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Intracranial pressure and cerebral haemodynamics
PHYSIOLOGY
Intracranial pressure and cerebral haemodynamics
Learning objectives After reading this article you should:
Ashwini Oswal
C
know the mathematical relationship between cerebral perfusion pressure, intracranial pressure, and mean arterial pressure, and therefore appreciate why increases in the intracranial pressure can be pathological
C
understand the profile of the relationship between intracranial volume and intracranial pressure
C
understand the concept of MonroeKellie homeostasis, which states that the intracranial pressure will remain constant if there is no change in the total intracranial volume e which comprises the volumes of brain, cerebrospinal fluid and blood
C
have an appreciation of the principle of autoregulation e which maintains cerebral blood flow despite variations in arterial pressure
Ahmed K Toma
Abstract Intracranial pressure (ICP) refers to the pressure within the skull, which is determined by the volumes of the intracranial contents; blood, brain and cerebrospinal fluid. MonroeKellie homeostasis stipulates that a change in the total intracranial volume is accompanied by a change in the ICP, which is more precisely described by the intracranial pressureevolume relationship. Maintenance of a relatively constant ICP is essential for maintenance of the cerebral perfusion pressure, which in turn determines global cerebral blood flow. Although the physiological process of autoregulation ensures that cerebral blood flow is tightly maintained over a range of cerebral perfusion pressures, large increases in the ICP can result in severely impaired autoregulation, meaning that cerebral blood flow may be compromised. In this review article we provide an overview of the physiological determinants of the ICP and cerebral blood flow. We go on to illustrate how pathological states can compromise physiological compensatory mechanisms in order to potentially dangerous disturbances of the ICP and cerebral blood flow.
the skull resulting in herniation. Some examples of herniation syndromes are: transtentorial (or uncal) herniation, which involves a shift of the uncus of the temporal lobe downwards through the tentorium resulting in compression of important structures such as the posterior cerebral artery, the third cranial nerve and corticospinal fibres subfalcine herniation is characterized by displacement of the brain (typically the cingulate gyrus) beneath the free edge of the falx cerebri tonsillar herniation, which is a potentially fatal complication of raised ICP and involves herniation of the cerebellar tonsils through the foramen magnum resulting in compression of the brainstem respiratory centres.
Keywords Cerebral blood flow; cerebral perfusion pressure; intracranial pressure; MonroeKellie doctrine Royal College of Anaesthetists CPD Matrix: 1A01
Intracranial pressure The term intracranial pressure (ICP) refers to the pressure of the contents contained within the skull. The normal ICP varies cyclically with respiration and the cardiac cycle, and there may also be transient changes in ICP with posture, coughing and straining. Measured in the supine position, the normal range of ICP in adults is 7e15 mmHg.1 Interestingly, there is no established consensus on a normal range of ICPs measured over a prolonged period of time in freely moving humans. When the ICP is persistently raised (>15 mmHg) intracranial hypertension develops and the cerebral perfusion pressure e which is the pressure gradient causing cerebral blood flow (CBF) to the brain e will be reduced, leading to focal and then global ischaemia. In addition to this, lesions producing a raised ICP may cause localized displacement of brain tissues across structures in
Intracranial components and the MonroeKellie doctrine The adult skull can be considered as a bony box of fixed volume whose contents are: brain, blood and cerebrospinal fluid (CSF). The MonroeKellie doctrine stipulates that the sum of the volumes of the three components is constant and therefore that an increase in the volume of any one component needs to be accompanied by a reduction in the volume of at least one of the remaining two components.2,3 A failure of this homoeostatic mechanism in certain pathological states may result in potentially dangerous increases in intracerebral volume and therefore intracranial pressure. Before considering ICP and cerebral blood flow in further detail, we will first outline the properties of the three intracranial components.
Ashwini Oswal MBBS MRCP PhD is an Academic Clinical Fellow in Neurosurgery at the National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared.
Brain Brain parenchyma has a mass of approximately 1.4 kg and consists of neurons, glial cells and extracellular fluid. There are three different types of neurons. Afferent neurons transmit information from sensory organs to the central nervous system (CNS), whilst
Ahmed K Toma MBBS MD FRCS (SN) is a Consultant Neurosurgeon at the National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared.
