/min (see

Fig. 3). This represents the average blood flow for thewhole brain; blood flow to the

graymatter is higher at 80mL/100 g/min, whereas flow to thewhitematter averages

20 mL/100 g/min. The average brain receives about 14% of the cardiac output.

Cerebral metabolic rate for oxygen (CMRO2) averages about 3.2 mL/100 g/min,

Fig. 3. The major factors affecting the control of the cerebral circulation. The response of the change in

CBF to change in viscosity is not shown.


with the gray matter consuming approximately 6 mL/100 g/min and white matter

consuming about 2mL/100 g/min. Consequently, the normal arteriovenous oxygen

content difference is about 6.4 vol %, corresponding to a jugular bulb oxygen

saturation of between 65–70% in an individual with a normal hemoglobin

concentration. Glucose is the main energy substrate used by the brain except

during periods of starvation or hyperglycemia where ketones are used as an

alternative energy source. At rest, up to 92% of the adenosine triphosphate

(ATP) in the brain comes from oxidative metabolism of glucose. Lactate is also

consumed in very small quantities by the brain under normal circumstances.

However, there is little storage capacity for energy substrate in the brain, as

demonstrated by the fall in ATP levels to zero within 7 minutes after termination of

the oxygen supply. Therefore, the brain is dependent upon a constant supply of

oxygen (aerobic metabolism) and glucose (glycolysis) by the blood (perfusion).

The energy requirements for the brain can be compartmentalized to basal and

functional needs. Basal energy is required for maintenance of cell integrity with

electrochemical gradients; cellular transport of molecules; synthesis of proteins,

lipids, and carbohydrates; and the production, storage, release, and reuptake of

transmitters. Functional energy is expended in neuronal functioning including

generation of electrical activity by the pyramidal cells. About 40% of the energy

is used for basal needs, whereas functional activity consumes about 60%.

Measurement of cerebral blood flow

Numerous techniques are now available for monitoring of CBF, although most

are expensive, time-consuming, and seldom practical for routine clinical uses.

These methods can measure global, regional, or local CBF.

Global CBF

The Kety-Schmidt technique of nitrous oxide washing is considered to be the

gold standard for measurement of hemispheric blood flow [4]. Modifications and

adaptations of this technique include argon washing and 133xenon clearance. Re-

cently, a double indicator method to measure hemispheric CBF was introduced [5].

Regional CBF

Regional CBF can be determined using multiple detectors with 133xenon

clearance. Regional CBF can also be mapped with xenon CT. Single photon

emission CT provides relative qualitative information but not absolute CBF,

whereas positron emission tomography will measure absolute regional CBF.

Transcranial Doppler sonography

Transcranial Doppler (TCD) sonography measures CBF velocity in the basal

cerebral arteries. Although TCD is not a direct measure of CBF, changes in flow


velocity generally correlate well with changes in CBF, except under specific

circumstances such as vasospasm. Because it is noninvasive, it allows repetitive,

bedside measurement of relative changes in regional CBF. It is particularly suited

for the repetitive assessment of cerebral autoregulation [6].

Local CBF

The Laser Doppler measures local CBF in a tissue volume of 1 mm3.

Experimental methods include hydrogen clearance, radioactive or fluorescent

microspheres, and autoradiographic measurements, which are only applicable in

animal models.

Control of the cerebral circulation

The cerebral circulation is tightly regulated with a number of homeostatic

mechanisms (see Fig. 4). The major influence of the cerebral circulation are (1)

metabolism, (2) partial pressure of carbon dioxide (PaCO2), (3) partial pressure of

oxygen (PaO2,) (4) viscosity, and (5) blood pressure/cerebral perfusion pressure.

Fig. 4. (A) An autoregulatory test demonstrating absent cerebral autoregulation. (B) A similar test in a

patient with preserved cerebral autoregulation. MABP = mean arteriala blood pressure. Vmca = mean

middle cerebral artery flow velocity. Lt/Rt = left/right.


Flow–metabolism coupling

In the absence of pathology, CBF flow is tightly coupled to cerebral

metabolism. This occurs both at a global and regional level. During periods of

central nervous system activation, CBF increases to accommodate the rapid

increase in CMRO2 necessitated by the increased energy requirements for

synaptic transmission. Thus, activation of the occipital cortex with light stimu-

lation of the retina is immediately followed with an increase in flow in the

posterior cerebral arteries. Epileptic seizures are accompanied by an almost

instant increase in global CBF. Flow–metabolism coupling is perhaps the most

important control of the cerebral circulation. It is a robust mechanism that is

preserved during sleep [7–9] as well as during general anesthesia [10]. It can be

observed during the different stages of sleep where light or deep sleep is

associated with a 10% decline in CBF, and rapid-eye-movement (REM) sleep

has CBF similar to the awake state [7]. Flow–metabolism coupling can also be

observed during deep inhalation anesthesia, where regional changes in metabo-

lism are coupled with regional changes in flow [11]. Recent studies have

Fig. 4 (continued ).


demonstrated that the increase in CBF may transiently exceed the increase in

CMRO2 (luxury perfusion), and that the regulation of CBF during neuronal

activity is independent of local tissue levels of oxygen [12].

Mediators of flow–metabolism coupling

Adenosine and nitric oxide are two purported mediators of flow–metabolism

coupling. Adenosine causes increased cyclic AMP production that results in cere-

brovasodilation. Nitric oxide (NO) is an intercellular messenger in the peripheral

circulation and in the central nervous system, and causes vascular smooth muscle

relaxation and inhibition of platelet aggregation. Antagonists of both adenosine

and NO will attenuate the rise in CBF associated with neuronal activation,

although neither mediator antagonist alone, nor in combination, will completely

abolish the CBF increase in response to neuronal activation [13]. Therefore, other

mediators such as H + ions, adenine nucleotides, potassium, prostaglandins, and

vasoactive intestinal peptide, may also be involved in flow–metabolism coupling.

Both sympathetic and parasympathetic neurons may contribute to the neuro-

genic regulation of flow–metabolism coupling. In rats, stimulation of the

sympathetic system causes both increased CBF and CMRO2, while stimulation

of the parasympathetic system causes an increase in CBF only. Activation of the

central sympathetic system causes a much greater increase in CBF and CMRO2

than activation of the extrinsic sympathetic system that originates extracranially.

The role of the sympathetic system in regulation of CBF in humans remains

unknown, although it is thought that sympathetic stimulation shifts the autore-

gulatory curve to the right.

Temperature effects on flow–metabolism coupling

Hypothermia causes a reduction in CMRO2, thereby decreasing CBF via

flow–metabolism coupling. CBF decreases approximately 5% to 7% per degree

Centigrade. Reduction of the brain temperature to 15�C will reduce CMRO2 to

10% of normothermic values. Hypothermia causes a reduction in both the basal

metabolism required for maintenance of cellular integrity and the functional

metabolism of the CNS. Anesthetic agents affect only the functional component

of the CMRO2.

CO2 vasoreactivity

The cerebral circulation is exquisitely sensitive to changes in PaCO2. In

normal subjects CBF increases linearly by 2% to 4% per mmHg PaCO2 within

the range of 25 to 75 mmHg. This makes PaCO2 the most potent physiologic

cerebral vasodilator. The change in CBF occurs within seconds after PaCO2 is

changed, and complete equilibration occurs within 2 minutes [14]. The brisk

response of the cerebral vasculature to carbon dioxide (CO2) is caused by the

rapid diffusion of arterial CO2 across the blood–brain barrier (BBB) and into the

perivascular fluid and cerebral vascular smooth muscle cell. CO2 causes a

reduction in the perivascular pH, which leads to cerebral vasodilation and


increased CBF. Both CO2 and bicarbonate ions exert their effects on the

cerebrovasculature via changes in the extracellular fluid pH, and not by direct

action [15]. Although CO2 is a potent cerebral vasodilator, arterial H + ions do

not affect the cerebrovasculature because they do not readily diffuse across the

intact BBB, and therefore, cannot lower the perivascular pH of the cerebral

vessels. Consequently, metabolic acidosis and alkalosis do not affect cerebral

vascular tone, as do respiratory acidosis and alkalosis [16].

The changes in CBF associated with alterations of arterial CO2 are not

maintained for prolonged periods. During chronic hypercapnia maintained for

6 hours in dogs, Warner et al. [17] demonstrated an adaptive increase in the

cerebrospinal fluid (CSF) pH that was associated with a decrease in CBF. The pH

change was accompanied by an increase in the CSF bicarbonate ion. Similarly,

during chronic hypocapnia, the CSF pH gradually decreases toward baseline as

CSF bicarbonate concentration decreases and CBF increases [18].

Mechanism of CO2 vasoreactivity

The mechanism for CO2 vasoreactivity appears to be regulated by local

mediators, rather than by chemoreceptors in the periphery because their denerva-

tion does not alter the CBF response to changes in arterial CO2. The molecular

pathway by which perivascular pH influences cerebral vascular tone has not been

clearly defined. Frommice to humans, it has been demonstrated that NO is partially

responsible for CO2-mediated cerebral vasodilation. Schmetterer et al. [19]

demonstrated a significant reduction in mean flow velocity of the middle cerebral

artery to hypercapnia in healthy human volunteers after administration of an NO

synthase (NOS) inhibitor. However, NOS inhibitors do not completely ablate CO2

vasoreactivity, and NO may be more important in regional rather than global

regulation of vasoreactivity. The cerebral cortex in primates was the only site in

which NOS inhibitor attenuated the CBF response to increasing arterial CO2

concentration [20]. Site-specific responses indicate either the existence of more

than one pathway of CO2-mediated vasodilation, or that different regulatory

mechanisms occur at different locations. Moreover, CO2 vasoreactivity in neuronal

NOS knockout mice was found to be the same as in wild-type mice [21]. Other

putative mediators of CO2 vasoreactivity include prostaglandin E2 (PGE2) and

cyclic guanosine monophosphate. Indomethacin, an inhibitor of prostaglandin

production, causes potent attenuation of CO2 vasoreactivity, which is restored

upon addition of PGE2 [22].

Conditions that alter CO2 vasoreactivity

Global CO2 vasoreactivity is relatively robust, and is only abolished in brain-

damaged patients in terminal conditions. However, there are many conditions in

which it may be attenuated. Patients with severe carotid stenosis, head injury,

subarachnoid hemorrhage (SAH), cardiac failure, or severe hypotension, in which

the compensatory cerebral vascular response is already exhausted, may have a

decreased response to changes in CO2 compared to healthy subjects. Local loss or

decrease in response to CO2 in carotid stenosis has been demonstrated, and can


be used to predict the need for intraoperative shunting, and to predict which

patients with asymptomatic disease might benefit from surgery [23]. Similarly,

impaired CO2 vasoreactivity can be used to prognosticate in severe head-injury

patients [24]. Patients with aneurysmal SAH frequently demonstrate a reduced

response to hypocapnia, and may have absent response to hypercapnia when

vasospasm is present [25,26]. Cardiac failure patients demonstrated reduced CO2

vasoreactivity that was associated with reduced left ventricular ejection fraction

[27]. Hypercapnia, under these pathologic conditions, may induce cerebral

ischemia by causing vasodilation of unaffected regions of the brain and vessels,

and diverting blood flow away from the maximally dilated, diseased regions. This

phenomenon is known as cerebrovascular ‘‘steal.’’ Severe hypotension would

also maximally vasodilate the cerebral vasculature, and results in a temporary

loss of CO2 vasoreactivity [28]. The extent of attenuation of CO2 vasoreactivity is

probably influenced by the choice of hypotensive agent, because different

hypotensive agents demonstrate different reductions in CO2 vasoreactivity [29].

Hypothermia does not seem to affect CO2 vasoreactivity [30,31], but advancing

age ( > fourth decade) in the female gender is associated with a decline in CO2

responsiveness unless subjects are on hormone replacement therapy [32].

Hypoxemia-induced cerebral vasodilation

Compared to PaCO2, the influence of PaO2 on the cerebral circulation is mild

and of much less clinical significance. CBF generally does not increase appreciably

until PaO2 decreases below 60 mmHg, although one study reported a 23% increase

in CBF in humans when PaO2 was decreased from 100 to 65 mmHg [33]. The

response to hypoxemia is not as brisk as the response to changes in PaCO2, because

equilibration of CBF takes approximately 6 minutes after the establishment of

hypoxemia. On the other hand, the effect of hyperoxemia is less certain, as studies

have shown either a slight decrease in CBF velocity or no change at all [19,33].

Traystman et al. [34] demonstrated that the mechanism of hypoxemia-induced

vasoreactivity is not dependent upon baroreceptors or chemoreceptors in dogs.

Hypoxemia may induce cerebral vasodilation via anaerobic glycolysis and lactic

acid production causing decreased extracellular pH and subsequent vasodilation.

However, Koehler et al. [35] demonstrated that pH changes during hypoxemia

are only partially responsible for the increased CBF. Many studies have demon-

strated that release of adenosine is necessary for the vasodilatory response to

hypoxemia [36,37]. In animal models, adenosine activates large conductance cal-

cium-activated potassium channels and ATP-sensitive potassium channels that

contribute to vasodilation [38]. NO has also been implicated as a mediator, because

NOS inhibitors will reduce the increase in CBF, which occurs during hypoxemia

[39,40].

Effects of viscosity on CBF

Viscosity of blood is primarily a function of the hematocrit. Decrease in

viscosity is usually secondary to hemodilution, and CBF increases as a result of


the improved rheology of the blood flow in the cerebral vessels, as well as a

compensatory response to decreased oxygen delivery [41].

Blood pressure or cerebral perfusion pressure (cerebral autoregulation)

Normal flow, pressure, and resistance relationships

The relationship between flow and pressure can be simplistically described by

the equation

F ¼ P=R

where F = flow, P = pressure, and R = resistance. However, the cerebral

vascular bed is not rigid. Resistance to flow is dependent on the length of the

blood vessel, the viscosity of the fluid going through it, and the caliber of the

vessels. Thus, laminar flow through a cerebral vascular bed can be described by

the Poiseuille’s equation:

F ¼ ðpr4DPÞ=8gL

where F = flow, r = vessel radius, DP = pressure gradient, h = viscosity, and L =

length. Thus, resistance = (8 hL)/(pr) [4].However, the brain and its blood vessels are encased in the rigid cranium and,

therefore, subjected to the surrounding pressure (intracranial pressure—ICP). The

net cerebral perfusion pressure (CPP) is generally defined as the difference

between mean arterial blood pressure (MAP) and ICP. It should be noted that the

cerebral venous pressure at the junction between the cerebral veins and the dural

sinuses is usually slightly greater than ICP (necessary to allow venous flow).

When ICP is low but jugular venous pressure (JVP) is high, (e.g., when there is

venous obstruction at the neck), then CPP = MAP � JVP.

Under normal physiologic conditions, changes in MAP between 60 and

160 mmHg in the average individual produces little or no change in CBF [42].

This homeostatic mechanism of cerebral autoregulation with in vivo vaso-

constriction and vasodilation in response to changes in blood pressure was first

observed by Fog [43]. Cerebral autoregulation ensures that as MAP increases

there is increased resistance from a reduction in the caliber of the small cerebral

arteries and arterioles. This protects the cerebral arterioles and the brain from

elevation in MAP. This adaptive mechanism also maintains adequate CBF when

MAP or CPP decreases. Thus, cerebral arterioles dilate as MAP decreases, and

constrict as MAP increases. Beyond these limits of autoregulation, CBF is

directly proportional to MAP and can be described as pressure-dependent or

pressure-passive. There are some areas of the brain that are more at risk for

ischemia than others. The watershed areas between the anterior, middle, and

posterior cerebral arteries, as well as the areas between the superior and inferior

cerebellar arteries are particularly susceptible to ischemia as MAP decreases.

These regions have resting MAP that is lower compared to more proximal

territories supplied by the major arteries and are, therefore, the first ones to


reach a critical threshold when systemic MAP decreases. When MAP exceeds

150–160 mmHg, CBF begins to increase, and vessels may begin to leak with

extravasation of blood into the extravascular space. The MAP at which CBF

increases is termed ‘‘breakthrough’’ or the upper limit of cerebral autoregulation

[44]. Sudden decrease in CBF occurs at the other inflection point, or the lower

limit of autoregulation.

Mechanisms of autoregulation

The precise physiologic process accounting for cerebral autoregulation is

unknown, and may represent a combination of metabolic, myogenic, and neuro-

genic mechanisms.

The metabolic mechanism

This stipulates that autoregulation is mediated by the release of vasodilator

substance that regulates the cerebrovascular resistance to maintain CBF constant.

Although no specific substance fits all experimental observations, adenosine, a

potent cerebral vasodilator, formed from breakdown of ATP when neuronal

demand of oxygen exceeds supply is a prime candidate [45]. Adenosine can be

found in increased concentration in cerebral tissue as systemic blood pressure

falls towards the lower limit of autoregulation. In fact, brain adenosine concen-

tration doubles within 5 seconds of decreasing blood pressure [46]. Cortical

activation via contralateral peripheral stimulation is also immediately followed by

adenosine release and regional vasodilation [47]. It has been suggested that NO

exerts an influence on basal and stimuli-mediated cerebrovascular tone. The

mechanism of NO-induced cerebral vasodilation probably involves cyclic gua-

nosine monophosphate and a decrease in intracellular calcium. It is unclear to

what extent NO affects cerebral autoregulation in both healthy patients and in

patients with traumatic brain injury. Although earlier studies suggest that NO has

no influence on cerebral autoregulation, Jones et al. [48] recently described an

increase in the lower limit of autoregulation with NOS inhibitors. Other trans-

mitters/substances that have been proposed as mediators of autoregulation

include protein kinase C [48], melatonin [49], prostacyclin, activated potassium

channels, and intracellular second messengers [50].

The myogenic mechanism

This theory of pressure-dependent myogenic tone, first proposed by Bayliss in

1902, was not experimentally verified until approximately 50 years later. The

myogenic theory states that the basal tone of the vascular smooth muscle is

affected by change in perfusion or transmural pressure, and the muscle contracts

with increased MAP and relaxes with decreased MAP. Studies suggest that there

may be two myogenic mechanisms involved in cerebral autoregulation: a rapid

fast reaction to pressure pulsations, and a slower reaction to change in MAP. This

adaptive process appears to be initiated within the first 400 milliseconds (rapid

and rate-dependent response), and is probably completed in a few minutes by the


slower and rate independent component of the autoregulatory process. The

slower secondary component appears to be the dominant force in regulating

CBF. Autoregulation might also be invoked by incremental and nonpalatial

pressure. However, constant pressure elevation is probably not a sufficient stim-

ulus to maintain sustained vascular contraction. Some investigators believe the

myogenic mechanism sets the limits of autoregulation, whereas the metabolic

mediators are responsible for cerebral autoregulation itself.

The neurogenic mechanism

Perivascular innervation of the cerebral resistance vessels and the specific

neurotransmitter contained within the perivascular nerve fibers may also modu-

late vascular response to changes in blood pressure. However, the specific

mechanisms by which the central nervous system exerts control on the cerebral

vasculature are poorly understood. Although acetylcholine is the most abundant

perivascular neurotransmitter, the list of neurotransmitters involved in this neural

response includes norepinephrine, neuropeptide Y, cholecystokinin, acetylcho-

line, vasoactive intestinal peptide, and calcitonin gene-related peptide [51].

Experimentally sympathetic stimulation can shift the autoregulatory curve to

the right, thus protecting the brain against severe elevation of MAP.

Abnormal autoregulation

Autoregulation can become impaired or abolished by a variety of causes

including trauma, hypoxemia, hypercapnia, and high-dose volatile anesthetics.

Physiologically, hypercapnia (PaCO2>60 mmHg) will consistently impair cere-

bral autoregulation [52]. Clinically, the neurologic disorders where autoregulatory

impairment may contribute to the pathophysiology include ischemic cerebrovas-

cular disease, subarachnoid hemorrhage, and traumatic brain injury (TBI).

Abnormal autoregulation can range from minimal impairment to complete loss

and can be classified as ‘‘intact,’’ ‘‘impaired,’’ or ‘‘abolished.’’ However, auto-

regulation is not an all-or-none phenomenon, but rather represents a continuous

spectrum of adaptive response in cerebrovascular resistance to a change in

perfusion pressure. In patients with absent autoregulation, systemic hypertension

may lead to cerebral hemorrhage and edema formation, whereas a decrease in

blood pressure may turns areas with ischemia into areas of infarction. In patients

with subarachnoid hemorrhage with impaired autoregulation, induced hyperten-

sion may ameliorate ischemic deficits and improve outcome; thus, the risk of

increased cerebral edema and hemorrhage must be balanced against the benefits

of improved perfusion. Patients with TBI frequently suffer from cerebral

ischemia and loss of autoregulation, and a relatively high-maintenance MAP

may be indicated. Because the compensatory vasoconstriction mediated by the

autoregulatory response would result in a decrease in ICP, elevation of MAP may

be beneficial even in patients with preserved cerebral autoregulation. Moreover,

some TBI patients may have a rightward shift of the lower limit of autoregu-


lation, necessitating the maintenance of a higher MAP than normal (see below).

Documentation of the cerebral autoregulatory capacity would often facilitate

clinical management of these patients.

Limits of autoregulation

Although the limits of cerebral autoregulation are often stated as 60 and

160 mmHg, there is considerable variation in the limits among normal individ-

uals. Pathologically, these limits can be affected by a number of conditions. The

classic examples are chronic hypertension and traumatic brain injury. In chroni-

cally hypertensive adults, the autoregulatory curve is shifted to the right, and a

MAP >160 mmHg may not cause any increase in CBF. In patients with traumatic

brain injury, cerebral autoregulation may be impaired or abolished, or similarly

shifted to the right [53,54].

Autoregulation testing

Determination of autoregulation requires monitoring of CBF (see above) with

simultaneous change in MAP effected either spontaneously or provocatively, and

in the latter category, either pharmacologically or nonpharmacologically. The gold

standard is static testing, with measurement of CBF at two different levels of

steady-state MAP. With the advent of TCD monitoring, it is now possible to test

static autoregulation repetitively in the bedside. Because of the high temporal

resolution of TCD, it is also possible to test dynamic as well as static cerebral

autoregulation. Dynamic autoregulation is performed by monitoring the change in

CBF velocity in response to a transient decrease in MAP from sudden deflation of

bilateral thigh cuffs that have been inflated for a duration of 3 minutes [55]. The

autoregulatory index (ARI) is derived from a mathematical model, and reflects

how quickly middle cerebral artery flow velocity (Vmca) returns to baseline while

the MAP remains low (Appendix 1). An abnormal ARI reflects either a decreased

capacity of the autoregulatory response or an increased latency in the response. An

ARI derived from static autoregulation measurements quantifies the change in

cerebrovascular resistance (CVR) in response to change in MAP during steady

state without regard to latency (Appendix 2) [6]. The autoregulatory stimulus

during static testing often necessitates pharmacologic manipulation of blood

pressure. On the other hand, dynamic testing offers the advantage of quantifying

the speed of the response without use of any pharmacologic agents and tests the

response to hypotension instead of hypertension. Despite the fact that each testing

method may assess different aspects of the cerebral autoregulatory response, good

correlation between them have been demonstration under conditions of both intact

and impaired autoregulation [56].

Recently, the transient hyperemic response (monitored by TCD) from unilate-

ral carotid compression has been proposed as a test of cerebral autoregulation


[57]. However, the uncontrolled nature of the provocative stimulus makes this

unreliable, and is at best a semiquantitative test.

Conclusion

Remarkable progress has been made in the understanding of the control of the

cerebral circulation in health and disease states during the last 20 years. This is in

part due to the multidisciplinary basic science research and clinical research into

the mechanisms of regulation of CBF. In this article we have attempted to

describe aspects of CBF physiology relevant to the practicing anesthesiologist.

Anesthesiologists, in their daily practice, knowingly and unknowingly manipulate

and modulate the cerebral circulation. A thorough understanding should improve

patient care and outcome in those with neurologic disease.

Appendix 1

Dynamic cerebral autoregulation was calculated by the computer using the

following algorithm. The Autoregulation Index (ARI) is scaled 0–9.

DP = (MAP� cMAP)/cMAP�CCP)�x2 = x2 + (x1� 2D�x2)/f�T)x1 = x1+(dP� x2)/(f�T)mV = cVmca�(1 + dP� k�x2)dP = change in MAP due to cuff release

cMAP = baseline MAP value before cuff release

CCP = critical closing pressure (calculated by the computer)

x1 and x2 = variables that were assumed to be zero during the control period

D = damping factor

f = sampling rate

T = time constant

mV = mean velocity

cVmca = mean middle flow velocity before cuff deflation

K = autoregulatory dynamic gain

Appendix 2

The ARI scaled 0–1 using the static method of testing is calculated as follows:

ARI = % DeCVR/% DMAP

And e CVR = MAP/Vmca

ARI = Autoregulation Index

e CVR = estimated cerebrovascular resistance

MAP = mean arterial pressure

Vmca = middle cerebral artery flow velocity


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Anesthetics and the brain

Tod B. Sloan, MD, PhD, MBADepartment of Anesthesiology, 7838 University of Texas Health Science Center,

7703 Floyd Curl Dr., San Antonio, TX 78229, USA

Site of action of anesthetic agents

The method by which general anesthesia is produced remains unclear.

Obscuring the search for a common method for production of anesthesia is the

observation that anesthetics comprise a wide variety of chemical structures

without any apparent common mechanism of action. The common trait of these

drugs, lipophilicity, and the lack of a specific antagonist for general anesthesia

further suggest that no one specific receptor is involved in the process. However,

all of the drugs do appear to produce an alteration of neuronal excitability either

through depression of synaptic function or axonal conduction. Because synaptic

function appears more sensitive to anesthetics than does axonal conduction, a

strong focus of research has examined the effects of anesthetic agents on the key

determinants of synaptic function [1].

Because of the importance of ion channels in synaptic transmission, they have

been considered a potential target for anesthetic-induced depression of synaptic

function. These channels can be opened or closed by direct action of drugs at

receptors, by action on the molecule through changes in the protein–lipid milieu

around it in the cell membrane, or secondarily through intermediary messengers

from other receptors affected by the anesthetics (such as guanosine nucleotide

binding protein–G-protein) [2,3].

Because of the lipophility of anesthetic drugs, substantial research has focused

on anesthetic-induced changes in the fluidity of the plasma membrane that may

alter receptor and ion channel function. This mechanism may be particularly

important for the inhalational anesthetic agents where specific receptor inter-

actions are lacking (unlike the intravenous anesthetic agents, where many

receptor interactions are known). Such changes in membrane fluidity leading

to membrane protein changes have been demonstrated in the Na/K ATP’ase

membrane protein [4] and the nicotinic acetylcholine receptor [5], supporting the

possibility for this mechanism of anesthetic action. However, as a sole mech-


PII: S0889 -8537 (01 )00002 -5

E-mail address: [email protected] (T.B. Sloan).


20 (2002) 265–292

anism of anesthetic action, this effect may not be sufficient to explain all the

effects leading to anesthesia.

Evidence suggests that the inhalational agents may exert effects by more

specific mechanisms than changes in membrane fluidity. Inhalational agents have

low-affinity binding sites on some proteins, and these may contribute to conforma-

tional or functional shifts in protein action. It is also possible that these agents

occupy pockets, patches, or cavities that result from folding or interfacial (protein–

protein or lipid–protein) contacts and alter the normal noncovalent binding sites,

resulting in a conformational shift that changes function. If these proteins control

the electrochemical functioning of a neuron, then depression or enhancement of

function could result. In contrast to the inhalational agents, the intravenous

anesthetic agents appear to have specific interactions with membrane receptors.

Molecular action of anesthetics

Studies have examined the interactions of anesthetic agents with several

receptors and ion channels. In general, differences between inhalational and

intravenous agents have been observed. Perhaps the best evidence for specific

mechanisms of anesthetic action comes from the study of the major inhibitory

(gama amino butyric acid) and major excitatory (glutamate) synaptic systems in

the central nervous system (CNS).

Gama amino butyric acid (GABA) receptors

As the main inhibitory neurotransmitter in the CNS, GABA is a prime candidate

for participating in anesthetic-induced neuronal depression. Two major receptor

types are known. The ionotropic GABAa receptor is expressed in virtually every

neuron in the CNS and gates an ion channel. The GABAb receptor is a

metabotropic receptor that activates a series of intracellular events when activated.

Several anesthetic agents have prominent effects at the GABAa receptor.

When this receptor is activated, a chloride channel is opened, resulting in an

inhibitory effect on the cell. Receptor activation also causes enhancement of

potassium conductance and depression of calcium conductance via a G-protein

coupling system. Because specific binding sites have been shown on the GABAa

receptor for barbiturates, etomidate, althesin, propofol, and benzodiazepines, the

GABA receptor may play an important role in anesthesia produced by these

agents (Fig. 1) [6]. Although specific binding sites have not been identified,

volatile anesthetic agents do appear to modulate GABAa receptor function,

specifically enhancing GABA and benzodiazepine binding [7], resulting in

neuronal depression.

The glutamate receptor

The synaptic receptors that respond to glutamate are the principle fast ex-

citatory neurotransmitter system of the CNS and may also participate in the an-

T.B. Sloan / Anesthesiology Clin N Am 20 (2002) 265–292266

esthetic state. These receptors are divided into three classes based on the binding

of N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-isoxazole pro-

pionic acid (AMPA), and kainate. These receptors are also believed to be

involved in learning, memory, motor coordination, neurotoxicity, and neuro-

degenerative disorders. The NMDA class has been studied extensively, and is

strongly voltage dependent due to a block by Mg2 + ions at negative membrane

potential [8]. When stimulated, calcium enters into the cell setting off a cascade

of events. AMPA and kainate receptors are believed to mediate the majority of

fast excitatory synaptic transmission in the brain, and inhibition would likely

cause profound changes in excitability of the brain.

The NMDA receptor probably plays a role in anesthesia because its antago-

nists (e.g., ketamine) produces a state of dissociative anesthesia (Fig. 2) [9,10].

When the receptor is at normal resting membrane potential, magnesium blocks

the calcium channel. When activated, the cell is depolarized, the magnesium

block is relieved, and calcium entry is permitted. This may be the predominant

site of action for ketamine in producing anesthesia. The evidence suggests a use-

dependent blockade; the anesthetic molecule enters the open channel, binds, and

then is trapped as the channel closes. Studies have shown that ketamine inhibits

NMDA receptor-mediated neurotransmitter release (e.g., regional effects involv-

ing acetylcholine, dopamine, GABA, norepinephrine [11–13]), as well as affect-

ing sodium flux and intracellular calcium levels [14].

Fig. 1. Depiction of GABAa receptor and hypothetical binding sites for several anesthetic agents.

(Reprinted from DeLorey TM, Olsen RW. GABA and glycine. In: Siegel GJ, et al, editors. Basic

neurochemistry: molecular, cellular, and medical aspects. 5th ed. New York: Raven Press; 1994.

p. 389–99; with permission.)

T.B. Sloan / Anesthesiology Clin N Am 20 (2002) 265–292 267

Ketamine may be unique among intravenous anesthetics in that it produces its

anesthetic effect by a mechanism not involving the GABA receptor. This may

account for the production of the anesthetic state called ‘‘dissociative’’ anesthesia

where, rather than general electroencephalographic (EEG) depression, there is

EEG evidence of dissociation between the thalamocortical and limbic systems

[15]. In this state, the thalamus and cortex exhibit synchronous delta bursts while

the ventral hippocampus and amygdala exhibit theta waves characteristic of

arousal. The anesthetic state produced, rather than an unresponsive sleep state, is

a cataleptic-like state of unresponsiveness with occasional purposeful move-

ments. There is intense analgesia, amnesia, and occasional hallucinations. Keta-

mine also appears to interact with mu and kappa opioid receptors, but because the

anesthetic state is not reversed by naloxone, the primary anesthetic effect is

probably via the NMDA mechanism.

A variety of evidence suggests that barbiturates also interact with the NMDA

receptor. Evidence suggests that they upregulate the receptor [16], and that they

may interact competitively with some of the binding sites [17]. However, the

exact role of this receptor in the production of anesthesia from barbiturates

remains unclear. With respect to inhalational agents, modulation of the NMDA

receptor is known to alter the potency of inhalational agents [18]. Studies have

also shown that inhalational agents inhibit the NMDA and AMPA/kainate

receptors [19–21]. Evidence suggests that the site of action may be near the

Fig. 2. Depiction of NMDA receptor and hypothetical binding sites for several anesthetic agents

including ketamine (Ket). (Reprinted with permission in adapted form from Peoples and Weight,

1998 [10]).


hydrophobic regions of the receptor near or in the plasma membrane. Alcohol

may play a role in NMDA receptor changes in a similar way.

Other receptors and ion channels

We have seen that anesthetic agents interact with the GABA and glutamate

receptors, thereby altering the balance of inhibitory and excitatory influences in

the nervous system. However, anesthetic agents also have effects on other ion

pores and receptor types, suggesting that other systems may play a role in the

neural state characteristic of anesthesia.

In the neural system, calcium channels play a role in the release of synaptic

transmitters via excitation–secretion coupling. Anesthetics could participate in

the depression of presynaptic release of neurotransmitters, thereby depressing

synaptic function through these calcium dependant processes. The effect of

anesthetic agents (volatile as well as intravenous) leading to the depression of

calcium channels in cardiac tissue is well described [22]. Similar effects have

been shown in sensory neurons. However, a clear connection with production of

the anesthetic state has yet to be proven.

The potassium channels represent a diverse set of channels involved in

maintenance of the resting membrane potential, repolarization after depolariza-

tion, reduction of the frequency of spikes during repetitive firing, and termination

of firing after a period of marked activity. Within the nervous system an increase

in potassium conductance has been associated with central a2 agonists, and with

m and d opioid receptor agonists [23–25]. This change is said to ‘‘stabilize’’ the

neuronal membrane because it hyperpolarizes it, making it less excitable. This

system could play a role in the anesthetic effects of opioids and central a2

agonists; however, further study will be needed to characterize the specific role

fully. The role of inhalational agents with potassium channels is still unclear.

The nicotinic acetylcholine receptor is a ligand-gated ion channel on the

postsynaptic membrane. It is found at the neuromuscular junction and in the

peripheral and CNS. Acetylcholine is released at the presynaptic membrane and

activates the synapse to receptors on the postsynaptic membrane. This action

opens sodium channels activating the postsynaptic membrane. The subsequent

depolarization then starts intracellular calcium-dependent muscle contraction.

Consistent with the known muscle relaxant properties of inhalational agents, the

volatile anesthetics interact with this receptor. Although this may occur at a

known hydrophobic site [26], it is not known whether the effect is by binding

within the channel pore or by inducing a conformational change in the receptor

by binding at a specific allerosteric site. This receptor is also the likely target for

the action of neuromuscular blocking agents.

The opioid receptors are a part of the G-protein coupling system. In this

system, the receptors (m, k, and d) are activated by their agonists, resulting in

depression of the cell by increasing the inward K + current and depressing the

outward Na + current via a G-protein mechanism linking the receptors to the ion

channels. Recetor activation also causes several other intracellular actions (Fig. 3)


[27]. Most opioid analgesics produce their effects via the m1 receptor while the

two other m receptor types mediate other effects. This mechanism is distinct from

the mechanisms of action of the volatile and other intravenous anesthetic agents.

Therefore, this may explain the fact that the net effect is different (e.g., analgesia

rather than anesthesia).

Fig. 3. Opioid receptor transduction mechansisms. Once activated by an opioid, G-proteins mediate

alterations in Na+ and K+ conductance and several intracellular processes. (Reprinted from Nestler EJ,

Aghajanian GK. Molecular and cellular basis of addiction. Science 1997;278:58–63. Copyright 1997

American Association for the Advancement of Science; with permission.)


The effect of local anesthesia on axonal conduction by interaction with

sodium channels is an excellent example of anesthetic-induced neuronal

depression. Both the charged and uncharged forms of the local anesthetic

molecule have blocking properties. Charged molecules, by virtue of their water

solubility, are restricted to blocking the channel by entering an open pore and

occluding the channel. The uncharged form, by virtue of its lipid solubility, can

enter the lipid membrane and interact with a site on the lipid–protein interface.

The interaction of lidocaine with the sodium channel is depicted in Fig. 4 [28].

The interference with the sodium channel is likely the major site of effect of

lidocaine on axonal conduction.

Fig. 4. Mechanism of Lidocaine action at binding sites within the plasma membrane. (Reprinted from

Hardman JG, Limbird LE. Goodman and Gilman’s the pharmacologic basis of therapeutics, 9th ed.

New York: McGrawHill; 1996; with permission of the McGraw-Hill Companies.)


Because of the numerous effects of anesthetic agents on various synaptic

receptors and ion channels, it is likely that general anesthesia and sedation are a

consequence of hyperpolarization of neurons and/or depression of excitatory

transmission (increasing K+ or Cl� currents or depressing Na+ or Ca+ currents).

Clearly, a large number of different mechanisms (axonal, pre- and postsynaptic)

and different CNS locations have been implicated such that one unifying

mechanism is not apparent. Studies in the hippocampus suggest several possible

mechanisms including: (1) depression of excitatory synaptic transmitter release,

(2) depression of action potential discharge in small diameter axons, (3) en-

hancement of presynaptic fiber discharge in GABA synapses, (4) depression of

postsynaptic responses to glutamate, (5) enhancement of GABA-mediated inhib-

itory transmission by presynaptic mechanisms, and (6) enhancement of postsy-

naptic responses to GABA [29]. Hence, anesthesia may be a change in the

balance of excitatory (especially glutamate), inhibitory (especially GABA), and

other neuronal or synaptic systems in brain structures with no single receptor or

ion channel playing the key role for all anesthetic drugs.

CNS site of action for anesthetic drugs

The CNS structure affected by anesthetics that has received the most

attention is the reticular activating system of the brainstem (RAS), in which

several neuronal systems interact with sensory pathways to the brain and

several mechanisms of arousal originate. However, gross lesions in this system

that result in major EEG disruptions can leave animals behaviorally awake [30].

Similarly, studies of this area show that anesthetics may or may not depress the

RAS activity [8,31,32]. Therefore, it is highly likely that general anesthesia also

involves an effect above the brainstem, such as a bilateral cerebral cortical

effect. Perhaps several types of regional disruptions can result in general

anesthesia [33], and no one neural structure plays the major role with all anes-

thetic drugs.

It is unclear from their mechanism of action whether drugs resulting in

increased depression or excitation of neurons and synapses may be advantageous

in different pathophysiological states. Given the increased cerebral blood flow

(CBF) associated with ketamine (see below) and the reduction in metabolism

associated with depressant agents, it would appear that preservation of a state of

reduced energy metabolism by depression would increase the margin of safety

during potential ischemia. Because the depressant effects may be regionally

specific (depending on the specific neural pathways involved), the possibility

exists that advancements in our knowledge will lead us to conclude that certain

pathophysiologic conditions may prompt certain anesthetics. For example, the

prominent anticonvulsant actions for the GABA related drugs (e.g., benzodiaze-

pines) suggest that these medications may be advantageous when EEG suppres-

sion is desirable (e.g., routine craniotomy with a seizure focus), but may be

detrimental when EEG activity must be preserved (e.g., electrocotigraphy).


The major implications of these anesthetic drug actions is that our knowledge

remains vague about defining the specific actions of anesthetic drugs and the

anesthetic state. There is insufficient knowledge about the regional action of

drugs, making it difficult to recommend preferential agents when specific

regional pathology exists. Certainly advancements in knowledge of mechanisms

of drug action will lead to a refinement of our understanding the anesthetic state,

the specific interaction of drugs and pathophysiology, and the design of future

anesthetic agents.

Effect of anesthetic agents on cerebral physiology

The effects of anesthetic drugs on cerebral physiology can also be viewed as

effects on cerebral metabolism and blood flow. In general, CBF, cerebral

metabolic rate (CMR), and alterations in vascular tone are interdependent such

that alterations in one (by anesthesia or other effects) can alter the others. In

Fig. 5. Data of CBF showing the relationship of CBF to CPP in isoflurane anesthetized dogs.

(Reprinted with permission from McPherson and Traystman, 1988 [68]).


general, anesthetic agents are thought to affect cerebral vascular physiology by

(1) direct effects on the cerebral vasculature, (2) effects on cellular metabolism,

and (3) uncoupling or changing the relationship between CBF or cerebrospinal

fluid pressure (CSFP) and the normal physiological control mechanisms [34].

Because synaptic activity accounts for 40–60% of the normal resting metabolic

activity of the cells, the relationship of metabolism and anesthetic action is

dependent on the mechanism of action discussed in the previous section. In

general, it is thought that an decrease in CMR will cause a decrease in CBF

(coupling) and result in an decrease in CBV with a subsequent decrease in

intracranial pressure (ICP).

Anesthetics have a direct effect on blood vessels (e.g., vasodilation) and

autoregulation. Shown in Figs. 5 and 6 is the effect of anesthetic action on

autoregulation [35,36]. It is likely that endothelial relaxing factor (nitric oxide)

plays a role in the regulation of vascular tone and the interaction of inhalational

Fig. 6. Idealized graph of inhalational anesthetic-induced changes in autoregulation at different

dosages. (Reprinted from Donegan J. Effect of anesthesia on cerebral physiology and metabolism In:

Newfield P, et al, editors. Neuroanesthesia: handbook of clinical and physiologic essentials. 2nd ed.

Boston: Little Brown and Co; 1991. p. 17–30; with permission.)


agents. A second mechanism of action of anesthetic agents is changes in CMR,

which also affects CBF via flow–metabolism coupling [37]. The effect of

anesthesia at clinically usable doses may represent a depression of neuronal

Fig. 7. CBF as a function of CMRO2 at different levels of isoflurane. Flow and metabolism remained

coupled for both anesthetics. (Data from Maekawa et al, 1986 [38]).

Fig. 8. CBF as a function of CMRO2 in different brain regions for isoflurane and halothane. Flow and

metabolism remained coupled for both anesthetics. (Reprinted with permission from Hansen et.al,

1989 [36]).


and synaptic related neural function rather than a depression of basal metabolism.

The depression of CMR by anesthetics with an associated decrease in CBF is

Fig. 9. CSF pressure has been modeled as an equilibrium between CSF production flow rate and the

resistance to absorption. The ICP occurs at the pressure that is at the intersection of the horizontal

production flow rate and the resistance to absorption line which varies with ICP. (Reprinted with

permission from Artru, 1998 [39]).

Fig. 10. The net effect on ICP due to anesthetic influence on CSF dynamics is depicted for etomidate.

Etomidate lowers the production flow rate and changes the slope of the resistance to absorption curve.

The net effect is a reduction in ICP. (Reprinted with permission from Artru, 1998 [39]).


an important anesthetic action. However, the coupling of CMR to CBF is

preserved under anesthesia, although the degree of coupling may be different

between anesthetic agents (Fig. 7) and at different dosages of the anesthetic

agents (Fig. 8) [36,38].

It is important to note that for a given patient, regions of the brain may behave

differently depending on regional pathology. Therefore, some physiologic

maneuvers may shunt blood preferentially from areas of good flow to areas of

poor flow (reverse steal or Robin Hood effect), or shunt blood from areas of poor

flow to areas already rich with flow (steal phenomena). It appears that these

shunting phenomena can occur using pharmacologic agents, but the clinical

significance is unclear.

Finally, anesthetic actions may also alter cerebral physiology by altering

cerebrospinal fluid (CSF) dynamics. The actual mechanisms of CSF pressure and

volume regulation are rather complex. However, CSFP has been modeled as the

equilibrium defined by the production flow and the resistance to absorption

(Fig. 9) [39]. Normal physiologic mechanisms that alter CSF production or

absorption include temperature and ventilation and anesthetic agents likely

produce changes by altering the rate of production and the resistance to

absorption (Fig. 10). Table 1 shows representative data for anesthetics taken

from Artru [39].

Table 1

Effect of anesthetic agents on CSF dynamics

Low dose High dose

Vf Ra ICP Vf Ra ICP

Inhaled anesthetics

Halothane dec inc inc

Enflurane none inc inc inc none inc

Isoflurane none none/inc none/inc none dec dec

Desflurane none/inc none/inc none/inc

Sevoflurane dec inc ?

Nitrous Oxide none none none

Opiods

Fentanyl none dec dec dec none/inc dec/?

Alfentanil none dec dec none none none

Sufentanil none dec dec none inc/none inc/none

Sedative-hypnotics

Thiopental none inc/none none dec none/dec none

Midazolam none inc/none inc/none dec none/inc dec/?

Etomidate none none none dec none/dec none/dec

Propofol none none none

Ketamine none inc inc

Abbreviations: Vf = Production rate of CSF flow; Ra = resistance to absorption; ICP = predicted effect

on ICP.

Data from Artu AA. Cerebral fluid dynamics. In: Cucchiara RF et al, editors. Clinical neuroanesthesia,

2nd ed. New York: Churchile-Livingstone; 1998. p. 41–72.


Effects of specific anesthetic agents on cerebral physiology

Potent inhalational agents

The potent inhalational agents (halothane, enflurane, isoflurane, sevoflurane,

desflurane) produce a multitude of changes in the normal brain, which suggest

that they should have adverse effects on patients with intracranial pathology (i.e.,

increase ICP). These agents produce at least three different effects that together

result in a dose-related change in cerebral physiology. First, they produce a dose-

dependent depression of metabolism that tends to reduce CBF through coupling.

Second, the inhalational agents change the coupling so that CBF is reset to a

higher level for each CMR (Fig. 8). Finally, the inhalational agents are direct

vasodilators producing a dose-dependent increase in CBF. Hence, at low doses

CBF is not elevated, but at higher doses it increases. The balance of these effects

is different between agents and determines the net effect at any given anesthetic

level. Depicted in Fig. 11 is the effect of three agents on CBF, suggesting above a

certain threshold (e.g., 1 minimal alveolar concentration [MAC] for isoflurane),

the net effect is vasodilation [40]. CBF increase appears as a consequence of

arterial dilation as well as increase in venous capacitance [41]. Nitric oxide likely

Fig. 11. CBF as a function of relative MAC value in volunteers for isoflurane, enflurane, and

halothane. Flow and metabolism remained coupled for both anesthetics. (Reprinted with permission

from Eger, 1981 [40]).


plays a role in the vasodilation effect that appears to decrease over time [22,42].

CBF responsiveness to carbon dioxide also appears to decrease over time [43].

Halothane is a potent cerebral vasodilator that can produce a marked increase

in ICP clinically. This has been attributed to increases in arterial blood volume

producing an increase in pressure in a cranial cavity rendered noncompliant by

pathology. This observation in 1969 resulted in an editorial condemning volatile

agents for neurosurgical procedures [44]. Fortunately, if hyperventilation (e.g.,

arterial carbon dioxide [PaCO2] 25 mmHg) is instituted prior to introduction of

halothane, the rise in ICP can be prevented. Halothane appears to enhance

vascular reactivity to PaCO2 and changes the relationship of mean arterial

pressure (MAP) and CBF (autoregulation). These reactivities appear to be lost

above 2 MAC.

