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Pharmacological and pathological modulation of cerebral physiology
NEUROSURGICAL ANAESTHESIA AND INTENSIVE CARE
to correlate with a jugular venous desaturation less than 50%. The longer the period of low PbO2, the greater the likelihood of an adverse outcome. Limitations include the extremely localized measurement and the position of the probe (contusion versus healthy brain).
Pharmacological and pathological modulation of cerebral physiology
Intracerebral microdialysis By monitoring cerebral metabolism, assumptions can be made about the adequacy of cerebral oxygenation and blood flow. A fine catheter with a dialysis membrane perfused with compound sodium chloride (Ringer’s solution) is inserted, either through a cranial access bolt or directly at the time of surgery, into the brain parenchyma. Substances in the brain extracellular fluid pass passively down their concentration gradients, across the semipermeable membrane. The lactate:pyruvate ratio reflects regional oxygen availability, and has been correlated with outcome. Microdialysis can also be used to measure levels of other metabolites and biologically important molecules. However, the technique of intracerebral microdialysis looks at only a localized area of brain.
Alison S Cunningham David K Menon
Anaesthetic agents, interventions and disease processes can all affect cerebral physiology. Understanding these effects is crucial to provide the safest possible operating conditions for neurosurgery and for optimal management of patients with cerebral pathology.
Pharmacological modulation of cerebral physiology Drugs used in anaesthetic practice can cause changes in cerebral perfusion pressure, cerebral blood flow (CBF) cerebral metabolic rate of oxygen utilization (CMRO2), cerebral blood volume (CBV), intracranial pressure (ICP) and the production and absorption of CSF (Figure 1).
Use of techniques Clinically, the cerebral perfusion pressure is the most commonly monitored variable assessing the adequacy of cerebral perfusion in head-injured patients. Increasing use is being made of continuous fibre-optic jugular venous oximetry and transcranial Doppler measurement of middle cerebral artery flow velocity. Research tools, intracerebral microdialysis and brain tissue oxygen measurement are seeing much wider use in specialist centres. Monitoring of the processed EEG and evoked potentials, provides information regarding the consequences of reduced cerebral blood flow (e.g. during carotid endarterectomy surgery).
Inhalational anaesthetic agents Volatile anaesthetic agents: all the fluorinated anaesthetic agents have effects on CMRO2, CBV, CBF and possibly ICP. They decrease CMRO2 in a dose-related manner, to a lower limit governed by the extent of metabolic suppression produced by the agent (Figure 2). It was thought that these agents caused ‘uncoupling’ of flowmetabolism, but recent studies have shown that, at clinically used concentrations, flow–metabolism coupling is maintained. However, owing to intrinsic vasodilatory effects, increasing concentrations of the inhalational agents increase the gradient of the flow–metabolism relationship (Figure 3). Changes in CBF thus reflect the balance of direct vasodilatory properties and metabolic suppression, though baseline physiology and other pharmacological agents can markedly affect the changes in CBF and CMRO2. CO2 reactivity is preserved in the healthy brain and hypocapnia attenuates the increases in CBF, while hypercapnia causes a more rapid increase in CBF. Increases in CBV as a result of vasodilatation increase brain volume, and can lead to clinically significant increases in ICP in patients with already increased intracranial volume. The inhalational agents impair autoregulation in a dosedependent manner, with CBF becoming increasingly dependent on mean arterial pressure.
FURTHER READING Fitch W. Physiology of the cerebral circulation. In: Moss E, Ellis F R, eds. Bailliere’s clinical anaesthesiology. Vol. 13 (4). London: Bailliere Tindall, 1999; 487–98. Johnston A J, Gupta A K. Advanced monitoring in the neurology intensive care unit: microdialysis. Curr Opin Crit Care 2002; 8: 121–7. Matta B F, Menon D K, Turner J M, eds. Textbook of neuroanaesthesia and critical care. London: Greenwich Medical Media, 2000. Menon D K. Cerebral circulation. In: Priebe H-J, Skarvan K, eds. Cardiovascular physiology. 2nd ed. London: BMJ Publishing Group, 2000; 240–77. Zauner A, Daugherty W P, Bullock M R et al. Brain oxygenation and energy metabolism: Part I – Biological function and pathophysiology. Neurosurgeryy 2002; 51: 289–302.
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Alison S Cunningham is Specialist Registrar at Addenbrooke's Hospital, Cambridge. She qualified f from Manchester University and trained in anaesthesia in Manchester before f joining the Anglia Registrar Rotation. David K Menon is Professor of Anaesthesia at the University of Cambridge and Consultant in the Neurosciences Critical Care Unit at Addenbrooke’s Hospital, Cambridge. He trained at the Jawaharlal Institute, India, Leeds General Infirmary, The Royal Free Hospital and Addenbrooke’s Hospital. His research interests include mechanisms of secondary neuronal injury, metabolic imaging of acute brain injury and imaging anaesthetic action in the brain.
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Effects of anaesthetic agents on cerebral physiology CBF
ICP
CMRO2
Autoregulation CO2 reactivity
CSF production
CSF absorption
Intravenous anaesthetics Thiopental Etomidate Propofol Ketamine
D D D I
D D D I
D D D I
N N N N
N N N N
N N N N
N N N D
Inhalational agents Halothane Enflurane Isoflurane Sevoflurane Desflurane
I I I/D1 I/D1 I
I I I I I
D D D D D
Impaired Impaired Impaired Impaired Impaired
N N N N N
D D I N N
Nitrous oxide Xenon
I I
I I
D ?
N ?
N ?
D I D D I (prolonged delivery) N ?
