Pharmacological and pathological modulation of cerebral physiology

Homeostatic mechanisms exist to enable the supply of oxygen and glucose for cerebral metabolism and neuronal function. In health, cerebral autoregulation, neurogenic and metabolic processes ensure that the supply of these nutrients is adequate to meet metabolic requirements, thus preventing neuronal cell damage. The goals of neuroanaesthesia are to provide optimal operating conditions and provide adequate cerebral blood flow, often in the context of a vulnerable brain which is exposed to the physiological stress of surgical trauma. This article outlines how delivery of anaesthesia and disease processes affecting the brain modulate the mechanisms that regulate cerebral blood flow and metabolism.     

Pharmacological and pathological modulation of cerebral physiology

Anaesthesia for neurosurgery aims to provide optimal surgical conditions whilst maintaining adequate cerebral blood flow in order to supply the brain with appropriate amounts of oxygen and glucose. Most anaesthetic drugs influence the normal cerebral physiology either directly or indirectly. They can cause changes in cerebral blood flow by influencing cerebral blood vessel calibre, by interfering with autoregulatory processes and by modifying cerebral metabolism. The brain's limited ability to store oxygen and glucose means that its supply must be continuous if neuronal damage is to be avoided. Ischaemic cerebral damage is the most important pathological mechanism in patients with stroke, subarachnoid haemorrhage and traumatic brain injury. Significant traumatic brain injury causes widespread derangement of cerebral physiology, including changes in cerebral blood flow, autoregulation and cerebral energy dynamics. This article outlines the effect of anaesthesia on cerebral physiology and reviews the pathophysiology of traumatic brain injury and subarachnoid haemorrhage.     

Pharmacological and pathological modulation of cerebral physiology

Anaesthesia for neurosurgery aims to provide optimal operating conditions whilst at the same time maintaining adequate cerebral blood flow to supply the brain with appropriate supplies of oxygen and glucose. Many anaesthetic drugs can influence normal cerebral physiology either directly or indirectly. They can cause changes in cerebral blood flow by influencing cerebral blood vessel calibre, by interfering with autoregulatory processes and by modifying cerebral metabolism. The brain’s limited ability to store oxygen and glucose means that its supply must be continuous if neuronal damage is to be avoided. Ischaemic cerebral damage is the most important pathological mechanism in patients with stroke, subarachnoid haemorrhage and traumatic brain injury. Significant traumatic brain injury causes widespread derangement of cerebral physiology, including changes in cerebral blood flow, autoregulation and cerebral energy dynamics. This article outlines the effect of anaesthesia on cerebral physiology and reviews the pathophysiology of traumatic brain injury and subarachnoid haemorrhage.     

Applied cerebral physiology

This article reviews cerebral metabolism and blood flow, and the pressure dynamics within the cranial cavity. The brain functions within the confines of the cranial cavity and it is important to understand the dynamics of the parenchyma, cerebrospinal fluid and blood in relation to intracranial pressure (ICP) and metabolic needs. It requires an uninterrupted supply of oxygen and glucose to maintain its basal energy requirements and these are increased during periods of enhanced activity. Cerebral blood flow (CBF) is therefore critical for normal cerebral function. Its control is dictated by local intrinsic metabolic needs as well as extraneous factors such as arterial blood pressure, arterial carbon dioxide and oxygen tension, temperature and neural factors; all of which can be measured to guide therapy.     

Applied cerebral physiology

The brain uses large amounts of glucose for its basal energy requirements, and these are further increased during cerebral activation. In order that glucose can provide this energy, a plentiful and uninterrupted supply of oxygen is necessary. Cerebral blood flow is therefore critical for normal cerebral function. Its control is dictated by local intrinsic metabolic needs as well as extraneous factors such as arterial blood pressure, arterial carbon dioxide and oxygen tension, temperature and neural factors. This article reviews cerebral metabolism and cerebral blood flow and techniques by which both can be monitored.     

Applied cerebral physiology

The brain uses large amounts of glucose for its basal energy requirements, and these are further increased during cerebral activation. In order that glucose can provide this energy, a plentiful and uninterrupted supply of oxygen is necessary. Cerebral blood flow is therefore critical for normal cerebral function. Its control is dictated by local intrinsic metabolic needs as well as extraneous factors such as arterial blood pressure, arterial carbon dioxide and oxygen tension, temperature and neural factors. This article reviews cerebral metabolism and cerebral blood flow and techniques by which both can be monitored.     

