Cerebrospinal fluid physiology and the management of increased intracranial pressure.

Subject Review Cerebrospinal Fluid Physiology and the Management of Increased Intracranial Pressure

MARK Κ LYONS, M.D., FREDRIC B. MEYER, M.D., Department of Neurologic

Surgery

I n c r e a s e d intracranial p r e s s u r e c a n result i n irreversible ii^jury t o t h e central n e r v o u s s y s t e m . A m o n g t h e m a n y f u n c t i o n s o f t h e c e r e b r o s p i n a l fluid, i t p r o v i d e s p r o t e c t i o n a g a i n s t a c u t e c h a n g e s i n v e n o u s a n d arterial b l o o d p r e s s u r e o r i m p a c t p r e s s u r e . N e v e r t h e l e s s , trauma, tiunors, infections, n e u r o s u r g i c a l p r o c e d u r e s , a n d o t h e r factors c a n c a u s e i n c r e a s e d intracranial p r e s s u r e . B o t h siurgical a n d nonsur gical t h e r a p e u t i c m o d a l i t i e s c a n b e u s e d i n t h e m a n a g e m e n t of i n c r e a s e d intracranial p r e s s u r e attributable t o t r a u m a t i c a n d n o n t r a u m a t i c c a u s e s . I n p a t i e n t s w i t h c e r e b r a l injury a n d i n c r e a s e d i n t r a c r a n i a l p r e s s u r e , m o n i t o r i n g o f t h e intracranial p r e s s u r e c a n p r o v i d e a n objective m e a s u r e o f t h e r e s p o n s e t o t h e r a p y a n d t h e p r e s s u r e d y n a m i c s . Intraventricular, i n t r a p a r e n c h y m a l , s u b a r a c h n o i d , a n d e p i d u r a l s i t e s c a n b e u s e d for m o n i t o r i n g , a n d t h e a d v a n t a g e s a n d d i s a d v a n t a g e s of t h e varioiis d e v i c e s available are d i s c u s s e d . With t h e p r o p e r u n d e r s t a n d i n g of t h e p h y s i o l o g i c features of t h e c e r e b r o s p i n a l fluid, t h e p h y s i c i a n c a n apply t h e m a n a g e m e n t prin c i p l e s r e v i e w e d h e r e i n t o m i n i m i z e d a m a g e from intracranial hsφerten8ion.

An increase i n intracranial pressure (ICP), also termed intracranial hypertension, c a n result i n irreversible injury to t h e central nervous s y s tem. ICP i s considered normal w h e n it i s less t h a n 10 m m Hg. W h e n ICP increases above 2 0 m m Hg, neuronal injury m a y develop. The major pathophysiologic problems associated w i t h increased ICP are ischemia and herniation. A s ICP approaches t h e level of the systolic blood pressure, cerebral perfusion pressure decreases, and t h e resultant failure of cerebrovascular autoregulation (described i n t h e subsequent paragraph) m a y lead to irreversible ischemic injury. Cerebral perfusion pressure is defined as the difference b e t w e e n m e a n systemic arterial blood pressure and the ICP. Intracranial hyper-

tension m a y also shift brain structures and cause herniation of brain tissue, B e c a u s e t h e skull is a rigid structure, a n increase i n I C P will cause compression of intracranial contents. The intracranial contents c a n be categorized into three compartments: brain parenchyma, vascular tissue, and the cerehrospinal fluid (CSF) of t h e ventricular a n d subarachnoid spaces. A n increase i n a n y one constituent a s a result of trauma, ischemia, space-occupying lesions, or metabolic causes will result i n a n increase i n ICP. A n increase i n cerebral blood volume occurs w i t h either vasodilatation or obstruction of venous outflow. Cerebral blood v e s s e l s dilate i n order to m a i n t a i n normal cerebral blood flow during periods of decline i n cerebral perfusion pressure. Conversely, cerebral v e s s e l s con-

Address reprint requests to Dr. F. B. Meyer, Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905.

strict w h e n systemic arterial blood pressure (arid t h u s cerebral perfusion pressure) increases;

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INCREASED INTRACRANIAL PRESSURE

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hence, blood flow is kept constant. This phe nomenon is termed cerebrovascular autoregu lation. With brain injury, however, vessel re activity is ofl;en affected and autoregulation m a y be impaired. W h e n autoregulation is im paired, blood flow corresponds to c h a n g e s in systemic arterial pressure. T h u s , w i t h increases in systemic arterial pressure in response to ele vated ICP in combination w i t h impaired or ab sent vasoreactivity, cerebral blood volume in creases. This situation l e a d s to further increases in ICP and eventually to a decline in cerebral perfusion pressure and resultant ischemic damage. M e a s u r e m e n t of CSF pressure is often u s e d to a s s e s s ICP. Although abnormal production of CSF or obstruction to its flow can cause in creased ICP, drainage of CSF can be an immedi ate treatment for intracranial hypertension from a variety of causes. Maximizing t h e s e principles ofthe physiologic aspects of CSF facilitates treat m e n t of patients w i t h dangerously increased ICP. In an effort to provide a better understand ing of t h e s e principles and their importance, herein we review the dynamic physiologic fea tures of the CSF, the t r e a t m e n t options for increased ICP, and t h e m e t h o d s of monitoring the ICP. CSF PHYSIOLOGY Anatomy.—^The major historical landmarks in CSF physiology are s u m m a r i z e d in Table 1. The CSF circulates through t h e ventricles and sub arachnoid space t h a t surrounds both the brain and the spinal cord. The two lateral ventricles communicate with the third ventricle through the foramina of Monro, which communicates with t h e fourth ventricle by m e a n s of t h e aque duct of Sylvius. Through the lateral foramina of Luschka and the foramen of Magendie, the CSF flows into the basal cisterns and subarachnoid space of the spinal cord (Fig. 1). From t h e s e bas al cisterns, CSF migrates over t h e convexities toward the cerebral s i n u s e s . S t u d i e s have shown that the interchange of electrolytes b e t w e e n C S F and capillaries is greater in the ventricles t h a n in the cisterns, and the exchange of water is greater in t h e cisterns t h a n in the ventricles.'"''

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The choroid plexus is derived embryologically from the primary layer of the neural epithelium. The plexus is most readily found in the walls of the lateral ventricles and the roofs of the third and fourth ventricles. The plexus of each lateral ventricle is contiguous with t h a t of t h e third ventricle. The choroid plexus is composed of two layers: e p e n d y m a (the lining epithelium of the ventricle) and pia mater. This outpouching of highly vascularized pia lined with epithelium is called t h e choroidal epithelium. This epithelium is folded into microvilli t h a t produce a brush border, not unlike that s e e n in the intestine. The choroidal epithelium, blood v e s s e l s , and inter stitial connective tissue constitute the choroid plexus. Pinocytosis, vesicular transport, and sophisticated organelles h a v e b e e n identified in t h e s e structures. The plexus blood supply is dependent on the choroidal arteries in the lat eral ventricles, the posterior cerebral artery in the third ventricle, and usually the posterior inferior cerebellar artery or t h e anterior infe rior cerebellar artery in the fourth ventricle. Not unexpectedly, the plexuses in the lateral ven tricles are the largest and form most of the CSF_

1,2,4-6

The ependjmia is a single layer with villous projections and cilia on its surface. In 1949, Voetmann'' calculated a surface area of 2 0 0 cm^ with t h e s e projections. Tanycytes are special ized ependymal cells without cilia located on the floor of the third ventricle. They have a soma directed toward t h e ventricle and a neck and tail that contact the capillary wall. These cells are thought to be involved in the transport of hypophysiotropic hormones from the hypothalamus to the portal circulation. The drainage of the CSF is considered primar ily a function of the arachnoid villi and granula tions that project into the dural sinuses. The arachnoid villi are herniations of arachnoid m e m b r a n e into the l u m e n of the s i n u s and are therefore an interface b e t w e e n blood and CSF (Fig. 2). T h e s e villi have also b e e n identified as developing along the spinal nerve roots, where further absorption m a y take place. Granula tions are simply large collections of villi. Inter estingly, in 1975 Gutierrez and associates* re-

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Table 1.—Historical

L a n d m a r k s i n C e r e b r o s p i n a l F l u i d (CSF) P h y s i o l o g y