Benzodiazepines
D
D
D
N
N
N
N
Muscle relaxants Non-depolarizing Suxamethonium
N I
N I
N N
N N
N N
N
N
Opioids (IPPV) Fentanyl Alfentanil Remifentanil Morphine
N/D2 N N/D2 N
N/I3 N/I3 N N
N/D2 N N/D2 N
N N N N
N N N N
N N N N
All produce small increase in CSF absorption at low doses
Opioids (SV)
I
I
N
N
N
N
Others Vasodilators Mannitol α2-agonists Anticholinesterase Nimodipine
I N D N I
I D D N I
N N D N N
Impaired N N N N
N N Impaired N N
N D N N N
N ?
N N N N N
CBF cerebral blood flow, ICP intracranial pressure, CMRO2 cerebral metabolic rate of oxygen utilization, I increased, D decreased, N no effect, ? unknown/uncertain. 1 At lower concentrations CBF is decreased; at higher concentrations it is increased. 2At high doses may decrease CBF and CMRO2. 3In large bolus doses may cause rise in ICP.
1
Enfluranee at low concentrations has effects similar to isoflurane. At higher concentrations epileptiform EEG activity may occur, particularly in the presence of hypocapnia. It is seldom used for neuroanaesthesia. Halothanee – the dose-related decrease in CMRO2 is less with halothane than with other inhalational agents. Halothane is a potent vasodilator and CBF is increased to a greater extent particularly in cortical regions. Thus, halothane has a greater effect on the gradient of flow–metabolism coupling. Clinically significant increases in ICP can occur in patients with decreased cerebral compliance. Although these changes can be attenuated by induced hypocapnia (unlike for isoflurane) this must be induced before the addition of halothane. Sevofluranee may have advantages over isoflurane for neuroanaesthesia. Sevoflurane enables more rapid onset of, and emergence from, anaesthesia and there is evidence that it causes less
Isofluranee has been considered the inhalational agent of choice for neuroanaesthesia because it produces less cerebral vasodilatation than other agents, except possibly sevoflurane.1 At low doses, global CMRO2 and CBF are reduced, and there is minimal impairment of autoregulation. Metabolic suppression is greater in cortical regions. At higher concentrations, CBF is increased secondary to vasodilatation, and the gradient of flow–metabolism coupling is increased. At minimum alveolar concentrations (MAC) over 1.5, autoregulation is impaired and CBF and ICP rise. These changes can be attenuated by induced hypocapnia. At MAC over 2 an isoelectric EEG can be achieved. Isoflurane is the only volatile agent that has been shown to increase CSF reabsorption and decrease production. Numerous studies in animals and in vitro models of global and focal brain ischaemia have demonstrated a neuroprotective effect of isoflurane, though the mechanisms responsible remain unclear. These effects have not been replicated in humans.
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induced before or at the time of the administration of desflurane. Cerebral autoregulation is impaired at a lower MAC than for sevoflurane. Some studies have shown clinically significant increases in ICP with prolonged administration; possibly because of an increase in CSF production. Like isoflurane, high-dose desflurane can produce EEG burst suppression, though this effect may be attenuated over time. Nitrous oxide is a more potent vasodilator than the volatile agents at equi-MAC doses. Used alone, it increases CBF and CMRO2, the flow–metabolism relationship being preserved. Increases in CBV can lead to clinically significant increases in ICP in patients with decreased cerebral compliance. The vasodilatation produced by nitrous oxide is not attenuated by induced hypocapnia. When combined with low concentrations of volatile agents, nitrous oxide counteracts the decrease in CBF, and can increase CBF to a level greater than that in the baseline awake state. At higher concentrations of volatile agent it appears to act synergistically in increasing CBF. Recent studies of sevoflurane and nitrous oxide have observed a decrease in oxygen extraction fraction suggesting that flow–metabolism coupling is disturbed.2 Nitrous oxide attenuates the decreases in CBF and CMRO2 produced by propofol or thiopental, though these remain below baseline values and the flow–metabolism relationship appears to be maintained.2 Xenon – there has been renewed interest in the use of xenon as an anaesthetic agent, following concerns about the environmental effects of nitrous oxide. Xenon may have advantages for neuroanaesthesia; including rapid induction and emergence due to a low blood gas coefficient, and possible neuroprotective effects (in animal studies of focal ischaemia), probably via NMDA antagonism. However, there has been limited research into its effects on CBF, CMRO2 and ICP, and it remains relatively expensive.