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PHYSIOLOGY
CBF will be discussed in detail below. Changes in the vessel radius have a fourth power effect meaning that halving the vessel radius may theoretically result in a 16-fold reduction in cerebral blood flow. The above description overlooks the fact that cerebral blood flow is cyclical and driven by the phases of the cardiac cycle. Nevertheless, there are physiological mechanisms which prevent large variations in ICP and cerebral blood flow during the cardiac cycle. Cardiac systole is associated with an expansion of the blood volume within elastic cerebral arteries and this is accompanied by CSF displacement through the foramen magnum and an increase in venous outflow, hereby maintaining MonroeKellie homeostasis and ICP. In contrast, during diastole CSF re-enters the cranial compartment and venous outflow decreases. Furthermore, arterial elasticity acts to dampen the arterial pulse pressure wave and this aids with the maintenance of a relatively stable blood flow (Windkessel effect). The concept of MonroeKellie homeostasis can be better understood by considering how changes in intracranial pressure can be caused by changes in the volumes of one or more of the intracranial components. Classically, the relationship between intracranial volume and pressure is described as having three parts, as follows. A flat part where the ICP remains low despite changes in volume due to effective MonroeKellie homeostasis. In this portion of the curve the intracranial contents are said to have high compliance as the gradient of the pressure evolume curve is low (compliance ¼ 1/gradient ¼ dV/ dP). A steep portion where compensatory mechanisms are no longer sufficient and the compliance progressively decreases i.e. increasing dV/dP. A plateau phase, indicating a terminal disturbance in cerebrovascular responses where the ICP begins to equilibrate with mean arterial pressure (MAP) and the cerebral perfusion pressure (CPP) is dangerously low. The principle of MonroeKellie homeostasis also explains why acute hydrocephalus is a neurosurgical emergency. The underlying pathology in this condition produces a state where the rate of CSF production is greater than the rate of CSF resorption. Given that the maximal rate of CSF production is 20 ml/hour it is possible for the intracranial volume to rapidly increase in acute hydrocephalus, resulting in a potentially fatal increase in the ICP.
efferent neurons transmit information from the CNS to the periphery. Interneurons facilitate communication between afferent and efferent neurons. There are also three types of glial cells, including astrocytes, oligodendrocytes and microglia. The barrier between the blood and the interstitial fluid of the brain (i.e. the blooddbrain barrier (BBB)) consists of tight junctions between capillary endothelial cells and facilitates the maintenance of an appropriate environment for neuronal activity. Pathological increases in the volume of brain tissue can result from tumours or cerebral oedema for example. Cerebrospinal fluid (CSF) CSF occupies the space between the arachnoid membrane and the pia mater. CSF is produced by the choroid plexus of the ventricular system and has a number of important functions for the brain including providing buoyancy, mechanical protection, and chemical stability. Importantly, the presence of CSF is thought to reduce the effective weight of the brain to around 25 g, allowing the brain to maintain its density without significant compression of its blood supply.4 A long postulated, and increasing recently recognized role of CSF is to provide a waste clearance pathway for the CNS that has a somewhat similar role to the lymphatic system found in other organs. This pathway is known as the Glymphatic system and consists of a para-arterial influx route for CSF to enter the brain parenchyma, coupled to a clearance mechanism for interstitial fluid.5 CSF is produced at a rate of approximately 500 ml/day (approximately 20 ml/hour), meaning that the entire CSF volume of 150 ml is replaced more than three times daily. Approximately 25 ml of the total CSF volume is present within at ventricular system of the brain. Although it had traditionally been believed that CSF resorption takes place at arachnoid granulations, recent evidence highlights that exchange between the CSF and interstitial fluid compartments is possible across the pia mater. Cerebral blood flow The brain receives arterial blood from the internal carotid and vertebral arteries, and its venous drainage is to cerebral veins, venous sinuses and the internal jugular veins. It is interesting to note that the cerebral blood flow is large in comparison to the volume of blood in the cranium at any point in time. Cerebral blood flow is approximately 700 ml/minute, corresponding to 15% of the cardiac output, whilst the intracranial blood volume is only 150 ml.6 Based on the simplification of blood being incompressible and uniformly viscous, factors determining cerebral blood flow can be revealed by consideration of the HagenePoiseuille equation, as follows: CBF ¼
Autoregulation The maintenance of cerebral blood flow is critical since the brain depends on the oxidative metabolism of glucose for its principal energy source and is therefore highly intolerant of both hypoxia and hypoglycaemia. The physiological mechanism which allows the brain to maintain a relatively stable blood flow in spite of large changes in arterial blood pressure is known as autoregulation.6 The principle of autoregulation is best understood by considering the relationship between cerebral perfusion pressure (CPP) and cerebral blood flow (CBF). The cerebral perfusion pressure is mathematically given by the difference between the mean arterial pressure and the ICP:6
CPP: p: R4 8:h: L
Here CBF represents cerebral blood flow, CPP denotes cerebral perfusion pressure, R denotes blood vessel radius and h represents the viscosity of the blood, with L indicating the vessel length. We may assume that blood viscosity and vessel length remain constant, leaving the major determinants of cerebral blood flow to be the cerebral perfusion pressure and the vessel radius. The complex, non-linear relationship between CPP and
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PHYSIOLOGY
CPP ¼ MAP ICP
