1 University of Cambridge Department of Anaesthetics, Box 93 and 2 Academic Neurosurgery, Addenbrookes Hospital, Cambridge CB2 2QQ, UK
Corresponding author. E-mail: ajj29@cam.ac.uk AJJ is supported by an unrestricted neurosciences intensive care research grant from Codman. LAS is supported by grants from the Margarete und Walter Lichtenstein-Stiftung (Basel, Switzerland), a Myron B. Laver Grant (Department of Anaesthesia, University of Basel, Switzerland) and the Swiss National Science Foundation, and is recipient of an Overseas Research Student Award (Committee of Vice-Chancellors and Principals of the Universities of the United Kingdom).
Accepted for publication: November 20, 2002
Abstract
There has long been an appreciation that cerebral blood flow is modulated to ensure adequate cerebral oxygen delivery in the face of systemic hypoxaemia. There is increasing appreciation of the modulatory role of hyperoxia in the cerebral circulation and a consideration of the effects of such modulation on the maintenance of cerebral tissue oxygen concentration. These newer findings are particularly important in view of the fact that cerebrovascular and tissue oxygen responses to hyperoxia may change in disease. Such alterations provide important insights into pathophysiological mechanisms and may provide novel targets for therapy. However, before the modulatory effects of hyperoxia can be used for diagnosis, to predict prognosis or to direct therapy, a more detailed analysis and understanding of the physiological concepts behind this modulation are required, as are the limitations of the measurement tools used to define the modulation. This overview summarizes the available information in this area and suggests some avenues for further research.
Br J Anaesth 2003; 90: 77486
Keywords: brain, blood flow
One of the prime purposes of cerebral perfusion is to ensure oxygen delivery to the brain. Cerebral blood flow (CBF) is coupled to cerebral oxygen metabolism to ensure appropriate oxygen delivery both at baseline and dynamically in response to cortical activity. There has long been an appreciation that CBF is modulated to ensure adequate cerebral oxygen delivery in the face of systemic hypoxaemia.6 28 43 There is increasing appreciation of the modulatory role of hyperoxia in the cerebral circulation and a consideration of the effects of such modulation on the maintenance of cerebral tissue oxygen levels.59 82 These newer findings are particularly important in view of the fact that cerebrovascular and tissue oxygen responses to hypoxia and hyperoxia may change in disease. Such alterations provide important insight into pathophysiological mechanisms and may provide novel targets for therapy. However, before the modulatory effects of hyperoxia can be used for diagnosis, to predict prognosis or to direct therapy, a more detailed analysis and understanding of the physiological concepts behind the modulation is required, as are the limitations of the measurement tools used to define the modulation. This review summarizes the available information in this area and suggests some avenues for further research.
Cerebral oxygen vasoreactivity
Cerebrovascular responses to hypoxia
Many factors influence CBF, including oxygen, carbon dioxide, metabolic demand and blood pressure. The classical response of CBF to changes in the arterial partial pressure of oxygen (PaO2) is shown in Figure 1.