Date

Event

400 BC

Hippocrates credited with first tapping the ventricle in hydrocephalus and con sidered the fluid a pathologic entity Galen first described the ventricular cavities as filled with a vital spirit Vesalius described content of ventricles as watery instead of gaseous humor Valsalva described CSF as "an ounce of a certain liquid in cutting the cord mem brane of a dog, a fluid resembling that seen in articulations" Pacchioni described dura as contractable and the intracranial fluid to be secreted by arachnoid granulations Contugno observed that early anatomists failed to find CSF because decapita tion was performed before dissection Magendie first tapped the cistema magna in animals, initiated chemical studies, and established the existence of a communicating foramen between the fourth ventricle and the subarachnoid space Burrows modified the "Monro-Kellie" hypothesis in that the blood volume could change but only with a reciprocal change in the volume of the brain and CSF Key and Retzius first conducted definitive studies on CSF and described CSF flow from the subarachnoid space to pacchionian granulations to cerebral venous sinuses Dandy and Blackfan showed development of hydrocephalus by blocking the aqueduct of Sylvius Weed and Mcffibben described relationship of osmolality versus intracranial pressure and basis for introduction of hyperosmolar agents for treatment of increased intracranial pressure Weed championed the concept that CSF was from the choroid plexus and perivascular space

200 AD 1543 1672 1705 1764 1825 1846 1875 1914 1919 1935

ported hydrocephalus in association with the absence of intracranial villi. CSF Composition.—Quincke is credited with first u s i n g lumhar spinal puncture a s a diagnos tic tool in 1891. In his method, a percutaneous needle with stylet and a m a n o m e t e r were used, similar to current techniques. In addition to m e a s u r i n g C S F pressure, the cell count, protein, and glucose were also a s s e s s e d . Since t h e n , m a n y advances h a v e heen m a d e in the analysis of CSF and in the u s e of this method for diagnos tic and therapeutic purposes. The C S F flows along blood v e s s e l s in the perivascular subarachnoid space (Fig. 3). Ionic concentrations in the C S F are believed to be governed by hydrostatic forces, osmotic forces, and transport m e c h a n i s m s . N u m e r o u s investi gators have determined t h a t secretion and ab sorption of C S F occur in the choroid plexus. Sodium, chloride, bicarbonate, calcium, and water are secreted into the CSF, w h e r e a s some amino acids, organic bases, and other compounds are absorbed from the C S F by the choroid plexus.

Sodium is the major osmotically active cation in the CSF, and its concentration parallels that of the plasma. Active transport and osmotic forces are primarily responsible for its distribu tion in the CSF. P o t a s s i u m remains relatively constant in the C S F at about two-thirds that of the serum. A proposed m e c h a n i s m for secretion of C S F by the choroid plexus is based on a balanced entry of solute and water at the base with a corresponding m o v e m e n t at the apical side of the cell. Water and other solutes enter intercellular clefts by capillary hydrostatic forces, and specific transport m e c h a n i s m s are respon sible for solute m o v e m e n t into and out of the cell (Fig. 4). Calcium homeostasis is tightly controlled, m e a s u r i n g approximately half the serum level, and is independent of the plasma protein level. This process is believed to be a carrier-mediated transport mechanism. Concentrations are un affected by intravenous calcium infusions, ethylenediaminetetraacetic acid, parathyroid hormone, or total parathyroidectomy. Of note.


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Supertor s a o t n a l sinus

Choroid plexus Arachnoid granulation

C o r p u s caHosum

Aqueduct ol Sylvius Cistema magna Fourth ventricle Central canal —

Fig. I. Pattern of circulation of cerebrospinal fluid.

calcium transport is inhibited by ouabain but not by acetazolamide; t h u s , calcium transport m a y be linked to t h e sodium-potassium adenosinetriphosphatase. M a g n e s i u m concentrations are higher in the CSF t h a n in the serum. The CSF concentration fluctuates minimally with varying serum levels. The proposed m e c h a n i s m of m a g n e s i u m move m e n t is active transport by t h e choroid plexus and glial cells. The chloride concentration is also higher in the CSF t h a n in the serum. C S F chloride levels tend to parallel serum levels, and the concentra tion is higher in cisternal fluid t h a n in the newly formed choroidal fluid. There is a relative ab sence of protein (anions) in the CSF. The concen tration of protein in the p l a s m a is about 2 6 0 times that in the CSF. The small a m o u n t of protein in the CSF and the D o n n a n effect are in part responsible for the higher concentration of chloride in the CSF t h a n in the serum. The Donnan effect is such t h a t w h e n an ion on one side of a membrane cannot diffuse through the membrane, the distribution of other ions to which the membrane is permeable is predictably af fected. The negative charge of protein in the serum favors transport of diffusible anions (that is, chloride) into the CSF. This process becomes

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readily apparent as a decrease in the CSF chlo ride concentration is noted w h e n the protein concentration increases, such a s in pathologic states. CSF chloride concentration decreases to serum levels in patients with meningitis. Its transport is linked to bicarbonate and sodium as an active m e c h a n i s m . Glucose is transported into the CSF by facili tated diffusion, in which a molecule combines with a proteolipid mobile carrier. This transport h a s been demonstrated in the plexus, capillar ies, synaptosomes, and glial cells. Many studies have investigated the kinetics of serum glucose transport into the CSF in h u m a n s . For example, the m e a n serum glucose level w a s calculated in five normal patients. They were t h e n given 50% dextrose intravenously at 0.75 mg/kg, after which they had a m e a n serum glucose level of 3 0 0 mg/ dl. In t h e s e volunteers, the serum glucose level decreased to the initial m e a n serum control concentration in approximately 2 to 3 hours. The C S F glucose concentration reached a peak in V/'i to 2 hours and returned to control levels in 4 to 6 hours after injection.^ In general, the CSF glucose concentration is approximately 60% of the serum glucose value. Because the CSF concentrations of sodium, chloride, and m a g n e s i u m are the same as or higher t h a n those in serum and the CSF concen trations of potassium, calcium, and glucose are lower t h a n those in serum, investigators believe

Arachnoid granulation Superior sagittal sinus /L Subdural space

Dura mater

Arachnoid and trabeculae Subaraclmoid space Pia mater

Falx cerebri

Fig. 2. Relationship of arachnoid granulations and dural sinuses, shown in coronal plane.

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proposed the term "blood-brain barrier" to de scribe this physiologic entity. Morphologically, Arachnoid Subdural space the choroidal epithelium, arachnoid membrane, and capillary endothelial cells have tight junc tions. In certain specialized areas in the brain— Subarachnoid the hypothalamus, area postrema, and subforni space cal and subcommissural organs—these tight _ Arachnoid junctions are absent. In contrast, ependymal trabeculae cells (except the tanycjd;es of the median emi nence) do not have tight junctions but rather gap -Pia mater junctions. Anatomic and pharmacologic factors affect the ability of certain solutes to cross the blood-brain barrier. -•Cerebral cortex The endothelial cell of the brain is different from t h a t of the systemic circulation. In the brain capillary, fenestra, clefts, and pinocjd;otic 'Perivascular space vesicles are noticeably absent. Conversely, the Artery mitochondria, tight junctions, and astroc3d;ic foot processes are increased in number in the brain capillary endothelial cell wall. The brain capil lary also h a s specific bidirectional transport Fig. 3. Diagram showing path of cerebrospinal fluid along s y s t e m s for glucose, ions, and amino acids. blood vessels in perivascular subarachnoid space. The choroid plexus h a s specific transport m e c h a n i s m s and is believed to be primarily responsible for the "sink action" of the CSF. As that the C S F is a secretory product t h a t involves polar solutes move from capillary to brain and active transport across the plexus. Simple diffu slowly reach s t a t e s of equilibrium, these solutes sion also h a s an important role in the transport t h e n move freely from the brain to the CSF to be removed more rapidly by bulk flow-reabsorpof CO2, lactate, H% and N H / . Regional differences in C S F concentrations of tion, a term that refers to the movement of CSF specific solutes h a v e b e e n observed. Ions tend to and its constituents together. Thus, the system enter the ventricular C S F sooner t h a n t h e cister for removal of solutes from the brain by trans nal or lumbar CSF. Water appears more rapidly port into the CSF results in rapid transfer to in cisternal fluid, perhaps because of the more venous outflow tracts. extensive surface area of cerebellar folia and The biochemical and physiologic characteris cortical gyri. Interestingly, the highest concen tics of the solute are also involved in determining tration of albumin is in the lumbar fluid, a permeability. Entry is inversely proportional to finding t h a t m a y s u g g e s t t h a t the endothelial molecular weight. Those compounds bound to barrier to larger molecules m a y be l e s s effective proteins also have a decreased propensity for in the lumbar v e s s e l s t h a n in those of t h e brain. entry into the central nervous system. The more Thus, the m e c h a n i s m s responsible for the lipid soluble the compound, the greater its ease composition of the CSF are primarily active and of entry into the central nervous system. The specific transport, simple diffusion, and carrier- concentration of a compound in the CSF, how ever, is not always an accurate guide to its mediated diffusion. Blood-Brain Barrier.—In 1885, Ehrlich concentration in the brain. As an example, demonstrated t h a t aniline dyes injected intrave phenytoin, an extremely lipid-soluble compound, nously failed to stain the brain, unlike other is in higher concentration in the brain t h a n in body tissues. Subsequently, Stern and Gautier plasma, but its concentration in the CSF apDura mater

