Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension.

BACKGROUND: The impact of osmotic therapies on brain oxygen has not been extensively studied in humans. We examined the effects on brain tissue oxygen tension (PbtO(2)) of mannitol and hypertonic saline (HTS) in patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension. METHODS: 12 consecutive patients with severe TBI who underwent intracranial pressure (ICP) and PbtO(2) monitoring were studied. Patients were treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP (>20 mm Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with mannitol. PbtO(2), ICP, mean arterial pressure, cerebral perfusion pressure (CPP), central venous pressure and cardiac output were monitored continuously. RESULTS: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), were analysed. HTS treatment was associated with an increase in PbtO(2) (from baseline 28.3 (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min; all p<0.01) while mannitol did not affect PbtO(2) (baseline 30.4 (11.4) vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p>0.1). Compared with mannitol, HTS was associated with lower ICP and higher CPP and cardiac output. CONCLUSIONS: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.

Intratracheal suctioning in sick preterm infants: prevention of intracranial hypertension and cerebral hypoperfusion by muscle paralysis.

In a prospective nonrandomized study, using each baby as his or her own control, we compared intracranial pressure (anterior fontanel pressure as measured with the Digilab pneumotonometer), cerebral perfusion pressure, BP, heart rate, transcutaneous Po2, and transcutaneous Pco2 before, during, and after endotracheal suctioning, with and without muscle paralysis, in 28 critically ill preterm infants with respiratory distress syndrome. With suctioning, there was a small but significant increase in intracranial pressure in paralyzed patients (from 13.7 [mean] +/- 4.4 mm Hg [SD] to 15.8 +/- 5.2 mm Hg) but a significantly larger (P less than .001) increase when they were not paralyzed (from 12.5 +/- 3.6 to 28.5 +/- 8.3 mm Hg). Suctioning led to a slight increase in BP with (from 45.3 +/- 9.1 to 48.0 +/- 8.7 mm Hg) and without muscle paralysis (from 45.1 +/- 9.4 to 50.0 +/- 11.7 mm Hg); but there was no significant difference between the two groups. The cerebral perfusion pressure in paralyzed infants did not show any significant change before, during, and after suctioning (31.5 +/- 9.1 mm Hg before v 32.0 +/- 8.7 mm Hg during suctioning), but without muscle paralysis cerebral perfusion pressure decreased (P less than .001) from 32.8 +/- 9.7 to 21.3 +/- 13.1 mm Hg. Suctioning induced a slight decrease in mean heart rate and transcutaneous Po2, but pancuronium did not alter these changes. There was no statistical difference in transcutaneous Pco2 before, during, and after suctioning with and without muscle paralysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of hydrogen peroxide-induced vasoconstriction in the isolated perfused rat kidney.

The vasoconstrictor effect of hydrogen peroxide (H(2)O(2)) on isolated perfused rat kidney was investigated. H(2)O(2) induced vasoconstriction in the isolated rat kidney in a concentration-dependent manner. The vasoconstrictor effects of H(2)O(2) were completely inhibited by 1200 U/ml catalase. Endothelium-removal potentiated the renal response to H(2)O(2). The H(2)O(2) dose-response curve was not significantly modified by administration of the NO inhibitor L-NAME (10(-4) mol/l), whereas it was increased by the non-specific inhibitor of K+-channels, tetraethylammonium (3.10(-3) mol/l). Separately, removal of extracellular Ca(2+), administration of a mixture of calcium desensitizing agents (nitroprusside, papaverine, and diazoxide), and administration of a protein kinase C (PKC) inhibitor (chelerythrine, 10(-5) mol/l) each significantly attenuated the vasoconstrictor response to H(2)O(2), which was virtually suppressed when they were performed together. The pressor response to H(2)O(2) was not affected by: dimethyl sulfoxide (7.10(-5) mol/l) plus mannitol (3.10(-5) mol/l); intracellular Ca(2+) chelation using BAPTA (10(-5) mol/l); calcium store depletion after repeated doses of phenylephrine (10(-5) g/g kidney); or the presence of indomethacin (10(-5) mol/l), ODYA (2.10(-6) mol/l) or genistein (10(-5) mol/l). We conclude that the vasoconstrictor response to H(2)O(2) in the rat renal vasculature comprises the following components: 1) extracellular calcium influx, 2) activation of PKC, and 3) stimulation of pathways leading to sensitization of contractile elements to calcium. Moreover, a reduced pressor responsiveness to H(2)O(2) in female kidneys was observed.

Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage.