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Cerebrovascular responses to hyperoxia
The response of CBF to hyperoxia (PaO2 >15 kPa, 113 mm Hg), the cerebral oxygen vasoreactivity (COVR), is less well defined. Kety and Schmidt originally described, using a nitrous oxide washout technique,45 a reduction in CBF of 13% and a moderate increase in cerebrovascular resistance in young male volunteers inhaling 85100% oxygen.46 Subsequent human studies (Table 1), using a variety of differing methods, have also shown CBF reductions with hyperoxia, although the reported extent of this change is variable.2 50 59 61 62 64 67 84 Omae and colleagues64 assessed how supra-atmospheric pressures influenced CBF, as estimated by changes in middle cerebral artery flow velocity (MCAFV) in healthy volunteers. Atmospheric pressure alone had no effect on MCAFV if PaO2 was kept constant. Increases in PaO2 did lead to a significant reduction in MCAFV; however, there were no further reductions in MCAFV when oxygen was increased from 100% at 1 atmosphere of pressure to 100% oxygen at 2 atmospheres of pressure. This suggests that the ability of the cerebral vasculature to constrict in response to increasing partial pressures of oxygen is limited. Although hyperbaric oxygen is thought to increase CBF in head-injured patients, when the CBF is measured before and after the period of hyperbaric oxygen; however, the acute response of CBF to hyperbaric oxygen after head injury is not known.66
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Cerebral vasoreactivity in clinical settings
Three studies have looked more specifically at the effects of pathology on COVR (Table 1). Nakajima and colleagues61 showed that COVR is reduced in patients with risk factors for cerebral arteriosclerosis, vertebrobasilar insufficiency and hemispheric infarction. In fact, in acute infarction there was a paradoxical change in CBF, flow increasing rather than decreasing in the infarcted hemisphere. Amano and colleagues2 showed reductions in COVR with age, and showed that COVR is reduced and more heterogeneous in patients with multi-infarct dementia than in age-matched controls. These studies suggest that there has been disruption of the normal ability of the cerebral vasculature to constrict in the presence of high levels of arterial oxygen. Both studies used an inhalation xenon 133 (133Xe) washout technique for determining CBF, a technique that is most suited to measurement of cortical blood flow and provides little information about the white matter compartment.56 The use of several regional detectors placed over each cerebral hemisphere gives a certain amount of information on regional perfusion, although precise anatomical correlations, and comparisons of the same region from one study to another, are only semiquantitative. Menzel and colleagues59 used stable xenon computed tomography (CT) to determine COVR, which makes use of the fact that stable xenon is radiodense, and therefore CBF can be calculated from the time course of tissue build-up of radiodensity. They demonstrated a mean reduction in CBF of approximately 9%, with an increase in inspired oxygen from 35 to 60%, in six patients with severe traumatic brain injury. The same group also assessed the response of CBF to hyperoxia in an undamaged region of interest in the right frontal lobe, and found an average reduction in CBF of 19.3%. Both globally and in the region of interest, the extent of the COVR was found to depend on the level of the baseline regional CBF (Fig. 2). It is difficult to draw firm inferences from Menzels work as only six patients were studied, one of whom had negligible CBF, but it does serve to demonstrate the paucity of human data regarding traumatic brain injury and COVR.
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Cerebral tissue oxygen partial pressures
Physiological premises
Measurement techniques
Several different types of tissue gas analysis probes are available which are capable of measuring the partial pressure of oxygen (PtO2) within a tissue of interest. The volume of tissue sampled by these sensors is probably only in the order of a few cubic millilitres.30 Although there is some uncertainty over the exact characteristics of the partial pressures that tissue sensors measure, for example whether recordings are representative of intracellular or extracellular gas pressures, and the influence of sensor position in relation to capillaries and arterioles, PtO2 is most probably a measure of extracellular oxygen tension and thus reflects the balance between oxygen supply and tissue demand. In metabolically active tissue, an oxygen concentration gradient exists from the arterial to the venous ends of a capillary as a result of oxygen extraction. Normally it is assumed that there is a minimal oxygen gradient between the extracellular space and the end-capillary compartment, and thus that PtO2 reflects end-capillary oxygen tension. This may not be the case after a severe head injury, when large end-capillarytissue oxygen gradients occur, probably reflecting endovascular oedema or microscopic arteriovenous shunts.27