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H2O proteln i^p

689

Na*cr other ionsy

Hydrostatic pressure

/ "

Cilia

Clioroidal epithelium

CA *Η!>0=Ή*+Η003

y

^

CI

CSF

Capillary

Fig. 4. Schematic representation of secretion and absorption of cerebrospinal fluid (CSF) in choroid plexus. Inset shows proposed molecular mechanisms.

proximates t h a t in the nonprotein-bound frac tion in the plasma. Polar compounds such a s bicarbonate enter more slowly, a s do watersoluble solutes. Osmotic differences in t h e plasma, brain, and C S F are short-lived because osmolality varies directly with changes in plasma osmolality. The pH of the C S F is generally lower t h a n t h a t of the blood. The ratio of concentration of a solute in the C S F v e r s u s t h a t i n t h e p l a s m a depends on its pK (the dissociation constant t h a t defines the pH at which 50% of t h e solute is in its ionized form) a s well a s the p l a s m a pH.'^ A s discussed, the l e s s ionized the solute the greater its permeability. Clinically, this becomes an important factor with t h e intravenous adminis tration of N a H C O g . There is an increase in plasma pH in conjunction with a paradoxic de crease in CSF pH that m a y rapidly induce coma. This result can e n s u e because the CO2 produced diffuses m u c h more rapidly across t h e bloodbrain barrier. 2® With the breakdown of this barrier in various pathologic conditions, several changes occur and are reflected in alterations in the normal compo

sition of CSF. Four major m e c h a n i s m s are believed to be involved in the increased vascular permeability noted in disease states: interendothelial passage across tight junctions, transendothelial flow, vesicular transport, and neovas cularization. Rapoport'^ described "osmotic openings" as a m e c h a n i s m w h e n he injected small v o l u m e s of hyperosmotic solutes into the carotid artery and found the horseradish peroxi d a s e b e t w e e n t h e endothelial cells and not through t h e m . H e proposed t h a t the tight junc tions m a y have widened a s a result of shrinkage of the cells. Penicillin is an example of t h e s e processes at work. A n organic acid w i t h poor lipid solubility and partially bound to albumin, penicillin is transported from the brain to the CSF through the choroid plexus. In patients with meningitis, the barrier is l e s s effective, and the antibiotic more effectively penetrates the CSF.^ A similar concept is involved i n the passage of radiographic iodinated compounds from the blood to contrastenhanced intracranial lesions. CSF Pressure.—Since the development of lumbar manometric pressure m e a s u r e m e n t s of

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the CSF, various factors and variations in w a v e formations have been u s e d to confirm clinical suspicions of pathologic states. In 1927, Fre mont-Smith'^ reported the lumbar C S F pres sures in 1,033 patients with normal blood pres sure a n d no pathologic lesions of the central nervous system. In 94% of t h e s e patients, C S F pressures were between 70 and 180 m m H2O. The generally accepted range for C S F pressure in the lumbar region is 5 to 15 m m H g o r 65 to 195 m m HÔ. Variations in C S F pressure are noted with both respiratory effort and blood pressure pulsa tions. CSF pressure decreases during normal in spiration and increases during expiration. These pulsations are thought to be related to the con comitant changes in intracranial venous pres sure. Arterial pulsations are also reflected by synchronous increases in C S F pressure. The elevation in CSF pressure with arterial pulsa tion s e e m s to follow a progression from the ven tricle to the basal cisterns to the lumbar region. ^ A third waveform s e e n in the CSF is the plateau wave.'"* These pathologic waveforms reflect acute increases in ICP t h a t last 5 to 2 0 minutes. Amplitudes of 6 0 0 to 1,300 m m HÔ (50 to 100 m m Hg) have been recorded. T h e s e waveforms have been recorded in rapid-eyem o v e m e n t sleep, but t h e y are generally consid ered reflective of potential d a m a g e to the central nervous system. The cause of plateau w a v e s m a y be related to a defect in cerebrovascular autoregulation.'^ The characteristics of plateau w a v e s are summarized in Table 2. As defined by the Monro-Kellie hypothesis, with an increase in the volume of the intracra nial compartment (brain, blood, and CSF), a concurrent increase m u s t occur in the ICP. Compliance is the volume distensibility of the intracranial cavity, and e l a s t a n c e is the change in pressure as a result of alterations in volume. With increasing ICP, the compliance decreases and the elastance increases. The pressure-vol u m e curve m a y not be a strictly exponential phenomenon. Considerable controversy remains in this area of research. A more physiologic pressure-volume relation ship is illustrated in Figure 5,'® which depicts


Table 2.—Characteristics of Cerebrospinal F l u i d P l a t e a u Waves Occur with advanced stages of intracranial hypertension May occur without any appreciable increase in blood pressure Usually not observed in hydrocephalic infants with an open fontanelle Often preceded by hypercarbia, painful stimuli, activity, or increase in blood pressure Temporarily controlled by ventricular drainage, adminis tration of hypertonic solution, hyperventilation Angiograms during spontaneous plateau waves show wider vessels in the arterial phase than interval between waves, but the venous phase is unaffected Reports of increase in cerebral blood volume and a reduction in cerebral blood flow during plateau waves

five distinct zones. Zone 1, which reflects nega tive pressure, is essentially flat as the venous s y s t e m expands with loss of CSF volume. Zone 2 is normal steady-state pressure, and the curve is flat. Zone 3 illustrates the compensation for increase in CSF volume by compression of the epidural and intracranial venous system. The slope of this portion increases a s venous com pression is maximized. Zone 4 is reached a s the ICP approaches the diastolic blood pressure level and the curve flattens, a pattern that perhaps represents expulsion of blood from the arterial system. W h e n ICP reaches the systolic blood pressure level in zone 5, the slope increases exponentially as the m e c h a n i s m s for compensa tion are exhausted. With new techniques and increased knowl edge of the physiologic features of the plexus, investigations into compounds that affect pro duction h a v e been undertaken. Ouabain, an inhibitor of sodium-potassium adenosinetriphosphatase, effectively decreases production of CSF but only w h e n it directly perfuses the p l e x u s . " Acetazolamide, by inhibiting carbonic anhydrase, decreases production of CSF, but the results are variable and short-lived.'* N o consis t e n t results have been found with furosemide or corticosteroids. Several other compounds have been investigated, but no clear-cut consistent compounds have been developed. As CSF is removed by m e a n s of bulk flow through the arachnoid villi and granulations,



Systolic BP Diastolic BP

"CSF

1 '

0

Volume

Fig. 5. Cerebrospinal fluid pressure-volume relationship. See text for descriptions of zones 1 through 5. BP = blood pressure; Ρ,,^.^, = cerebrospinal fluid pressure; = normal steady-state pressure. (Modified from Sullivan and Alli son.'" By permission of McGraw-Hill.)

one can plot curves t h a t depict t h e transport and pressure-dependent valvelike characteristics of C S F outflow as a function of resistance. The resistance m a y he calculated a s t h e pressure difference b e t w e e n t h e C S F and t h e v e n o u s s y s t e m divided by t h e rate of absorption. Figure 6 depicts t h e relationship b e t w e e n resistance to outflow a n d C S F pressure.'^ N o t e t h a t resting outflow resistance is slightly to t h e left of t h e peak resistance in h u m a n s , which decreases at progressively higher C S F pressures. M a n n and others, w h o h a v e investigated t h i s relation ship in m a m m a l s , found a progressive phylogenetic ability of species to transport C S F from t h e ventricles to t h e v e n o u s s y s t e m . In t h e rat, some villi but no observed granulations are present. The ultrastructure and m e c h a n i s m s of response to increased C S F pressure are similar in t h e various species, but apparently in those w i t h a more complex and larger brain, there is a paral lel increase in t h e number and size of villi. T h u s , t h e curve for h u m a n s is virtually flat in compari son and r e m a i n s m o s t constant. CSF Formation and Absorption.—As dis cussed earlier, t h e production of C S F is primar ily a function of t h e choroid plexus, with smaller contributions from t h e ependymal lining and perivascular spaces. S o m e investigators claim

691

t h a t more t h a n 50% of the C S F is formed from t h e ependymal w a l l s and perivascular spaces.^" The choroid plexus arterioles m a y exhibit some autoregulatory response. The rate of production in cats s e e m s to r e m a i n stable until the perfu sion pressure of the choroid decreases to 50 to 60 m m H g and thereafter declines a s a function of t h e m a g n i t u d e of t h e blood pressure.^' In addi tion, nerve terminals have been demonstrated to innervate the plexus arterioles and secretory e p i t h e l i u m . " Sympathetic activity s e e m s to inhibit production of CSF, w h e r e a s parasympa thetic activity increases production. Production of C S F s e e m s to be independent of hydrostatic forces and t h e development of hydrocephalus.^^ Absorption of t h e C S F is believed to be due primarily to the arachnoid villi. As mentioned earlier, t h e s e structures are in contact with the dural v e n o u s s i n u s e s . Their function is not totally understood, and w h e t h e r t h e s e struc tures are closed m e m b r a n e s , open tubules, or a combination r e m a i n s controversial.'•^•''•^••''•'^•'^ S o m e consider t h e villi a s y s t e m for vacuolar transport by which bulk flow-reabsorption of C S F from t h e subarachnoid space to t h e cerebral v e n o u s s y s t e m occurs.' Tripathi'2 removed 1 ml of CSF and replaced it w i t h 1 ml of thorium dioxide a s a 10-nm colloid

Fig. 6. Cerebrospinal fluid outflow resistance versus pres sure in various mammalian species. Dots on curves = normal resting outflow resistance. (Modified from Mann and associates.' ^ By permission of the American Neurologi cal Association.)