Effect of fluorinated volatile anaesthetic agents on cerebral blood flow (CBF) and cerebral metabolic rate of oxygen utilization (CMRO2) Halothane Enflurane Isoflurane Sevoflurane Desflurane Relative changes in CBF and CMRO2 from baseline CMRO2
CBF
2 vasodilatation than the other inhalational agents.1 Up to 1.5 MAC, autoregulation is maintained and there is little effect on ICP. There is some evidence that sevoflurane at high concentrations can produce epileptiform activity on the EEG. Desfluranee – it was thought that the effects of desflurane on the cerebral circulation were similar to those of isoflurane, but recent studies have shown differences between them.1 In common with other inhalational agents, desflurane causes a dose-dependent decrease in CMRO2. However, it is a more potent vasodilator and increases in CBF are greater than for isoflurane or sevoflurane, especially at high concentrations. This can be attenuated by hypocapnia,
Effect of drugs used in anaesthetic practice and hypocapnia on cerebral metabolic rate and cerebral blood flow Nitrous oxide Hypocapnia Total cerebral metabolic rate for oxygen (CMRO2) 5 ml/100 g brain/minute Lowest level (isoelectric EEG)
Ketamine (limbic system) Benzodiazepines Opioids
Barbiturates Propofol Etomidate
Decreased CBF
Ketamine (total CBF)
Increasing doses of inhalational anaesthetics Increased MAC leads to increased CBF after an initial decrease in CBF Cerebral blood flow (CBF) 50 ml/100 g brain/minute
Increased CBF
Hyperventilation and the resulting hypocapnia can lead to vasoconstriction (decreased CBF) and an increase in CMRO2, which is a particularly unfavourable situation. Increasing the inhalational anaesthetic agent concentration (minimum alveolar concentration – MAC) does not decrease CMR below a lower limit. However, it does increase CBF thereby increasing cerebral blood volume and intracranial pressure. This is hazardous for patients with poor intracranial compliance
3
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Intravenous anaesthetic agents Barbiturates – in common with propofol and etomidate, thiopental causes a coupled reduction in CMRO2 and CBF, and a decrease in CBV (Figure 3). Autoregulation and CO2 responsiveness are not affected. Thiopental causes a dose-dependent reduction of global CMRO2 to a minimum of 50% baseline, corresponding to an isoelectric EEG (the non-suppressible remainder of CMRO2 being required for maintenance of cellular integrity). Thiopental may have neuroprotective effects in focal ischaemia and during cardiac surgery, but there is less evidence of neuroprotection in global ischaemia. Propofol has favourable effects on cerebral haemodynamics. Progressive reductions in CBF are coupled to reduction of CMRO2, and autoregulation and CO2 responsiveness are maintained. EEG burst suppression and an isoelectric EEG can be achieved. However, propofol is a potent systemic vasodilator, it is cardiodepressant and can lead to significant falls in mean arterial pressure; consequently cerebral perfusion pressure can be compromised. In vitro and animal studies indicate propofol may have significant neuroprotective effects in focal and global ischaemia, but evidence from human clinical trials is lacking. Etomidatee – the effects of etomidate on CMRO2 and CBF are similar to those of the barbiturates and propofol. Burst suppression and an isoelectric EEG can be achieved. Etomidate may cause myoclonus in some patients, can elicit seizure activity and causes adrenal suppression (evident after a single induction dose); these disadvantages have limited its use. However, because it has less cardiovascular depressant activity, it is the drug of choice if the maintenance of mean arterial pressure at induction is crucial. Ketaminee – the effects of ketamine on CNS physiology have limited its use in neuroanaesthesia and neurocritical care. Ketamine produces global increases in CBF and ICP, and regionally specific increases in CMRO2 (particularly in limbic structures). These changes can be attenuated by hypocapnia, or the administration of benzodiazepines or thiopental. Autoregulation and CO2 responsiveness appear to be maintained. CSF absorption is impaired by ketamine. Recently there has been renewed interest in the possible neuroprotective properties of ketamine (which appear to be related primarily to NMDA antagonism), and in particular the stereoisomer S+ ketamine, which has fewer adverse effects than the racemic mixture, and appears to have greater neuroprotective efficacy.
effect is not significant when these agents are administered slowly to euvolaemic patients. All the opioids maintain CO2 reactivity and autoregulation, and at low doses increase CSF absorption. Neuromuscular blocking agents All the commonly used non-depolarizing neuromuscular blocking agents have little effect on CBF or CMRO2. Suxamethonium can increase ICP and CBF, but these increases are transient and clinically insignificant and should not preclude its use in neurosurgical patients. Other drugs Vasodilators, such as nitrates and sodium nitroprusside, impair autoregulation, increase CBF and CBV in the absence of hypertension, and predispose to raised ICP. When autoregulation is impaired, vasopressors increase cerebral perfusion pressure, CBF and CBV. However, in the presence of intact autoregulation, increases in cerebral perfusion pressure result in reductions in CBV and ICP. α2-agonists (e.g. clonidine, dexmedetomidine) reduce CBF if there is no significant decrease in arterial pressure; CMRO2 may also be reduced and CO2 reactivity is attenuated. Mannitol decreases ICP by improving microcirculatory flow and oxygen delivery, which decreases CBV secondary to reflex vasoconstriction; it also reduces brain water, thereby reducing intracranial volume.
Effects of anaesthetic interventions on cerebral physiology Laryngoscopy, intubation and extubation can cause sudden increases in mean arterial pressure leading to increases in CBF and ICP. Increased intrathoracic pressures such as with intermittent positive-pressure ventilation (IPPV), positive end-expiratoty pressure (PEEP) and coughing, increase central venous pressures and lead to decreased venous drainage and CSF absorption and thus elevated ICP. Cerebral venous drainage is also reduced by obstruction of jugular veins (e.g. by neck rotation or tube ties), and head-down positioning. Head-up positioning reduces ICP but can also reduce CPP; 30° head-up positioning may provide the optimal balance. Hyperventilation causes vasoconstriction and reduced CBV and ICP, but CBF is also reduced, which may precipitate or worsen ischaemia.
Pathological modulation of cerebral physiology
Benzodiazepines The benzodiazepines produce small decreases in CBF, CMRO2 and ICP and preserve autoregulation and CO2 responsiveness. However, these effects are less marked than with the intravenous anaesthetic agents, and a ceiling effect occurs. An isoelectric EEG cannot be achieved nor can EEG burst suppression. All the benzodiazepines are anticonvulsant and increase seizure threshold.
Ischaemia Graded reductions in CBF are associated with specific electrophysiological and metabolic consequences (Figure 4). Cell death is not merely a function of the severity of ischaemia, but also depends on its duration and other circumstances that modify its effects. Thus, the effects of ischaemia may be ameliorated by the cerebral metabolic suppression produced by hypothermia or drugs, or exacerbated by the increased metabolic demand associated with excitatory neurotransmitter release or other mechanisms of secondary neuronal injury.