Applied cerebral physiology

The brain is an exquisitely sensitive organ, requiring a constant supply of blood, oxygen, and glucose to function. Cerebral blood flow is autoregulated to provide a near constant blood supply despite fluctuations in whole body physiology. The blood–brain barrier acts to ensure that the brain microenvironment remains tightly regulated. The pressure within the cranium must also be tightly controlled to maintain optimal cerebral perfusion and ultimately prevent herniation of brain parenchyma. Several physiological parameters can be monitored including intracranial pressure, cerebral oxygenation and metabolic stress and clinical use is increasing including in traumatic brain injury and subarachnoid haemorrhage patients.     

Negative BOLD with large increases in neuronal activity

Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used in neuroscience to study brain activity. However, BOLD fMRI does not measure neuronal activity directly but depends on cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO(2)) consumption. Using fMRI, CBV, CBF, neuronal recordings, and CMRO(2) modeling, we investigated how the signals are related during seizures in rats. We found that increases in hemodynamic, neuronal, and metabolic activity were associated with positive BOLD signals in the cortex, but with negative BOLD signals in hippocampus. Our data show that negative BOLD signals do not necessarily imply decreased neuronal activity or CBF, but can result from increased neuronal activity, depending on the interplay between hemodynamics and metabolism. Caution should be used in interpreting fMRI signals because the relationship between neuronal activity and BOLD signals may depend on brain region and state and can be different during normal and pathological conditions.     

Coupling of function,metabolism, and blood flow in the brain

Functional activity, metabolism and blood flow are locally heterogeneous in the brain, but tightly coupled. This adjustment occurs in two different ways: 1. Shortterm, dynamic coupling mediated by local vasoactive factors that ensure second-to-second regulation. 2. Long-term, static coupling apparently mediated by capillary density and developed in response to local functional and metabolic activity. Recognizing these two mechanisms permits one to distinguish apparent from real uncoupling. It allows the conclusion that there is no indication of an uncoupling of metabolism and blood flow during physiological conditions.     

The clinical role of PET in cerebrovascular disease

In normal subjects cerebral oxygen metabolism and blood flow are closely coupled, both grey and white matter extracting about 40% of their arterial oxygen supply. During acute ischaemia blood flow falls and oxygen extraction rises to 100% so that cerebral metabolism becomes totally blood flow dependent. Once acute infarction has occurred both cerebral oxygen metabolism and arterial oxygen extraction fall to low levels, while blood flow often paradoxically rises — the state of luxury perfusion. Once luxury perfusion becomes established the use of pharmacological or surgical methods to increase cerebral blood flow is inappropriate. PET will measure regional cerebral metabolism and blood flow non-invasively in man. Using PET ischaemic tissue can be distinguished from infarcted tissue, and the presence of luxury perfusion can be confirmed. In this way strokes in evolution can be detected, and the use of revascularisation procedures rationalised.Not only are regional cerebral metabolism and blood flow closely coupled, but blood volume is also coupled to blood flow. When >60% stenosis of extracranial arteries occurs, reactive vasodilatation of the distal circulation with an increase in rCBV results in order to reduce vascular resistance. By monitoring rCBV with PET, haemodynamically compromised regions of brain can be detected. It has been shown that patients with local areas of raised rCBV due to carotid artery stenosis are at a higher risk of infarction. PET will identify such patients and follow the haemodynamic effects of endarterectomy or EC-IC bypass.Finally PET can look at the distant functional effects of lacunar infarction. In this way more information about the functional anatomy of the brain can be obtained, and mechanisms of functional recovery from stroke can be monitored.     

What will jugular bulb oxygen saturation monitoring tell?]

Global cerebral oxygenation can be measured by means of a catheter introduced in the internal jugular vein and placed retrograde in the jugular bulb. The measure of oxygen saturation sampled from the jugular vein (SjvO2) depends on cerebral metabolism and blood flow. This parameter describes the relative balance between oxygen delivery to the brain and oxygen consumption by the brain. SjvO2 remains normal until cerebral blood flow is proportional to cerebral metabolic demands. Any disturbances that increase cerebral metabolism and/or diminishes cerebral oxygen supply determines a reduction of SjvO2. Correspondingly, a decrease of oxygen consumption and/or an increase of oxygen supply may induce an increase of SjvO2. Therefore, SjvO2 is a useful monitor to assess the adequacy of cerebral circulation in patients with neurologic illness, allowing detection of state of hypoperfusion. Monitoring cerebral oximetry in comatose patients is of great importance in order to prevent, detect, control and understand secondary brain insults and damage which are mainly ischemic/hypoxic in nature. Although SjvO2 was shown to be highly sensitive in the presence of global hypoxia or ischemia, the occurrence of focal ischemia may still go undetected. Besides this, elevated SjvO2 should not be universally interpreted as hyperaemia. Instead, the presence of an elevated SjvO2 is a heterogeneous condition. Increased SjvO2 may be alarming prognostic indicators that carry important implications for comatose patients management.     

