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Brain Tissue Oxygen Monitoring in Neurocritical Care Michael A. De Georgia J Intensive Care Med published online 6 April 2014 DOI: 10.1177/0885066614529254 The online version of this article can be found at: http://jic.sagepub.com/content/early/2014/04/03/0885066614529254
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Article
Brain Tissue Oxygen Monitoring in Neurocritical Care
Journal of Intensive Care Medicine 1-11 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066614529254 jic.sagepub.com
Michael A. De Georgia, MD1
Abstract Brain injury results from ischemia, tissue hypoxia, and a cascade of secondary events. The cornerstone of neurocritical care management is optimization and maintenance of cerebral blood flow (CBF) and oxygen and substrate delivery to prevent or attenuate this secondary damage. New techniques for monitoring brain tissue oxygen tension (PtiO2) are now available. Brain PtiO2 reflects both oxygen delivery and consumption. Brain hypoxia (low brain PtiO2) has been associated with poor outcomes in patients with brain injury. Strategies to improve brain PtiO2 have focused mainly on increasing oxygen delivery either by increasing CBF or by increasing arterial oxygen content. The results of nonrandomized studies comparing brain PtiO2-guided therapy with intracranial pressure/cerebral perfusion pressure-guided therapy, while promising, have been mixed. More studies are needed including prospective, randomized controlled trials to assess the true value of this approach. The following is a review of the physiology of brain tissue oxygenation, the effect of brain hypoxia on outcome, strategies to increase oxygen delivery, and outcome studies of brain PtiO2-guided therapy in neurocritical care. Keywords brain tissue oxygen tension, monitoring, neurocritical care, brain injury, brain ischemia
Introduction Brain injury results from ischemia, tissue hypoxia, and a cascade of secondary events. Because these secondary events usually occur while patients are in the intensive care unit, the cornerstone of management includes optimization of cerebral blood flow (CBF) and oxygen and substrate delivery. New techniques for continuous monitoring of brain tissue oxygen tension (PtiO2) are now available that can provide a better understanding of complex brain physiology and help guide this management. The following is a review of the physiology of brain tissue oxygenation, the effect of brain hypoxia on outcome, strategies to increase oxygen delivery, and outcome studies of brain PtiO2-guided therapy in neurocritical care.
Physiology of Brain Tissue Oxygenation Normal brain metabolism has several unique features including limited intrinsic stores of high-energy phosphate compounds and a high metabolic demand (cerebral metabolic rate of oxygen [CMRO2]). The brain is therefore critically dependent upon a continuous blood-borne supply of oxygen and glucose to meet that demand. Oxygen delivery is the product of CBF arterial oxygen content. Cerebral blood flow is governed by the Hagen-Poiseuille equation, correlating directly with cerebral perfusion pressure (CPP), the difference between mean arterial pressure (MAP) and intracranial pressure (ICP), and
vessel radius and inversely with blood viscosity and vessel length (CBF ¼ DPpr4/8ZL, where r ¼ radius, P ¼ pressure, Z ¼ viscosity, and L ¼ length). Oxygen is carried in blood both bound to hemoglobin and dissolved in plasma. Each gram of hemoglobin carries 1.34 mL of oxygen. Dissolved oxygen follows Henry’s law: the amount of oxygen dissolved is proportional to the partial pressure. For each mm Hg of PaO2, there is 0.0031 mL of O2/dL dissolved. Thus, arterial oxygen content, the total amount of oxygen in arterial blood, can be estimated by the following formula: (1.34 hemoglobin arterial oxygen saturation) þ (0.0031 PaO2). It is the oxygen dissolved in plasma that diffuses into tissue according to the oxygen pressure differential between the capillary and the tissue, specifically the mitochondria in the cell.1 The physics of oxygen diffusion were determined at the turn of the 20th century by a Danish physiologist named August
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Case Western Reserve University School of Medicine, Neurological Institute, University Hospitals Case Medical Center, Cleveland, OH, USA
Received November 14, 2013, and in revised form December 31, 2013. Accepted for publication January 14, 2013. Corresponding Author: Michael A. De Georgia, Case Western Reserve University School of Medicine, Neurological Institute, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA. Email: [email protected]
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Journal of Intensive Care Medicine
Figure 1. Oxygen supply and transport. A, Oxygen supply to tissue is generally conceptualized based on the simple Krogh tissue cylinder model in which all oxygen exchange occurs across the walls of the capillaries. As such, oxygen content within the capillary falls linearly as oxygen diffuses out of the vessel at a constant rate. B, Our current understanding of the complex oxygen transport pathways controlling oxygen supply includes convective oxygen transport through the microvessels (solid line) coupled with diffusive oxygen exchange (broken lines) among all orders of microvessels. With permission from the American Physiological Society.7
Krogh, the recipient of the 1920 Nobel Prize in Physiology or Medicine.2 His model assumes a central capillary surrounded by a homogenously respiring tissue cylinder. Under these conditions, the oxygen content of the capillary blood decreases linearly from the arterial to the venous end of the capillary as oxygen diffuses perpendicularly away from the vessel. The diffusion rate is determined by the partial pressure of oxygen difference between the capillary and the cell divided by the oxygen solubility and the oxygen diffusion coefficient the radius of the cylinder, the radius of the capillary, and the radius to the point of measurement.3 Although the Krogh model is intuitive, nevertheless it is overly simplistic in many ways. First, it assumes that oxygen diffuses evenly and uniformly through the tissue. With brain injury, however, diffusion barriers often develop as a result of microvascular collapse, endothelial swelling, and perivascular edema that can impede oxygen delivery.4 Second, the model assumes that oxygen is consumed in the tissue at a constant rate and fails to explain the tight coupling between oxygen delivery and metabolism. In order to increase oxygen delivery to meet an increase in demand, the Krogh model requires an increase in capillary density, so-called ‘‘capillary recruitment.’’ Recent evidence, however, suggests that oxygen delivery is directly regulated mainly by changes in vessel caliber at the microcirculatory level, this is in addition to changes in vessel
caliber in larger resistance vessels.5,6 At the microcirculatory level, because the oxygen content of the erythrocyte is directly linked to the level of oxygen consumption of the tissue, it has been proposed that the erythrocytes themselves, by releasing adenosine triphosphate, may be able to sense oxygen need and dilate the microcirculatory vessels through which they are traversing, thus exquisitely matching oxygen delivery with metabolic demand.7 Finally, the original Krogh model assumes that each capillary is the sole supplier of a single cylinder of tissue. The current understanding of oxygen transport is more complex. The circulation supplies oxygen to tissue at multiple levels, including directly from the arteriole.8,9 The result is spatial heterogeneity of perfusion and oxygen delivery10,11 (Figure 1). The normal brain PtiO2 usually ranges from 20 to 35 mm Hg.12-14 Most likely this represents the ‘‘pool’’ of oxygen that accumulates within the tissue. This ‘‘pool’’ is influenced by both oxygen delivery and consumption but it is not a simple balance between these 2. The exact PtiO2 threshold that represents ischemia is not known. In the literature, ischemic thresholds have ranged between 10 and 19 mm Hg.15-17 However, a threshold of 10 to 15 mm Hg has been most often used primarily based on positron emission tomography (PET)validated studies.4,18 Brain PtiO2 < 5 mm is associated with cell death.19-21