Finally, although CMR is decreased, CBF increases, suggesting an uncoupling

of CBF and CMR [45]. The effect is not uniform, as the most prominent

vasodilation occurs in the cerebral cortex. In fact, there is a positive correlation

of MAC multiples and the CBF/CMR ratio for all volatile inhalational agents. Of

interest, the decrease in CMR does not appear to be linear, with a major shift to

lower metabolism at 0.5–0.6%. High doses of halothane (above 2.3%) appear to

be associated with toxicity apparently due to interference with mitochondrial

electron transport.

Halothane appears to be a direct vasodilator through an effect on vascular

smooth muscle. This effect occurs faster than metabolic suppression, explaining

why hyperventilation needs to be instituted prior to introduction of the drug. This

effect may be potent enough to overcome beneficial vasoconstriction associated

with decreases in CMR. The net effect is that at low doses (less than 0.5 MAC)

the reduction in CBF offsets the vasodilation effect, resulting in no major cerebral

vascular effect. However, at higher doses the vasodilation is prominent, resulting

in a rise in ICP. It is also of interest that the effect on CBF is time dependent so

that the effects may be different for longer duration exposure. Halothane appears

to increase the resistance to CSF resorption decreases in production. Studies with

cerebral injury show that brain protrusion is worse with halothane than some

other agents. These effects may also contribute to increases in ICP.

Enflurane has similar effects to halothane but appears to be a less potent

cerebral vasodilator and a more potent depressant of CMR. Whereas halothane

has marked effects on cerebral dynamics above 0.5 MAC, enflurane does not

have marked effects until values above 1 MAC. Higher doses of enflurane (over

1.5 MAC) combined with hypocarbia (PaCO2 less than 30 mmHg) produce

cerebral seizure activity with an increase in CMR that is associated with increases

in CBF and ICP. Enflurane increases ICP by mechanisms affecting CSFP. At low

doses, resistance to absorption is increased (with flow unchanged), and at high

doses there is increased production (with normal resistance).

Isoflurane is the least potent cerebral vasodilator and the most potent

metabolic suppressant. It produces a decline in CMR until 2 MAC, when an

isoelectric EEG occurs. Further increases do not decrease CMR further. Like

halothane, ICP increases with the use of isoflurane. However, the effects are


minimal if hyperventilation is used. Unlike halothane, the hyperventilation need

not be introduced prior to the agent. The net effect appears to be a reduction in

CBF below 0.5% with increased CBF above 0.95%. Also, unlike halothane, high

doses of isoflurane do not appear to be toxic.

Because of these favorable properties, isoflurane has been recommended as a

better choice for patients with intracranial pathology. The regional effects of

isoflurane are not uniform. CBF is affected in deeper structures more than in the

superficial cortex. The metabolic effects of isoflurane appear disproportionately

greater in the neocortex. As with halothane, reactivity to PaCO2 is maintained

below 2 MAC. This reactivity appears to be more prominent with isoflurane than

with halothane. In studies of brain surface protrusion, isoflurane produced less

effect than halothane. However, following cryoinjury edema formation was

worse. Isoflurane appears to have no adverse effect on CSFP. Production is

unchanged at all doses, and resistance to absorption is decreased at high doses

(some questionable increases at low doses).

Desflurane is similar to isoflurane in many respects [46]. It produces a steady

decrease in CMR with increases in CBF and ICP with the production of EEG

burst suppression at 2 MAC. Reactivity to PaCO2 remains intact at least to 1.5

MAC, and hyperventilation appears to minimize the ICP consequences of its use.

Also, like isoflurane, it appears to be nontoxic at doses associated with burst

suppression. Desflurane appears to produce no change in resistance to CSF

absorption but may increase production, raising the possibility of some contri-

bution to a rise in ICP [47]. The lower blood-gas solubility of desflurane does

offer some potential advantages over isoflurane for more prompt awakening.

Sevoflurane also appears to have properties similar to isoflurane, with minimal

impact on cerebral dynamics below 1.5 MAC [48]. The effects on CBF and CMR

are similar to that of isoflurane, with burst suppression at about 2 MAC.

Response to PaCO2 and autoregulation appear intact up to 1 MAC. Studies have

shown that ICP can be increased even without CBF changes indicating dilation of

cerebral capacitance vessels. This suggests that the relationship of CBF and

cerebral blood volume (CBV) is nonlinear.

Sevoflurane appears to produce offsetting effects on CSFP, with decreases in

production and increases in resistance to absorption. The net effect of this is

unclear. Sevoflurane is metabolized to inorganic fluoride, and this metabolism is

increased in patients treated with pentobarbitol and phenytoin [49]. The clinical

significance of this in neurosurgical patients is unclear. Sevoflurane is similar to

desflurane, in that the lower blood-gas solubility may have some advantages for

faster awakening.

Nitrous oxide

The impact of nitrous oxide on cerebral dynamics has been controversial for

some time, because studies in humans and animals have produced conflicting

results. For example, it has little to no effect in the rat, but major adverse changes

are seen in other species. Some of these differences are species specific, but they


may also be related to the background physiologic state and the presence of other

anesthetics. In contrast to the other inhalational agents, nitrous oxide appears to

stimulate cerebral metabolism, which increases CBF and ICP. Without other

agents, nitrous oxide also appears to be a potent cerebral vasodilator (by

mechanisms other than by stimulation of metabolism) with the potential to

increase ICP. Increases in ICP in humans have been demonstrated [50–52].

Fortunately, when combined with barbiturates, narcotics, and hypocarbia, the

potential effects of nitrous oxide on CBF and ICP appear to be minimal.

However, when added to volatile agents, nitrous oxide may increase ICP. Nitrous

oxide does not appear to alter CSF dynamics.

Intravenous agents

Opioid agents have also shown conflicting results in studies depending on the

background anesthetic and physiologic state. For example, in the presence of vas-

Fig. 12. Mean arterial blood pressure (MABP) and ICP following an intravenous dose of sufentanil.

As shown in group 1, ICP did not rise when MABP did not fall, but a transient rise in ICP was seen

with a transient fall in MABP (group 2). (Reprinted with permission from Werner et al., 1995 [53]).


odilating agents (e.g., halothane), opioids produce a decrease in CBF and CMR.

However, in the presence of vasoconstricting agents, or no other agents, opioids

had no effect or were associated with an increase in CBF and CMR (Fig. 12) [53].

These effects have led to some reports that opioids have increased CBF and ICP

[54]. However, there is presently no clinical evidence that opioids increase ICP

significantly if ventilation is maintained [55]. Fortunately, opioids do not appear to

alter the CBF changes with PaCO2. Seizures have been reported in some cir-

cumstances with opioid agents. When these occur, CBF and CMR increase. The

opioid agents appear to either decrease CSFP or produce no change through a

variety of effects lowering resistance to absorption or lowering production. How-

ever, sufentanil at high doses may increase resistance to absorption, raising the

possibility of a contribution to increased ICP.

The barbiturates (thiopental, methohexitol, pentobarbitol) have been charac-

terized as cerebral vasoconstrictors. This is because increasing doses cause

decreasing CBF. This is likely due to a steady decrease in CMR until burst

suppression is produced by reduction in synaptic function (Fig. 13) [56]. Unlike the

inhalational agents, the barbiturates do not appear to uncouple or change the

relationship of CBF and CMR. Reactivity to PaCO2 is maintained, and hyper-

ventilation appears to decrease CBF further in the presence of barbiturates. Large

doses do not appear to be toxic. However, as with the inhalational agents, maximal

CMR depression occurs at doses that produce burst suppression on the EEG. Doses

beyond those producing maximal CMR reduction may produce vasodilation. The

metabolic depression of the barbiturates is uniform throughout the brain except for

the habenulo-interpeduncular system, which is unchanged on increased [57]. The

barbiturates appear to produce no major effects on CSFP except at high doses,

when thiopental may decrease production and resistance to flow.

Fig. 13. Reduction in resting cerebral metabolism following a massive dose of thiopental in a dog. The

CMRO2 is progressively decreased until the EEG becomes isoelectric. (Reprinted with permission

from Michenfelder, 1974 [56]).


Etomidate resembles thiopental in its effects on CBF and CMR. Increasing

doses produce depression of CMR until burst suppression, when further doses do

not decrease metabolism. In dogs, etomidate reduces CBFmore rapidly than CMR,

suggesting an intrinsic vasoconstricting property. The depression of metabolism is

not uniform, with the major effect in the forebrain. As with the barbiturates,

toxicity at higher doses was not seen. One caveat with etomidate is that myoclonic

activity on induction might be misinterpreted as seizure activity. Etomidate in low

doses does appear to activate seizure foci in epileptic patients. Toxicity when used

for prolonged periods appears to be related to the propylene glycol solvent [58].

Reactivity to PaCO2 is preserved. Etomidate appears to produce no change in

CSFP at low doses with a decrease in CSFP at high doses caused by decreased

production and possibly by decreased resistance to absorption.

Propofol, also like the barbiturates, produces a dose-related decrease in CBF

and CMR. The metabolic depression appears to be more prominent in cortical

tissue. Also, similar to the barbiturates, propofol does not appear to alter

autoregulation or reactivity to PaCO2. Some case reports have suggested that

propofol can induce seizures; however, it appears to be safe in epileptic patients

[59]. Concerns have also been raised about reductions in MAP with induction

causing reductions in cerebral perfusion pressure, which can be mitigated by

proper dose and application of the agent. Propofol appears to produce no major

Fig. 14. CBF, CMRO2, and mean arterial pressure (MAP) following ketamine (2 mg/kg). (Reprinted

with permission from Dawson et al, 1972 [62]).


changes in CSFP. Prolonged infusions in intensive care setting have resulted in

lactic acidemia and death [60].

The benzodiazepines also resemble the barbiturates, but the effect on CMR

has a limitation of 25% decrease in metabolism rather than the 50–60% decrease

seen at burst suppression with the barbiturates [61]. Midazolam may increase

CSFP at low doses by an increase in resistance to absorption. At high doses it

reduces production and may increase resistance, with a net reduction in CSFP.

Ketamine is unusual in that it produces an increase in CBF with little or no

effect on overall CMR (Fig. 14) [62]. The rise in CBF may be related to

cholinergic mechanisms. In the presence of cerebral vasodilators like halothane or

nitrous oxide, ketamine reduces CBF. Some effects on metabolism have been

seen, particularly in the hippocampus and extrapyramidal systems with decreases

in somatosensory and auditory systems. Reports have shown that ICP is increased

in patients with intracranial pathology. However, the rises in ICP may be related

to inadequate ventilation, because they were prevented with mechanical ventila-

tion. These changes also appear to be blocked or attenuated with prior use of

barbiturates or benzodiazepines [62]. Ketamine appears to produce an increase in

CSFP by increasing resistance to absorption.

Other drugs also have some important effects. Local anesthetics have a

biphasic effect, with low doses producing sedation and reductions of CBF and

CMR. Larger doses produce seizures, severe CNS sedation, and ultimately death.

Succinylcholine produces a transient increase in ICP (Fig. 15) [63]. This appears

to be attenuated or blocked by defasciculating doses of nondepolarizing neuro-

muscular blockers, suggesting that the cerebral afferent effects from muscle

spindles may mediate the effect. The rise can also be attenuated by pretreatment

Fig. 15. The observed increase in CBF following 1.0 mg/kg succinylcholine. Also shown is the

calculated rise in CBF for the rise in PaCO2 in these dogs. (Reprinted with permission from Lanier

et al., 1989 [63]).


with thiopental. It is important to recall the excessive potassium release in

denervated muscle (e.g., stroke or spinal cord injury). Muscle relaxants, which

produce histamine release, can cause an increase in CBF associated with the

consequent vasodilation. This effect can be blocked by pretreatment with

diphenhydramine. Atracurium is metabolized to laudanosine, which can cause

seizures in animals. There is presently no evidence for this effect in clinically

relevant doses in humans. Chronic use of anticonvulsants (especially phenytoin

and possibly carbamazine) increases the dose requirements of nondepolarizers

(with the possible exception of atracurium) by changes in protein binding and the

number of acetylcholine receptors [64].

Choice of anesthetic—does it matter?

This understanding of probable mechanisms of anesthetic action leads to a

better understanding of the anesthetic state. Because general anesthesia appears to

be mediated by synaptic mechanisms, then the measurement of inhalational

anesthetic effect (MAC) by looking at peripheral reflex activity may be a

measurement of the anesthetic effect at the spinal level and not by the cerebral

effects that likely control wakefulness and memory. This sets the stage for a

dissociation of these two systems and awareness under anesthesia, which has been

observed. Further, because the action of the opioids is by receptor mechanisms that

do not involve the traditional GABA or NMDA systems, the possibility also exists

that awareness may be produced if only opioids are used during surgery.

In terms of anesthetic choice for specific procedures in patients with

intracranial pathology, some drugs appear to have specific advantages, however,

but few drugs are contraindicated.

Anesthesia in patients where ICP is an issue

In general, we have traditionally thought that anesthetic agents that increase

CMR or CBF result in increased CBV and ICP. However, the relationship

between these agents and ICP is complex, and adjuvant techniques (e.g., hyper-

ventilation) and medications (mannitol) often mitigate the possible adverse

effects. In addition, the actual effect of short-term drug-induced ICP increases

on outcome in the operating room is not clear.

Because of the propensity to induce seizures with hypocapnea, enflurane has

largely been abandoned from anesthesia protocols during intracranial surgery.

Based on the effects of the volatile agents in the normal brain, isoflurane,

sevoflurane, and desflurane would appear to be a better choice than halothane

for patients with intracranial pathology. However, neither drug appears to have

adverse effects when hypocapnea is present. Any ICP rises seen with either drug

(both raise ICP during normocapnea) have not been shown to produce adverse

outcomes. Further, studies in rabbits with raised ICP have shown that the two

drugs were identical [65]. This raises the possibility that the differences described

for the drugs in the normal brain are not as clinically significant in the pathologic


brain. Sevoflurane and desflurane would appear to have advantages in intracranial

neurosurgery because of the possibility of faster awakening. At present, these

effects aside, clinical differences between these drugs and halothane or isoflurane

are not clear [19]. It is possible that all of the inhalational agents are actually

similar in patients with intracranial pathology who are at risk for raises in ICP, and

that it is more important how the drugs are used than the specific drug chosen.

The situation with nitrous oxide is probably different. A growing appreciation

of the ability of nitrous oxide to increase CBF and ICP, and the fact that hypo-

capnea does not appear to reduce the effect, has suggested that it may be a poor

choice in patients at risk for high ICP. Certainly, nitrous oxide is a poor choice

when closed air-filled cavities are present (e.g., pneumothorax, air embolism, and

pneumocephalus). At present, ketamine also remains controversial because of

CBF increases and the observation of ICP increases in some patients. However,

contradictory and even beneficial observations have been made suggesting a

possible role for ketamine. At present, ketamine is probably not appropriate as a

sole drug in intracranial neurosurgery.

The issue of the significance of the transient rise in ICP with succinylcholine

in emergency patients remains controversial. Studies in acute head-injured

patients suggest that the advantages for rapid intubation offered by succinylcho-

line may offset the potential disadvantages on the ICP rise (especially when the

magnitude of the rise can be reduced by pretreatment and other techniques which

lower ICP). Another area of controversy with head trauma revolves around the

appropriateness of hyperventilation. With CBF reduced from the trauma, it is

possible that concurrent hyperventilation may produce regional ischemia.

Because the actual circumstance in any given patient is difficult to discern, no

recommendations can be made.

Anesthesia when brain protection is desired

Discussion of anesthetic choice during procedures in which brain ischemia

and stroke can occur has revolved around the possible use of anesthetic agents for

brain protection. The possibility of protection appears to be related, in part, to the

depression of metabolism of the synapse by the anesthetic agents. Barbiturates

have a clear track record for protection during focal ischemia. However, they may

produce delayed awakening from anesthesia. The results of studies with other

agents that can lower CMR by producing burst suppression (e.g., isoflurane,

etomidate, propofol) are less clear. Lidocaine, ketamine, and certain other agents

has been shown to be protective in some models but clinical significance as not

yet been established in humans. Of interest is one study with halothane, in which

CMR depression was associated with better cellular energy stores during

ischemia, but a worse infarct resulted.

These observations suggest that the protective effects of anesthetics are

probably related to mechanisms other than CMR depression. For example,

barbiturates have been associated with free radical scavenging, reduced calcium

flux, reduced cerebral edema, enhancing cyclic AMP production, blocked Na


channels, and other potentially advantageous effects. Because hypothermia also

protects by some of these mechanisms, there is a growing appreciation that

metabolic rate reduction may not be as protective as once thought. Thus,

anesthetic choice in these circumstances probably relates to the other effects of

anesthesia aside from brain protection.

In this context, it should be remembered that ketamine has the property of

increasing CBF. Although this may cause detrimental elevations in ICP when

pathology is present, when the ICP is not an issue the increase in blood flow

might be helpful with ischemia in the same way nitroglycerine is useful in cardiac

ischemia. Theoretically, an increase in flow might also be detrimental by a

‘‘steal’’ of blood from ischemic areas by increasing flow to nonischemic areas.

Sufficient studies are not available at present to determine if or when this property

of ketamine is advantageous when a rise in ICP is not a problem.

Also of interest is anesthetic choice for carotid endarterectomy. EEG monitor-

ing has shown that the mean CBF at which 50% of patients show EEG

abnormalities (so-called critical blood flow) is lower with isoflurane than with

halothane. This has suggested to some that isoflurane may reduce the possibility

of cerebral ischemia. However, no improvement in outcome has been shown.

Anesthetic choice for general anesthesia in these patients probably still remains

focused on cerebral perfusion and considerations for cardiac disease.

Anesthesia where neurophysiological monitoring is conducted

There are clear differences in anesthetic effects on neurophysiologic monitor-

ing. The anesthetic choice depends on the modality of monitoring chosen for the

patient and the other anesthetic considerations applicable to the patient and

surgery [66]. When the choice of anesthetic is not constricted by the pathology

and physiology, the specific effects of the medications on cerebral neurophysi-

ology should be considered.

Because the major target of anesthetic action appears to be synaptic function,

electrophysiological recordings that depend on these structures will be most

susceptible to depressant agents. Hence, monitoring which does not record or

stimulate the cortex and does not record muscle activity has little influence on

anesthetic choice. On the other hand, if recordings are to be taken from the

cerebral cortex (e.g., somatosensory-evoked potentials: SSEP, visual-evoked

potentials), then inhalational agents need to be used in restricted concentrations

(less than 0.5 MAC) unless monitoring suggests larger concentrations are

tolerated and intravenous agents have been titrated to acceptable levels. Opioids

appear to have minimal effects on these recordings, possible because of their

unique mechanism of action.

Etomidate or ketamine may be used to enhance cortical SSEP recordings,

possibly because of an altered balance of effects on the depressant and excitatory

neural pathways. The beneficial effect appears to be restricted to the cortical

recordings of sensory modalities, suggesting that the shift in synaptic balance is

primarily in the cortex.


Routine EEG recording can usually be done with most anesthetics as long as

the doses are not excessive (e.g., where the depressant effects stop the synaptically

produced EEG) (Fig. 16) [67]. However, if the EEG is being recorded for seizure

focus detection, all medications that depress seizure activity must be avoided.

Muscle relaxants are preferred when there is recording from the epidural space

or peripheral nerves, but should be controlled carefully when monitoring record-

ings from muscles (and not used when recording spontaneous or mechanically

elicited muscle responses). Transcranial stimulated motor-evoked potentials

severely restrict anesthetic choice to largely intravenous agents probably due to

the combined anesthetic effects in the cerebral motor cortex and the synapses of the

anterior horn cell of the spinal cord. The anesthetic choice is further complicated by

the need to restrict muscle relaxation so as to record muscle responses. As with the

cerebral cortical responses, etomidate and ketamine appear to make the neuro-

Fig. 16. Stages of EEG for various anesthetics at various doses. Two basic types of anesthetic action are

noted (e.g., EEG activation and EEG depression). (Reprinted fromWinters WD. Effects of drugs on the

electrical activity of the brain: anesthestics. AnnuRev Pharm Toxicol 1976;16:413–26; with permission

from the Annual Review of Pharmacology and Toxicology, volume 16 D 1976 by Annual Reviews

www.AnnualReviews.org. <http://www.AnnualReviews.org>


physiologic environment more favorable for recording these responses. Finally, the

newer multipulse stimulation techniques appear to overcome some of the depress-

ant effects, and that inhalational agents may be usable in some patients at low

concentrations. Clearly, examining the actual monitoring and then holding steady

during periods of neural risk should evaluate the choice of anesthetic.

Summary

The action of anesthetics on the nervous system can be understood by

considering their possible interactions with neuronal function. Anesthesia may

be produced by a change in the balance of inhibitory synapses (notable via

GABAa receptors) and excitatory synapses (notably glutamate receptors). Our

knowledge of the specific mechanisms of anesthetic drugs and the structures in

the CNS remains inadequate to explain the anesthetic state by one mechanism.

The action of anesthetics can also be considered based on the action of the drugs

on cerebral physiology, notably CMR, CBF, metabolic coupling, and autoregu-

lation. Some specific anesthetic recommendations can be made for certain

neurosurgical procedures and pathology based on the effects on physiology.

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Monitors of cerebral oxygenation

Paul R. Smythe, MD, DDS*, Satwant K. Samra, MBBS, MDDepartment of Anesthesiology, University of Michigan Medical Center, 1500 E. Medical Center Drive,

1H247-UH, Box 0048, Ann Arbor, MI 48109, USA

The central nervous system (CNS) differs from other organ systems in that it is

both the intended target of anesthesia and, at the same time, it is the organ system

that is least monitored in anesthetized patients. Intraoperative monitoring is well

recognized as the ‘‘anesthesiologist’s domain.’’ We are able monitor the function

of the cardiovascular, pulmonary, hepatic, and renal systems with varying degrees

of accuracy, but we are not able to know with certainty the neurological status

of the unconscious patient. There are several reasons why CNS monitoring has

not gained popularity among anesthesiologists. CNS monitoring is technically

difficult and demanding, anesthetics interfere with electrophysiological monitor-

ing (adding to the difficulties in interpretation), and there is only limited data to

support the contention that CNS monitoring improves outcome. On the contrary,

there is ample data suggesting that CNS monitoring frequently gives ‘‘false-

positive’’ alarms; that is, the monitor indicates impending CNS injury while the

patients awaken without a neurological deficit even if no intervention is made

based on the abnormalities observed. The pathophysiologic basis that can easily

explain this dichotomy is that neurological deficit results from infarction of

neuronal tissue while alterations in electrical activity of CNS are observed in the

presence of ischemia. Neuronal ischemia does not always lead to infarction.

Cerebral infarction results from a combination of both the severity and duration

of ischemia. Mild ischemia (enough to result in alteration of electrical activity) of

variable duration can be present without cerebral infarction. Fortunately, neuro-

logical complications of anesthesia are rare, unless the surgical procedure itself is

accompanied by significant changes in blood supply of CNS (e.g., cardiovas-

cular, major orthopedic, and neurosurgical procedures). However, neurological

complications, when they do occur, are devastating for the patients and family,

and costly for the society. It is for this reason that there will always be an interest

in the development of user-friendly, reliable, CNS monitoring systems.


PII: S0889 -8537 (01 )00003 -7


E-mail address: [email protected] (P.R. Smythe).


20 (2002) 293–313

Most CNSmonitors are designed to monitor cerebral hemodynamics or cerebral

electrical activity. Monitors of cerebral hemodynamics include the measurement of

intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood

flow (CBF) or cerebral blood flow velocity (TCD). Monitors of CNS electrical

activity include electroencephalography (EEG), sensory-evoked potentials (SEPs),

and motor-evoked potentials (MEPs). These monitors give a warning of lack of

blood (and hence oxygen) supply to CNS and its impact on electrical activity. None

of these monitors are meant to directly measure the presence of oxygen within the

brain tissue. Direct monitoring of brain oxygenation, representing the balance

between cerebral oxygen consumption and supply, may be of greater clinical

utility. There are three monitors of cerebral oxygenation currently in clinical use:

(1) monitoring of jugular venous oxygen saturation (SjvO2), (2) transcranial

cerebral oximetry measuring regional cerebrovascular oxygen saturation (rSO2),

and (3) monitoring of the brain tissue oxygen tension (PbtO2). This manuscript is

devoted to a review of historic developments, underlying technology, limitations,

and clinical use of three monitors of cere-bral oxygenation.

Jugular venous bulb oxygen saturation

History and methodology

The measurement of SjvO2 of hemoglobin was first performed by insertion of

a needle into the jugular bulb located about 1 centimeter anterior and inferior to

the mastoid process. Blood was then analyzed for oxygen saturation of hemo-

globin. A reading of saturation < 50% was deemed ‘‘critical,’’ indicating cerebral

hypoxia. Generally, the technique was used either to calculate arteriovenous

oxygen difference in neurosurgical intensive care units (NICUs) or during carotid

endarterectomy (CEA). A single sample of blood was drawn after occlusion of

internal carotid artery as a monitor to determine the adequacy of collateral blood

flow, and hence, the need for placement of an intravascular shunt. Later, it was

appreciated that taking a single sample was not adequate because cerebral

hypoxia could develop at a variable interval after carotid occlusion. Central

venous catheters were thus placed in the jugular bulb by insertion into the internal

jugular vein and advancement of the catheter in a cephalad direction. Placement

was confirmed radiographycally. This method allowed repeated sampling of

jugular bulb venous blood without repeated needle punctures, and increased the

use of this monitoring both during CEA as well as in patients in NICUs.

Development of in vivo reflectance oximetry (using fiber optic bundles) has

allowed continuous monitoring of SjvO2 without sampling blood except for

initial calibration. Each catheter has at least two optical bundles. One bundle

transmits light into the bloodstream, and second transmits the reflected light to a

photo sensor that is able to distinguish the intensity of the light at various

wavelengths. A computer algorithm uses the relative intensities of appropriate

wavelengths to determine the saturation of hemoglobin in the jugular bulb.

P.R. Smythe, S.K. Samra / Anesthesiology Clin N Am 20 (2002) 293–313294

Catheters with three fiberoptic bundles are able to estimate hemoglobin concen-

tration in addition to determining the relative concentrations of oxy- and reduced

hemoglobin. Catheters with only two fiberoptic bundles must have hemoglobin

concentration values entered into the algorithm. The value of SjvO2 is then

continuously displayed as a percentage of saturated hemoglobin. These techno-

logic advances in development of catheters have made continuous monitoring of

SjvO2 possible, resulting in a rejuvenation of interest in this monitoring in

patients in NICU [1–3].

Hemoglobin saturation in the jugular venous bulb is primarily dependent on

the relative balance of oxygen consumption and oxygen supply to the cerebrum.

The absolute values for cerebral metabolic rate of oxygen consumption (CMRO2)

are impossible to measure directly, and are estimated only indirectly. The absolute

value for oxygen supply is somewhat easier to estimate, but, like oxygen demand,

is remarkably heterogeneous and in a constant state of flux. SjvO2 theoretically

reflects the relationship between global cerebral oxygen supply and global

cerebral oxygen demand. It is therefore possible to miss regional cerebral hypoxia

with this monitoring tool.

In patients with normal CMRO2–CBF coupling, changes in cerebral blood

flow will initially compensate for changes in CMRO2. When changes in CBF can

no longer compensate for increased CMRO2, decrease in SjvO2 will be seen. The

changes in SjvO2 are also different in cases of anemia versus hypoxia. With a fall

in hemoglobin, SjvO2 remains relatively constant until CBF can no longer

compensate for lower oxygen content of arterial blood (CaO2). SjvO2 will then

fall linearly with falling hemoglobin values. With hypoxia, SjvO2 decreases more

linearly immediately after a decrease in CaO2. In brain-injured patients, CMRO2

is approximately half of that of the normal patients [4]. CBF is uncoupled from

CMRO2 in many such patients to an unpredictable degree. CBF can increase or

decrease in response to a decrease in CMRO2. Thus, the CMRO2/CBF ratio may

increase or decrease and, therefore, SjvO2 may increase or decrease in the

presence of decreased CMRO2. As a result, SjVO2 readings in brain-injured

patients become difficult to interpret. Despite the possibility for inaccuracies,

some recommendations are made for interpretation of SjvO2 values. Normal

values range from 55% to 71% (mean 61.8%) in healthy individuals, and any

SjvO2 greater than 50% is considered to be within normal limits [5,6]. An SjvO2

between 45% and 50% is suggestive of mild cerebral hypoxia, while SjvO2

< 45% indicates severe cerebral hypoxia [2,3,7,8]. Jugular venous PO2 equivalent

of an SjvO2 of 40% has been shown to be associated with EEG changes in

humans [9]. Mental confusion has been found to occur when SjvO2 has decreased

below 45%, and loss of consciousness has occurred when SjvO2 has decreased

below 24% [10].

Clinical use

Lack of a ‘‘gold standard’’ with which the accuracy of SjvO2 monitors can be

compared is well recognized. Clinical utility of SjvO2 has therefore been

P.R. Smythe, S.K. Samra / Anesthesiology Clin N Am 20 (2002) 293–313 295

determined either by association with clinical findings in patients in the ICU and

during surgery or SjvO2 readings have been compared with measurements from

other monitors, like transcranial cerebral oximeters and brain tissue oxygen

probes. It is difficult to draw definitive conclusions from these comparisons

because SjVO2 is a monitor of global hypoxia while cerebral oximetry and PbtO2

are monitors of regional hypoxia. Further, it should be emphasized that other

monitors have their own limitations and their own lack of proven validity. There

have been no randomized, prospective clinical trials correlating the use of SjvO2

monitoring with improved clinical outcome. Despite these limitations, availabil-

ity of oximetric catheters has led to a renewed interest in SjvO2 monitoring, and

several clinical studies have been recently published. SjvO2 monitoring has been

used in NICUs in patients with traumatic brain injury and for intraoperative

monitoring during neurosurgical and cardiovascular surgical procedures

Head-injury patients

In patients with traumatic brain injury with a Glasgow Coma Scale (GCS) < 8,

even a single episode of SjvO2 < 50% lasting more than 10 minutes was

associated with doubling of mortality [11]. One episode of desaturation increased

the risk of poor outcome from 55% to 70%.

During anesthesia for neurosurgical procedures

Matta et al [12] have examined the feasibility and usefulness of SjvO2

monitoring during neurosurgical procedures. One hundred patients having

craniotomy for variety of indications were studied. Episodes of desaturation

were discovered in 50–72% of these patients, which would not have otherwise

been detected. This study only reported observations and did not address

differences in outcomes.

During anesthesia for cardiovascular surgical procedures

Intraoperative monitoring of SjvO2 in patients undergoing cardiopulmonary

bypass has undergone extensive study [13–15]. SjvO2 remains normal (or may

increase) during the hypothermic phase of extracorporeal circulation, but desatu-

ration ( < 50%) occurs with rewarming, and is associated with more neurologic

deficits. Desaturation during rewarming is likely to be associated with mean

arterial pressure < 60 mmHg, low hematocrit and rapid rate of rewarming.

Limitations

There are several limitations that make routine use of SjvO2 catheters

less attractive:

1. SjvO2 monitoring is an invasive procedure, and has inherent risks

associated with central catheter placement and maintenance; that is, carotid

artery puncture, bleeding, nerve damage, and infection. SjvO2 catheters are

directed away from the lungs and heart; therefore, there is less risk of


pneumothorax and cardiac arrhythmias when compared to central venous

catheters for hemodynamic monitoring.

2. There can be damage to catheters during continuous use that gives

inaccurate readings.

3. Migration of a catheter is a problem. The catheter may get displaced and

sample blood proximal to opening of the facial vein into the internal

jugular vein. This will result ‘‘false’’ high values of SjvO2, and cerebral

hypoxia may be missed.

4. There is extracerebral contribution to jugular venous blood, which means

that blood from the jugular bulb at least partially represents drainage from

areas other than just the brain. Sources of extracranial contamination in-

clude blood from emissary and frontal veins (via sagittal sinus), ophthalmic

vein, and pterygoid plexus (via cavernous sinus). Facial and retromandib-

ular veins open directly into jugular veins, usually below the jugular bulb.

But they may have an aberrant course with an opening at the level of the

jugular bulb.

5. Rate of aspiration of the blood sample may effect SjvO2 readings. Matta

et al [7] found that the faster the blood was withdrawn from the bulb, the

higher the reading for SjvO2. It is possible that, with the faster withdrawal

rate, more extracerebral blood was incorporated into the sample, but the

reason is not known with certainty.

6. The SjvO2 is a monitor of global oxygenation and not a monitor of regional

ischemia or hypoxia.This means that there may be focal areas of ischemia

that are not detected with a global monitor.

All these limitations have prevented clinical studies that are necessary to

validate the use of SjvO2 as a means of altering treatment in a way that would

improve clinical outcome. Although SjvO2 may be a useful monitor in a limited

set of circumstances, the search for a better monitor will continue.

Transcranial cerebral oximetry

Like pulse oximeters and mixed venous oximeters, development of cerebral

oximeters is based on principles of transmission and absorption of light in a near-

infrared (NIR) spectrum. Cerebral oximetry theoretically offers a technique for

continuous, noninvasive, bedside monitoring that reflects a balance between

cerebral oxygen consumption and supply. These attributes make near-infrared

spectroscopy (NIRS) almost the ideal monitor for monitoring cerebral oxygena-

tion. In addition to differentiation between oxygenated and deoxygenated

hemoglobin based on their light absorption characteristics, NIRS can also

measure the oxidation state of Cytochrome aa3 (Cyt aa3), the terminal cyto-

chrome of the electron transport chain. Indeed, when Jobsis [16] first described a

spectroscopic technique for measuring oxygenation in a tissue bed, he did so by

measuring, in the rat heart and cat brain, the oxidation state not of hemoglobin


but of Cyt aa3. However, transforming the spectroscopic technique developed by

Jobsis into an everyday, easy-to-use bedside instrument has proven to be a

difficult task. Nearly 2.5 decades after Jobsis’s original experiments, there is only

one Federal Drug Administration (FDA)-approved device commercially available

for clinical use in United States, and there is a fair amount of criticism regarding

the performance of that device. As a result, there is some degree of skepticism

surrounding the utility of cerebral oximetry in clinical practice.

Methodology

NIR spectroscopy is based on few relatively simple physical principles:

1. Light in the NIR range readily penetrates skin and bone. A small amount

of light absorption by skin pigments, that is, melanin and bilirubin, is

independent of the tissue oxygenation status, and hence, represents a

source of fixed scattering of light only. However, in cases of severe jaun-

dice, serum bilirubin concentrations can reach levels that will interfere with

NIRS [17].

2. Very few biological substances absorb NIR.

3. Hemoglobin and Cyt aa3 are the only absorbers (chromophores) that show

a detectable change in NIR absorption in response to hypoxia or ischemia.

These, therefore, are the chromophores of interest.

4. Each chromophore has a characteristic and unique (although somewhat

overlapping) absorbance spectrum. For example, oxygenated hemoglobin

(HbO2) absorbs less red light (600–750 nm) and more infrared light (850–

1000 nm) than does deoxygenated hemoglobin (Hb). As a result, Hb has an

absorption peak at 740 nm while HbO2 does not. HbO2 and Hb absorb NIR

of a 810-nm wavelength in equal amounts, and this wavelength of NIR is

referred to as the isobestic point. Similarly, Cyt aa3 has a broad band of

light absorption with a peak at 840 nm. There are also other pigments, such

as cerebrocuprein and erythrocuprein, that change their absorption spectra

when they are bound to oxygen, but these do not have significant ab-

sorption in the NIR range [18,19]. Some other pigments that can absorb

NIR (like nitrosyl hemoglobin, glucose, and indocyanine green) either do

not normally exist in the body or their absorbance is too limited to affect

NIRS spectrometry [20,21].

The basic components of an NIR oximeter are: (1) a light source that can

generate known wavelengths and intensities of NIR light; (2) optical bundles

(optodes) to transmit the light from the source across the tissue site; (3) a light

detector (photo diode or photomultiplier); (4) a computer with proper algorithms

to process the information obtained from the recovered light and translate it into

useful information (i.e., hemoglobin saturation). It should be noted that NIRS

technology can and has been applied to the study of skeletal muscle, heart, and

other organs, and that NIRS can be used for other purposes, such as the


calculation of cerebral blood flow. We shall limit our discussion in this chapter to

the use of NIRS in cerebral oximetry.

Cerebral oximeters can be divided in to two main groups: (a) saturation

monitors, and (b) concentration monitors. Saturation monitors, like pulse oxim-

eters, measure the ratio of hemoglobin and oxyhemoglobin. These monitors do

not include path length in the algorithm used for calculation of rSO2. Concen-

tration monitors measure the amount of oxy- and reduced hemoglobin, as well as

Cyt aa3, and some monitors even incorporate blood volume measurement.

Concentration monitors are further subdivided into relative and absolute concen-

tration monitors. Relative concentration monitors measure a ratio of substrates,

and do not require exact knowledge of the path length.

Two cerebral oximeters have been frequently used in the majority of

published clinical studies: the INVOS series (Somanetics, Troy, MI), and NIRO

500/1000 (Hamamatsu Photonics, UK). These two types of cerebral oximeters

differ in the types of light emitters and light detectors used. The INVOS is a

saturation monitor. It uses a light-emitting diode that transmits NIR at two

wavelengths (735 and 810 nm) as the light source and two silicon photodiodes

(SiPDs) as light detectors. Both the light source and detectors are enclosed in a

common adhesive strip assembly, which is applied to the patient’s forehead.

Two light detectors are placed at a distance of 3 cm and 4 cm from the light

source. The light detected by the closer sensor reads light that has traveled

a shorter distance and is reflected primarily from extracranial tissues like skin

and bone. The light detected by the farther sensor has travelled through both

superficial structures and the cerebrum. Information from the former is ‘‘sub-

tracted’’ from information gained from the latter to exclude extracranial con-

tamination. The light source of the NIRO 500, a relative concentration monitor,

is comprised of four pulsed laser diodes that produce NIR in the range of 775,

825, 850, and 905 nm. The advantage of laser diodes is that the intensity and

wavelength of NIR delivered is more precise. Disadvantage is that laser diodes

are more expensive and add to the cost of the instrument. The light detector

used in the NIRO series of cerebral oximeters is a photomultiplier tube (PMT).

Once again, the PMT amplifies the reflected NIR making the measurements

more accurate than SiPDs. The disadvantage is that PMT requires an additional

connection to the patient, and it must be precisely spaced from the light source;

greater separation allows a reading of deeper tissue but also results in greater

scatter and less accuracy. Because of its high sensitivity, the PMT is more

vulnerable to contamination by ambient light. The advantages of the SiPDs

over PMT are their small size and high efficiency, which allows it to be

mounted as part of the forehead sensor assembly.

Two cerebral oximeters (INVOS and NIRO) measure different things and

provide different outputs for interpretation by the clinicians. INVOS presents a

single numerical value for regional rSO2, persumably of the cerebrovascular

tissue bed under the sensor applied to the forehead. A trend of changes over time

is continuously displayed on the oscilloscope. NIRO-oximeters continuously

display values for reduced oxygenated and total hemoglobin and Cyt aa3. It


should be emphasized that with both types of instruments, monitoring of trends

(changes over time) are more important than absolute values.

Despite the greater sophistication of the NIRO 500, Cho et al [22] found the

INVOS (in its earlier version, INVOS 3100A) to be as accurate as the NIRO,

and Grubhofer et al [23] found the INVOS 3100 to be the more accurate of

the two.

Jobsis used transmitted light, shown across the greatest length of the tissue

beds, in his original experiments. To decrease the path length (to minimize light

attenuation), commercially available instruments use reflected light, measured a

shorter distance from the source of the light. In the reflective method, light passes

across a parabolic path, which can be made longer (deeper) or shorter (shallower),

depending on the distance between the light source and detector. Regional

monitoring of cerebral oxygenation thus becomes possible [24].

There is no gold standard against which to measure the accuracy and validity

of NIRS. There has been much work to best quantify what is being measured by

NIRS and how valid NIRS is. The major difference between pulse oximeters and

cerebral oximeters is that transmission of NIR is ‘‘gated’’ by the arterial pulse in

pulse oximeters but is more or less continuous in cerebral oximeters. Therefore,

pulse oximeters measure oxygen saturation of hemoglobin in arterial blood while

cerebral oximeters measure hemoglobin in the entire tissue bed, which includes a

mixture of brain tissue, arterial, and venous blood. Because the ratio of arterial

and venous blood is about 16:84 and, because this ratio stays the same during

normoxia, hypoxia, and hypocapnia [25,26], NIRS primarily measures cerebral

venous saturation.

Clinical use

Even before cerebral oximeters became commercially available for clinical

use, the first publication of the NIR absorption spectrum of Cyt aa3 by Jobsis in

1977 had stimulated a keen interest of clinicians in this technology, resulting in

quite a few laboratory and clinical studies. In the last decade, the INVOS cerebral

oximeter became commercially available in the United States, and has been more

frequently used in clinical studies from the United States, while NIRO 500 or

NIRO 1000 oximeters have been more frequently used in England and other

European countries. A large body of literature dealing with transcranial oximetry

has thus accumulated in the last 2 decades. However, the majority of publications

are in the form of case reports or a small series of a few patients and number of

well-designed prospective clinical studies clearly showing clinical utility is rel-

atively small. For the sake of brevity, we will review only the pertinent clinical

studies here instead of burdening the readership with an exhaustive review of the

literature on this subject.

Early studies used concentration monitors, which were prototypes instru-

ments, for validation of technology in small animals, and were quickly followed

by clinical studies in pediatric patients in the 1980s. These studies established that

concentration monitors (which used the NIR technology similar to that used in


NIRO 500) were successful in tracking changes in the concentration of Hb,

HbO2, and oxidized Cyt aa3. These instruments used a variety of algorithms and

reported results in arbitrary units, such that it is not possible to compare the

results obtained in different investigations. In these investigations each subject

(patient) acted as its own control. Therefore, one could only track changes in Hb,

HbO2, and Cyt aa3, and it was not possible to define normative data for the entire

patient population. However, combined results of several clinical investigations

[27–33] established that cerebral oximetry, using concentration monitors based

on NIR technology, can track changes in the cerebral oxygen supply and

utilization as well as changes in the intracranial blood volume secondary to

changes in PaCO2, hypoxemia, drug therapy, mental work [34,35], cardiopulmo-

nary bypass, induction of anesthesia, and extracorporeal membrane oxygenation.

Cerebral oxygenation determined by these instruments has been shown to

correlate with cerebral blood flow changes produced by acetazolamide injection

or carotid occlusion [36–38] as well as with PaO2.

More recently, it has been shown that cerebral oximetry with an NIRO 500

type of instrument (NIRO 1000) can register changes in cerebral oxygenation due

to carotid cross-clamping and shunt insertion (during carotid endarterectomy)

without significant contamination from extracranial circulation [39]. A decrease

in HbO2 corresponded with a decrease in middle cerebral artery blood flow

velocity measured by a transcranial Doppler. However, an association (or lack

thereof ) between the decrease in HbO2 and changes in sensorium was not

studied, as the operations were performed under general anesthesia. In patients

with closed-head injury [40], admitted to the neurointensive care unit, it has been

shown that cerebral oximetry (using NIR 1000) successfully detected 97%

episodes of brain hypoperfusion (related to changes in cerebral perfusion

pressure, accompanied by changes in middle cerebral artery blood flow velocity),

while only 53% of the episodes were detected by continuous monitoring of

jugular venous saturation. Although this finding emphasized the potential use of

cerebral oximetry in the neurointensive care unit, it also pointed out the potential

for contamination by electronic artifacts in the ICU setting. In this study, after

886 hours of continuous monitoring, data for only 376 hours (42.4%) could be

considered artifact free. Once again, this investigation did not comment on the

findings of cerebral oximetry and clinical outcome. From a brief review of the

literature it can be seen that lack of outcome studies and the cost and FDA

approval remained major hurdles for widespread clinical use of these instruments

in the United States.

In 1991, Somanetics1 developed a saturation monitor (INVOS series) based

on technology similar to that used in pulse oximeters. Prototype instruments

based on the technology used in the development of INVOS 3100 were validated

first in animals and then in clinical studies [41]. At that time this technology was

different then previously used spectroscopy techniques in that it used a

reflectance mode rather than a transillumination mode of spectroscopy. Since

then, prototypes of NIRO 500 have also been developed to work in the

reflectance mode. It should be emphasized that instruments which use reflect-


ance spectroscopy provide a measure of ‘‘regional’’ rather than ‘‘global’’ cerebral

oxygenation. The second major difference in this category of instruments is that

mathematical modeling used avoids any attempt to generate a definitive value for

the tissue content of a given chromophore, and generates a ratio of two

chromophores, Hb and HbO2. The algorithm used in the calculation of cere-

brovascular saturation (rSO2) measured by INVOS instruments is based on the

assumption that path length is not dependent on wavelength, and remains

relatively constant over a narrow range of NIR wavelengths (between 650 and

850 nm) used in this instrument. Simplification of technology used in the

development of saturation monitors may result in some potential sources of

error. As mentioned before, and common to all instruments, the effect of light

reflection and scattering is unknown. Another potential limitation of the

measurement obtained is the validity of using a molar extinction in vivo that

is inferred from in vitro work. The assumption that path length remains constant

for NIR in wavelengths used may not be absolutely correct. The potential

influence of contamination by extracranial blood flow and changes in cerebral

blood flow and intracranial blood volume secondary to head injury or surgical

trauma remains unknown. These limitations in technology were somewhat off set

by the small size suitable for bedside use, low cost, user friendliness, and easy

availability in the United States. A fair number of clinical studies have been

conducted in recent years using INVOS monitors, with controversial results.

These investigations have also been conducted during a time when the monitors

and the sensors used with those monitors were being constantly upgraded. It is,

therefore, difficult to compare the results reported in different studies even

though the same equipment was used. One can say that, in a sense, the FDA

approval of this instrument was somewhat premature, as became evident by the

fact that in 1994 FDA rescinded the approval and required further data

collection, and has only very recently (June 1996) approved this device again

for clinical use in adult patients only. The clinical studies using this device

between 1991 and 1994 have reported mixed results regarding the efficacy of

prototypes of this device. Results of these studies are briefly reviewed below.

McCormick and associates [42] demonstrated the sensitivity of rSO2, measured

by INVOS, to transient cerebral hypoxia produced by inhalation of a hypoxic gas

mixture in humans. Ausman and associates [43] used INVOS to monitor rSO2 in

seven patients undergoing intracranial aneurysm surgery facilitated by deep

hypothermic circulatory arrest. They observed that circulatory arrest at 18�C was

associated with a significant progressive decrease in rSO2. In five patients with

no neurological damage, rSO2 remained above 35%, and in one who had rSO2

less than 35% there was postmortem evidence of global cerebral hypoxia. They

suggested that a value of rSO2 of 35% may be critical, and values below that

may be used to predict poor neurological injury. We [44] have reported a patient

in whom an rSO2 reading of 32% was observed for 15 minutes during 30 minutes

of induced deep hypothermic circulatory arrest, without development of any

neurological deficit. Williams and associates [45] have reported a significant

correlation among SjvO2, rSO2, and middle cerebral artery blood flow velocity


during carotid cross-clamping in patients undergoing carotid endarterectomy

under general anesthesia.