Effects of metabolic pH–alterations on cerebral blood flow and oxygen uptake following E. coli endotoxin in dogs

The aim of the present study was to investigate if metabolic pH–alterations have an influence on cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRo₂) after an injection of E. coli endotoxin. Following endotoxin in dogs with normal pH a decreased CBF and an increased CMRo₂ have earlier been found. Thirteen anaesthetized dogs were subjected to metabolic pH–variations in blood by infusion of hydrochloric acid or sodium bicarbonate. Ten dogs received E. coli endotoxin in a dose of 1 mg kg"' bodyweight. CBF, CMRo₂ and noradrenaline and adrenaline concentrations in blood and cerebrospinal fluid were measured repeatedly during normoxia and normocarbia. Measurements before endotoxin served as controls, together with three additional animals, where endotoxin was never given. In control measurements pH showed no influence on the variables studied. After endotoxin CBF, CMRo₂ and noradrenaline in cerebrospinal fluid increased with decreasing arterial blood pH. The influence exerted by metabolic pH alterations in blood after endotoxin may be explained by hydrogen ions and monoamines passing over a blood–brain barrier (BBB), damaged by endotoxin, into the brain tissue causing vasodilation and neuronal activation.     

Alterations in cerebral metabolic rate and blood supply across the adult lifespan

With age, the brain undergoes comprehensive changes in its function and physiology. Cerebral metabolism and blood supply are among the key physiologic processes supporting the daily function of the brain and may play an important role in age-related cognitive decline. Using MRI, it is now possible to make quantitative assessment of these parameters in a noninvasive manner. In the present study, we concurrently measured cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), and venous blood oxygenation in a well-characterized healthy adult cohort from 20 to 89 years old (N = 232). Our data showed that CMRO(2) increased significantly with age, while CBF decreased with age. This combination of higher demand and diminished supply resulted in a reduction of venous blood oxygenation with age. Regional CBF was also determined, and it was found that the spatial pattern of CBF decline was heterogeneous across the brain with prefrontal cortex, insular cortex, and caudate being the most affected regions. Aside from the resting state parameters, the blood vessels' ability to dilate, measured by cerebrovascular reactivity to 5% CO(2) inhalation, was assessed and was reduced with age, the extent of which was more prominent than that of the resting state CBF.     

Intracranial pressure and cerebral haemodynamics

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. Monro–Kellie 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 pressure–volume 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.     

Pathophysiology of traumatic brain injury

The knowledge of the pathophysiology after traumatic head injuryis necessary for adequate and patient-oriented treatment. Asthe primary insult, which represents the direct mechanical damage,cannot be therapeutically influenced, target of the treatmentis the limitation of the secondary damage (delayed non-mechanicaldamage). It is influenced by changes in cerebral blood flow(hypo- and hyperperfusion), impairment of cerebrovascular autoregulation,cerebral metabolic dysfunction and inadequate cerebral oxygenation.Furthermore, excitotoxic cell damage and inflammation may leadto apoptotic and necrotic cell death. Understanding the multidimensionalcascade of secondary brain injury offers differentiated therapeuticoptions.     

Cerebral Blood Flow and Oxygen Metabolism During Mild Hypothermia in Patients with Subarachnoid Haemorrhage

Cerebral blood flow and O2 metabolism during hypothermia (33-34 degrees C) was evaluated in 5 patients with aneurysmal subarachnoid haemorrhage by positron emission tomography (PET). Their preoperative clinical condition was WFNS scale IV or V. The patients received surface cooling postoperatively, and were maintained in a hypothermic state during transfer for radiological examination. Positron emission tomography revealed a decrease in cerebral blood flow and O2 metabolic rate. Cerebral blood flow was 34.8+/-15.1 ml/100 ml/min and the O2 metabolic rate was 1.85+/-0.61 ml/100 ml/min in areas of the middle cerebral artery ipsilateral to the ruptured aneurysms, whereas these values were 30.8+/-7.1 and 2.21+/-0.45 ml/100 ml/min, respectively, on the contralateral side. This represents a decrease of 37+/-27% compared to normal cerebral blood flow and 52+/-16% compared to normal O2 metabolic rate (p < 0.02) in the ipsilateral areas, and decreases of 44+/-13% and 43+/-12%, respectively, on the contralateral side. The present results reflected the luxury perfusion state in almost all cases and provide the first PET evidence of decreased cerebral blood flow and metabolic rate of O2 during hypothermia in humans.     