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Methods to Measure Brain PtiO2 There are 2 methods used to measure brain PtiO2, the optical luminescent method and the polarographic method. In the optical luminescent method, oxygen molecules diffuse into a silicone matrix and change the color of a Ruthenium dye. A pulse of light is sent down a fiber optic filament and as it penetrates the dye it changes frequency. The change in frequency is then converted into a partial pressure of oxygen. This is the method that was used in the Neurotrend (Diametrics Medical, St Paul, Minnesota; no longer commercially available in the United States) and currently used in the OxyLab pO2 (Oxford Optronix Ltd, Oxford, United Kingdom) and the Neurovent-PTO (Raumedic AG, Munchberg, Germany). In the polarographic method, a Clark electrode is used to estimate the PtiO2. A Clark electrode is similar to a battery in that it is composed of a silver electrode (the anode) and a platinum electrode (the cathode) covered by a membrane. Oxygen diffuses through the membrane and is reduced at the cathode. That is, electrons flow from the anode to the cathode as electrons there combine with oxygen and hydrogen to produce water. The rate at which electrons ‘‘boil off’’ is proportional to the concentration of oxygen available to ‘‘grab’’ them. The generated ‘‘galvanic’’ current is then converted to a partial pressure of oxygen. This reaction is temperature dependent and therefore a temperature probe is included in the catheter. This technique was developed initially for measurement of oxygen tension in muscle tissue22 and was introduced for brain tissue monitoring in 1993.12 Using this method, the Licox Brain Oxygen Monitor (Integra Neuroscience, Plainsboro, New Jersey) was Food and Drug Administration approved in the United States in 2001. Most of the studies in the literature have been performed using the Licox Brain Oxygen Monitor. In comparing the 2 methods, both measure oxygen tension with high accuracy and stability during in vitro testing, although the precision tends to be slightly higher using the optical luminescent method. Response times to changes in oxygen concentration tend to be slightly shorter with the optical luminescent method (56.2 + 22 seconds) compared with the polarographic method (78.2 + 21 seconds), although these differences are not likely to be clinically significant. Both methods are associated with minimal drift (less than 1 mm Hg) over a 10-day period.23,24 The Licox monitor is inserted into the brain parenchyma in a manner similar to fiberoptic ICP monitor, generally 3.5 cm below the dura. The active tip of the catheter lies 2.5 to 3 cm below the dura in the frontal white matter. It measures the partial pressure of oxygen in a 13-mm tissue cylinder around the catheter. Brain PtiO2 measurements vary depending on whether the monitor is placed into lesioned or nonlesioned tissue.15,25 In patients with traumatic brain injury (TBI), most centers tend to place the monitor into tissue that appears normal on the brain computed tomography (CT) scan in the frontal lobe of the most severely injured hemisphere. When there is diffuse injury, the monitor is usually placed in the nondominant hemisphere. Although placement in penumbral areas can theoretically provide information about impending secondary
damage, accurately identifying those areas by brain CT scan is often difficult.26 Lower brain PtiO2 values and longer durations of low PtiO2 have also been reported when the monitor has been placed in pericontusional tissue.27 In patients with aneurysmal subarachnoid hemorrhage (SAH), the monitor is usually placed on the side of the ruptured aneurysm or the side where the hemorrhage is thickest, the area most at risk of vasospasm. Although the optimal location for monitor placement in various disease states is still being studied, knowledge about where the monitor is placed is important in interpreting brain oxygen monitoring literature.28
Effect of Brain Hypoxia on Outcome Several studies have examined the effect of brain hypoxia on outcome in patients with SAH and TBI. For example, KettWhite and colleagues reported 36 patients with aneurysmal SAH monitored with the Neurotrend, inserted into the frontal region, close to the midline in patients with anterior communicating artery aneurysms or in a more posterolateral location otherwise. Overall, 13 patients had severe brain hypoxia defined as 5 or more 30-minute episodes of PtiO2 60 mm Hg) and the brain PtiO2 target was higher (>25 mm Hg). In the ICP/CPP group, patients received management that consisted of vasopressors, mannitol, external ventricular drainage of cerebrospinal fluid, and pharmacological paralysis. They also received ‘‘optimized hyperventilation’’ using jugular bulb oximetry and, in refractory patients, barbiturate infusions to achieve burst suppression or decompressive craniectomy. In the brain PtiO2 group to counteract hypoxic episodes, patients were treated with intermittent hyperoxia and blood transfusion to maintain hemoglobin >10 g/dL. Although there were no significant differences in the average ICP or CPP values between the 2 groups, the ICPs tended to be slightly higher in the brain PtiO2 group (25.5 + 9.5) than in the ICP/ CPP group (21.5 + 6.9) consistent with the authors’ ‘‘tolerance’’ of mild ICP elevation (25-30 mm Hg) as long as the brain PtiO2 was adequate. The results showed that patients had lower mortality rates in the brain PtiO2 group (25%) compared with the ICP/CPP group (34%; P ¼ .05).85 The authors postulated that the benefits of brain PtiO2-guided therapy may have stemmed not only from reducing brain hypoxia but also potentially from minimizing systemic complications from overzealous treatment of CPP with vasopressors and fluids.86,87 In 2010, the same group reported their further experience with this approach (ICP/CPP group, n ¼ 53; brain PtiO2 group, n ¼ 70). The PtiO2 target was reduced to 20 mm Hg and, as before, patients had reduced mortality rates with brain PtiO2-guided therapy (26% vs 35%, P ¼ .05).88 Narotam and colleagues reported a retrospective review of ICP/CPP-guided therapy (n ¼ 41, 1998-2000) versus brain PtiO2-guided therapy (n ¼ 139, 2001-2005). In this study, the ICP/CPP group underwent ICP monitoring only and the brain PtiO2 group underwent both ICP and PtiO2 monitoring. Licox monitors placed mainly in the nondominant hemisphere (73%). The ICP/CPP group was treated targeting an ICP < 20 mm Hg and CPP > 60 mm Hg with vasopressors, external ventricular drainage of cerebrospinal fluid, mannitol, hyperventilation, barbiturate infusions, or decompressive craniectomy. The PtiO2 goal was >20 mm Hg using, if needed, hyperoxia and blood transfusions to maintain hemoglobin >12.5 g/dL. The results showed a reduction in mortality in the brain PtiO2 group (26%) compared with the ICP/CPP group (42%), although the mean Glasgow Coma Scale score on admission was lower in the brain PtiO2 group (5.9 + 3.7 vs 7.3 + 4.8, P < .05). Among survivors at 6 months, the average GOS score was also higher in the brain PtiO2 group (3.55 + 1.75 vs 2.71 + 1.65, P < .01).89 Green and colleagues reported a retrospective analysis of 37 patients who underwent ICP monitoring only versus 37 patients who concurrently underwent ICP and brain PtiO2 monitoring.