Opioids If ventilation is not controlled, use of opioids can lead to respiratory depression and hypercapnia, and consequent increases in CBF, CBV and ICP. During controlled ventilation low doses of opioids have little effect on CBF and CMRO2; at high doses some studies have shown CBF and CMRO2 to be decreased by fentanyl. Rises in ICP may occur after bolus administration of fentanyl or alfentanil; probably due to autoregulatory vasodilatation of cerebral vessels following an initial decrease in cerebral perfusion pressure. This
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Head injury Head injury causes changes in CBF and metabolism that vary temporally and spatially. Soon after the initial injury, CBF is typically reduced, and reductions are associated with an unfavourable outcome: studies have shown 100% mortality at 48 hours following
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barrier. There is extravasation of plasma, protein and red blood cells from the vasodilated vessels, resulting in cerebral oedema and petechial damage.
Blood flow thresholds for physiological processes in cerebral ischaemia Cerebral blood flow (ml/100 g brain/minute) >50 ? ? ? 20–23 12–18 8–10 <8
Electrophysiological/metabolic consequences Normal neuronal function Immediate early gene activation Cessation of protein synthesis Cellular acidosis Reduction in electrical activity Cessation of electrical activity ATP rundown, loss of ionic homeostasis Cell death (also depends on other modifiers, such as duration and metabolic rate)
Subarachnoid haemorrhage After subarachnoid haemorrhage, cerebral autoregulation and CO2 responsiveness are grossly distorted, more so in patients with poorer clinical grades. Patients may be unable to compensate for reductions in mean arterial pressure, and develop clinically significant neurological deficits. In the past, the main cause of morbidity and mortality, excluding the initial haemorrhage, was rebleeding. However, early clipping has reduced this problem and cerebral vasospasm is now a major cause of disability or death, killing 7% of patients and causing severe neurological deficits in a further 7%.4 Delayed ischaemia, conventionally attributed to vasospasm, typically occurs several days after the initial bleed and causes decreased CBF and CMRO2 in affected regions. The exact pathophysiology is unknown though experimental evidence suggests that red cell haemolysis of extravasated blood leads to the formation of ferrous haemoglobin, which acts as a nitric oxide scavenger, and reactive oxygen species, which may cause lipid peroxidation of vessel walls. Thus, the incidence of vasospasm appears to correlate with the severity of the bleed. The mainstays of treatment are the calcium-channel blocker, nimodipine, and triple-H therapy (hypertensive, hypervolaemic haemodilution). Nimodipine significantly reduces the number of patients with poor outcome after subarachnoid haemorrhage. A randomized controlled trial has never been undertaken, but studies have shown triple-H therapy improves outcome; hypertension protects non-autoregulating parts of the cerebral circulation from hypoperfusion; and haemodilution improves flow and oxygen delivery. Recent meta-analyses have concluded that antiplatelet therapy reduces the risk of delayed ischaemic deficit after subarachnoid haemorrhage; a randomized controlled trial is awaited.
4
global hypoperfusion and significant neurological deficits following regional hypoperfusion. The mechanisms responsible for this decrease in CBF have not been fully elucidated. Initial decreases in CBF are followed, especially in patients who achieve good outcomes, by a period of relative increase in CBF. Towards the end of the first week after injury there may be another decrease in CBF due to vasospasm associated with tra matic subarachnoid haemorrhage. Changes in CBF are non-uniform in the injured brain. CBF tends to be reduced in perilesional areas, though it may also be reduced in structurally normal brain. Thus, global monitors of cerebrovascular adequacy may not reflect regional hypoperfusion or hyperperfusion, and interventions such as hyperventilation may worsen ischaemia in hypoperfused regions without this being reflected by global monitors. After head injury, regional differences in cerebral metabolism occur. There may be uncoupling of CBF and metabolism, and there is evidence of early ischaemia and increased anaerobic oxygen utilization. Elevations in ICP can reduce cerebral perfusion pressure and cause cerebral ischaemia, leading to secondary neuronal damage. Furthermore, impairment of autoregulation is often observed after head injury, and experimental studies suggest that the lower shoulder of the autoregulatory curve is shifted to the right, indicating that a higher than normal cerebral perfusion pressure is required. Although the optimal cerebral perfusion pressure is debated, there is strong evidence that maintaining it above 60 mm Hg provides adequate perfusion for most patients with head injury and improves neurological outcome.3
KEY REFERENCES 1 Holmstom A, Akeson J. Cerebral blood flow at 0.5 and 1.0 MAC desflurane or sevoflurane compared with isoflurane in normoventilated pigs. J Neurosurg Anesthesiol 2003; 15: 90–7. 2 Kaisti K, Langsjo J, Aalto S. Effects of sevoflurane, propofol and adjunct nitrous oxide on regional CBF, oxygen consumption and CBV in humans. Anesthesiologyy 2003; 99: 603–13. 3 Robertson C. Management of cerebral perfusion pressure after traumatic brain injury. Anesthesiologyy 2001; 95: 1513–17. 4 Sen J, Belli A. Triple-H therapy in the management of subarachnoid haemorrhage. Lancett 2003; 614–20.
Hypertension and hypertensive encephalopathy When the blood pressure is chronically elevated, autoregulation is impaired. The autoregulatory range is shifted to the right, and cut-off points for autoregulation are increased. Higher mean arterial pressures are needed for an adequate cerebral perfusion pressure. Current concepts of the causation of hypertensive encephalopathy are based on the forced vasodilatation hypothesis. Severe acute or sustained increases in blood pressure that exceed the cerebral autoregulatory range disrupt the tight junctions of the blood–brain
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FURTHER READING Menon D K. Cerebral circulation. In: Priebe H-J, Skarvan K, eds. Cardiovascular physiology. 2nd ed. London: BMJ Publishing Group, 2000, 240–77. Turner J M. Intracranial pressure. In: Matta B F, Menon D K, Turner J M, eds. Textbook of neuroanaesthesia and critical care. London: Greenwich Medical Media, 2000, 51–64.
