Brain tissue oxygen monitoring: physiologic principles and clinical application

Brain Tissue Oxygen Monitoring: Physiologic Principles and Clinical Application Venu M. Nemani, MD, and Geoffrey T. Manley, MD, PhD

Traumatic brain injury, stroke, and subarachnoid hemorrhage remain a significant cause of death and disability. Cerebral ischemia plays a pivotal role in the pathogenesis of brain injury. Patients with these insults are also at risk for secondary injury from hypoxia and hypotension. The focus of care for these patients is the detection and prevention of secondary insults to the brain. However, standard neuromonitoring is limited to the measurement of intracranial pressure and calculation of cerebral perfusion pressure. Recently, new devices have been developed for the direct monitoring of cerebral oxygenation and metabolism. One of these devices, the brain tissue oxygen monitor, has been gaining acceptance as studies have detailed its ease of use, accuracy, and prognostic value for pathological events. The technical aspects and physiological principles of brain tissue oxygen monitoring are reviewed, and the clinical application of this technology is discussed. Copyright 2004, Elsevier Inc. All rights reserved.

he understanding of the basic pathophysiological events that occur after brain injury, including traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), stroke, and intracranial hematoma (ICH), has increased dramatically. Secondary brain injury underlies the destructive damage of these events.1 Although secondary brain injury can occur through many pathways, the final common event resulting in eventual neuronal cell loss is cerebral ischemia. The current focus of neurointensive care monitoring is the detection and prevention of secondary insults to the brain. This is done primarily by monitoring arterial blood pressure, maintaining a secure airway, and ensuring adequate oxygenation using mechanical ventilation. In addition, using intracranial pressure (ICP) probes to guide ICP and cerebral perfusion pressure (CPP)targeted therapy is a must. However, especially in brain-injured patients, additional endpoints are needed to ensure adequate substrate delivery of glucose and oxygen to the brain. Continuous monitoring of the partial pressure brain tissue oxygen tension (PbrO2) using probes inserted directly into the cerebral matter has been gaining acceptance as studies detailing their ease of use, accuracy, and prognostic value for pathological events have emerged. This article reviews the technical aspects and physiological principles of PbrO2 monitoring and discusses the clinical application of this technology.

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From the Department of Neurosurgery, University of California, San Francisco, CA. Address reprint requests to Geoffrey T. Manley, MD, PhD, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Bldg. 1, Room 101, San Francisco, CA 94110. Copyright 2004, Elsevier Inc. All rights reserved. 1092-440X/04/0701-0002$30.00/0 doi:10.1053/j.otns.2004.04.002

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Types of Brain Tissue Oxygen Monitors Clarke-Type Electrodes Clark reported the properties of a polarographic electrode that could be used to measure the partial pressure of oxygen (pO2) in blood or tissue. Diffusion of O2 through a permeable membrane enclosing an electrolyte solution creates a current proportional to the O2 tension of the blood or tissue being measured.2 Before these electrodes could be used in clinical applications, however, the problems of stability of the electrode over time and deposition of coagulation products onto the electrode surface had to be overcome. Subsequently, two companies developed these Clark-type electrodes into catheters for use as neuromonitoring tools. The Licox system was introduced by Gesellschaft fu¨r Medizinishe Sondentechnik (GMS) mbH (Kiel, Germany), and the Paratrend system was introduced by Diametrics Medical (High Wycombe, UK). The Licox catheter has a diameter of 0.8 mm and a measurement surface of 5 mm. The 5-mm sensing area was chosen empirically to reduce the variability of tissue O2 measurements in the heterogeneous brain. Because this catheter lacks an integrated temperature sensor, an additional temperature probe must be introduced into the brain to correct measured pO2 values for variations in temperature. The Paratrend catheters were designed for multimodal intravascular monitoring of pO2, pCO2, pH, and temperature but were quickly adopted as intraparenchymal monitors for neurosurgical applications. These probes also have a diameter of 0.5 mm, but the sensors in the probe are spaced over a length of 4 cm.2

Fluorescent-Based Technologies In 1999 the Neurotrend catheter, based on the Paratrend system but incorporating fluorescent rather than fiberoptic technology, was approved for use in the United States. This catheter has a shortened measuring length of 2 cm and was specifically designed for intraparenchymal monitoring. However, the O2sensing area of this probe is only 1.4 mm. Because the sensing area is small, there is more variability in tissue measurements of O2 compared with probes with a larger sensing area. Despite this technical limitation, the improvements in the Neurotrend catheter seem to have ameliorated the deficits found in the Paratrend system during measurement of PbrO2 near ischemic levels.3,4