Licox monitors were placed in ‘‘noninjured brain tissue’’ (the side was not specified). In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, the goal was to maintain the PtiO2 >20 mm Hg using optimization of CPP, hyperoxia, and transfusion (hemoglobin >10 g/dL) to counteract hypoxic episodes. The ICP and CPP values were similar in both groups; however, patients in the brain PtiO2 group underwent decompressive craniectomy more frequently than in the ICP group (18 vs 9, P ¼ .03). Overall, there was no difference in mortality rates or functional outcome (GOS or Functional Independence Measure Score, FIMS).90 Martini and colleagues reported a retrospective analysis of 506 patients who underwent ICP monitoring only compared with 127 patients who concurrently underwent ICP and brain PtiO2 monitoring at the ‘‘discretion of the treating neurosurgeon.’’ In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, Licox monitors were placed in normal tissue on the side of the more severely injured hemisphere, and a PtiO2 >20 mm Hg was targeted. Patients in the brain PtiO2 group received more aggressive management including use of vasopressors, hypertonic saline, mannitol, and sedation with a longer duration of mechanical ventilation, and an increased ICU length of stay. The results showed no difference in mortality rates, but among survivors, the functional outcome was actually worse in the brain PtiO2 group (functional independence in 64.4%) than in the ICP group (functional independence in 77.3%; P ¼ .01).91 The reason this group did worse is not clear but may reflect inherent differences in the 2 groups; patients in the brain PtiO2 group had more severe brain injuries at baseline. However, it may also be the result of the more aggressive management the patients received leading to complications that outweighed any benefits from preventing brain hypoxia. There have been only 2 prospective studies in patients with TBI. Adamides and colleagues reported a prospective study of 10 patients who underwent ICP and brain PtiO2 monitoring following ICP/CPP-guided therapy compared with 20 patients who underwent ICP and brain PtiO2 monitoring following brain PtiO2-guided therapy. Licox monitors were placed contralateral to the more severely injured side. In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, a PtiO2 >20 mm Hg was targeted using a standard algorithm that included increasing the CPP to 70 mm Hg, hyperoxia (adjusting ventilation for a PaO2 > 100 mm Hg), and blood transfusion to maintain hemoglobin >10 g/dL. Average ICP was lower in the brain PtiO2-guided therapy (13.4 + 0.7) compared with the ICP/CPP-guided therapy group (16.7 + 1.0; P ¼ .01), although CPP and PtiO2 levels were the same. At 6 months, there was no statistically significant difference in neurological outcome between those patients treated with and those without brain PtiO2-guided therapy. The outcome of a third group of 18 matched control patients who underwent ICP monitoring only was the same as in the PtiO2-guided therapy.92 McCarthy and colleagues reported a prospective study of 64 patients who underwent ICP monitoring only compared with 81 patients who underwent
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Table 1. Studies of Brain PtiO2-Guided Therapy Versus ICP/CPP-Guided Therapy. ICP/CPP-Guided Therapy
PtiO2-Guided Therapy
Meixensberger et al36
39
52
GOS at 6 months
2005
Stiefel et al85
25
28
Mortality at discharge
2009
Martini et al91
506
123
FIM at discharge
2009 2009
Adamides et al92 McCarthy et al93
10 48
20 63
GOS at 6 months GOS at 3 months
2009
Narotam et al89
41
127
GOS at 6 months
2010
Spiotta et al88
53
70
GOS at 3 months
2013
Green et al90
37
37
Mortality at discharge
Year
Author
2003
Outcome Measure
Results No benefit 54% vs 65% P ¼ .27 Reduced mortality 34% vs 25% P < .05 Worse outcome 8.6 vs 7.6 P < .01 No benefit Trend toward better outcome 61% vs 79% P ¼ .09 Better outcome 2.7 vs 3.5 P ¼ .01 Reduced mortality 35% vs 26% P ¼ .01 No benefit 54% vs 65% P ¼ .34
Abbreviations: CPP, cerebral perfusion pressure; FIM, Functional Independence Measure; ICP, intracranial pressure; GOS, Glasgow Outcome Scale; PtiO2, brain tissue oxygen tension.
both ICP and brain PtiO2 monitoring with Licox monitors placed in the nondominant hemisphere, regardless of the site of injury. In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, a PtiO2 >20 mm Hg was targeted using hyperoxia and blood transfusion if needed although the hemoglobin threshold for transfusion was not specified. Outcome measures were GOS scores at 3, 6, 12, and 24 months after discharge. The results showed no difference in mortality rates, although among the survivors, there was a trend toward a better outcome in the brain PtiO2 group at 3 months (79% good outcome) compared with the ICP/CPP group (61%; P ¼ .09). Outcomes at 6 months were also better in the PtiO2 group (83% vs 70%) but the difference was not significant. There were too few patients at 12 and 24 months for comparison93 (see Table 1). In summary, the results of these nonrandomized studies in patients with TBI comparing brain PtiO2-guided therapy with ICP/CPP-guided therapy, while promising, have been mixed. Fundamentally, though, the brain tissue PtiO2 catheter is a monitoring tool. If it is used to direct therapy and there is no improvement in outcome, then the therapy is not effective, or worse, potentially harmful. Thus, there is a need for better treatment strategies based on the measurements obtained and prospective, randomized trials of those strategies to determine whether the benefits outweigh the risks and whether ultimately this approach leads to better patient outcomes. A phase II randomized clinical trial examining the value of brain oxygen monitoring in TBI is currently in the planning stages94.
Conclusions Continuous brain tissue oxygen monitoring offers the opportunity to gain better insight into complex brain physiology in order to optimize the management and potentially improve patient outcomes after acute brain injury. Some general conclusions can be made about brain tissue oxygen monitoring: Brain PtiO2 reflects both oxygen delivery and consumption and likely represents the ‘‘pool’’ of oxygen that accumulates within the tissue. The normal brain PtiO2 usually ranges from 20 to 35 mm Hg, and the ischemic threshold ranges from 10 to 15 mm Hg. Low brain PtiO2 is associated with poor outcome and can only be detected with continuous brain PtiO2 monitoring; the sensitivity of ICP and CPP monitoring for detecting brain hypoxia is low. Low brain PtiO2 can be increased by strategies aimed at increasing oxygen delivery (CBF arterial oxygen content). Increasing the CPP can improve brain PtiO2, especially when cerebral autoregulation is impaired and the baseline PtiO2 is low. Impaired cerebral autoregulation (ORx) is associated with a poor outcome. Increasing the FiO2 (hyperoxia) can improve brain PtiO2, especially when oxygen autoregulation is impaired and the baseline PtiO2 is high.
