PHYSIOLOGY

Cerebral blood ow and intracranial pressure

Emily Shardlow Alan Jackson

Learning objectives
After studying this article the reader should understand the: C components determining intracranial pressure and the MonroeKellie hypothesis C controls of cerebral blood ow, ow-metabolism coupling and the relationships between cerebral blood ow and arterial partial pressures of CO2 and O2 C concept of cerebral autoregulation C availability of techniques for monitoring neurological function, cerebral blood ow and cerebral oxygenation and how the results obtained can be used to guide patient management

Abstract
The MonroeKellie hypothesis states that if the skull is intact, then the sum of the volumes of the brain, cerebrospinal uid (CSF) and intracranial blood volume is constant. An increase in volume in one of the three components within the skull must be compensated for by a decrease in the volume of the other remaining components, otherwise the intracranial pressure (ICP) will increase. Brain tissue is not easily displaced; therefore changes in venous blood or CSF volumes initially act as the major buffers against a rise in ICP. In the normal adult, the ICP is 5e13 mmHg, with minor cyclical variations owing to the effects of the arterial pressure waveform and respiration. Cerebral blood ow (CBF) is determined by a number of factors. It is closely linked to the metabolic activity of the brain to ensure adequate delivery of oxygen and substrates. The relationship between partial pressure of carbon dioxide in arterial blood (PaCO2) and CBF is almost linear. CBF increases by 25% for each kPa increase in PaCO2. Hypoxia (PaO2 <6.7 kPa) is also a potent stimulus for increasing CBF. The brain is intolerant of hypo- or hyperperfusion and therefore requires a constant ow of blood over a range of pressures, which is achieved by autoregulation. Below the lower limit of autoregulation, CBF mirrors mean arterial pressure (MAP), and eventually a reduced ow causes cerebral ischaemia. Monitoring of the central nervous system, including measurements of neuronal function, ICP, CBF and cerebral oxygenation, can guide pharmacological and surgical treatment according to the individual status of the patient.

and removes the need for lymphatic drainage of the brain. Pathological increases in brain tissue are the result of cell membrane failure with increased intracellular water (cytotoxic oedema), disruption of the bloodebrain barrier (vasogenic oedema) or CSF outow obstruction (interstitial oedema).

Cerebrospinal uid
CSF is the clear uid occupying the space between the arachnoid and pial layers of the meninges. CSF provides a constant supply of glucose, maintains a chemically stable environment, and supports the transport of metabolites and neurotransmitters. It bathes the spinal cord as well as the brain, which in effect oats within the CSF with a resultant effective weight reduction of approximately 97%. CSF reduces the effects of mechanical forces on the brain by displacing in response to linear and shearing forces. CSF is produced at a rate of approximately 500 ml per day, so that the entire CSF volume (150 ml) is replaced three times per 24-hour period. The conventional view of CSF production by the choroid plexus and absorption at the arachnoid granulations due to a pressure differential (bulk ow theory) has been replaced by a more modern concept of CSF production and absorption. It is generally accepted that CSF is absorbed far more widely than previously believed. Interstitial uid produced by cerebral capillaries exchanges across the pial membrane into the subarachnoid space, where the interstitial uid substitutes for the CSF. The brain capillaries actively take up plasma proteins and other molecules from the CSF, causing absorption of interstitial uid and CSF into the capillary space and hence into the venous outow.

Keywords brain; cerebral blood ow; cerebrospinal uid; injury; intracranial pressure

The MonroeKellie hypothesis states that if the skull is intact, then the sum of the volumes of the brain, cerebrospinal uid (CSF) and intracranial blood volume is constant. Hence if one of these elements within the cranium increases in volume, it must occur at the expense of the volume of the other two. Management of patients with intracranial pathology requires an understanding of this fundamental hypothesis.

Blood
The brain is supplied with blood via the internal carotid and vertebral arteries. Venous drainage is via the cerebral veins, sinuses and internal jugular veins. Under normal conditions there is approximately 150 ml of blood in the skull, most of which (about 100 ml) is within the venous system. Although cerebral blood volume (CBV) is small, cerebral blood ow (CBF) is relatively high compared with other organs. Normal global CBF is about 50 ml/100 g/minute, grey matter receiving 80 ml/100 g/minute and white matter 20 ml/100 g/minute. This equates to 700 ml/minute or 15% of the cardiac output to an organ that is only 2% of body weight. Because the contents of the skull are incompressible, the transient increase in blood volume during systole induces a complex compensatory mechanism known as MonroeKellie homeostasis.
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Brain
The brain has a mass of approximately 1400 g and consists of neural and supporting (glial) elements and intracellular and extracellular water. Tight junctions of the capillary endothelium and choroid plexus endothelium form the bloodebrain barrier. In health, this maintains an environment suitable for nerve function

Emily Shardlow MBChB FRCA is an Anaesthetic Registrar in the North West Region, UK. Conicts of interest: none declared. Alan Jackson PhD FRCR FRCP FBIR is Professor of Radiology at the University of Manchester, UK. Conicts of interest: none declared.