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to correlate with a jugular venous desaturation less than 50%. The longer the period of low PbO2, the greater the likelihood of an adverse outcome. Limitations include the extremely localized measurement and the position of the probe (contusion versus healthy brain).
Pharmacological and pathological modulation of cerebral physiology
Intracerebral microdialysis By monitoring cerebral metabolism, assumptions can be made about the adequacy of cerebral oxygenation and blood flow. A fine catheter with a dialysis membrane perfused with compound sodium chloride (Ringer’s solution) is inserted, either through a cranial access bolt or directly at the time of surgery, into the brain parenchyma. Substances in the brain extracellular fluid pass passively down their concentration gradients, across the semipermeable membrane. The lactate:pyruvate ratio reflects regional oxygen availability, and has been correlated with outcome. Microdialysis can also be used to measure levels of other metabolites and biologically important molecules. However, the technique of intracerebral microdialysis looks at only a localized area of brain.
Alison S Cunningham David K Menon
Anaesthetic agents, interventions and disease processes can all affect cerebral physiology. Understanding these effects is crucial to provide the safest possible operating conditions for neurosurgery and for optimal management of patients with cerebral pathology.
Pharmacological modulation of cerebral physiology Drugs used in anaesthetic practice can cause changes in cerebral perfusion pressure, cerebral blood flow (CBF) cerebral metabolic rate of oxygen utilization (CMRO2), cerebral blood volume (CBV), intracranial pressure (ICP) and the production and absorption of CSF (Figure 1).
Use of techniques Clinically, the cerebral perfusion pressure is the most commonly monitored variable assessing the adequacy of cerebral perfusion in head-injured patients. Increasing use is being made of continuous fibre-optic jugular venous oximetry and transcranial Doppler measurement of middle cerebral artery flow velocity. Research tools, intracerebral microdialysis and brain tissue oxygen measurement are seeing much wider use in specialist centres. Monitoring of the processed EEG and evoked potentials, provides information regarding the consequences of reduced cerebral blood flow (e.g. during carotid endarterectomy surgery).
Inhalational anaesthetic agents Volatile anaesthetic agents: all the fluorinated anaesthetic agents have effects on CMRO2, CBV, CBF and possibly ICP. They decrease CMRO2 in a dose-related manner, to a lower limit governed by the extent of metabolic suppression produced by the agent (Figure 2). It was thought that these agents caused ‘uncoupling’ of flowmetabolism, but recent studies have shown that, at clinically used concentrations, flow–metabolism coupling is maintained. However, owing to intrinsic vasodilatory effects, increasing concentrations of the inhalational agents increase the gradient of the flow–metabolism relationship (Figure 3). Changes in CBF thus reflect the balance of direct vasodilatory properties and metabolic suppression, though baseline physiology and other pharmacological agents can markedly affect the changes in CBF and CMRO2. CO2 reactivity is preserved in the healthy brain and hypocapnia attenuates the increases in CBF, while hypercapnia causes a more rapid increase in CBF. Increases in CBV as a result of vasodilatation increase brain volume, and can lead to clinically significant increases in ICP in patients with already increased intracranial volume. The inhalational agents impair autoregulation in a dosedependent manner, with CBF becoming increasingly dependent on mean arterial pressure.
FURTHER READING Fitch W. Physiology of the cerebral circulation. In: Moss E, Ellis F R, eds. Bailliere’s clinical anaesthesiology. Vol. 13 (4). London: Bailliere Tindall, 1999; 487–98. Johnston A J, Gupta A K. Advanced monitoring in the neurology intensive care unit: microdialysis. Curr Opin Crit Care 2002; 8: 121–7. Matta B F, Menon D K, Turner J M, eds. Textbook of neuroanaesthesia and critical care. London: Greenwich Medical Media, 2000. Menon D K. Cerebral circulation. In: Priebe H-J, Skarvan K, eds. Cardiovascular physiology. 2nd ed. London: BMJ Publishing Group, 2000; 240–77. Zauner A, Daugherty W P, Bullock M R et al. Brain oxygenation and energy metabolism: Part I – Biological function and pathophysiology. Neurosurgeryy 2002; 51: 289–302.
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Alison S Cunningham is Specialist Registrar at Addenbrooke's Hospital, Cambridge. She qualified f from Manchester University and trained in anaesthesia in Manchester before f joining the Anglia Registrar Rotation. David K Menon is Professor of Anaesthesia at the University of Cambridge and Consultant in the Neurosciences Critical Care Unit at Addenbrooke’s Hospital, Cambridge. He trained at the Jawaharlal Institute, India, Leeds General Infirmary, The Royal Free Hospital and Addenbrooke’s Hospital. His research interests include mechanisms of secondary neuronal injury, metabolic imaging of acute brain injury and imaging anaesthetic action in the brain.
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Effects of anaesthetic agents on cerebral physiology CBF
ICP
CMRO2
Autoregulation CO2 reactivity
CSF production
CSF absorption
Intravenous anaesthetics Thiopental Etomidate Propofol Ketamine
D D D I
D D D I
D D D I
N N N N
N N N N
N N N N
N N N D
Inhalational agents Halothane Enflurane Isoflurane Sevoflurane Desflurane
I I I/D1 I/D1 I
I I I I I
D D D D D
Impaired Impaired Impaired Impaired Impaired
N N N N N
D D I N N
Nitrous oxide Xenon
I I
I I
D ?
N ?
N ?
D I D D I (prolonged delivery) N ?