Cerebral tissue oxygen partial pressures (PbO2) can be measured using one of the two commercially available sensors. The Licox system (GMS, Kiel-Mielkendorf, Germany) consists of a sensor that includes a polarographic Clark-type electrode, and a thermocouple for temperature measurement. The electrode consumes tiny quantities of the available tissue oxygen in an electrochemical reaction that produces an electrical signal that is proportional to PbO2. The NeurotrendTM system (Codman, Raynam, MA, USA) is made up of four different sensors (temperature, PbO2, PbCO2 and pH) staggered over approximately 2 cm. The oxygen sensor consists of a fibre in which the holes are filled with silicone rubber that contains entrapped ruthenium-based dye. Blue light at 450470 nm is passed down the fibre and is absorbed by the dye. The dye emits a proportion of the energy it has absorbed as light of wavelength 620 nm. However, in the presence of oxygen, the amount of this fluorescent light is reduced (so-called oxygen quenching). The amount of quenching is proportional to the concentration of oxygen and thus, if the amount of fluorescent light is measured, an estimate of PbO2 can be made. Both sensors are approximately 0.5 mm in diameter but the oxygen-sensing areas are of different lengths; both can be implanted directly into brain tissue. The accuracies of the two sensors are quoted at between 0.1 and 0.5 kPa (13.5 mm Hg), but their accuracy declines when oxygen levels are supraphysiological. The two sensors have never been compared in a clinical situation. Before the Neurotrend sensor was developed, a Paratrend sensor (Codman) was used in some studies;58 59 early models of the Paratrend used a modified Clark electrode to measure oxygen partial pressure, but more recently oxygen-quenching technology has been introduced. The Clark electrode Paratrend has been compared in vivo with the Licox, with various reports on the comparability between the two sensors.68 79 The Paratrend sensor is designed for arterial blood gas monitoring. It is calibrated to work at higher oxygen tensions and therefore may be more accurate in the measurement of supranormal oxygen levels.
Several other monitoring tools and imaging techniques are available to assess cerebral oxygenation, including jugular bulb oximetry, microdialysis parameters, near infrared spectroscopy and positron emission tomography with 15O; detailed descriptions of these techniques are beyond the scope of this review. Interested readers are directed to recent reviews on the subject.29 41
Normal values and modulators
Few data exist on normal values of PbO2 in humans.82 In cats and dogs, normal values have been reported at 3.7 (SD 0.9) kPa [28 (7) mm Hg].52 Values of 4.34.7 kPa (3236 mm Hg) have been reported in normal tissue in three patients undergoing brain tumour surgery,4 and values of 3.413.7 kPa (25104 mm Hg) were reported in seven patients having elective clipping of intracranial aneurysms.15 The variability in these figures may be explained in part by variations in the factors determining brain tissue oxygen, which are outlined below.
Cerebral blood flow. There is conflicting evidence as regards the relationship between PbO2 and CBF. Menzel and colleagues59 and Doppenberg and colleagues16 have used a single stable xenon-CT scan to measure CBF in a region of interest around a Paratrend probe and have found reasonable correlations with PbO2. However, Gupta and colleagues27 did not find a significant correlation between CBF and PbO2, using a Neurotrend sensor to determine PbO2 and H215O positron emission tomography imaging to determine CBF. All of these studies were in brain-injured patients.
Cerebral perfusion pressure. After traumatic brain injury, episodes of reductions in cerebral perfusion pressure (CPP) undoubtedly contribute to reductions in PbO2, various thresholds for CPP having been reported.1 3 47 49 Kiening and colleagues49 were able to show a third-order regression correlation between PbO2 and CPP when a Licox sensor was inserted into non-injured frontal tissue.
PaCO2 and PaO2. In most head-injured patients, hyperventilation results in a decrease in PbO2 when the sensor is placed in an uninjured part of the brain,26 37 although increases are more commonly seen when the sensor is in an area of pathology.26 Various studies have shown that episodes of hypoxaemia may contribute to reductions in PbO2.1 49 82 The changes in PbO2 in response to hyperoxia are discussed below (see Cerebral tissue oxygen reactivity).