Determinants of Brain Tissue Oxygenation (PbrO2) Although the brain makes up only 2% of body weight, it consumes a disproportionately large amount of the body’s resources: 15% of the cardiac output, 20% of the oxygen, and 25%

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of the glucose.5 Because the brain lacks the ability to store substrates for energy production, it is highly dependent on a constant blood supply delivering sufficient oxygen to support its metabolic functions. The supply of O2 to the brain depends on the complex interaction of several factors as discussed below.

O2-Carrying Capacity of Blood The uptake of O2 into the bloodstream depends on a patent airway and effective matching of ventilation and perfusion in the lung parenchyma. In adequately perfused alveoli, atmospheric O2 diffuses down its concentration gradient into the lung capillary beds where it is delivered to all tissues in the body. Because the solubility of O2 into blood itself is quite low, most of the O2 transported is reversibly bound to hemoglobin. The amount of O2 dissolved in the blood is thought to be negligible. Therefore, a decrease in the concentration of hemoglobin in the blood, as can occur through dilution after acute hemorrhage, results in a corresponding reduction in the O2carrying capacity of the blood.

Cerebral Blood Flow In humans, normal cerebral blood flow (CBF) ranges between 45 and 60 mL/100g/min.5 As CBF is reduced, O2 delivery to brain tissue sufficient to maintain metabolic activity becomes impaired, and clinical and molecular signs of tissue hypoxia begin to appear. The body has exquisite control over CBF through the process of cerebral autoregulation. When mean arterial pressure (MAP) is between about 60 mmHg and 150 mmHg, CBF is maintained within a narrow range.5 When MAP increases and arteriolar smooth muscle is stretched, a reactive vasoconstriction reduces blood flow back to its original level. Conversely, when MAP decreases and the stretch on arteriolar smooth muscle is reduced, vasodilation restores blood flow. Above and below these levels of MAP, constriction and dilation are insufficient to maintain CPP at a constant level and the relationship of CPP and CBF with MAP becomes linear.6 In addition to these myogenic factors, local metabolites such as CO2, H⫹, adenosine, K⫹, NO, and prostaglandins produced by endothelial cells also play a role in the control of autoregulation.5,7-11 Several other peptides and neurotransmitters have been implicated in the control of CBF,12-14 but further research is needed to clarify and elucidate their contribution to this process.

Dissociation of O2 and Hemoglobin The binding properties of the hemoglobin tetramer favor the binding of O2 in the lungs and unloading of O2 in the periphery. This spatial regulation of binding is the essence of hemoglobin’s ability to deliver O2 to tissues in demand. The ability of O2 to unload from hemoglobin and to diffuse into tissues depends on the difference in the pO2 between blood and tissue. Tissue O2 tension remains lower than capillary O2 tension because mitochondria are continuously using O2 as the final electron acceptor in oxidative phosphorylation to generate ATP. In addition to this partial pressure gradient, several other factors affect the dissociation properties of O2 from hemoglobin. As blood passes through a capillary bed, it progressively accumulates acidic metabolites from surrounding cells and blood pH decreases accordingly. This decrease shifts the O2-hemoglobin saturation curve to the right, facilitating the release of O2 into the tissue. BRAIN TISSUE OXYGEN MONITORING

Fig 1. Effects of increasing FiO2 on PbrO2 levels. Data represent the means from eight animals. Mean arterial PbrO2 levels were 84, 254, 369, and 525 mmHg when FiO2 was 0.21, 0.50, 0.70, and 1.00 mmHg, respectively.

This shift is termed the Bohr effect.15 Temperature also regulates O2-hemoglobin binding. Hyperthermia facilitates unloading of O2 into tissue.15 As a result of these processes, blood passing through the capillary system of the brain parenchyma reduces the pO2 from 90 mmHg in the precapillary arterioles to about 35 mmHg in the postcapillary venules.16

Effects of Ventilation The goal of immediate and aggressive resuscitation of patients with brain injury is to prevent secondary brain injury. To avoid these events and to preserve normal function, the brain must be constantly supplied with enough O2 to meet its metabolic demands.17,18 Ultimately, this is the factor most critical to patient outcome.19 Insults such as head trauma and hemorrhagic shock confer increased sensitivity to secondary injury on the brain, which further restricts the delivery of O2 to tissue.17,20 Currently, the only endpoints available in the early stages of cerebral resuscitation are systemic blood pressure and mental status. Unfortunately, the degree of head injury often precludes the use of mental status as an endpoint. Furthermore, the complicated relationships between systemic blood pressure and CBF make the critical appraisal of ventilatory factors in brain tissue oxygenation an important exercise. Several basic and clinical studies examining these parameters are discussed below.