perfusion pressure and the brain is hypoperfused. In contrast, at the upper end of this graph, the autoregulation mechanism is exhausted and resistance vessels are maximally constricted so that any further increases in CPP result in disruption of the BBB and cerebral oedema. Despite the importance of autoregulation in maintaining cerebral perfusion, there are circumstances in which autoregulation can have a deleterious effect. For example, if the ICP is acutely raised by a haematoma, the cerebral perfusion pressure falls, resulting in vasodilation which serves to maintain the cerebral perfusion pressure. Vasodilation also increases cerebral blood volume however, which has the effect of further increasing the ICP, thereby setting up a cascade which exacerbates raised
Autoregulation allows cerebral blood flow to remain relatively stable over a broad range of cerebral perfusion pressure values. Although the precise mechanisms governing autoregulation remain to be fully elucidated, myogenic reactivity of cerebral arterioles is thought to be of critical importance. Vascular smooth muscle constricts in response to increases in cerebral perfusion pressure and relaxes in responses to reductions in pressure. This property of the cerebral vasculature allows for the control of cerebral perfusion, independently of pressure and is known as the Bayliss effect. At the lower end of the graph shown in Figure 2, cerebral blood flow rises approximately linearly with increases in cerebral
a The principle of Monro–Kellie homeostasis Equilibrium state in health – normal ICP Arterial Venous blood blood
Brain
CSF
Compensated state in disease – normal ICP Arterial Venous blood blood
Brain
Mass
CSF
Decompensated state in disease – high ICP Arterial Venous blood blood
Brain
Mass
CSF
Volume b The relationship between intracranial volume and intracranial pressure Steep portion
Intracranial pressure
Flat portion
Exhausted compensatory reserve
δP
δP
δv
δv Volume Figure 1 (a) In the healthy physiological state, the cranial volume is composed of blood (arterial and venous), cerebrospinal fluid (CSF) and brain tissue. In a compensated pathological state, such as an intracranial haematoma, the haematoma occupies a volume which can be accommodated by the displacement of CSF and venous blood. As a result, there is a relatively small change in the total intracranial volume and therefore also the intracranial pressure (ICP). If the haematoma occupies a large volume, however, MonroeKellie homeostasis fails to provide adequate compensation and the total intracranial volume increase giving rise to an increase in the ICPs. (b) The curve can be divided into three portions with the compliance being given by the inverse of the gradient, dV/dP. The gradient progressively decreases and the compliance progressively decreases until the point where compensatory reserve is exhausted.
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PHYSIOLOGY
intracranial pressure. This example illustrates that it is important to try to prevent the cerebral perfusion pressure from falling outside the autoregulatory range in acute head injury by maintaining the mean arterial pressure at greater than 90 mmHg.
arterioles by causing hyperpolarization and relaxation via the opening of KATP channels. Conversely, hyperoxia produces vasoconstriction and recent studies have shown a reduction in CBF of up to 30% with inspired oxygen concentrations of 100%.
The role of the venous system in determining ICP
Autonomic nervous system
The well-known relationship, described above, relating cerebral perfusion pressure to the mean arterial pressure and ICP would suggest the lack of a dependence of the ICP on venous haemodynamics. This notion is however at odds with the well-known phenomenon that applying gentle pressure over the neck veins produces a rise in the ICP. Furthermore, intuition suggests that a failure of venous outflow to match arterial inflow will result in a progressive rise in intracranial volume and therefore a rise ICP. Interestingly recent studies suggest that focal venous sinus stenosis is associated with idiopathic intracranial hypertension (IIH, characterized by headache and visual loss) and that increasing the calibre of stenotic venous sinuses by stenting may reduce intracranial pressures.6
The cerebral vasculature is innervated by the autonomic nervous system. Sympathetic supply to the extraparenchymal vessels arises from the cervical ganglia and the supply to parenchymal vasculature arises from the locus coeruleus. Sympathetic stimulation results in vasoconstriction. Parasympathetic innervation, in contrast arises from the pterygopalatine and otic ganglia, and has a vasodilatory effect.
Monitoring of blood flow and intracranial pressure Monitoring of cerebral blood flow and intracranial pressure can play an important role in guiding the management of patients with certain neurological illnesses. Current guidelines recommend that ICP monitoring may be indicated in patients who meet the following criteria: Glasgow Coma Scale (GCS) score 3e8 and an abnormal CT scan (e.g. haematoma, swelling, herniation) GCS score 3e8, a normal CT scan and any two of the following: age over 40 years, motor posturing, systolic BP less than 90 mmHg. A major advantage of ICP monitoring is that it allows computation of the CPP, thereby allowing therapy to be directed towards maintaining adequate cerebral perfusion. It is also a continuous measure which can alert doctors quickly to changes in the clinical state of a patient. At present there are no effective means of noninvasively performing ICP monitoring. ICP monitoring usually requires insertion of an external ventricular drain (EVD) or another specialized type of monitoring wire either into the extradural or intraparenchymal space. Therefore, one must
Activity dependent regional cerebral blood flow It is important to note that in addition to maintaining global cerebral blood flow, the cerebral vasculature is also able to regulate regional blood flow. In fact, regional cerebral blood flow closely matches regional cerebral metabolic demand for oxygen in a process known as flow-metabolic coupling.6,7 Although the precise mechanisms of flow-metabolic coupling remain to be fully characterized, astrocytes are thought to play a crucial role. Anatomically, they possess foot processes which invest capillaries at one end and neurones at the other, meaning that they are ideally placed to couple changes in the activity of neurones to vascular reactivity. In fact, it has also been proposed that astrocytes facilitate glucose uptake from the blood in response to increases in synaptic activity, thereby facilitating increases in neuronal activity. A number of other factors are also important in determining cerebral blood flow and these will be discussed in detail below.