Ischaemia. Imbalances between metabolic demand and supply will lead to increases in oxygen extraction fraction and thus to reductions in end-capillary oxygen tension. Tissue oxygen levels should therefore reflect changes in oxygen supplydemand relationships. Although some correlations have been found between PbO2 and other indicators of ischaemia, such as jugular venous oxygen saturation (SjO2)23 26 37 49 and regional lactate levels,78 a poor correlation was found between PbO2 and end-capillary oxygen tension, as calculated from 15O positron emission tomography data.27 Poor correlations are not necessarily surprising, as differences in the mechanisms of ischaemia and the ischaemic burden will influence different monitoring modalities in different ways, as will the compartment from which the measurement is made. Ischaemic thresholds for PbO2 have been variably described using a number of different approaches, such as outcome analysis after head injury,5 16 17 47 59 79 81 85 relating PbO2 to recognized threshold limits for CBF,17 59 relating PbO2 to SjO2 limits,49 assessing PbO2 in patients with a compromised cerebral circulation,31 and assessing thresholds for infarction during cerebral aneurysm clipping.44 The threshold for ischaemia that is most commonly used is approximately 1.3 kPa (10 mm Hg).
Pharmacological and pathological modulation of CMRO2. If flowmetabolism coupling is intact, changes in the cerebral metabolic rate of oxygen (CMRO2) should not result in changes in PbO2. However, normal coupling of CBF is only retained in 45% of comatose head-injured patients,63 and pharmacological manipulation of CMRO2 may also disrupt normal coupling. Two studies have suggested that etomidate can lead to reductions in PbO2, sometimes to levels considered ischaemic;19 32 this is probably a result of a reduction in oxygen supply attributable to vasoconstriction, which is over and above the reduction in metabolic oxygen requirements. Desflurane has the opposite effect, with increases in PbO2 as inhaled desflurane increases from 3% to 9%, probably as a result of vasodilatation and hyperaemia. PbO2 falls with a reduction in temperature, the fall becoming significant at a brain temperature below 35°C.25 This reduction in PbO2 is associated with increases in SjO2 and therefore may represent a change in oxygen off-loading at the capillary level as the oxygen dissociation curve shifts to the left. Mitochondrial dysfunction will result in impaired ability to utilize oxygen and a low CMRO2, and could arguably result in vasodilatation; consequently PbO2 will be raised. This constellation of findings would seem plausible in mitochondrial dysfunction, but has not been confirmed by robust experimental data in humans or experimental models.
Cerebral tissue oxygen reactivity
The expected changes in PbO2 that occur with changes in PaO2 [cerebral tissue oxygen reactivity (CTOR)] are not immediately intuitive. If brain tissue oxygen were dependent on arterial oxygen content, then, because of the shape of the oxygen dissociation curve, one would expect to see little change in PbO2 during normoxia and hyperoxia. If brain tissue oxygen were dependent on PaO2, one would expect changes in PaO2 to be exactly reflected by changes in PbO2. In practice, changes in PbO2 with changes in PaO2 do not fit either of these models. The experimental evidence suggests that PbO2 increases with an increase in PaO2, but the increase is damped (Fig. 3).
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CTOR=%PbO2/
PaO2 (mm Hg)
One of the problems with the van Santbrink method is that, for the same change in PaO2, a small, and probably clinically insignificant, increase in PbO2 from 0.1 to 0.2 kPa (0.8 to 1.6 mm Hg) would give the same CTOR as an increase in PbO2 from 5 to 10 kPa (38 to 76 mm Hg).
Brain tissue oxygen normally has a linear relationship to PaO2.59 82 This relationship provides an alternative method of determining CTOR, which avoids the problems inherent in the van Santbrink method, CTOR being quantified by the gradient of the linear regression line. It is also essential to make measurements during periods of stable physiology. We have seen that that the process of equilibration between arterial and brain oxygen may be extremely prolonged (Fig. 4), which is probably a result of low perfusion. Therefore, in order to determine an accurate CTOR, sufficient time must be given for PbO2 to reach a steady state.