Fraction of Inspired O2 In a large animal model, we have shown that increasing the fraction of inspired O2 (FiO2) increases PbrO2 (Fig 1). A significant and rapid increase in PbrO2 occurs within 30 seconds of increasing FiO2. Oxygen probes consistently achieve almost 90% of new baseline values within 3 minutes over a wide range of FiO2.21 Zauner and co-workers and Menzel and co-workers both showed that increasing FiO2 in patients with severe brain injury increased O2 delivery to the brain and significantly decreased the level of lactate in brain tissue levels as measured by microdialysis techniques.22,23 The importance of these findings is highlighted by the prognostic relevance of elevated lactate levels in the brain of patients with severe TBIs.24 Increased

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lactate levels alone, however, are not entirely specific as a marker for tissue hypoxia.25 Lactate levels can increase in headinjured and critically ill patients with adequate delivery of O2 to brain tissue because of a condition known as hyperglycolysis, in which glucose supply outstrips O2 delivery.26,27 Patients with TBI often have decreased brain tissue O2 tension on the first day after injury.28,29 Furthermore, microdialysis monitoring has shown that decreased O2 tension is correlated with increased levels of lactate, which some authors suggest reflects a shift to anaerobic metabolism in the acute setting.29 To provide the brain with sufficient O2 to prevent secondary insults, researchers have examined the effect of increasing FiO2 on brain tissue O2 tension. The first investigation of this intervention was performed by van Santbrink and colleagues, who measured O2 reactivity in 22 head-injured patients in response to increased FiO2.28 They showed that PbrO2 increased linearly with increasing FiO2 and that patients with higher O2 reactivity had worse outcomes than patients with lower O2 reactivity. They attributed the higher O2 reactivity to a disruption in the autoregulatory mechanisms of O2. McLeod and co-workers compared the Neurotrend catheter, near infrared spectroscopy, and monitoring of O2 jugular venous saturation (SjvO2) as measures of O2 delivery in response to normobaric hyperoxia.30 All three modalities correlated well with changes in FiO2. Other groups have expressed concern about the findings that normobaric hyperoxia alone can improve cerebral oxygenation. Blood hemoglobin, which is almost completely responsible for O2 delivery to tissues, is almost fully saturated at room air. In contrast, the amount of O2 dissolved in blood is negligible. Therefore, increasing FiO2 does not significantly increase the O2 content carried by blood to hypoxic tissue. Although PbrO2 increases with an increase in FiO2, the increase does not necessarily correlate with an increase in the supply of O2 to tissue.31 With improvements in microdialysis technology, researchers have found that the ratio between lactate and pyruvate provides a more accurate and specific measurement of the redox state of the cell than measurement of lactate alone.32 To provide further evidence that normobaric hyperoxia does not improve cerebral metabolism, Magnoni and co-workers showed that while hyperoxia slightly reduced lactate levels in brain tissue after TBI, the redox status of the cells as measured by the lactate-pyruvate ratio did not change and that cerebral O2 extraction was impaired.33 Thus, increasing FiO2 may increase PbrO2 as a result of the effect on arterial oxygenation [pressure of arterial oxygenation (PaO2)] without actually supplying more oxygen to brain tissue. To show an improvement in cerebral metabolism in response to increased FiO2, studies must show that ATP generation and the cerebral metabolic rate of O2 (CMRO2) consumption increases after this type of therapy as measured by microdialysis. Until these studies and additional clinical outcome studies are performed, hyperoxia should not be used for the routine treatment of TBI patients.

Hyperventilation Hyperventilation has been a mainstay in the treatment of neurosurgical patients for many years. It is an effective means of reducing elevated ICP by inducing hypocapnic vasoconstriction of the cerebral vasculature, causing a reduction in intracranial blood volume and a corresponding decrease in pressure.