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into the c i s t e m a m a g n a of monkeys. Twenty m i n u t e s later, the brain w a s fixed and sliced. H e opened the superior wall of the dural sinus, and scanning electron micrographs demonstrated w h a t appeared to be large vacuoles in a cell of the arachnoid villus w i t h tracer substance in the subarachnoid space, vacuoles, and sinus. He noted t h a t the junctional complexes of the endo thelial cell were intact and found no tracer leak ing through the intracellular route. R e s u l t s of t h e s e experiments are suggestive of in vivo bulk flow of CSF. More recent studies in m o n k e y s by Levine and associates'^ h a v e prompted questions about t h e significance of t h e s e vacuoles or pores. They found that more vesicles were present in villi subjected to a negative pressure differential between the superior sagittal s i n u s and the subarachnoid space (pressure greater in the former t h a n in the latter) and presumably under going no C S F transport t h a n i n those villi sub jected to a positive pressure differential. They also noted t h a t particles larger t h a n the vesicle diameter passed through the villi; t h u s , t h e y questioned t h e importance of t h e s e ultrastruc tural entities. As Levine and colleagues^'' pointed out, however, the data of M a n n and co-workers'" indicate t h a t arachnoid villi of different species m a y not be comparable. T h e y also reported t h a t pores were frequently encountered in the experi mental setting consistent with increased CSF transport, and pores were not s e e n in those a n i m a l s with no CSF transport. P e r h a p s the development of t h e s e pores is in part responsible for increasing CSF transport in conjunction with increasing the positive pressure differential. During the past 6 0 years, several investiga tors have developed methods for m e a s u r i n g rates of production and absorption of CSF.'''-^''-^^ In 1962, Pappenheimer and associates'" developed the technique of open ventriculocistemal perfu sion in goats for investigating CSF physiology. Ekstedt'^'" reported on 7 8 3 diagnostic investi gations in 705 patients w i t h suspected C S F hydrodynamic problems by simply infusing mock CSF and recording pressure a s it related to flow. H e found a linear relationship b e t w e e n C S F pressure and flow. Sklar and colleagues^^ devel

Mayo Clin Proc. May 1990, Vol 65

oped a s y s t e m of variable-rate infusion of mock CSF into the lumbar subarachnoid space with u s e of a pump. The CSF pressure w a s con currently measured. By m a i n t a i n i n g the CSF pressure constant w i t h the infusion pump, they calculated absorption and formation character istics at various CSF pressures. A s a constant CSF pressure, the change in volume over time should be zero; t h u s , the rate of infusion should equal C S F absorption m i n u s formation. In adults, approximately 4 3 0 to 4 5 0 ml of C S F is produced each day. The total volume of t h e CSF is about 140 ml, of which only about 25 ml is in t h e ventricles; therefore, the total CSF volume is replaced approximately every 8 hours. The rate of formation is approximately 0.35 ml/min, and the rate remains unchanged over CSF pressure ranges from 0 to 2 2 0 m m Η^0.6·'2.

damage of t h e central nervous system. "Vasodilatory cascade" refers to decreasing cerebral perfusion pressure a s a s t i m u l u s for vasodilata tion. Vasodilatation increases cerebral blood volume a n d causes a n increase in t h e ICP. T h e increased I C P causes a further decline in t h e cerebral perfusion; thus, t h e cascade i s perpet uated. If m o s t vasodilatation occurs a t a cere bral perfusion pressure of l e s s t h a n 8 0 m m Hg, perhaps t r e a t m e n t of t h e I C P to m a i n t a i n the cerebral perfusion pressure at greater t h a n 80 m m H g would minimize t h e vasodilatory cascade.*^ R e s t r i c t i o n o f Fluids.—^The administration of intravenous fluid in patients with increased ICP can be restricted i n a n a t t e m p t to minimize the degree of vasogenic cerebral edema. T h e sjTidrome of inappropriate antidiuretic hor mone and diabetes insipidus, however, are com mon in patients with h e a d injuries; t h u s , fluid

intake and output m u s t be strictly monitored in t h e s e patients. H 3 φ e r g I y c e m ί a . — I n patients with head injury, hyperglycemia i s generally a consistent finding.""*^ The osmotically active glucose serves to aggravate cerebral edema. Another reason for the avoidance of hyperglycemia in these pa t i e n t s i s t h e concern for brain acidosis. Hyper glycemia m a y aggravate acidosis by enhancing anaerobic glycolysis.''*'*® Alternatively, some data s u g g e s t a protective effect of hyperglycemia during cerebral ischemia.'*'' The transport mecha n i s m s to remove harmful substances from the brain to t h e C S F for rapid disposal into the venous s y s t e m are critical in this setting. In an investigation of t h e relationship among C S F lactate levels, hyperglycemia, a n d cerebral blood flow in the acute phase after head injury, De Salles and colleagues'*'' found that although hyperglycemia m a y potentiate brain tissue lac tic acidosis, a s reflected by higher C S F lactate concentrations, this increase in C S F lactate outlasted t h e acute response to injury. Further more, w h e n cerebral blood flow decreased, it was not correlated w i t h higher C S F lactate concen trations. They concluded that perhaps CSF lactic acidosis m a y be a manifestation of brain dysfunction at t h e cellular level, regardless of the glucose levels. Nonetheless, hyperglycemia in t h e head-injured patient is controversial, but the avoidance of extreme hyperglycemia in these patients is probably warranted. V e n t i l a t o r y Support.—Hyperventilation h a s long been advocated a s an effective method of immediately lowering ICP.*®'**'*" T h e mecha n i s m of action i s m o s t likely related to pHmediated cerebrovascular constriction, which occurs in response to decreases in Paco^. In addition, hypocarbia m a y restore cerebral au toregulation,"*" alkalinize CSF,^"-^' and increase perfusion to ischemic brain tissue.^' Complica tions related to hyperventilation h a v e been reported in t h e literature, including cerebral hypoxia,^^'^'* "inverse steal" in hyperemic ischemia,^^'^® rebound intracranial hypertension, and myocardial ischemia.^' With intact vasomotor regulation, hypocarbia can minimize injury by reducing ICP. In head-


injured patients, normal vasoresponsiveness to hypocarbia m a y no longer exist; t h u s , consider able controversy r e m a i n s about the usefulness of hyperventilation in such patients. Prolonged or excessive hyperventilation m a y lead to isch e m i a and t i s s u e acidosis.'*® The concept of vasoparalysis associated with head injury sug g e s t s that decreasing Paco2 m a y lead to focal ischemia by "shunting" a w a y from responsive vascular beds and increasing vasogenic e d e m a in regions of ischemia.^'^'^®'^* The duration of vasoresponsiveness to hypocarbia and the ef fects of acute reductions in Paco2 in patients with traumatic brain injury remain areas of i n t e n s e controversy.''^'*^'^^ Perhaps intermit tent, brief hyperventilation m a y be beneficial in the t r e a t m e n t of acute increases in ICP. Despite t h e possible existence of posttraumatic vasopa ralysis, hyperventilation r e m a i n s a useful treat m e n t modality for increased ICP. In the head-injured patient, difficulty w i t h oxygenation often occurs, and the u s e of positive end-expiratory pressure (PEEP) is considered. Physiologically, one m i g h t anticipate a concomi t a n t increase in ICP w i t h the addition of P E E P by potentially interfering w i t h venous outflow. In 1985, Cooper and co-workers^^ e x a m i n e d this concern and found t h a t the addition of 10 cm of P E E P resulted i n a statistically signifi cant but clinically insignificant increase in ICP. In t h e eight patients w h o s e initial ICP exceeded 20 m m Hg, no change w a s detected in ICP w i t h the addition of P E E P . N o patient h a d a neuro logic deterioration w i t h the addition of P E E P . T h e s e investigators concluded t h a t the addition of 10 cm H2O of P E E P in a patient w i t h a severe h e a d injury poses no demonstrable deleterious effect on t h e s t a t u s of ICP. Diuretics.—^The work of Weed and McKibben®° in 1919 w a s fundamental for t h e u s e of hyperosmolal therapy in intracranial hyperten sion. Several diuretic a g e n t s have been advo cated for the t r e a t m e n t of increased ICP, includ ing hypertonic sucrose, albumin, glycerol, urea, and furosemide. The most commonly u s e d agent, however, is mannitol. Wise and Chater®' are credited with first us ing mannitol to reduce ICP. As w i t h other