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Normal values
Using van Santbrinks formula, Menzel and colleagues57 described a normal CTOR, measured in the frontal lobe of healthy anaesthetized piglets, as 0.21 (SD 0.12). CTOR has been assessed in humans, in non-pathological brain tissue of patients undergoing neurosurgery for brain tumours.21 Changes in PaO2 may not only affect PbO2 but also its homogeneity in tissues. Eintrei and Lund21 used a multiwire electrode to measure cortical tissue oxygen and showed that, once the inspired oxygen reached 30%, brain tissue oxygen became more scattered, heterogeneity increasing as the inspired oxygen increased to 100%. Only three of the six patients studied had an increase in mean brain tissue oxygen when on oxygen 100% compared with normoxia. The same group also studied the effects of hyperoxia on pig cerebral cortex,21 where a similar increase in tissue oxygen heterogeneity was seen. All six pigs showed an increase in mean tissue oxygen with hyperoxia but the reactivity varied widely. Regional CBF was estimated in the pigs using a washout curve of locally applied 133Xe. Although, when compared with levels at an inspired oxygen fraction of 0.21, CBF fell by an average of 40% at an inspired oxygen fraction of 1.0, the extent of the reduction in CBF did not correlate with the changes in brain tissue oxygen.
Pathological values
Four studies have investigated oxygen reactivity in humans with cerebral pathology (Table 4).48 55 59 82 Both van Santbrink and colleagues82 and Menzel and colleagues59 found a significant correlation between high oxygen reactivity and poor outcome (Glasgow Outcome Score 1, 2 or 3) after traumatic brain injury, the differences in reactivity being most significant on day 1. Neither study was powered to find a difference; this was an incidental statistical finding. Van Santbrink and colleagues82 also found that patients who had high brain oxygen levels had significantly higher oxygen reactivity, perhaps representing deranged oxygen reactivity during the hyperaemic stage after a head injury. The same group also looked at the response of PbO2 to induced changes in PaCO2, and found that the response on day 1 was significantly lower than on days 3 and 5 after traumatic brain injury, a result also found by Carmona Suazo and colleagues.8 Impairments in brain oxygen carbon dioxide reactivity are further evidence of impaired vascular reactivity after traumatic brain injury, which did not correlate with outcome. Meixensberger and colleagues55 found higher CTORs in pathological brain tissue than in normal brain tissue, whereas Kiening and colleagues48 found a lower CTOR close to lesioned areas.
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Clinical significance
Pathophysiological implications. A high CTOR could represent one of two possible scenarios. It could either represent vasomotor paralysis or it could be an appropriate physiological response to ischaemia. Even normal or high PbO2 values do not exclude tissue hypoxia. Mitochondrial dysfunction is being increasingly recognized after severe traumatic brain injury, and this could certainly result in high tissue oxygen levels despite histotoxic hypoxia.83
Prognostic inferences. As mentioned previously, a significant relationship between CTOR and outcome after traumatic brain injury has been found in two studies.59 82
Therapeutic interventions. Only one study has assessed the impact of hyperoxia on cerebral ischaemia after severe TBI.58 It was found that increasing inspired oxygen from 35% to 100% for 6 h led to a 359 (SD 39)% increase in brain tissue oxygen and a 40% decrease in brain lactate concentration. The lactate/pyruvate ratio, which is more commonly used as an indicator of the redox state of the brain,41 was not assessed.
It is certainly possible to increase brain tissue oxygen levels from an ischaemic level to a non-ischaemic level by increasing the inspired fraction of oxygen, but there are no randomized controlled trials assessing the impact of brain tissue oxygen-targeted therapy after traumatic brain injury. The effects of hyperoxia on cerebral metabolism and ischaemia require further exploration using techniques such as microdialysis, phosphorus and proton magnetic resonance spectroscopy, and magnetic resonance diffusion-weighted imaging.