Carotid endarterectomy (CEA) is potentially a human model of regional

cerebral ischemia, and hence, provides an ideal opportunity for validation of

rSO2 as a monitor of cerebral ischemia. It is therefore not surprising that cerebral

oximetry has been used in multiple studies in patients undergoing CEA. Un-

fortunately, most of these investigations have been done in patients under general

anesthesia, and performance of cerebral oximeters has been compared to other

monitors (SjvO2 EEG, SEPs, and TCD) that have their own limitations and

pitfalls. We have recently studied rSO2 changes in patients undergoing carotid

endarterectomy under regional anesthesia in two separate investigations [44,46],

and attempted to determine if there is an association between a decrease in rSO2

and development of a clinically detectable neurological deficit. In the first

investigation we observed a + 2.6% to � 28.6% change in ipsilateral rSO2

following carotid occlusion, but we were unable to identify a critical change that

may be associated with a clinically identifiable neurologic deficit. In a larger

series we determined that a mean ipsilateral decrease in rSO2 after carotid

occlusion was significantly greater (12.2 versus 4.8 units) in patients who

developed clinical signs suggestive of cerebral ischemia than in those who did

not. A 20% decrease (from preclamp value) after carotid occlusion provided the

best sensitivity (80%) and specificity (82.2%) for predicting cerebral ischemia.

The false-positive rate of this cutoff point was 66.7% and false-negative rate was

2.3%, thus providing a positive predictive value of 33.3% and a negative

predictive value of 97.4%.

Several investigators [47,48] have reported a lack of correlation between rSO2

readings recorded by INVOS and jugular bulb oxygen saturation (SjvO2)

measured by indwelling oximetric catheters. Such a lack of correlation is not

entirely surprising when one considers the fact that rSO2 reflects a regional value

while SjvO2 is a global measurement. In other words, the two are measuring

similar but not the same phenomenon. Lack of correlation between rSO2 and

SjvO2 may also suggest a limitation of the current algorithm used, which has

been recently validated by Pollard and associates [49,50]. rSO2 measured by

INVOS has also been reported to change with a change in PaCO2 as well as a

change in position (Trendelenburg) of the subject [51]. Some investigators

[48,52] have proposed that rSO2 readings recorded by INVOS-3100 are signifi-

cantly affected by changes in extracranial blood flow. Germon et al produced

changes in extracranial blood flow either by application of a tourniquet around

the forehead or by constant exercise of the temporalis muscle. Both these

maneuvers are capable of adding potential sources of error either by venous

congestion of the scalp or by movement artifact due to repeated muscle con-

tractions. We have assessed the contribution by extracranial blood flow to rSO2

recorded by INVOS by studying the changes in rSO2 in response to selective

clamping of external and internal carotid arteries. A mean decrease in rSO2 (from

67.4 ± 8.5 to 65.6 ± 8.3) after external carotid artery occlusion was not

statistically significant, while that following internal carotid artery (65.6 ± 8.3 to


61.4 ± 9.6) was significant [53]. These data suggest that although the algorithm

used in INVOS does not entirely eliminate extracranial contamination, the rSO2

readings provided by this oximeter are predominantly derived from the intracra-

nial compartment. Lam and associates [54] have reported similar findings using

NIRO 500.

Recent case reports have suggested that cerebral oximetry may be useful in

monitoring response to therapy in patients with intracranial vasospasm [55,56].

However, more rigorous investigations are required before any firm conclusions

can be drawn.

An investigation by Schwarz et al has supplied data that is interesting and also

disturbing [78]. These investigators used INVOS 3100 to measure rSO2 in

18 dead subjects and 15 healthy volunteers. The mean value for rSO2 in dead

subjects was 51 ± 26.8% compared to 68.4 ± 5.2% in volunteers. Six of the

dead subjects had values above the lowest values observed in healthy volunteers.

In five dead subjects, after removal of the brain at autopsy, a mean rSO2 reading

of 73.4 ± 13.3% was noted. This is an unusual use of transcranial cerebral

oximetry, and one for which this technology is not designed.

Based on the review of published literature, a few general statements can be

made regarding clinical use of cerebral oximeters:

1. Cerebral oximeters are only trend monitors where each patient acts as his/

her own control and no normative or comparative data applicable across

the entire patient population are available. Basically, these monitors

provide a number (or set of numbers) that still awaits accurate inter-

pretation and utility in clinical practice.

2. The use of prototype instruments and changing technology as the instru-

ments are being constantly upgraded adds to the difficulty in interpreting

results and in comparing the results of different studies. Instrumentation

used in many studies is not commercially available.

3. Only a few studies [43,46] have attempted to study the role of cerebral

oxygen saturation monitoring in predicting neurologic outcome in small

numbers of patients, and the data are far from conclusive. It is fair to

conclude that, at present, there are very few sizable prospective studies

evaluating the place of cerebral oximetry in either predicting or improving

the clinical outcome.

Limitations

Limitations of NIRS are the limitations of the technology itself. The most

important limitation may be the lack of definition of the boundaries of the brain

tissue being monitored. Superficial tissues will give the most accurate readings,

yet those tissues are usually of the least interest. Constructing an algorithm to

compensate for all the variables is a formidable task. The lack of a gold standard

against which to test such an algorithm makes validation difficult. More

prospective outcome studies involving sufficient numbers of patients are needed.


Lactate is the byproductof anaerobic glucose metabolism, and its accumula-

tion in cerobrospinal fluid is an indication that oxygen availability to the brain has

decreased to a level that cannot support aerobic mitochondrial respiration.

Menzel et al [76] used a Neurotrend probe in severe head-injury patients to

study, among other things, the effects of increased FiO2 and increased CBF on

PbtO2 and lactate levels in dialysate. Oxygen reactivity was calculated by a

change in PbtO2 in response to increased FiO2. Oxygen reactivity was then

related to clinical outcome 3 months later. Under normoxic conditions, there was

significant correlation between CBF and PbtO2, while FiO2 had an inverse

correlation with CBF. Under hyperoxic (FiO2=100%) conditions PbtO2 increased

and lactate in dialysate decreased, but the increase in PbtO2 was more

pronounced (87%) than the decreased in lactate (38%). Surprisingly, PbtO2

response to hyperoxia was also inversely related to the outcome at 3 months.

Taking that study a step further, Valadka also used intracerebral microdialysis as

well as PbtO2 and cerebral concentrations of lactate, glucose, glutamate, and

aspartate in five patients with refractory intracranial hypertension after severe

head injury. Glutamate and aspartate are intracellular amino acids that are

released with cellular necrosis. Lactate/glucose ratios correlated well with PbtO2

[77]. The group also noted that

Cerebral oxygen tension monitors

Monitors of PbtO2 have been developed as a modification of small intra-

vascular electrodes that were originally designed for continuous arterial blood gas

monitoring in patients with severe pulmonary disease, who required prolonged

mechanical ventilation. These monitors place a miniaturized oxygen detector

directly over or into brain parenchyma. The readings are direct, focal, and

accurate. For the measurement of oxygen tension within the brain matter

surrounding the oxygen probe, this is as close to a gold standard as we now

have [57].

Methodology

Currently, probes made by two manufacturers are available for PbtO2

monitoring. The Licox probe (G.MS. Kiel-Mielkendorf, Germany) consists of

a miniaturized Clark-type polarized amperometric (also known as ‘‘polaro-

graphic’’) circuit separated from brain tissue by a membrane across which only

oxygen can diffuse. The oxygen sensor is at the very tip of the catheter. The

catheter is 0.8 mm in diameter. The probe monitors oxygen tension in 7.9 sq mm

of brain tissue. The catheter is normally placed into the frontal cortex and held in

place by a screw in the frontal bone. The Neurotrend probe (Diametrics, St. Paul,

MN) has been developed as a modification of the multiple electrode system

(paratrend) that was originally designed for intra-arterial insertion for continuous

monitoring of arterial blood gasses. The Neurotrend probe combines fiber optics,


a modified Clark-type oxygen sensor, as well as carbon dioxide and hydrogen ion

concentration sensors (spectrophotometry), and a thermocouple temperature

sensor. The oxygen sensor on the Neurotrend is about 2.5 mm from the catheter

tip, which means the catheter must be placed at a greater depth in to the brain

parenchyma (than the Licox probe) to measure oxygen tension. This makes it

difficult to know (with certainty) whether the oxygen sensor is in gray or white

matter of the cerebral cortex. The catheter width is 0.5 mm, and is placed in a

manner similar to the Licox catheter [58].

Validation and clinical use

Dings et al [59,60] have extensively studied the Licox probes (one series of

118 probes in 101 patients and another in a series of 73 probes in 70 patients).

They found only two iatrogenic hematomas and no infections after an average of

6.7 days of monitoring. After 7 days of monitoring, a drift was found to occur in

the readings (a sensitivity drift of � 10.3 ± 17.3% in the first 1–4 days of use to

� 6.8 ± 13.4% after a week). No infections were seen, and the only complica-

tions noted were four clinically insignificant hematomas. In the larger study,

dislocation of or defect in the catheter occurred 13.6% of the time.

Sarrafzadeh et al [61] did a side-by-side comparison of the Licox and

Paratrend probes in seven severely head-injured patients (GCS < 8). Probes were

placed in various combinations into nonlesioned, pericontusional, or contusioned

brain tissue, and catheter position was checked with a CT scan. In similar tissue,

there was a close correlation of readings obtained by the two probes (mean

difference of < 5 mmHg after 20 hours of monitoring). A similar decrease in

readings was observed during periods of significant reductions of mean arterial

blood pressure and CPP. They noted that the contusioned and pericontusional

regions had the lowest oxygen readings and were, therefore, most at risk for

reinjury. However, they also noted that these injured areas were less reactive to a

significant decreases in CPP than areas of noninjured brain. Their conclusion was

that probes should be placed in nonlesioned areas because those areas were most

responsive to changes in oxygen delivery.

Critical values of PbtO2

Most of the clinical studies with PbtO2 have involved the patients in NICU,

and have attempted to correlate the observations of PbtO2 with clinical outcome.

Valadka et al [62] used either a Licox (n = 39) or Paratrend (n = 4) probe in 43

severely head-injured patients. PbtO2 data were analyzed by comparing average

time duration for which PbtO2 was < 2, 4, 6, 8, 15, or 20 Torr, and its association

with outcome as determined by survival, 3 months after initial head injury. It was

concluded that the likelihood of death increased with increasing duration of

PbtO2 < 15 Torr or with any occurence of PbtO2 < 6 Torr.

Bardt et al [63] studied 35 patients with severe head injury and found that

56% of the patients with more than 300 minutes of PbtO2 < 10 mmHg died,


22% had an unfavorable outcome, and 22% had a favorable outcome. In a

study of 22 patients with severe head injury van Santbrink et al [64] found that

PbtO2 values of � 5 mmHg within 24 hours after trauma were associated with

poor outcome.

Doppenberg et al [65,66] have attempted to determine a ‘‘critical’’ value of

PbtO2 that will be associated either with cerebral infarction (in cats) or cerebral

ischemia or poor clinical outcome in humans. Cerebral infarction was produced

by occlusion of middle cerebral artery in cats. In humans, regional CBF was

measured using a stable Xenon-CT.CBF technique. In the model of cerebral

infarction (after 4–6 hours of MCA occlusion), observed values of PbtO2 were

between 19–23 Torr. CBF decrease to ischemic threshold (18 mL/100 g/min) in

humans was also accompanied by PbtO2 reading of 22 Torr. They, therefore,

suggested that PbtO2 values between 19–23 should be considered critical, and

are likely to be associated with cerebral ischemia.

Critical values for cerebral perfusion pressure/CCP to maintain PbtO2

Several authors have used PbtO2 probes to study the effect of raising

cerebral perfusion pressure either by increasing mean arterial pressure or

lowering intracranial pressure [67–71]. The conclusions were strikingly similar.

PbtO2 was best maintained with a CPP of 60 mmHg. Raising it above that

figure did not improve oxygenation. Further, the best way of raising CPP was

by increasing mean arterial pressure. Using hyperventilation or mannitol

successfully raised CPP by lowering ICP, but the use of those modalities

caused a decrease in PbtO2.

Effect of inhaled anesthetics on PbtO2

Hoffman et al [72–75] have performed a series of studies comparing the effect

of an intravenous anesthetic with that of an inhaled anesthetic on PbtO2. In each

case, the i.v. anesthetic (Pentothal, etomidate, or propofol), in a dose sufficient to

produce EEG burst suppression, produced a lowering of PbtO2. This is to be

expected, because these agents lower cerebral metabolic rate, decrease cerebral

blood flow, and, therefore, decrease oxygen delivery to the brain. When the

inhaled anesthetic was used at a high dose (i.e., 3% isoflurane), PbtO2 was found

to rise from baseline in each case. The conclusion was that high-dose isoflurane

(or desflurane) had an attenuating effect on CMRO2–CBF coupling. This is not

surprising, and is in keeping with known effects of inhalation anesthetics on CBF

and CMRO2. The importance of cerebral CMRO2–CBF coupling was also

emphasized in a study by van Santbrink et al [64] using PbtO2 in patients with

severe head injury, who found that a significant rise in PbtO2 following an increase

of FiO2 to 100% was associated with a bad outcome. The authors suggested that

the loss of CMRO2–CBF coupling may reflect severity of cerebral injury.


Effect of change of PBTO2 on lactate levels

Lactate is the byproduct of anaerobic glucose metabolism, and its accumula-

tion in cerebrospinal fluid is an indication that oxygen availability to the brain has

decreased to a level that cannot support aerobic mitochondrial respiration.

Menzel et al [76] used a Neurotrend probe in severe head-injury patients to

study, among other things, the effects of increased FiO2 and increased CBF on

PbtO2 and lactate levels in dialysate. Oxygen reactivity was calculated by a

change in PbtO2 in response to increased FiO2. Oxygen reactivity was then

related to clinical outcome 3 months later. Under normoxic conditions, there was

significant correlation between CBF and PbtO2, while FiO2 had an inverse

correlation with CBF. Under hyperoxic (FiO2 = 100%) conditions PbtO2 in-

creased and lactate in dialysate decreased, but the increase in PbtO2 was more

pronounced (87%) than the decrease in lactate (38%). Surprisingly, PbtO2

response to hyperoxia was also inversely related to the outcome at 3 months.

Taking that study a step further, Valadka also used intracerebral microdialysis as

well as PbtO2 to study the relationship between PbtO2 and cerebral concen-

trations of lactate, glucose, glutamate, and aspartate in five patients with re-

fractory intracranial hypertension after severe head injury. Glutamate and

aspartate are intracellular amino acids that are released with cellular necrosis.

Lactate/glucose ratios correlated well with PbtO2 [77]. The group also noted that

glutamate and aspartate concentrations both correlated with PbtO2, and did not

rise until PbtO2 reached zero in these fatally injured patients. Glucose concen-

trations lagged behind PbtO2, and continued to decline for a short time after

PbtO2 reached zero. An increases in extracellular glutamate and aspartate were

not observed until both oxygen and glucose concentrations reached zero, sug-

gesting that glucose is used by the cells anaerobically once oxygen is depleted so

as to maintain structural integrity.

Limitations

The main limitation of PbtO2 monitoring is the fact that it is an invasive

procedure involving puncture of the brain parenchyma. It is, therefore, reserved

for patients who have either had severe traumatic injuries or are undergoing

neurosurgical procedures. Once the probe is properly in place, complications

have proven to be few. The Licox probe appears to be less likely to cause

complications because it is applied less deeply into brain tissue, while Neurotrend

probes will have to be inserted to a depth of at least 3 mm.

Summary

None of the monitors of cerebral oxygenation discussed above has proven to

be effective enough to have become a standard of care in any given area of

medical treatment. As described above, each has specific and well-defined

shortcomings that prevent its widespread use. These shortcomings may not be


so much a failure of technology as an acknowledgement of the complexity of our

goal: a monitor that can divide the entire brain into small, focal, and discrete areas

and accurately measure the oxygen tension in each one. Because we are asking

for the functional equivalent of 30 or 40 simultaneous PbtO2 probes, it is small

wonder that we are not yet satisfied.

Of the three monitors discussed here, the greatest potential may lie with the

transcranial cerebral oximetry. The cerebral oximeter has the biggest potential for

improvement because it holds the most potential for technical advancement.

Although, for instance, jugular venous bulb oximetric catheters may become

somewhat more accurate, the biggest drawbacks in that monitor’s usefulness lie in

human anatomy and intracerebral blood mixing, not catheter accuracy. PbtO2

probes, also, have little room for improvement. Although every technology can be

refined, the PbtO2 probes are already accurate. The fact that they are an invasive

monitor, and a regional one at that, will relegate them to a limited number of cases.

Cerebral oximeters hold more potential. Their greatest limitations lie in technical

aspects that can be, and hopefully will be, improved upon in terms of computer

technology as well as algorithm accuracy. The fact that cerebral oximeters can be

used on any patient, at any time, on almost any case, makes it, potentially, truly an

ideal monitor for anesthesiologists and intensivists alike. There is no certainty that

any of these limitations will be surmounted, at least to the degree necessary to

achieve desired accuracy. But there is much to anticipate.

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Brain protection during neurosurgery

Verna L. Baughman, MDDivision of Neuroanesthesiology, Departments of Anesthesiology and Neurosurgery,

University of Illinois at Chicago, Suite 3200, 1740 W. Taylor Street (M/C 515),

Chicago, IL 60612, USA

Protecting the brain from ischemia during neurosurgery is one of the most im-

portant concerns for anesthesiologists. It is amazing that, to my knowledge, there

is a paucity of prospective randomized controlled clinical trials comparing

different treatments upon which to base cerebral protectant therapy. However,

there is a wealth of laboratory research, both in vivo and in vitro, which supply the

neuroanesthesiologist with theories that guide the management of patients at risk

for cerebral ischemia.

There are three major themes to this chapter. The first section reviews the

research that led to the establishment of barbiturates as the gold standard for

cerebral protection. The second discusses current methods of providing intra-

operative cerebral protection. The third examines new and exciting possibilities

regarding therapy/drugs that may become important tools in the future for

cerebral protection.

The past: the development of barbiturates as the gold standard for

cerebral protection

A brief examination of the historical sequence of barbiturate use for cerebral

protection provides insight into not only the choice of this drug category but also

the proposed mechanisms of ischemia. The classic theory of cerebral protection is

based on the concept that by decreasing cerebral metabolic demand, the neuronal

survival will improve during periods of inadequate cerebral blood flow (CBF).

Because barbiturates decrease cerebral metabolism, it was the first drug group to

be considered as a potential cerebral protectant.

In the 1970s Michenfelder demonstrated that barbiturates decreased cerebral

metabolic activity in a dose-dependent manner, which produced a progressive

decrease in EEG activity, a reduction in the rate of ATP depletion, and protection


PII: S0889 -8537 (01 )00004 -9

E-mail address: [email protected] (V.L. Baughman).


20 (2002) 315–327

from incomplete cerebral ischemia [1–3]. Elimination of the metabolic require-

ment for EEG activity permitted this energy to be available for neuronal basal

metabolic needs. Current clinical practices of providing cerebral protection are

based on this concept. When the EEG is isoelectric, neuronal energy consumption

is decreased by approximately 50%. Therefore, with barbiturate treatment to an

isoelectric EEG during ischemia, all metabolic energy is used for maintenance of

cellular integrity. Additional barbiturate dosing produces no further reduction in

cerebral metabolism.

An early study by Bleyaert [4] supported the use of barbiturates as a

cerebral protectant. Using a neck tourniquet to completely eliminate blood

flow to the brain, the authors reported good neurologic outcome in barbiturate-

pretreated (thiopental, 90 mg/kg) monkeys compared to control animals. How-

ever, when Gisvold [5] repeated this experiment he was unable to reproduce

the positive results. This difference is probably due not to the drug treatment

but rather to the postoperative care. In the first study the barbiturate-treated

monkeys remained intubated and ventilated following reperfusion due to the

large barbiturate dose, whereas the control animals were extubated early and

returned to their cages without additional oxygen or intravenous fluids. In

the second study both barbiturate and control animals received similar post-

ischemia care. The difference in outcome disappeared when both groups

received identical ICU supportive treatment. In both studies EEG activity

disappeared with the initiation of complete cerebral ischemia (neck tourniquet

inflation), so it is reasonable to conclude that the drug-induced suppression of

EEG metabolic activity was immaterial because the EEG was abolished by the

study design.

The Brain Resuscitation Clinical Trial [6] confirmed the lack of barbiturate

protection in humans following complete absence of CBF. After resuscitation from

cardiac arrest patients were randomized to receive either thiopental (30 mg/kg,

infusion over time as blood pressure would permit) or saline. Mortality was high in

both groups (77% versus 80%). This human experiment confirmed that barbitu-

rates were ineffective in preventing or ameliorating cerebral ischemic damage that

occurred in the setting of complete ischemia (ie, no blood flow to the brain). With

cessation of CBF, the EEG becomes isoelectric within 1–2 minutes. Therefore,

any drug that suppresses EEG activity will be ineffective because the EEG is

already isoelectric.

Following up on the theory that barbiturates work only during incomplete

ischemia (ie, when EEG activity is still present during the ischemic period),

Nussmeier examined the protective potential of barbiturates when CBF was

substantially decreased but not completely interrupted [7]. She randomized

normothermic cardiac surgery patients to either thiopental 39.5 mg/kg infusion

or placebo. Neurologic outcome was improved in thiopental-treated patients

having valve replacement operations (in which the left ventricle was open, which

presumably resulted in cerebral air emboli with the reestablishment of circula-

tion). Zaidan [8] replicated Neussmeier’s study; however, he used hypothermic

cardiopulmonary bypass and found no difference between the two groups. The

V.L. Baughman / Anesthesiology Clin N Am 20 (2002) 315–327316

most logical explanation for the difference in outcome between these two cardiac

surgery studies is that the barbiturate protective effect was invisible in the face of

the hypothermia treatment.

Summary

The conclusions derived from this research have shaped our clinical approach

to cerebral protection. Barbiturates decrease cerebral metabolism in a dose-

dependent manner until the EEG becomes isoelectric. Additional drug doses after

an isoelectric EEG provide no additional metabolic depression. Barbiturates

provide cerebral protection in the face of incomplete ischemia, but not with

complete cessation of CBF (complete ischemia). In situations where CBF is

completely arrested, EEG activity disappears within 90 seconds, so the admin-

istration of a drug to depress EEG metabolic activity would be irrelevant.

The present: current cerebral protection treatments

One would expect any anesthetic that depresses cerebral metabolism and EEG

activity to be similar to barbiturates in providing cerebral protection from

ischemia. The following section reviews current anesthetic drugs and evaluates

their potential for cerebral protection.

Etomidate

Etomidate, an intravenous sedative-hypnotic, is similar to barbiturates in

decreasing cerebral metabolism progressively until an isoelectric EEG appears

[9]. Unlike barbiturates, etomidate has very little effect on blood pressure, and a

short duration of action. For these reasons it was frequently used as a cerebral

protectant because it produced approximately 50% reduction in cerebral oxygen

demand while preserving cerebral perfusion pressure. Etomidate has demonstrat-

ed protection in some laboratory research models [10–12]; however, the results

are not universally positive [13,14], suggesting that etomidate might provide

protection only during mild to moderate ischemia. In some animal models,

etomidate initially decreases CBF to a greater degree than cerebral metabolism,

potentially putting the brain at risk of inadequate substrate delivery [15]. It

must also be remembered that etomidate produces adrenal depression (inhibition

of 11-B-hydroxylase), which caused increased mortality when it was used as a

continuous infusion for sedation in the ICU [16]. This inhibition lasts 4–6 hours

with a single dose, but is prolonged with continuous infusion or in elderly

critically ill patients [17].

Propofol

Propofol, introduced into clinical practice in the late 1980s, depresses cerebral

metabolism in a dose dependent manner, similar to barbiturates, producing

V.L. Baughman / Anesthesiology Clin N Am 20 (2002) 315–327 317

isoelectric EEG at clinically relevant doses [18]. Rapid emergence from burst

suppression EEG may permit more accurate postanesthesia neurologic evalu-

ation. It has been used to provide brain protection in multiple laboratory studies;

however, no clinical studies compare its cerebral protection potency to barbitu-

rates. Because propofol has significant negative inotropic activity in addition

to vasodilatory properties, it can decrease cerebral perfusion pressure when

a large dose is administered over a short period of time. Propofol has been

shown to be superior to fentanyl–nitrous oxide anesthesia in a rat model of

incomplete ischemia [19] and equal to halothane in a regional cerebral ischemic

rat model [20]. Additionally, propofol may afford cerebral protection by its

antioxidant potential [21] or by acting as a glutamate antagonist at the N-methyl-

D-asparate (NMDA) receptor [22].

Opioids

Narcotic-based anesthesia has been a foundation for neuroanesthesia because

opioids have little effect on cerebral metabolism and blood flow while supporting

the cardiovascular system and cerebral perfusion pressure. Some literature ques-

tions the safety of narcotics (increased intracarnial pressuse—ICP) [23]. These

changes are small, and appear to be due to cerebral vasodilation in response to a

decrease in blood pressure [24]. Maintenance of blood pressure appears to reduce

or eliminate the mild increase in ICP. It has been reported that large doses of

opioids can produce seizure activity in animals [25]. However, the wide-spread

use of opioids in neuroanesthesia without evidence of seizure activity speaks to

the safety of this class of drugs. Evidence as to whether opioids produce neuro-

protection and the possible mechanism of this action is lacking.

Benzodiazepines

Benzodiazepines also depress cerebral metabolism in a dose-response manner;

however, they are not as potent as barbiturates (maximal decrease in cerebral

metabolism is 25–30%), and do not produce isoelectricity [13,26]. Because they

are unable to maximally suppress EEG activity, they have not been seriously

considered for cerebral protection.

Ketamine

Ketamine is a controversial drug in neuroanesthesia because it has been shown

to increase both cerebral metabolism and blood flow [27]. Animal studies re-

garding the effectiveness of ketamine as a cerebral protectant are both supportive

[28,29] and contradictory [30]. Recently, however, ketamine has been proposed

as an anesthetic drug that may provide cerebral protection because it blocks the

NMDA receptor, which is highly activated via enhanced excitatory neurotrans-

mitter release during ischemia [31]. In vitro studies show ketamine can also

interfere with transmembrane calcium influx [32]. Initial concern that ketamine


increases intracranial pressure in spontaneously breathing subjects has been

eliminated by demonstrating no increase in pressure when administered to

anesthetized, ventilated patients [33]. Ketamine’s place as a neuroprotectant is

still debatable.

Nitrous oxide

Nitrous oxide has been used in neuroanesthesia for many years. Its rapid on/

off action makes it a useful addition to the anesthetic plan. Despite its track

record, nitrous oxide possesses undesirable characteristics. Nitrous oxide

increases CBF, which could cause problems in patients with increased intracra-

nial pressure [34,35]. When used alone, nitrous oxide can increase CBF by 37%

and cerebral metabolism [36]. When used in combination with inhalational

anesthetics, the CBF increase persists, but to a lesser degree [37]. Whether these

vascular effects translate into ischemic injury is debatable, with some animal data

demonstrating worse outcome [38] while other studies show no effect [39].

Because it readily diffuses into air containing spaces, and because pneumo-

cephalus is evident in computerized tomography (CT scans) for up to 2 weeks

postcraniotomy, nitrous oxide should not be used during this time frame. Whether

or not the use of nitrous oxide is harmful has not been established in clini-

cal studies.

Inhalation anesthetics

Almost all of the inhalational anesthetic agents are similar to barbiturates in

producing progressive EEG depression in a dose-dependent manner until

obtaining electrical silence. This occurs at approximately 1.5–2 MAC. Concur-

rent with EEG suppression is a reduction in cerebral metabolism by approx-

imately 50% when the EEG is isoelectric. Because of this similarity to

barbiturates, inhalational anesthetics are frequently used for cerebral protection.

They produce less cardiovascular depression than the barbiturates, and are more

rapidly eliminated at the end of surgery. The exceptions are halothane and

enflurane. Halothane requires about 4 MAC for isoelectricity, which is clinically

impractical. Halothane also increases intracranial pressure by cerebral vaso-

dilation unless hyperventilation is initiated prior to the introduction of halothane.

Enflurane has been reported to produce seizure like activity on EEG, especially

when paired with hyperventilation.

Are there differences among the inhalational anesthetics in brain protection?

Laboratory and clinical studies suggest that they all provide cerebral protection,

but a direct comparison among all of the agents is lacking. Are they as good or

better than barbiturates? Multiple experiments have compared inhalational

anesthetics to barbiturates and other intravenous drugs. The results are variable.

A comparison between desflurane and thiopental in neurosurgical patients

showed an increase in brain oxygen (using a brain probe) with desflurane

when both were administered to EEG burst suppression [40]. Blood pressure


was supported to maintain adequate CBF due to a loss of autoregulation. Are

these results drug specific or do they reflect the cerebral vascular effects of

these drug categories? A recent isoflurane study reported on its ability to mod-

ulate release of excitatory neurotransmitters and delay apoptosis (programmed

cell death), which may provide a window of opportunity for the administration

of other protective agents [41]. Detailed neuropsychiatric outcome studies are

needed to determine if there is a difference in neuroprotection among the

inhalational agents.

Temperature

The beneficial effect of hypothermia is well known. Hypothermia has long

been used during cardiopulmonary bypass and circulatory arrest surgery to

provide protection from cerebral ischemia. Initially it was felt that hypothermic

protection was based on a significant decrease in cerebral metabolism, allowing

the neurons to exist in almost a suspended energy consumption state. However, it

has subsequently been shown that profound hypothermia is not required to

protect the brain. Even mild levels have proven to be protective [42–44]. For

example, with rat global ischemia studies, marked hippocampal injury was seen

in 100% of rat brains following 20 minutes of ischemia when tested at 36�C.The injury decreased to 20% when studied at 34�C and 0% at 33�C [45]. This

protective effect, which has been reproduced by many investigators, cannot be

explained by changes in energy consumption during ischemia. For every degree

Centigrade decrease in temperature, cerebral metabolism is reduced by 5–7%.

Therefore, a reduction in temperature from 37�C to 34�C produces a 15–20%

reduction in cerebral metabolism, which is far less than the 50% decrease seen

with EEG silence. Obviously hypothermia’s protective effect is not mediated

solely by metabolic depression. Proposed mechanisms include suppression of

glutamate release [46,47], blunted nitric oxide production [48] which is involved

in producing oxygen free radicals, formation of free fatty acids [46], reduced

calcium influx [49], and increased gamma-aminobutyric acid (GABA) release

during ischemia. Glutamate release is increased 10-fold when temperature is

increased to 39�C during ischemia [45,50].

Unfortunately, intraoperative cerebral temperature is usually not monitored.

Instead, temperature is measured with esophageal, bladder, rectal, or tympanic

membrane probes. Even pulmonary artery catheter measurement may not be

reflective of cerebral temperature. To compound this problem, brain temper-

ature during surgery varies from cortical surface to deep intracerebral. It is

frustrating that a brain protectant therapy with few side effects is so difficult

to correctly implement because of our inability to measure the temperature of

the brain region at risk for ischemia. If this were possible, the local cooling

methodologies could be used instead of subjecting the entire body to hypo-

thermia. Currently, a multicenter study evaluating the effect of normothermic or

mild hypothermic management during cerebral aneurysmal clipping is under-

way [51]. This is the first time that a study sufficiently large enough to


evaluate a single intraoperative manipulation on neurologic outcome in humans

has been initiated.

Blood pressure

Control of blood pressure is possibly one of the most important aspects of

preventing brain injury and promoting cerebral protection. The direction and

extent of this control depends on the surgical procedure. For example, if an-

eurysm clipping includes trapping the aneurysm, maintenance of normal or

slightly increased blood pressure is indicated to increase collateral perfusion to

the area of brain transiently robbed of it blood supply due to the temporary clip.

Conversely, a reduction of blood pressure during direct aneurysm clipping may

reduce the intra-aneurysm pressure and decrease its potential for rupture during

surgical manipulation. Similarly, maintenance or increasing blood pressure

during carotid endarterectomy or the anastomosis of an extracranial-intracranial

(ECIC) bypass may also improve collateral perfusion to the tissue bed distal to

the occluded cerebral blood vessel. The effectiveness of these manipulations

depends on the state of vascular patency. For example, if the angiogram shows a

complete Circle of Willis, then increasing blood pressure during carotid

endarterectomy is appropriate; on the other hand, if the flow through the carotid

artery is minimal or the surgeon places a shunt, blood pressure need not be

elevated. Increasing blood pressure risks producing myocardial ischemia or

vasogenic edema in previously poorly perfused brain tissue because these

vessels are not governed by cerebral pressure autoregulation.

The amount and direction of blood pressure control depends upon knowledge of

the preoperative flow pattern (it is essential to review the angiogram preoper-

atively) and the surgical approach, rather than a cookbook methodology. Post-

operative management also requires a consideration of the surgical procedure.

Glucose

Serum glucose concentration at the time of ischemia contributes substantially

to the ischemic injury. The deleterious effects of hyperglycemia have been well

reported in both clinical and laboratory reports [52,53]. Hyperglycemia markedly

increases damage in both global and focal ischemia [54,55]. Even moderately

elevated serum glucose worsens outcome. During incomplete ischemia the

continuous delivery of glucose with an inadequate oxygen supply converts aerobic

to anaerobic metabolism, increasing brain lactic acid, which decreases brain pH.

Buffering capacity is overwhelmed, free oxygen radicals are generated, neuronal

pH decreases, and cell membrane rupture occurs, producing tissue necrosis [56].

There are several specific situations where elevated glucose concentrations

may be beneficial. First, in a rat model of cardiac arrest, administration of glucose

plus insulin (to moderate hyperglycemia) improved functional and histologic

outcome [57]. Second, abrupt normalization of hyperglycemia in patients with

chronically elevated glucose worsens ischemic damage.


The future

The concept of providing cerebral protection in the future will probably not

focus on decreasing cerebral metabolism, but rather on blocking the cascade of

events that occur during ischemia (see boxed text).

The ischemic cascade

During cerebral ischemia large amounts of excitatory neurotransmitters (glu-

tamate and aspartate) are released by presynaptic neurons. The amount released

correlates with the severity of the ischemic insult and subsequent neuronal

damage. Glutamate and aspartate activate postsynaptic receptors (NMDA,

amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid [AMPA], kainate), result-

ing in an increase in intracellular calcium and stimulation of enzyme systems that

produce ischemic damage and ultimately neuronal death. Nitric oxide synthase is

stimulated, producing large amounts of neuronal nitric oxide. Lipid peroxidases,

proteases, and phospholipases are activated, increasing intracellular free fatty

acids and free radicals. Capsase, translocase, and endonuclease activity results in

DNA fragmentation. Cell membranes become permeable, leading to edema and

additional calcium influx. ATP stores are depleted, energy-dependent membrane

pumps fail, and neuronal death occurs.

New concepts

Current philosophies of cerebral protection are focusing on these excitatory

neurotransmitters and their receptors with the hopes of finding ways to interrupt

the cascade of neuronal damage. This section briefly outlines some of the areas

and drugs under consideration and currently being evaluated (see boxed text).

Potential cerebral protective mechanisms

Decrease cerebral metabolismIncrease cerebral blood flowMild hypothermiaPrevent hyperthermiaMaintain normoglycemiaInhibit release of excitatory neurotransmitters (eg, glutamate,

aspartate)Enhance release of inhibitory neurotransmitters (eg, GABA)Block neuronal calcium influxDecrease nitric oxide formationDecrease Neuronal free radical formationPrevent apoptosisScavenge free radicalsPrevent Ca++ and Na+ influx


Some of the drugs that block glutamate release include inhalation anesthetics

(70% reduction), adenosine A1 blockers, and a2 agonists. Inhalational anestheticsmay also increase reuptake of neurotransmitters from the synaptic space. Drugs

that competitively block postsynaptic receptors include barbiturates (primarily

AMPA and kainate receptors) and possibly inhalation anesthetics. Noncompetitive

receptor antagonists include MK801 (dizoclipine), phencyclidine, dextromethor-

phan, ketamine, and magnesium. Recently, sodium channel inhibition has been

reported to decrease both potassium-evoked and spontaneous glutamate release.

Methods to block the ischemic cascade

Inhibit glutmate releaseInhalational anestheticsAdenosine A1 receptor blockersa2 agonistsHypothermiaSodium channel inhibitorsLamotrigenEtomidate

NMDA, AMPA, and kainate receptor blockersBarbiturates (mainly AMPA, Kainate)? Inhalational anesthetics

Noncompetative receptor blockersDizoclipine (MK801)PhencyclidineDextromethorphanKetamineMagnesiumPropofol

Block calcium influxPropofolKetamineInhalational anestheticsLidocaineHypothermia

Prevent apoptosisIsofluranceHalothane

Inhibit lipid peroxidationLazariods (21 aminosteroids)Hypothermia

Reduce inflammatory cytokinesStatinsAnti-inflammatory drugs


Examples of other interesting approaches include aspirin, statins, and free

radical scavengers. Aspirin has shown laboratory evidence of neuronal protection

(delay in energy depletion and functional recovery), probably due to its antiin-

flammatory action [58]. Development of COX-2 inhibitors may make this

approach feasible. Recent work suggests that the statins, in addition to decreasing

atheromatous plaque, may also posses beneficial effects during ischemic stroke

and reperfusion [59]. The proposed mechanisms include upregulation of endo-

thelial nitric oxide synthase (which promotes vasodilation) while inhibiting

inducible nitric oxide synthase (which increases ischemic damage). They also

attenuate the inflammatory cytokine response to ischemia, possess antioxidant

properties, and reduce ischemic oxidative stress.

Drugs that decrease free radical formation or enhance free radical scavenging

are currently being evaluated as cerebral protectants. These include many well-

known drugs such as mannitol and steroids in addition to some new ones. Although

laboratory studies are promising, the human studies have not been very encour-

aging. Because cerebral ischemia is a complex event, a multifocal approach will

probably be necessary, focusing at different steps in the pathway of ischemia.

Outlook

The future for developing methodologies to protect the brain from ischemia is

bright. The scope and range of potential interventions appears unending. As

understanding of the cellular and molecular mechanisms that promote ischemic

damage or provide neuronal protection increases, research will become even more

exciting. The focus will not be on a single method or drug, but rather a cocktail of

options will be used to inhibit the harmful effects of the ischemic cascade.

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Fluids and the neurosurgical patient

Concezione Tommasino, MD*

Institute of Anesthesiology and Intensive Care, University of Milano,

Department of Anesthesia and Intensive Care, San Raffaele Hospital, Via Olgettina,

60 20132, Milano, Italy

The fluid management of neurosurgical patients presents special challenges for

anesthesiologists and intensivists [1]. Neurosurgical patients often receive diu-

retics (eg, mannitol, furosemide) to treat cerebral edema and/or to reduce

intracranial hypertension. Conversely, they may also require large amounts of

intravenous fluids to correct preoperative dehydration and/or to maintain intra-

operative and postoperative hemodynamic stability as part of therapy for vaso-

spasm, for blood replacement, or for resuscitation.

For a long time restrictive fluid management has been the treatment of choice

in patients with brain pathology, growing from fear that fluid administration

could enhance cerebral edema [2]. It is well known that fluid restriction, if

pursued to excess (hypovolemia), may result in episodes of hypotension, which

can increase intracranial pressure (ICP) and reduce cerebral perfusion pressure,

and the consequences can be devastating [3].

It is unfortunate that little substantial human data exist concerning the impact of

fluids on the brain, or which can guide rational fluid management in neurosurgical

patients. However, it is possible to examine those factors that influence water

movement into the brain, and to make some reasonable recommendations.

This review will address some of the physical determinants of water move-

ment between the intravascular space and the central nervous system (CNS).

Subsequent sections will address specific clinical situations with suggestions for

the types and volume of fluids to be administered.

Osmolality/osmolarity, osmotic and oncotic pressure, hemodilution

With intravenous fluid therapy, three properties of the blood can be manipu-

lated: osmolality (owing to concentrations of large and small molecules), colloid

oncotic pressure (COP; owing to large molecules only), and hematocrit.


PII: S0889 -8537 (01 )00013 -X

* Department of Anesthesia and Intensive Care, San Raffaele Hospital, Via Olgettina, 60 20132,

Milano, Italy.

E-mail address: [email protected] (C. Tommasino).


20 (2002) 329–346

Osmotic pressure

This is the hydrostatic force acting to equalize the concentration of water on

both sides of the membrane that is impermeable to substances dissolved in that

water. Water will move along its concentration gradient. Osmolarity describes the

molar number of osmotically active particles per liter of solution. In practice, the

osmolarity of a solution can be ‘‘calculated’’ by adding up the mEq concen-

trations of the various ions in the solution. Osmolality describes the molar

number of osmotically active particles per kilogram of solvent. This value is

directly ‘‘measured’’ by determining either the freezing point or the vapor

pressure of the solution. For most dilute salt solutions, osmolality is equal to

or slightly less than osmolarity.

Colloid oncotic pressure

Osmolarity/osmolality is determined by the total number of dissolved ‘‘par-

ticles’’ in a solution, regardless of their size. COP is nothing more that the

osmotic pressure generated by large molecules (eg, albumin, hetastarch, dextran).

The COP becomes particularly important in biological systems where vascular

membranes are often permeable to small ions, but not to large molecules.

Fluid movement between capillaries and tissues

As defined by the Starling equation [4], the major factors that control the

movement of fluids between the intravascular and extravascular spaces are the

transcapillary hydrostatic gradient, the osmotic and oncotic gradients, and

the relative permeability of the capillary membranes that separate these spaces.

The Starling equation is as follows:

FM ¼ kðPc þ pi � Pi � pcÞ

where FM = fluid movement, k = the filtration coefficient of the capillary wall

(= how leaky it is), Pc = hydrostatic pressure in the capillaries, Pi = hydrostatic

pressure (usually negative) in the interstitial space, and pi and pc are interstitial

and capillary osmotic pressures, respectively. In a simplified fashion, fluid

movement is proportional to the hydrostatic pressure gradient minus the osmotic

gradient across a vessel wall. The magnitude of the osmotic gradient will depend

on the relative permeability of the membrane.

In the periphery (muscle, lung, and other areas), the capillary endothelium has

a pore size of 65 A, and is freely permeable to small molecules and ions (Na+,

Cl�), but not to large molecules, such as proteins [5] (Fig. 1A). Thus, in the

periphery, movement of water is governed by the plasma concentration of large

molecules (oncotic gradient). If COP is reduced, fluid will begin to accumulate in

the interstitium, producing edema. In the cerebral capillaries, Fenstermacher [5]

calculated the effective pore size to be only 7 to 9 A. This small pore size of the

blood–brain barrier (BBB) prevents not only the movement of proteins, but also

C. Tommasino / Anesthesiology Clin N Am 20 (2002) 329–346330

sodium, chloride, and potassium ions [5] (Fig. 1B). The fluid movement across

the BBB is determined by the ‘‘total’’ osmotic gradient, generated both by large

molecules and small ions. Because there are so few protein molecules compared

with the number of inorganic ions, their effect on total osmolality is minimal

(normal COP � 20 mmHg � 1 mOsm/kg). Clearly, the influence of changes in

osmolality on cerebral water distribution dwarfs the effects of alteration in COP.

These differences explain why the administration of large volumes of isotonic

crystalloids, with dilutional reduction of COP, results in peripheral edema, but

does not increase brain water content and/or ICP [6–8].

When plasma osmolality decreases, the osmotic gradient drives water into the

brain tissue. Even small changes in plasma osmolality ( < 5%) increase brain

water content and ICP [7].

The above scenario describes the situation in conditions of normal BBB. After

a brain lesion, according to the severity of the damage (head trauma, tumor,

seizure, abscess, or other damage), there can be varying degrees of BBB integrity,

which can respond differently to the osmotic/oncotic changes. With complete

breakdown of the BBB, no osmotic gradient can be established [9–11]. It is

possible that with a less severe injury to the BBB, the barrier may function

similarly to the peripheral tissue [12]. Finally, there is usually a significant

Fig. 1. Schematic diagram of capillary membrane in the periphery. (A) The vessel wall is permeable to

both water (H2O) and small ions, but not to proteins (P), in the brain. (B) The blood–brain barrier is

permeable only to water.

C. Tommasino / Anesthesiology Clin N Am 20 (2002) 329–346 331

portion of the brain where the BBB is normal. The presence of a functionally

intact BBB is essential if osmotherapy is to be successful [13].

Hematocrit and hemodilution

One common accompaniment of fluid infusion is a reduction in hemoglobin/

hematocrit. This hemodilution is typically accompanied by an increase in cerebral

blood flow (CBF) [7,14,15]. In the normal brain, the increase in CBF produced

by hemodilution is an active compensatory response to a decrease in arterial

oxygen content, and this response is essentially identical to that seen with

hypoxia [16–18]. However, it should be stressed that in the face of brain injury,

the normal CBF responses to hypoxia and to hemodilution are attenuated, and

both changes may contribute to secondary tissue damage [19].

A hematocrit level of 30–33% gives the optimal combination of viscosity and

O2 carrying capacity, and may improve neurologic outcome [6,20,21]. However,

marked hemodilution (Hct < 30%) exacerbates neurologic injury [20,22].

Fluids for intravenous administration

The anesthesiologists and the intensivists can choose among a variety of fluids

suitable for intravenous administration, commonly categorized as crystalloids

and colloids.

Crystalloids and cerebral effects of plasma osmolality

Crystalloid solutions do not contain any high molecular weight compound,

and have an oncotic pressure of zero. Crystalloids may be hypo-osmolar, iso-

osmolar or hyperosmolar, and may or may not contain glucose. Commonly used

crystalloid solutions are illustrated in Table 1.

Hypo-osmolar crystalloids

Since the early years of the last century, scientists have known that fluid

regimens provide free water (eg, 0.45% saline or 5% glucose in water, D5W), and

cause a concomitant reduction in plasma osmolality, can cause cerebral edema.

One of the first animal studies on the cerebral effects of fluid administration

showed that hypotonic solutions expanded the brain [23]. The osmotic gradient

drives water across the BBB into the cerebral tissue, increasing brain water

content (= edema) and ICP. As a consequence, the use of fluid therapy that avoids

excess free water has been a standard element of management in patients with

brain and spinal cord damage.

Iso-osmolar crystalloids

Although some clinicians have long believed that iso-osmolar crystalloids

induce and/or aggravate brain edema, the many attempts to demonstrate experi-


mentally this phenomenon have not yielded scientifically convincing proof or

have generated negative results [7–11,24–27]. Iso-osmolar solutions, with an

osmolality � 300 mOsm/L, such as plasmalyte, 0.9% saline, do not change

plasma osmolality, and do not increase brain water content. The same does not

apply to solutions that are not truly iso-osmolar with respect to plasma. For

example, commercial lactated Ringer’s solution has a calculated osmolarity of

� 275 mOsm/L, but a measured osmolality of � 254 mOsm/kg, indicating

incomplete dissociation [7]. The administration of large volumes of this solution

(> 3 l in humans) can reduce plasma osmolality and increase brain water content

and ICP [7,28], as approximately 114 mL of free water is given for each liter of

lactated Ringer’s solution.