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The homeostatic mechanism not only compensates for increased intracranial systolic blood volume, but results in signicant smoothing of the systolic/diastolic pressure differences to which the brain is exposed. Failure of this homeostasis has been implicated in the pathogenesis of a wide range of cerebral disorders. In health, systolic expansion of the basal cerebral arteries produces a pressure wave within the CSF, causing an outow of CSF through the foramen magnum into the compliant spinal CSF space, equivalent to 50% of the increase in intracerebral volume. Similarly, with diastolic relaxation of the artery, CSF ows back into the cranium. The systolic CSF pressure wave is also transmitted to the major dural venous sinuses by expansion of the arachnoid granulations, therefore dissipating the systolic pressure wave. In addition, the elastic arterial walls absorb part of the energy of the systolic arterial pulse wave, which is then released during diastole to maintain constant capillary ow (Windkessel effect). The combination of these processes maintains a constant perfusion pressure and ow in the cerebral capillary bed despite the major changes in arterial feeding pressure between diastole and systole.

Pressurevolume curve
Arterial CSF Venous Composite curve

Pressure generated

Displaced volume
Reproduced with permission from Rosner M J. Pathophysiology and management of increased intracranial pressure. In: Andrews BT, ed. Neurosurgical intensive care. New York: McGraw-Hill, 1993

Intracranial pressure
The relationship between the volumes of brain tissue, CSF and blood gives rise to the intracranial pressure (ICP). In the normal adult, the ICP is 5e13 mmHg, with minor cyclical variations owing to the effects of the arterial pressure waveform and respiration. ICP also varies with posture, coughing and straining. A sustained increase in ICP to more than 15 mmHg is termed intracranial hypertension. At an ICP of more than 20 mmHg, areas of focal ischaemia appear, and at values of ICP more than 50 mmHg, global ischaemia supervenes. As previously described by the MonroeKellie hypothesis, an increase in volume in one of the three components within the skull must be compensated for by a decrease in the volume of the other remaining components. Brain tissue is not easily displaced; therefore changes in venous blood or CSF volumes initially act as the major buffers against a rise in ICP. The ability to compensate is inuenced by the time-scale involved, with slow-growing lesions better tolerated than acute insults. When compensatory mechanisms are no longer sufcient the compliance (change in volume per unit change in pressure, dV/dP) of the intracranial cavity is greatly reduced and ICP rises. Within the skull, it is the change in ICP for unit change in volume that is of interest, or dP/dV, and the term elastance should be used. The pressureevolume curve is the traditional method of expressing this relationship (Figure 1). This suggests that pathological increases in ICP occur as a result of continuing increase in intracranial volume. If we accept that the volume of the skull is xed, it is therefore more accurate to regard the relationship as the force required to displace volume from the cranium to accommodate the new volume. As the force generated is difcult to measure, it is the resultant pressure (ICP) that is normally measured (force pressure area). The resultant curve is actually a composite of pressure versus displaced volume curves for venous blood, CSF and arterial blood, each of which is successively more difcult to displace.
Figure 1

Flow-metabolic coupling
The cerebral blood ow is normally closely matched to the cerebral metabolic rate for oxygen (CMRO2). The ow-metabolic coupling was described by Roy and Sherrington in 1890 and stated that the brain possesses an intrinsic mechanism by which vascular supply can be varied locally or globally in correspondence with local variations in functional activity. The mediator of this coupling is subject to continuing research. At present nitric oxide (NO) is being investigated as a possible mediator which may be modied with NO synthetase inhibitors to alter pathophysiological responses to brain injury. CMRO2 under normal conditions is 3.5 ml/100 g/minute. It accounts for 20% of the total body oxygen consumption and 25% of basal glucose utilization. CBF is closely linked to the metabolic activity of the brain to ensure adequate delivery of oxygen and substrates. At any time, some regions may have relatively increased activity and blood ow, while other areas are less active. Any condition that reduces global metabolic activity will reduce CMRO2 and CBF. At a brain temperature of 27 C, CMRO2 and CBF are approximately halved, and CBF is about 10% at 20 C, as neuronal activity virtually ceases at this temperature. There is evidence of benets of hypothermia in preventing secondary brain injury after a primary insult. However, as moderate and severe hypothermia can be detrimental to outcome, only mild hypothermia has been accepted as a therapeutic manoeuvre. Controversy lies in the fact that the results of studies using hypothermia are conicting. Such studies include the National Acute Brain Injury Study trial, which concluded that mild hypothermia after head injury does not reduce mortality or brain dysfunction; but studies of head-injured patients with severe intracranial hypertension have demonstrated a benecial effect and improved outcome. Conversely, hyperthermia and seizures increase CMRO2 and CBF. Hyperglycaemia is associated with an increase in cerebral metabolism. Reduced CBF subsequent to an acute head injury results in additional anaerobic metabolism, and therefore blood glucose should be tightly controlled.