The relationship between cerebral perfusion pressure and cerebral blood flow
Carbon dioxide The relationship between arterial PCO2 and cerebral blood flow is roughly linear within the physiological range.7 When PCO2 is 10.6 kPa, CBF is approximately double that at normocapnoea and no further increase in CBF is possible due to maximal dilation of the cerebral resistance vessels. Conversely, at a PCO2 of 2.7 kPa the cerebral vasculature is maximally constricted meaning that CBF is halved compared to the normocapnic state. This response of CBF to PCO2 is thought to be driven by changes in the extracellular Hþ concentration and can be used to therapeutic advantage in patients with raised ICP. Hyperventilation, reduces PCO2 resulting in vasoconstriction and a consequent reduction in cerebral blood volume, which in turn allows for a leftward shift in the pressureevolume curve shown in Figure 1. Very low PCO2 levels should be avoided however since excessive vasoconstriction can lead to cerebral ischaemia.
50
75
Oxygen Hypoxia is a potent stimulus for vasodilation, causing a rapid increase in CBF associated with metabolic acidosis.7 Hypoxia may have a direct effect on smooth muscle cells of cerebral arteries and
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150
Cerebral perfusion pressure (mmHg) Figure 2 The process of autoregulation ensures that cerebral blood flow is maintained at around 50 ml/100 g/minute over a relatively wide range of cerebral perfusion pressures.
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PHYSIOLOGY
always perform a careful assessment of the potential benefits of ICP monitoring prior to exposing the patient to a surgical procedure which carries risks including life threatening bleeding and infection. It is also interesting to note that despite the widespread use of ICP monitoring, there is no high level evidence at present which demonstrates beneficial outcomes from CPP directed therapy compared to clinical and radiological examination.8 One current approach for non-invasively monitoring cerebral blood flow velocity is transcranial Doppler ultrasonography. This method may be used to distinguish vasospasm and hyperaemia in brain injury and subarachnoid haemorrhage. Similarly, it is also possible to measure cerebral oxygenation and metabolism.9 Calculation of the jugular venous oxygen saturation (SjvO2) is possible after cannulation of the internal jugular vein and insertion of a spectrophotometric probe. Fick’s principle can then be used to determine the regional oxygen consumption. Broadly speaking, a high SjvO2 indicates either an abnormally high cerebral blood flow (due to loss of autoregulation) or raised ICP, leading to shunting of blood past capillary beds. A low SjvO2 in contrast, is indicative of increased tissue oxygen extraction.10 Near infrared spectroscopy (NIRS) is a non-invasive technique for determining brain oxygenation. A forehead sensor shines an infrared light through the skull and surface layers of the brain whilst a detector senses reflected light. Blood oxygenation may then be determined by application of the BeereLambert law.10 Other experimental approaches for invasively determining tissue oxygenation include microdialysis.10 A
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REFERENCES 1 Steiner LA, Andrews PJ. Monitoring the injured brain: ICP and CBF. Br J Anaesth 2006; 97: 26e38. 2 Monro A. Observations on the structure and function of the nervous system. Edinburgh: Creech and Johnson, 1783. 3 Kellie G. An account of the appearances observed in the dissection of two of the three individuals presumed to have perished in the storm of the 3rd, and whose bodies were discovered in the vicinity of Leith on the morning of the 4th November 1821 with some reflections on the pathology of the brain. Transac Medico Chir Soc Edinb 1824; 1: 84e169. 4 Saladin K. Anatomy and physiology. 6th edn. 2012. McGraw Hill, 2012. 5 The glymphatic system: a beginner’s guide. Neurochem Res 2015; 40: 2583e99. 6 Wilson MH. MonroeKellie 2.0: the dynamic vascular and venous components of intracranial pressure. J Cereb Blood Flow Metabolism 2016; 36: 1338e50. 7 Partington T, Farmery A. Intracranial pressure and cerebral blood flow. Anaesth Intensive Care Med 2014; 15: 189e94. 8 Chesnut RM, Temkin N, Carney N, et al. A trial of intracranialpressure monitoring in traumatic brain injury. N Engl J Med 2012; 367: 2471e81. 9 Purkayastha S, Sorond F. Transcranial Doppler ultrasound: technique and application. Semin Neurol 2012; 32: 411e20. 10 Hemphill JC, Andrews P, De Georgia M. Multimodal monitoring and neurocritical care bioinformatics. Nat Rev Neurol 2011; 7: 451e60.