Hyperosmolar crystalloids

Crystalloids may be made hyperosmolar by the inclusion of electrolytes (eg,

Na+ and Cl�, as in hypertonic saline), or low molecular weight solutes, such as

mannitol (molecular weight 182), or glucose (molecular weight 180). Hyper-

osmolar solutions exert their beneficial effects by osmotically shifting water

from the nervous tissue (intracellular and interstitial space) to the intravascular

space. This effect has been demonstrated in brain tissue with normal a BBB

[13,28–31], and is the cornerstone treatment of intracranial hypertension. Fur-

thermore, the increased serum osmolality reduces cerebrospinal fluid (CSF)

secretion rate, and this effect can contribute to improve the intracranial com-

pliance [32–34].

Table 1

Composition of commonly used intravenous fluids: Crystalloids

mEq/l

g/l

Intravenous fluids MOsm/la Na+ Cl� K Ca Mg Lactate

Dextrose

(g/l)

5% Dextrose in water (D5W) 278 50

5% Dextrose in 0.45% NaCl 405 77 77 50

5% Dextrose in 0.9% NaCl 561 154 154 50

5% Dextrose in Ringer’s solution 525 130 109 4 3 50

Ringer’s solution 309 147 156 4 4–4.5

Lactated Ringer’s solution 275 130 109 4 3 28

5% Dextrose in Lactated

Ringer’s solution

525 130 109 4 3 28 50

Plasmalyteb 298 140 98 5 3

0.45% NaCl 154 77 77

0.9% NaCl 308 154 154

3.0% Saline 1026 513 513

5.0% Saline 1710 855 855

7.5% Saline 2566 1283 1283

20% Mannitol 1098

a osmolarity = calculated value (osm/l = mg�molecular weigh � 10 � valence).b Acetate 27 mEq/l and gluconate 23 mEq/l.


Colloids and cerebral effects of colloid oncotic pressure

Colloid is the term used to denote solutions that have an oncotic pressure

similar to that of plasma. Colloidal solutions share the presence of large

molecules that are relatively impermeable to the capillary membranes. Frequently

used colloids are illustrated in Table 2. Colloids include albumin, plasma,

hetastarch (hydroxyethylstarch, molecular weight 450), pentastarch (a low

molecular weight, 264, hydroxyethylstarch), and the dextrans (molecular weights

40 and 70). Dextran and hetastarch are dissolved in normal saline, so the

osmolarity of the solution is approximately 290 to 310 mOsm/L, with a sodium

and chloride content of about 154 mEq/L each.

Although it is accepted that a reduction in serum osmolality will cause

cerebral edema [7,12,23], there is not uniform agreement about the potential

effect of reduction in COP. Carefully conducted investigations have system-

atically sought a cerebral edema effect of COP reduction but have failed to

identify one [6,8–11]. Only a recent and elegant study by Drummond et al.

[12] has reported that COP reduction has the potential to aggravate brain

edema. The different results can be explained by the nature and severity of the

brain injury. In the study of Drummond et al. [12], the injury was deliberately

mild. It seem reasonable to suspect that this type of mechanical injury made the

BBB permeable to low molecular weight solutes while remaining impermeable

to colloids.

From the above-mentioned studies we can postulate that, depending on the

severity of the BBB damage, we will have brain areas where the osmotic/

oncotic gradient is totally effective (normal BBB), areas where only the colloid

oncotic gradient is effective (mild opening of the BBB, with pore size similar to

the periphery), and areas where there is no osmotic/oncotic gradient effect

(BBB breakdown).

The message is to avoid and/or correct, in patients with brain or spinal cord

injury, a decrease in ‘‘both’’ serum osmolality and COP. This message, however,

is part of the ‘‘common clinical sense.’’ As anesthesiologists and intensivists, we

treat not only brains but patients, and a COP reduction, even if it could not

directly affect brain water content, affects other organs and perfusion (eg,

pulmonary edema) [35], which in turn, can influence brain homeostasis.

Table 2

Composition of commonly used intravenous fluids: Colloids

mEq/lOsmolaritya Oncotic pressure

Intravenous fluids Na + Cl � K Ca (mOsm/l) (mm Hg)

Fresh-frozen plasma 168 76 3.2 8.2 � 300 21

5% Albumin 290 19

Dextran (10%) 40 in 0.9% saline 154 154 � 310 61

Dextran (6%) 70 in 0.9% saline 154 154 � 310 19

Hetastarch (6%) in 0.9% saline 154 154 31

Hetastarch (10%) in 0.9% saline 154 154 � 310 82

a Osmolarity = calculated value (osm/l = mg�molecular weigh � 10 � valence).


Glucose-containing solutions

Intravenous salt-free solutions containing glucose should be avoided in

patients with brain and spinal cord pathology. Once glucose is metabolized, only

free water remains only free water, which reduces serum osmolality and increases

brain water content. Furthermore, several studies in animals as well as in humans

have demonstrated that glucose administration increases neurologic damage and

can worsen outcome from both focal and global ischemia [36–40], presumably

because in ischemic areas glucose metabolism enhances tissue acidosis [40,41].

Glucose-containing solutions should be withheld in adult neurosurgical patients,

with the exception of neonates and patients with diabetes, in whom hypoglycemia

can occur very rapidly and be detrimental. It should be noted that this caveat does

not appear to apply to the use of hyperalimentation fluids in neurosurgical

patients, perhaps because these hyperglycemic fluids are typically started several

days after the primary insult, and/or because concomitant insulin is used. In

humans, it has not been carefully studied whether aggressive control of hyper-

glycemia with insulin will improve outcome, but laboratory evidence supports

the concept that preischemic correction of hyperglycemia with insulin im-

proves outcome.

In neurosurgical patients blood sugar level should be controlled frequently,

and the goal should be to avoid either hypo-and hyperglycemia, and maintain

sugar levels between 100 and 150 mg/dL.

Fluids to control ICP and brain swelling

Diuretics: mannitol and furosemide

Both mannitol and furosemide are extensively used to control ICP and brain

swelling. Mannitol accomplishes this goal by establishing an osmotic gradient

between the intravascular compartment and the cerebral parenchyma, in the

presence of a relatively intact BBB. The increased plasma osmolality promotes

removal of water from areas of normal brain [29,33]. Several issues related to

mannitol have also been clarified in recent years. Mannitol can transiently elevate

ICP. The mechanism of this effect is clearly due to the vasodilator effects of

hyperosmolality, with a resultant increase in cerebral blood volume (CBV)

[42,43]. However, it has been shown in both dogs and humans that this is a

phenomenon that does not occur in the presence of intracranial hypertension, or

when mannitol is given at moderate rates [42,43]. Thus, there is no important

reason to avoid mannitol in most neurosurgical patients, other than in patients

with significant cardiovascular disease, in whom the transient volume expansion

might precipitate congestive heart failure.

The other important concern is the excessive and/or repeated use of the drug,

because excessive hyperosmolality can be detrimental. In addition, mannitol does

progressively accumulate in the interstitium with repeated doses, and may even

aggravate brain edema [44,45]. If interstitial osmolality rises excessively, it is


possible that the normal brain–blood gradient might be reversed, with resultant

worsened edema. Furthermore, if brain osmolality is increased, there is a risk of

enhancing edema by subsequent normalization of serum osmolality.

Although mannitol is extensively used in patients with intracranial hyperten-

sion, a larger dose-finding study in humans has not been performed, and single

doses of mannitol from 0.25 up to 2.27 g/kg have been reported in the literature.

Marchall et al. [46] studied the effect of different mannitol doses in patients, and

concluded that small doses (0.25 g/kg) were as effective as larger doses. At our

institution mannitol is used at a dose range of 0.25–1.0 g/kg, and we always

choose the smallest possible dose, which is infused in at least in 10–15 min.

The mechanism of furosemide’s action remains controversial (although it

certainly is related to the drug’s ability to block Cl� transport) [47]. Furosemide

and similar drugs may also act primarily by reducing cell swelling, rather than by

changing extracellular fluid volume. In several studies it has been demonstrated

that furosemide decreases CSF production, and this effect can explain the

synergism between mannitol and furosemide on intracranial compliance [48].

Furosemide’s maximal effect is delayed compared with mannitol [49,50]. For this

reason, mannitol probably remains the agent of choice for rapid ICP control.

Hypertonic saline solutions

Hypertonic salt solutions have been primarily used for small-volume resus-

citation in patients with hemorrhagic shock. Because hyperosmolality is known

to reduce brain volume [23], hypertonic saline may become part of standard

resuscitation in patients with concomitant head injury. Laboratory and clinical

data suggest that hypertonic solutions are effective for volume resuscitation, and

result in a lesser degree of cerebral edema [51,52]. In humans, acute resuscitation

from hemorrhagic shock with 7.5% hypertonic saline is associated with improved

outcome in traumatized head-injured patients, and clinical studies suggest that

hypertonic saline may be efficacious in hypotensive, brain-injured patients during

transport to the hospital [53,54].

Various animal experiments have indicated that hypertonic saline solutions

lower ICP and improve cerebral perfusion pressure [3,30,31,51]. The CNS effects

of hypertonic saline are similar to mannitol [30,55]; however, the fact that

hypertonic saline does not produce an osmotic diuresis simplifies perioperative

fluid management. There are a number of case reports and a few controlled trials

that suggest that hypertonic saline may produce significant and sustained

reductions in ICP where mannitol has failed [56,57]. The mechanism by which

hypertonic saline succeeded when mannitol failed, however, remains unclear.

The principal disadvantage of hypertonic saline is related to the possible

danger of hypernatremia. In a recent study in neurosurgical patients during

elective procedures, we have shown that equal volumes of 20% mannitol and

7.5% hypertonic saline reduce brain bulk and cerebrospinal fluid pressure to the

same extent [55]. Serum sodium levels increased during the administration of

hypertonic saline, and peaked at over 150 mEq/L at the end of the infusion [55].


However, initial concerns regarding the adverse nurologic sequelae of hypertonic

saline appear to have been premature. First, the increment in serum sodium in

response to addition of concentrated sodium is less than would be predicted [55].

Second, patients tolerate acute increases in serum sodium to 155–160 mEq/L,

without apparent harm [53–55,58]. Third, central pontine myelolysis has not

been observed in a clinical trial of hypertonic resuscitation [53]. One concern is

that hypertonic saline solutions have the potential to cause rebound intracranial

hypertension, similar to other osmotic agents [59,60].

Hypertonic/hyperoncotic solutions

More recent attention has been directed at hypertonic/hyperoncotic solutions

(typically hypertonic hetastarch or dextran solutions). Because of the powerful

hemodynamic properties of these fluids in circulatory shock, administration in

patients with multiple traumas and head injury might be particularly advantage-

ous for the prevention of secondary ischemic brain damage [58]. Small volumes

of such solutions can restore normovolemia rapidly, without increasing ICP

[28,61]. They have been successfully used to treat intracranial hypertension in

head-injured patients and in patients with stroke [53,54,62,63].

Implications for patient care

The available information can be used to make a series of ‘‘reason-

able’’ suggestions, useful either in the perioperative period as well as for

fluid resuscitation.

Fluid restriction

Despite a lack of convincing experimental evidence that iso-osmolar crystal-

loids are detrimental, fluid restriction is still widely practiced in patients with

mass lesions, cerebral edema, and/or at risk for intracranial hypertension. The

only directly applicable data indicate that clinically acceptable fluid restriction

has little effect on edema formation; however, there is some ‘‘logic’’ behind

modest fluid restriction. One of the few human studies on fluid therapy in

neurosurgical patients demonstrated that patients given standard ‘‘maintenance’’

amounts of intravenous fluids (eg, 2000 mL/day) in the postoperative period

developed a progressive reduction in serum osmolality [2]. On the other hand,

patients given half this volume over a period of about 1 week showed a

progressive increase in serum osmolality, which could account for dehydration

of the brain (Fig. 2) [55]. Although no CNS-related parameters were measured in

this study, the results suggest that the maintenance fluids used (0.45% NaCl in

5% dextrose) contain excess-free water for the typical postoperative craniotomy

patient. In this light, fluid restriction can be viewed as ‘‘preventing’’ hypo-

osmotically driven edema. This does not imply that even greater degrees of fluid


restriction are beneficial, or that the administration of a fluid mixture that does

not reduce osmolality is detrimental.

Intraoperative volume replacement/resuscitation

As a general rule, intraoperative fluid administration should be given at a rate

sufficient to replace the urinary output and insensible losses. Table 3 illustrates

the intravascular volume expansion obtained with different types of fluids.

The available data indicate that volume replacement/expansion will have no

effect on cerebral edema as long as normal serum osmolality and oncotic pressure

are maintained, and as long as cerebral hydrostatic pressures are not markedly

increased (eg, due to true volume overload and elevated right heart pressures).

Whether this is achieved with crystalloids or colloids seems irrelevant. Serum

osmolality should be checked repeatedly, with the goal being to maintain this

value either as constant or slightly increased.

Table 3

Fluid replacement and intravascular volume

Fluid infused Intravascular volume increase

1 liter isotonic crystalloid � 250 ml

1 liter 5% albumin � 500 ml

1 liter hetastarch � 750 ml

Fig. 2. Effect of fluid restriction (1 L/day) on serum osmolality in neurosurgical patients. (From Shenkin

HA, Benzier HO, BouzarthW. Restricted fluid intake: rational management of the neurosurgical patient.

J Neurosurg 1976;45:432–6; with permission by Lippincott Williams & Wilkins D.)


Fluid administration that results in a reduction in osmolality should be

avoided. Small volumes of Lactated Ringer’s (not strictly iso-osmotic, measured

osmolality 252–255 mOsm/kg) are unlikely to be detrimental, and can be safely

used. If large volumes are needed (blood loss or other source of volume loss), a

change to a more isotonic fluid is advisable. It is also important to remember that

large and rapid infusion of 0.9% NaCl can induce a dose-dependent hyper-

chloremic metabolic acidosis [64,65]. Whether this acid-base abnormality is, in

fact, harmful remains unclear, although animal studies suggest that hyperchlore-

mia causes renal vasoconstriction [66]. If large volumes are needed, a combina-

tion of isotonic crystalloids and colloids may be the best choice. The combined

use of these fluids can avoid reductions both is serum osmolality and COP.

Hetastarch should be used with caution due to coagulation factor VIII depletion

and possible coagulation difficulties encountered with volumes >1000 mL

[67,68]. Pentastarch, a new formulation of hydrolyzed amylopectin, causes fewer

effects on coagulation than hetastarch; it does not prolong the bleeding time, and

has little effect on factor VIII [69]. Dextran 40 interferes with normal platelet

function, and therefore is not advisable for patients with intracranial pathology,

other than to improve rheology, such as in ischemic brain diseases.

These recommendations should not be interpreted as ‘‘give all the isotonic–

iso-oncotic fluid you like.’’ Volume overload can have detrimental effects on ICP,

via increasing CBV or via hydrostatically driven edema formation.

Postoperative period

In the postoperative period, large fluid requirements should cease. In such

cases, the recommendations of Shenkin et al. [2] are probably reasonable, and we

recommend periodic measurements of serum osmolality, particular if neurologic

status deteriorates. If cerebral edema does develop, further restriction is unlikely

to be of value, and can result in hypovolemia. Specific treatment with mannitol,

furosemide, and other drugs, combined with normovolemia achieved with fluids

that will maintain the increased osmolality, appears to be reasonable.

Head injury

Prompt restoration of systemic pressure is essential in head-injuried patients.

In patients in whom multiple trauma complicates head injury, no resuscitation

fluid has proven ideal [70]. Hypotonic solutions (including Lactated Ringer’s

solutions) should be avoided, and therapy should rely on fluids with osmolalities

around 300 mOsm/L. In cases of large-volume fluid administration, oncotic

pressure should be checked, and colloid solutions administered as needed.

Hypertonic saline solutions have been used successfully to treat hypovolemia

and intracranial hypertension in these patients [51–54,62]. Glucose-containing

solutions should be avoided, because hyperglycemia is associated with poorer

neurologic outcome in head-injured patients [37,39].


Subarachnoid hemorrhage

When treating patients with subarachnoid hemorrhage two problems should be

kept in mind: hyponatremia and hypovolemia.

In these patients, relative hypovolemia develops very often. The cause is

multifactorial, and includes bed rest, negative nitrogen balance, decreased

erythropoiesis, iatrogenic blood loss, and dysregulation of the autonomic nervous

system. Hyponatremia appears to develop as the result of a central salt-wasting

syndrome, and the causative factor seems to be an increased release of a

natriuretic factor from the brain [71]. Excessive renal excretion of sodium

precedes the development of ischemic symptoms [72], and patients appear to

be at increased risk for delayed cerebral infarction [73]. Hyponatremia should not

be a serious concern if electrolytes and type of fluids administered are carefully

monitored. With the administration of a large volume of isotonic crystalloids and

restriction of free water (hypotonic intravenous fluids and oral fluids) the severity

of the fall in serum sodium concentration is ameliorated, and usually does not

require further intervention. If hyponatremia is more severe or significant cere-

bral edema exists, the use of mild hypertonic fluids (1.25 or 1.5% saline) and

strict avoidance of free water administration are usually successful in reversing

the hyponatremia.

Fluid restriction should be abandoned, as it worsens volume contraction and

exacerbates symptoms from vasospasm. Hypertensive/hypervolemic therapy is

widely accepted to prevent/treat symptomatic cerebral vasospasm [74]. This

therapeutic treatment, however, has never been carefully studied (control group

with no therapy, or other treatments), and it is not clear whether hypertension and/

or hypervolemia is the critical factor. Volume loading is usually performed with

colloids, and great care is required to avoid reduction in serum osmolality,

because this will increase brain water content in ischemic as well as normal

cerebral regions [75].

Ischemic injury

The one situation where hemodilution may be beneficial is in the period

immediately during/after a focal cerebral ischemic event. Several studies have

shown that regional O2 delivery in this situation may be increased (or at least

better maintained) in the face of modest hemodilution (Hct � 30%), and animal

studies demonstrate improvement in CBF and some reductions in infarction

volumes [20,76]. Unfortunately, several trials have failed to demonstrate any

benefit of hemodilution in stroke, except in polycythemic patients [77–80].

Spinal cord injury

Although the literature lacks specific studies on the spinal cord effects of fluid

therapy, in patients with acute spinal cord injury, a prevalence of hyponatremia

much higher than in the general medical or surgical patient population has been

reported [81]. This study did not elucidate the ethiology of hyponatremia, and did


not consider type and amount of fluids administered. However, the occurrence of

hyponatremia after acute spinal cord injury stresses the importance of appropriate

fluid management in these patients, mostly to prevent the consequences of

reduced plasma osmolality, which might exacerbate spinal cord edema. Labo-

ratory researches have demonstrated that hypertonic saline decreases spinal cord

water content [13], and may provide protection after mechanical injury [82].

Water and electrolytes disturbances

Diabetes insipidus

Diabetes insipidus (DI) is a common sequelae of pituitary and hypothalamic

lesions, but it can also occur after head trauma or intracranial surgery. Patients

with brain death also commonly develop DI, and it should be remembered that

DI may also occur during phenytoin use, in alcohol intoxication, and bacte-

rial meningitis.

DI is a metabolic disorder due to a decreased secretion of antidiuretic hormone

(ADH), resulting in failure of tubular reabsorbtion of water. Polyuria (>30 mL/

kg/h or, in an adult, >200 mL/h), progressive dehydration, and hypernatremia

subsequently occur. Diabetes insipidus is present when the urine output is

excessive, the urine osmolality is inappropriately low relative to serum osmolality

(above normal because of water loss), and the urine specific gravity is lower than

1.002 (Table 4).

Management of DI requires careful balancing of intake and output, mostly to

avoid fluid overload

Each hour the patient should receive maintenance fluids plus three quarters

of the previous hour’s urine output, or plus the previous hour’s urine output minus

50 mL. Half-normal saline and D5W are commonly used as replacement fluids,

Table 4

Principal water-electrolytes disorders

DI SIADH CSWS

Etiology Reduced secretion

of ADH

Excessive release

of ADH

Release of brain

natriuretic factor

Urine Output > 30 ml/kg/h

specific gravity < 1.002

Sodium < 15 mEq/l > 20 mEq/l > 50 mEq/l

Osmolality vs.

serum osmolality

Lower Higher Higher

Serum Sodium Hypernatremia Hyponatremia Hyponatremia

Osmolality Hyperosmolality Hypoosmolality

Intravascular

volume

Reduced Normal or increased Reduced

Abbreviations: ADH, antidiuretic hormone; CSWS, celebral salt-wasting syndrome; DI, Diabetes

insipidus; SIADH, syndrome of inappropriate antidiuretic hormone secretion.


with appropriate potassium supplementation. Serum sodium, potassium, and gly-

cemic values should be checked frequently. In the presence of urine output higher

than 300 mL/h, at least for 2 hours, it is now standard practice to administer

aqueous vasopressin [5-10 IU, intramuscularly (i.m.), or subcutaneously (s.c.),

q 6 h] or the synthetic analog of ADH, desmopressin acetate (DDAVP: 0.5–2 mg,

intravenously (i.v.), q 8 h; or by nasal inhalation, 10–20 mg).

Syndrome of inappropriate antidiuretic hormone secretion

Various cerebral pathologic processes (mostly head trauma) can result in

excessive release of ADH, which causes continued renal excretion of sodium,

despite hyponatremia and associated hypo-osmolality. Urine osmolality is there-

fore high, relative to serum osmolality (Table 4). It should be remembered that

the syndrome of inappropriate antidiuretic hormone secretion (SIADH) can also

be the result of overadministration of free water (D5W) in patients who cannot

excrete free water, because of excess of ADH.

Management

The mainstay of treatment of SIADH is fluid restriction, usually to about

1000 mL/24 h of an iso-osmolar solution. If hyponatremia is severe (lower than

110–115 mEq/L) administration of hypertonic (3–5%) saline and furosemide

may be appropriate. Great care is required to avoid rapid correction of severe

hyponatremia. A good rule is to restore serum sodium levels at a rate of about

2 mEq/L/h.

Cerebral salt-wasting syndrome

Cerebral salt-wasting syndrome (CSWS) is frequently seen in patients with

subarachnoid hemorrhage, and is characterized by hyponatremia, volume con-

traction, and high urine sodium concentration (Table 4).

Management

The therapy is to reestablish normovolemia with the administration of sodium-

containing solutions.

The distinction between SIADH and CSWS is very important, because fluid

treatment of theses two syndromes is quite different (fluid restriction versus fluid

infusion). It should be stressed that in patients with SAH, in whom normo/

hypervolemia is advocated, fluid restriction (that is, further volume contraction)

may be especially deleterious.

Conclusion

Fluid management has progressed rapidly in the last 3 decades. Current

regimens are sufficient to restore systemic perfusion in the majority of pa-

tients undergoing surgery. However, important questions still remain to be

answered regarding the frequency of complications of current fluid therapy


and the comparative advantages of different fluid formulations in a variety of

clinical circumstances.

As neuroanesthesiologists/intensivists, we should always remember that we

treat patients and not only brains. Thus, with the exception of patients with

SIADH, the old dogma that states that patients with intracranial pathology should

be kept ‘‘dry’’ (‘‘run them dry’’) should be abandoned, and be replaced by ‘‘run

them isovolemic, isotonic, and isooncotic.’’

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Interventional neuroradiology—anesthetic

considerations

Tomoki Hashimoto, MDa,d, Dhanesh K. Gupta, MDa,d,William L. Young, MDa,b,c,d,*

aDepartment of Anesthesia and Perioperative Care, University of California,

San Francisco, CA 94110, USAbDepartment of Neurological Surgery, University of California, San Francisco, CA 94110, USA

cDepartment of Neurology, University of California, San Francisco, CA 94110, USAdCenter for Cerebrovascular Research, University of California, San Francisco,

San Francisco General Hospital, 1001 Potrero Avenue, Room 3C-38,

San Francisco, CA 94110, USA

Interventional neuroradiology (INR) is a hybrid of traditional neurosurgery

and neuroradiology, with certain overlaps with aspects of head-and-neck

surgery. It can be broadly defined as treatment of central nervous system (CNS)

disease by endovascular access for the purpose of delivering therapeutic

agents, including both drugs and devices [1]. Because of a recent advance-

ment in the field of INR [2], more anesthesiologists are involved in care of

patients undergoing INR procedures. Anesthesiologists have several important

concerns when providing care to patients who undergo INR procedures,

including (1) maintenance of patient immobility and physiologic stability; (2)

manipulating systemic or regional blood flow; (3) managing anticoagulation;

(4) treating and managing sudden unexpected complications during the pro-

cedure; (5) guiding the medical management of critical care patients during

transport to and from the radiology suites; and (6) rapid recovery from

anesthesia and sedation during or immediately after the procedure to facilitate

neurologic examination and monitoring [3,4]. To achieve these goals, anes-

thesiologists should be familiar with specific radiological procedures and their

potential complications.


PII: S0889 -8537 (01 )00005 -0

This work is supported in part by National Institutes of Health, Grants K24-NS02091 (W.L.Y.).

* Corresponding author. Center for Cerebrovascular Research, University of California, San

Francisco General Hospital, 1001 Potrero Ave., Room 3C-38, San Francisco, CA 94110, USA.

E-mail address: [email protected] (W.L. Young).


20 (2002) 347–359

Preanesthetic considerations

The preanesthetic evaluation of a patient undergoing a potentially long

diagnostic and therapeutic procedure in the neuroradiology suite expands on

the routine preanesthetic examination of the neurosurgical patient. Airway eval-

uation should include routine evaluation of the potential ease of laryngoscopy in

an emergent situation, and also take into the account the fact that, with the head

and neck kept in a neutral position, sedation may compromise airway patency.

Further, this patient population often includes head-and-neck tumor patients with

their associated airway considerations.

Baseline blood pressure and cardiovascular reserve should be assessed care-

fully, especially when blood pressure manipulation and perturbations are antici-

pated. A careful neurologic examination should be performed to characterize any

deficits that may be present prior to the procedure, and special note should be

made of the patient’s sensorium. Furthermore, careful padding of pressure points

may assist in the patient’s ability to tolerate a long period of lying supine and

motionless and decrease the requirement for sedation, anxiolysis, and analgesia.

In addition to the issues normally considered during the preanesthetic evaluation

of the neurosurgical patient, the anesthesiologist should review the patient’s

previous experiences with angiography, noting if there were adverse reactions to

radiographic contrast agents, such as allergy or excessive dehydration. Because

of the possibility of significant radiation exposure, the possibility of pregnancy in

female patients should be explored.

Prophylaxis for cerebral ischemia is in a state of development. Some centers

use a variety of agents such as oral nimodipine for this purpose. The use of

calcium channel blockers has been suggested to decrease catheter-induced vaso-

spasm as well; transdermal nitroglycerin has also been used for this purpose.

Monitoring and vascular access

Secure intravenous (i.v.) access should be available with adequate extension

tubing to allow drug and fluid administration at maximal distance from the image

intensifier during fluoroscopy. Access to i.v. or arterial catheters can be difficult

when the patient is draped and the arms are restrained at the sides. Stopcocks and

nonlocking tubing connections under the drapes should be minimized. Prior to

covering the patient, the tightness of connections between segments of tubing

should be verified. Infusions of anticoagulant or potent medications, such as

nitroprusside and remifentanil, should be through minimal dead space, into ports

that are as proximal to the patient as possible (e.g., into a T-connector at an i.v.

catheter). This allows the infusion of medications to be relatively independent of

the rate of the i.v. carrier fluid.

Standard monitors should be applied, regardless of anesthetic technique. For

i.v. sedation, capnography sampling via the sampling port of special nasal

cannula is especially useful. A pulse oximeter probe can be placed on the great

T. Hashimoto et al. / Anesthesiology Clin N Am 20 (2002) 347–359348

toe of the leg that will receive the femoral introducer sheath. This may give an

early warning of femoral artery obstruction or distal thromboembolism.

For intracranial procedures and postoperative care, beat-to-beat arterial pres-

sure monitoring and blood sampling can be facilitated by an arterial line. A side

port of the femoral artery introducer sheath can be used, but most radiologists will

remove the sheath immediately after the procedure. Using a coaxial or triaxial

catheter system, arterial pressure at the carotid artery, vertebral artery, and the

distal cerebral circulation can be measured [5]. The presence of a coaxial catheter

frequently underestimates the systolic and overestimates the diastolic pressure;

however, mean pressures are reliable, and may be used to safely monitor the

induction of either hyper- or hypotension. In a patient who requires continuous

blood pressure monitoring postoperatively, it is convenient to have a separate

radial arterial blood pressure catheter. Bladder catheters are required for most of

the procedures; they assist in fluid management as well as patient comfort. A

significant volume of heparinized flush solution and radiographic contrast is

often used.

Radiation safety

There are three sources of radiation in the INR suite: direct radiation from the

x-ray tube, leakage (through the collimators’ protective shielding), and scattered

(reflected from the patients and the area surrounding the body part to be imaged).

A fundamental knowledge of radiation safety is essential for all staff members

working in an INR suite. It must be realized that the amount of exposure de-

creases proportionally to the square of the distance from the source of radiation

(inverse square law). It should also be realized that digital subtraction angiog-

raphy delivers considerably more radiation than fluoroscopy.

Optimal protection would dictate that all personnel should wear lead aprons,

thyroid shields, and radiation exposure badges. The lead aprons should be

periodically evaluated for any cracks in the lead lining that may allow accidental

radiation exposure. Movable lead glass screens may provide additional protection

for the anesthesia team. Clear communication between the INR and anesthesia

teams is crucial for limiting radiation exposure. With proper precautions, the

anesthesia team should be exposed to less than the annual recommended limit for

health care workers (see http://pdg.lbl.gov/).

Anesthetic technique

Choice of anesthetic technique is a controversial area, and varies between

centers. There are no data that support improved outcome with one technique or

another. There appears to be a trend to move more towards general endotracheal

anesthesia, but it is highly dependent on local practice and training.

T. Hashimoto et al. / Anesthesiology Clin N Am 20 (2002) 347–359 349

Intravenous sedation

Primary goals of anesthetic choice for i.v. sedation are to alleviate pain,

anxiety and discomfort, and to provide patient immobility. A rapid recovery from

sedation is often required for neurologic testing.

Many neuroangiographic procedures, while not painful per se, can be psycho-

logically stressful. This is especially true when there is a risk of serious stroke or

death, particularly patients who have already suffered a preoperative hemorrhage

or stroke. There may be an element of pain associated with injection of contrast

into the cerebral arteries (burning) and with distention or traction on them (head-

ache). A long period of lying can cause significant pain and discomfort.

A variety of sedation regimens are available, and specific choices are based on

the experience of the practitioner and the aforementioned goals of anesthetic

management. Common to all i.v. sedation techniques is the potential for upper

airway obstruction. Placement of nasopharyngeal airways may cause troublesome

bleeding in anticoagulated patients, and is generally avoided. Laryngeal Mask

Airways may be useful in rare emergencies in patients with difficult airway.

Endotracheal intubation, however, remains a mainstay for securing the airway

during neurological crises.

General anesthesia

The primary reason for employing general anesthesia is to reduce motion

artifacts and to improve the quality of images, especially in small children and

uncooperative adult patients. This is especially pertinent to INR treatment of

spinal pathology, in which extensive multilevel angiography may be performed.

The specific choice of anesthesia may be guided primarily by other cardio- and

cerebrovascular considerations. Total i.v. anesthetic techniques, or combinations

of inhalational and i.v. methods, may optimize rapid emergence [6]. To date,

pharmacologic protection against ischemic injury during neurosurgical proce-

dures has not been proven. A theoretical argument could be made for eschewing

the use of N2O because of the possibility of introducing air emboli into the

cerebral circulation, but there are no data to support this.

Anticoagulation

Careful management of coagulation is required to prevent thromboembolic

complications during and after the procedures. Whether heparinization should be

used for every case of intracranial catheterization is not clear to date. Generally,

after a baseline activated clotting time (ACT) is obtained, i.v. heparin (70 units/kg)

is given to a target prolongation of two to three times baseline. Heparin can then be

given continuously or as an intermittent bolus with hourly monitoring of ACT.

Occasionally, a patient may be refractory to attempts to obtain adequate anti-

coagulation. Switching from bovine to porcine heparin or vice versa should be


considered. If antithrombin III deficiency is suspected, administration of fresh-

frozen plasma may be necessary. At the end of the procedure, heparin may need to

be reversed with protamine.

Antiplatelet agents (aspirin, ticlopidine, and the glycoprotein IIb/IIIa receptor

antagonists) are used quite extensively in patients with coronary stents, and may

have great relevance for patients undergoing INR procedures. Activation of the

glycoprotein IIb/IIIa receptor is a final common pathway for platelet aggregation.

Abciximab (ReoPro), a chimeric murine–human monoclonal antibody that di-

rectly binds to the receptor, has been shown to decrease mortality and morbidity

after coronary stenting [7]. Other agents in this class include the peptide receptor

antagonists, Eptifibatide (Integrilin) and Tirofiban (Aggrastat).

These agents have various pharmacokinetic and pharmacodynamic properties.

Based on experiences in coronary stenting, several basic observations on their use

become clear. First, the effects of these agents on platelet aggregation are difficult

to monitor clinically because there is no accurate bedside test of platelet aggre-

gation. Second, the duration of the effects is approximately 12–24 hours. Rapid

reversal of antiplatelet activity can only be achieved by platelet transfusion. Final-

ly, use of these agents along with heparin may result in unexpected hemorrhage.

Therefore, reducing procedural heparin dosage and early removal of vascular

access sheaths should be carefully considered to decrease bleeding complications.

The sustained long-term reduction in morbidity and mortality of coronary throm-

bosis patients (undergoing angioplasty/stenting or thrombolysis) by an antiplatelet

agent has led to great interest for use in endovascular procedures of the CNS, but

their use is not clearly defined in the setting of cerebrovascular disease.

Superselective anesthesia functional examination (SAFE)

SAFE is carried out to determine, prior to therapeutic embolization, if the tip

of the catheter has been inadvertently placed proximal to the origin of nutritive

vessels to eloquent regions, either in the brain or spinal cord [8]. Such testing is

an extension of the Wada and Rasmussen test in which amobarbital is injected

into the internal carotid artery to determine hemispheric dominance and language

function. Its primary application is in the setting of brain arteriovenous mal-

formation (BAVM) treatment, but it may also be used for tumor or other vascular

malformation work. Prior to the testing, the patient should be fully awake from

sedation or general anesthesia. Careful selection of motivated patients and

preoperative teaching may decrease the anxiolytic requirements of these patients

and ensure ideal testing conditions. This topic is reviewed elsewhere [4].

Deliberate hypotension

The two primary indications for induced hypotension are (1) to test cerebro-

vascular reserve in patients undergoing carotid occlusion, and (2) to slow flow in

a feeding artery of BAVMs before glue injection.


Themost important factor in choosing a hypotensive agent is the ability to safely

and expeditiously achieve the desired reduction in blood pressure while maintain-

ing the physiological stability of the patients. The choice of agent should be

determined by the experience of the practitioner, the patient’s medical condition,

and the goals of the blood pressure reduction in a particular clinical setting.

Intravenous adenosine has been used to induce transient cardiac pause, and

may be a viable method of partial flow arrest [9,10]. Further study for its safety

and efficacy is needed.

Deliberate hypertension

During acute arterial occlusion or vasospasm, the only practical way to in-

crease collateral blood flow may be an augmentation of the collateral perfusion

pressure by raising the systemic blood pressure. The Circle of Willis is a primary

collateral pathway in cerebral circulation. However, in as many as 21% of other-

wise normal subjects, the circle may not be complete. There are also secondary

collateral channels that bridge adjacent major vascular territories, most importantly

for the long circumferential arteries that supply the hemispheric convexities. These

pathways are known as the pial-to-pial collateral or leptomeningeal pathways.

The extent to which the blood pressure has to be raised depends on the condition

of the patient and the nature of the disease. Typically, during deliberate hyperten-

sion the systemic blood pressure is raised by 30–40% above the baseline or until

ischemic symptoms resolve. Phenylephrine is usually the first line agent for delib-

erate hypertension, and is titrated to achieve the desired level of blood pressure.

Management of neurologic and procedural crises

Complications during endovascular instrumentation of the cerebral vascu-

lature can be rapid and life threatening, and require a multidisciplinary collab-

oration. Having a well thought-out plan for dealing with intracranial catastrophe

may make the difference between an uneventful outcome and death. Rapid and

effective communication between the anesthesia and radiology teams is critical.

The primary responsibility of the anesthesia team is to preserve gas exchange

and, if indicated, secure the airway. Simultaneous with airway management, the

first branch in the decision-making algorithm is for the anesthesiologist to

communicate with the INR team and determine whether the problem is hemor-

rhagic or occlusive. In the setting of vascular occlusion, the goal is to increase

distal perfusion by blood pressure augmentation with or without direct throm-

bolysis. If the problem is hemorrhagic, immediate cessation of heparin and re-

versal with protamine is indicated. As an emergency reversal dose, 1 mg protamine

can be given for each 100 units heparin total dosage during the case. The ACT

can then be used to fine tune the final protamine dose.

Bleeding catastrophes are usually heralded by headache, nausea, vomiting,

and vascular pain related to the area of perforation. Sudden loss of consciousness


is not always due to intracranial hemorrhage. Seizures, as a result of contrast

reaction or transient ischemia, and the resulting post-ictal state can also result in

an obtunded patient. In the anesthetized patient, the sudden onset of bradycardia

or the radiologist’s diagnosis of extravasation of contrast may be the only clues to

a developing hemorrhage.

Postoperative management

After INR procedures, patients spend the immediate postoperative period in a

monitored setting to watch for signs of hemodynamic instability or neurologic

deterioration. Blood pressure control, either induced hypotension or induced

hypertension, may be continued during the postoperative period. Complicated

cases may go first to CT or some kind of physiologic imaging such as single

photon emission computed tomography (SPECT) scanning; only rarely is an

emergent craniotomy indicated.

Specific procedures

Brain arteriovenous malformations (BAVMs).

BAVMs are typically large, complex lesions made up of a table of abnormal

vessels (called the nidus) frequently containing several discrete fistulae [5]. They

are often called cerebral or pial arterio-venous malformations. There are usually

multiple feeding arteries and draining veins. The goal of the therapeutic embo-

lization is to obliterate as many of the fistulae and their respective feeding arteries

as possible. BAVM embolization is usually an adjunct for surgery or radiotherapy

[11]. In rare cases, embolization treatment is aimed for total obliteration. SAFE is

frequently used during BAVM embolization.

There are generally two schools of thought on how to manage anesthesia in the

patient undergoing endovascular therapy, especially with permanent agents such as

cyanoacrylate glues. One must rely on the knowledge of neuroanatomy and

vascular architecture to ascertain the likelihood of neurologic damage after

deposition of the embolic agents. The ‘‘anatomy’’ school, therefore, will prefer

to embolize under general anesthesia. Arguments for this approach include

improved visualization of structures with the absence of patient movement,

especially if temporary apnea is used. Further, it is argued that if the glue is placed

‘‘intranidal,’’ then, by definition, no normal brain is threatened. There are two

major concerns for this approach. A considerable variation in the normal local-

ization of function exists, and cerebral pathology may cause neurologic function to

shift from its native location to another one. The other school, which we might call

the ‘‘physiologic’’ school, trades off the potential for patient movement for the

increased knowledge of the true functional anatomy of a given patient. Localization

of cerebral function may not always follow textbook descriptions, as described in


the section on SAFE. Furthermore, the BAVMnidus or a previous hemorrhage may

result in a shift or relocalization of function. The ‘‘physiologic’’ approach demands,

at the present, careful titration of sedation to wake the patient for SAFE before

injection of embolic material.

The cyanoacrylate glues offer relatively ‘‘permanent’’ closure of abnormal

vessels. Although less durable, polyvinyl alcohol microsphere embolization is

also commonly used. If surgery is planned within days after PVA embolization, the

rate of recanalization is low and PVA is felt to be easier and safer to work with.

Advances in polymer development may obviate some of the risks of glue therapy.

Dural arterio-venous malformations

Dural AVM is currently considered an acquired lesion resulting from venous

dural sinus stenosis or occlusion, opening of potential arterio-venous shunts, and

subsequent recanalization. Symptoms are variable according to which sinus is

involved. Dural AVMs may be fed by multiple meningeal vessels, and therefore,

multistaged embolization is usually performed. SAFE is performed in certain

vessels such as the middle meningeal artery and the ascending pharyngeal artery

to evaluate the blood supply to peripheral cranial nerves and the possible

existence of dangerous extra- to intracranial anastomosis. Complete obliteration

is not always necessary considering the purpose of treatment, which is to reduce

risk of bleeding or to alleviate symptoms. Subsequent spontaneous thrombosis

can be expected in view of pathogenesis of this disease.

It is important to bear in mind that dural AV fistulas can induce increased venous

pressure. Venous hypertension of pial veins is a risk factor for intracranial

hemorrhage. Additionally, the venous hypertension should be factored into

estimating safe levels of reductions in systemic arterial, and therefore, cerebral

perfusion pressure.

Carotid cavernous and vertebral fistulae

Carotid cavernous fistulae (CCF) are direct fistulae usually caused by trauma

to the cavernous carotid artery leading to communication with the cavernous

sinus, usually associated with basal skull fracture. Treatment of CCF, a challeng-

ing surgical procedure, has become relatively easier with the development of

detachable balloons [12]. Vertebral artery fistulae are connections to surrounding

paravertebral veins, usually as a result of penetrating trauma, but may be

congenital, associated with neurofibromatosis, or result from blunt trauma. In

addition to cerebral involvement, spinal cord function may also be impaired.

Vein of Galen malformations

These are relatively uncommon but complicated lesions that present in infants

and require a multidisciplinary approach including an anesthesiologist skilled in


the care of critically ill neonates. The patients may have intractable congestive

heart failure, myocardial lesions, intractable seizures, hydrocephalus, and mental

retardation [13].

Spinal cord lesions

Embolization may be used for intramedullary spinal AVMs, dural fistulae, or

tumors invading the spinal canal. Often, general endotracheal anesthesia with

controlled ventilation is used to provide temporary apnea that may increase the

ability to see small spinal cord arteries at the limits of angiography imaging re-

solution and exquisitely sensitive to motion artifact. For selected lesions, intra-

operative somatosensory and motor-evoked potentials may be helpful in both

anesthetized and sedated patients. Intraoperative wake-up tests may be requested

to test neurologic function during embolization.

In cases where wake-up tests might be needed, preoperative discussion of the

logistics of the wake-up procedure and the testing process may facilitate the

intraoperative management of this part of the procedure.

Carotid test occlusion and therapeutic carotid occlusion

Carotid occlusion, both permanent and temporary, may be used in several

circumstances. Skull base tumors frequently involve the intracranial or petrous

portion of the carotid artery or its proximal Willisian branches. Large or other-

wise unclippable aneurysms may be partly or completely treated by proximal

vessel occlusion. To assess the consequences of carotid occlusion in anticipation

of surgery, the patient may be scheduled for a test occlusion in which ce-

rebrovascular reserve is evaluated in several ways. A multimodal combination of

angiographic, clinical, and physiologic tests can be used to arrive at the safest

course of action for a given patient’s clinical circumstances. The judicious use of

deliberate hypotension can increase the sensitivity of the test [14,15].

Intracranial aneurysm ablation

The two basic approaches for INR therapy of cerebral aneurysms are occlusion

of proximal parent arteries and obliteration of the aneurysmal sac. The aneu-

rysmal sac may be obliterated by use of coils and balloons. However, obliterating

the aneurysmal sac while sparing the parent vessel is still challenging [16].

Manipulation of the sac may cause distal thromboembolism and rupture. In-

complete obliteration may result in recurrence and hemorrhage. The anesthesi-

ologist should be prepared for aneurysmal rupture and acute SAH at all times,

either from spontaneous rupture of a leaky sac or direct injury of the aneurysm

wall by the vascular manipulation. It should be noted after coil ablation of

aneurysms, that at the present time, there is not the same degree of certainty that


the lesion has been completely removed from the circulation as with application

of a surgical clip. There may be areas of the aneurysmal wall that are still in

contact with the arterial blood flow and pressure. Therefore, attention to post-

operative blood pressure control is warranted.

Balloon angioplasty of cerebral vasospasm from aneurysmal SAH

Angioplasty may be used to treat symptomatic vasospasm with correlating

angiographic stenosis refractory to maximal medical therapy [17]. Angioplasty is

usually reserved for patients that have already had the symptomatic lesion sur-

gically clipped (for fear of rerupture), or for patients in the early course of symp-

tomatic ischemia to prevent transformation of a bland infarct into a hemorrhagic

one. A balloon catheter is guided under fluoroscopy into the spastic segment and

inflated to mechanically distend the constricted area.

It is also possible to perform a ‘‘pharmacologic’’ angioplasty. There is the

greatest experience with papaverine, but there are potential CNS toxic effects (see

ref. [18] for a review), but other agents such as calcium channel blockers may

find a place for this purpose.

Sclerotherapy of venous angiomas

Craniofacial venous malformations are congenital disorders causing significant

cosmetic deformities, that may impinge on the upper airway and interfere with

swallowing. Absolute alcohol (95% ethanol) opacified with contrast is injected

percutaneously into the lesion, resulting in a chemical burn to the lesion and

eventually shrinking it. The procedures are short (30–60 minutes) but painful, and

general endotracheal anesthesia is used. Complex airway involvement may require

endotracheal intubation with fiberoptic techniques [19]. Because marked swelling

often occurs immediately after alcohol injection, the ability of the patient to

maintain a patent airway must be carefully assessed in discussion with the

radiologist before extubation. Alcohol has several noteworthy side effects. First,

upon injection it can cause changes in the pulmonary vasculature and create a short-

lived shunt or a ventilation-perfusion mismatch. Desaturation on the pulse

oximeter is frequently noted after injection. Absolute alcohol may also cause

hypoglycemia, especially in younger children. Finally, the predictable intoxication

and other side effects of ethanol may be evident after emergence from anesthesia.

Angioplasty and stenting for atherosclerotic lesion

Angioplasty with or without stenting for atherosclerosis has been tried in

cervical and intracranial arteries with favorable results [20,21]. Risk of distal

thromboembolism is the major issue to be resolved in this procedure and methods.

A catheter system that employs an occluding balloon distal to the angioplasty


balloon has been proposed [22]. Carotid angioplasty and stenting may provide a

therapeutic option for patients particularly at risk of surgery. However, efficacy and

indications in relation to carotid endarterectomy remain to be determined.

Preparation for anesthetic management include, in additional to the usual

monitors and considerations already discussed, placement of transcutaneous pac-

ing leads in case of severe bradycardia or asystole from carotid body stimulation

during angioplasty. Intravenous atropine or glycopyrrolate may be used in an

attempt to mitigate against bradycardia, which almost invariably occurs to some

degree with inflation of the balloon. This powerful chronotropic response may be

difficult or impossible to prevent or control by conventional means. If indicated by

hemodynamic instability, the anesthesiologist must have the ability to immediately

administer advanced cardiac life support, including catecholamine and temporary

cardiac pacing therapy.