Control of cerebral blood ow

Several protective mechanisms control CBF. The brain is intolerant of hypoxia and depends on oxidative phosphorylation of glucose to generate ATP (adenosine triphosphate).

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Carbon dioxide
The relationship between partial pressure of carbon dioxide in arterial blood (PaCO2) and CBF is almost linear. CBF changes by 25% for each kPa change in PaCO2. At a PaCO2 of 10.6 kPa, CBF is approximately doubled. Beyond this, there is no further increase in ow because the cerebral resistance vessels are maximally vasodilated. Conversely, at a PaCO2 of 2.7 kPa ow is halved and plateaus as a result of maximum vasoconstriction. This is thought to be mediated by changes in hydrogen ion concentration in the extracellular uid surrounding the vascular smooth muscle. The response of cerebral vasculature to changes in PaCO2 can be used therapeutically in patients with raised ICP. Hyperventilation causes vasoconstriction with a reduction in CBV and ICP. Extreme hypocarbia (PaCO2 <4 kPa) may be harmful, because the degree of vasoconstriction may cause ischaemia. In prolonged hyperventilation, CSF pH and cerebral blood ow return to normal by bicarbonate buffering. Subsequent normalization of the PaCO2 can then result in hyperaemia, causing reperfusion injury to previously ischaemic brain regions.

CPP MAP ICP The brain is intolerant of hypo- or hyperperfusion, and therefore requires a constant ow of blood over a wide range of mean arterial pressures, which is achieved by autoregulation. This is thought to be a myogenic mechanism, whereby pressure changes are sensed and induce reex constriction of vascular smooth muscle to increased pressure or relaxation to low pressure. The stimulus to this response is CPP not MAP. Under normal circumstances the two are closely correlated and CBF is held constant over the range 50e150 mmHg (Figure 2). The lower limit represents the point of maximal vasodilation and below this point the ow is described as pressure-passive and correlates linearly with MAP. As the latter falls, the vessels gradually collapse, thereby reducing CBF and CBV. At the upper limit, there is maximal vasoconstriction and further increases in CPP are accompanied by disruption of the bloodebrain barrier, oedema formation and cerebral ischaemia (hypertensive encephalopathy). In patients with chronic untreated hypertension, the autoregulatory curve is shifted to the right to protect against these changes. This has important implications in the injured brain, when autoregulation appears to be intact but ICP is increased, for example haematoma. If the CPP falls, cerebral vasodilation occurs, increasing CBV and leading to a rise in ICP. This decreases CPP, leading to further vasodilation, increased CBV and ICP. This process has been termed the vasodilation cascade. If CPP is maintained or increased by increasing MAP, it will result in vasoconstriction, reducing CBV and ICP. This is termed the vasoconstriction cascade. For this reason, it is recommended that in the resuscitation phase of acute head injury, MAP is maintained greater than 90 mmHg or CPP greater than 70 mmHg. Paradoxically, if CPP is allowed to fall below the lower limit of autoregulation, passive collapse of the cerebral vessels will reduce CBV and ICP. However, this is achieved at the expense of CBF and oxygenation.

Oxygen
Hypoxia (PaO2 <6.7 kPa) is a potent stimulus for increasing CBF. It causes a rapid increase in CBF secondary to the development of a metabolic acidosis. The effects of hyperoxia on CBF were classically described by Kety and Schmidt, who demonstrated a 13% decrease in CBF with FiO2 85e100% attributed to an increase in cerebral vascular resistance. More recent studies have conrmed a reduction in CBF by up to 30% with inspired oxygen concentrations of 100%.

Autoregulation
The effective perfusion pressure of the brain is the difference between the mean arterial pressure (MAP) and the ICP, termed the cerebral perfusion pressure (CPP). There is an additional component to the calculation, further subtracting the jugular bulb pressure (effective venous pressure) from the MAP, but this is usually omitted as being insignicant clinically.

Autonomic nervous system

The cerebral vasculature is innervated by the autonomic nervous system. The sympathetic supply to the extraparenchymal vessels

Autoregulation

Autoregulation

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PaCO2 Cerebral blood flow (ml/100 g/minute)

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CPP

PaO2

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CPP (mmHg) PaO2/PaCO2 (kPa)

CPP, cerebral perfusion pressure; PaO2/PaCO2 partial pressure of oxygen/carbon dioxide in arterial blood

Figure 2

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arises from the cervical ganglia and the supply to the parenchymal microvasculature from the locus ceruleus. Their main action is vasoconstriction, which probably serves to protect the brain by shifting the autoregulation curve to the right in hypertension. The parasympathetic nerves arise from the pterygopalatine and otic ganglia and contribute to cerebral vasodilatation. This is most apparent in conditions such as hypotension and post-ischaemia reperfusion. It is also thought that initial changes in CBF to meet metabolic demands are initiated via neurogenic mechanisms and then sustained by local chemical factors.