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Intracranial pressure and cerebral haemodynamics
Learning objectives After reading this article you should:
Ashwini Oswal
C
know the mathematical relationship between cerebral perfusion pressure, intracranial pressure, and mean arterial pressure, and therefore appreciate why increases in the intracranial pressure can be pathological
C
understand the profile of the relationship between intracranial volume and intracranial pressure
C
understand the concept of MonroeKellie homeostasis, which states that the intracranial pressure will remain constant if there is no change in the total intracranial volume e which comprises the volumes of brain, cerebrospinal fluid and blood
C
have an appreciation of the principle of autoregulation e which maintains cerebral blood flow despite variations in arterial pressure
Ahmed K Toma
Abstract Intracranial pressure (ICP) refers to the pressure within the skull, which is determined by the volumes of the intracranial contents; blood, brain and cerebrospinal fluid. MonroeKellie homeostasis stipulates that a change in the total intracranial volume is accompanied by a change in the ICP, which is more precisely described by the intracranial pressureevolume relationship. Maintenance of a relatively constant ICP is essential for maintenance of the cerebral perfusion pressure, which in turn determines global cerebral blood flow. Although the physiological process of autoregulation ensures that cerebral blood flow is tightly maintained over a range of cerebral perfusion pressures, large increases in the ICP can result in severely impaired autoregulation, meaning that cerebral blood flow may be compromised. In this review article we provide an overview of the physiological determinants of the ICP and cerebral blood flow. We go on to illustrate how pathological states can compromise physiological compensatory mechanisms in order to potentially dangerous disturbances of the ICP and cerebral blood flow.
the skull resulting in herniation. Some examples of herniation syndromes are: transtentorial (or uncal) herniation, which involves a shift of the uncus of the temporal lobe downwards through the tentorium resulting in compression of important structures such as the posterior cerebral artery, the third cranial nerve and corticospinal fibres subfalcine herniation is characterized by displacement of the brain (typically the cingulate gyrus) beneath the free edge of the falx cerebri tonsillar herniation, which is a potentially fatal complication of raised ICP and involves herniation of the cerebellar tonsils through the foramen magnum resulting in compression of the brainstem respiratory centres.
Keywords Cerebral blood flow; cerebral perfusion pressure; intracranial pressure; MonroeKellie doctrine Royal College of Anaesthetists CPD Matrix: 1A01
Intracranial pressure The term intracranial pressure (ICP) refers to the pressure of the contents contained within the skull. The normal ICP varies cyclically with respiration and the cardiac cycle, and there may also be transient changes in ICP with posture, coughing and straining. Measured in the supine position, the normal range of ICP in adults is 7e15 mmHg.1 Interestingly, there is no established consensus on a normal range of ICPs measured over a prolonged period of time in freely moving humans. When the ICP is persistently raised (>15 mmHg) intracranial hypertension develops and the cerebral perfusion pressure e which is the pressure gradient causing cerebral blood flow (CBF) to the brain e will be reduced, leading to focal and then global ischaemia. In addition to this, lesions producing a raised ICP may cause localized displacement of brain tissues across structures in
Intracranial components and the MonroeKellie doctrine The adult skull can be considered as a bony box of fixed volume whose contents are: brain, blood and cerebrospinal fluid (CSF). The MonroeKellie doctrine stipulates that the sum of the volumes of the three components is constant and therefore that an increase in the volume of any one component needs to be accompanied by a reduction in the volume of at least one of the remaining two components.2,3 A failure of this homoeostatic mechanism in certain pathological states may result in potentially dangerous increases in intracerebral volume and therefore intracranial pressure. Before considering ICP and cerebral blood flow in further detail, we will first outline the properties of the three intracranial components.
Ashwini Oswal MBBS MRCP PhD is an Academic Clinical Fellow in Neurosurgery at the National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared.
Brain Brain parenchyma has a mass of approximately 1.4 kg and consists of neurons, glial cells and extracellular fluid. There are three different types of neurons. Afferent neurons transmit information from sensory organs to the central nervous system (CNS), whilst
Ahmed K Toma MBBS MD FRCS (SN) is a Consultant Neurosurgeon at the National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared.