Potential complications include vessel occlusion, perforation, dissection,

spasm, thromboemboli, occlusion of adjacent vessels, transient ischemic epi-

sodes, and stroke. Furthermore, compared to carotid endarterectomy, there ap-

pears to be an increased incidence of cerebral hemorrhage and/or brain swelling

after carotid angioplasty [23]. Although the etiology of this syndrome is

unknown, it has been associated with cerebral hyperperfusion, and it may be

related to poor postoperative blood pressure control.

Thrombolysis of acute thromboembolic stroke

In acute occlusive stroke, it is possible to recanalize the occluded vessel by

superselective intra-arterial thrombolytic therapy. Thrombolytic agents can be

delivered in high concentration by a microcatheter navigated close to the clot.

Neurologic deficits may be reversed without additional risk of secondary

hemorrhage if treatment is completed within 6 hours from the onset of carotid

territory ischemia and 24 hours in vertebrobasilar territory. One of the impedi-

ments in development in this area has been the fear of increasing the risk of

hemorrhagic transformation of the acute infarction patient. Despite an increased

frequency of early symptomatic hemorrhagic complications, treatment with intra-

arterial pro-urokinase within 6 hours of the onset of acute ischemic stroke with

middle cerebral artery (MCA) occlusion significantly improved clinical outcome

at 90 days [24].

Important points and objectives

There is a rapidly expanding list of application of INR procedures in the field

of the treatment of CNS disease. Anesthesiologists should be familiar with

specific procedures and their potential complications. Constant and effective

communication between the anesthesia and radiology teams is critical to safely

carry out INR procedures and to deal with intracranial catastrophe.


Acknowledgments

The authors wish to thank Broderick Belenson, Mark Espinosa, Sabrina Larson,

and Gaurab Basu for assistance in preparation of the manuscript; Van V. Halbach,

MD, and Christopher F. Dowd, MD, John Pile-Spellman, MD, Lawrence Litt, MD,

PhD, and Nancy J. Quinnine, RN, for development of clinical protocols discussed

herein; members of the UCSF Center for Stroke and Cerebrovascular Disease,

UCSF Center for Cerebrovascular Research, and the Columbia University AVM

Study Group for continued support.

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Anesthesia for minimally

invasive neurosurgery

Joel O. Johnson, MD, PhDDepartment of Anesthesiology and Perioperative Medicine, University of Missouri–Columbia,

N314 UMHC, DC005.00, One Hospital Drive, Columbia, MO 65212, USA

There is ever-increasing literature on ‘‘minimally invasive’’ surgical tech-

niques. Changes in anesthetic practice must be made to accommodate surgical

requirements, which are dependent upon the specific procedure. Publications

outlining the surgical technique and outcomes of these procedures have included

the specialties of cardiothoracic surgery, otolaryngology, and general surgery, but

reports span the spectrum of other surgical specialties. Anesthesia for minimally

invasive procedures has been covered in some of these specialty areas [1–6].

Anesthesia for neuroendoscopy has recently been covered in an article by

Ambesh and Kumar [7].

Improvements in imaging, computing, and surgical instrumentation have

advanced the field of minimally invasive surgery. Direct imaging systems using

fiberoptic technology have allowed access to areas of the body formerly

accessible only through large openings in the skin. In addition, radiological

breakthroughs such as magnetic resonance imaging (MRI) and CT, combined

with the speed of modern computing, have resulted in the development of

three-dimensional assisted surgery. Brain tumor removal [8], functional endo-

scopic sinus surgery [9], and spinal instrumentation surgery [10] are now

improved by decreasing the amount of viable brain tissue removed, decreasing

surgical times, and better placement of pedicle screws resulting in improve-

ments in patient outcome. The development of open MRI systems has allowed

this imaging modality to move into the operating room, improving surgical

excision of intracranial tumors [11]. Finally, those same imaging systems can be

used to focus noninvasive gamma radiation on remote tumors, allow accurate

placement of biopsy needles or electrocoagulation probes, and possibly avoid

surgical trespass altogether (see boxed text). More recently, in utero fetal


PII: S0889 -8537 (01 )00006 -2

E-mail address: [email protected] (J.O. Johnson).


20 (2002) 361–375

surgery has progressed to the coverage of myelomeningocoele defects, possibly

leading to improved neurologic outcomes in patients with spinal dysraphism

[12]. The ability to repair cardiac congenital defects in utero and correction of

twin-to-twin transfusion syndrome is also making great strides [13,14].

These developments have impacted neurosurgery and anesthetic care of the

neurosurgical patient. Specific anesthetic considerations for neurosurgery remain

essentially unchanged; preservation of the integrity of brain tissue, intracranial

pressure control, modulation of the systemic hemodynamics to achieve optimal

surgical conditions, and a rapid return to the preanesthetic state, the details of

which are covered elsewhere in this text. However, numerous procedures once

done with an open technique or through a craniotomy are now accessible using a

minimally invasive approach with endoscopic or radiologic methods (Table 1).

Modification in anesthetic techniques must take place in some of these proce-

dures to account for special risks and considerations. This review will focus

Technological advances

CT, MRI guided stereotaxyOpen MRIInterventional radiology techniques [9]Frameless stereotaxyLaser surgery [40]Operating microscopicOptical fiberscopeRadio frequency ablationRobotics

Table 1

Minimally invasive neurosurgery

Endoscopic techniques Indications

Hydrocephalus, choroid plexus cauterization, third

ventriculostomy tumor biopsy myeloscopy,

fenestration of colloid, arachnoid cysts and the

septum pellucidum

Transphenoidal approach to supracellar masses

Acoustic neuroma

Thoracoscopic discectomy

Lumbar laminectomy [19]

Hematoma/abscess removal

Radiosurgery Arteriovenous malformation (AVM) ablation, Parkinson’s Disease

Stereotactic MRI and CT guidance

Frameless stereotaxy

J.O. Johnson / Anesthesiology Clin N Am 20 (2002) 361–375362

specifically on anesthetic concerns for neuroendoscopy, stereotactic procedures,

synostosis repair, and radiosurgery.

Neuroendoscopy

The first endoscopic neurosurgical procedure was performed by Lespinasse, a

urologist, in 1910. He used a cystoscope to fulgurate the choroid plexus in two

children, one of whom died at the time of operation, and the other survived

5 years [15]. A rigid cystoscope (called by Walter Dandy a ‘‘ventriculoscope’’)

was used for treatment of hydrocephalus via choroid plexus fulguration or third

ventriculostomy [16], but fell out of favor with the development of cerebral spinal

fluid (CSF) diversion catheters. In the 1970s, advances in fiberoptics led to the

construction of steerable neuroendoscopes, allowing the neurosurgeon to perform

complex surgery within the confines of the ventricular space in adults, children,

infants, and neonates [17].

The neurosurgeon utilizes neuroendoscopy for treatment of hydrocephalus,

stereotactic biopsy, treatment of intracranial cysts, evacuation of hematomas or

abscesses, and treatment of syringomyelia. Endoscopy has been used for spine

surgery, and of course, for transphenoidal approaches to the pituitary [18,19]. An

innovative approach to craniosynostosis combines techniques used in plastic

surgery (endoscopic brow lift surgery) with neuroendoscopy to perform minimally

invasive strip craniectomies. Unique anesthetic considerations exist depending

upon positioning and surgical needs. Surgical complications have been reported,

but overall morbidity is less than 2% with a mortality of 0% to 1% [8,20–22].

Hydrocephalus

Neuroanesthesiologists caring for the pediatric neurosurgical population can

attest to the fact that shunts and shunt malfunctions constitute a large proportion

of pediatric cases. Those patients with hydrocephalus due to aqueductal stenosis

can have their CSF flow internally corrected through the creation of an opening in

the floor of the third ventricle. This procedure was first performed endoscopically

in 1923 by Jason Mixter with good results. The ensuing 70 years saw limited use

of stereotactic coordinates to percutaneously create a third ventriculostomy,

which was usually associated with a high complication rate [23]. Improvements

over those decades in the flow characteristics and valve designs of extracranial

peritoneal shunt systems led to their preferred use. However, the advent of

improved endoscopes has created a resurgence of interest in third ventriculos-

tomy for select patients [24].

Patients with acqueductal stenosis are the ideal candidates for endoscopic third

ventriculostomy, with late onset (older patients) obstruction having a more

successful long-term outcome. Other patient populations such as those with

neoplastic obstruction of the acqueduct of Sylvius, patients with meningomye-

locoele, and those with deep cisternal arachnoid cysts have undergone successful

J.O. Johnson / Anesthesiology Clin N Am 20 (2002) 361–375 363

internal shunting. Relative contraindications include patients with abnormal

ventricular anatomy, those with an intraventricular hemorrhage or a history of

meningitis. Several authors use a cutoff of a minimum third ventricular size of

7 mm. Damage (hypothalamic) to the walls of the third ventricle may occur in

patients with a smaller ventricle. Preoperative surgical evaluation usually

includes imaging studies to define the anatomy and size of the ventricular

system. There are currently no reliable functional tests of the patency of the

acqueduct of Sylvius or the absorptive capability of the arachnoid villi that can be

performed intraoperatively.

Patient position for endoscopic entry into the third ventricle is routine supine.

The table is usually positioned at a 90-degree angle to the anesthesiologist, with

the operative side ‘‘out.’’ At our institution, cranial fixation is not utilized in most

cases. A coronal burr hole is placed that optimizes the angle of approach to the

floor of the third ventricle. The frontal horn is accessed and the endoscope is

advanced to the third ventricle, where the mamillary bodies can be visualized.

The tuber cinereum is located just beyond these structures. Beneath this mem-

brane is the basilar artery and cisterns. Fenestration of this membrane creates an

opening through which CSF is diverted, a bypass of the aqueduct of Sylvius.

Several methods have been described for creating this hole, including using a

rigid endoscope itself, a smaller blunt probe, or lasers. The opening is then dilated

with a Fogarty catheter to ensure patency and stop any venous bleeding that may

occur. The most important factor in maintaining patency is the continued CSF

flow through the newly created opening.

Surgical complications have been described, including acute increases in

intracranial pressure, injury to brain structures and bleeding complications, most

notably damage to the basilar artery [25]. Warmed (37�C) lactated Ringers

solution is the perfusate commonly used to clear the CSF and irrigate the

operating area. Normal saline irrigant has been reported to cause inflammatory

neurologic complications including high fever and headache [26]. Increases in

intracranial pressure will occur if egress of the irrigating fluid is not maintained.

In addition, rapid flow of the irrigation fluid has been reported to acutely distend

the third ventricle or activate specific hypothalmic nuclei resulting in acute

hemodynamic collapse [27].

Injury to brain structures may result in short-term memory loss (injury to

the fornix) [18], syndrome of inappropriate secretion of antidiuretic hormone

(SIADH)(hypothalamus) [28], and rare nerve palsies. A host of anecdotal compli-

cations without specific etiologies have particular interest to the anesthesiologist,

including transient confusion [18], headaches [24], and unresponsiveness. [29].

Hemorrhagic complications may have significance both intraoperatively and

in the postoperative period. Intraoperative hemorrhage is rare, and is usually

controlled with saline irrigation. Bleeding that obliterates the endoscopic image is

treated by aborting the procedure, external drainage, and angiography if neces-

sary. Case reports of bleeding or pseudoaneurysm formation after injury to the

basilar artery have been generated [25]. Intraventricular clots from any sources

may subsequently be removed endoscopically.


Anesthetic considerations

Patients presenting for endoscopic treatment of hydrocephalus may range in

age from newborn to geriatric. Many of these cases are completed in an urgent

or semiurgent fashion, often with the pre-existing presence of a ventriculos-

tomy. A routine complete preoperative work-up addresses the patients systemic

illnesses and need for further preoperative consultation or treatment. Fasting

guidelines should be followed if possible. Patients with hydrocephalus may

have hypovolemia due to vomiting, fluid restriction, contrast agents, or os-

motic diuretics. Adequate volume replacement is a necessary consideration

prior to induction.

The newborn or infant less than 6 months of age represents a challenge in

several ways. Lack of suture fusion leads to increasing head circumference and

fewer classic clinical signs of intracranial hypertension. Although cerebral blood

flow (CBF) in the adult may is 50 mL/100 g/min, newborn flow is 23–40 mL/

100 g/min, and is even less in the premature infant [30]. The range of

autoregulation is shifted to the right in the infant; thus, normal CBF is maintained

at lower arterial pressures in the young. The metabolic rate of oxygen consump-

tion is 5.2 mL O2/100 g/min in 3–11-year-old children, indicating that although

there appears to be room to spare on the lower end of the arterial pressure scale

and CBF, the oxygenation requirements mandate careful attention to the avoid-

ance of hypoxia.

Preoperative medication is often not required in the adult patient, and is not

desirable in the newborn or infant less than 6 months of age. There is a risk of

hypoventilation leading to hypercarbia and arterial desaturation when premed-

ication with narcotics or barbiturates is instituted in infants or children [31,32].

However, the use of oral midazolam (0.5 mg/kg) does not caused changes in

oxygen saturation in preschool-aged children [33]. It is our practice to plan an

inhalation induction 10 to 15 minutes after oral midazolam premedication

(0.5 mg/kg) in children scheduled for neuroendoscopy. This approach avoids

excessive agitation during parental separation, preserves spontaneous breathing,

and facilitates inhalation induction without delaying awakening. Pediatric

patients with diminished consciousness or that have major medical problems

should undergo an intravenous (i.v.) induction. This category of patients often

have been admitted to the hospital and have indwelling intravenous access.

Monitoring for neuroendoscopy depends on the procedure, accompanying

medical problems, and the age of the patient. Routine American Society of

Anesthesiologists (ASA) monitors are placed upon arrival to the operating room.

Measurement of end-tidal carbon dioxide and end-tidal gas concentration is

necessary. An arterial catheter is inserted in the adult patient prior to induction.

Children, infants, and newborns benefit from direct arterial pressure measure-

ment, partially because of the opportunity to easily obtain blood samples. The

proportionate increase in dead space, high flow rates, and small tidal volumes

may underestimate PaCO2 and result in hypoventilation. Intermittent arterial

sampling allows for adjustment of the ventilation parameters, as well as


measurement of the hematocrit, serum electrolytes, and osmolality. Arterial

access is usually obtained in this subgroup after induction of anesthesia and

securing of the airway.

Intraoperative complications during endoscopic treatment of third ventricu-

lostomy include cardiac arrest [27], hypertension [27], bradycardia [9,21,27,34],

and anecdotal reports of massive intraoperative hemorrhage [23]. In preparation

for these emergencies, resuscitation drugs including atropine and epinephrine

must be available, and used judiciously to avoid large increases in blood pressure,

which would accentuate hemorrhage. Immediate postoperative complications

such as SIADH [35], nerve palsies [34], and hemiparesis [34] may have to be

dealt with in the recovery room.

Neuroendoscopy has also been used in ascertaining the correct placement of

traditional ventricular shunt systems [36]. This technique offers visual confirma-

tion of the position of the tip of the implanted catheter.

Stereotactic-guided endoscopic biopsy

Image-guided biopsy within the ventricular system has been made possible

by combining improvements in three-dimensional graphics with endoscopy

[37]. Further improvements include the Toronto open MR unit that can be used

in the OR for real-time operative guidance [38]. Stereotactic-guided endoscopic

biopsy is useful for a less-invasive biopsy of intraventricular and subarachnoid

tumors, including pineal tumors [39]. When the surgeon biopsies a lesion in the

ventricular system, immediate hemostasis of the site is possible with visual

confirmation of the differences between normal and pathologic tissue [8]. This

offers improved reliability in obtaining an appropriate histologic specimen.

Advances in the field of pathology offer ‘‘smear’’ techniques that utilize smaller

biopsy specimens, which is especially important for tumors in or near func-

tionally important areas [40]. The risk profile is otherwise the same as that seen

with endoscopy.

Anesthetic considerations are similar to those described above, with a

special emphasis on the risk for intraventricular hemorrhage. The intraoperative

use of pressor agents and excessive coughing or bucking on emergence can

hypothetically cause a biopsy site to rebleed. In comparison to stereotactic

biopsy done with conventional head-frame devices (see below), patients are

under a general anesthetic.

Intracranial cysts, hematomas, and abscesses

This heterogeneous group of space-occupying lesions has been successfully

treated with neuroendoscopic techniques [8,20,27,28,41]. Although the operative

mortality is lower than with conventional therapy, there is distinct differences

depending on pathology. Fenestration of intracerebral cystic lesions appears to be

the most benign, with an operative morbidity of 1.4% [8]. Laser fenestration or

sectioning of the cyst wall is accomplished with a yttrium-aluminum-garnet


(YAG) or potassium-tytanil-phosphate (KTP) source [20,42]. Intracerebral and

intraventricular hematomas may be evacuated through the endoscope if the

operation is completed within 2 hours of the onset of bleeding and the volume

is less than 50 cc. The reported morbidity (10.4%) and mortality (10.7%) remain

lower than conventional surgical techniques, although the value of the surgery

compared to conservative (nonsurgical treatment) remains in doubt [8]. Finally,

although most brain abscesses are approached through stereotactic techniques,

endoscopic methods allow for microbiologic samples, visual confirmation of the

content, and visual evaluation of the success of draining the lesion.

Anesthetic considerations focus primarily on positioning concerns. Positioning

for this subgroup of patients depends on the location of the lesion. Entry to the

ventricular system [43] may be accomplished through frontal, lateral, and posterior

approaches. This necessitates careful planning and communication between the

surgeon and the anesthesia providers. The use of the laser for endoscopic sec-

tioning often reduces visibility in the operating room due to protective eyewear.

Syringomyelia

Spinal endoscopy was described as early as 1931, and has been explored as a

treatment for septated syringomelia [41]. Miniature endoscopes (1.2 mm)

with single irrigating channels are used to visualize the inside of the syringo-

melic cavity and bluntly fenestrate septations. Anesthetic concerns include

prone positioning, assurance of lack of movement, and rapid awakening to assess

neurologic function.

Endoscopic strip craniectomy

Strip craniectomy is the removal of a strip of bone containing a fused cranial

suture, for the treatment of cranial synostosis. This technique has a long history in

neurosurgery, beginning with the first reports in the late 1800s and progressing to

the present day. The extent of the procedure spans the range from a simple open-

strip craniectomy or wide-strip craniectomy [44] to total cranial vault remodeling

[45]. The combination of endoscopic techniques such as those used in plastic

surgical forehead lifts with strip craniectomy has led to an innovative approach to

these often bloody surgical procedures [46,47].

Positioning plays a major role in the surgical requirements for craniosynos-

tosis procedures [48,49]. A prone position with neck extension is used to

facilitate surgical exposure (sometimes referred to as a ‘‘sea lion’’ or ‘‘sphinx’’

position) [50]. An inflatable bean bag holds the patients head in a fixed position

(Fig. 1) [49].

Anesthetic concerns include airway control, patient positioning, and the

potential for intraoperative blood loss. The patient population specific for this

surgical procedure is limited to those under 6 months of age. Thus, an inhalation

induction, i.v. placement, and intubation after a dose of nondepolarizing neuro-

muscular blocking agent is accomplished while maintaining a warm environment.


Head position for intubation can be challenging in a patient with severe

scaphocephaly, necessitating a second pair of hands for stabilization.

Optimal placement and securing of the endotracheal (ET) tube is of the

utmost importance, as inadvertent extubation is a risk during prone positioning

and extension of the neck. Extension leads to an average 1.7-cm cephalad

movement of the tip of the ET tube [51], with a cords to carina distance of 4 to

6 cm. To ensure that the tip of the ET tube remains in the trachea, a maximum

depth without mainstem intubation or contact with the carina is achieved. With

the head in a neutral position, the ET tube is advanced until the right mainstem

bronchus is intubated, then withdrawn until bilateral breath sounds are

appreciated. After careful securing of the ET tube, the patient is positioned

prone with the arms at the side, and the head extended as described above. The

endotracheal tube is carefully positioned to ensure that ‘‘kinking’’ does not

occur with the beanbag assembly (Fig. 2). Breath sounds are checked and a

warming blanket applied.

The prone, head-extended position places the incision sites from 8 to 14 cm

above the level of the right heart, creating a gradient that allows for possible

venous air embolism (VAE). A precordial Doppler probe should be placed to

detect such an occurrence. Open craniectomy procedures for synostosis repair

have a reported incidence of VAE greater than 80%, with 30% of these

incidents being associated with hypotension [52]. Endoscopic techniques have

a decreased incidence of VAE (8%) as well as a lack of hemodynamic effect

(0%) (personal data).

Fig. 1. A child placed in the ‘‘sea-lion’’ or ‘‘sphinx’’ position prior to endoscopic strip craniectomy.


Blood loss during craniosynostosis repair can be significant. One recent report

indicated that 96.3% of patients undergoing open calvarial surgery required

transfusion of packed red blood cells [53]. However, minimally invasive

techniques have been reported to cut the blood to an average of 35 mL in

patients undergoing endoscopic strip craniectomy for sagittal synostosis [54].

Involved craniofacial procedures are being done with minimally invasive

endoscopic techniques. Monoblock osteotomies using these procedures have

been reported to result in a decrease in surgical bleeding and surgical time [55].

Anesthetic considerations remain the same as discussed above.

Stereotactic procedures

Neurosurgeons began using stereotactic surgery for psychiatric and movement

disorders in the late 1940s. Published atlases of human stereotactic coordinates

allowed for the placement of specific brain lesions to treat psychosis, depression,

Parkinson’s disease, chorea, and a host of psychiatric disorders. The use of CT

combined with MRI led to the development of clinical tools that minimize the

error in accessing deep brain structures and also assist in the choice of an

approach path. Until recently, stereotactic devices were routinely used to hold the

surgical instrumentation, and as directional and depth gauges to arrive at the

appropriate site. These ‘‘head frames’’ represented an obstacle to the airway for

the anesthesiologist.

Fig. 2. The endotracheal tube is carefully secured to prevent kinking of the tube or displacement

during the surgical procedure.


Such an obstacle is the Brown-Robert-Wells frame, a ring structure affixed to

the skull in the horizontal plane by four pins. The patient then is imaged with the

ring in place, to provide an external relationship to the internal structures of the

brain. An interlocking arc is placed on the ring, with the coordinates provided by

computer. An innovation to the ring structure involved a hinged portion, which

could be swung out of the way to provide for airway access. Occasionally,

however, the required position of the ring placed the hinged part at the back of the

head, making access to the airway difficult.

These devices have since given way to ‘‘frameless stereotaxy.’’ External

markers are placed on the patients head prior to imaging. These scalp markers are

left on and used as fiducial points to relate the surgical instrumentation (such as a

bipolar coagulation device) to the computer generated three-dimensional image

(Fig. 3). A pair of cameras mounted above the operating field supply a stereo-

scopic view of the surgical instrument to the computer, which then locates the tip

of the instrument within its three-dimensional image. In this way, the surgeon is

presented with a horizontal, sagittal, and coronal view of the position of the tip of

the instrument on the operating field. These innovations have eliminated the

problem of access to the airway encountered with many stereotactic head-frame

systems. In addition, these imaging techniques have been modified to provide for

stereotactic guidance during spine surgery [56].

Guidance devices continue to be used during stereotactic-guided endoscopy,

biopsy, and lesioning. These are generally attached to the cranial fixation devise

Fig. 3. Fiducial markers are placed prior to ‘‘frameless’’ stereotactic surgery.


(pins), including ‘‘frame’’ devices similar to the aforementioned stereotactic

headframes. In particular, Parkinson’s disease in patients who have developed

resistance to levodopa treatment may present for stereotactic thalamotomy or

pallidotomy. Deep brain lesions are produced with a probe utilizing radio-

frequency current causing ionic oscillations and temperature increases to 80�Cfor 1 to 2 minutes in the target brain tissue.

Anesthetic considerations

Many stereotactic surgical procedures are done on an awake patient. Routine

ASA monitors are placed, and arterial pressure measurement is generally not

required. Because patients are commonly in a sitting or semirecumbent position,

the use of a precordial Doppler is prudent. Venous air embolism has been

reported associated with burr hole placement [57].

Placement of the burr hole can be accomplished with local anesthesia

infiltration by the surgeon. The use of sedatives or analgesics is highly depend-

ent upon the procedure being performed. The presence of a space-occupying

lesion and increased intracranial pressure precludes the use of medications,

which may increase pCO2. Sedatives such as midazolam are acceptable in many

situations, while narcotic medications are generally not required. Lesioning,

particularly for Parkinson’s disease, requires active participation by the patient to

assess the amount of rigidity and cogwheeling present on the contralateral side;

therefore, no medications are used. However, that does not negate the need for

an anesthesiologist.

Intraoperative complications include the possibility of venous air embolus,

seizure [58], bleeding [59], and failed biopsy [60]. The author’s experience has

included one patient who had an intraoperative seizure, requiring removal of the

stereotactic headframe, and a patient exhibiting severe bradycardia during pallid-

otomy. These examples underline the fact that although the anesthetic may be

minimal or nonexistent, the presence of an anesthesiologist for immediate

medical care of the surgically compromised patient is a necessity.

The pediatric patient having stereotactic procedures usually requires a light

general anesthetic. Although awake craniotomy has been reported in a 12 year

old [61], most children do not understand medical rationale. The use of

‘‘frameless stereotaxy’’ may decrease the number of pediatric patients that have

to be anesthetized for both their imaging and surgical portions of their stereo-

tactic surgery.

Thoracoscopic sympathectomy

Neurosurgeons are doing thoracic sympathectomies for hyperhidrosis and

pain syndromes [62,63]. A thoracoscopic approach offers good surgical results

while decreasing postoperative pain and complications. Neuroanesthesiologists


experienced in the placement of double-lumen endotracheal tubes or bronchial

blockers and single-lung ventilation physiology will experience little problem

with this procedure. Postoperative pain control may be accomplished with local

anesthesia at the portal sites. This surgical procedure has moved into the same-

day surgery arena when the patient does not require chest tubes [64].

Keyhole foraminotomy

The use of small incisions and a posterior approach has led to good surgical

results in the treatment of radicular pain. Decompression of an involved nerve

using microsurgical approaches has been found to avoid the use of an anterior

approach to the cervical spine with or without fusion [65]. Anesthetic consid-

erations revolve around positioning the prone patient. Careful positioning and

padding are a priority. Respiratory function actually improves in the prone

position compared to the supine anesthetized position, which is associated with

a decrement in functional residual capacity. Care must be taken to avoid kinking

or compression of the endotracheal tube.

A more recently revealed consideration for neuroanesthesiologists is the rare

occurrence of blindness following surgery and anesthesia in the prone position

[66,67]. This complication may be due to anterior ischemic optic neuropathy, and

has been associated with prolonged prone positioning. Other possible factors

include hypotension, changes in central venous pressure [66] or orbital pressure,

anemia, or a combination of any of the above. There is at present no reliable

method for detecting persons at risk for this complication [68].

Radiosurgery

Since 1951, stereotactic radiosurgery has treated patients with particle radi-

ation, photon radiation, and multisource cobalt-60 gamma units [39]. The

‘‘gamma knife’’ has been used to treat acoustic neuromas [69], AVM [70],

trigeminal neuralgia [71], and pituitary tumors. The advantage of this type of

radiation surgery is that radiation is delivered via multiple narrow beams,

coalescing at the target site. Thus, a much larger amount of brain tissue is

exposed through multiple-beam pathways, limiting the damage to normal tissue.

Focusing the beams to a single small area where the cumulative energy is

destructive necessitates an anesthetic technique that prevents movement of the

patient. The pediatric population is benefited by airway control and at times a

light general anesthetic. However, the advantage of this noninvasive technique

lies in the avoidance of general anesthesia. Most adult patients require only mild

sedation, while heavy sedation may result in involuntary movement. General

anesthesia is indicated for adults who have movement disorders or who cannot

tolerate the long duration (4 hours) of these procedures.


Summary

Neurosurgerical techniques utilizing minimally invasive approaches will

continue to emerge. For some of these future possibilities, anesthesia may not

be required. Other types of neurosurgery, whether performed by humans or a

machine, will require entry through the cranium and an absolute lack of move-

ment. Anesthesia will keep pace with these innovations by accurately controlling

the delivery of anesthetic to achieve optimal conditions. This control will allow

for a safer, more comfortable surgical procedure while decreasing blood loss and

morbidity associated with neurosurgery.

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Intracranial vascular surgery

Audree A. Bendo, MDDepartment of Anesthesiology, SUNY/Downstate Medical Center, 450 Clarkson Avenue,

Box 6, Brooklyn, NY 11203, USA

Intracranial aneurysms

Epidemiology

Subarachnoid hemorrhage (SAH) from rupture of an intracranial aneurysm is a

devastating disease, affecting an estimated 21,000 patients annually in North

America [1,2]. Despite considerable advances in the management of these pa-

tients, outcome remains poor, with overall mortality rates of 25% and significant

morbidity among approximately 50% of survivors [1,2].

In the most recent studies, the overall incidence of SAH is six to eight per

100,000 people [1,2]. The peak incidence for rupture is in the fifth and sixth

decades of life, and is greater for woman than men. Several potential risk factors

for aneurysm rupture have been identified (Table 1) [1,2].

The management of patients with unruptured intracranial aneurysms (UIAs)

remains controversial [2–4]. The International Study of Unruptured Intracranial

Aneurysms found the rupture rate of small aneurysms (< 10 mm diameter) was

0.05% per year in patients with no prior SAH, and 0.5% per year for large (>10 mm

diameter) aneurysms and for all aneurysms in patients with previous SAH [4]. This

study revealed that surgery did not reduce the rate of disability and death in patients

with unruptured aneurysms smaller than 10 mm in diameter and no history of

SAH [4]. Current recommendations for the treatment of UIAs have been published

by the Stroke Council of the American Heart Association [4].

A patient with aneurysmal SAH may be classified according to one of several

grading systems: Botterell’s original classification [5], the modification by Hunt

and Hess (Table 2) [6], or the more recent World Federation of Neurosurgeons

(WFNS) SAH scale (Table 3) [7]. These classifications are used by neuro-

surgeons to estimate surgical risk and outcome. Higher grades, or patients who

are clinically more impaired, are associated with the presence of cerebral


PII: S0889 -8537 (01 )00007 -4

E-mail address: [email protected] (A.A. Bendo).


20 (2002) 377–388

vasospasm, intracranial hypertension, and increased surgical mortality. In general,

the poorer the grade on hospital admission, the worse the prognosis.

The disease: clinical features and complications

The presence of blood in the subarachnoid space causes an abupt, marked rise

in intracranial pressure (ICP), which often results in systemic hypertension and

dysrhythmias. The abrupt increase in ICP accounts for the acute onset of a

sudden, severe headache. The classic presentation of aneurysmal SAH is that of

severe headache associated with stiff neck, photophobia, nausea, vomiting, and

often transient loss of consciousness. With this presentation, the diagnosis of

SAH is obvious. In about 50% of patients, a small bleed or ‘‘warning leak’’

precedes a major aneurysmal rupture [8]. Warning symptoms and signs tend to

be mild and nonspecific (headache, dizziness, orbital pain, slight motor or

sensory disturbance), and are generally ignored or misidagnosed by both patient

and physician.

The diagnosis of SAH is made by the combination of clinical findings and a

noncontrast CT scan of the head. When performed within a day of aneurysm

rupture, CT reveals a high-density (white) blood clot in basal subarachnoid

cisterns in about 95% of patients. This is followed by selected cerebral angiog-

raphy to document the presence and anatomic features of the aneurysm. Aneu-

rysms are classified according to location and size. They arise at a branch or

bifurcation, usually at a point where a major vessel makes a turn, changing the

axial flow of blood.

Table 1

Potential risk factors for aneurysm rupture

. Cigarette smoking

. Hypertension

. Alcohol consumption

. Cocaine and amphetamine abuse

. Oral contraceptive use

. Plasma cholesterol > 6.3 mmol/L

. Genetic conditions, e.g., ADPKD

. Familial (first-degree relatives)

Table 2

Hunt and Hess classification of patients with subarachnoid hemorrhage

Grade Criteria

0 Unruptured aneurysm.

I Asymptomatic, or minimal headache and slight nuchal rigidity.

II Moderate to severe headache, nuchal rigidity, no neurological deficit other than cranial nerve palsy.

III Drowsiness, confusion, or mild focal deficit.

IV Stupor, moderate to severe hemiparesis, early decerebration, vegetative disturbance.

V Deep coma, decerebrate rigidity, moribund.

A.A. Bendo / Anesthesiology Clin N Am 20 (2002) 377–388378

Complications

There are several potential complications of SAH and surgical treatment of

aneurysms (Table 4). The most important of these are rebleeding, vasospasm,

intracranial hypertension, and hydrocephalus.

Rebleeding occurs most comonly during the first 24 hours following initial

SAH. The chance of rebleeding is abour 4% within the first day; after 48 hours, it

is 1.5% per day, with a cumulative rebleeding rate of 19% by the end of 2 weeks

[9]. Recurrent aneurysmal hemorrhage is a devastating complication associated

with increased morbidity and mortality.

Because of the incidence of rebleeding with conservative management of

SAH, early aneurysm clipping (days 0–3) is currently recommended for patients

who are alert on admission. The debate over ‘‘early versus late’’ surgery was

largely resolved following the report of The International Cooperative Study on

the Timing of Aneurysm Surgery [10,11]. In this trial, overall management results

demonstrated a similar mortality (20%) and good outcome (60%) for patients

with surgery planned for early (0–3 days) and late (11–14 days) intervals. The

least favorable outcome and highest mortality occurred in patients with planned

surgery for days 7 to 10 after SAH. Patients who were alert on admission did best

with early surgery. When only the North American patients were analyzed, early

surgery (days 0–3) provided the best results in lower grade patients [12]. There

was no difference in the incidence of intraoperative rupture between early and

late surgery, and although there was a relationship between ‘‘tightness’’ of the

brain during surgery and the interval from SAH to operation, aneurysm dissection

was no more difficult in early than in late surgery [11]. The timing of surgery

does not influence the risk for cerebral vasospasm [13].

Table 4

Potential complications of subarachnoid hemorrhage

. Rebleeding

. Vasospasm

. Intracranial hypertension

. Hydrocephalus

. Hyponatremia/volume contraction

. Seizures

Table 3

World Federation of Neurosurgeons (WFNS) SAH Scale [9]

WFNS grade GCS scale Motor deficit

I 15 Absent

II 13–14 Absent

III 13–14 Present

IV 7–12 Present or absent

V 3–6 Present or absent

Abbreviations: SAH, subarachnoid hemorrhage; GCS, Glasgow Coma Scale.

A.A. Bendo / Anesthesiology Clin N Am 20 (2002) 377–388 379

Cerebral vasopasm is a major cause of morbidity and mortality in SAH

patients [10,14]. Angiographic evidence of vasospasm can be detected in up to

70% of patients. However, clinical vasospasm with ischemic deficits is observed

in approximately 30% of patients, most often between days 4–12, with a peak at

6–7 days following SAH [10]. The diagnosis of vasospasm is confirmed by

angiography. The transcranial Doppler (TCD) is a safe, repeatable, noninvasive

method to identify and quantify vasospasm, and can be used to evaluate the

effectiveness of various therapies [15].

The mechanism responsible for vasospasm is unknown; however, structural

and pathologic changes have been demonstrated in the vessel wall [16]. There is

also evidence that vasospasm after SAH correlates with the amount of blood in

the subarachnoid space, and removal of extravasated blood decreases the

occurrence and severity of ischemic deficits [14,16]. The component in blood

implicated in causing cerebral arterial vasospasm is oxyhemoglobin.

Many drugs have been investigated for prevention or treatment of vasospasm,

but most are ineffective. The calcium channel blocker, nimodipine, has become

standard prophylactic therapy. However, the efficacy of prophylactic nimodipine

after SAH has been seriously challenged [17]. A recent meta-analysis showed a

reduction in vasospasm in nimodipine groups, but a corresponding reduction in

mortality was slight and not statistically significant compared to control groups.

‘‘Triple H’’ therapy—hypervolemia, hypertension, and hemodilution—has

become the mainstay of treatment for ischemic neurologic deficits caused by

cerebral vasospasm [18–20]. To improve cerebral blood flow to areas of impaired

autoregulation, cerebral perfusion pressure is increased by intravascular volume

expansion and induced hypertension. Intravascular volume expansion is accom-

plished with infusion of crystalloid, colloid, or blood to a pulmonary capillary

wedge pressure of 12–18 mmHg or a central venous pressure of 10–12 mmHg. If

this regimen does not reverse the deficit, a vasopressor (eg, dopamine) is

introduced to raise systemic blood pressure until the neurologic deficits subside

or reverse. This therapy can worsen cerebral edema, increase ICP, and cause

hemorrhagic infarction. Systemic complications include pulmonary edema and

cardiac failure in patients at risk. Hemodilution, the last component of ‘‘triple H’’

therapy, decreases blood viscosity and improves cerebral blood flow. The optimal

hematocrit thought to maximize the oxygen delivery to tissues has been estimated

at 33%, but may be higher in the ischemic brain.

Another method for treating symptomatic vasospasm is cerebral angioplasty.

Transluminal angioplasty can be used to dilate constricted major cerebral vessels

in patients refractory to conventional treatment [21,22]. Superselective intra-

arterial infusion of papaverine dilates distal vessels not accessible to angioplasty

[23]. These procedures are usually performed under general anesthesia to

minimize movement and permit accurate placement of the intraarterial balloon

used to dilate the cerebral vessels. The risks of angioplasty include aneurysm

rupture, intimal dissection, vessel rupture, ischemia, and infarction.

Intacranial hypertension is present to some degree in most patients following

a SAH. In the uncomplicated case, intracranial hypertension does not require


specific treatment. Intracranial pressure gradually returns to normal by the end

of the first week. If an intracerebral hemorrhage, intraventricular hemorrhage,

vasospasm, or hydrocephalus develops, intracranial hypertension may be se-

vere and require treatment. Patients may require emergency ventriculostomy,

steroids, diuretics, or intubation and hyperventilation. ICP should be lowered

gradually, especially in patients with unclipped aneurysms. Abrupt lowering of

ICP by lumbar puncture, ventricular drainage, or rapid infusion of mannitol can

induce rebleeding.

Acute (obstructive) hydrocephalus after SAH complicates approximately

20% of the cases [24]. Although controversial, ventriculostomy has been re-

commended for treating acute hydrocephalus in patients with a diminished level

of consciousness after SAH [24]. Ventriculostomy has been associated with

increased rebleeding and infection.

Anesthetic management

Preoperative evaluation

When the neurologic examination is performed, the patient’s clinical grade is

noted. The patient’s CT scan or MR image is evaluated to assess the presence and

severity of intracranial hypertension. The severity, acuteness, and stage of the

SAH, the presence of intracranial hypertension, and the timing of surgery will

determine the anesthetic management.

Electrolyte abnormalities frequently occur secondary to the syndrome of

inappropriate antidiuretic hormone (SIADH) secretion or diabetes insipidus.

Hyponatremia is the most common electrolyte disturbance detected, and is often

associated with a high urinary sodium and osmolality, which is expected with

SIADH. Unlike a patient with SIADH, however, the patient with SAH usually

has a contracted intravascular volume despite hyponatremia. This cerebral salt-

wasting syndrome may be caused by release of an atrial natriuretic factor from the

damaged brain. The recommended therapy is to maintain normovolemia with

isotonic saline solutions. Other factors contributing to intravascular volume

contraction in these patients are supine diuresis secondary to increased thoracic

blood volume, negative nitrogen balance, decreased erythropoiesis, increased

catecholamine levels, and iatrogenic blood loss. Fluid balance and electrolyte

abnormalities should be corrected prior to surgery.

Electrocardiographic abnormalities are commonly associated with ruptured

cerebral aneurysms [25]. The ECG changes include ST-segment depression or

elevation, T-wave inversion or flattening, U-waves, prolonged Q-T intervals, and

dysrhythmia. The ECG changes are not necessarily associated with increased

operative morbidity and mortality or consistent increases in serum myoglobin or

creatine kinase. They usually resolve within 10 days following SAH, and require

no special treatment. When indicated, cardiac troponin-I levels should be drawn

to determine the clinical significance of these abnormalities [26]. When cardiac

dysrhythmia and occasional frank subendocardial ischemia result in cardiac

failure, appropriate treatment must be instituted.


Intraoperative management

The anesthetic goals for intracranial aneurysm surgery are to avoid aneurysm

rupture, maintain cerebral perfusion pressure and transmural aneurysm pressure,

and provide, a ‘‘slack’’ brain. Patients in WFNS scale I or II who appear anxious

should receive premedication. Cerebral perfusion pressure (CPP) is maintained by

using drugs in doses that avoid sudden or profound decreases in systemic blood

pressure or increases in ICP. Similarly, transmural pressure, which is defined as the

difference between mean arterial pressure and ICP, must be maintained. (The

pressure within an aneurysm is equal to the systemic blood pressure.) The

relationship between transmural pressure and wall stress or tension of the

aneurysm is linear. An increase in mean arterial pressure or fall in ICP will

increase transmural pressure, wall stress, and risk of aneurysm rupture. Methods to

control brain volume and ICP, such as hyperventilation, diuretics, spinal drainage,

and head position, facilitate surgical exposure and minimize the retraction pressure

that can cause tissue injury.

Standard monitoring plus an arterial pressure catheter are routinely used. A

central venous pressure (CVP) or pulmonary artery (PA) catheter is recommen-

ded in WFNS scale III or higher to provide a more accurate measure of the

patient’s volume status and cardiac function intraoperatively and postoperatively

in the prevention or management of cerebral vasospasm. Electrophysiologic

monitoring with the electroencephalogram (EEG) or somatosensory evoked

potentials (SSEPs) may be used to monitor the adequacy of cerebral perfusion

during induced hypotension or temporary/permanent aneurysm clip application.

When barbiturates are administered for brain protection, the EEG is used to guide

the dose required to achieve a burst suppression pattern.

To minimize the risk of hypertension and aneurysmal rupture during induction

of anesthesia, intravenous lidocaine and the beta-adrenergic antagonist (esmolol)

or labetalol are recommended. Following induction, ventilation is mechanically

controlled to maintain normocarbia, if ICP is normal. If intracranial hypertension

is present, the PaC02 is lowered to 30–35 mmHg. A deep plane of anesthesia

must be established prior to insertion of head pins, scalp incision, turning the

bone flap, and opening the dura to avoid a hypertensive response. When intra-

cranial hypertension is present, anesthesia should be deepened with additional

doses of thiopental and fentanyl until the skull is opened. Several techniques can

be instituted during aneurysm surgery to provide a ‘‘slack’’ brain and facilitate

dissection. These are hyperventilation of the lungs, osmotic diuresis, barbiturate

administration, and CSF drainage during the procedure.

The drugs most frequently used to maintain anesthesia during aneurysm

surgery are fentanyl and thiopental (bolus dosing or infusions) in conjunction

with isoflurane in oxygen. A propofol infusion instead of thiopental may also be

used for these procedures. In conditions of poor intracranial compliance, a

continuous infusion of thiopental (1–3 mg�kg�1�h�1) following a bolus dose

of 5 mg�kg�1 is recommended as the primary anesthetic for aneurysm surgery in

conjunction with a fentanyl infusion (1–4 mg�kg�1�h�1) and one-half MAC

concentration of isoflurane in oxygen. The total dose of fentanyl should not


exceed 10–12 mg�kg�1, unless postoperative ventilation is planned. Potential

disadvantages to using thiopental are blood pressure instability and prolonged

recovery from anesthesia. With this technique, a pulmonary artery catheter should

be inserted to monitor and optimize cardiovascular performance and intravascular

volume. Following an uneventful aneurysm clip application, the thiopental

infusion is discontinued to prevent a delay in recovery.

Prior to aneurysm clipping, isotonic crystalloid solutions without glucose are

administered to replace overnight fluid losses and provide hourly maintenance

fluid requirements. When the aneurysm is secured, intraoperative fluid deficits

are replaced and additional volume is administered. At the time of aneurysm

dissection, blood is available for transfusion in case the aneurysm ruptures. A

bolus of thiopental (3–5�mg�kg�1) may be given before temporary occlusion of a

major intracranial vessel and before aneurysm clipping. If temporary occlusion

lasts longer than 10 minutes, recirculation should be established, and additional

thiopental administered before reapplying the temporary clip. Following aneu-

rysm clipping, the central venous pressure and pulmonary capillary wedge

pressure are raised to 10–12 mmHg or 12–18 mmHg, respectively, with crys-

talloid, colloid, or blood. A postoperative hematocrit between 30–35% is

desirable. As discussed previously, intravascular volume expansion with hemo-

dilution is recommended to reduce the risk of postoperative cerebral vasospasm.

When considering the use of deliberate hypotension during aneurysm

dissection, the risk-benefit ratio must be assessed for each patient [27]. The

potential benefit of hypotension must be weighed against the risk of causing

cerebral ischemia or ischemia to other organs. Patients with a history of cardio-

vascular disease, occlusive cerebrovascular disease, intracerebral hematoma,

fever, anemia, and renal disease are not good candidates for induced hypotension.

Such patients should only be subjected to moderate reductions in systemic blood

pressure (20–30 mmHg), if at all. The most commonly used agents to induce

hypotension are sodium nitroprusside, isoflurane, and esmolol. Overall, induced

hypotension has declined in use and has been replaced by temporary clipping

[28,29]. The temporary occlusion of a feeding artery produces an acute reduction

in focal blood flow and a slack aneurysm, thus eliminating the need for induced

hypotension and its systemic effects. Depending on the location of the aneurysm,

either somatosensory evoked potentials or brain stem auditory evoked potentials

can be used to monitor the safety of temporary occlusion [28].

The major intraoperative complication of aneurysm surgery is hemorrhage.

When an aneurysm ruptures intraoperatively, there is potential for major ischemic

damage from hypotension and the surgical efforts to control bleeding. Hemor-

rhagic death is also possible. When the leak is small and the dissection is complete,

it may be possible for the surgeon to gain control with suction and then apply the

permanent clip to the neck of the aneurysm. Alternatively, temporary clips can be

applied proximal and distal to the aneurysm to gain control. Thiopental may be

given to provide some protection prior to the placement of the temporary clip.

During temporary occlusion, normotension should be maintained to maximize

collateral perfusion. If temporary occlusion is not planned or not possible and


blood loss is not significant, the mean arterial pressure may be transiently

decreased to 50 mmHg or lower to facilitate surgical control. When bleeding is

excessive, aggressive fluid resuscitation and blood transfusion must commence

immediately. Administration of cerebroprotective agents may not be possible

because of associated hemodynamic effects. Under these conditions, induced

hypotension is not advised, as the intravascular volume must be restored first.

Intraoperative cerebral protection

Thiopental has been the drug of choice for intraoperative cerebral protection

during aneurysm surgery. In animal models, barbiturates have shown protection

during incomplete focal ischemia, but not during global ischemia [30]. Barbitu-

rates are the only agents shown to be useful in humans [30].

Many practitioners institute mild intraoperative hypothermia (32–34�C)during aneurysm surgery [31] to enhance the brain’s ability to tolerate ischemia

[32]. Its value is unproven, and its use may produce harmful side effects [33]. A

large multi-institutional study is underway to determine whether mild intraoper-

arive hypothermia will benefit this patient population [34].

