Brain tissue oxygen and outcome after severe traumatic brain injury: A systematic review* Eileen Maloney-Wilensky, MSN; Vicente Gracias, MD; Arthur Itkin, PhD; Katherine Hoffman, MS; Stephanie Bloom, MSN; Wei Yang, PhD; Susan Christian, MBA; Peter D. LeRoux, MD T raumatic brain injury (TBI) is a major cause of morbidity and mortality particularly among young people (1). Se- vere TBI, clinically defined as any head injury that results in a Glasgow Coma Scale (GCS) of 8 or less within the first 48 hours posttrauma, has a mortality rate between 20% and 40%. Another 20% of patients remain severely disabled (2). Much of this unfavorable outcome is due to secondary brain damage that occurs in the hours, days, and weeks after the pri- mary insult (3). In fact, secondary cerebral ischemic injury has been observed in greater than 90% of patients who died of a head injury (4, 5). Secondary cerebral in- jury is associated with impaired cerebral metabolism, hypoxia, and ischemia, which result in a complex, potentially irreversible pathophysiologic cascade of events. Current therapies to manage second- ary brain injury, while effective in the laboratory, have disappointed in the clin- ical environment (6 –14). This lack of ef- ficacy results, in part, because we are only now beginning to elucidate methods to effectively monitor brain physiology after TBI. Neurologic monitoring can be clas- sified broadly into four types: 1) pressure, e.g., intracranial pressure (ICP) from which cerebral perfusion pressure (CPP) is estimated; 2) blood flow, e.g., thermal diffusion or blood flow velocity e.g., transcranial Doppler; 3) electrophysiol- ogy, e.g., electroencephalogram; and 4) metabolic measures such as jugular ve- nous oximetry, cerebral microdialysis, and direct brain tissue oxygen (BtO 2 ). It is believed that with effective neuromoni- toring, secondary brain injury can be rec- ognized early and better managed before irreversible injury occurs, thereby im- proving patient outcome. Current Guide- lines for the Management of Severe Head Injury (15) as described by such orga- nizations as the American Association of Neurologic Surgeons and Congress of Neurologic Surgeons Joint Section on Neurotrauma and Critical Care and the European Brain Injury Consortium em- phasize the use of ICP monitors. The re- lationship between poor patient outcome, particularly mortality and increased ICP is well known (3, 15, 16, 17). In addition, ICP monitor use in some studies appears to be associated with better patient out- come although this has never been tested in a clinical trial (17). However, second- ary brain injury is not always associated with pathologic changes in ICP or CPP (18 –20) and adequate resuscitation (i.e., normal ICP and CPP) after TBI does not always prevent brain hypoxia (21). Recent positron emission tomography studies in humans after TBI (22) also suggest that mechanisms other than simple perfu- sion-limited ischemia e.g., intravascular microthrombosis (23), cytotoxic edema *See also p. 2134. From the Department of Neurosurgery (EM-W, SB, PDL), Division of Trauma Surgery and Surgical Critical Care (VG), and Department of Biostatistics and Epide- miology and Center for Clinical Epidemiology and Bio- statistics (WY), University of Pennsylvania School of Medicine, Philadelphia, PA; and Stat-Trade, Inc. (AI, KH, SC), Morrisville, PA. The authors have not disclosed any potential con- flicts of interest. For information regarding this article, E-mail: lerouxp@uphs.upenn.edu Copyright © 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3181a009f8 Objective: In this study, available medical literature were re- viewed to determine whether brain hypoxia as measured by brain tissue oxygen (BtO 2 ) levels is associated with increased risk of poor outcome after traumatic brain injury (TBI). A secondary objective was to examine the safety profile of a direct BtO 2 probe. Data Source and Extraction: Clinical studies published be- tween 1993 and 2008 were identified from electronic databases, Index Medicus, bibliographies of pertinent articles, and expert consultation. The following inclusion criteria were applied for outcome analysis: 1) more than 10 patients described, 2) use of a direct BtO 2 monitor, 3) brain hypoxia defined as BtO 2 <10 mm Hg for >15 or 30 minutes, 4) 6-month outcome data, and 5) clear reporting of patient outcome associated with BtO 2 . For the anal- ysis, each selected article had to have adequate data to determine odds ratios (ORs) and confidence intervals (CIs). Thirteen studies met the initial inclusion criteria and three were included in the final outcome analysis. Safety data were abstracted from any report where it was mentioned. Data Synthesis: The three studies included 150 evaluable pa- tients with severe TBI (Glasgow Coma Scale <8). Brain hypoxia was identified in 71 (47%) of these patients. Among the patients with brain hypoxia, 52 (73%) had unfavorable outcome including 39 (55%) who died. In the absence of brain hypoxia, 34 (43%) patients had an unfavorable outcome, including 17 (22%) who died. Overall brain hypoxia (BtO 2 <10 mm Hg >15 minutes) was associated with worse outcome (OR 4.0; 95% CI 1.9 – 8.2) and increased mortality (OR 4.6; 95% CI 2.2–9.6). We reviewed pub- lished safety data; in 292 patients monitored with a BtO 2 probe, only two adverse events were reported. Conclusion: Summary results indicate that brain hypoxia (<10 mm Hg) is associated with worse outcome after severe TBI and that BtO 2 probes are safe. These results imply that treating patients to increase BtO 2 may improve outcome after severe TBI. This question will require further study. (Crit Care Med 2009; 37:2057–2063) KEY WORDS: brain tissue oxygen; Licox; intracranial pressure; monitoring; traumatic brain injury 2057 Crit Care Med 2009 Vol. 37, No. 6