Benzodiazepines
D
D
D
N
N
N
N
Muscle relaxants Non-depolarizing Suxamethonium
N I
N I
N N
N N
N N
N
N
Opioids (IPPV) Fentanyl Alfentanil Remifentanil Morphine
N/D2 N N/D2 N
N/I3 N/I3 N N
N/D2 N N/D2 N
N N N N
N N N N
N N N N
All produce small increase in CSF absorption at low doses
Opioids (SV)
I
I
N
N
N
N
Others Vasodilators Mannitol α2-agonists Anticholinesterase Nimodipine
I N D N I
I D D N I
N N D N N
Impaired N N N N
N N Impaired N N
N D N N N
N ?
N N N N N
CBF cerebral blood flow, ICP intracranial pressure, CMRO2 cerebral metabolic rate of oxygen utilization, I increased, D decreased, N no effect, ? unknown/uncertain. 1 At lower concentrations CBF is decreased; at higher concentrations it is increased. 2At high doses may decrease CBF and CMRO2. 3In large bolus doses may cause rise in ICP.
1
Enfluranee at low concentrations has effects similar to isoflurane. At higher concentrations epileptiform EEG activity may occur, particularly in the presence of hypocapnia. It is seldom used for neuroanaesthesia. Halothanee – the dose-related decrease in CMRO2 is less with halothane than with other inhalational agents. Halothane is a potent vasodilator and CBF is increased to a greater extent particularly in cortical regions. Thus, halothane has a greater effect on the gradient of flow–metabolism coupling. Clinically significant increases in ICP can occur in patients with decreased cerebral compliance. Although these changes can be attenuated by induced hypocapnia (unlike for isoflurane) this must be induced before the addition of halothane. Sevofluranee may have advantages over isoflurane for neuroanaesthesia. Sevoflurane enables more rapid onset of, and emergence from, anaesthesia and there is evidence that it causes less
Isofluranee has been considered the inhalational agent of choice for neuroanaesthesia because it produces less cerebral vasodilatation than other agents, except possibly sevoflurane.1 At low doses, global CMRO2 and CBF are reduced, and there is minimal impairment of autoregulation. Metabolic suppression is greater in cortical regions. At higher concentrations, CBF is increased secondary to vasodilatation, and the gradient of flow–metabolism coupling is increased. At minimum alveolar concentrations (MAC) over 1.5, autoregulation is impaired and CBF and ICP rise. These changes can be attenuated by induced hypocapnia. At MAC over 2 an isoelectric EEG can be achieved. Isoflurane is the only volatile agent that has been shown to increase CSF reabsorption and decrease production. Numerous studies in animals and in vitro models of global and focal brain ischaemia have demonstrated a neuroprotective effect of isoflurane, though the mechanisms responsible remain unclear. These effects have not been replicated in humans.
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induced before or at the time of the administration of desflurane. Cerebral autoregulation is impaired at a lower MAC than for sevoflurane. Some studies have shown clinically significant increases in ICP with prolonged administration; possibly because of an increase in CSF production. Like isoflurane, high-dose desflurane can produce EEG burst suppression, though this effect may be attenuated over time. Nitrous oxide is a more potent vasodilator than the volatile agents at equi-MAC doses. Used alone, it increases CBF and CMRO2, the flow–metabolism relationship being preserved. Increases in CBV can lead to clinically significant increases in ICP in patients with decreased cerebral compliance. The vasodilatation produced by nitrous oxide is not attenuated by induced hypocapnia. When combined with low concentrations of volatile agents, nitrous oxide counteracts the decrease in CBF, and can increase CBF to a level greater than that in the baseline awake state. At higher concentrations of volatile agent it appears to act synergistically in increasing CBF. Recent studies of sevoflurane and nitrous oxide have observed a decrease in oxygen extraction fraction suggesting that flow–metabolism coupling is disturbed.2 Nitrous oxide attenuates the decreases in CBF and CMRO2 produced by propofol or thiopental, though these remain below baseline values and the flow–metabolism relationship appears to be maintained.2 Xenon – there has been renewed interest in the use of xenon as an anaesthetic agent, following concerns about the environmental effects of nitrous oxide. Xenon may have advantages for neuroanaesthesia; including rapid induction and emergence due to a low blood gas coefficient, and possible neuroprotective effects (in animal studies of focal ischaemia), probably via NMDA antagonism. However, there has been limited research into its effects on CBF, CMRO2 and ICP, and it remains relatively expensive.