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PHYSIOLOGY
CBF will be discussed in detail below. Changes in the vessel radius have a fourth power effect meaning that halving the vessel radius may theoretically result in a 16-fold reduction in cerebral blood flow. The above description overlooks the fact that cerebral blood flow is cyclical and driven by the phases of the cardiac cycle. Nevertheless, there are physiological mechanisms which prevent large variations in ICP and cerebral blood flow during the cardiac cycle. Cardiac systole is associated with an expansion of the blood volume within elastic cerebral arteries and this is accompanied by CSF displacement through the foramen magnum and an increase in venous outflow, hereby maintaining MonroeKellie homeostasis and ICP. In contrast, during diastole CSF re-enters the cranial compartment and venous outflow decreases. Furthermore, arterial elasticity acts to dampen the arterial pulse pressure wave and this aids with the maintenance of a relatively stable blood flow (Windkessel effect). The concept of MonroeKellie homeostasis can be better understood by considering how changes in intracranial pressure can be caused by changes in the volumes of one or more of the intracranial components. Classically, the relationship between intracranial volume and pressure is described as having three parts, as follows. A flat part where the ICP remains low despite changes in volume due to effective MonroeKellie homeostasis. In this portion of the curve the intracranial contents are said to have high compliance as the gradient of the pressure evolume curve is low (compliance ¼ 1/gradient ¼ dV/ dP). A steep portion where compensatory mechanisms are no longer sufficient and the compliance progressively decreases i.e. increasing dV/dP. A plateau phase, indicating a terminal disturbance in cerebrovascular responses where the ICP begins to equilibrate with mean arterial pressure (MAP) and the cerebral perfusion pressure (CPP) is dangerously low. The principle of MonroeKellie homeostasis also explains why acute hydrocephalus is a neurosurgical emergency. The underlying pathology in this condition produces a state where the rate of CSF production is greater than the rate of CSF resorption. Given that the maximal rate of CSF production is 20 ml/hour it is possible for the intracranial volume to rapidly increase in acute hydrocephalus, resulting in a potentially fatal increase in the ICP.
efferent neurons transmit information from the CNS to the periphery. Interneurons facilitate communication between afferent and efferent neurons. There are also three types of glial cells, including astrocytes, oligodendrocytes and microglia. The barrier between the blood and the interstitial fluid of the brain (i.e. the blooddbrain barrier (BBB)) consists of tight junctions between capillary endothelial cells and facilitates the maintenance of an appropriate environment for neuronal activity. Pathological increases in the volume of brain tissue can result from tumours or cerebral oedema for example. Cerebrospinal fluid (CSF) CSF occupies the space between the arachnoid membrane and the pia mater. CSF is produced by the choroid plexus of the ventricular system and has a number of important functions for the brain including providing buoyancy, mechanical protection, and chemical stability. Importantly, the presence of CSF is thought to reduce the effective weight of the brain to around 25 g, allowing the brain to maintain its density without significant compression of its blood supply.4 A long postulated, and increasing recently recognized role of CSF is to provide a waste clearance pathway for the CNS that has a somewhat similar role to the lymphatic system found in other organs. This pathway is known as the Glymphatic system and consists of a para-arterial influx route for CSF to enter the brain parenchyma, coupled to a clearance mechanism for interstitial fluid.5 CSF is produced at a rate of approximately 500 ml/day (approximately 20 ml/hour), meaning that the entire CSF volume of 150 ml is replaced more than three times daily. Approximately 25 ml of the total CSF volume is present within at ventricular system of the brain. Although it had traditionally been believed that CSF resorption takes place at arachnoid granulations, recent evidence highlights that exchange between the CSF and interstitial fluid compartments is possible across the pia mater. Cerebral blood flow The brain receives arterial blood from the internal carotid and vertebral arteries, and its venous drainage is to cerebral veins, venous sinuses and the internal jugular veins. It is interesting to note that the cerebral blood flow is large in comparison to the volume of blood in the cranium at any point in time. Cerebral blood flow is approximately 700 ml/minute, corresponding to 15% of the cardiac output, whilst the intracranial blood volume is only 150 ml.6 Based on the simplification of blood being incompressible and uniformly viscous, factors determining cerebral blood flow can be revealed by consideration of the HagenePoiseuille equation, as follows: CBF ¼
Autoregulation The maintenance of cerebral blood flow is critical since the brain depends on the oxidative metabolism of glucose for its principal energy source and is therefore highly intolerant of both hypoxia and hypoglycaemia. The physiological mechanism which allows the brain to maintain a relatively stable blood flow in spite of large changes in arterial blood pressure is known as autoregulation.6 The principle of autoregulation is best understood by considering the relationship between cerebral perfusion pressure (CPP) and cerebral blood flow (CBF). The cerebral perfusion pressure is mathematically given by the difference between the mean arterial pressure and the ICP:6
CPP: p: R4 8:h: L
Here CBF represents cerebral blood flow, CPP denotes cerebral perfusion pressure, R denotes blood vessel radius and h represents the viscosity of the blood, with L indicating the vessel length. We may assume that blood viscosity and vessel length remain constant, leaving the major determinants of cerebral blood flow to be the cerebral perfusion pressure and the vessel radius. The complex, non-linear relationship between CPP and
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PHYSIOLOGY
CPP ¼ MAP ICP