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Because CPP ⫽ MAP ⫺ ICP, a decrease in ICP has been assumed to increase cerebral perfusion and oxygenation. However, CBF actually decreases in response to hyperventilation therapy,34 placing patients at risk for iatrogenic tissue ischemia. This risk was recently confirmed by a positron-emission tomography study (PET) that showed a marked increase in the amount of tissue that was severely hypoperfused in response to hyperventilation.35 In response to hyperventilation in animals (Fig 2A), PbrO2 was reduced by 40% in swine21 and by 29% in cats.36 In humans with a severe brain injury, hyperventilation to a PaCO2 of 21 and 22 mmHg reduced PbrO2 by 27%.37 Recently, Sarrafzadeh and colleagues showed that 69% of headinjured patients undergoing PbrO2 monitoring experienced hypoxic episodes (PbrO2 ⬍ 10 mmHg for ⬎5 minutes), most of which were related to hyperventilation.38 In a close examination of cerebral metabolites in response to hyperventilation, Marion and co-workers found significant increases in extracellular glutamate and lactate and in the lactate-pyruvate ratio when patients were hyperventilated for 30 minutes 24 to 36 hours after injury.39 These results indicate that hyperventilation therapy is associated with a potential for further brain injury, underscoring the recommendation that it only be used when clinical signs of cerebral herniation are present.40

Hypoventilation In a study performed on swine, hypoventilation was more effective at achieving a maximum PbrO2 than hyperoxia. The former caused a mean increase in PbrO2 of 75%; the mean PaCO2 was 58 mmHg (Fig 2B).21 Another group found a 20% to 30% increase in cerebrospinal fluid O2 levels in cats in response to hypercapnia.41 Hypercapnia can increase tissue O2 tension through several mechanisms. In 1948 Kety and Schmidt showed that CO2 is highly effective in causing an increase in cerebral blood flow (CBF).42 Alexander and colleagues also showed that arterial CO2 is an extremely potent cerebral vasodilator, resulting in a decrease in vascular resistance and a corresponding increase in CBF.43 Hypercapnia has the additional effect of shifting the hemoglobin-O2 saturation curve, facilitating unloading of O2 in tissues and further contributing to the increase in tissue O2 tension.44 In addition to the increase in tissue O2, some investigators believe that hypercapnic acidosis itself may have a neuroprotective effect.45 Providing that CPP and arterial oxygenation can be maintained, there may be a future therapeutic role for hypoventilation in brain-injured patients. Further studies are required to clarify the potential benefit of increasing FiO2, hyperventilation, and hypoventilation in brain-injured patients. Other areas for investigation include the realm of hyperbaric O2 administration to improve O2 delivery to tissues. Cerebral oxygenation increases in response to hyperbaric O2 therapy.46 This and other interventions need to be studied in greater detail before they are adopted in clinical practice for patients with brain injury.

Effects of Blood Pressure Through the process of cerebral autoregulation, the body is able to maintain constant CBF over a wide range of blood pressure.47 As described earlier, both myogenic mechanisms and local metabolites are important in the control of this finely tuned process. The response of cerebral blood vessels can be used theraNEMANI AND MANLEY

Fig 2. Characteristic effects of hyperventilation and hypoventilation on PbrO2, end-tidal CO2 (ETCO2), and mean arterial pressure (MAP) from a representative experiment. (A) Hyperventilation for 10 minutes simultaneous decreased PbrO2 and ETCO2. A notable decrease in MAP was also observed. (B) Hypoventilation for 10 minutes increased PbrO2 and ETCO2 with no significant change in MAP. All values are in mmHg.

peutically in patients with elevated ICP. Relaxation and constriction of the cerebral vasculature and the respective increase and decrease in cerebral blood volume are responsible for ventilation-induced changes in ICP.48 In patients with TBI49,50 and in rat models of TBI,51,52 CBF is significantly reduced immediately after injury. CBF returns to normal or increases slightly 24 to 72 hours after injury. These changes imply a disruption of normal cerebral autoregulatory mechanisms, which often occurs after both mild and severe TBI.53-58 In fact, this disruption is thought to contribute both to secondary brain insults and elevated ICP after TBI.50,59 In clinical practice, pressors are frequently used to maintain cerebral perfusion in response to elevations in ICP, presumably to maintain oxygenation to brain tissue. Several studies have examined the relationship between changes in blood pressure and brain tissue oxygenation. In two separate studies in a swine model of hypovolemic shock, Manley and co-workers showed that a decrease in MAP related to hemorrhage led to a marked decrease in PbrO2.21,60 In one of these studies, resuscitation of the animals using the shed blood and crystalloid dramatically increased PbrO2 to levels greater than baseline. Recovery to baseline followed soon thereafter.21 Another study performed in uninjured, anesthetized swine showed that the relationship between PbrO2 and MAP (as well as CPP) clearly demonstrated pressure autoregulation. Studies using other animal systems BRAIN TISSUE OXYGEN MONITORING