Blood viscosity
Blood viscosity is directly related to the haematocrit. Reductions in haematocrit improve ow, but this is offset by a reduction in the oxygen-carrying capacity of the blood. The optimum haematocrit at which there is a balance between ow and oxygen capacity is approximately 30%.

There are four main anatomical sites used in the measurement of ICP: intraventricular, intraparenchymal, subarachnoid and epidural. Non-invasive and metabolic monitoring of ICP has also been studied, but the clinical value of these methods is currently unclear. Each technique has advantages and disadvantages and requires a unique monitoring system. Intraventricular monitors are considered the gold standard of invasive ICP monitoring catheters. A number of non-invasive devices to record ICP have been studied, but none have demonstrated reproducible clinical success. However, tissue resonance analysis (TRA), an ultrasound-based method, has shown good correlation with invasive techniques. Other non-invasive techniques include transcranial Doppler, which estimates ICP from changes in the waveform that occur in response to increased resistance to CBF. Intraocular pressure and tympanic membrane displacement may also prove valuable in monitoring ICP.

Critical cerebral blood ow

Below the lower limit of autoregulation, CBF mirrors MAP, and eventually a reduced ow causes cerebral ischaemia. At a CPP of approximately 25 mmHg, CBF is 20e25 ml/100 g/minute, and this is accompanied by slowing of electrical activity on electroencephalography (EEG). When perfusion pressure reaches 15 mmHg (CBF 15 ml/100g/minute), electrical activity ceases, and below 10 mmHg, cellular integrity is lost with a massive efux of potassium and eventually cell death.

Cerebral haemodynamics
Transcranial Doppler ultrasonography measures blood ow velocity (cm/second) in the cerebral arterial system both noninvasively and continuously. It allows discrimination of changes in CBF and has several uses in anaesthesia and critical care. It determines the quality of collateral circulation and detects microemboli in carotid surgery. It can also differentiate between vasospasm and hyperaemia in brain injury and subarachnoid haemorrhage.

Monitoring
Monitoring of the central nervous system, including measurements of neuronal function, CBF and cerebral oxygenation, can guide pharmacological and surgical treatment according to the individual status of the patient. Multimodality monitoring of more than one parameter can help overcome some of the limitations of each method used.

Cerebral oxygenation and metabolism

The metabolic state of the brain can be assessed using jugular venous oxygen saturation (SjvO2) monitoring by cannulating the internal jugular vein in a retrograde direction with a spectrophotometric probe. This method uses the Fick principle to monitor regional oxygen consumption. Low SjvO2 may be due to increased oxygen extraction or increased oxygen demand. High SjvO2 may occur with abnormally high CBF due to loss of autoregulation or high ICP causing shunting of blood past capillary beds. Normal SjvO2 ranges from 55% to 71%. Near-infrared spectroscopy is also used as a non-invasive monitor of brain oxygenation. A forehead sensor shines infrared light through the surface layers of the brain and the light that re-emerges is sensed by a detector system. A computer algorithm based upon the BeereLambert law is used to display concentrations of oxygenated and deoxygenated blood. Invasive brain tissue oximetry is available to measure brain oxygen levels directly. This technique uses a polarographic or breoptic probe to measure local changes in regional oxygenation. Microdialysis can also be used to assess cerebral oxygenation. It is achieved via a catheter inserted into the brain. The catheter has a dialysis membrane on the outside and low ow rates of dialysis uid are passed through the catheter using a pump mechanism. The concentration of any substance passing across the dialysis membrane can be measured. This technique currently remains a research tool. A

Intracranial pressure monitoring

The guidelines for the Management of Severe Head Injury suggest that ICP monitoring is indicated in head-injury patients with a Glasgow Coma Scale (GCS) score between 3 and 8 and with an abnormal CT scan. ICP monitoring in patients with a normal CT scan and with two or more of the following risk factors is suggested:  age over 40 years  motor posturing  systolic BP less than 90 mmHg. Patients at risk of elevated ICP requiring general anaesthesia should also have ICP monitoring. Derived values from ICP and its waveform give useful information.  Estimation of the pressureevolume compensatory reserve of the brain can be calculated by correlating the amplitude of the ICP pulse waveform with the mean ICP; and  The cerebrovascular pressureereactivity index is calculated by correlation of the ICP response to slow spontaneous changes in arterial blood pressure. This can be used to assess disturbances of cerebral autoregulation.

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