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osmotic a g e n t s , t h e classic concept of action of mannitol is that it induces an osmotic pressure difference b e t w e e n the blood and the brain and thereby causes extraction of water from the cerebral compartment into the intravascular space. Mannitol is excluded from the CSF and brain to a greater degree t h a n other agents. Although this property l e s s e n s its rebound ef fect, rebound still occurs w h e n doses exceed urinary excretion capabilities. Rosner and Coley®^ proposed that the development of dehydra tion and hemoconcentration from mannitol is in part responsible for the rebound effect noted in some patients and that the maintenance of normovolemia m a y prevent it. Evidence has shown t h a t the effect of mannitol m a y be pro longed with the u s e of loop diuretics after the infusion of mannitol.®^ The concept of mannitol producing an osmotic gradient b e t w e e n the blood and the brain that causes water to leave the extracellular space of the brain h a s recently been questioned, at least insofar that this property is primarily respon sible for the observed reductions in ICP after administration of mannitol.®^®^ In addition to the osmotic dehydration effects of mannitol, several potential effects on circulation m a y in crease vasoconstriction. These factors include increased erythrocyte deformity,®'' increased systemic arterial blood pressure by increasing intravascular volume,*^®^ and hemodilution with a resultant decrease in blood viscosity.®'' These variables m a y all play a role in decreasing ICP a n d y e t m a i n t a i n i n g cerebral oxygenation. A decrease in blood viscosity after the administra tion of mannitol h a s been implicated in the observation of increased cerebral blood flow without an increase in ICP in head-injured pa tients.®''®^ In addition to the decrease in blood viscosity, delivery of oxygen is increased after administration of mannitol. Low oxygen deliv ery potentiates vasodilatation, perhaps by m e a n s of production of adenosine; therefore, any agent t h a t increases delivery of oxygen should help minimize vasodilatation. The increased resis tance to flow a s a result of vasoconstriction is counterbalanced by a decrease in resistance attributable to mannitol-induced decreased

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blood viscosity; t h u s , cerebral blood flow re m a i n s unchanged. In the absence of intact autoregulation, no vasoconstriction occurs w i t h increased oxygen availability, and cerebral blood flow increases in response to decreased blood viscosity.®® Recent work by Rosner and Coley®' suggested t h a t t h e effects of ICP reduction after adminis tration of mannitol m a y be partly dependent on hemodynamic factors. They investigated 16 patients with increased ICP w h o received m a n nitol and found t h a t those w i t h cerebral perfu sion pressure of 70 torr or l e s s responded better t h a n those w i t h cerebral perfusion pressure t h a t exceeded 70 torr. B e c a u s e the onset of this action w a s almost immediate, t h e y concluded that the response w a s a hemodynamic effect of the mannitol. Specifically, patients with cere bral perfusion pressure of more t h a n 70 torr m a y already have m a x i m a l vasoconstriction and t h u s m a y have little to gain from infusion of mannitol. This conclusion, however, is b a s e d on the as sumption t h a t autoregulation is intact and t h a t vasoconstriction is occurring in a normal physi ologic manner. Muizelaar and co-workers,®® who examined the effects of infusion of mannitol in a group of patients with severe h e a d injuries, noted that ICP decreased by 27.2% and cerebral blood flow w a s unchanged in those patients with intact cerebrovascular autoregulation, w h e r e a s ICP decreased by 4.7% and the cerebral blood flow increased by 17.9% after infusion of manni tol in those patients with defective autoregula tion. With intact autoregulation, a normal vaso constrictive response occurs.'^®®'®* The dosage of mannitol administered intrave nously in the setting of head t r a u m a varies from 0.25 to 1.00 g/kg during a period of 15 to 3 0 minutes. Lower doses are usually given if repeat administration is expected. Miller a n d Leech®" found that the maximal reduction in a pressurevolume response after the infusion of 0.5 g/kg of mannitol occurred at approximately 15 m i n u t e s . Obviously, the dose of mannitol should be ta pered to the patient's clinical condition. Close attention m u s t be paid to osmolality, electro lytes, blood pressure, and ICP w h e n e v e r manni tol is used.


The osmolality of the blood, brain, and CSF is essentially the s a m e in normal patients—ap proximately 2 9 0 to 3 0 0 mosmol/liter. The physi ologic principle on which the effectiveness of hyperosmolal therapy is based is the develop m e n t of an osmotic gradient sufficient to drive water out of the brain cell and into the plasma. Insufficient data are available about the range of osmolality achievable with respect to the dose of mannitol and about the existence of a "critical osmotic threshold" to modulate an alteration in intracerebral volume.' The effectiveness of man nitol therapy is limited by at least two considera tions: (1) substances eventually cross the bloodbrain barrier and thereby disrupt the gradient and (2) osmotically active solutes—idiogenic osmoles—appear within the brain a s an adap tive response to increased serum osmolality. For t h e s e reasons, t h e monitoring of serum osmolal ity is of critical importance during hyperosmolal therapy. In general, serum osmolality of more t h a n 3 2 0 mosmolAiter should be avoided. The concept of rebound intracranial hyper tension is applicable to all hyperosmolal ther apy. Although mannitol is excluded from the CSF and brain more t h a n other agents, it can still induce rebound intracranial hypertension. F i s h m a n ' outlined four pathophysiologic mecha n i s m s involved in this phenomenon. The first two h a v e b e e n mentioned previously—the de velopment of idiogenic osmoles and the progres sive crossing of solute from plasma into brain cells. Third, a s the solute reaches equilibrium in the CSF, water diffuses into the CSF and causes an increase in pressure. Any impairment in the m e c h a n i s m s of absorption of CSF induced by the increased ICP can adversely affect the ability of the ventricular s y s t e m to respond to this in creased CSF volume. Fourth, a defective bloodbrain barrier m a y allow e a s y passage of hyper osmolal agents into the brain and potentially aggravate intracranial hypertension. Hyperosmolal therapy in t h e setting of acutely increased ICP can be effective; however, one m u s t bear in mind that associated problems can occur. Mannitol m u s t be used cautiously, and its limitations m u s t be recognized by those who initiate such therapy.


C o r t i c o s t e r o i d s . — T h e effectiveness of glu cocorticoids in t h e m a n a g e m e n t of severe head injury remains controversial. The efficacy of corticosteroids h a s been proved in t h e setting of vasogenic e d e m a from brain tumors,''" but serious questions have arisen about their use fulness in t h e clinical setting of acute head trauma.^"* '· Membrane stabilization and the suppression of formation of e d e m a are t h e most attractive a r g u m e n t s for their clinical u s e in treating increased ICP. The two m o s t commonly u s e d glucocorticoids are d e x a m e t h a s o n e and methylprednisolone. The recommended dosage varies substantially, but t h e recent trend h a s favored t h e "high-dose" range. High-dose glucocorticoid therapy gener ally consists of 15 to 3 0 mg/kg of methylpredni solone or 3 to 6 mg/kg of d e x a m e t h a s o n e at various intervals.'''*·'^·^° B e c a u s e t h e s e doses are considerably higher t h a n t h e amount needed to achieve normal glucocorticoid actions, t h e phar macologic effects of t h e s e a g e n t s at such doses m a y differ.^" In addition, t h e injured central nervous s y s t e m m a y require t h e s e doses to yield any benefit. The time interval b e t w e e n t h e occurrence of injury to t h e central nervous s y s t e m and t h e initiation of corticosteroid t r e a t m e n t h a s also been a consideration, in light of t h e higher suc cess rate of therapy in experimental settings t h a n in clinical settings. J a n e and associates^' reported a significant decrease in mortality in head-injured patients, 16 years of age or younger, who received high-dose methylprednisolone at the scene of t h e injury. In a study by Giannotta and colleagues,''* however, a similar decrease in mortality w a s found in patients younger t h a n 4 0 years of age w h o received high-dose methyl prednisolone after arrival at the hospital. These results m a y reflect t h e potential for a better outcome in younger patients and m a y be unre lated to t h e i m m e d i a t e initiation of corticoste roid therapy. The classic glucocorticoid side effects of con cern to t h e physician are immunosuppression, peptic ulceration, wound breakdown, infection, and disruption of glucose and nitrogen metabo l i s m . T h e s e problems, however, occur primar