have shown similar reductions in PbrO2 during hypotensive episodes.61,62 Few studies have examined the relationship between brain tissue oxygenation and blood pressure in humans. Two studies using continuous monitoring of SjvO2 showed that sudden drops in CPP caused cerebral O2 desaturation and poorer outcomes.63,64 Another study using a Licox brain tissue O2 probe in patients with severe brain injury showed that large decreases in MAP and decreases in CPP below 60 mmHg were associated with a negative effect on cerebral oxygenation.65 Because hypotension plays an important role in causing secondary brain injury,66 more studies are needed to delineate the relationship between blood pressure and brain tissue O2.

Correlation with CBF Sensitive and continuous measurement of substrate delivery to the brain is important in brain-injured patients to ensure that enough glucose and O2 reach tissues to maintain CMRO2. In these patients, however, measurement of CBF alone is insufficient because this parameter does not account for brain metabolism.67 An increase in the O2 extraction fraction (OEF) of tissue can sometimes compensate for a modest decrease in CBF, thereby, sustaining the delivery of O2 and preventing hypoxia. In this case, however, measurement of CBF alone would indi-

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cate impending ischemia and warrant aggressive therapy. Therefore, direct measurement of O2 tension in the brain is a superior method of assessing tissue oxygenation. It is important to demonstrate, however, that marked changes in CBF affect measured PbrO2 values to ensure that this measure is sensitive enough for use in clinical practice. In brain-injured patients, regional CBF measured by xenon-enhanced computed tomography (CT) strongly correlates with PbrO2 measured by a brain tissue O2 probe inserted into the cerebral cortex.68 This finding is important because measurement of PbrO2 with a brain tissue O2 probe is an accurate, reliable, and continuous method of assessing O2 delivery to the brain. Further experimentation is needed to better understand the precise relationship of CBF with PbrO2, but these results suggest a promising future for multimodal monitoring in lieu of direct CBF measurements in brain-injured patients.

Normal PbrO2 in Humans To identify thresholds of PbrO2 associated with a risk of ischemic injury to brain tissue, the normal range of values for this parameter must be known. Under normal physiological conditions, brain tissue O2 varies linearly with arterial pO2.5 Oxygen is used in tissue along a gradient as it diffuses from the terminal capillaries to the postcapillary venules. Tissue closest to the capillaries has a higher O2 tension than tissue further from the capillaries. Resolving such fine differences in location in brain tissue is neither possible with current technologies nor clinically relevant. Brain tissue O2 probes enable measurement of average cerebral oxygenation in a small volume of tissue, which is a clinically relevant parameter.4,28,69 Measurements of PbrO2 from probes situated within the same local area of brain correlate well with each other, suggesting that PbrO2 values are consistent in local brain regions.70 Several studies have been performed in animals to determine PbrO2 in normal cerebral white matter. Maas and co-workers recorded values of 28 mmHg using Licox probes placed in the frontal lobe of dogs.61,62 Using the Paratrend system, Zauner and co-workers found that the normal PbrO2 in the feline brain was 42 mmHg.36 Studies in swine using Licox probes show baseline PbrO2 values ranging from 34.4 mmHg to 41.9 mmHg.21,60,71 Recently, several groups have tried to quantify PbrO2 in normal human brain tissue to better interpret these values in pathological brain tissue. These studies are limited by ethical constraints that prohibit the placement of O2 probes into the brain tissue of healthy people. However, patients undergoing craniotomy for various neurosurgical procedures have been studied. In 14 patients undergoing craniotomy for cerebrovascular surgery, Hoffman and co-workers showed that PbrO2 was 37 mmHg in the eight patients with noncompromised cerebral circulation as demonstrated by single photon emission CT.72 Using a polarographic surface electrode for measurements, Assad and co-workers found cortical PbrO2 values between 33 and 36 mmHg in patients undergoing craniotomy for brain tumor resection.73 Meixensberger and co-workers found even higher values. The mean PbrO2 value was 47.9 mmHg using a surface Licox probe in the normal cortex of patients undergoing elective craniotomies, mostly for tumor.74 Movement of the surface probes because of an inability to secure them well and possible contamination of the reading from room air are potential confounding variables that could skew the reading from surface probes PbrO2 upward.4