perfusion pressure and the brain is hypoperfused. In contrast, at the upper end of this graph, the autoregulation mechanism is exhausted and resistance vessels are maximally constricted so that any further increases in CPP result in disruption of the BBB and cerebral oedema. Despite the importance of autoregulation in maintaining cerebral perfusion, there are circumstances in which autoregulation can have a deleterious effect. For example, if the ICP is acutely raised by a haematoma, the cerebral perfusion pressure falls, resulting in vasodilation which serves to maintain the cerebral perfusion pressure. Vasodilation also increases cerebral blood volume however, which has the effect of further increasing the ICP, thereby setting up a cascade which exacerbates raised
Autoregulation allows cerebral blood flow to remain relatively stable over a broad range of cerebral perfusion pressure values. Although the precise mechanisms governing autoregulation remain to be fully elucidated, myogenic reactivity of cerebral arterioles is thought to be of critical importance. Vascular smooth muscle constricts in response to increases in cerebral perfusion pressure and relaxes in responses to reductions in pressure. This property of the cerebral vasculature allows for the control of cerebral perfusion, independently of pressure and is known as the Bayliss effect. At the lower end of the graph shown in Figure 2, cerebral blood flow rises approximately linearly with increases in cerebral
a The principle of Monro–Kellie homeostasis Equilibrium state in health – normal ICP Arterial Venous blood blood
Brain
CSF
Compensated state in disease – normal ICP Arterial Venous blood blood
Brain
Mass
CSF
Decompensated state in disease – high ICP Arterial Venous blood blood
Brain
Mass
CSF
Volume b The relationship between intracranial volume and intracranial pressure Steep portion
Intracranial pressure
Flat portion
Exhausted compensatory reserve
δP
δP
δv
δv Volume Figure 1 (a) In the healthy physiological state, the cranial volume is composed of blood (arterial and venous), cerebrospinal fluid (CSF) and brain tissue. In a compensated pathological state, such as an intracranial haematoma, the haematoma occupies a volume which can be accommodated by the displacement of CSF and venous blood. As a result, there is a relatively small change in the total intracranial volume and therefore also the intracranial pressure (ICP). If the haematoma occupies a large volume, however, MonroeKellie homeostasis fails to provide adequate compensation and the total intracranial volume increase giving rise to an increase in the ICPs. (b) The curve can be divided into three portions with the compliance being given by the inverse of the gradient, dV/dP. The gradient progressively decreases and the compliance progressively decreases until the point where compensatory reserve is exhausted.
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PHYSIOLOGY
intracranial pressure. This example illustrates that it is important to try to prevent the cerebral perfusion pressure from falling outside the autoregulatory range in acute head injury by maintaining the mean arterial pressure at greater than 90 mmHg.
arterioles by causing hyperpolarization and relaxation via the opening of KATP channels. Conversely, hyperoxia produces vasoconstriction and recent studies have shown a reduction in CBF of up to 30% with inspired oxygen concentrations of 100%.
The role of the venous system in determining ICP
Autonomic nervous system
The well-known relationship, described above, relating cerebral perfusion pressure to the mean arterial pressure and ICP would suggest the lack of a dependence of the ICP on venous haemodynamics. This notion is however at odds with the well-known phenomenon that applying gentle pressure over the neck veins produces a rise in the ICP. Furthermore, intuition suggests that a failure of venous outflow to match arterial inflow will result in a progressive rise in intracranial volume and therefore a rise ICP. Interestingly recent studies suggest that focal venous sinus stenosis is associated with idiopathic intracranial hypertension (IIH, characterized by headache and visual loss) and that increasing the calibre of stenotic venous sinuses by stenting may reduce intracranial pressures.6
The cerebral vasculature is innervated by the autonomic nervous system. Sympathetic supply to the extraparenchymal vessels arises from the cervical ganglia and the supply to parenchymal vasculature arises from the locus coeruleus. Sympathetic stimulation results in vasoconstriction. Parasympathetic innervation, in contrast arises from the pterygopalatine and otic ganglia, and has a vasodilatory effect.
Monitoring of blood flow and intracranial pressure Monitoring of cerebral blood flow and intracranial pressure can play an important role in guiding the management of patients with certain neurological illnesses. Current guidelines recommend that ICP monitoring may be indicated in patients who meet the following criteria: Glasgow Coma Scale (GCS) score 3e8 and an abnormal CT scan (e.g. haematoma, swelling, herniation) GCS score 3e8, a normal CT scan and any two of the following: age over 40 years, motor posturing, systolic BP less than 90 mmHg. A major advantage of ICP monitoring is that it allows computation of the CPP, thereby allowing therapy to be directed towards maintaining adequate cerebral perfusion. It is also a continuous measure which can alert doctors quickly to changes in the clinical state of a patient. At present there are no effective means of noninvasively performing ICP monitoring. ICP monitoring usually requires insertion of an external ventricular drain (EVD) or another specialized type of monitoring wire either into the extradural or intraparenchymal space. Therefore, one must
Activity dependent regional cerebral blood flow It is important to note that in addition to maintaining global cerebral blood flow, the cerebral vasculature is also able to regulate regional blood flow. In fact, regional cerebral blood flow closely matches regional cerebral metabolic demand for oxygen in a process known as flow-metabolic coupling.6,7 Although the precise mechanisms of flow-metabolic coupling remain to be fully characterized, astrocytes are thought to play a crucial role. Anatomically, they possess foot processes which invest capillaries at one end and neurones at the other, meaning that they are ideally placed to couple changes in the activity of neurones to vascular reactivity. In fact, it has also been proposed that astrocytes facilitate glucose uptake from the blood in response to increases in synaptic activity, thereby facilitating increases in neuronal activity. A number of other factors are also important in determining cerebral blood flow and these will be discussed in detail below.