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ily with prolonged administration of these drugs and are unusual in a setting of short-term highdose t h e r a p y . ' e - ' 9 8 o - s 2 Several clinical investigations have evaluated the effectiveness of glucocorticoids in the treat m e n t of h e a d injury. Initial studies by Gobiet*^ and Faupel and co-workers^"* revealed promis ing results, w i t h suggested reductions in mortal ity. Two factors, however, made t h e s e results l e s s encouraging—an insufficient number of patients to produce a statistically significant result*^ and an increase in t h e number of se verely disabled patients.** Subsequently, stud ies by Cooper and associates,''^ G u d e m a n and colleagues,'^ Saul and Ducker,''' Pitts and Katkis,'® B r a a k m a n and co-workers,''* Giannotta and associates,''* and Dearden a n d colleagues''^ failed to show t h a t head-injured patients benefit from corticosteroid therapy. Although a de crease in mortality h a s been noted in certain subgroups of corticosteroid-treated patients, this reduction in mortality does not result in less morbidity and, in fact, increases the number of patients in t h e severely disabled group.'*'*'''''*'* Therefore, most current studies in which the u s e of glucocorticoids in head-injured patients h a s been a s s e s s e d have reported no demonstra ble benefit. Although t h e mortality rate m a y be decreased in t h e s e patients, their functional out come is unimproved. B a r b i t u r a t e s . — B a r b i t u r a t e s are often used in a final attempt to control increased ICP in head-injured patients, those with Reye's syn drome, or those in w h o m ICP increases after hepatic transplantation. The pharmacologic basis for barbiturate therapy in intracranial hypertension is t h e ability of these drugs to lower ICP and protect against brain ischemia. Barbiturates can protect t h e brain from isch emic insult in part by causing vasoconstriction in normal t i s s u e and t h u s s h u n t i n g of blood to ischemic tissue.*® This vasoconstrictor property is one reason for t h e decrease in ICP after administration of barbiturates. Other poten tially beneficial properties of barbiturates are suppression of vasogenic edema, decreased metabolic demand for oxygen, reduction of intra cellular calcium, free radical scavenging, and

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stabilization of lysosomes.®**°*'^*' The m a i n issue is w h e t h e r t h e s e properties play an impor tant role in cerebral protection in the case of increased ICP. Pentobarbital is one of the m o s t common barbiturates u s e d in the setting of increased ICP. High-dose "barbiturate coma" is generally instituted w i t h an intravenous loading dose of 5 to 3 0 mg/kg and maintained as either an hour ly bolus or a continuous infusion. Control of ICP and burst suppression on t h e electroen cephalogram are the initial goals of therapy, rather t h a n specific drug levels because t h e y are often unreliable indicators of effectiveness or toxicity.*'** In this setting, the most common and critical side effect of barbiturate therapy is hypotension, probably due to peripheral vaso dilatation and decreased cardiac contractility. Consequently, meticulous monitoring of arterial blood pressure and the u s e of more invasive cardiac monitoring m a y be indicated w i t h barbi turate therapy. It is logical to treat increased ICP with an a g e n t t h a t lowers ICP, decreases cerebral m e tabolism, and reduces brain acidosis. Undoubt edly, barbiturates can effect a reduction in the ICP, but one m u s t distinguish b e t w e e n a reduc tion in ICP and an improvement in outcome.*'"' Reports by Marshall and associates*" and Rea and Rockswold"' of improved outcome in headinjured patients treated with barbiturates were not confirmed by other studies such a s the one by Ward and colleagues.** The patients in the study by Marshall and co-workers*" were treated only after failure of all other modalities to de crease ICP and with much smaller doses of pentobarbital t h a n the randomized prophylactic trial conducted by Ward and associates.** It is generally believed that cerebral ischemia is a major factor t h a t contributes to progressive damage in acute intracranial hypertension. Variable success in the t r e a t m e n t of intracranial hypertension w i t h barbiturates h a s been re ported in Reye's syndrome. Marshall and col leagues"' reported excellent control and good outcomes, w h e r e a s V e n e s and co-workers"^ and others*® h a d severe problems in controlling ICP in this patient population.


In traumatic injury, ischemia m a y be related to increasing ICP and decreasing cerebral per fusion pressure, direct vascular injury, cere bral herniation, and vascular distortion."* Al though barbiturate therapy can reduce ICP, the question is w h e t h e r such therapy h a s been beneficial. In a recent study of patients with traumatic brain injury, Nordstrom and asso ciates®* a s s e s s e d cerebral blood flow, vasoreac tivity, and oxygen consumption during barbitu rate therapy. They found t h a t in patients with preserved cerebral vasoreactivity, barbiturate therapy resulted in "probably beneficial" de creases i n ICP, cerebral blood flow, and cerebral metabolism. In those patients with defective vasoreactivity, no such decreases occurred. Although the outcomes were not analyzed sta tistically, those with preserved reactivity had better outcomes t h a n those whose reactivity w a s impaired. Similar results have been noted by others.^®'®''*" Although no definitive a n s w e r is available for the question of barbiturate therapy in the set t i n g of increased ICP, research suggests that certain patients (that is, those with preserved vasoreactivity) m a y benefit and that the treat m e n t should be initiated in t h e s e patients w h e n ICP continues to increase despite maximal use of the other previously discussed modalities. Surgical.—Both traumatic and nontraumatic causes of increasing ICP need to be assessed from a surgical standpoint a s well. In patients with traumatic h e a d injuries, progressive neu rologic deterioration can often be due to an expanding intracranial hematoma, and surgical decompression can be an expeditious and lifesav i n g procedure. Some patients w i t h intracerebral h e m a t o m a s , depending on their clinical status and the location of the clot, are candidates for surgical decompression. Subdural and epidural h e m a t o m a s are often surgically treatable. Diffi culty arises in patients who have neurologic deterioration attributable to increasing ICP without a discrete lesion. This group of patients is treated primarily with nonsurgical modalities to decrease the ICP. Difficulty also arises in determining which patients most likely will ultimately have severely increased ICP. Inves-


tigators have reviewed numerous factors in a variety of cUnical settings in an attempt to an swer that question. ^^"''' Patients with an initial Glasgow Coma Scale of 6 to 8 and absent or compressed basal cisterns on initial computed tomographic scans of the head are likely to have substantially increased ICP.*'®'^' The initial find ings suggestive of the potential for development of severely increased ICP are hypotension (sys tolic blood pressure l e s s t h a n 9 0 m m Hg), com pressed or absent basal cisterns, and increased ICP within the first 24 hours after injury.^^ In t h e patient with cerebral injury and in creased ICP, monitoring of the ICP can be useful in the t r e a t m e n t of t h e patient by enabling the physician to m e a s u r e the response to therapy objectively. Indications for ICP monitoring are variable, but t h e following guidelines have b e e n advocated in the setting of severe h e a d injury: (1) physician's inability to perform and follow serial clinical e x a m i n a t i o n s , (2) absent or com pressed basal cisterns on initial computed to mographic scans of t h e head, (3) Glasgow Coma Scale l e s s t h a n or equal to 7, (4) hypotension, (5) abnormal posturing, and (6) associated severe pulmonary injury.''95««6-90'92.95-ioi The decision to monitor ICP and to initiate t r e a t m e n t to decrease it n e c e s s i t a t e s considera tion about the type of monitor and the location, the accuracy, and the potential complications of monitoring. Interest in monitoring and record ing of ICP began in 1866 w h e n Leyden recorded ICP from t h e epidural space. N o t until the work of Lundberg and associates^® in t h e 1960s w a s the true potential of recording of the ICP real ized. Harvey Cushing's suggestion that blood pressure would be a useful variable to monitor intraoperatively initially m e t with some criti cism, in that it w a s considered an unnecessary exercise w i t h technical difficulties. Similarly, skepticism arose about the monitoring of ICP in the head-injured patient a s well a s in other situations of increased ICP. Lundberg and col l e a g u e s illustrated t h e specific and recognizable patterns of dangerous ICP. As discussed previ ously, plateau w a v e s represent episodic increas e s in the ICP of 50 to 100 m m H g and signal potentially irreversible brain damage. The major


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rationale for monitoring of ICP is to detect the development of plateau waves. N u m e r o u s reports in the literature describe individual series of ICP monitoring; however, very few series comprehensively report their techniques and results. Before 1960, ventricu lostomy w a s the most common method used. Although specific data on infections were gener ally not available, the "rule of thumb" w a s to monitor for only about 72 hours. 102.103 rpj^g major sites of m e a s u r e m e n t are illustrated in Figure 8. M o n i t o r i n g S y s t e m s . — D u r i n g the past century, monitoring of ICP h a s benefited from developments in engineering capabilities. The "gold standard" for monitoring of ICP h a s been the intraventricular catheter connected to a m a n o m e t e r by m e a n s of a fluid-filled tube. The intraventricular catheter is placed after sterile preparation of the scalp over the frontal lobe. A burr hole or twist drill hole is made 2 to 3 cm anterior to the coronal suture and 3 cm off midline. The dura is pierced, and the catheter is inserted into the lateral ventricle with the tip near the foramen of Monro. The subarachnoid screw or "bolt" is a device t h a t w a s developed to m e a s u r e the ICP indi rectly, as transmitted from the subarachnoid space to the device. Pressure recorded over the convexities is thought to represent the ICP.'"'**"^ The screw is essentially a hollow tube bolted to

Intraventrtcular Epidural

' Subarachnoid

Intraparenchymal

Parenchyma

SubarachtxjM space

Fig. 8. Schematic representation of sites for monitoring of intracranial pressure.