Mechanisms
The mechanisms that lie behind hyperoxia-induced changes in tissue blood flow and the regulation of tissue oxygen partial pressures remain unclear. In human skeletal muscle, hyperoxia causes an increase in the mean tissue oxygen partial pressure, but with significant heterogeneities, with some regions of the tissue actually showing reduced oxygen pressures compared with normoxia.51 This increase in tissue oxygen heterogeneity with hyperoxia is also seen in the brain in both pigs21 72 and man.21 The increase in heterogeneity is speculated to be a result of redistribution of blood flow, with vasoconstriction in some areas and shunting in others. Various mediators and mechanisms have been suggested to play a role in COVR, including increased effects of serotonin,75 76 nitric oxide synthase inhibition,71 inhibition of endothelial prostaglandin synthesis60 and increased leukotriene production.39 40
Despite a number of advances in the last decade, the exact site and mechanism of the oxygen sensor is yet to be fully elucidated and, indeed, there may be more than one sensor.38 Many physiologically relevant genes are activated during conditions of hypoxia, including those encoding erythropoietin, vascular endothelial growth factor, inducible nitric oxide synthase and glycolytic enzymes. Remarkably, at the transcriptional level, these diverse genes are all under the control of a crucial transcription factor: hypoxia-inducible factor 1 (HIF-1).24 HIF-1 is a heterodimeric protein complex composed of two subunits: a constitutively expressed ß-subunit and an -subunit, the expression and activity of which are controlled by the intracellular oxygen concentration. During normoxia, HIF-1
is rapidly degraded by the ubiquitin proteasome system, whereas exposure to hypoxic conditions prevents its degradation.35 36 This oxygen-dependent instability may provide a means by which gene expression is controlled during changes in oxygen tension (Fig. 5). We speculate that hyperoxia reduces the intracellular HIF-1 concentration, thus reducing the activity of important enzymes involved in glycolysis, such as phosphofructokinase and 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase. A reduction in glycolysis would reduce lactic acid production and intracellular buffering, and thus modulate CBF. Indeed, we have seen that, in healthy volunteers, hyperoxia modulates the haemodynamic response to hyperventilation, and we speculate that this is a result of reduced HIF-1 concentration and a decrease in lactic acid production and intracellular buffering.42 The effects of hyperoxia on cerebral glycolysis, metabolism and ischaemia could be further explored using techniques such as microdialysis, phosphorus or proton magnetic resonance spectroscopy, and magnetic resonance diffusion-weighted imaging. However, it is unlikely that it will be possible to measure HIF-1 concentrations in vivo because of its intracellular position, large size and instability. It should certainly be possible to explore the effects of hyperoxia on HIF-1 in the laboratory using cultured cell lines.
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There is substantial evidence that CBF falls during periods of hyperoxia, this fall having been variably reported between 10 and 27% in healthy volunteers. There is some evidence that COVR is disturbed by vascular disease and traumatic brain injury.
Normal CTOR has not been well defined but it seems to be influenced by carbon dioxide, isoflurane anaesthesia and cerebral pathology, including traumatic brain injury. Although CTOR has been shown in two studies to have prognostic significance after traumatic brain injury, further work needs to be done in this field. Temporal and spatial profiles of brain tissue oxygen reactivity need to be better defined, as do the influences of anaesthesia and sedation, temperature and vasoactive agents. We have seen that brain tissue oxygen does not always have a linear relationship with arterial oxygen, and that the process of equilibration between arterial and brain oxygen may be extremely prolonged (Fig. 4). For these reasons, definitions for CTOR need to be more tightly defined.
If COVR and CTOR are to be used for diagnostic or prognostic purposes, or to direct therapy, then the methodological issues surrounding their measurement must be taken into account and future studies must be based on a firm methodological foundation.
Whether poor COVR and supranormal CTOR describe the same phenomenon is not yet known. How COVR and CTOR integrate with more classic autoregulatory mechanisms requires investigation, as do the basic physiological mechanisms that lie behind COVR and CTOR. Abnormal pressure autoregulation and carbon dioxide reactivity are known to correlate with poor outcome after traumatic brain injury;12 53 63 70 73 further work is required to assess whether COVR and CTOR offer complementary information. Positron emission tomography, and magnetic resonance imaging using hyperpolarized gases or perfluorocarbons, may allow further exploration of the relationships between brain tissue oxygen, CBF, end-capillary oxygen tension, COVR and CTOR.18 20 27
Further studies are required to determine whether hyperoxia can provide clinical benefits in patients with brain injury. At an appropriate stage, such studies should include a randomized controlled trial assessing the use of high fractions of inspired oxygen in the management of severe traumatic brain injury.
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