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Journal of Intensive Care Medicine Impaired oxygen autoregulation (TOR) is associated with a poor outcome. It is not clear whether hyperoxia actually improves brain metabolism. Other strategies may improve brain PtiO2 but not always (eg, intra-arterial intervention and barbiturates). Blood transfusion may improve brain PtiO2. Whether it improves brain metabolism and leads to a cellular benefit that outweighs the risk is not clear. The results of nonrandomized studies comparing brain PtiO2-guided therapy with ICP/CPP-guided therapy in the setting of TBI have been mixed. More studies are needed including prospective, randomized controlled trials to assess the benefit of this approach.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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26. Coles JP, Fryer TD, Smielewski P, et al. Defining ischemic burden after traumatic brain injury using 15O PET imaging of cerebral physiology. J Cereb Blood Flow Metab. 2004;24(2):191-201. 27. Longhi L, Pagan F, Valeriani V, et al. Monitoring brain tissue oxygen tension in brain-injured patients reveals hypoxic episodes in normal-appearing and in peri-focal tissue. Int Care Med. 2007; 33(12):2136-2142. 28. Ponce LL, Pillai S, Cruz J, et al. Position of probe determines prognostic information of brain tissue PO2 in severe traumatic brain injury. Neurosurgery. 2012;70(6):1492-1502; discussion 1502-1493. 29. Kett-White R, Hutchinson PJ, Al-Rawi PG, Gupta AK, Pickard JD, Kirkpatrick PJ. Adverse cerebral events detected after subarachnoid hemorrhage using brain oxygen and microdialysis probes. Neurosurgery. 2002;50(6):1213-1221; discussion 12211212. 30. Va¨th A, Kunze E, Roosen K, Meixensberger J. Therapeutic aspects of brain tissue pO2 monitoring after subarachnoid hemorrhage. Acta Neurochir Suppl. 2002;81:307-309. 31. Chen HI, Stiefel MF, Oddo M, et al. Detection of cerebral compromise with multimodality monitoring in patients with subarachnoid hemorrhage. Neurosurgery. 2011;69(1):53-63; discussion 63. 32. Bardt TF, Unterberg AW, Hartl R, Kiening KL, Schneider GH, Lanksch WR. Monitoring of brain tissue PO2 in traumatic brain injury: effect of cerebral hypoxia on outcome. Acta Neurochir Suppl. 1998;71:153-156. 33. van den Brink WA, van Santbrink H, Steyerberg EW, et al. Brain oxygen tension in severe head injury. Neurosurgery. 2000;46(4): 868-876; discussion 876-868. 34. Maloney-Wilensky E, Gracias V, Itkin A, et al. Brain tissue oxygen and outcome after severe traumatic brain injury: a systematic review. Crit Care Med. 2009;37(6):2057-2063. 35. Eriksson EA, Barletta JF, Figueroa BE, et al. The first 72 hours of brain tissue oxygenation predicts patient survival with traumatic brain injury. J Trauma Acute Care Surg. 2012;72(5):1345-1349. 36. Meixensberger J, Jaeger M, Va¨th A, Dings J, Kunze E, Roosen K. Brain tissue oxygen guided treatment supplementing ICP/CPP therapy after traumatic brain injury. J Neurol Neurosurg Psychiatry. 2003;74(6):760-764. 37. Oddo M, Levine JM, Mackenzie L, et al. Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurgery. 2011;69(5):1037-1045; discussion 1045. 38. Rohlwink UK, Zwane E, Fieggen AG, Argent AC, le Roux PD, Figaji AA. The relationship between intracranial pressure and brain oxygenation in children with severe traumatic brain injury. Neurosurgery. 2012;70(5):1220-1230; discussion 1231. 39. Radolovich DK, Czosnyka M, Timofeev I, et al. Transient changes in brain tissue oxygen in response to modifications of cerebral perfusion pressure: an observational study. Anesth Analg. 2010;110(1):165-173. 40. Stocchetti N, Chieregato A, De Marchi M, Croci M, Benti R, Grimoldi N. High cerebral perfusion pressure improves low values of local brain tissue O2 tension (PtiO2) in focal lesions. Acta Neurochir Suppl. 1998;71:162-165.
41. Jaeger M, Schuhmann MU, Soehle M, Meixensberger J. Continuous assessment of cerebrovascular autoregulation after traumatic brain injury using brain tissue oxygen pressure reactivity. Critical Care Medicine. 2006;34(6):1783-1788. 42. Czosnyka M, Smielewski P, Kirkpatrick P, Laing RJ, Menon D, Pickard JD. Continuous assessment of the cerebral vasomotor reactivity in head injury. Neurosurgery. 1997;41(1):11-17; discussion 17-19. 43. Czosnyka M, Balestreri M, Steiner L, et al. Age, intracranial pressure, autoregulation, and outcome after brain trauma. J Neurosurg. 2005;102(3):450-454. 44. Jaeger M, Schuhmann MU, Soehle M, Nagel C, Meixensberger J. Continuous monitoring of cerebrovascular autoregulation after subarachnoid hemorrhage by brain tissue oxygen pressure reactivity and its relation to delayed cerebral infarction. Stroke. 2007; 38(3):981-986. 45. Jaeger M, Soehle M, Schuhmann MU, Meixensberger J. Clinical significance of impaired cerebrovascular autoregulation after severe aneurysmal subarachnoid hemorrhage. Stroke. 2012; 43(8):2097-2101. 46. Radolovich DK, Czosnyka M, Timofeev I, et al. Reactivity of brain tissue oxygen to change in cerebral perfusion pressure in head injured patients. Neurocritical Care. 2009;10(3):274-279. 47. Dengler J, Frenzel C, Vajkoczy P, Horn P, Wolf S. The oxygen reactivity index and its relation to sensor technology in patients with severe brain lesions. Neurocritical Care. 2013;19(1):74-78. 48. Steiner T, Pilz J, Schellinger P, et al. Multimodal online monitoring in middle cerebral artery territory stroke. Stroke. 2001;32(11): 2500-2506. 49. Jaeger M, Soehle M, Meixensberger J. Effects of decompressive craniectomy on brain tissue oxygen in patients with intracranial hypertension. J Neurol Neurosurg Psychiatry. 2003;74(4):513-515. 50. Stiefel MF, Heuer GG, Smith MJ, et al. Cerebral oxygenation following decompressive hemicraniectomy for the treatment of refractory intracranial hypertension. J Neurosurg. 2004;101(2):241-247. 51. Oddo M, Levine JM, Frangos S, et al. Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension. J Neurol Neurosurg Psychiatry. 2009;80(8):916-920. 52. Chen HI, Malhotra NR, Oddo M, Heuer GG, Levine JM, LeRoux PD. Barbiturate infusion for intractable intracranial hypertension and its effect on brain oxygenation. Neurosurgery. 2008;63(5): 880-886; discussion 886-887. 53. Reisch R, Mauer D, Ringel K, Perneczky A. The effect of intra-arterial infusion of papavarine hydrochloride on brain tissue oxygen pressure and cerebral blood flow in the management of severe vasospasm following aneurysmal subarachnoid hemorrhage. Zentralbl Neurochir. 1999;60:33-54. 54. Charbel FT, Du X, Hoffman WE, Ausman JI. Brain tissue PO(2), PCO(2), and pH during cerebral vasospasm. Surg Neurol. 2000; 54(6):432-437; discussion 438. 55. Deshaies EM, Jacobsen W, Singla A, Li F, Gorji R. Brain tissue oxygen monitoring to assess reperfusion after intra-arterial treatment of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm: a retrospective study. AJNR Am J Neuroradiol. 2012;33(7):1411-1415.