Effect of fluorinated volatile anaesthetic agents on cerebral blood flow (CBF) and cerebral metabolic rate of oxygen utilization (CMRO2) Halothane Enflurane Isoflurane Sevoflurane Desflurane Relative changes in CBF and CMRO2 from baseline CMRO2
CBF
2 vasodilatation than the other inhalational agents.1 Up to 1.5 MAC, autoregulation is maintained and there is little effect on ICP. There is some evidence that sevoflurane at high concentrations can produce epileptiform activity on the EEG. Desfluranee – it was thought that the effects of desflurane on the cerebral circulation were similar to those of isoflurane, but recent studies have shown differences between them.1 In common with other inhalational agents, desflurane causes a dose-dependent decrease in CMRO2. However, it is a more potent vasodilator and increases in CBF are greater than for isoflurane or sevoflurane, especially at high concentrations. This can be attenuated by hypocapnia,
Effect of drugs used in anaesthetic practice and hypocapnia on cerebral metabolic rate and cerebral blood flow Nitrous oxide Hypocapnia Total cerebral metabolic rate for oxygen (CMRO2) 5 ml/100 g brain/minute Lowest level (isoelectric EEG)
Ketamine (limbic system) Benzodiazepines Opioids
Barbiturates Propofol Etomidate
Decreased CBF
Ketamine (total CBF)
Increasing doses of inhalational anaesthetics Increased MAC leads to increased CBF after an initial decrease in CBF Cerebral blood flow (CBF) 50 ml/100 g brain/minute
Increased CBF
Hyperventilation and the resulting hypocapnia can lead to vasoconstriction (decreased CBF) and an increase in CMRO2, which is a particularly unfavourable situation. Increasing the inhalational anaesthetic agent concentration (minimum alveolar concentration – MAC) does not decrease CMR below a lower limit. However, it does increase CBF thereby increasing cerebral blood volume and intracranial pressure. This is hazardous for patients with poor intracranial compliance
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Intravenous anaesthetic agents Barbiturates – in common with propofol and etomidate, thiopental causes a coupled reduction in CMRO2 and CBF, and a decrease in CBV (Figure 3). Autoregulation and CO2 responsiveness are not affected. Thiopental causes a dose-dependent reduction of global CMRO2 to a minimum of 50% baseline, corresponding to an isoelectric EEG (the non-suppressible remainder of CMRO2 being required for maintenance of cellular integrity). Thiopental may have neuroprotective effects in focal ischaemia and during cardiac surgery, but there is less evidence of neuroprotection in global ischaemia. Propofol has favourable effects on cerebral haemodynamics. Progressive reductions in CBF are coupled to reduction of CMRO2, and autoregulation and CO2 responsiveness are maintained. EEG burst suppression and an isoelectric EEG can be achieved. However, propofol is a potent systemic vasodilator, it is cardiodepressant and can lead to significant falls in mean arterial pressure; consequently cerebral perfusion pressure can be compromised. In vitro and animal studies indicate propofol may have significant neuroprotective effects in focal and global ischaemia, but evidence from human clinical trials is lacking. Etomidatee – the effects of etomidate on CMRO2 and CBF are similar to those of the barbiturates and propofol. Burst suppression and an isoelectric EEG can be achieved. Etomidate may cause myoclonus in some patients, can elicit seizure activity and causes adrenal suppression (evident after a single induction dose); these disadvantages have limited its use. However, because it has less cardiovascular depressant activity, it is the drug of choice if the maintenance of mean arterial pressure at induction is crucial. Ketaminee – the effects of ketamine on CNS physiology have limited its use in neuroanaesthesia and neurocritical care. Ketamine produces global increases in CBF and ICP, and regionally specific increases in CMRO2 (particularly in limbic structures). These changes can be attenuated by hypocapnia, or the administration of benzodiazepines or thiopental. Autoregulation and CO2 responsiveness appear to be maintained. CSF absorption is impaired by ketamine. Recently there has been renewed interest in the possible neuroprotective properties of ketamine (which appear to be related primarily to NMDA antagonism), and in particular the stereoisomer S+ ketamine, which has fewer adverse effects than the racemic mixture, and appears to have greater neuroprotective efficacy.
effect is not significant when these agents are administered slowly to euvolaemic patients. All the opioids maintain CO2 reactivity and autoregulation, and at low doses increase CSF absorption. Neuromuscular blocking agents All the commonly used non-depolarizing neuromuscular blocking agents have little effect on CBF or CMRO2. Suxamethonium can increase ICP and CBF, but these increases are transient and clinically insignificant and should not preclude its use in neurosurgical patients. Other drugs Vasodilators, such as nitrates and sodium nitroprusside, impair autoregulation, increase CBF and CBV in the absence of hypertension, and predispose to raised ICP. When autoregulation is impaired, vasopressors increase cerebral perfusion pressure, CBF and CBV. However, in the presence of intact autoregulation, increases in cerebral perfusion pressure result in reductions in CBV and ICP. α2-agonists (e.g. clonidine, dexmedetomidine) reduce CBF if there is no significant decrease in arterial pressure; CMRO2 may also be reduced and CO2 reactivity is attenuated. Mannitol decreases ICP by improving microcirculatory flow and oxygen delivery, which decreases CBV secondary to reflex vasoconstriction; it also reduces brain water, thereby reducing intracranial volume.
Effects of anaesthetic interventions on cerebral physiology Laryngoscopy, intubation and extubation can cause sudden increases in mean arterial pressure leading to increases in CBF and ICP. Increased intrathoracic pressures such as with intermittent positive-pressure ventilation (IPPV), positive end-expiratoty pressure (PEEP) and coughing, increase central venous pressures and lead to decreased venous drainage and CSF absorption and thus elevated ICP. Cerebral venous drainage is also reduced by obstruction of jugular veins (e.g. by neck rotation or tube ties), and head-down positioning. Head-up positioning reduces ICP but can also reduce CPP; 30° head-up positioning may provide the optimal balance. Hyperventilation causes vasoconstriction and reduced CBV and ICP, but CBF is also reduced, which may precipitate or worsen ischaemia.
Pathological modulation of cerebral physiology
Benzodiazepines The benzodiazepines produce small decreases in CBF, CMRO2 and ICP and preserve autoregulation and CO2 responsiveness. However, these effects are less marked than with the intravenous anaesthetic agents, and a ceiling effect occurs. An isoelectric EEG cannot be achieved nor can EEG burst suppression. All the benzodiazepines are anticonvulsant and increase seizure threshold.
Ischaemia Graded reductions in CBF are associated with specific electrophysiological and metabolic consequences (Figure 4). Cell death is not merely a function of the severity of ischaemia, but also depends on its duration and other circumstances that modify its effects. Thus, the effects of ischaemia may be ameliorated by the cerebral metabolic suppression produced by hypothermia or drugs, or exacerbated by the increased metabolic demand associated with excitatory neurotransmitter release or other mechanisms of secondary neuronal injury.