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Pathological PbrO2 in Humans: Critical Thresholds In severe brain injury, the prevention of cerebral ischemia is crucial. Cerebral ischemia that occurs in both the prehospital theater75 and in the first few days after injury76 correlates with poor outcomes. To guide appropriate decisions of patient management in the intensive care unit (ICU), ischemic thresholds for PbrO2, below which targeted therapies are instituted, must be established. Many studies examining the relationship between SjvO2 and outcome76-79 support the accepted threshold of SjvO2 ⬍50% as indicative of ischemia. However, many technical problems with SjvO2 monitoring make the data unreliable.64,65 Therefore, more credence should be ascribed to the trend of SjvO2 values over time than to a single data point. In contrast, PbrO2 monitors are extremely reliable and remarkably stable in situ.65,80 Unlike jugular bulb saturation monitors, which require frequent recalibration, brain tissue O2 probes only need to be calibrated before insertion.65 Most data examining these critical values have been collected in patients suffering from TBI or otherwise undergoing a neurosurgical procedure. The recent data using the Licox system suggests that outcomes are poorer the longer cerebral white matter O2 tension is less than 15 mmHg.4,65,69 Individual PbrO2 values less than 6 mmHg at any point after injury have been prognostic of a poor outcome4 while PbrO2 values less than 5 mmHg within 24 hours of trauma have correlated negatively with outcome.28 These values, however, must be examined critically based on the technology used. The Paratrend system overestimates PbrO2 when values are near zero,4 and these are the values important in determining a critical threshold. In fact, using the Paratrend system, Doppenberg and co-workers found that all patients with PbrO2 below 25 mmHg remained vegetative or died.68 In another study using the Paratrend system, Zauner and co-workers showed that patients who suffered moderate disability had mean PbrO2 values of 31 mmHg, and lower values were associated with poorer outcomes.29 Using the Paratrend probe, the ischemic threshold for CBF of 18 mL/100 g/min81 was associated with a PbrO2 of 26 mmHg.68 Further studies are warranted to determine whether rigid cutoffs for PbrO2 values indicative of ischemia will be established or whether trends over time will be the strongest predictors of patient outcome.

Utility In Detecting Pathological Events: Comparison to SjvO2 Low values of SjvO2 correlate strongly with poor outcomes.63,76 In certain cases, abnormally high values of SjvO2 have also been associated with poor outcomes after TBI, presumably because ischemic cerebral matter loses its ability to extract O2 from the blood.82 The limitation of SjvO2 measurement is that it can only detect global ischemic insults. Focal disruption of blood flow to a particular area of brain can be detected only if the brain tissue O2 probe is placed appropriately. A major topic of continuing debate is whether these probes should be placed in relatively uninjured white matter as a marker of global cerebral oxygenation or in the penumbra of injured brain to monitor tissue at greatest risk for ischemic insult. Several studies have examined the utility of both brain tissue NEMANI AND MANLEY

O2 probes and SjvO2 monitors in the care of TBI patients. van Santbrink and co-workers simultaneously performed jugular bulb oximetry in 17 of 22 patients who were also monitored with a Licox brain tissue O2 probe. The jugular bulb oximeter was highly unreliable, providing unusable data 13.6% of the total recording time and 17.6% of the time during the first 24 hours after trauma. More importantly, frequent episodes of hypoxia were measured by the Licox system, during which high SjvO2 values were present.28 Similarly, Kiening and co-workers found that during concurrent monitoring of jugular bulb saturation and brain tissue O2 in 15 patients, good quality data for SjvO2 were present only 43% of the time compared with 95% of the time for brain PbrO2.65 The finding suggests that brain tissue O2 probes are more practical for continuous monitoring. Gopinath and co-workers assessed the ability of the two technologies to detect hypoxic events. Measurements of SjvO2 and PbrO2 were equally sensitive in detecting decreases in oxygenation below their defined threshold.83 In this study, however, the threshold for ischemia was PbrO2 ⬍ 8 mmHg. Increasing that value to 10 mmHg or 15 mmHg, values commonly used by other researchers, might have improved the sensitivity of that technique compared with SjvO2. They also found that SjvO2 best detected a reduction in oxygenation during hyperventilation, but that PbrO2 was the better measure of oxygenation during severe global ischemia. In contrast, Licox PbrO2 monitoring has detected several cases of local hypoxia related to hyperventilation in patients with severe TBI that were not detected by SjvO2 monitoring.84 This finding further emphasizes the superior role of brain tissue O2 probes in detecting local versus global hypoxic events. In addition to its use in TBI patients, brain tissue O2 has been monitored in several other clinical situations in which monitoring of SjvO2 would be inadequate. These probes can be very useful for monitoring patients at risk for ischemia, including patients with strokes or patients with vasospasm after aneurysmal SAH.85 PbrO2 monitors have also been used intraoperatively to detect regional ischemic events during aneurysm clipping86 and cardiopulmonary bypass procedures.87 As more medical centers become familiar with this technology, it will likely find widespread use in many different clinical arenas.