Intracranial pressure and cerebral haemodynamics

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. Monro–Kellie 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 pressure–volume 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.     

Cerebral glucose and energy metabolism,cerebral oxygen consumption,and blood flow in arterial hypoxaemia

Summary The influence of moderately reduced arterial oxygen tension (aPO₂ of about 45 Torr) on the metabolism and the blood flow of the brain was tested in 20 anaesthetized, artificially ventilated normotensive, normocapnic beagle dogs. It is demonstrated that the decrease in systemic oxygen delivery to the brain is countered by an appropriate increase in flow (CBF being 60.3 ml/100 g min at normoxia and 84.5 mg/100 g min m hypoxaemia) which maintained the cerebral oxygen consumption unchanged (CMRO₂ 3.80 versus 3.32 ml/100 g min). The cortical tissue content of energy-rich phosphates such as ATP, ADP, AMP, and phosphocreatine was also found to be unaltered. Neuropathological examinations excluded any hypoxic cell damage. This reactive vasodilatory reaction of the cerebral vessels is apparently a sensitive regulatory process which protects the brain against marked oxygen lack. However, a normal carbohydrate metabolism is not restored by this cerebrovascular mechanism. For, significantly increased CMRlactate (0.32 versus 1.46 ml/100 g min) indicated raised cerebral glycolysis, and the tissue metabolites of glucose suggested an increased glycolytic flux in the brain. It is concluded that in moderate arterial hypoxaemia, which is not uncommon in clinical practice, cerebral blood flow plays an effective homeostatic role in preventing a disturbance of the energy metabolism of the brain.     

Perioperative neuroprotection

The endpoint of all cerebral injuries like stroke, global cerebral ischemia during cardiac arrest, cardiac, vascular, or brain surgery or head trauma is the inadequate supply of the brain with oxygen and glucose, which triggers a characteristic pathophysiologic cascade leading to neuronal death. Many methods and agents have been investigated to produce neuroprotection from cerebral ischemia along this cascade (e.g., hypothermia, anaesthetics, free radical scavengers, excitatory amino acid antagonists, calcium channel blockers, ionic pump modulators, growth factors, heparinization, antineutrophil/platelet factors, steroids, and gene products). However, essentially none of the pharmacological approaches was identified as useful in humans though most agents have been successfully tested in animal models. Expert opinion suggests that neuroprotective approaches have failed in human trials because there are multiple mechanisms of injury from local and cerebral ischemia. Furthermore, adequate timing might essential because of the temporal sequence of cerebral injury. However, because there are multiple mechanisms of injury, there are most likely also multiple mechanisms of neuroprotection. The most important strategy is profound knowledge on cerebral physiology and homeostasis in health and disease. This review discusses essential physiological mechanisms to warrant adequate supply of glucose and oxygen to the brain. In addition, the influence of potential neuroprotective strategies and agents are reviewed in the perioperative setting.     

Applied cerebrovascular physiology

The understanding and manipulation of cerebrovascular physiology is essential in the management of head injuries and anaesthesia for neurosurgery. The high metabolic requirements (20% of basal oxygen and 25% of basal glucose consumption) and blood flow (15% of the cardiac output) emphasize the need to ensure adequate substrate delivery for the production of energy to transmit electrical impulses and maintain ionic gradients across cell membranes. The cerebral microenvironment is responsible for a blood-brain barrier with unique properties affecting ionic and fluid distribution, active transport mechanisms and drug distributions. The rigid cranium with its contents of parenchyma, CSF, blood and interstitial fluid creates pressure and volume relationships with implications in pathological processes as well as targets for therapy. Physiological determinants of cerebral blood flow and volume include flow-metabolism coupling, autoregulation, carbon dioxide and oxygen arterial tensions, temperature, haematocrit, venous pressures, and the autonomic nervous system. Local metabolic control of regional cerebral blood flow is mediated by actions on vascular tone (vasodilators and vasoconstrictors). The roles of nitric oxide, prostaglandins, adenosine, cations (potassium and calcium) and endothelin are noteworthy. Estimations of cerebral blood flow and oxygenation are essential to assess and to manipulate cerebrovascular physiology. Global and local techniques are briefly discussed including the Kety-Schmidt technique, xenon-133 washout, imaging (dynamic CT, SPECT, PET, and fMRI) jugular venous oximetry, transcranial Doppler, brain tissue oxygenation and intracerebral microdialysis.