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56. Stiefel MF, Spiotta AM, Udoetuk JD, et al. Intra-arterial papaverine used to treat cerebral vasospasm reduces brain oxygen. Neurocrit Care. 2006;4(2):113-118. 57. Stuart RM, Helbok R, Kurtz P, et al. High-dose intra-arterial verapamil for the treatment of cerebral vasospasm after subarachnoid hemorrhage: prolonged effects on hemodynamic parameters and brain metabolism. Neurosurgery. 2011;68(2):337-345; discussion 345. 58. Oddo M, Nduom E, Frangos S, et al. Acute lung injury is an independent risk factor for brain hypoxia after severe traumatic brain injury. Neurosurgery. 2010;67(2):338-344. 59. Reinprecht A, Greher M, Wolfsberger S, Dietrich W, Illievich UM, Gruber A. Prone position in subarachnoid hemorrhage patients with acute respiratory distress syndrome: effects on cerebral tissue oxygenation and intracranial pressure. Crit Care Med. 2003;31(6):1831-1838. 60. Hlatky R, Valadka AB, Gopinath SP, Robertson CS. Brain tissue oxygen tension response to induced hyperoxia reduced in hypoperfused brain. J Neurosurg. 2008;108(1):53-58. 61. Longhi L, Valeriani V, Rossi S, De Marchi M, Egidi M, Stocchetti N. Effects of hyperoxia on brain tissue oxygen tension in cerebral focal lesions. Acta Neurochir Suppl. 2002;81:315-317. 62. Figaji AA, Zwane E, Graham Fieggen A, Argent AC, Le Roux PD, Peter JC. The effect of increased inspired fraction of oxygen on brain tissue oxygen tension in children with severe traumatic brain injury. Neurocrit Care. 2010;12(3):430-437. 63. van Santbrink H, vd Brink WA, Steyerberg EW, Carmona Suazo JA, Avezaat CJ, Maas AI. Brain tissue oxygen response in severe traumatic brain injury. Acta Neurochir (Wien). 2003;145(6): 429-438; discussion 438. 64. Floyd TF, Clark JM, Gelfand R, et al. Independent cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1 ATA. J Appl Physiol (1985). 2003;95(6): 2453-2461. 65. Nakajima S, Meyer JS, Amano T, Shaw T, Okabe T, Mortel KF. Cerebral vasomotor responsiveness during 100% oxygen inhalation in cerebral ischemia. Arch Neurol. 1983;40(5):271-276. 66. Jaeger M, Lang EW. Cerebrovascular pressure reactivity and cerebral oxygen regulation after severe head injury. Neurocrit Care. 2013;19(1):69-73. 67. Magnoni S, Ghisoni L, Locatelli M, et al. Lack of improvement in cerebral metabolism after hyperoxia in severe head injury: a microdialysis study. J Neurosurg. 2003;98(5):952-958. 68. Diringer MN, Aiyagari V, Zazulia AR, Videen TO, Powers WJ. Effect of hyperoxia on cerebral metabolic rate for oxygen measured using positron emission tomography in patients with acute severe head injury. J Neurosurg. 2007;106(4):526-529. 69. Oddo M, Milby A, Chen I, et al. Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2009;40(4):1275-1281. 70. Chang JJ, Youn TS, Benson D, et al. Physiologic and functional outcome correlates of brain tissue hypoxia in traumatic brain injury. Criti Care Med. 2009;37(1):283-290. 71. Smith MJ, Stiefel MF, Magge S, et al. Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med. 2005; 33(5):1104-1108.
72. Zygun DA, Nortje J, Hutchinson PJ, Timofeev I, Menon DK, Gupta AK. The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med. 2009;37(3):1074-1078. 73. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group [see comment; erratum appears in N Engl J Med. 1999;340(13):1056]. N Engl J Med. 1999;340(6):409-417. 74. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes [see comment]. JAMA. 2004;292(13): 1555-1562. 75. Smith MJ, Le Roux PD, Elliott JP, Winn HR. Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage [see comment]. J Neurosurg. 2004;101(1):1-7. 76. Taylor RW, Manganaro L, O’Brien J, Trottier SJ, Parkar N, Veremakis C. Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient [see comment]. Crit Care Med. 2002;30(10):2249-2254. 77. Shorr AF, Jackson WL. Transfusion practice and nosocomial infection: assessing the evidence. Curr Opin Crit Care. 2005; 11(5):468-472. 78. Zallen G, Offner PJ, Moore EE, et al. Age of transfused blood is an independent risk factor for postinjury multiple organ failure. Am J Surg. 1999;178(6):570-572. 79. Moore FA, Moore EE, Sauaia A. Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132(6):620-624; discussion 624-625. 80. Webert KE, Blajchman MA. Transfusion-related acute lung injury. Curr Opin Hematol. 2005;12(6):480-487. 81. Heddle NM, Klama LN, Griffith L, Roberts R, Shukla G, Kelton JG. A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion. 1993;33(10):794-797. 82. Silliman CC, Boshkov LK, Mehdizadehkashi Z, et al. Transfusionrelated acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood. 2003;101(2):454-462. 83. Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005; 33(4):721-726. 84. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the critically ill–current clinical practice in the United States [see comment]. Crit Care Med. 2004;32(1):39-52. 85. Stiefel MF, Spiotta A, Gracias VH, et al. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg. 2005;103(5):805-811. 86. Fletcher JJ, Bergman K, Blostein PA, Kramer AH. Fluid balance, complications, and brain tissue oxygen tension monitoring following severe traumatic brain injury. Neurocrit Care. 2010;13(1):47-56. 87. Contant CF, Valadka AB, Gopinath SP, Hannay HJ, Robertson CS. Adult respiratory distress syndrome: a complication of induced hypertension after severe head injury. J Neurosurg. 2001;95(4): 560-568.
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88. Spiotta AM, Stiefel MF, Gracias VH, et al. Brain tissue oxygen-directed management and outcome in patients with severe traumatic brain injury. J Neurosurg. 2010;113(3): 571-580. 89. Narotam PK, Morrison JF, Nathoo N. Brain tissue oxygen monitoring in traumatic brain injury and major trauma: outcome analysis of a brain tissue oxygen-directed therapy. J Neurosurg. 2009;111(4):672-682. 90. Green JA, Pellegrini DC, Vanderkolk WE, Figueroa BE, Eriksson EA. Goal directed brain tissue oxygen monitoring versus conventional management in traumatic brain injury: an analysis of in hospital recovery. Neurocrit Care. 2013;18(1):20-25.