The relationship between cerebral perfusion pressure and cerebral blood flow
Carbon dioxide The relationship between arterial PCO2 and cerebral blood flow is roughly linear within the physiological range.7 When PCO2 is 10.6 kPa, CBF is approximately double that at normocapnoea and no further increase in CBF is possible due to maximal dilation of the cerebral resistance vessels. Conversely, at a PCO2 of 2.7 kPa the cerebral vasculature is maximally constricted meaning that CBF is halved compared to the normocapnic state. This response of CBF to PCO2 is thought to be driven by changes in the extracellular Hþ concentration and can be used to therapeutic advantage in patients with raised ICP. Hyperventilation, reduces PCO2 resulting in vasoconstriction and a consequent reduction in cerebral blood volume, which in turn allows for a leftward shift in the pressureevolume curve shown in Figure 1. Very low PCO2 levels should be avoided however since excessive vasoconstriction can lead to cerebral ischaemia.
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Oxygen Hypoxia is a potent stimulus for vasodilation, causing a rapid increase in CBF associated with metabolic acidosis.7 Hypoxia may have a direct effect on smooth muscle cells of cerebral arteries and
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150
Cerebral perfusion pressure (mmHg) Figure 2 The process of autoregulation ensures that cerebral blood flow is maintained at around 50 ml/100 g/minute over a relatively wide range of cerebral perfusion pressures.
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Please cite this article in press as: Oswal A, Toma AK, Intracranial pressure and cerebral haemodynamics, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.03.002
PHYSIOLOGY
always perform a careful assessment of the potential benefits of ICP monitoring prior to exposing the patient to a surgical procedure which carries risks including life threatening bleeding and infection. It is also interesting to note that despite the widespread use of ICP monitoring, there is no high level evidence at present which demonstrates beneficial outcomes from CPP directed therapy compared to clinical and radiological examination.8 One current approach for non-invasively monitoring cerebral blood flow velocity is transcranial Doppler ultrasonography. This method may be used to distinguish vasospasm and hyperaemia in brain injury and subarachnoid haemorrhage. Similarly, it is also possible to measure cerebral oxygenation and metabolism.9 Calculation of the jugular venous oxygen saturation (SjvO2) is possible after cannulation of the internal jugular vein and insertion of a spectrophotometric probe. Fick’s principle can then be used to determine the regional oxygen consumption. Broadly speaking, a high SjvO2 indicates either an abnormally high cerebral blood flow (due to loss of autoregulation) or raised ICP, leading to shunting of blood past capillary beds. A low SjvO2 in contrast, is indicative of increased tissue oxygen extraction.10 Near infrared spectroscopy (NIRS) is a non-invasive technique for determining brain oxygenation. A forehead sensor shines an infrared light through the skull and surface layers of the brain whilst a detector senses reflected light. Blood oxygenation may then be determined by application of the BeereLambert law.10 Other experimental approaches for invasively determining tissue oxygenation include microdialysis.10 A
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REFERENCES 1 Steiner LA, Andrews PJ. Monitoring the injured brain: ICP and CBF. Br J Anaesth 2006; 97: 26e38. 2 Monro A. Observations on the structure and function of the nervous system. Edinburgh: Creech and Johnson, 1783. 3 Kellie G. An account of the appearances observed in the dissection of two of the three individuals presumed to have perished in the storm of the 3rd, and whose bodies were discovered in the vicinity of Leith on the morning of the 4th November 1821 with some reflections on the pathology of the brain. Transac Medico Chir Soc Edinb 1824; 1: 84e169. 4 Saladin K. Anatomy and physiology. 6th edn. 2012. McGraw Hill, 2012. 5 The glymphatic system: a beginner’s guide. Neurochem Res 2015; 40: 2583e99. 6 Wilson MH. MonroeKellie 2.0: the dynamic vascular and venous components of intracranial pressure. J Cereb Blood Flow Metabolism 2016; 36: 1338e50. 7 Partington T, Farmery A. Intracranial pressure and cerebral blood flow. Anaesth Intensive Care Med 2014; 15: 189e94. 8 Chesnut RM, Temkin N, Carney N, et al. A trial of intracranialpressure monitoring in traumatic brain injury. N Engl J Med 2012; 367: 2471e81. 9 Purkayastha S, Sorond F. Transcranial Doppler ultrasound: technique and application. Semin Neurol 2012; 32: 411e20. 10 Hemphill JC, Andrews P, De Georgia M. Multimodal monitoring and neurocritical care bioinformatics. Nat Rev Neurol 2011; 7: 451e60.
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Oswal A, Toma AK, Intracranial pressure and cerebral haemodynamics, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/j.mpaic.2017.03.002