The primary goals at the conclusion of surgery are to avoid coughing, strain-

ing, hypercarbia, and hypertension. For patients in WFNS grades I and II who

have no intraoperative complications, the endotracheal tube should be removed in

the operating room and a neurologic examination performed. Patients who have

intraoperative complications or have depressed consciousness preoperatively

(WFNS grades III–V) should remain intubated and receive mechanical ventila-

tion until their neurologic status improves.

Postoperative concerns

Variation in systemic blood pressure is common postoperatively, and contri-

butes significantly to morbidity and mortality in patients following aneurysm

repair. Causes of hypertension include preexisting hypertension, pain, and CO2

retention from residual anesthesia. The treatment of postoperative hypertension is

critical to prevent the formation of cerebral edema or hematoma. Antihypertensive

drugs should be administered after respiratory depression and pain are eliminated

as causes. The hypertensive response usually subsides within 12 hours. When

indicated, preoperative antihypertensive drugs are reinstituted and maintained.

After clipping of the aneurysm, cerebral vasospasm continues to pose a threat

to neurologic integrity. Postoperative hypotension must be avoided, and the

patient’s intravascular volume must be accurately assessed with either a central

venous pressure or pulmonary artery catheter. As previously discussed, a higher

than normal intravascular fluid volume should be maintained.

Arteriovenous malformations

An arteriovenous malformation (AVM) of the brain consists of a tangle of

congenitally malformed blood vessels that forms an abnormal communication


between the arterial and venous systems. The arterial afferents flow directly into

venous efferents without the usual resistance of an intervening capillary bed;

thus, oxygenated blood is shunted directly into the venous system, leaving

surrounding brain tissue transiently or permanently ischemic.

Neurological AVMs affect about 1% of the population in the United States, and

are about one tenth as common as aneurysms [35]. They occur at roughly equal

rates in males and females of all racial or ethnic backgrounds. Seizures (partial or

total) and headaches are the most frequent symptoms of AVMs. The onset of

complaints is usually between the ages of 20 and 40. Approximately 80% of

patients with AVMs develop symptoms by the time they are 40 years old. If the

patient does not develop symptoms by 40 or 50 years old, the lesions tend to remain

stable and asymptomatic (approximately 20%) [36]. The most common initial

presentation is spontaneous hemorrhage, followed by seizures, then less frequently

by progressive focal neurologic sensory/motor deficits occurring in a child or

young adult. Avein of Galen AVM in infants may present with hydrocephalus and/

or high-output cardiac failure. The natural history of AVMs is not completely

understood. The risk of hemorrhage is approximately 1–3% per year. The rate of

rebleeding is 6% in the first year after a hemorrhage and about 2% per year

thereafter [36]. Mortality from initial hemorrhage is high, with reports between

10–30%. Recurrence of hemorrhage with a fatal outcome is a constant danger.

There are several options for the management of AVMs, incuding surgical

excision, embolization, stereotactic radiosurgery (proton beams, gamma rays, or

linear accelerator), a combination of the above, and leaving AVMs alone. AVMs

of suitable size and location can be managed successsfully with surgical excision.

Surgical mortality ranges from 0.6% to 14%, and correlates with size, location,

and pattern of involvement of the AVM [36]. Early postoperative morbidity

ranges from 17% to 28%; however, outcome studies report improvement in

morbidity over time [37]. To avoid intraoperative or postoperative massive brain

swelling or hemorrhage of large AVMs, operations may be staged or follow

preoperative embolization.

Special anesthetic considerations

In addition to providing anesthesia for craniotomy and resection of the AVM,

anesthesia may be required for radiologic embolization of the AVM. Closed

embolization of cerebral AVMs is uncomfortable and invasive. This procedure

may be performed under local anesthesia with sedation or under general anes-

thesia. It has been performed successfully with various combinations of sedative

drugs (opioids, droperidol, midazolam, or propofol) that allow neurologic exami-

nations during the procedure and permit immediate diagnosis of complications

[21,36]. Children, uncoopeative patients, and those with intracranial hypertension

or airway problems usually require general anesthesia. General anesthesia does

not allow direct neurologic assessment. Potential complications of embolization

procedures are embolic or ischemic stroke and hemorrhage from the AVM, either


acute or delayed. New onset or preexisting seizures may occur during the

embolization procedure requiring treatment with benzodiazepines or barbiturates.

The anesthetic management of patients with AVMs is similar to the management

of patients for aneurysm surgery. Depending on the presentation, the anesthetic

approach is modified. For example, a large bleed may present with symptoms

relating to mass effects and require maneuvers to reduce ICP. High flow through a

large intact AVMmay cause a ‘‘steal,’’ with resulting cerebral ischemia, and require

different techniques to improve CPP. With more extensive lesions, hypothermia

and high-dose barbiturates have been recommended for brain protection. Induced

hypotension may also be required to reduce lesion size and blood flow.

Hyperemic complications, defined as perioperative edema or hemorrhage,

may occur after removel of the AVM. Although the mechanism is unclear, one

theory proposes that breakthrough cerebral edema and hemorrhage result when

blood flow from the surgically obliterated AVM is diverted to the surrounding

brain. The smaller vessels in the brain surrounding the AVM are not accustomed

to the higher pressure-flow state, and autoregulation is exceeded, resulting in

severe brain swelling, edema, and hemorrhage. The clinical syndrome of cerebral

hyperperfusion with normal CPP has been called normal perfusion pressure

breakthrough [38]. Other studies report information that is not consistent with this

theory [39,40]. Immediate treatment should include the simultaneous application

of high-dose barbiturates, osmotic diuretics, hyperventilation, and maintenance of

a low normal mean arterial pressure (MAP). Hypothermia may also be instituted.

When marked brain swelling occurs intraoperatively, the patient should remain

intubated, hyperventilated, and sedated postoperatively. Hypertension during

emergence and postoperatively must be controlled, preferably with beta-blockers,

to prevent bleeding into the bed of the AVM.

Summary

The management of patients for intracranial vascular surgery is very challen-

ging, requiring an aggressive multidisciplinary approach to provide care and

improve outcome. This ensures early identification and treatment of the disease,

resuscitation when indicated, and continuous and intensive perioperative mon-

itoring to identify and treat potential complications. With advances in neuro-

imaging, interventional, and surgical techniques, we are increasingly involved in

providing neuroanesthetic skills and insightful care to facilitate the successful

management of these high-risk patients.

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Pediatric neuroanesthesia

Sulpicio G. Soriano, MD*, Elizabeth A. Eldredge, MD,Mark A. Rockoff, MD

Children’s Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA

Recent advances in pediatric neurosurgery have dramatically improved the

outcome in infants and children afflicted with surgical lesions of the central

nervous system (CNS). Although most of these techniques were first applied to

adults, the physiologic and developmental differences that are inherent in

pediatric patients present challenges to neurosurgeons and anesthesiologists alike.

The aim of this paper is to highlight these age-dependent approaches to the

pediatric neurosurgical patient.

Developmental considerations

Age-dependent differences in cerebrovascular physiology and cranial bone

development influence the approach to the pediatric neurosurgical patient.

Cerebral blood flow is coupled tightly to metabolic demand, and both increase

proportionally immediately after birth. Estimates from animal studies place the

autoregulatory range of blood pressure in a normal newborn between 20 and

60 mmHg [1]. This range is consistent with relatively low cerebral metabolic

requirements and low blood pressure during the perinatal period. More impor-

tantly, the slope of the autoregulatory slope drops and rises significantly at the

lower and upper limits of the curve, respectively. This narrow range, with sudden

hypotension and hypertension at either end of the autoregulatory curve, places the

neonate at risk for cerebral ischemia and intraventricular hemorrhage, respec-

tively. Another developmental difference between adults and pediatric patients is

the larger percentage of cardiac output that is directed to the brain, because the

head of the infant and child accounts for a large percentage of the body surface

area and blood volume. These factors place the infant at risk for significant

hemodynamic instability during neurosurgical procedures.


PII: S0889 -8537 (01 )00008 -6


E-mail address: [email protected] (S.G. Soriano).


20 (2002) 389–404

The infant cranial vault is also in a state of flux. Open fontanels and cranial

sutures lead to a compliant intracranial space. The mass effect of a tumor or

hemorrhage are often masked by a compensatory increase in the intracranial

volume through the fontanels and sutures. As a result, infants presenting with

signs and symptoms of intracranial hypertension have fairly advanced pathology.

Preoperative evaluation and preparation

Closed-claim studies have revealed that neonates and infants are at higher risk

for morbidity and mortality than any other age group [2,3]. Respiratory and

cardiac-related events account for a majority of these complications. However, a

major pitfall in the management of infants and children for neurosurgery is the

presence of coexisting diseases. Given the urgent nature of most pediatric

neurosurgical procedures, a thorough preoperative evaluation may be difficult.

However, a complete airway examination is essential, because some craniofacial

anomalies may require specialized techniques to secure the airway [4]. Most

cardiac morbidity due to congenital heart disease occurs during the first year of

life [5]. Congenital heart disease may not be apparent immediately after birth, and

the hemodynamic alterations caused by anesthetic agents, mechanical ventilation,

and blood loss during surgery can unmask these cardiac defects. Echocardiog-

raphy can be helpful in the assessment of the heart, and a pediatric cardiologist

should evaluate patients with suspected problems to help optimize cardiac

function prior to surgery. Other coexisting diseases that can alter the conduct

of anesthesia are list in Table 1.

Table 1

Perioperative concerns for infants and children with neurological disease

Condition Anesthetic implications

Congenital heart disease Hypoxia and cardiovascular collapse

Prematurity Postoperative apnea

Upper respiratory tract infection Laryngospasm and postoperative hypoxia/pneumonia

Craniofacial abnormality Difficulty with airway management

Denervation injuries Hyperkalemia after succinycholine

Resistance to nondepolarizing muscle relaxants

Chronic anticonvulsant therapy for epilepsy Hepatic and hematological abnormalities

Increased metabolism of anesthetic agents

Arteriovenous malformation Potential congestive heart failure

Neuromuscular disease Malignant hyperthermia

Respiratory failure

Sudden cardiac death

Chiari malformation Apnea

Aspiration pneumonitis

Hypothalamic/pituitary lesions Diabetes insipidus

Hypothyroidism

Adrenal insufficiency

S.G. Soriano et al. / Anesthesiology Clin N Am 20 (2002) 389–404390

Preoperative sedatives given prior to induction of anesthesia can ease the

transition from the preoperative holding area to the operating room [6]. Midazolam

given orally is particularly effective in relieving anxiety and producing amnesia. If

an indwelling intravenous (i.v.) catheter is in place, midazolam can be slowly

administered to achieve sedation. Alternatively, sedatives such as barbiturates can

be given rectally to induce sleep in preschool children who are uncooperative, and

this avoids the use of intramuscular injections. However, methohexital adminis-

tered rectally has been shown to induce seizures in patients with epilepsy [7].


Induction of anesthesia

The patient’s neurological status and coexisting abnormalities will dictate the

appropriate technique and drugs for induction of anesthesia. General anesthesia

can be established by inhalation of sevoflurane and nitrous oxide with oxygen. A

nondepolarizing muscle relaxant such as pancuronium is then administered to

facilitate intubation of the trachea. Alternatively, if the patient has i.v. access,

anesthesia can be rapidly induced with sedative/hypnotic drugs such thiopental

(5–8 mg/kg) or propofol (3–5 mg/kg). Patients at risk for aspiration pneumonitis

should have a rapid-sequence induction of anesthesia performed with thiopental

or propofol, immediately followed by a rapid-acting muscle relaxant such as

succinylcholine or rocuronium.

Airway management

Developmental differences in the cricoidthyroid and tracheobrochial tree have

a significant impact on management of the pediatric airway. The infant’s larynx is

funnel shaped, and narrowest at the level of the cricoid, making this the smallest

cross-sectional area in the infant airway. This feature places the infant at risk for

subglotic obstruction secondary to mucosal swelling after prolonged endotracheal

intubation with a tight-fitting endotracheal tube. Because the trachea is relatively

short, an endotracheal tube can migrate into a mainstem bronchus if the infant’s

head is flexed, as is the case for a suboccipital approach to the posterior fossa or

the cervical spine. Therefore, the anesthesiologist should auscultate both lung

fields to rule out inadvertent intubation of a mainstem bronchus after positioning

the patient. Nasotracheal tubes are best suited for situations when the patient will

be prone and when postoperative mechanical ventilation is anticipated. Further-

more, the endotracheal tube can kink at the base of the tongue when the head is a

flexed and also lead to pressure necrosis of the oral mucosa.

Maintenance of anesthesia

The choice of anesthetic agents for maintenance of anesthesia has been

shown not to affect the outcome of neurosurgical procedures [8]. The most

S.G. Soriano et al. / Anesthesiology Clin N Am 20 (2002) 389–404 391

frequently utilized technique for neurosurgery consists of the opioid fentanyl

administered at a rate of 2–5 mg/kg/h intravenously along with inhaled nitrous

oxide (70%) and low-dose isoflurane (0.2–0.5%). Deep neuromuscular block-

ade is maintained during most neurosurgical procedures to avoid patient

movement. Patients on chronic anticonvulsant therapy will require larger doses

of muscle relaxants and narcotics because of induced enzymatic metabolism of

these agents (Fig. 1) [9,10] .Muscle relaxation should be withheld, or should

not be maintained when assessment of motor function during seizure and spinal

cord surgery is planned.

Fluid restriction and diuretic therapy may lead to hemodynamic instability and

even cardiovascular collapse if sudden blood loss occurs during surgery.

Therefore, normovolemia should be maintained through the procedure. Normal

saline is commonly used as the maintenance fluid during neurosurgery because it

is mildly hyperosmolar (308 mOsm/kg), and it theoretically attenuates brain

edema. However, rapid infusion of normal saline (30 mL/kg/h) is associated with

hyperchloremic acidosis [11]. Hyperventilation and maximization of venous

Fig. 1. Patients on chronic anticonvulsant therapy have increased requirements for nondepolarizing

muscle relaxants. The recovery times for return of muscle function in the anticonvulsant was

significantly faster than the control group ( * p < 0.05, mean ± SD) [10].


drainage of the brain by elevating the head can minimize brain swelling. Should

these maneuvers fail, mannitol can be given at a dose of 0.25 to 1.0 g/kg

intravenously. This will transiently alter cerebral hemodynamics and raise serum

osmolality by 10–20 mOsm/kg [12]. However, repeated dosing can lead to

extreme hyperosmolality, renal failure, and further brain edema. Furosemide is a

useful adjunct to mannitol in decreasing acute cerebral edema, and has been

shown in vitro to prevent rebound swelling due to mannitol [13]. All diuretics

will interfere with the ability to utilize urine output as a guide to intravascular

volume status.

Vascular access

Due to limited access to the child during neurosurgical procedures, optimal

intravenous access is mandatory prior to the start of surgery. Typically, two large-

bore venous cannulae are sufficient for most craniotomies. Should initial attempts

fail, central vein cannulation may be necessary. Cannulation of femoral vein

avoids the risk of pneumothorax associated with subclavian catheters, and does

not interfere with cerebral venous return.

Monitoring

Given the potential for sudden hemodynamic instability due to venous air

emboli (VAE), hemorrhage, herniation syndromes, and manipulation of cranial

nerves, the placement of an intra-arterial cannula for continuous blood pressure

monitoring is mandatory for most neurosurgical procedures. An arterial catheter

will also provide access for sampling serial blood gases, electrolytes, and

hematocrit. The issue of central venous catheterization is controversial. Large-

bore catheters are too large for infants and most children, and central venous

pressures may not accurately reflect vascular volume, especially in a child in

the prone position. Therefore, the risks may outweigh the benefits of a central

venous catheter.

Standard neurosurgical technique may elevate the head of the table to improve

venous drainage, and is conducive to air entrainment into the venous system

through open venous channels in bone and sinuses (Fig. 2) [14]. Patients with

cardiac defects, such as patent foramen ovale or ductus arteriosus, are at risk for

arterial air emboli through these defects, and should be monitored carefully. A

precordial Doppler ultrasound can detect minute VAE, and should be routinely

used in conjunction with an end-tidal carbon dioxide analyzer and arterial

catheter in all craniotomies to detect VAE. Doppler probe is best positioned on

the anterior chest usually just to the right of the sternum at the fourth intercostal

space. An alternate site on the posterior thorax can be used in infants weighing

approximately 6 kg or less [15].

Recent advances in neurophysiologic monitoring have enhanced the ability to

safely perform more definitive neurosurgical resections in functional areas of the

brain and spinal cord. However, the CNS depressant effects of most anesthetic

agents limit the utility of these monitors. A major part of preoperative planning


should include a thorough discussion of the modality and type of neurophysio-

logic monitoring to be used during any surgical procedure. In general, electro-

corticography (ECoG) and electroencephalography (EEG) require low levels of

volatile anesthetics and barbiturates. Somatosensory-evoked potentials used

during spinal and brainstem surgery can be depressed by volatile agents and to

a lesser extent, nitrous oxide. An opioid-based anesthetic is the most appropriate

agent for this type of monitoring. Spinal cord and peripheral nerve surgery may

require electromyography (EMG) and detection of muscle movement as an end

point. Therefore, muscle relaxation should be avoided or not maintained during

the monitoring period.

Positioning

Patient positioning for surgery requires careful preoperative planning to allow

adequate access to the patient for both the neurosurgeon and anesthesiologist.

Table 2 describes various surgical positions and their physiologic sequelae. The

prone position is commonly used for posterior fossa and spinal cord surgery,

although the sitting position may be more appropriate for obese patients who

may be difficult to ventilate in the prone position (Fig. 3). In addition to the

physiologic sequelae of this position, a whole spectrum of compression and

stretch injuries has been reported. Padding under the chest and pelvis can

support the torso. It is important to ensure free abdominal wall motion because

increased intra-abdominal pressure can impair ventilation, cause venocaval

Fig. 2. Supine infant. Note that the infant’s head lies at a higher plane than the rest of his body. This

increases the likelihood for venous air embolism during craniotomies.


compression, and increase epidural venous pressure and bleeding. Fig. 4

illustrates proper positioning for these patients. Soft rolls are used to elevate

and support the lateral chest wall and hips to minimize increase abdominal and

thoracic pressure. In addition, this should allow a Doppler probe to be on the

chest without pressure. Many neurosurgical procedures are performed with

the head slightly elevated to facilitate venous and cerebral spinal fluid (CSF)

drainage from the surgical site. However, superior sagittal pressures decreases

with increasing head elevation, and this increases the likelihood of VAE [14].

Fig. 3. Sitting position. The sitting position affords optimal chest wall compliance in children with

respiratory disease and obesity.

Table 2

Physiologic effects of patient positioning

Position Physiological effect

Head-elevated Enhanced cerebral venous drainage

Decreased cerebral blood flow

Increased venous pooling in lower extremities

Postural hypotension

Head-down Increased cerebral venous and intracranial pressure

Decreased functional residual capacity (lung function)

Decreased lung compliance

Prone Venous congestion of face, tongue, and neck

Decreased lung compliance

Increased abdominal pressure can lead to venocaval compression

Lateral decubitus Decreased compliance of down-side lung


Extreme head flexion can cause brainstem compression in patients with posterior

fossa pathology, such as mass lesions or an Arnold-Chiari malformation.

Extreme rotation of the head can impede venous return through the jugular

veins and lead to impaired cerebral perfusion, increased intracranial pressure,

and cerebral venous bleeding.

Postoperative management

Close observation in an intensive care unit with serial neurologic examinations

and invasive hemodynamic monitoring is helpful for the prevention and early

detection of postoperative problems. Respiratory dysfunction is the leading

complication after posterior fossa craniotomies [16]. Airway edema is usually

self-limited, and may require endotracheal intubation as a stent. Occasionally,

ischemia or edema of the respiratory centers in the brainstem will interfere with

respiratory control and lead to postoperative apnea. Children with Chiari

malformations may be more prone to the respiratory depression [17]. Diabetes

insipidus can occur after surgery in the region of the hypothalamus and pituitary

gland, and can be managed acutely with an intravenous vasopressin infusion.

Postoperative nausea and vomiting can cause sudden rises in intracranial

pressure, and should be treated with a nonsedating antiemetic. However,

prophylactic administration of ondansteron during surgery is not effective in

decreasing the incidence of vomiting following craniotomies in children [18].

Fig. 4. Prone infant. Lateral rolls are used to elevate the infant and minimize thoracic and

abdominal pressure.


Clinical approaches

Neonatal emergencies

Most neonatal surgery is performed on an emergent basis [19], and there is more

than a 10-fold increase in perioperative morbidity and mortality in neonates when

compared with other pediatric age groups [2]. In addition to existing congenital

heart defects, congestive heart failure can occur in neonates with large cerebral

arteriovenous malformations, and this condition requires aggressive hemodynamic

support. Management of the neonatal respiratory system may be difficult because

of the diminutive size of the airway, craniofacial anomalies, laryngotracheal

lesions, and acute (hyaline membrane disease, retained amniotic fluid) or chronic

(bronchopulmonary dysplasia) disease. Because these conditions are in a state of

flux, they should be addressed preoperatively to minimize morbidity.

The neonatal central nervous system is capable of sensing pain and

mounting a stress response after a surgical stimulus [20]. However, neonatal

myocardial function is particularly sensitive to both inhaled and intravenous

anesthetics, and the use of these agents needs to be judicious to block surgical

stress without causing myocardial depression. An opioid-based anesthetic is

generally the most stable hemodynamic technique for neonates. The hepatic and

renal systems are also not fully developed, and neonates anesthetized with a

narcotic technique will often have delayed emergence and may require post-

operative mechanical ventilation.

Closure of a myelomeningocele or encephalocele presents special problems.

Positioning the patient for tracheal intubation may rupture the membranes

covering the spinal cord or brain. Therefore, careful padding of the lesion

(Fig. 5), and in some cases intubation of the neonate’s trachea in the left lateral

decubitus position, may be necessary. Most surgical closures of simple myelo-

meningoceles have relatively minimal blood loss. However, large lesions may

requirement significant undermining of cutaneous tissue to cover the defect and

pose larger risks for blood loss and hemodymanic instability. Recent advances in

the management of myelomeningoceles have lead to early intervention into the

intrauterine period [21]. The management of the fetus and mother during fetal

surgery has been reviewed extensively elsewhere [22,23].

Hydrocephalus

The most common neurosurgical procedure performed in major pediatric

centers is for the management of hydrocephalus. Regardless of the etiology,

whether it be overproduction of CSF due to choroid plexus papillomas or

obstruction of CSF flow secondary to a tumor or Chiari malformation, diagnosis

and alleviation of life-threatening intracranial hypertension should proceed

expeditiously. The mental status of the child should dictate the anesthetic

management as noted above, and intracranial hypertension can be managed

with hyperventilation and diuretics. Most neonates undergoing a closure of a


myelomeningocele are potential candidates for a ventriculo-peritoneal shunt

(VPS), and may have both procedures performed in one sitting. The long-term

management of hydrocephalus with VPS invariably increases the incidence of

mechanical failure and shunt infections. Should the peritoneum be infected,

alternate sites for the drainage limb of these extracranial shunts include the right

atrium and pleural cavity.

Craniosynostosis

Repairs of craniosynostosis are likely to have the best result if done early in

life [24]. However, these procedures are associated with loss of a significant

percentage of an infant’s blood volume, with great losses occurring when more

Fig. 5. Positioning of a neonate with a myelomeningocele. (A) Prior to induction of general anesthesia,

the neonate is elevated on a soft padding with a center cutout to relieve pressure on the

myelomeningocele. (B) Positioning of the neonate for closure of the myelomeningocele.


sutures are involved [25]. Venous air embolism detected by echocardiography

and precordial Doppler occurred in 66% to 83% of craniectomies in infants

[25,26]. Fortunately, direct morbidity and mortality rarely occur. Venous air

emboli can be minimized by early detection with continuous precordial Doppler

ultrasound and maintaining euvolumia. When hemodynamic instability does

occur, the operating table can be placed in the Trendelenburg position, flooding

the surgical field with warm saline and sealing the sites of egress with bone wax

and direct pressure. These maneuvers will augment the patient’s blood pressure

and prevent further entrainment of intravascular air.

Tumors

Because the majority of intracranial tumors in children occurs in the posterior

fossa, CSF flow is often obstructed, and intracranial hypertension and hydro-

cephalus is often present. Most neurosurgeons approach this region with children

in the prone position. The patient’s head is often secured with a Mayfield head

frame. Pins used in small children can cause skull fractures, dural tears, and

intracranial hematomas. Elevation of the bone flap can tear the transverse and

straight sinuses, and massive blood loss and/or VAE can occur. Surgical resection

of tumors in the posterior fossa can also lead to brainstem and/or cranial nerve

damage. Sudden changes in blood pressure and heart rate may be sentinel signs

of encroachment on these structures. Damage to the respiratory centers and

cranial nerves can lead to apnea and airway obstruction after extubation of the

patient’s trachea. Children requiring stereotactic-guided radiosurgery or craniot-

omies need general anesthesia to tolerate the procedures. Special head frames

have been devised to allow airway manipulations, and should be used in these

patients [27].

Epilepsy

Surgical treatment has become a viable option for many patients with

medically intractable epilepsy. Two major considerations should be kept in mind.

Chronic administration of anticonvulsant drugs, phenytoin and carbamazepine,

induces rapid metabolism and clearance of several classes of anesthetic agents

including neuromuscular blockers and opioids [9,28]. Therefore, the anesthetic

requirements for these drugs are increased, and require close monitoring of their

effect and frequent redosing. Intraoperative neurophysiologic monitors can be

used to guide the actual resection of the epileptogenic focus, and general

anesthetics can compromise the sensitivity of these devices [29].

Because some epileptogenic foci are in close proximity to cortical areas

controlling speech, memory, and motor or sensory function, monitoring of patient

and electrophysiologic responses are frequently utilized to minimize iatrogenic

injury to these areas [30,31]. Cortical stimulation of the motor strip in a child

under general anesthesia will require either EMG or direct visualization of muscle

movement. Neuromuscular blockade should not be used in this situation. Neural


function is best assessed in an awake and cooperative patient. Awake cranioto-

mies in children can be accomplished with local anesthesia and propofol and

fentanyl for sedation and analgesia, respectively [32]. Positioning of the patient is

critical for success of this technique. The patient should be in a semilateral

position to allow both patient comfort as well as surgical and airway access to the

patient. Propofol does not interfere with the ECoG if it is discontinued 20 minutes

before monitoring. Highly motivated children older that 10 years of age were able

to withstand the procedure without incident. However, it is imperative that

candidates for an awake craniotomy be mature and psychologically prepared to

participate in this procedure. Therefore, patients who are developmentally

delayed or have a history of severe anxiety or psychiatric disorders should not

be considered appropriate for an awake craniotomy. Very young patients cannot

be expected to cooperate for these procedures, and usually require general

anesthesia with extensive neurophysiologic monitoring to minimize inadvertent

resection of the motor strip and eloquent cortex. Repeat craniotomies for removal

of ECoG leads and depth electrodes used for chronic invasive EEG monitoring

and subsequent resection of the seizure focus are at risk for expansion of residual

pneumocephalus. It is important to avoid nitrous oxide until the dura is opened,

because intracranial air can persist up to 3 weeks following a craniotomy [33].

Vascular

Vascular anomalies are rare in infants and children. Most of these conditions

are congenital anomalies, and present early in life. Large arteriovenous malfor-

mations (AVM) in neonates may be associated with high output congestive heart

failure and require vasoactive support. Initial treatment of large AVMs often

consists of intravascular embolization in the radiologic suite [34]. Operative

management is commonly associated with massive blood loss, and these patients

require several i.v. access sites and invasive hemodynamic monitoring. Ligation

of an AVM can lead to sudden hypertension with hyperemic cerebral edema

[35]. Vasodilators such as labetalol or nitroprusside can be used to control a

hypertensive crisis.

Moyamoya syndrome is a rare chronic vaso-occlusive disorder of the internal

carotid arteries that presents as transient ischemic attacks and/or recurrent strokes

in childhood. The etiology is unknown, but the syndrome can be associated with

prior intracranial radiation, neurofibromatosis, Down’s syndrome, and a variety

of hematological disorders. The anesthetic management of these patients is

directed at optimizing cerebral perfusion by maintaining euvolumia and the

blood pressure within the patient’s preoperative levels [36]. Maintenance of

normocapnia is also essential in patients with Moyamoya syndrome because both

hyper- and hypocapnia can lead to stealing phenomenon from the ischemic region

and further aggravate cerebral ischemia [37]. A nitrous oxide and narcotic-based

anesthetic provides a stable level of anesthesia for these patients, and are

compatible with intraoperative EEG monitoring. Once the patient emerges from

anesthesia, the same maneuvers that optimize cerebral perfusion should be


extended into the postoperative period. These patients should receive i.v. fluids to

maintain adequate cerebral perfusion, and be given adequate narcotics to avoid

hyperventilation induced by pain and crying.

Trauma

Pediatric head trauma requires a multiorgan approach to minimizing mor-

bidity and mortality [38]. A small child’s head is often the point of impact in

injuries, but other organs can also be damaged. Basic life support algorithms

should be immediately applied to assure a patent airway, spontaneous respira-

tion, and adequate circulation. Immobilization of the cervical spine is essential

to avoid secondary injury with manipulation of the patient’s airway until

radiologic clearance is confirmed. Blunt abdominal trauma and long bone

fractures frequently occur with head injury, and can be major sources of blood

loss. To assure tissue perfusion during the operative period, the patient’s blood

volume should be restored with crystalloid solutions and/or blood products.

Ongoing blood loss can lead to coagulopathies, and should be treated with

specific blood components.

Infants with ‘‘Shaken Baby Syndrome’’ often present with a myriad of chronic

and acute subdural hematomas [39]. As with all traumatic events, the presence of

other coexisting injuries, fractures, and abdominal trauma should be identified.

Craniotomies for the evacuation of either epidural or subdural hematomas are at

high risk for massive blood loss and VAE. Postoperative management of these

victims is marked by the management of intracranial hypertension, and in the

most severe cases, determination of brain death.

Spine surgery

Spinal dysraphism is the primary indication for laminectomies in pediatric

patients. Many of these patients have a history of a meningomyelocele closure

followed by several corrective surgeries. These patients have been exposed to

latex products, and may develop hypersensitivity to latex. Latex allergy can

manifest itself by a severe anaphylactic reaction heralded by hypotension and

wheezing, and should be rapidly treated by removal of the source of latex, and

administration of fluid and vasopressors [40]. Patients at risk for latex allergy

should have a latex-free environment.

Tethered cord releases require EMG monitoring to help identify functional

nerve roots. EMG of the anal sphincter and muscles of the lower extremities is

performed intraoperatively to minimize inadvertent injury to nerves innervating

these muscle groups [41]. Muscle relaxation should be discontinued or antago-

nized to allow accurate EMG monitoring.

Neuroradiology

Recent advances in imaging technology have provided less invasive proce-

dures to diagnose and treat lesions in the CNS. Most neuroradiological studies


such as CT scans and magnetic resonance imaging can be accomplished with

light sedation. Recommendations have been published by consensus groups of

anesthesiologists and pediatricians, and can serve as guidelines for managing

these patients [42,43]. General anesthesia is typically used for uncooperative

patients, patients with coexisting medical problems, and potentially painful

procedures such as intravascular embolization of vascular lesions [34].

Summary

The perioperative management of pediatric neurosurgical patients presents

many challenges to neurosurgeons and anesthesiologists. Many conditions are

unique to pediatrics. Thorough preoperative evaluation and open communication

between members of the health care team are important. A basic understanding of

age-dependent variables and the interaction of anesthetic and surgical procedures

are essential in minimizing perioperative morbidity and mortality.

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Major spine surgery

Patricia H. Petrozza, MDNeuroanesthesia Department of Anesthesiology (Section on Neuroanesthesia),

Wake Forest University School of Medicine, Medical Center Boulevard,

Winston-Salem, NC 27157-1009, USA

Rheumatoid arthritis

The cervical spine undergoes inflammatory and erosive changes in a sub-

stantial portion of patients with rheumatoid arthritis. It is estimated that as many

as 80% of patients with rheumatoid arthritis who manifest the condition for more

than 10 years time have cervical spine involvement [1]. Systemically, this disease

is characterized by inflammatory changes in the connective tissue of the patient’s

body. Chronic proliferative inflammation affects synovial membranes, producing

irreversible damage to joint capsules and articular cartilage. A rheumatoid

pannus refers to an inflammatory exudate overlying the lining layer of synovial

cells within a joint, but this term also may be used to demarcate an inflammatory

mass of fibrous tissue resulting from synovial joint degeneration. Erosion

occurring in cartilage and bone, together with infiltration and disruption of

supporting ligaments, leads to anatomic destruction of multiple joints with

subsequent malalignment.

More than 80% of all rheumatoid disease in the cervical spine is found at the

affected level of C1–C2 [2]. Most commonly, the body of C1 slips forward on

C2 as the vertebrae become malaligned. Destruction of the atlanto-occipital and

the atlanto-axial joints leads to loss of height of the lateral masses of C1 and

subsequent upward subluxation of the odontoid process through the foramen

magnum. This condition is termed vertical subluxation.

It is important to remember that normal vertebral alignment does not

necessarily correlate with the absence of spinal cord compression, especially at

C1–C2, where there may be a large mass of fibrous or inflammatory tissue (a

pannus) replacing or lying adjacent to the odontoid process. In a magnetic

resonance imaging (MRI) study, the posterior atlanto-dens interval (PADI) is an

important measurement. The PADI is the distance between the posterior cortex of

the odontoid and the nearest point on the posterior arch of the atlas. This distance

has been found to correlate with the presence and severity of myelopathy.


PII: S0889 -8537 (01 )00009 -8

E-mail address: [email protected] (P.H. Petrozza).


20 (2002) 405–415

Commonly, patients with spine involvement from rheumatoid arthritis com-

plain of midline cervical pain, occasionally referred to the trapezius or sub-

occipital areas. Sensory symptoms include paresthesias, numbness, and loss of

proprioception in various combinations usually involving the upper limbs.

Progressive myelopathy is the clearest indication for surgical intervention, and

evidence is accumulating that better surgical results are obtained in patients who

are less severely affected neurologically and systemically at the time of surgery

[3]. Surgical intervention may be inappropriate for some patients in whom

neurologic deficits are severe and movement is restricted. In one series, only

15% of such severely symptomatic patients regained independent ambulation

after surgery [4].

Preoperative evaluation1

The anesthesiologist must be cognizant of the systemic nature of rheumatoid

arthritis. Often, patients are prone to malnutrition, anemia, and poor wound

healing. Particular attention must be addressed to the cardiovascular system, as

cardiovascular disease is the leading cause of death in the rheumatoid patient.

Myocardial infarction secondary to coronary arteritis has been reported. A

common manifestation of rheumatoid-related cardiovascular disorders is pericar-

dial disease, and up to 45% of patients with pericardial involvement may exhibit

no symptoms [5]. Following a careful review of the cardiovascular system and

physical examination, an echocardiogram may add significant information if

clinically indicated.

The respiratory system is also likely to become compromised in the patient with

long-standing rheumatoid arthritis. The patient may be subject to pleural disease,

nodules within the lungs, interstitial pulmonary fibrosis, and obliterative bron-

chiolitis. Occasionally, pulmonary vasculitis leads to pulmonary hypertension.

Additional physiologic systems that must be evaluated include the renal

system, where amyloidosis or vasculitis may result in impaired renal function.

Similarly, if hepatic tissue has been destroyed by the systemic vasculitis, patients

may manifest hypoalbuminemia and elevated hepatic transaminases. Therapeutic

agents such as nonsteroidal anti-inflammatory agents may cause hepatotoxicity

and increased enzyme levels of alkaline phosphatase [6]. Patients on chronic

steroids will most likely require perioperative supplementation, while drugs such

as penicillamine, methotrexate, and azathioprine have immunosuppressant prop-

erties, and may retard wound healing.

Assessment of the airway is one of the critical tasks for the anesthesiologist,

and the patient with rheumatoid arthritis is likely to present several challenges.

More than 50% of rheumatoid patients will have jaw symptoms at some time

during the course of their illness [5]. Clinicians should palpate the temporoman-

dibular joint for tenderness and ascertain the extent of mouth opening.

1 The report by Matti and Sharrock [5] is the source for much of the discussion here on

preoperative evaluation in the rheumatoid patient.

P.H. Petrozza / Anesthesiology Clin N Am 20 (2002) 405–415406

Cricoarytenoid joint arthritis is a frequent finding in patients with rheumatoid

arthritis, and laryngeal involvement is common (59%) in patients with classic

symptoms [7]. Extrathoracic airway obstruction is also reported. Signs and

symptoms should be sought including hoarseness, shortness of breath or

wheezing, and dysphasia. Involvement of the cricoarytenoid joint with synovitis

maybe asymptomatic, allowing aspiration of pharyngeal contents, while severe

arthritis diminishes the mobility of the vocal cords and may result in narrowing of

the glottic opening so markedly that laryngeal obstruction and stridor result. If the

anesthesiologist’s suspicions are aroused by the preoperative assessment, evalu-

ation by an otolaryngologist is indicated.

Much of the previously mentioned pathologic lesions of the cervical spine are

of interest in a discussion of airway management. For instance, in patients with

atlanto-axial involvement, excessive flexion may cause cord compression. This

may be exaggerated if the odontoid process is unstable and migrates rostrally.

Patients with subaxial involvement (subluxation below C2) experience spinal

cord compromise with extension. Laryngeal deviation has also be noted in a

number of rheumatoid patients. The larynx may be angulated anteriorly, or

displaced caudally as well as rotated to the right or to the left. This angulation

may present difficulties with airway equipment like the laryngeal mask airway

[5]. Most often, for procedures involving the cervical spine, a carefully performed

fiberoptic intubation is preferred.


In many cases anterior subluxation of C1 on C2 can be corrected by extension

of the cervical spine, which results in better alignment. Posterior fixation and

fusion in this position are often sufficient. Careful perioperative imaging

examination [5] are necessary, however, to be certain that even with normal

vertebral realignment, soft tissue does not compress the spinal cord, necessitating

a direct decompression by an anterior approach.

Removal of the odontoid process leads to significant instability in most patients

with cervical rheumatoid disease and, consequently, a stabilization procedure fol-

lowing decompression is necessary. When vertical odontoid subluxation occurs,

access to this fragment can be obtained through a transoral-transpharyngeal route.

Often a tracheostomy may be necessary, although the highly motivated patient will

be able to tolerate endotracheal intubation for approximately 48 hours postoper-

atively to allow healing of the pharyngeal incision. If the surgeon suspects a breach

of the dura during odontoid resection, a lumbar cerebrospinal fluid (CSF) drain

may prevent formation of a significant CSF fistula.

Following anterior decompression of the upper cervical spine, often the patient

is placed prone for stabilization of the posterior spinal elements. Proper intra-

operative positioning is assured while the surgeon controls the head and neck.

Somatosensory evoked potential monitoring is often useful as instrumentation is

placed for fusion. Because the spinal cord is known to be compromised, direct

arterial pressure measurement through an arterial line is recommended, and the

P.H. Petrozza / Anesthesiology Clin N Am 20 (2002) 405–415 407

anesthesiologists should remain vigilant for blood loss, as occasionally the cervical

spine anatomy may be difficult and the vertebral arteries displaced [8].

As imaging of spinal column pathology in patients with rheumatoid arthritis

becomes more sophisticated, operations can be performed that are more likely

tailored to each patient’s specific pathology. Certainly, patients with fewer

systemic manifestations of the illness tend to have better outcomes, and many

patients who undergo posterior fusion procedures at C1–C2 exhibit good pain

relief despite the fact that often bone fusion at least by radiographic measures is

incomplete [1]. These patients will continue to present interesting challenges for

neurosurgeons and anesthesiologists in the decades to come.

Metastatic tumors of the spine

Metastatic tumors occur three to four times more frequently than primary

neoplasms within the vertebral column, and solitary vertebral lesions are often

metastatic. The four most common primary sites for the origin of tumors are the

breast, lung, prostate system, and hematopoietic system, and these sites account

for one half to two thirds of all causes of neoplastic cord compression [9].

Seventy percent of metastatic cord compression involves the thoracic segments of

the spine, while the lumbosacral segments and cervical segments are each

involved 15% of the time. Prognosis is affected by the tumor biology, pretreat-

ment neurologic status, and the choice of therapy.

Magnetic Resonance Imaging (MRI) scanning is extremely sensitive for

metastatic bone disease, and spinal CToften provides complimentary information.

In patients with hypervascular tumors, such as those related to metastatic kidney

and thyroid neoplasms, spinal angiography may be indicated to decrease tumor

vascularity and to locate critical spinal arterial supplies. Presurgical embolization

often reduces surgical morbidity [10].

A treatment plan must be individualized based on the patient’s general

condition, extent of cancer, type of tumor, and the degree and speed of onset

of neurologic deficit. Tokuhashi and associates have proposed a scoring system

using six parameters: general condition, number of vertebral metastases, addi-

tional spine lesions, metastases to internal organs, primary site, and severity of

spinal palsy. A maximum score of 12 can be obtained with each parameter given

a score of 0 to 2 points. Excisional surgery may be indicated for a total score of 9

or more, whereas palliative surgery may be used for a score of 5 or less [11].

Until recently, laminectomy through a posterior approach was considered to be

the surgical treatment of choice for epidural metastatic tumors. Unfortunately,

laminectomy offers inadequate access to the anterior aspect of the cord and

vertebral body, and may subject the patient to loss of spinal column stability. A

posterior lateral approach may be useful if the tumor is soft and can be removed

by suction or curettage. This method is often a useful method of palliation in a

severely debilitated patient.

An anterior approach has become the most widely favored for decompression

of the patient with spinal metastases, because most tumors involve the vertebral


body and secondarily involve the posterior vertebral elements. Anterior decom-

pression of the spinal cord by vertebral body resection (corpectomy) gives

superior results in terms of pain relief and recovery of neurologic function

compared with posterior laminectomy [12]. Following tumor resection, stabi-

lization requiring instrumentation is most frequently indicated to maintain spinal

alignment and prevent progressive deformity.

Although pain is the initial symptom of metastatic disease in the spine, it is

often difficult to make the exact diagnosis because the pain may be nonspecific or

referred to other sites. Often neurologic signs become common by the time of

diagnosis and these include various degrees of muscle weakness, bowel and

bladder dysfunction, and sensory symptoms. When patients begin to demonstrate

motor signs, 28% become paraplegic in less than 24 hours [13]. Early diagnosis is

crucial, as outcome depends on neurologic function before treatment.

Preoperative evaluation and assessment

Most operations for resection of tumors located anterior to the spinal cord are

performed in the thoracic spine. A thoracotomy is required, and preoperative

spirometry may be helpful. An arterial blood gas obtained prior to anesthesia will

likely aid postoperative pulmonary care, and a preoperative regimen of broncho-

dilators and nebulizing treatments often optimizes the patient’s condition for

surgery. An assessment of the patient’s coagulation status as well as platelet count

is important in planning intraoperative care, and at least 4 units of packed red

blood cells should be available at the start of surgery.


A double lumen endotracheal tube optimizes surgical exposure of the spine,

particularly in the thoracic region. A fiberoptic bronchoscope is required after the

patient is placed in the lateral position to verify endotracheal tube placement and

promote optimal lung isolation. If a patient’s cardiopulmonary status makes

single-lung ventilation inadequate, insufflation of oxygen or application of low

levels of continuous positive airway pressure to the deflated lung can often

maintain oxygenation.

Blood loss may be substantial, particularly during the tumor debulking, and

intra-arterial access for blood samples and a continuous monitor of mean arterial

blood pressure is necessary, while central venous pressure or pulmonary artery

pressure measurements may be advantageous for patients with cardiovascular

compromise. Optimally, the anesthetic technique should assure stable spinal cord

perfusion, appropriate monitoring, and assessment of the patient’s neurologic

status early in the recovery period.

A deflatable ‘‘bean bag’’ helps stabilize the torso as the patient is positioned

on his or her side. An axillary roll will be necessary to protect the brachial

nerve vascular bundle from compromise, and the arm on the side of the incision

must be carefully padded and positioned to allow access to the upper thoracic


cage. Excessive lateral neck flexion should be avoided, as postoperative

congestion with significant neck pain may be a cause of patient morbidity.

Additionally, the common peroneal nerve of the dependent leg must be pro-

tected from pressure ischemia.

During decompressive surgery blood loss from epidural veins in the tumor bed

is often quite profuse. Frequent measurements of platelet count, coagulation

factors, and assessment of hemostasis by the surgical team will be necessary to

detect a dilutional coagulopathy and guide factor therapy. Transfusion-sparing

techniques such as the ‘‘cell saver’’ are not options when dealing with oncologic

surgery. As tumor resection often involves a vertebral body corpectomy, the patient

will require stabilization with spinal instrumentation to replace the vertebral body/

bodies and allow maximum rehabilitation in the postoperative period.

Postoperative care

Spinal decompressive surgery for metastatic tumors is often lengthy (in excess

of 8 hours). Common postoperative problems include hypothermia, coagulo-

pathy, residual pulmonary insult, and pain. Intravenous antibiotics are continued,

and perioperative dexamethasone is tapered. Drains are removed over time, and

most patients remain ventilated for 12 to 24 hours postoperatively. Sedation may

be obtained with mixtures of midazolam and fentanyl intravenously. Chest

physiotherapy (PT) is initiated, and careful postoperative fluid balance is

achieved. Pain is often managed with patient-controlled analgesia.

Surgical mortality rates after vertebral body resection range from 4% to 8%,

while the risk of neurologic deterioration as a result of a surgery occurs in 2% to

6% of patients [14]. Obviously, the use of modern and novel surgical techniques

for spinal decompression and stabilization must be balanced against the indi-

vidual patient’s overall prognosis for an improved quality of life.

Lumbar interbody fusion

Spondylolisthesis, trauma, and congenital abnormalities of the lumbar spine

predispose the spine to abnormal motion of the vertebral elements and supporting

structures resulting in neurologic deficits, deformity, and pain. Pain may continue

following one or more surgical procedures, and MRI demonstrates loss of disk

space, but no gross deformities of the motion segments such as the spinal facet

joints. Procedures that are designed to strengthen the unstable vertebral segments

with fusion are offered to limit motion within the spine and treat pain. Recent

studies have demonstrated improved functional outcomes in patients who

underwent posterior lateral lumbar fusion with or without instrumentation [15].

It appears that lumbar interbody fusion operations will continue to increase, while

instrumentation becomes more sophisticated.

Posterior lumbar interbody fusion techniques use corticocancellous bone strips

with or without pedicle screw instrumentation to achieve spine stability. The


posterior approach involves many challenges for the anesthesiologist and

surgeon. The patient must be positioned carefully in the prone position while

avoiding compression of the epidural veins. Bone dissection is quite lengthy, and

both arterial and venous bleeding may be problematic. Fluoroscopy is necessary

to facilitate placement of an interbody fixation or ‘‘pedicle’’ screw support.

Briefly, the approach to the lumbar spine involves extensive dissection so that

instrumentation can be placed through the interbody space with minimal

retraction of the spinal elements or nerve roots. Fusion is facilitated by multiple

types of fluoroscopically placed instrumentation including BAK and Ray cages,

or allograft bone dowels. Blood loss correlates with the number of vertebral

levels, which are instrumented as dissection is extensive.