91. Martini RP, Deem S, Yanez ND, et al. Management guided by brain tissue oxygen monitoring and outcome following severe traumatic brain injury. J Neurosurg. 2009;111(4):644-649. 92. Adamides AA, Cooper DJ, Rosenfeldt FL, et al. Focal cerebral oxygenation and neurological outcome with or without brain tissue oxygen-guided therapy in patients with traumatic brain injury. Acta Neurochir. 2009;151(11):1399-1409. 93. McCarthy MC, Moncrief H, Sands JM, et al. Neurologic outcomes with cerebral oxygen monitoring in traumatic brain injury. Surgery. 2009;146(4):585-590; discussion 590-581. 94. Brain Tissue Oxygen Monitoring in Traumatic Brain Injury, BOOST 2. Identifier NCT00974259. www.ClinicalTrials.gov
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Brain Tissue Oxygen Monitoring in Neurocritical Care Michael A. De Georgia J Intensive Care Med published online 6 April 2014 DOI: 10.1177/0885066614529254 The online version of this article can be found at: http://jic.sagepub.com/content/early/2014/04/03/0885066614529254
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Article
Brain Tissue Oxygen Monitoring in Neurocritical Care
Journal of Intensive Care Medicine 1-11 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066614529254 jic.sagepub.com
Michael A. De Georgia, MD1
Abstract Brain injury results from ischemia, tissue hypoxia, and a cascade of secondary events. The cornerstone of neurocritical care management is optimization and maintenance of cerebral blood flow (CBF) and oxygen and substrate delivery to prevent or attenuate this secondary damage. New techniques for monitoring brain tissue oxygen tension (PtiO2) are now available. Brain PtiO2 reflects both oxygen delivery and consumption. Brain hypoxia (low brain PtiO2) has been associated with poor outcomes in patients with brain injury. Strategies to improve brain PtiO2 have focused mainly on increasing oxygen delivery either by increasing CBF or by increasing arterial oxygen content. The results of nonrandomized studies comparing brain PtiO2-guided therapy with intracranial pressure/cerebral perfusion pressure-guided therapy, while promising, have been mixed. More studies are needed including prospective, randomized controlled trials to assess the true value of this approach. The following is a review of the physiology of brain tissue oxygenation, the effect of brain hypoxia on outcome, strategies to increase oxygen delivery, and outcome studies of brain PtiO2-guided therapy in neurocritical care. Keywords brain tissue oxygen tension, monitoring, neurocritical care, brain injury, brain ischemia
Introduction Brain injury results from ischemia, tissue hypoxia, and a cascade of secondary events. Because these secondary events usually occur while patients are in the intensive care unit, the cornerstone of management includes optimization of cerebral blood flow (CBF) and oxygen and substrate delivery. New techniques for continuous monitoring of brain tissue oxygen tension (PtiO2) are now available that can provide a better understanding of complex brain physiology and help guide this management. The following is a review of the physiology of brain tissue oxygenation, the effect of brain hypoxia on outcome, strategies to increase oxygen delivery, and outcome studies of brain PtiO2-guided therapy in neurocritical care.
Physiology of Brain Tissue Oxygenation Normal brain metabolism has several unique features including limited intrinsic stores of high-energy phosphate compounds and a high metabolic demand (cerebral metabolic rate of oxygen [CMRO2]). The brain is therefore critically dependent upon a continuous blood-borne supply of oxygen and glucose to meet that demand. Oxygen delivery is the product of CBF arterial oxygen content. Cerebral blood flow is governed by the Hagen-Poiseuille equation, correlating directly with cerebral perfusion pressure (CPP), the difference between mean arterial pressure (MAP) and intracranial pressure (ICP), and
vessel radius and inversely with blood viscosity and vessel length (CBF ¼ DPpr4/8ZL, where r ¼ radius, P ¼ pressure, Z ¼ viscosity, and L ¼ length). Oxygen is carried in blood both bound to hemoglobin and dissolved in plasma. Each gram of hemoglobin carries 1.34 mL of oxygen. Dissolved oxygen follows Henry’s law: the amount of oxygen dissolved is proportional to the partial pressure. For each mm Hg of PaO2, there is 0.0031 mL of O2/dL dissolved. Thus, arterial oxygen content, the total amount of oxygen in arterial blood, can be estimated by the following formula: (1.34 hemoglobin arterial oxygen saturation) þ (0.0031 PaO2). It is the oxygen dissolved in plasma that diffuses into tissue according to the oxygen pressure differential between the capillary and the tissue, specifically the mitochondria in the cell.1 The physics of oxygen diffusion were determined at the turn of the 20th century by a Danish physiologist named August
1
Case Western Reserve University School of Medicine, Neurological Institute, University Hospitals Case Medical Center, Cleveland, OH, USA
Received November 14, 2013, and in revised form December 31, 2013. Accepted for publication January 14, 2013. Corresponding Author: Michael A. De Georgia, Case Western Reserve University School of Medicine, Neurological Institute, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA. Email: [email protected]
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Figure 1. Oxygen supply and transport. A, Oxygen supply to tissue is generally conceptualized based on the simple Krogh tissue cylinder model in which all oxygen exchange occurs across the walls of the capillaries. As such, oxygen content within the capillary falls linearly as oxygen diffuses out of the vessel at a constant rate. B, Our current understanding of the complex oxygen transport pathways controlling oxygen supply includes convective oxygen transport through the microvessels (solid line) coupled with diffusive oxygen exchange (broken lines) among all orders of microvessels. With permission from the American Physiological Society.7
Krogh, the recipient of the 1920 Nobel Prize in Physiology or Medicine.2 His model assumes a central capillary surrounded by a homogenously respiring tissue cylinder. Under these conditions, the oxygen content of the capillary blood decreases linearly from the arterial to the venous end of the capillary as oxygen diffuses perpendicularly away from the vessel. The diffusion rate is determined by the partial pressure of oxygen difference between the capillary and the cell divided by the oxygen solubility and the oxygen diffusion coefficient the radius of the cylinder, the radius of the capillary, and the radius to the point of measurement.3 Although the Krogh model is intuitive, nevertheless it is overly simplistic in many ways. First, it assumes that oxygen diffuses evenly and uniformly through the tissue. With brain injury, however, diffusion barriers often develop as a result of microvascular collapse, endothelial swelling, and perivascular edema that can impede oxygen delivery.4 Second, the model assumes that oxygen is consumed in the tissue at a constant rate and fails to explain the tight coupling between oxygen delivery and metabolism. In order to increase oxygen delivery to meet an increase in demand, the Krogh model requires an increase in capillary density, so-called ‘‘capillary recruitment.’’ Recent evidence, however, suggests that oxygen delivery is directly regulated mainly by changes in vessel caliber at the microcirculatory level, this is in addition to changes in vessel