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the calvaria. P l a c e m e n t is either subarachnoid or subdural. Usually, t h e device is connected to a fluid-filled s y s t e m w i t h a pressure transducer external to t h e device.'°^'°® This device is ofi;en irrigated with saline every 6 hours to m a i n t a i n patency. Its a d v a n t a g e s reportedly include e a s e of insertion a n d lower risks of infection a n d brain injury. Major disadvantages arise in t h e inability to drain CSF for therapeutic purposes and its questionable accuracy. Although several such devices are currently available, t h e t w o most common are t h e Richmond screw a n d t h e Leeds device. T h e Richmond screw i s a singleaperture monitor, w h e r e a s t h e Leeds device i s a m u l t i l u m e n system. Difficulty with occlusion of the aperture by herniation of brain t i s s u e led in part to t h e development of t h e m u l t i l u m e n device. The epidural space is a n attractive alterna tive for t h e location of a monitoring system. Theoretically, t h e epidural pulsation should be an indirect m e a s u r e of ICP. P l a c e m e n t of t h e device i n the epidural space obviates the need to violate t h e dura a n d therefore decreases t h e risks of infection a n d brain injury. T h e Ladd fiberoptic system, Gaeltec strain gauge. Philips strain g a u g e transducer, a n d CardioSearch pneumatic s y s t e m s all have been advocated a s safe and accurate for monitoring iCP.'o^"''"** The Ladd s y s t e m works by transmission of light through one optical fiber a n d reflection of light by a mirror back through two other fibers. These t w o "afferent" fibers receive t h e s a m e amount of light w h e n t h e mirror is i n a central position. W h e n t h e position of t h e mirror is deflected by transmitted epidural pressure, t h e amount of light received by t h e t w o fibers is analyzed. On t h e basis of t h e results of this analysis, air pressure is activated within t h e monitor to centralize t h e mirror. The air pres sure needed to centralize the mirror reflects t h e epidural pressure.""'"* The Gaeltec s y s t e m h a s a pressure transducer in i t s tip that allows direct m e a s u r e m e n t of epidural pressure. T h e Philips epidural pres sure transducer is similar in i t s physics to t h e Gaeltec s y s t e m a n d in i t s design to t h e sub arachnoid device.""


The CardioSearch pneumatic system w a s developed to improve on the response time of the fiberoptic system."''"* The sensor membrane is deflected by t h e transmitted epidural pressure, which in turn increases t h e pressure in t h e plenum. The plenum is the chamber, juxtaposed to t h e sensor membrane, that h o u s e s t h e inlet and e x h a u s t s y s t e m s . Air enters t h e plenum through t h e inlet s y s t e m a n d exits through t h e e x h a u s t system. The inlet air pressure needed to overcome t h e pressure in t h e plenum and rees tablish e x h a u s t flow represents t h e ICP.'^ The processing unit records pressure each second and averages four v a l u e s to produce 15 digital readings per minute. With t h e CardioSearch monitor, a s i n most monitoring systems, t h e mechanics of the sensor are excellent; however, the in vivo accuracy of the s y s t e m is the relevant issue in a s s e s s i n g i t s clinical usefulness. The fiberoptic s y s t e m developed by Camino Laboratories can be used intraventricularly, intraparenchymally, a n d epidurally.'""'" The 4-F catheter h a s a fiberoptic transducer in the tip. A mirror diaphragm moves in response to changes in pressure, which are transmitted through optic fibers to display a digital pressure reading. The s y s t e m m a y be interfaced with a n external monitor for a s s e s s m e n t of waveform and cerebral perfusion pressure. The intraven tricular transducer is attached to t h e skull by m e a n s of a housing unit, similar to t h e bolt device. The transducer-tipped catheter fits in side t h e ventricular catheter; therefore, drain age of C S F a n d constant ICP recordings are possible.'""-'" A relatively n e w capability for monitoring the ICP is by intraparenchymal pressure recording. The Camino fiberoptic s y s t e m a n d t h e Hon eywell microtransducer are two currently avail able s y s t e m s . The advantage with this approach is the ability to monitor, especially in the setting of severe closed head injury, w h e n ventricular access is difficult. Usually, the probe is inserted 2 to 3 cm into the white matter; thus, t h e risk of severe brain injury m a y be no greater t h a n with the intraventricular catheter. A disadvantage is the inability to secure CSF drainage. The initial problem of catheter breakage h a s been reduced



in the clinical setting w i t h design modifications and increased familiarity with the system. The major a d v a n t a g e s and d i s a d v a n t a g e s of ICP monitoring based on specific location are s u m marized in Table 4. Accuracy.—^The major reason for monitor ing of ICP is to enable t h e physician to obtain a reliable m e a s u r e of ICP dynamics. Most studies evaluating ICP monitors consider t h e intraven tricular pressure a s the control value. In 1973, Vries and co-workers"*® reported the u s e of t h e subarachnoid bolt in 56 patients (33 with closed head injury), with "good recordings" a s judged by blood pressure and respiratory fluctuations. They noted occasional d a m p i n g of t h e tracing, which w a s attributed to a slow leak. The fluid-filled s y s t e m s , which include the intraventricular catheter, are all prone to inaccuracy because of m i n i l e a k s in t h e s y s t e m . Several investigators have noted inaccurate m e a s u r e m e n t s with u s e o f t h e subarachnoid bolts.""''"'^"^-"^ Miller and associates"* reported the u s e of a subarachnoid bolt in a patient w i t h Reye's syndrome and a patient w i t h a n epidural h e m a t o m a . Despite both patients h a v i n g clinical and computed tomographic evidence of increasing ICP, the bolts provided readings of low pressure with good "waveform." In another study by North and

Reilly,"^ the intraventricular monitor (pediatric feeding tube), the subdural catheter (pediatric feeding tube), and the subarachnoid Richmond screw were concurrently compared in patients w i t h h e a d trauma, subarachnoid hemorrhage, and hydrocephalus. T h e s e investigators found t h a t the Richmond screw had a significantly higher rate of damping—and t h u s inaccuracy— t h a n t h e other devices. (The rates were 16% for the Richmond screw, 2.7% for the subdural cathe ter, and 2.5% for the intraventricular catheter.) Alternatively, Winn and colleagues"*^ reported good success with t h e subarachnoid bolt in 147 patients monitored because of trauma, tumors, or vascular events. Their control method, how ever, w a s occasional lumbar punctures in some patients, and only 11 patients had ventricular catheters in place simultaneously. The group from Leeds, England, evaluated the accuracy of their subarachnoid device in 18 patients who were monitored because of closed head injury. With a m e a n duration of 5.7 days of monitoring, infusion t e s t i n g revealed that less t h a n 50% of t h e m e a s u r e m e n t s were "normal." Although the majority of the erroneous record ings were "correctable," the accuracy of the device in this setting is questionable. In a report by Mendelow and a s s o c i a t e s , 1 0 patients with

Table 4.-—Monitoring of Intracranial P r e s s u r e * Location

Advantages

Disadvantages

Intraventricular

"Gold standard" Reliability CSF drainage Waveform

Increased risk of infection Potential for brain injury Placement Fluid-filled system Transducer repositioning

Intraparenchymal

Ease of placement Non fluid-filled

Potential for brain injury Increased risk of infection No CSF drainage Catheter breakage

Subarachnoid

Ease of placement No brain penetration Less risk of infection

Questionable accuracy No CSF drainage Fluid-filled system Brain tissue obstruction

Epidural

Dura remains intact Non fluid-filled Ease of insertion

Questionable accuracy No CSF drainage "Wedge effect"

*CSF = cerebrospinal fluid.