Opioids If ventilation is not controlled, use of opioids can lead to respiratory depression and hypercapnia, and consequent increases in CBF, CBV and ICP. During controlled ventilation low doses of opioids have little effect on CBF and CMRO2; at high doses some studies have shown CBF and CMRO2 to be decreased by fentanyl. Rises in ICP may occur after bolus administration of fentanyl or alfentanil; probably due to autoregulatory vasodilatation of cerebral vessels following an initial decrease in cerebral perfusion pressure. This
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Head injury Head injury causes changes in CBF and metabolism that vary temporally and spatially. Soon after the initial injury, CBF is typically reduced, and reductions are associated with an unfavourable outcome: studies have shown 100% mortality at 48 hours following
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barrier. There is extravasation of plasma, protein and red blood cells from the vasodilated vessels, resulting in cerebral oedema and petechial damage.
Blood flow thresholds for physiological processes in cerebral ischaemia Cerebral blood flow (ml/100 g brain/minute) >50 ? ? ? 20–23 12–18 8–10 <8
Electrophysiological/metabolic consequences Normal neuronal function Immediate early gene activation Cessation of protein synthesis Cellular acidosis Reduction in electrical activity Cessation of electrical activity ATP rundown, loss of ionic homeostasis Cell death (also depends on other modifiers, such as duration and metabolic rate)
Subarachnoid haemorrhage After subarachnoid haemorrhage, cerebral autoregulation and CO2 responsiveness are grossly distorted, more so in patients with poorer clinical grades. Patients may be unable to compensate for reductions in mean arterial pressure, and develop clinically significant neurological deficits. In the past, the main cause of morbidity and mortality, excluding the initial haemorrhage, was rebleeding. However, early clipping has reduced this problem and cerebral vasospasm is now a major cause of disability or death, killing 7% of patients and causing severe neurological deficits in a further 7%.4 Delayed ischaemia, conventionally attributed to vasospasm, typically occurs several days after the initial bleed and causes decreased CBF and CMRO2 in affected regions. The exact pathophysiology is unknown though experimental evidence suggests that red cell haemolysis of extravasated blood leads to the formation of ferrous haemoglobin, which acts as a nitric oxide scavenger, and reactive oxygen species, which may cause lipid peroxidation of vessel walls. Thus, the incidence of vasospasm appears to correlate with the severity of the bleed. The mainstays of treatment are the calcium-channel blocker, nimodipine, and triple-H therapy (hypertensive, hypervolaemic haemodilution). Nimodipine significantly reduces the number of patients with poor outcome after subarachnoid haemorrhage. A randomized controlled trial has never been undertaken, but studies have shown triple-H therapy improves outcome; hypertension protects non-autoregulating parts of the cerebral circulation from hypoperfusion; and haemodilution improves flow and oxygen delivery. Recent meta-analyses have concluded that antiplatelet therapy reduces the risk of delayed ischaemic deficit after subarachnoid haemorrhage; a randomized controlled trial is awaited.
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global hypoperfusion and significant neurological deficits following regional hypoperfusion. The mechanisms responsible for this decrease in CBF have not been fully elucidated. Initial decreases in CBF are followed, especially in patients who achieve good outcomes, by a period of relative increase in CBF. Towards the end of the first week after injury there may be another decrease in CBF due to vasospasm associated with tra matic subarachnoid haemorrhage. Changes in CBF are non-uniform in the injured brain. CBF tends to be reduced in perilesional areas, though it may also be reduced in structurally normal brain. Thus, global monitors of cerebrovascular adequacy may not reflect regional hypoperfusion or hyperperfusion, and interventions such as hyperventilation may worsen ischaemia in hypoperfused regions without this being reflected by global monitors. After head injury, regional differences in cerebral metabolism occur. There may be uncoupling of CBF and metabolism, and there is evidence of early ischaemia and increased anaerobic oxygen utilization. Elevations in ICP can reduce cerebral perfusion pressure and cause cerebral ischaemia, leading to secondary neuronal damage. Furthermore, impairment of autoregulation is often observed after head injury, and experimental studies suggest that the lower shoulder of the autoregulatory curve is shifted to the right, indicating that a higher than normal cerebral perfusion pressure is required. Although the optimal cerebral perfusion pressure is debated, there is strong evidence that maintaining it above 60 mm Hg provides adequate perfusion for most patients with head injury and improves neurological outcome.3
KEY REFERENCES 1 Holmstom A, Akeson J. Cerebral blood flow at 0.5 and 1.0 MAC desflurane or sevoflurane compared with isoflurane in normoventilated pigs. J Neurosurg Anesthesiol 2003; 15: 90–7. 2 Kaisti K, Langsjo J, Aalto S. Effects of sevoflurane, propofol and adjunct nitrous oxide on regional CBF, oxygen consumption and CBV in humans. Anesthesiologyy 2003; 99: 603–13. 3 Robertson C. Management of cerebral perfusion pressure after traumatic brain injury. Anesthesiologyy 2001; 95: 1513–17. 4 Sen J, Belli A. Triple-H therapy in the management of subarachnoid haemorrhage. Lancett 2003; 614–20.
Hypertension and hypertensive encephalopathy When the blood pressure is chronically elevated, autoregulation is impaired. The autoregulatory range is shifted to the right, and cut-off points for autoregulation are increased. Higher mean arterial pressures are needed for an adequate cerebral perfusion pressure. Current concepts of the causation of hypertensive encephalopathy are based on the forced vasodilatation hypothesis. Severe acute or sustained increases in blood pressure that exceed the cerebral autoregulatory range disrupt the tight junctions of the blood–brain
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FURTHER READING Menon D K. Cerebral circulation. In: Priebe H-J, Skarvan K, eds. Cardiovascular physiology. 2nd ed. London: BMJ Publishing Group, 2000, 240–77. Turner J M. Intracranial pressure. In: Matta B F, Menon D K, Turner J M, eds. Textbook of neuroanaesthesia and critical care. London: Greenwich Medical Media, 2000, 51–64.
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