caliber in larger resistance vessels.5,6 At the microcirculatory level, because the oxygen content of the erythrocyte is directly linked to the level of oxygen consumption of the tissue, it has been proposed that the erythrocytes themselves, by releasing adenosine triphosphate, may be able to sense oxygen need and dilate the microcirculatory vessels through which they are traversing, thus exquisitely matching oxygen delivery with metabolic demand.7 Finally, the original Krogh model assumes that each capillary is the sole supplier of a single cylinder of tissue. The current understanding of oxygen transport is more complex. The circulation supplies oxygen to tissue at multiple levels, including directly from the arteriole.8,9 The result is spatial heterogeneity of perfusion and oxygen delivery10,11 (Figure 1). The normal brain PtiO2 usually ranges from 20 to 35 mm Hg.12-14 Most likely this represents the ‘‘pool’’ of oxygen that accumulates within the tissue. This ‘‘pool’’ is influenced by both oxygen delivery and consumption but it is not a simple balance between these 2. The exact PtiO2 threshold that represents ischemia is not known. In the literature, ischemic thresholds have ranged between 10 and 19 mm Hg.15-17 However, a threshold of 10 to 15 mm Hg has been most often used primarily based on positron emission tomography (PET)validated studies.4,18 Brain PtiO2 < 5 mm is associated with cell death.19-21
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Methods to Measure Brain PtiO2 There are 2 methods used to measure brain PtiO2, the optical luminescent method and the polarographic method. In the optical luminescent method, oxygen molecules diffuse into a silicone matrix and change the color of a Ruthenium dye. A pulse of light is sent down a fiber optic filament and as it penetrates the dye it changes frequency. The change in frequency is then converted into a partial pressure of oxygen. This is the method that was used in the Neurotrend (Diametrics Medical, St Paul, Minnesota; no longer commercially available in the United States) and currently used in the OxyLab pO2 (Oxford Optronix Ltd, Oxford, United Kingdom) and the Neurovent-PTO (Raumedic AG, Munchberg, Germany). In the polarographic method, a Clark electrode is used to estimate the PtiO2. A Clark electrode is similar to a battery in that it is composed of a silver electrode (the anode) and a platinum electrode (the cathode) covered by a membrane. Oxygen diffuses through the membrane and is reduced at the cathode. That is, electrons flow from the anode to the cathode as electrons there combine with oxygen and hydrogen to produce water. The rate at which electrons ‘‘boil off’’ is proportional to the concentration of oxygen available to ‘‘grab’’ them. The generated ‘‘galvanic’’ current is then converted to a partial pressure of oxygen. This reaction is temperature dependent and therefore a temperature probe is included in the catheter. This technique was developed initially for measurement of oxygen tension in muscle tissue22 and was introduced for brain tissue monitoring in 1993.12 Using this method, the Licox Brain Oxygen Monitor (Integra Neuroscience, Plainsboro, New Jersey) was Food and Drug Administration approved in the United States in 2001. Most of the studies in the literature have been performed using the Licox Brain Oxygen Monitor. In comparing the 2 methods, both measure oxygen tension with high accuracy and stability during in vitro testing, although the precision tends to be slightly higher using the optical luminescent method. Response times to changes in oxygen concentration tend to be slightly shorter with the optical luminescent method (56.2 + 22 seconds) compared with the polarographic method (78.2 + 21 seconds), although these differences are not likely to be clinically significant. Both methods are associated with minimal drift (less than 1 mm Hg) over a 10-day period.23,24 The Licox monitor is inserted into the brain parenchyma in a manner similar to fiberoptic ICP monitor, generally 3.5 cm below the dura. The active tip of the catheter lies 2.5 to 3 cm below the dura in the frontal white matter. It measures the partial pressure of oxygen in a 13-mm tissue cylinder around the catheter. Brain PtiO2 measurements vary depending on whether the monitor is placed into lesioned or nonlesioned tissue.15,25 In patients with traumatic brain injury (TBI), most centers tend to place the monitor into tissue that appears normal on the brain computed tomography (CT) scan in the frontal lobe of the most severely injured hemisphere. When there is diffuse injury, the monitor is usually placed in the nondominant hemisphere. Although placement in penumbral areas can theoretically provide information about impending secondary
damage, accurately identifying those areas by brain CT scan is often difficult.26 Lower brain PtiO2 values and longer durations of low PtiO2 have also been reported when the monitor has been placed in pericontusional tissue.27 In patients with aneurysmal subarachnoid hemorrhage (SAH), the monitor is usually placed on the side of the ruptured aneurysm or the side where the hemorrhage is thickest, the area most at risk of vasospasm. Although the optimal location for monitor placement in various disease states is still being studied, knowledge about where the monitor is placed is important in interpreting brain oxygen monitoring literature.28
Effect of Brain Hypoxia on Outcome Several studies have examined the effect of brain hypoxia on outcome in patients with SAH and TBI. For example, KettWhite and colleagues reported 36 patients with aneurysmal SAH monitored with the Neurotrend, inserted into the frontal region, close to the midline in patients with anterior communicating artery aneurysms or in a more posterolateral location otherwise. Overall, 13 patients had severe brain hypoxia defined as 5 or more 30-minute episodes of PtiO2 60 mm Hg) and the brain PtiO2 target was higher (>25 mm Hg). In the ICP/CPP group, patients received management that consisted of vasopressors, mannitol, external ventricular drainage of cerebrospinal fluid, and pharmacological paralysis. They also received ‘‘optimized hyperventilation’’ using jugular bulb oximetry and, in refractory patients, barbiturate infusions to achieve burst suppression or decompressive craniectomy. In the brain PtiO2 group to counteract hypoxic episodes, patients were treated with intermittent hyperoxia and blood transfusion to maintain hemoglobin >10 g/dL. Although there were no significant differences in the average ICP or CPP values between the 2 groups, the ICPs tended to be slightly higher in the brain PtiO2 group (25.5 + 9.5) than in the ICP/ CPP group (21.5 + 6.9) consistent with the authors’ ‘‘tolerance’’ of mild ICP elevation (25-30 mm Hg) as long as the brain PtiO2 was adequate. The results showed that patients had lower mortality rates in the brain PtiO2 group (25%) compared with the ICP/CPP group (34%; P ¼ .05).85 The authors postulated that the benefits of brain PtiO2-guided therapy may have stemmed not only from reducing brain hypoxia but also potentially from minimizing systemic complications from overzealous treatment of CPP with vasopressors and fluids.86,87 In 2010, the same group reported their further experience with this approach (ICP/CPP group, n ¼ 53; brain PtiO2 group, n ¼ 70). The PtiO2 target was reduced to 20 mm Hg and, as before, patients had reduced mortality rates with brain PtiO2-guided therapy (26% vs 35%, P ¼ .05).88 Narotam and colleagues reported a retrospective review of ICP/CPP-guided therapy (n ¼ 41, 1998-2000) versus brain PtiO2-guided therapy (n ¼ 139, 2001-2005). In this study, the ICP/CPP group underwent ICP monitoring only and the brain PtiO2 group underwent both ICP and PtiO2 monitoring. Licox monitors placed mainly in the nondominant hemisphere (73%). The ICP/CPP group was treated targeting an ICP < 20 mm Hg and CPP > 60 mm Hg with vasopressors, external ventricular drainage of cerebrospinal fluid, mannitol, hyperventilation, barbiturate infusions, or decompressive craniectomy. The PtiO2 goal was >20 mm Hg using, if needed, hyperoxia and blood transfusions to maintain hemoglobin >12.5 g/dL. The results showed a reduction in mortality in the brain PtiO2 group (26%) compared with the ICP/CPP group (42%), although the mean Glasgow Coma Scale score on admission was lower in the brain PtiO2 group (5.9 + 3.7 vs 7.3 + 4.8, P < .05). Among survivors at 6 months, the average GOS score was also higher in the brain PtiO2 group (3.55 + 1.75 vs 2.71 + 1.65, P < .01).89 Green and colleagues reported a retrospective analysis of 37 patients who underwent ICP monitoring only versus 37 patients who concurrently underwent ICP and brain PtiO2 monitoring.