Corticocancellous bone fusion was the initial method offered to achieve

stability in patients with ‘‘failed back syndrome,’’ but several new interbody

methods have been developed that show promise. These types of instruments are

simultaneously osteoconductive and stabilizing, and utilize approaches that are

often less invasive. For instance, using an anterior approach with BAK (Salzer-

SpineTech, Minneapolis, MN) fusion cages, neurologic complications occurred

in 2% of cases [16]. If the instrumentation is inserted through a direct anterior

approach, there is an approximately 2% incidence of permanent retrograde

ejaculation in men, which may lead to sterility [17]. This complication is thought

to be related to dissection of the sacral plexus near the disk space. Despite this

complication, implants and bone dowels combined with the anterior approach

have several advantages. Often patients achieve very good postoperative pain

relief because of the large amount of disk space distraction achieved with

instrumentation and implants. Also, an external rigid orthosis is not necessary,

and hospital costs are reportedly reduced compared with a 360� fusion [18].

Some central disk fragments may also be removed through an anterior approach

if necessary.

In general, the operative approach for an anterior lumbar interbody fusion

requires a second general or vascular surgeon to collaborate with the neuro-

surgeon. The patient undergoes a bowel preparation protocol the night before

surgery, and is placed supine upon an imaging compatible operating room table

such that both anterior-posterior (AP) and lateral images can be obtained through

the lumbar spine. Monitoring includes an arterial line, large bore venous access,

and Foley catheter. Occasionally, fusion bone may be obtained from the posterior

iliac crest with the patient lying in the lateral decubitus position prior to making

the abdominal incision. Infiltrating morphine locally may help with postoperative

pain from the bone donor site [19].

A left-sided paramedian incision is used to expose the spine. Peritoneum and

abdominal contents are retracted to the patient’s right, and the sigmoid colon is

retracted to the patient’s left. Dissection continues in the retroperitoneal plane.

Several structures are encountered, including the middle sacral vessels and

sympathetic nerves as well as left iliac vein and left gluteal vein on an approach

to the L4–L5 disk space. Anterior exposure is not recommended above the L3 to

L4 disk space due to the presence of large aortic branch vessels.


Once the proper spinal level has been identified byAP fluoroscopy, approximate

implant size and spacing are determined by a preoperative templating process.

Large-diameter implants are utilized to give maximal distraction and at least 3 mm

of penetration into both vertebral bodies. If it is necessary to remove fragments in

the spinal canal, an operating microscope may be used to perform a discectomy

through one of the access holes created by retractors while others are left in place to

maintain separation of the vertebral bodies. Patients are most likely extubated

immediately following surgery, mobilized the next day, and despite minor levels of

bowel dysfunction generally have a smooth postoperative course [16].

A laparoscopic method has been developed for an anterior lumbar interbody

fusion that has the advantage of reducing morbidity related to movement of the

abdominal contents and trauma to the abdominal wall. Due to the large amount of

vascular structures overlying the L4–S1 lumbar spine anteriorly, this approach

requires quite a bit of experience and tutelage under a laparoscopic surgeon, and

can only be offered to patients in whom a preoperative MRI does not show large

vessels overlying the disk space.

A common technique utilizes four portals for installation of carbon dioxide

and placement of the laparoscopic instrument and retractors. The patient is placed

in the Trendelenburg position, which often helps to mobilize the small intestines,

and sigmoid colon. Regan and colleagues recently reported on 240 consecutive

patients who underwent laparoscopic-instrumented interbody fusion and com-

pared these patients to a cohort of 591 consecutive patients who underwent open

anterior fusion with the same device [20]. In general, the laparoscopy group had

shorter hospital stays and reduced blood loss, but increased operative time.

Operative time decreased as the surgeon’s experience increased, but overall still

totalled approximately 1 hour longer for the laparoscopic anterior approach as

opposed to the open anterior approach. Blood loss was significantly less, totaling

approximately 207 cc for the anterior approach versus 41.7 cc for the laparo-

scopic approach. The operative complications were comparable in both groups,

and it was necessary to convert to an open procedure in the laparoscopy group

approximately 10% of the time.

Spinal instrumentation and techniques for fusion will no doubt continue to

evolve. In patient groups reported to the Food and Drug Administration under

prospective trials, titanium cages have shown high rates of apparent fusion.

Almost half of the eligible patients returned to work [21].

Visual loss after spine surgery

According to a report filed recently with the American Society of Anesthesi-

ologists Closed Claim Project, claims for postoperative blindness appear to be

rising [22]. Although the incidence of this concern has been reported to occur

with all types of surgery, a recent study on spine surgery patients gave the

incidence as 0.2%. This is approximately 10 times the risk of eye injury as after

other nonocular surgery [23].


The majority of lesions accounting for visual loss following surgery are

located within the optic nerve. Loss of central vision as well as loss of peripheral

visual fields can occur when this nerve sustains damage. Ischemic insult to the

optic nerve is separated into anterior ischemic optic neuropathy (AION) and

posterior ischemic optic neuropathy (PION). Each of these areas of the optic

nerve has a different blood supply and distinct predisposing factors that could

lead to infarction. Clinically, PION can be distinguished from AION by the

absence of acute disk swelling in PION.

The portion of the optic nerve, which involves the optic disk and the nerve

within the scleral canal, receives a blood supply from 8 to 10 small posterior ciliary

arteries that rise as branches from the ophthalmic artery. Posterior ciliary arteries

communicate with one another in the form of an incomplete anastomotic ring.

Often, the anastomotic ring is poorly developed so that downstream watershed

zones may form at the boundaries of areas supplied by specific posterior ciliary

artery branches. These zones may be vulnerable to ischemic nerve injury under

conditions of anemia, hypotension, and increases in venous pressure.

Postoperative AION often includes painless visual loss identified 1 or more

days following surgery [24]. Upon examination of the eye, disk edema will often

correlate with an area of field loss clinically. Ophthalmologic consultation should

be sought without delay, if the patient experiences new onset, postoperative

blindness, although vision loss may be permanent in this scenario.

PION presents with acute visual field loss similar to AION. This problem,

however, may develop more slowly than AION, and a symptom-free period may

precede the loss of vision [25]. Funduscopic examination will reveal no disk

swelling in PION. Blood supply to the posterior portion of the optic nerve arises

from branches of the ophthalmic artery, and the central retinal artery often sup-

plies branches to the central nerve fiber. At baseline, blood flow to the posterior

optic nerve is significantly less than that of the anterior portion. The segment of

the nerve most distal from the arterial supply is nourished primarily by readily

compressible centripetal pial vessels.

Ischemic optic neuropathy has been reported after spine procedures almost

exclusively in the prone position, and has most often been associated with lengthy

procedures involving multiple levels, long operative times, and significant blood

loss. Notable risk factors include pressure on the eye, hypotension, and anemia.

Meyer identified 37 patients who experienced visual loss after spine surgery

through a survey of members of the Scoliosis Research Society and a review of

the literature [26]. The patients had a mean age of 46.5 years. The average

operative time was 410 min, and blood loss was 3500 cc. Although most cases

had significant intraoperative hypotension (mean drop in systolic blood pressure

from 130 to 77 mmHg), comparison with a matched group of patients with no

visual symptoms showed no difference in the hematocrit or blood pressure

values. In his survey, Myers identified 37 patients, 8 or whom had AION, while

another 14 had PION.

Studies point to intraoperative hypotension and anemia as the most consistent

observations in patients developing postoperative ischemic optic neuropathy.


Certain patient factors such as diabetes mellitus or hypertension may predispose

patients to inadequate delivery of blood to watershed perfusion zones. Addi-

tionally, the perfusion pressure of the anterior optic nerve is influenced by

arterial, venous, and intra-ocular pressures problems, each of which may be

exacerbated by the prone position. Concern over this very serious complication

has prompted the American Society of Anesthesiologists to develop a post-

operative visual loss registry, which will aid in establishing causes and circum-

stances of this particular problem.

It is not currently possible to specifically identify high-risk patients, and many

of the speculative factors that appear to be related to this complication are as yet

unproven in prospective trials. Certainly, efforts should be made to optimize

oxygen delivery and prevent tissue edema as well as increases in intraocular

pressure to assure adequate care of the visual system. Extremes of hemodilution

or hypotension should most likely be avoided, and consideration should be given

to staging very long planned operative procedures. An early postoperative check

for vision should be included in the routine examination.

References

[1] Santavirta S, Konttinen YT, Laasonen E, et al. Ten-year results of operations for rheumatoid

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[2] Mathews JA. Atlanto-axial subluxation in rheumatoid arthritis. A 5-year follow-up study. Ann

Rheum Dis 1974;33:526–31.

[3] Peppelman WC, Kaus DR, Donaldson WF III, et al. Cervical spine surgery in rheumatoid

arthritis: improvement of neurologic deficit after cervical spine fusion. Spine 1993;18:2375–9.

[4] Casey ATH, Crockard HA, Bland JM, et al. Surgery on the rheumatoid cervical spine for the

non-ambulant myelopathic patient—too much, too late? Lancet 1996;347:1004–7.

[5] Matti MV, Sharrock NE. Anesthesia on the rheumatoid patient. Rheum Dis Clin North Am

1998;24(1):19–34.

[6] MacKenzie CR, Sharrock NE. Perioperative medical considerations in patients with rheumatoid

arthritis. Rheum Dis Clin North Am 1998;24(1):1–17.

[7] Geterud A, Bake B, Berthelsen B, et al. Laryngeal involvement in rheumatoid arthritis. Acta

Otolaryngol 1991;111:990–8.

[8] Johnston RA, Borthwick JM. Surgical management of the rheumatoid cervical spine. In: Schmi-

dek HH, editor. Schmidek & Sweet operative neurosurgical techniques: indications, methods,

and results. Philadelphia: W.B. Saunders, Co.; 2000. p. 1808–21.

[9] Byrne TN. Spinal cord compression from epidural metastases. N Engl J Med 1992;327:614–9.

[10] Sundaresan N, Choi IS, Hughes JEO, et al. Treatment of spinal metastases from kidney cancer by

presurgical embolization and resection. J Neurosurg 1990;73:548–54.

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metastatic spine tumor prognosis. Spine 1990;15:1110–3.

[12] Siegal T, Siegal T. Surgical decompression of anterior and posterior malignant epidural tumors

compressing the spinal cord: a prospective study. Neurosurgery 1985;17:424–32.

[13] Barcena A, Lobato RD, Rivas JJ, et al. Spinal metastatic disease: analysis of factors determining

functional prognosis and the choice of treatment. Neurosurgery 1984;15:820–7.

[14] Siegal T, Siegal T. Surgical management of malignant epidural tumors compressing the spinal

cord. In: Schmidek HH, editor. Schmidek & Sweet operative neurosurgical techniques: indica-

tions, methods, and results. Philadelphia: W.B. Saunders, Co.; 2000. p. 2171–97.

[15] Fischgrund JS, Mackay M, Herkowitz HN, et al. Degenerative lumbar spondylolisthesis with


spinal stenosis: a prospective, randomized study comparing decompressive laminectomy and

arthrodesis with and without spinal instrumentation. Spine 1997;22:2807–12.

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1997;22:660–6.

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anesthetics from 1988 to 1992. Anesthesiology 1996;85:1020–7.

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a review of 37 cases. Spine 1997;22:1325–9.


Anesthetic management of traumatic

brain injury

Eric Bedell, MD*, Donald S. Prough, MDDepartment of Anesthesiology, University of Texas Medical Branch, 301 University Blvd.,

Galveston, TX 77555-0591, USA

Traumatic brain injury (TBI) represents a significant health issue in the United

States, with rates of 175–300 per 100,000 per year and a death rate of 15 to 30

per 100,000, accounting for up to 56,000 deaths [1,2]. Although brain injury,

secondary to vehicular injury, was historically the most common form of TBI, in

the latter part of the twentieth century, gunshot wounds became the most common

form of fatal brain injury, surpassing motor vehicle accidents [3]. Between 1979

and 1992 in the United States, brain injury secondary to vehicular trauma

decreased from 11.4/100,000 to 6.6/100,000 persons (43%), while injury from

firearms increased from 7.7/100,000 to 8.5/100,000 (10%) [3]. Even with modern

diagnosis and treatment, the prognosis for the patient with TBI remains poor. In a

recent study of hypothermia as a treatment for acute brain injury, a mortality of

27% occurred in the control group [4]. Because of the prevalence of TBI, an

understanding of the management of this group of patients is vital to the modern-

day health care provider in general, and the clinical anesthesiologist specifically.

In head-injured patients, the concepts of primary and secondary brain injury must

be considered to correctly prioritize interventions. Primary brain injury, which is

the damage caused directly by the traumatic insult, can result from contusion of

the brain (either at the site of impact or distant from the impact site), shock wave

disruption, depressed bone fragments, vascular occlusion, expanding intracranial

masses (eg, epidural, subdural, or intraparenchymal hematomas) and other

mechanisms. This form of damage may require rapid induction of anesthesia to

facilitate surgical intervention. Secondary brain injury occurs after the primary

injury, often as a result of correctable or preventable causes such as hypotension,

hypoxemia, or intracranial hypertension, and may markedly influence outcome.

Care begins with a structured care team following an orderly treatment plan. A

neurosurgeon or trauma surgeon is usually the leader of the neurotrauma care


PII: S0889 -8537 (01 )00010 -4


E-mail address: [email protected] (E. Bedell).


20 (2002) 417–439

team, which also may include anesthesiologists, intensivists, radiologists, radio-

logic technicians, laboratory personnel, general surgeons, and nursing personnel.

The actual care then provided depends upon the individual patient’s needs and the

resources available.

This article reviews concepts of anesthetic management for the patient with

TBI. The recommended approaches to management are based upon physiologic

and pharmacologic data. Whenever possible, specific recommendations will

be made. At other times, conflicting information will be presented for readers

to consider.

Evaluation and stabilization

Upon initial presentation, a patient with TBI is usually considered to be at risk

for increased intracranial pressure (ICP), but this probability and its treatment

cannot become the only concern of the health care team. In any trauma patient,

priority must be first given to general evaluation and stabilization, with particu-

lar attention to the ‘‘ABC’s’’ of airway, breathing, and circulation. Although

these activities will be discussed sequentially, they proceed concurrently in

most situations.

Initial evaluation includes a rapid review of all injuries and determination of

baseline vital signs and level of consciousness. The head injury may not be the

only injury, and other injuries, such as chest or abdominal wounds, may be life-

threatening. A primary survey of the undressed patient, both front and back, with

a careful search for associated injuries should be performed. In moving the

patient, manual in-line axial stabilization of the cervical spine should be used

because of the risk that cervical spine injury could accompany head injury (see

below). A baseline level of consciousness should be ascertained. The Glasgow

Coma Scale (GCS) is a useful tool for such evaluation (Table 1). Studies

comparing the association between long-term outcome and GCS scores after

TBI have demonstrated that a lower initial GCS score is associated with higher

morbidity and mortality (Table 2). Changes from the initial GCS score are im-

portant in following clinical progress.

After rapid evaluation, the team directs attention to primary resuscitation,

particularly to the maintenance and protection of an adequate airway. In comatose

patients, an artificial airway usually must be established. The airway must be

reevaluated frequently, as a secure airway can rapidly be compromised. The

second priority is to provide adequate oxygenation and ventilation. The third

priority is to ensure the adequacy of circulation (including adequate peripheral

venous access and, if necessary, central venous or arterial access). Only after

addressing the ABCs should further care occur. The status of the ABC’s must be

reviewed frequently to recognize and reverse deterioration.

When a trauma patient first presents for care, an individual (or group) should

be assigned to assess the airway. The decision to provide an artificial airway (ie,

intubate or perform a tracheostomy) can be difficult and can have long-term

E. Bedell, D.S. Prough / Anesthesiology Clin N Am 20 (2002) 417–439418

implications for management. It is important to appreciate the difference between

airway maintenance and airway protection. Airway maintenance means providing

an unobstructed pathway for gas flow between the atmosphere and the terminal

alveoli. Airway protection means either the ability to recognize and overcome

compromise within the airway (eg, tongue, vomitus, or pharyngeal secretions) or

the presence of a patent mechanical airway.

When evaluating the adequacy of the natural airway, quickly assess the level

of consciousness, examine the face and oropharynx for signs of injury or

obstruction, determine the presence or absence of bilateral breath sounds,

carefully examine for signs of airway obstruction (eg, stridor, retractions,

abdominal rocking), and establish the adequacy of arterial oxygenation using

pulse oximetry or arterial blood gas analysis. Also note vital signs (heart rate,

respiratory depth and frequency, blood pressure, temperature), review skin color,

and provide supplemental oxygen by means of a transparent, non-rebreathing

Table 2

Relationship of acute Glasgow Coma Scale (GCS) score to Glasgow Outcome Scale

Number (%) of cases

GCS score 3–4 GCS score 5–6 GCS score 7–9 Total cases

Dead/PVS 15 (78.9%) 19 (45.2%) 9 (25.7%) 43

SD/MD/GR 4 (21.2%) 23 (54.8%) 26 (74.3%) 53

Total cases 19 42 35 96

Abbreviations: The Glasgow Outcome Scale consists of five categories: death; PVS, persistent

vegetative state; SD, severe disability; MD, moderate disability; GR, good recovery.

From Jaggi JL, Obrist WD, Gennarelli TA, Langfitt TW. Relationship of early cerebral blood flow and

metabolism to outcome in acute head injury. J Neurosurg 1990;72:176–182 [113]; with permission.

Table 1

Glasgow coma scale (GCS)

Component Response Score

Eye opening Spontaneously 4

To verbal command 3

To pain 2

None 1

Motor response (best limb) Obeys verbal command 6

Localizes pain 5

Flexion withdrawal 4

Flexion (decortication) 3

Extension (decerebration) 2

No response (flaccid) 1

Best verbal response Oriented and converses 5

Disoriented and converses 4

Inappropriate words 3

Incomprehensible sounds 2

No verbal response 1

Total score eye opening + motor response + verbal response 3B15

Reprinted from Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical

scale. Lancet 1974;2:81–84 [112]; with permission from Elsevier Science.

E. Bedell, D.S. Prough / Anesthesiology Clin N Am 20 (2002) 417–439 419

mask with high-flow 100% oxygen. The decision to provide an artificial airway

should be made by the team leader, and those managing the airway and should be

based upon specific indications. Table 3 lists some of the indications for tracheal

intubation. Individualization of care is important in managing the patient with

TBI, and as such, established protocols may require modification.

It is important to note that concern about increased ICP influences the

approach to the airway but does not contraindicate endotracheal intubation.

Endotracheal intubation in an unanesthetized patient will increase blood pressure,

heart rate, and ICP [5,6]. However, of greater clinical importance is the fact that

cerebral blood volume (CBV) is increased by hypoxia and hypercarbia [7], that

ICP is increased by untreated hypoxia [8], or hypercarbia [9], and that aspiration

of oral or gastric contents not only interferes with gas exchange but also increases

long-term morbidity and mortality [10,11]. The increase in ICP with airway

manipulation can be reduced by appropriate use of medications [12–14].

Having made the decision to provide an artificial airway, many techniques of

intubation and choices of drugs are possible. In general, the best technique is the

one with which the team members are most proficient. Head-trauma patients are

high-risk individuals in whom experimentation with new techniques or training

of inexperienced personnel may be imprudent. In general, there are two

approaches to the tracheal intubation of head-trauma patients: oral intubation

using direct laryngoscopy and nasal intubation (either blind or fiberoptically

guided). Each approach has advantages and disadvantages.

Associated cervical spine injury is present in approximately 2% [15] to 21%

[16] of trauma patients. Uncontrolled movement of the neck in patients with

cervical spine injury can precipitate neurologic injury, and is therefore to be

Table 3

Indications for endotracheal intubation

Absolute

Apnea, bradypnea (respiratory frequency < 6/min)

Hypoxia on 100% O2 (PaO2 < 70 mmHg, SpO2 < 90%)

Hypercarbia (PaCO2 > 65 mmHg)

Absence of airway protective reflexes (cough, gag, swallow)

Mechanical airway obstruction

Expanding oral or neck mass

Need for the administration of barbiturates, sedatives, or muscle relaxants

Hemodynamic instability/severe hypotension

Glasgow Coma Scale score < 8 (see Table 1)

Relative

Progressive tachypnea (respiratory frequency >35/min)

Flail chest

Pulmonary aspiration

Combative behavior

Hypothermia (core temperature < 34.5�C)Seizures

Increased intracranial pressure

Mild hypoxia or hypercarbia

Metabolic acidosis (pH < 7.25)


avoided. Because of this possibility, the use of awake/sedated nasal intubation,

which does not require head movement, has been advocated [17]. Contra-

indications to awake nasal intubation include fractures of the skull base, La

Forte fractures, bleeding diatheses, and midface disruption [18,19]. The technique

is much more difficult in patients with slow or absent respirations, and is

relatively contraindicated [20,21]. Fiberoptic visualization is often utilized but

has a number of limitations, including the requirement of a cooperative patient,

need for specialized equipment and training, and vastly increased difficulty when

the airway is contaminated with blood, vomitus, or excessive secretions [20–22].

Direct laryngoscopy of patients with cervical injury can be used if accompanied

by manual in-line axial stabilization of the head and neck by an assistant [23]. In

the absence of in-line stabilization, neck movement, especially in the upper

cervical spine, has been demonstrated in patients without neck injury [24].

Manual in-line stabilization (previously termed in-line axial traction) decreases

movement of the neck in cadaveric models of cervical spine injury [25], which

theoretically reduces the risk of aggravating cervical spine injury, but also

increases difficulty with visualization and tracheal intubation [26]. Regardless

of the intubation technique chosen, adequate planning and preparation should

precede intubation. The patient should be preoxygenated with 100% oxygen (O2)

by mask; intubating equipment and suction should be present and functioning; all

desired and emergency drugs should be present; and a means of establishing a

surgical airway should be available if endotracheal intubation fails.

Intravenous drugs can be used as adjuvants during intubation to create more

controlled and stable intubating conditions and to blunt the systemic effects of

intubation (increased blood pressure and ICP) [12–14]. Drugs also can precip-

itate hypotension, result in total airway loss if intubation is unsuccessful, generate

life-threatening electrolyte imbalances (eg, hyperkalemia after succinylcholine in

chronically paraplegic or quadriplegic patients), trigger an anaphylactic or

anaphylactoid reaction, or interact in unexpected ways with the patient’s other

medications or other medical conditions. Only trained, experienced individuals

who are prepared to recognize and manage drug-induced complications should

administer drugs.

Induction agents such as sodium thiopental, etomidate hydrochloride, and

propofol have been used to induce anesthesia before intubation. Each decreases

the systemic response to intubation, blunts ICP changes, and decreases the

cerebral metabolic rate for oxygen (CMRO2). Induction agents also cause apnea

and loss of protective airway reflexes; thus, an artificial airway must be secured,

and controlled ventilation must be initiated after their administration. Another

concern includes cardiovascular depression with propofol and thiopental, which

can lead to hypotension, especially in the presence of uncorrected hypovolemia.

Hypotension is a primary risk factor for poor outcome after head trauma [27–31].

Etomidate is unique in that induction doses usually cause little change in blood

pressure, although it reduces CMRO2 [32]. Etomidate administration, however,

can result in an exaggerated response to intubation, such as tachycardia, and has

been associated with myocardial ischemia in patients with high cardiac risk [33].


Finally, ketamine, a dissociative anesthetic that preserves spontaneous ventilation

with limited cardiovascular compromise, would seem to be an appropriate agent

for use in establishing an airway in patients with TBI. This agent though, has

been associated with increased cerebral blood flow and increased ICP, and as

such, is relatively contraindicated as a single agent for patients with risk for or

preexisting increased ICP [34–36]. Whatever agent is chosen to blunt the

response to intubation, the individual providing the medication must be imme-

diately prepared to assume control of the airway, protect the patient from

pulmonary aspiration, assure adequate oxygenation and ventilation, and treat

systemic hemodynamic responses such as hypotension and tachycardia.

Muscle relaxants are often combined with induction drugs to secure the

airway. Succinylcholine hydrochloride, which is the only ultrashort-acting,

depolarizing muscle relaxant presently approved by the Federal Drug Adminis-

tration, produces complete muscle relaxation within 60 to 120 seconds of

administration, with return of muscle strength in a matter of minutes. However,

it can lead to life-threatening hyperkalemia, trigger malignant hyperthermia, and

increase ICP [37,38]. The increase in ICP can be blunted by administration of an

adequate dose of an induction agent such as thiopental [39]. However, even

without treatment, the increase in ICP is transient and of questionable clinical

significance [39]. Increases in ICP secondary to hypoxia and hypercarbia are well

documented and much more likely to be clinically important.

Nondepolarizing neuromuscular blocking agents, such as vecuronium bro-

mide, cis-atracurium bresylate, and rocuronium bromide, do not carry the risks of

hyperkalemia, malignant hyperthermia, and increased ICP. Given in large doses,

these drugs produce good-to-excellent intubating conditions within 120 to 180

seconds. However, profound relaxation will persist for 30 to 120 minutes,

mandating expeditious placement of an artificial airway.

All sedative/hypnotics and muscle relaxants used to facilitate endotracheal

intubation compromise protective airway reflexes. In trauma patients, it is

impossible to know when food was last ingested. There may be food, gastric

secretions, or blood within the stomach that may be aspirated into the lungs if

passive or active regurgitation occurs. Because of the risk of ‘‘a full stomach,’’ a

rapid sequence induction technique should be used when drugs are given that

remove protective reflexes. The rapid sequence induction consists of preoxygen-

ation and denitrogenation with 100% oxygen, application of cricoid pressure

[40], administration of induction agents and muscle relaxants, and immediate

direct laryngoscopy with intubation of the trachea. Positive-pressure ventilation is

avoided between the time of drug administration and intubation. Correctly

applied cricoid pressure is believed to decrease the risk of passive regurgitation

and aspiration of gastric contents by mechanically occluding the esophagus at the

level of the cricoid ring. However, application of cricoid pressure in cadavers

caused cervical spine displacement in cases of ligamentous or bony disruption

[41], raising concerns about the safety of cricoid pressure in situations in which

cervical spine injury is present or likely. Even in healthy patients with no

identified risks for cervical spine instability, single-handed cricoid pressure


(applied to only the anterior neck without posterior support) was associated with

a mean neck displacement of 4.6 mm (range of 0–8 mm) [42]. Therefore, the risk

of iatrogenic cervical cord injury in such patients must be weighed against the

risk of gastric aspiration. Even with the risks of direct laryngoscopy, several

retrospective studies have suggested that direct laryngoscopy, even in the

presence of known cervical spine injuries, is as safe as alternate techniques

[43]. If endotracheal intubation is needed in a patient with known cervical spine

injury, other options such as blind nasal or fiberoptic intubation should be

considered if time and clinical circumstances permit. If direct laryngoscopy with

the application of cricoid pressure is to be used, the use of bi-manual cricoid

pressure (anterior compression of the cricoid cartilage with simultaneous support

of the posterior neck) has also been proposed [44]. Effective evaluation and acute

stabilization of the head-trauma patient must precede all other interventions.

Necessary airway management should not be delayed or withheld because of fear

of increased ICP or the need for other diagnostic studies such as computed

tomographic (CT) scans, angiography, or cervical radiographs.

Having evaluated and dealt with airway, ventilation, and oxygenation issues,

the trauma team can proceed to hemodynamic evaluation. This evaluation

includes an estimation of intravascular volume, establishment of adequate

vascular access (peripheral venous, central venous, and arterial catheterization),

review of estimated blood loss, acquisition of baseline laboratory studies, and

resuscitation. Because of the potential for unrecognized blood and fluid loss,

hypovolemia is always a possibility. Heart rate and blood pressure are insensitive

indicators of volume status. Young, previously healthy patients can lose nearly

30% of their blood volume yet not manifest overt hypotension in the supine

position. Reflex systemic hypertension is commonly observed with head trauma,

further confounding clinical assessment of intravascular volume.

The importance of avoiding hypotension cannot be overemphasized. Tables 4

and 5 illustrate the effects of hypotension on outcome after head injury. Fig. 1

graphically represents the influence of in-hospital hypotension on the long-term

Table 4

Outcome by secondary insult occurring from time of injury through resuscitation at Traumatic Coma

Data Bank Hospital Emergency Department for mutually exclusive insults

Number % of totalOutcome (%)

Secondary insults of patients patients GR or MD SD or PVS Dead

Total cases 717 100 43.0 20.2 36.8

Neither 308 43.0 53.9 19.2 26.9

Hypoxia 161 22.4 50.3 21.7 28.0

Hypotension 82 11.4 32.9 17.1 50.0

Both 166 23.2 20.5 22.3 57.2

Hypoxia, PaO2 < 60 mmHg; hypotension, systolic blood pressure < 90 mmHg.

Abbreviations: GR, good recovery; MD, moderate disability; SD, severe disability; PVS, persistent

vegetative state.

From Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining

outcome from severe head injury. J Trauma 1993;34:216–222 [29]; with permission.


outcomes of patients with head injury. Failure to recognize, intervene, and correct

hypotension, even at the earliest stages of management, is associated with poorer

outcome, and blood pressure should be the primary focus of initial evaluation and

resuscitation of the head-injured patient after airway management. Although

hypoxemia should be avoided, head injury appears to be much more adversely

influenced by hypotension.

The choice of resuscitation fluid after head trauma is a matter of ongoing debate.

Relatively isotonic crystalloid solutions (lactated Ringer’s solution and 0.9%

saline) have been used extensively for years. It is important to remember that the

osmolarity of lactated Ringer’s solution is only 273 mOsm/L, while that of 0.9%

saline is 308 mOsm/L. Large volumes of lactated Ringer’s solution will decrease

serum osmolarity and thus increase total brain water [45,46]. Some institutions

limit the volume of lactated Ringer’s solution to 2000 mL, while others use 0.9%

saline as the crystalloid of choice. Because of crystalloid distribution throughout all

extracellular spaces, a ratio of 5:1 is required to replace blood loss (ratio of

interstitial fluid volume to plasma volume). In major blood loss, this may represent

a considerable volume, especially because the ratio of crystalloid to blood loss

increases as protein dilution occurs [47]. Also, rapid infusion of unwarmed fluid

can lead to hypothermia. Despite years of treatment with fluid restriction of head-

injured patients, experimental and clinical data strongly suggest that there is little

correlation between total fluid administration and clinical outcome [48]; moreover,

if inadequate resuscitation results in hypotension, ICP may increase [49].

Hypertonic crystalloid solutions such as 3% and 7.5% saline have been used to

avoid the large volumes of isotonic crystalloids necessary for resuscitation.

Hypertonic solutions increase intravascular volume by shifting water from the

intracellular to the extracellular space [50]. These agents increase intravascular

volume and improved hemodynamic stability in hypovolemic shock [51] and

reduce ICP but do not reliably restore cerebral oxygen delivery after experimental

head trauma [52]. The total volume of hypertonic saline should be limited to

minimize electrolyte imbalance and hyperosmolality.

Table 5

Outcome by secondary insult present at time of arrival at Traumatic Coma Data Bank Hospital

Emergency Department for mutually exclusive insults

Number % of totalOutcome (%)

Secondary insults of patients patients GR or MD SD or PVS Dead

Total cases 699 100.0 42.9 20.5 36.6

Neither 456 65.2 51.1 21.9 27.0

Hypoxia 78 11.2 44.9 21.8 33.3

Hypotension 113 16.2 25.7 14.1 60.2

Both 52 7.4 5.8 19.2 75.0

Hypoxia, PaO2 < 60 mmHg; hypotension, systolic blood pressure < 90 mmHg.

Abbreviations: GR, good recovery; MD, moderate disability; SD, severe disability; PVS, persistent

vegetative state.

From Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining

outcome from severe head injury. J Trauma 1993;34:216–222 [29]; with permission.


Fig. 1. Outcome (Glasgow Outcome Scale at 12 months after injury) as influenced by in-hospital hypotension (one or more episodes of systolic blood pressure #90 mmHg)

for 493 patients in the Traumatic Coma Data Bank (TCDB). Early hypotension is that present on arrival at the TCDB hospital. Late hypotension occurred any time during

the patient’s stay in the intensive care unit beginning after the first shift. From Chesnut RM. Secondary brain insults after head injury: clinical perspectives. New Horiz

1995;3:366–375 [114]; with permission.

E.Bedell,

D.S.Prough/Anesth

esiologyClin

NAm

20(2002)417–439

425

Isotonic colloidal solutions (hetastarch, pentastarch, albumin, and blood) are

useful for acute volume expansion, and are given in a ratio of 1:1 to replace blood

loss. Because of concerns about compatibility, infection, and availability, the use

of blood products for initial resuscitation should be restricted to severe ongoing

hemorrhage, severely compromised oxygen delivery, and bleeding diatheses

[53,54]. Six percent hetastarch and 5% albumin are frequently given instead of

packed red cells or crystalloid. Hetastarch, in volumes greater than 20 mL/kg, has

been associated with abnormal clotting profiles and a risk of increased bleeding

[55,56], while 5% albumin, as a human product, is expensive, limited in

availability, and has been associated in rare instances with anaphylactic reactions.

Meta-analyses suggest that overall survival is not increased by the use of albumin

or colloid [57] and perhaps is even worsened [58]. In the future, synthetic blood

products, such as recombinant hemoglobin, may become available for use in

resuscitation. These agents would allow rapid volume expansion without the risks

of incompatibility, infection, or scarcity while improving oxygen delivery [59].

To date though, these agents have not been efficacious, and the only agent studied

in a clinical setting was withdrawn because of increased patient mortality [60].

Hypotonic solutions and glucose-containing solutions deserve special men-

tion. Because of redistribution of hypotonic solutions throughout total body

water, 5% dextrose in water (D5W) is ineffective as a resuscitation fluid. Only

7% of intravenously administered D5W remains intravascularly after equili-

bration; therefore, the volumes required to resuscitate even limited blood loss

may cause severe hyponatremia and may aggravate cerebral edema. Hyper-

glycemia in conjunction with TBI has been associated with worsened outcome

both in animal and human studies [61–63]. Consequently, glucose-containing

solutions, unless required to correct hypoglycemia, should be avoided in head

trauma. Because hypovolemia, hypotension, and shock are so important, and

because it is not clear which fluid is best (given the above caveats), the choice of

resuscitation fluid is more a matter of personal preference than a choice based

upon clear scientific outcome studies.

With the ABC’s addressed, attention can shift to the management of specific

injuries. For the purposes of this article, we will assume an isolated TBI. (In

clinical practice, other injuries could be of higher priority and require more

prompt attention. The early goals of management are to diagnose the extent of all

injuries, to resuscitate and stabilize the head-injured patient, and to expedite

needed surgical intervention.)

Management

After the initial evaluation and resuscitation are completed, the management of

blood pressure and ICP becomes paramount and is based on the interrelationships

between brain trauma, intracranial pressure, and hemodynamic manipulations.

Conventionally, invasive ICP monitoring is used if GCS is � 8. This is usually

deferred for patients scheduled for immediate craniotomy. In those patients


scheduled for non-neurosurgical procedures under general anesthesia (eg, extrem-

ity surgery), one should consider placement of ICP monitoring devices for those

with GCS � 12 as they are at risk for intraoperative deterioration, and strongly

consider placement for those with an initial GCS � 8.

Irreversible ischemic cell damage occurs rapidly when there is inadequate

cerebral blood flow (CBF) that contributes to brain injury [27] on a global,

regional, or focal level. The actual determinants of CBF are complex, and

there are no tests or studies to monitor CBF real-time in an emergency setting.

The supervisory physician must thus make empirical management decisions

about the adequacy of CBF, based on the clinical situation and on an estimation

of cerebral perfusion pressure (CPP), which is defined as mean arterial blood

pressure (MAP) minus ICP or central venous pressure (CVP), whichever is

higher. In clinical practice, a CPP of 60–80 mmHg generally is considered

adequate [64].

CPP represents the blood pressure gradient across the brain’s vascular bed, and

thus determines blood flow through the brain. This relationship can be modeled

through a modification of Ohm’s Law, which states that the pressure gradient

(arterial pressure minus venous pressure) equals the flow times the resistance:

Pressure ¼ Flow� Resistance

This model must be used with care. It would be easy to mistakenly assume that

the resistive element in the equation is fixed. In reality, there is great variability in

cerebral vascular resistance due to local and systemic factors. Both experimental

and clinical brain trauma are associated with acutely increased cerebrovascu-

lar resistance.

In healthy, nontraumatized patients, cerebral vascular resistance is regulated

predominantly at the precapillary arterioles to maintain a constant blood flow

adequate to supply the needs of the brain tissue. Classic examples of these

changes are listed in Table 6. These changes in resistance are the foundation for

the concept of cerebral autoregulation, which holds that CBF is regulated through

alterations in arteriolar muscular tone under a wide variety of situations to

maintain a balance between CBF and CMRO2. Normal autoregulatory profiles

for humans are well described, and are shown in Fig. 2, although these responses

are altered in disease states and after TBI. In normal individuals, there is a direct

relationship between blood pressure and cerebral vascular resistance, allowing for

a constant blood flow over a wide range of MAPs.

Table 6

Effect of systemic and local factors on cerebrovascular resistance

Causes of cerebral vasoconstriction Causes of cerebral vasodilation

Increased blood pressure Decreased blood pressure

Decreased PaCO2 Increased PaCO2

Decreased blood viscosity Increased blood viscosity

Barbiturates Hypoxia (SaO2 < 60 mmHg)

Decreased cerebral metabolic demands Increased cerebral metabolic demands


After TBI, vascular reactivity is acutely altered [65]. Pressure autoregulation

is lost at lower levels of CPP [66]. In experimental animals, loss of autoregu-

lation has led to increased neurologic injury with even mild hemorrhagic hypo-

tension [67]. Moreover, in the acute interval after both experimental [67]

and clinical [27] traumatic brain injury, CBF is substantially reduced; one third

of patients have decreased regional or global CBF to a level that can cause

cerebral ischemia within 8 hours of injury [68]. Posttraumatic impairment of

pressure autoregulation may further reduce CBF at blood pressures that might

otherwise be considered safe, which may explain the worsened outcome

associated with hypotension.

In contrast, hypertension after TBI could increase intracranial hemorrhage or

disrupt the upper limits of pressure autoregulation leading to excessive CBV

[69,70]. Initially, a patient with TBI may manifest systemic hypertension. In

some patients, an increase in MAP may be necessary to overcome increased ICP

(and thus maintain CPP). Treating systemic hypertension before ruling out

increased ICP may lead to inadequate CPP [71], while failure to treat systemic

hypertension in the presence of an intracranial bleed may lead to hematoma

expansion and higher ICP. Evidence of increased ICP and the presence of

systemic hypertension should be an indication for early diagnostic procedures.

A judgment should be made about the presence of increased ICP or about

Fig. 2. The relationship of cerebral blood flow (CBF) to cerebral perfusion pressure (CPP), PaCO2,

and PaO2. Units on the abscissa are in mmHg. From Michenfelder JD. The awake brain. In:

Michenfelder, JD, editor. Anthesthesia and the brain: clinical, functional, metabolic, and vascular

correlates. New York: Churchill Livingstone; 1998. p. 3–21 [115]; with permission.


whether the hypertension is leading to further patient compromise before treating

systemic hypertension aggressively. With the availability of CT scanners in most

medical centers, the rapid diagnosis of intracranial mass lesions should be

possible without significant delay. In summary, it is prudent to keep in mind

the possible alterations in cerebral vascular reactivity and avoid even mild

hypotension, while at the same time guarding against uncontrolled or sustained

hypertension. A reasonable guideline for blood pressure management is a CPP of

60 to 100 mmHg.

Changes in arterial carbon dioxide tension (PaCO2) also influence CBF.

Cerebral vascular reactivity to PaCO2 was noted in the early 1950s in association

with high-altitude military aircraft [72]. It was hypothesized that severe hypo-

capnia had deleterious effects [73], reflecting the basic question, ‘‘Can hypocarbia

produce cerebral vasoconstriction sufficient to precipitate cerebral ischemia?’’

Animal studies and clinical electrophysiologic data have not supported the concept

that hypocarbia induces cerebral ischemia in normal brain [74,75]. The study of the

effects of hypocarbia on abnormal brains (eg, TBI) has yielded different results.

Animal studies have demonstrated that hypocarbia, in association with anemia,

hypotension, or brain retraction, can lead to ischemia injury, and there is growing

evidence that hypocarbia may be associated with worsened long-term outcome in

head-trauma patients [76–78]. The routine use of hyperventilation in head-trauma

patients is, therefore, no longer recommended. Two relative indications for the use

of hyperventilation include acute increases in ICP and the need to improve surgical

exposure. Use of prolonged hyperventilation may require the insertion of a

regional or focal measure of the adequacy of cerebral oxygenation, such as jugular

venous oximetry or brain tissue oxygen sensors (see below).

Management of ICP also contributes to maintaining an adequate CPP.

Intracranial pressure is the relationship between the volume of the skull and its

contents. This relationship is described by the elastance curve, which relates ICP

and intracranial volume (Fig. 3). As the volume of the intracranial contents ap-

proaches the available space (the knee of the curve), the pressure increases

rapidly. Beyond this point, even small additional volume increases can dramat-

ically increase ICP.

The intracranial contents can be arbitrarily divided into four groups: solid

mass, water, cerebrospinal fluid (CSF), and intravascular blood. Management

techniques can be aimed at all four areas with varying degrees of success. Solid

intracranial contents include nonwater brain parenchyma plus missile compo-

nents, bone fragments, and hematomas. These elements cannot be pharmacolog-

ically or physiologically manipulated. Surgical decompression or decreasing the

relative volume of the other intracranial contents remain the only practical

options. Therefore, it is vital to understand the techniques, risks, and potential

benefits of altering the volume of the other intracranial components in the

management of ICP.

CSF drainage can be used to decrease ICP as well as to control hydrocephalus

and improve surgical exposure. Pharmacologic manipulation of CSF production

and elimination using acetazolamide is slow in onset and difficult to titrate. The


intraoperative adjustment of CSF volume is not a primary technique for the

management of ICP during anesthesia unless a ventriculostomy is in place.

However, graded CSF drainage is used to control ICP in some centers.

Reducing intracranial water content is important in the management of

intracranial hypertension associated with TBI. Brain water content depends upon

the cellular integrity and function of the blood–brain barrier, the osmolality of

blood, and the osmolality of the fluid administered. Brain water is minimally

influenced by changes in colloid osmotic pressure, but is highly influenced by

acute changes in osmolality [79]. Hypotonic fluids increased brain water [46],

and hypertonic fluids decreased brain water in animals [50]. Overall brain water

can also be reduced through administration of osmotic agents such as mannitol

(in doses of 0.5–1 g/kg). Although countless clinicians have observed decreased

ICP after administration of these agents, the precise mechanism of action of

mannitol has been questioned [80]. In contrast, glucocorticoids do not decrease

traumatic brain edema [81], despite their established efficacy in reducing vaso-

genic edema associated with brain tumors. Glucocorticoids are indicated for the

acute treatment of spinal cord injury, and should be initiated as soon as

reasonable following injury [82].

Adjustment of intracranial blood volume remains the mainstay of acute ICP

management. CBV is approximately 3.5 mL/100 g brain tissue in healthy

individuals [83], or about 50 mL, approximately one-fourth of which is arterial

and three-fourths venous. It is important to appreciate the difference between CBV

and CBF, and the difference between arterial and venous blood volume. CBF is the

Fig. 3. Elastance curve for the cranial vault. Additional volume is well tolerated if reserves are good;

however, as intracranial volume increases to a critical point, intracranial pressure (ICP) increases

rapidly with further small increments in intracranial volume.


rate at which blood traverses the cerebral vascular bed (generally 55 mL/min-

100 g), while CBV is the actual volume of blood contained within the vascular bed.

CBF and CBV are not directly coupled; an increase in CBF does not necessarily

lead to an increase in CBV. An acute increase in CBF may lead to reflex arteriolar

vasoconstriction and an overall decrease in CBV (and thus a decrease in ICP)

[64,84]. Similarly, the management of arterial and venous blood volumes must be

considered separately. The arterial vascular system will autoregulate based upon

local and systemic factors, while the volume in the venous circuit usually responds

passively to external factors such as venous distending pressure.

Alteration of arterial CBV remains a principal tool in management of ICP after

head trauma. By manipulating the reactive arterial vascular system, it is possible

to induce arterial vasoconstriction and to decrease arterial CBV. Table 6 lists

some of the arterial responses to various local and systemic challenges. Peri-

arteriolar hydrogen ion concentration ([H+]) powerfully influences cerebral

arteriolar tone. Clinical management usually emphasizes PaCO2. As the PaCO2

increases, [H+] increases. Arteriolar diameter increases, leading to a concomitant

decrease in cerebral vascular resistance, an increase in CBF, and an increase in

CBV. The opposite occurs with decreased [H+] (decreased PaCO2). The effects of

lowering PaCO2 are rapid in onset (2–3 minutes) and remain for a number of

hours. This acute effect is lost, however, as buffering of periarteriolar [H+]

diminishes the effect of hyperventilation on arteriolar vascular tone. By 24 hours,

the initial vasoconstriction is gone, and an abrupt return to normal PaCO2 may

lead to cerebral vasodilation and increased ICP [85]. In normal brain, increases in

CO2 to greater than 80 mmHg do not lead to greater cerebral vasodilation, as

relaxation is maximal. Similarly, in normal brain, hyperventilation to PaCO2

below 20 mmHg does not lead to further vasoconstriction, as either local factors

or mechanical factors inhibit further vasoconstriction.

After cerebral ischemia or TBI, the role of PaCO2 is less clear. Excessively

low PaCO2 may contribute to or cause ischemia [78] and worsen long-term

cellular survival. The measurement of cerebral oxygenation using cerebral

venous oxygen saturation has shown that hyperventilation can lead to significant

decreases in saturation [86]. Although low PaCO2 may constrict normal arterio-

les, thereby shunting blood to ischemic areas [87], this ‘‘Robin Hood’’ process of

stealing blood from ‘‘rich’’ tissue beds to give to ‘‘poor’’ regions has been

difficult to prove. Redistribution of blood flow from normal areas to ischemic

areas has been unpredictable [88] and ideally requires continuous real-time

monitoring for proof of efficacy. Hyperventilation should thus be restricted to

short intervals with specific goals such as acutely decreasing ICP or improving

surgical exposure, and consideration for the use of jugular venous saturation

monitoring should be made [89]. PaCO2 should be allowed to return toward

normal as soon as the acute indications pass. It is intriguing to note that the

effects of hyperventilation can be modified in patients with TBI. Use of

supplemental inspired oxygen to develop hyperoxia (arterial oxygen tension

[PaO2] > 200 mmHg) has been shown to ameliorate the effects of hyperventila-

tion and improve jugular saturation in patients with TBI [90,91]. The utility of


hyperoxia as a clinical tool is as yet unproven, but represents an ongoing area of

provocative research.

Hypoxia remains one of the most potent arteriolar cerebrovascular dilators.