Response to ICU Treatments With the increasing acceptance of brain tissue O2 monitoring as a critical neuromonitoring tool, investigators are beginning to study the effects of common therapeutic interventions in the ICU on PbrO2 measurements. These treatments, such as hyperventilation, hyperoxia, and mannitol, are focused on reducing elevated ICP and on improving blood flow to the brain. However, these interventions alone do not guarantee adequate oxygenation of brain tissue, which only can be assessed by PbrO2 catheters and microdialysis techniques. The effects of changes in ventilation on PbrO2 were discussed earlier, but the effects of mannitol and antihypotensive agents are important to review. Infusion of mannitol has become a mainstay of therapy in the treatment of elevated ICP. Mannitol both decreases blood viscosity and causes osmotic diuresis, both of which combine to lower ICP.88,89 Hartl and colleagues prospectively studied the effect of mannitol infusion on PbrO2, CPP, and SjvO2 in 11 TBI patients.90 Patients whose initial ICP was greater than 20 mmHg before mannitol infusion exhibited a decrease in ICP and an increase in CPP after treatment. These findings did not BRAIN TISSUE OXYGEN MONITORING

correlate with an increase in PbrO2 or SjvO2. In fact, PbrO2 and SjvO2 remained unchanged throughout the observation period. The authors argued that the increase in CPP did not improve brain oxygenation because the baseline CPP in these patients was sufficient for O2 delivery (⬎60 mmHg) to the brain before mannitol infusion. However, patients with severe intracranial hypertension might show improved brain tissue oxygenation when ICP decreases after treatment with mannitol. Another common intervention used in the care of neurosurgical patients is the use of catecholamine pressors, such as norepinephrine, phenylephrine, or dopamine to improve MAP and CPP to improve brain tissue perfusion. Kroppenstedt and co-workers studied the effect of intravenous norepinephrine infusion on cortical perfusion and PbrO2 in rats subjected to a focal cortical contusion.91 Norepinephrine caused an increase in MAP that correlated with both increased cortical perfusion and an increase in PbrO2. This effect was most pronounced 4 hours after injury compared with 24 hours after injury, emphasizing the need for early intervention in head-injured patients.

Brain Tissue O2 as an Endpoint for Treatment Monitoring brain tissue O2 is a safe and reliable technique for monitoring cerebral oxygenation. Controversy still exists over the optimal placement of these probes. Some argue that they should be placed in the subcortical white matter of relatively undamaged brain as a measure of global cerebral oxygenation while others emphasize that PbrO2 should be monitored in the penumbra of an intracranial lesion or vascular territory. Additional studies of TBI in large animals using multiple PbrO2 probes in and around the injury are required to address these issues. Current clinical practice aims to reduce elevated ICP and to increase CPP to improve blood flow to the brain, thereby improving tissue oxygenation. However, the endpoints used in neurosurgical patients do not directly measure O2 in the brain parenchyma and only provide indirect measures of O2 delivery. PbrO2 monitoring provides a direct measurement of O2 tension in the brain and provides clinicians with an accurate endpoint with which to guide CPP-targeted therapy. The use of PbrO2 probes in combination with monitoring of SjvO2 and the use of microdialysis instruments provides great detail about the metabolic condition of the brain. Further experience in using these technologies will lead to improvements in patient outcomes. Randomized clinical trials must be performed to confirm the efficacy of PbrO2 monitoring as an appropriate endpoint to O2-targeted therapy in these patients.

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