Licox monitors were placed in ‘‘noninjured brain tissue’’ (the side was not specified). In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, the goal was to maintain the PtiO2 >20 mm Hg using optimization of CPP, hyperoxia, and transfusion (hemoglobin >10 g/dL) to counteract hypoxic episodes. The ICP and CPP values were similar in both groups; however, patients in the brain PtiO2 group underwent decompressive craniectomy more frequently than in the ICP group (18 vs 9, P ¼ .03). Overall, there was no difference in mortality rates or functional outcome (GOS or Functional Independence Measure Score, FIMS).90 Martini and colleagues reported a retrospective analysis of 506 patients who underwent ICP monitoring only compared with 127 patients who concurrently underwent ICP and brain PtiO2 monitoring at the ‘‘discretion of the treating neurosurgeon.’’ In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, Licox monitors were placed in normal tissue on the side of the more severely injured hemisphere, and a PtiO2 >20 mm Hg was targeted. Patients in the brain PtiO2 group received more aggressive management including use of vasopressors, hypertonic saline, mannitol, and sedation with a longer duration of mechanical ventilation, and an increased ICU length of stay. The results showed no difference in mortality rates, but among survivors, the functional outcome was actually worse in the brain PtiO2 group (functional independence in 64.4%) than in the ICP group (functional independence in 77.3%; P ¼ .01).91 The reason this group did worse is not clear but may reflect inherent differences in the 2 groups; patients in the brain PtiO2 group had more severe brain injuries at baseline. However, it may also be the result of the more aggressive management the patients received leading to complications that outweighed any benefits from preventing brain hypoxia. There have been only 2 prospective studies in patients with TBI. Adamides and colleagues reported a prospective study of 10 patients who underwent ICP and brain PtiO2 monitoring following ICP/CPP-guided therapy compared with 20 patients who underwent ICP and brain PtiO2 monitoring following brain PtiO2-guided therapy. Licox monitors were placed contralateral to the more severely injured side. In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, a PtiO2 >20 mm Hg was targeted using a standard algorithm that included increasing the CPP to 70 mm Hg, hyperoxia (adjusting ventilation for a PaO2 > 100 mm Hg), and blood transfusion to maintain hemoglobin >10 g/dL. Average ICP was lower in the brain PtiO2-guided therapy (13.4 + 0.7) compared with the ICP/CPP-guided therapy group (16.7 + 1.0; P ¼ .01), although CPP and PtiO2 levels were the same. At 6 months, there was no statistically significant difference in neurological outcome between those patients treated with and those without brain PtiO2-guided therapy. The outcome of a third group of 18 matched control patients who underwent ICP monitoring only was the same as in the PtiO2-guided therapy.92 McCarthy and colleagues reported a prospective study of 64 patients who underwent ICP monitoring only compared with 81 patients who underwent
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Table 1. Studies of Brain PtiO2-Guided Therapy Versus ICP/CPP-Guided Therapy. ICP/CPP-Guided Therapy
PtiO2-Guided Therapy
Meixensberger et al36
39
52
GOS at 6 months
2005
Stiefel et al85
25
28
Mortality at discharge
2009
Martini et al91
506
123
FIM at discharge
2009 2009
Adamides et al92 McCarthy et al93
10 48
20 63
GOS at 6 months GOS at 3 months
2009
Narotam et al89
41
127
GOS at 6 months
2010
Spiotta et al88
53
70
GOS at 3 months
2013
Green et al90
37
37
Mortality at discharge
Year
Author
2003
Outcome Measure
Results No benefit 54% vs 65% P ¼ .27 Reduced mortality 34% vs 25% P < .05 Worse outcome 8.6 vs 7.6 P < .01 No benefit Trend toward better outcome 61% vs 79% P ¼ .09 Better outcome 2.7 vs 3.5 P ¼ .01 Reduced mortality 35% vs 26% P ¼ .01 No benefit 54% vs 65% P ¼ .34
Abbreviations: CPP, cerebral perfusion pressure; FIM, Functional Independence Measure; ICP, intracranial pressure; GOS, Glasgow Outcome Scale; PtiO2, brain tissue oxygen tension.
both ICP and brain PtiO2 monitoring with Licox monitors placed in the nondominant hemisphere, regardless of the site of injury. In the ICP/CPP group, the goals were to maintain ICP 60 mm Hg. In the brain PtiO2 group, a PtiO2 >20 mm Hg was targeted using hyperoxia and blood transfusion if needed although the hemoglobin threshold for transfusion was not specified. Outcome measures were GOS scores at 3, 6, 12, and 24 months after discharge. The results showed no difference in mortality rates, although among the survivors, there was a trend toward a better outcome in the brain PtiO2 group at 3 months (79% good outcome) compared with the ICP/CPP group (61%; P ¼ .09). Outcomes at 6 months were also better in the PtiO2 group (83% vs 70%) but the difference was not significant. There were too few patients at 12 and 24 months for comparison93 (see Table 1). In summary, the results of these nonrandomized studies in patients with TBI comparing brain PtiO2-guided therapy with ICP/CPP-guided therapy, while promising, have been mixed. Fundamentally, though, the brain tissue PtiO2 catheter is a monitoring tool. If it is used to direct therapy and there is no improvement in outcome, then the therapy is not effective, or worse, potentially harmful. Thus, there is a need for better treatment strategies based on the measurements obtained and prospective, randomized trials of those strategies to determine whether the benefits outweigh the risks and whether ultimately this approach leads to better patient outcomes. A phase II randomized clinical trial examining the value of brain oxygen monitoring in TBI is currently in the planning stages94.
Conclusions Continuous brain tissue oxygen monitoring offers the opportunity to gain better insight into complex brain physiology in order to optimize the management and potentially improve patient outcomes after acute brain injury. Some general conclusions can be made about brain tissue oxygen monitoring: Brain PtiO2 reflects both oxygen delivery and consumption and likely represents the ‘‘pool’’ of oxygen that accumulates within the tissue. The normal brain PtiO2 usually ranges from 20 to 35 mm Hg, and the ischemic threshold ranges from 10 to 15 mm Hg. Low brain PtiO2 is associated with poor outcome and can only be detected with continuous brain PtiO2 monitoring; the sensitivity of ICP and CPP monitoring for detecting brain hypoxia is low. Low brain PtiO2 can be increased by strategies aimed at increasing oxygen delivery (CBF arterial oxygen content). Increasing the CPP can improve brain PtiO2, especially when cerebral autoregulation is impaired and the baseline PtiO2 is low. Impaired cerebral autoregulation (ORx) is associated with a poor outcome. Increasing the FiO2 (hyperoxia) can improve brain PtiO2, especially when oxygen autoregulation is impaired and the baseline PtiO2 is high.
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Journal of Intensive Care Medicine Impaired oxygen autoregulation (TOR) is associated with a poor outcome. It is not clear whether hyperoxia actually improves brain metabolism. Other strategies may improve brain PtiO2 but not always (eg, intra-arterial intervention and barbiturates). Blood transfusion may improve brain PtiO2. Whether it improves brain metabolism and leads to a cellular benefit that outweighs the risk is not clear. The results of nonrandomized studies comparing brain PtiO2-guided therapy with ICP/CPP-guided therapy in the setting of TBI have been mixed. More studies are needed including prospective, randomized controlled trials to assess the benefit of this approach.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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