701

702


closed head injury were monitored with a Richmond screw and an intraventricular cathe ter. In 4 1 % of the readings, t h e bolt and catheter results were within 10 m m Hg. N o n e t h e l e s s , in 46% of the readings, the bolt underread the catheter by more t h a n 10 m m Hg. This discrep ancy w a s e v e n more apparent w h e n the ICP w a s greater t h a n 20 m m H g and w h e n peak pres sures occurred. They also compared t h e Leeds device and an intraventricular catheter in 10 patients w i t h closed h e a d injury. T h e y noted a 58% correlation, with 27% of the readings from the Leeds device lower t h a n the catheter value. The results with t h e Leeds device were similar to those with the Richmond screw. The most common reasons for t h e malfunction and inaccu racy of the subarachnoid bolt s e e m to be minileaks in the s y s t e m and herniation of the brain into the device. Frequent injections of saline are often needed for malfunctioning subarachnoid bolts. This practice m a y increase the risk of infection. In comparisons of intraparenchymal cathe ters and intraventricular catheters, relatively good correlations have b e e n found.'""® The errors tend to be a higher reading with the intraparenchymal t h a n with the intraventricu lar catheter. Some investigators have u s e d the subarach noid devices in the epidural space.'°*·"^ The e a s e of insertion of the subarachnoid bolt, combined with the desire to avoid violating the dura, led to t h e development of t h e epidural monitors. The advancing technology and miniaturization re sulted in the development of the Ladd fiberoptic monitor. L e v i n r e p o r t e d that this monitor provided accurate data w h e n u s e d in 140 pa tients, half of w h o m had s u s t a i n e d trauma. The accuracy of the monitor w a s a s s e s s e d by normal functioning of the sensor after removal from the patient. Except for a few isolated examples, no controls were included in the study. The CardioSearch s y s t e m h a s an excellent response time a n d in vitro accuracy.'" As with all epidural monitors, however, the question of in vivo accuracy and t h e "wedge effect" of brain tissue remain important considerations. Re cently, Powell and Crockard"** evaluated the


CardioSearch s y s t e m in 19 patients with chroni cally increased ICP and 12 patients with acutely increased ICP. Concurrent intraventricular catheter and CardioSearch sensor recordings of ICP were compared. The chronically increased ICP m e a s u r e m e n t s corresponded with use ofthe two devices; however, in the patients with acutely increased ICP, no relationship w a s found be t w e e n the epidural pressure and the intraven tricular pressure. The time needed for the differ ence between the epidural sensor readings and the intraventricular v a l u e s to be greater t h a n 8 m m H g w a s 0 to 9 hours. This difference ranged for -1-25 m m H g to - 3 0 m m H g in the seven patients with severe closed head injuries. These results s e e m to indicate t h a t the sensor is accu rate but t h a t the epidural space m a y not be an ideal location for the monitor in the head-injured patient. C o m p l i c a t i o n s . — ^ A s s e s s m e n t of the true occurrence of complications associated with in tracranial monitoring s y s t e m s is difficult. Many studies do not report their complications, and of those that do, the data are often incomplete. The major complications are malfunction, hemor rhage, and infection. Malfunction of the monitoring device is most commonly attributable to inherent flaws in the s y s t e m or to herniation of brain tissue. North and Reilly's review'"^ of 340 patients (378 moni tors) during a 10-year period found that the premature cessation rate as a result of a damped tracing or catheter dislodgment w a s 5.5% for subdural catheters, 7.1% for intraventricular catheters, and 20.3% for the Richmond screw. Winn and a s s o c i a t e s r e p o r t e d an 8% failure rate of subarachnoid screws attributable to place m e n t or brain herniation. The failure rate with epidural monitors is generally about 10%."*·"^ Hemorrhage is a risk with any "blind" intra cranial procedure. N a r a y a n and associates"" reported three intraparenchymal hemorrhages (one of which necessitated surgical evacuation) in 188 insertions of intraventricular catheters (1.6%). North and Reilly' '•'^ reported two hemor rhages in 199 placements of intraventricular catheters. Subarachnoid screws can result in subdural or epidural h e m a t o m a s . Published


studies report complications t h a t range from 0 to 1%. 1 0 1 . ' 0 6 , 1 1 5 Approximately 1% of epidural monitors are also reported to be associated w i t h epidural hematomas.'"*"" The third major concern with a n y monitoring s y s t e m is t h e risk of infection. Difficulty in predicting t h e relative risk of infection arises from t h e fact t h a t m a n y s t u d i e s do n o t (1) report infections, (2) offer a definition of "monitor-asso ciated" infection, (3) c o m m e n t on t h e u s e of anti biotics or corticosteroids, or (4) u s e a wide range of monitoring times. In t h e interest of uni formity, infections proved by positive cultures and clearly related to t h e device are considered "monitor-related" episodes. Intraventricular catheter-related infections range from 0 to 2 2 % . 5 8 , i o 2 . i o 3 , i o 5 , i i o , i i 5 , i 2 o - i 2 6 Subarachuoid screws h a v e a s o m e w h a t lower risk of infection—^be t w e e n 0 and 7 . 5 % . i o i , i o 2 , i o 4 , i o 5 . n 5 , i 2 o , i 2 3 T h e s e in fections are primarily meningitis, osteomyelitis, and superficial wound infections. T h e rate of infection with u s e of epidural monitors is from 0 to 1%.'"«·"" The organisms isolated from t h e s e infections are s o m e w h a t surprising in t h a t about half are gram-positive bacteria (most commonly. Staphy lococcus epidermidis or S. aureus), w h e r e a s t h e other half are gram-negative bacilli (including Escherichia coli, Klebsiella, Pseudomonas, and //aemopîZMs).'«3-"e''2"'''-'2'^''26

The prophylactic u s e of antibiotics h a s b e e n reviewed by several investigators, some of w h o m indicate t h a t such m e a s u r e s do not influence t h e rate of infection'"""""' and others of w h o m have shown prophylaxis to be useful. "''•"® Some investigators h a v e found a n associated increased risk of infection w h e n t h e s y s t e m is flushed with bacitracin."" This observation m a y actually indicate a n increased risk with manipulation of the monitoring system. T h e u s e of corticoste roids h a s also b e e n implicated as a risk factor for infection.'"""" A n almost universal observation i s that t h e longer the duration of monitoring, t h e greater the possibility of infection. T h e infection rate for virtually any s y s t e m is l e s s t h a n 1% if t h e monitor is in place for fewer t h a n 4 days, and after 5 days the rates increase. Minimizing t h e manipula


703

tion of the s y s t e m is of primary importance. The monitoring s y s t e m should be inserted under sterile conditions i n t h e operating room when ever possible. In order to ensure t h e most accurate recording of ICP, especially in patients w h o have sus tained head trauma, t h e intraventricular moni tor is t h e most reliable. Although probably associated with a greater propensity for infec tion and perhaps brain injury, this device pro vides t h e most accurate data a n d therapeutic capabilities. With t h e foregoing factors in mind, the intraventricular catheter should be changed after 4 or 5 days to minimize t h e possibility of infection. CONCLUSION The brain, surrounded by a rigid cranial vault, enveloped by t h e m e n i n g e s , a n d bathed by the CSF, i s naturally protected from noxious exter nal events. Ironically, t h e s e protective struc tures can adversely affect t h e brain during its response to injury. T h e brain is limited in its response w h e n t h e delicate homeostatic envi ronment is disrupted by injury. E d e m a (vaso genic and cytotoxic) is the m a i n response of the central nervous s y s t e m to injury. The brain swells, a n d because it i s constrained by the protective skull, t h e ICP increases. The pa thophysiologic response of t h e C S F serves to slow t h e increase in ICP, but it is often insuffi cient to avoid damage to the central nervous system. With t h e proper understanding of t h e physiologic aspects of the CSF, the physician can apply t h e m a n a g e m e n t principles reviewed herein to minimize damage from intracranial hypertension. Monitoring of the ICP provides objective data about success or failure of thera peutic intervention. Considering t h e group of patients in which t h e s e principles of care are instituted, one can easily develop a feeling of overwhelming dismay. Individually, however, m a n y of t h e s e patients can benefit from this intensive care. With appre ciation of the limitations of therapeutic modali t i e s a n d the establishment of realistic goals, t h e physician can treat t h e patient with increased ICP based on physiologic principles and clinical

704


j u d g m e n t in a n a t t e m p t to preserve t h e most critical h u m a n structure—the brain. ACKNOWLEDGMENT We t h a n k Mary M. Soper for her secretarial assistance with the preparation of t h e submitted manuscript.


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Management of increased intracranial pressure.

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A nonlinear analysis of the cerebrospinal fluid system and intracranial pressure dynamics.

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