Hypoxia or ischemia leads to marked vasodilation, increased arterial vascular

volume, and increased ICP. Normal systemic oxygenation does not necessarily

imply adequate cerebral oxygenation; CBF and oxygen-carrying capacity must

also be adequate. Techniques for monitoring transcranial cerebral oxygen

saturation [92,93], jugular venous oxygen saturation [94], and brain tissue partial

pressure of oxygen (PO2) are being developed or are available to provide real-

time information about the adequacy of cerebral oxygenation. In the future, these

techniques may become available for routine evaluation of head-injured patients.

At present, maintenance of adequate CPP and oxygen-carrying capacity remain

the primary tools for preserving cerebral oxygenation.

The phenomenon of pressure autoregulation is also critical in regulating CBV.

Cerebral arteriolar smooth muscle responds to increased intravascular pressure

with increased vascular tone within the range of pressure autoregulation. As

blood pressure increases, arteriolar vasoconstriction maintains constant flow and

decreases arterial blood volume. By the same mechanism, decreased blood

pressure (or hypotension) produces arteriolar dilation and increases arterial blood

volume. Because hypotension-induced reflex vasodilation may increase CBVand

ICP in head-injured patients [49], protection against hypotension remains a key

component in the management of arterial blood volume and ICP.

Red cell rheology and blood viscosity play a role in arterial vasoconstriction.

Decreasing hematocrit decreases blood viscosity, which leads to vasoconstriction

of normal brain arterioles [95]. Thus, hemodilution increases CBF and results in

reflex vasoconstriction, which has been termed ‘‘blood viscosity autoregulation’’

[96]. The clinical importance of this phenomenon is controversial [97]. Admin-

istration of mannitol alters red cell deformability and decreases viscosity

unrelated to changes in hematocrit [98]. This observation may explain mannitol-

induced decreases in ICP that are not related to total brain water or hemodilu-

tion [99–101].

Vascular autoregulation is determined by many factors, including viscosity and

CBF. In addition, if oxygen-carrying capacity is decreased below the metabolic

requirements of the brain, cerebral vasodilation will occur. The difference of the

impact of hemodilution-induced vasoconstriction and vasodilation secondary to

inadequate oxygen delivery is difficult to determine clinically. In practice, the

optimal hematocrit for head-injured patients remains undefined.

Pharmacologic interventions are another important means of altering arteriolar

resistance and arterial blood volume. Table 7 lists some commonly administered

drugs and their effects on cerebral arterial tone. Volatile inhalational agents and

nitrous oxide cause arterial vasodilation; although hyperventilation modifies

drug-induced cerebral vasodilation, it does not reliably prevent increases in

ICP. Therefore, intravenous agents such as narcotics, benzodiazepines, and short-

acting hypnotics have been used for anesthesia in cases of head trauma. With

either inhalational or intravenous techniques, hypotension must be avoided. Some


intravenous agents, including propofol and thiopental [102], cause systemic

vasodilation or myocardial depression, which may lead to hypotension, especially

in conjunction with uncorrected hypovolemia. Therefore, blood pressure must be

monitored and hypotension treated promptly and aggressively. Because of the

risks and benefits of different anesthetic approaches, the clinician should be

careful about the choice of drugs for individual patients.

Cerebral venous blood volume depends upon CBF, gravity, and restriction to

outflow. Increased blood viscosity decreases flow (by increasing resistance),

leading to increased blood volume. Decreasing the venous pressure differential

(by increasing CVP [103], lowering the head [104], or inducing cerebral

venodilation) will increase venous CBV. Increasing the resistance to venous

outflow by bandaging the neck or extreme lateral rotation of the head can

increase venous CBV [83,105]. Maneuvers that facilitate cerebral venous

drainage and therefore potentially decrease venous CBV, are listed in Table 8.

However, if such maneuvers decrease CPP (eg, head elevation leading to

hypotension), the benefits of improved venous return may be negated [106].

Attempts to limit secondary brain injury should ideally include the initiation of

protective measures that would improve the outcome of damaged cells and protect

normal tissue from harm. The concept of brain protection is used extensively in

Table 7

Effects of selected drugs on cerebral vascular resistance, systemic vascular resistance, and myocar-

dial contractility

Drug CVR SVR Myocardial

Ketamine Decreased Increased Increased

Halothane Decreased Unchanged Decreased

Isoflurane Decreased Decreased Unchangeda

Sevoflurane Decreased Decreased Unchangeda

Nitrous oxide Decreased Unchanged Decreased

Barbiturates Increased Decreased Decreased

Benzodiazepines Increased Decreased Unchanged

Narcotics Variable Decreased Unchanged

Etomidate Increased Unchanged Unchanged

Propofol Increased Decreased Decreased

Abbreviations: CVR, cerebral vascular resistance; SVR, systemic vascular resistance.a Note that systemic arterial dilation may preserve cardiac output, thus masking myocar-

dial depression.

Table 8

Techniques to decrease cerebral venous blood volume

Avoid extremes of neck rotation

Avoid direct jugular compression

Elevate head (caution: hypotension negates effect on CPP)

Decrease blood viscosity (mannitol)

Avoid sustained increases in intrathoracic pressure

Avoid cerebral venodilators (e.g., nitroglycerine, etc.)

Abbreviations: CPP, cerebral perfusion pressure; ICP, intracranial pressure.


cardiac surgery and neurosurgery. Techniques to decrease the likelihood of

permanent ischemic injury to brain, such as active hypothermia preceding

complete circulatory arrest, are now accepted practices [107]. The efficacy of

these techniques after ischemic or traumatic insults is less established. Preliminary,

single-institution studies evaluating hypothermia and long-term outcome after

head trauma suggested that decreasing the temperature of the brain shortly after

injury improved morbidity and mortality [108–110]; however, a recent multicenter

trial did not reproduce these earlier findings [4]. An interesting finding in that trial

was the fact that the worst outcome occurred in patients who arrived at the hospital

and were rapidly rewarmed. A variety of drugs that influenced outcome after

ischemic and traumatic brain injury in experimental animals have also been studied

in clinical trials but to date have not been shown to improve outcome. At present,

the most important goal is the reestablishment of adequate brain tissue oxygenation

to limit further cellular compromise. Based upon the clinical presentation, a

specific care plan should encompass patient needs, and allow for rapid evaluation

and treatment and flexibility based upon new research.

Summary

The management of TBI remains an important and frustrating component of the

practice of anesthesiology and critical care medicine. The difficulties in manage-

ment of TBI as well as the poor response rates to medical therapy after TBI are not

new. The following passage appeared in the introductory chapter of a text on TBI

from 1897: ‘‘The manner of treatment is of importance in only a minority of cases,

since many subjects of intracranial injury are fated to die whatever measures may

be adopted for their relief, and a still greater number are destined to recover though

left entirely to the resources of nature. It is probable that in by far the larger

proportion of cases in which the issue is determined by treatment it is met in the

initial stage, and by insuring restoration from primary shock’’ [111].

Although secondary insults from factors such as hypotension, hypoxemia, and

hyperventilation increase morbidity and mortality, data are not yet available to

indicate whether scrupulous prevention and prompt treatment of secondary

injuries will reduce morbidity and mortality. In addition, no specific intervention

to date has improved overall long-term outcome. With ongoing research, perhaps

active interventions will become available. Until that time, thoughtful and care-

ful attention to physiologic management provides the greatest opportunity for a

good outcome.

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Current concepts in neurocritical care

Brenda G. Fahy, MD*, Vadivelu Sivaraman, MDDepartment of Anesthesiology, University of Maryland Medical System, 22 S. Greene Street,

Suite S11C00, Baltimore, MD 21201, USA

Stroke

Stroke is the third leading cause of death and the leading cause of adult

disability in the United States. The National Institute of Neurological Disorders

and Stroke defines stroke as sudden loss of brain function resulting from an

interference with brain blood supply. This includes both ischemic and hemor-

rhagic insults with ischemic stroke predominant (85%). Subarachnoid hemorrhage

(SAH), with its specialized management, will be covered in the next section. Once

only supportive, therapy for acute ischemic stroke now includes therapeutic

options with tissue plasminogen activator (tPA).

Acute vascular occlusion, although rarely complete, limits oxygen and glucose

delivery to that respective region of the brain. This results in a core area of tissue

that infarcts almost immediately due to lack of blood and nutrient supply with a

surrounding area of ischemic penumbra. The penumbra may not result in tissue

infarction if ischemia can be reversed. Medical interventions target the potentially

salvageable brain tissue.

Intracranial hemorrhage (ICH), although less frequent than ischemic stroke, has

a high mortality rate due to the extent of cerebral damage. Thrombolytics and

anticoagulation are contraindicated with recent ICH. The mainstays of therapy

include blood pressure management (as hypertensive disease is common), in-

tracranial pressure (ICP) control, and optimization of cerebral perfusion. A de-

cision for emergent surgical evacuation should be made in consultation with

neurosurgery. These patients may require intraventricular catheter (IVC) place-

ment for ICP monitoring and cerebrospinal fluid (CSF) drainage.

Because time is crucial to minimize tissue death, there must be rapid as-

sessment of the stroke patient including neurologic and physical examination and

general medical assessment. It is crucial to establish the timing of the onset of

stroke symptoms for possible administration of tPA. A head CT should be per-

formed to rule out ICH, but this stage rarely shows ischemic changes. Although


PII: S0889 -8537 (01 )00011 -6


E-mail address: [email protected] (B.G. Fahy).


20 (2002) 441–462

not a complete neurologic examination, the National Institute of Health Stroke

Scale Score (NIH-SSS) [1] (Table 1) utilizes a standardized scale to indicate the

severity of neurological dysfunction.

Table 1

NIH-SSS [1]

Level of consciousness (LOC) Alert 0

Drowsy 1

Stuporous 2

Coma 3

LOC questions (month and age) Answers both correctly 0

Answers one correctly 1

Incorrect 2

LOC commands (close eyes, make fist) Obeys both correctly 0

Obeys one correctly 1

Incorrect 2

Best gaze Normal 0

Partial gaze palsy 1

Forced deviation 2

Visual No visual loss 0

Partial hemianopia 1

Complete hemianopia 2

Bilateral hemianopia 3

Facial palsy Normal 0

Minor paresis 1

Partial paresis 2

Complete palsy 3

Best motor (repeat for each arm and leg) No drift 0

Drift 1

Can’t resist gravity 2

No effort against gravity 3

Limb ataxia Absent 0

Present in upper or lower 1

Present in both 2

Sensory Normal 0

Partial loss 1

Dense loss 2

Dysarthria Normal articulation 0

Mild to moderate dysarthria 1

Near unintelligible or worse 2

Mute 3

Best language No aphasia 0

Mild to moderate aphasia 1

Severe aphasia 2

Mute 3

Change from previous exam Same 0

Better 1

Worse 2

Change from baseline Same 0

Better 1

Worse 2

Abbreviation: NIH-SSS, National Institute of Health Stroke Severity Score.

B.G. Fahy, V. Sivaraman / Anesthesiology Clin N Am 20 (2002) 441–462442

During patient evaluation measures should be instituted to optimize blood

flow. Hypertension is common in acute stroke, and should be treated cautiously

to prevent cerebral ischemia. Treatment exceptions include hypertension asso-

ciated with ICH and during the period surrounding tPA administration in

ischemic strokes. The American Heart Association has established blood pressure

guidelines (Table 2). Blood pressure should not exceed 185/110 at the time of tPA

Table 2

Therapy guidelines for thrombolytic candidates

Blood pressure (mmHg) Treatment

Pretreatment SBP > 185

or DBP >110

Nitroglycerin paste or 1 to 2 doses of intravenous labetalol,

10 to 20 mg each. If these do not reduce blood pressure to

< 185/110 mm Hg over 1 h, the patient should not be treated

with rtPA.

During and after Thrombolytics

Monitor BP Every 15 minutes x 2 hours, then 30 minutes for 6 hours,

then hourly x 16 hours

SBP: 180–230 or

DBP: 105–130

Labetalol, 10 mg IV over 1–2 min, repeat or double every

10–20 min; total maximum dose 150 mg

SBP >230 or

DBP: 121–140

Use labetalol, 10 mg IV over 1–2 min, repeat or double every

10 min, to a maximum of 150 mg

DBP >140 Sodium nitroprusside with continuous blood pressure monitoring

Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 3

Inclusion and exclusion criteria for use of thrombolysis in acute ischemic stroke

Inclusion criteria

Ischemic stroke with a measurable defect on NIHSSS

Clearly defined time of onset within 3 h of the start of treatment

Age >18 y

Exclusion criteria

Contraindications include:

Evidence of intracranial hemorrhage on pretreatment CT scan

Suspicion of SAH, even if CT scan normal

Known arteriovenous malformation, aneurysm, or intracranial neoplasm

Prior intracranial hemorrhage

Intracranial or spinal surgery, serious head injury, or prior stroke in previous 3 mos

Active internal bleeding

Known bleeding diathesis including but not limited to: a) platelet count <100,000/mm3, (b)

prothrombin time >15 seconds, (c) international normalized ratio >1.7, (d) current use of oral

anticoagulants; (e) use of heparin within 48 h and prolonged partial thromboplastin time

Uncontrolled blood pressure at time of treatment (refer to Table 2)

Recent (in previous 3 months): intracranial surgery, serious head trauma, or previous stroke

Major surgery (in past 14 days)

Pregnancy

Seizure at stroke onset

Abbreviations: NIHSSS, National Institute of Health Stroke Severity Score; SAH, subarachnoid

hemorrhage.

B.G. Fahy, V. Sivaraman / Anesthesiology Clin N Am 20 (2002) 441–462 443

treatment [2]. Hypotension, or relative hypotension in a hypertensive patient,

should be treated aggressively and an etiology sought. Cerebral blood flow

during stroke is blood pressure dependent. Hypotension must be reversed to

prevent further ischemia with subsequent infarction.

Intravenous tPA is the only Federal Drug Administration approved primary

treatment for acute ischemic stroke, and must be started within 3 hours of stroke

onset. Appropriate indications and contraindications are detailed in Table 3. The

most serious tPA complication is ICH. The risk of ICH after tPA increases with

higher NIH-SSS scores [1]. Chronic anticoagulation in patients with atrial

fibrillation is clearly warranted [3]. A comprehensive review of all therapies

following acute stroke management is beyond the scope of this paper, and has

been reviewed elsewhere [4].

Other neurologic complications following stroke include seizure and uncon-

trolled ICP. Seizures occur in 5% of strokes, usually with large strokes or cortical

involvement. No evidence exists for prophylactic anticonvulsants; however, sei-

zures can be treated acutely with benzodiazepines followed by phenytoin. Uncon-

trolled ICP is the leading cause of death in the first week following stroke. ICP

measurements may be helpful with acutely deteriorating patients and help guide

therapy. If an IVC is placed for ICP monitoring, it can permit therapeutic CSF

drainage. Other therapeutic measures include elevating the head of the bed and

hyperosmolar therapy with mannitol. Hyperventilation should be instituted cau-

tiously due to concerns of worsening cerebral ischemia by hypocapnia-induced ce-

rebral vasoconstriction decreasing cerebral blood flow. High-dose barbiturates may

be used with uncontrolled ICP refractory to other therapies. Appropriate intensive

supportive care must assure maintenance of hemodynamic stability during high-

dose barbiturates. Decompressive craniectomy has been used with intracranial hy-

pertension in hemispheric infarctions [5], but its value requires further clarification.

Medical complications are common following stroke. Coronary artery disease

is present in a majority of stroke patients. Monitoring for detection and treatment

of myocardial ischemia and infarction, arrhythmias, and congestive heart failure

is warranted. Pulmonary complications include pneumonia, which can occur with

dysphagia when oropharyngeal contents are aspirated. Stroke patients have a high

risk of deep venous thrombosis (DVT), and may develop a pulmonary embolism

(PE). Current prophylaxis recommendations in ischemic stroke for DVT and PE

include low-dose unfractionated heparin, low molecular weight heparin, or

danaparoid [6]. If anticoagulation is contraindicated, elastic stockings (ES) and

intermittent pneumatic calf compression (IPC) can be used. Hyperthermia in the

poststroke period increases morbidity and mortality [7]. Fever increases brain

metabolic demand, and should be avoided following stroke.

Subarachnoid hemorrhage

Nontraumatic subarachnoid hemorrhage (SAH) occurs in an estimated 30,000

Americans each year. Despite recent diagnostic and treatment advances, 25% of


SAH patients will die, and 50% of survivors will suffer significant morbidity [8].

These patients require intensive care unit admission for neurologic observation

and cardiopulmonary monitoring. The majority of SAH patients will have a

cerebral aneurysm. [9]. SAH therapy is aimed at prevention and early detection of

neurologic complications, and treatment of medical complications.

Neurologic complications include rebleeding, hydrocephalus, seizure, and cere-

bral vasospasm. The most immediate concern is the risk of rebleeding with a mor-

tality rate of 70%. The risk of rebleeding is 4% during the first 24 hours and 1–2%

per day during the following 4 weeks [ 10]. Because rebleeding rates are increased

with high systolic blood pressure, simple treatment measures include blood

pressure management, adequate pain control, and stool softeners until the aneu-

rysm is secured. Early securing of the aneurysm is important not only to prevent

rebleeding but also to allow more therapeutic options for subsequent cerebral

vasospasm [11]. Antifibrinolytic therapy is no longer recommended because it

increased secondary ischemia risk [12] and failed to improve outcome [13].

Acute hydrocephalus occurs in approximately 25% of patients after initial SAH,

and can impair consciousness. Treatment is CSF drainage via an IVC. Over-

drainage of CSF should be avoided, as it increases the risk of rebleed and cerebral

vasospasm [14]. Blood in the ventricular system can obstruct the CSF drainage and

absorption. Some SAH patients will require permanent shunt procedures following

IVC drainage.

Seizures occur in approximately 10% to 20% of patients with SAH, typically in

the first 24 hours. Seizures may increase cerebral blood flow, potentially causing a

rebleed. Respiratory compromise may occur with resultant hypoxemia. To prevent

these complications, prophylactic intravenous phenytoin therapy is administered.

Cerebral vasospasm following SAH is the most significant cause of mortality

and morbidity in survivors of the initial SAH [9]. Cerebral vasospasm is an is-

chemic neurologic deficit associated with focal narrowing of intracranial arteries.

Although the amount of SAH initially visualized on the CT scan is related to

vasospasm [15], the pathogenic mechanisms of cerebral vasospasm need to be

better defined. This is due to the complex nature of the pathophysiology of

vasospasm and difficulty with its reproduction in animal models [16]. Blood

products, especially oxyhemoglobin, have long been accepted as contributors to

cerebral vasospasm [17]. More recent studies have examined oxyhemoglobin as an

initiator of arterial wall contraction during cerebral vasospasm [18]. Although not

completely elucidated, it has been postulated that cerebral vasospasm may result

from oxyhemoglobin through a variety of pathways including arterial muscle

fibers effects, local release of vasoactive compounds from the arterial wall,

superoxide free radical production, and increased activity of lipid peroxidases.

Cerebral vasospasm usually begins 4 days following SAH, peaks at 7–10 days,

and may continue for several weeks [19]. Transcranial doppler studies with ele-

vated velocities can identify potential vasospasm. Angiography, however, is the

gold standard for confirming the diagnosis of cerebral vasospasm. Clinical signs

of vasospasm may manifest as altered level of consciousness or focal neurologic

deficits over the course of minutes to hours. Because the neurologic signs can be


subtle (pronator drift or slight change in consciousness level), serial neurologic

examinations are crucial. The specific neurologic signs manifested will depend

on the location of vasospasm and whether collateral circulation exists. Any acute

neurologic deterioration needs to be investigated to rule out other etiologies in-

cluding ICH and hydrocephalus.

Early recognition and treatment of the potentially reversible ischemic deficit of

vasospasm is the key. Delaying therapy until the appearance of a significant

neurologic deficit may result in cerebral infarction. Clinical signs of vasospasm

occur in approximately 30% of SAH, while angiographic evidence may occur in

up to 70% [20].

Currently, hypervolemia, hemodilution, and hypertension therapy (HHH) are

the main therapies for cerebral ischemia secondary to cerebral vasospasm. During

cerebral vasospasm, cerebral blood flow regulation is assumed to become

pressure dependent [21]. Hypovolemia occurs after SAH [22], correlating with

symptomatic vasospasm [23]. Hypervolemic therapy with volume expansion has

reversed neurologic deficits and increased cerebral blood flow. The resultant

hemodilution as a result of hypervolemia therapy theoretically decreases blood

viscosity, improving circulation to the ischemic area. After securing of the

aneurysm to prevent the risk of a rebleed, hypertensive therapy becomes an

additional option to improve pressure-dependent cerebral blood flow. Despite its

widespread use, there is only one prospective randomized study of hypervolemic

therapy involving 30 hypertensive patients with SAH [24]. They were random-

ized to begin volume expansion and antihypertensive therapy with vasodilators

and centrally acting drugs compared to controls that received diuretics. The

incidence of vasospasm and mortality was significantly higher in the group

treated with diuretics without volume expansion.

Several reports from studies describe improvement in neurologic deficits with

elevating blood pressure, augmenting cardiac output, volume replacement, and/or

hemodilution [25–27] when compared with historic controls. There were no

control groups for these studies. However, studies have yet to determine which

component(s) of HHH are most critical. Potential complications include pulmo-

nary edema, myocardial ischemia, hemorrhagic infarction, and worsening cereb-

ral edema [28].

Calcium antagonists usage to prevent or treat cerebral ischemia was based on

the assumption that these drugs counteracted calcium influx in the vascular

smooth. A meta-analysis of all published randomized nimodipine confirmed the

benefit of prophylactic nimodipine in reducing neurologic deficits, cerebral

infarction, and mortality, and improving outcome secondary to vasospasm [29].

Nimodipine, 60 mg orally every 4 hours for 21 days, usually is well tolerated, and

may cause a mild degree of hypotension. It is one of the corner stones of therapy

for prophylaxis against vasospasm. Another calcium antagonist, nicardipine,

failed to show prophylactic benefit, and had side effects including hypotension,

pulmonary edema, and renal failure [30]. The calcium antagonist, fausidil

hydrochloride, in a prospective randomized trial reduced angiographic and

symptomatic vasospasm with improved outcomes [31].


Endovascular treatment for vasospasm with balloon angioplasty or selective

arterial injection of vasodilators such as papaverine may improve neurologic

symptoms when other medical therapies have failed.

Lysis of the intracisternal blood clot by injection of intracisternal recombinant

tPA has been shown to decrease angiographic and symptomatic vasospasm but not

outcome [32]. One study suggested a nonstatistical trend toward decreased

occurrence of severe vasospasm with intracisternal recombinant tPA [33].

Tirilizad, a 21-aminosteroid, inhibits lipid peroxidation and prevented cerebral

vasospasm in an SAH animal model [34]. A European-Australian multicenter

study showed tirilizad mesylate at 6 mg/kg was associated with better neurologic

outcomes and reduced mortality versus controls [35]. However, it was felt that

anticonvulsant therapy may increase drug clearance, and women received less

benefit due to increased metabolism. However, the beneficial effects could not be

reproduced in the North American Study [36] or in two additional trials with a

higher dose (15 mg/kg) [37,38].

Other drugs tested clinically include the hydroxyl radical scavenger, nicara-

ven. It decreased symptomatic vasospasm; but did not alter outcome at 3 months

[39]. Ebselen, a seleno-organic compound that inhibits lipid peroxidation,

improved 3-month outcome without effecting symptomatic vasospasm [40].

Decreased nitric oxide (NO) activity may play a role in the pathogenesis of

vasospasm. Preliminary data with intrathecal administration of NO donors such

as sodium nitroprusside to a small group of patients with clinical or radiographic

evidence of Grade III SAH (Table 4) resulted in 12 of 15 having at least a good or

better outcome. Intrathecal sodium nitroprusside was also prophylactically

administered to 10 patients with Grade III SAH; none developed vasospasm

[41]. Side effects included three hypotensive episodes and frequent nausea.

Medical complications following SAH are common, and are responsible for

23% of deaths [42]. Sepsis and pneumonia occur in 14.8% of patients [43]. Due

to an inability to protect the airway, this patient population is prone to aspiration

and subsequent pneumonia. Aggressive pulmonary hygiene to prevent atelec-

tasis and antibiotics for bacterial pneumonia may be necessary. Neurogenic

pulmonary edema [44] and non-neurogenic pulmonary edema may occur

following SAH. Therapy includes inotropic support, if indicated, and gentle

diuresis due to concerns over maintaining adequate volume status with the risk

of cerebral vasospasm.

Table 4

Hunt and Hess Scale for Subarachnoid Hemorrhage

Grade Neurological status

I Asymptomatic

II Severe headache or nuchal rigidity; no neurological deficit

III Drowsy; minimal neurological deficit

IV Stuporous; moderate to severe hemiparesis

V Deep coma; decerebrate posturing


Cardiac arrhythmias are frequent following SAH including sinus tachycardia or

bradycardia, ventricular or atrial extrasystole, and atrial fibrillation. Life threat-

ening arrhythmias (asystole, AV block) occur 5% of the time. EKG abnormalities

and cardiac enzyme elevations [creatine kinase (CPK) or troponin] are frequent

following SAH. In a small retrospective series of 72 patients, nine patients had

echocardiographic wall motion abnormalities. All were Grade III–IV (Table 4); all

had CPK mb >2% [45]. There is currently no large prospective study examining

cardiac enzyme elevation and echocardiographic changes.

Hyponatremia is common after SAH, typically developing several days after

hemorrhage. In the general medical population the etiology is often the syndrome

of inappropriate antidiuretic hormone secretion (SIADH), necessitating fluid

restriction. However, in the SAH population, there is evidence that cerebral salt

wasting causing hypovolemia, and sodium depletion can occur following SAH

[22]. Due to concerns over hypovolemia aggravating cerebral vasospasm, appro-

priate therapy for cerebral salt wasting includes sodium and fluid replacement.

DVT (incidence 1% to 5%) and PE (incidence 0.8%) can occur following

SAH. During the acute phase these patients are not candidates for anticoagulation

due to recent SAH and often recent cranial surgery. ES or IPC can be used. If

diagnosed with DVT or PE, an inferior vena caval filter can be placed.

New potential monitoring modalities for SAH patients may include intra-

cerebral microdialysis. These microdialysis catheters inserted in the cortex at the

end of aneurysm surgery can measure markers of cellular injury and ischemia as

well as neurotransmitters. During bedside microdialysis monitoring in a small

series of SAH patients, impending ischemia was signaled by changes in lactate

and glutamate, while increases in glycerol were associated with ischemic deficits

[46]. This early detection of impending ischemia may lead to earlier intervention

and prevention of cerebral infarction.

Traumatic brain injury

Each year in theUnited States, traumatic brain injury (TBI) causes 52,000 deaths

and 80,000 permanent severe disability, and is themost common cause of death and

disability in young people. If TBI causes coma, there is a significant risk of

hypotension, hypoxia, and intracranial hypertension. Any of these sequelae can

exacerbate the degree of neurologic injury or cause death.

Although primary injury occurs at the moment of impact, secondary injury

due to the physiologic and metabolic processes caused by the primary injury

occurs later. Secondary injury processes at the cell level may include calcium

toxicity, lipid peroxidation, free radical generation, and excitatory neurotrans-

mitter release [47].

Secondary brain injury is the primary cause of hospital deaths after TBI.

Within hours of injury, vasogenic fluid accumulates in the brain, causing cerebral

edema. This causes an increase in ICP, allowing cerebral ischemia to occur at a

lower blood pressure threshold. Numerous pharmacologic agents including free


radical scavengers, antagonists of excitatory neurotransmitters, and calcium

channel antagonists have been investigated to attempt to block the secondary

injury resulting from TBI. Efficacy remains to be proven [47].

Secondary insults to the brain caused by hypoxemia and hypotension can

worsen outcome [48]. To decrease theses risks, attention must be given to airway,

breathing, and circulation. TBI patients may present with other traumatic injuries

such as a pneumothorax, hemothorax, or flail chest that require treatment to

prevent hypoxemia. Airway protective reflexes may be absent with impaired

consciousness. Appropriate establishment of an airway if needed is of paramount

importance. Patients with a Glasgow Coma scale (see Table 5) of 8 or less are

unable to protect their airway, and should be endotracheally intubated to prevent

hypoxemia. Endotracheal intubation of these patients decreases the mortality

significantly [49]. An orotracheal tube placement is usually preferred until a

basilar skull fracture can be excluded due to possible brain entry via the cribiform

plate with nasal placement. TBI patients are prone to aspiration pneumonia, and

should receive aggressive pulmonary toilet and appropriate antibiotics if bacterial

pneumonia ensues.

Hypotension needs to be prevented to decrease the risk of secondary brain

insult. A single episode of 90 mmHg or less systolic blood pressure with TBI

worsens outcome [48]. If hypotension cannot be prevented, diagnosis and

treatment should be rapid.

Table 5

Glasgow Coma Scale (GCS)

Criteria points awarded best eye opening

Spontaneously 4

To speech 3

To pain 2

None 1

Best verbal response

Oriented 5

Confused 4

Inappropriate 3

Incomprehensible 2

None 1

Best motor response

Obeys commands 6

Localized pain 5

Withdraws 4

Flexion to pain 3

Extension to pain 2

None 1

The highest level of response in each command is recorded and the sum of the three categories

provides the GCS.


The most significant cause of morbidity and mortality in TBI who survive to

hospitalization is uncontrolled intracranial hypertension [50]. As already ad-

dressed above, initial management should be directed to opening, protecting,

and maintaining the airway to prevent hypoxia and the deleterious effects of hy-

percarbia. If the patient has a clear cervical spine, the head of the bed may be

elevated to improve cerebral venous drainage. Although static, CT scanning

rapidly shows pathology and allows immediate intervention. CT scan signs of

elevated ICP include midline shift, compression or obliteration of mesencephalic

cisterns and the presence of subarachnoid blood (Fig. 1) [51]. ICP monitoring to

allow appropriate interventions is vital. Indications for ICP monitoring include

Fig. 1. CT scan illustrating hemorrhage with obliteration of mesencephalic cisterns and right to left

midline shift. (From Prys-Roberts C, Brown Burnell R Jr. International Practice of Anesthesia; 2(4),

2/125/2 and 2/125/3; reprinted by permission of ButterworthHeinemann, a division of Reed Educational

& Professional Publishing Ltd.)


Glasgow Coma Score of 8 or less and lesions prone to cerebral edema. Several

continuous ICP monitoring devices are illustrated in the following diagram

(Fig. 2), with advantages and disadvantages listed in Table 6. The most reliable

for CSF drainage and ICP measurement is the IVC. The intraparenchymal

Fig. 2. Intracranial pressure monitoring sites. (From Prys-Roberts C, Brown Burnell R Jr. International

Practice of Anesthesia; 2(4), 2/125/2 and 2/125/3; reprinted by permission of Butterworth Heinemann,

a division of Reed Educational & Professional Publishing Ltd.)


fiberoptic ICP monitoring system (Fig. 3) measures brain tissue pressure that has

been shown to correlate well with ventricular pressure [52].

After correction of hypoxia and hypercarbia and proper positioning, if possible,

to improve central venous drainage, ICP therapy involves elevation of serum

osmolality (300 mosmol/kg approximately) by the use of osmotic diuretics or loop

diuretics. The administration of mannitol should ideally occur with consultation of

the neurosurgical team in TBI. If intracranial bleeding is present, mannitol may

allow an intracerebral hematoma to expand by shrinking healthy brain tissue. In

the pediatric population, hyperemia often causes diffuse swelling, and mannitol

may further elevate ICP by increasing cerebral blood volume.

Because of concerns that large doses of mannitol may cause a reverse

osmotic gradient by removing so much tissue water that water and mannitol are

Table 6

Intracranial pressure monitor comparison

IVC SAB Fibreoptic

Accuracy ± ± ± ± ± ± ± ±

CSF drainage ± ± ± ± ± ± �Infection potential ± ± ± ± ± ± ± ± ±

Recalibration possible ± ± ± ± ± ± ± �Brain tissue disruption ± ± ± ± � ± ± ±

Abbreviations: CSF, cerebrospinal fluid; IVC, Intraventricular catheter; SAB, subarachnoid bolt,

Fig. 3. Fiberoptic Camino Intracranial Pressure Monitoring System. (From Prys-Roberts C, Brown

Burnell R Jr. International Practice of Anesthesia; 2(4), 2/125/2 and 2/125/3; reprinted by permission

of Butterworth Heinemann, a division of Reed Educational & Professional Publishing Ltd.)


drawn in to the cell [53], smaller doses (0.25 mg/kg) have been effective

especially when repetitive dosing is required in the intensive care unit [54]. The

osmotic diuretics have a faster onset of action (15 minutes) than the loop

diuretics (30 minutes). Loop diuretics such as furosemide can lower ICP and

potentiate the ICP-lowering effects of mannitol. Hypertonic saline in an animal

hemorrhagic shock model [55] and a small human TBI series showed improved

ICP [56]. More controlled studies are required assessing other variables to fully

assess this therapy. Diuretic therapy may produce dehydration, hypotension,

and electrolyte disturbances including hypernatremia, hypokalemia, hypophos-

phatemia, and hypomagnesemia. These electrolyte disturbances can precipitate

cardiac arrhythmias.

Hyperventilation due to hypocapnia causes cerebral vasoconstriction, which

decreases cerebral blood flow and thus decreases ICP. Due to concern that

hyperventilation can decrease cerebral blood flow in areas after TBI to the point

of ischemia hyperventilation, it is used cautiously [57]. Prophylactic hyper-

ventilation has been shown to worsen outcome following TBI.

With acute ICP elevations, seizure must be considered, particularly if the

patient recently received paralytic drugs, preventing observation of tonic–clonic

seizure activity. Seizures can rapidly increase cerebral blood flow, and thus ICP.

The first priority in a nonventilated seizing patient is to establish a patent airway

and ensure adequate oxygenation. Arresting the seizure is paramount, and an

intravenous barbiturate may be required. Diazepam decreases cerebral blood

flow, cerebral metabolic rate, and ICP while raising the seizure threshold. When

treatment fails to reduce ICP, other etiologies must be sought such as intracranial

bleeding, status epilepticus, or worsening cerebral edema. Due to the high

incidence of posttraumatic seizures, anticonvulsant drugs are routinely admini-

stered prophylactically. Prophylactic phenytoin is indicated in the first week

following TBI [58]. If a seizure occurs beyond the initial injury phase, longer

administration of anticonvulsant therapy is indicated.

Although some centers have advocated the use of paralysis for ICP control, the

trend is to avoid paralytics due to adverse effects including the inability to monitor

neurologic changes, higher incidence of pneumonia, and prolonged weakness

[59]. Adequate pain control and sedation are important to prevent ICP elevations;

however, serial neurologic examinations are important for frequent assessment,

and should be obtained if possible. Shorter acting sedatives, which can be stopped

intermittently to allow serial neurologic examinations, are often being utilized.

Propofol has resulted in better control of ICP with improved outcome in TBI

patients but required more vasopressors [60].

With refractory ICP elevations (>25 mmHg), high-dose barbiturates can be

used if the patient is hemodynamically stable. Satisfactory ICP control may occur

in approximately one-quarter of patients with barbiturate infusion [61]. Due to the

potential complications associated with high-dose barbiturate infusion, its use is

limited to critical care settings that can provide appropriate monitoring and

support. Consideration should be given to monitoring for oligemic cerebral

hypoxia during high-dose barbiturate therapy [62].


Although effective in reducing cerebral edema with brain tumors, the routine

use of steroids in TBI is not recommended [63]. A review of 13 steroid trials

revealed no reduction in mortality [64]. The administration of steroids can result

in hyperglycemia, which may worsen outcome with head injury.

The generation of free radicals may worsen secondary injury. However,

clinical trials involving two free radical scavengers, polyethylene glycol-super-

oxidedismutase and tirilizad, did not effect outcome [65]. Other potential

therapies to decrease secondary injury include blockade with glutamate antago-

nists to prevent excitatory neurotransmission. Although still under investigation,

glutamate antagonists have not shown significant improved [65] outcome, and

may have behavioral side effects, limiting its use [66].

Hypothermia has been explored as a possible therapy to provide protection

from cerebral ischemia following TBI. A multicenter US trial in TBI did not show

improvement with hypothermia [67]. However, hyperthermia has been shown to

worsen brain infarct during cerebral ischemia [68], and thus should be avoided.

In controlling ICP, maintaining adequate cerebral perfusion pressure is

important. Unless there is brainstem failure, hypotension with an isolated head

injury should force one to search for other causes including hemorrhage or spinal

cord injury. With traumatic brain injuries, a minimum CPP of 70 mmHg has been

shown to result in improved morbidity, mortality, and outcome [69]. The absolute

level of CPP required is still under investigation [70], and whether higher CPP

levels will improve outcome have yet to be proven.

Other bedside monitoring methods to detect cerebral ischemia and intervene to

prevent secondary injury following TBI are being investigated. Jugular bulb

hemoglobin saturation (SjvO2) measures the saturation of the brain effluent blood

providing an estimating global cerebral oxygenation. It can provide information on

effectiveness of therapeutic interventions [71]. Desaturations are strongly associ-

ated with poor outcome [72]. Limitations of SjvO2 include the inability to detect

small ischemia regions. Still experimental, direct brain tissue partial pressure of

oxygen (PO2) can be measured by probes placed in brain parenchyma that detect

tissue oxygenation changes in small focal areas of the brain. Changes in brain tissue

PO2 correlate with outcome [73] and elevations in lactate and glutamate [74].

Intracerebral microdialysis can also detect cerebral ischemia during TBI. Cerebral

ischemia increased lactate, and was associated with a poor outcome [75].

Other imaging modalities are being developed that may permit monitoring of

the metabolic state of the brain following TBI. Although static, the CT scan has

the ability to identify pathology and allow immediate intervention. Portable CT

scanners are currently under development and may avoid transportation for CT

scans of the intensive care unit patients. Xenon CT may provide cerebral blood

flow information following TBI [76]. Magnetic resonance imaging (MRI) use

early after TBI is limited due to the lengthy scan time for images compared to

CT. MRI compatibility limits monitoring, and may hamper supportive and

resuscitative abilities while in the MRI scanner. However, newer MRI tech-

nologies under development may reveal early cerebral edema and allow func-

tional imaging.


Medical complications can further complicate the course during head injury.

Abnormal coagulation tests are common after head injury, and the severity of

coagulopathy worsens outcome [77]. Because of the high risk of hemorrhage in

this patient population, correction of clotting abnormalities should be attempted.

Pulmonary complications are frequent with head injury. Neurogenic pulmo-

nary edema is more common with severe isolated TBI. The chest radiograph

typically shows fluffy infiltrates, and requires positive pressure ventilation and

supportive care to prevent hypoxemia. Pulmonary infections are the most

common infection and a major source of morbidity. Aggressive pulmonary

hygiene is the key, including postural drainage. However, Trendelenburg posi-

tioning to accomplish optimal postural drainage may be poorly tolerated due to

ICP elevations. These patients often lose airway protective reflexes and aspirate.

Those who require long-term ventilation or require suctioning for pulmonary

hygiene will require tracheostomies. Due to the prolonged bed rest and additional

injuries, the TBI patient is at risk for DVT and PE. With recent trauma and

potential for ICH, TBI patients are often not candidates for anticoagulation.

Devices such as IPC or ES are usually employed. If a patient with an ICH is

diagnosed with a DVT or PE, an inferior vena caval filter can be placed.

Blood pressure and heart rate elevation occurs following TBI probably due to

a sympathetic response. This can result in hypertension, which may raise ICP and

cause ICH. It may also precipitate myocardial ischemia.

With TBI, diabetes insipidus and SIADH can occur. Diabetes insipidus is

common following severe head injury, and can be permanent or transient with

eventual resolution. Serum hyperosmolality, urine hyposmolality, and ultimately

the response to exogenous antidiuretic hormone (ADH) administration (intra-

venous pitressin in the acute setting), confirm diagnosis. The diagnosis of

SIADH is confirmed with serum hyposmolality, urinary hyperosmolality, and

adequate blood volume. The mainstay of treatment is fluid restriction. Active

correction of hyponatremia with hypertonic saline should be reserved for those

patients with extreme hyponatremia (serum sodium < 120 mmol/L) or life-

threatening side effects. Serum sodium correction should be done judiciously due

to the concern of central pontine myelinolysis from a rapid increase in the serum

sodium concentration.

TBI is a risk factor for stress-induced gastritis and erosions. Prophylactic

therapy requires more solid data. Potential complications include gastrointestinal

hemorrhage. Due to the hypermetabolic state during TBI, early enteral feeding is

advocated. These patients often require placement of a chronic feeding tube

because of swallowing difficulties.

Spinal cord injury

There are approximately 10,000 new cases of spinal cord injury in the United

States yearly, with the average age at time of injury in the early thirties. The

most common cause of spinal cord injuries is motor vehicle accidents. Spinal


cord injuries occur in 2.6% of major trauma victims. Cervical spine injuries are

most common followed by thoracic and lumbar spine injuries. Of these spine

injuries, a little less that half will suffer complete loss of sensory and motor func-

tions [78].

All trauma victims with a suspicion of spinal trauma as well as those patients

with a high index for a spinal cord injury (head injury, altered mental status, neck

or back pain, drug or alcohol intoxication) should have spinal immobilization.

The primary injury to the spinal cord happens at the time of impact, and is

irreversible. The forces may cause spinal cord contusion, hemorrhage, or shear

injury. Maximizing the medical management of the patient can minimize

secondary injury. Prehospital spinal immobilization has become a standard of

care in the United States. These measures include placement of a rigid cervical

collar, log rolling only of the patient, and transportation on a rigid spine board.

During the initial hospital assessment of the spinal cord-injured patient, evalu-

ation of airway, breathing, and circulation are critical. One most ensure and

maintain a patent airway, maintain adequate oxygenation, and restore and

maintain an adequate blood pressure. Patients with high cervical lesions often

present with apnea, requiring mechanical ventilation. If apnea or respiratory

failure ensues, options for intubation include orotracheal intubation with in-line

traction, fiberoptic intubation, or if these fail, cricothyroidotomy or tracheostomy.

Failed intubation is more common with spinal cord because in-line immobiliza-

tion prevents optimal positioning for intubation. Cervical injuries at the level of

the phrenic nerve (C3 through C5) risk acute respiratory failure due to loss of

diaphragmatic muscles of breathing. With spinal cord injuries above T6 sym-

pathetic denervation leads to unopposed parasympathetic activity. Patients often

experience bradycardia, caused by loss of vascular tone and hypotension.

Aggressive intravenous fluid replacement should occur. Adequate blood pressure

should be maintained to decrease the risk of spinal cord ischemia. Aggressive

blood pressure maintenance with a mean arterial blood pressure of above

85 mmHg has improved neurologic outcome [79].

Complete neurologic examination should be performed on admission. This

includes evaluation of motor strength, sensory assessment, deep tendon reflexes,

and Babinski’s responses. Anal sphincter tone must also be examined. Further

evaluation to assess for spinal trauma is directed by patient’s clinical condition.

Spinal evaluation to clear the spine is controversial [80,81]. Trauma victims with

suspected spinal cord injury should undergo radiographic examination of the

cervical, thoracic, and lumbar spines. Any patient with persistent neck pain needs

further studies to rule out a ligamentous injury with normal plain cervical

radiographs. A patient with a fixed neurologic deficit presumed secondary to

spinal cord with normal plain spine radiographs warrants further imaging to rule

out soft tissue spinal cord compression. Initial assessment of the trauma patient

with a spinal cord injury can be complicated by the lack of sensation. These

patients are often multitrauma victims, and being insensate may lack physical

signs of intra-abdominal or thoracic trauma. A high index of suspicion must be

maintained, and the diagnosis must often be made radiographically.


Primary injury occurs at the time of impact followed by secondary injury

processes. These may include autoregulatory loss, edema, and ischemia. Postu-

lated cellular mechanisms following secondary injury include calcium toxicity,

lipid peroxidation, free radical generation, and excitatory neurotransmitter release

[82–84]. Several clinical trials have attempted to limit these secondary injury

processes. A multicenter trial conducted by the National Acute Spinal Cord

Injury Study revealed a methylprednisolone bolus (30 mg/kg) followed by

continuous infusion (5.4 mg/kg) for 24 hours improved neurologic outcome

after spinal cord injury if administered within 8 hours of injury [85]. Postulated

mechanisms included decreased edema, inflammation, and lipid peroxidation. A

follow-up study revealed spinal cord injury patients treated with the above

methylprednisolone regime 3 to 8 hours after injury had better neurologic

outcome [85] but a higher infection rate if the methylprednisolone infusion

continued for 48 compared to 24 hours [86]. An additional study group compared

tirilazad administration (2.5 mg/kg) every 6 hours for 48 hours with the previous

methylprednisolone regime. All patients received 30 mg/kg bolus of methyl-

prednisolone due to ethical concerns [87]. At 24 hours tirilazad and methyl-

prednisolone were equally effective; however, 48-hour outcomes were better for

the methylprednisolone group. Infection rates were higher in the methylpredni-

solone group.

Gangliosides are glycolipids located in cell membranes and enhanced neurite

outgrowth and neuronal regeneration in animals [88]. In a prospective clinical

trial comparing GM-1 ganglioside to placebo, the treated spinal cord patients had

significant improvement in motor function [89], even allowing enrollment up to

72 hours after injury.

Spinal cord injury patients are at risk for a multitude of medical problems. An

upper or midcervical injury involving the phrenic nerve (C3–C5) will often cause

acute respiratory failure. More cephalad injuries will require tracheostomy for

permanent mechanical ventilation to prevent apnea. Intercostal nerve transfer

with phrenic nerve pacemaker implant has shown promising results in six patients

after high cervical spine injury [90]. Any patient who has a spinal cord injury C6

or higher must be closely monitored for respiratory insufficiency over the first

several days of admission postinjury. Those who have initially have an adequate

airway status may deteriorate due to spinal cord edema raising the cervical injury

level. These patients require aggressive pulmonary hygiene, and frequently

develop pneumonia, which may require antibiotic therapy. Due to prolonged

immobilization, spinal cord-injured patients are at risk for pressure necrosis and

decubitus ulcers. Frequent turning may not prevent long-term skin breakdown,

and these patients may require specialty beds to minimize further skin breakdown

and prevent decubiti ulcers.

Acute spinal cord injury patients have the highest risk of DVT among hospital

admission [91], with PE being the third most common cause of death [92]. The

highest risk period for venous thromboembolism occurs in the acute injury phase.

Although several small randomized trails of prophylaxis have been performed in

the spinal cord patient [93–95] large well-controlled studies of prophylaxis for


DVT have yet to be done. Low-dose fractionated heparin, IPC, or ES probably do

not provide adequate protection alone [96,97]. Duplex surveillance scanning for

spinal cord injury patients may be beneficial. If a DVT or PE develop, these

patients may not be candidates for systemic anticoagulation due to concomitant

trauma injuries or spinal cord hematoma. An inferior vena caval filter may be

placed. Prophylaxis recommendations include low molecular weight heparin in

the absence of contraindications [6].

Conclusion

The management of the neurologic critical care patient (stroke, SAH, TBI,

spinal cord injury) requires rapid recognition and treatment to limit or ideally

prevent further neurologic sequelae. Medical complications further increase the

morbidity and mortality in this patient population. New therapies and interven-

tions are currently under investigation. These may lead to further advances in the

management of this specialized patient population.

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