Subarachnoid haemorrhage (SAH) is a form of stroke that is associated with substantial morbidity, often as a result of cerebral ischaemia that occurs in the following days. These delayed deficits in blood flow have been traditionally attributed to cerebral vasospasm (the narrowing of large arteries), which can lead to cerebral infarction and poor neurological outcome. Data from recent studies, however, show that treatment of vasospasm in patients with SAH, using targeted medication, does not translate to better neurological outcomes, and argue against vasospasm being the sole cause of the delayed ischaemic complications. Cerebral autoregulation-a mechanism that maintains stability of cerebral blood flow in response to changes in cerebral perfusion pressure-has been reported to fail after SAH, often before vasospasm becomes apparent. Failure of autoregulation, therefore, has been implicated in development of delayed cerebral ischaemia. In this Review, we summarize current knowledge about the clinical effect of disturbed cerebral autoregulation following aneurysmal SAH, with emphasis on development of delayed cerebral ischaemia and clinical outcome, and provide a critical assessment of studies of cerebral autoregulation in SAH with respect to the method of blood-flow measurement. Better understanding of cerebral autoregulation following SAH could reveal mechanisms of blood-flow regulation that could be therapeutically targeted to improve patient outcome.

Hemoglobin concentration and cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The optimal hemoglobin (Hgb) target after aneurysmal subarachnoid hemorrhage is not precisely known. We sought to examine the threshold of Hgb concentration associated with an increased risk of cerebral metabolic dysfunction in patients with poor-grade subarachnoid hemorrhage. METHODS: Twenty consecutive patients with poor-grade subarachnoid hemorrhage who underwent multimodality neuromonitoring (intracranial pressure, brain tissue oxygen tension, cerebral microdialysis) were studied prospectively. Brain tissue oxygen tension and extracellular lactate/pyruvate ratio were used as markers of cerebral metabolic dysfunction and the relationship between Hgb concentrations and the incidence of brain hypoxia (defined by a brain tissue oxygen tension <20 mm Hg) and cell energy dysfunction (defined by a lactate/pyruvate ratio >40) was analyzed. RESULTS: Compared with higher Hgb concentrations, a Hgb concentration <9 g/dL was associated with lower brain tissue oxygen tension (27.2 [interquartile range, 21.2 to 33.1] versus 19.9 [interquartile range, 7.1 to 33.1] mm Hg, P=0.02), higher lactate/pyruvate ratio (29 [interquartile range, 25 to 38] versus 36 [interquartile range, 26 to 59], P=0.16), and an increased incidence of brain hypoxia (21% versus 52%, P<0.01) and cell energy dysfunction (23% versus 43%, P=0.03). On multivariable analysis, a Hgb concentration <9 g/dL was associated with a higher risk of brain hypoxia (OR, 7.92; 95% CI, 2.32 to 27.09; P<0.01) and cell energy dysfunction (OR, 4.24; 95% CI, 1.33 to 13.55; P=0.02) after adjusting for cerebral perfusion pressure, central venous pressure, PaO(2)/FIO(2) ratio, and symptomatic vasospasm. CONCLUSIONS: A Hgb concentration <9 g/dL is associated with an increased incidence of brain hypoxia and cell energy dysfunction in patients with poor-grade subarachnoid hemorrhage.

Barbiturate infusion for intractable intracranial hypertension and its effect on brain oxygenation.

OBJECTIVE: Barbiturate-induced coma can be used in patients to treat intractable intracranial hypertension when other therapies, such as osmotic therapy and sedation, have failed. Despite control of intracranial pressure, cerebral infarction may still occur in some patients, and the effect of barbiturates on outcome remains uncertain. In this study, we examined the relationship between barbiturate infusion and brain tissue oxygen (PbtO2). METHODS: Ten volume-resuscitated brain-injured patients who were treated with pentobarbital infusion for intracranial hypertension and underwent PbtO2 monitoring were studied in a neurosurgical intensive care unit at a university-based Level I trauma center. PbtO2, intracranial pressure (ICP), mean arterial pressure, cerebral perfusion pressure (CPP), and brain temperature were continuously monitored and compared in settings in which barbiturates were or were not administered. RESULTS: Data were available from 1595 hours of PbtO2 monitoring. When pentobarbital administration began, the mean ICP, CPP, and PbtO2 were 18 +/- 10, 72 +/- 18, and 28 +/- 12 mm Hg, respectively. During the 3 hours before barbiturate infusion, the maximum ICP was 24 +/- 13 mm Hg and the minimum CPP was 65 +/- 20 mm Hg. In the majority of patients (70%), we observed an increase in PbtO2 associated with pentobarbital infusion. Within this group, logistic regression analysis demonstrated that a higher likelihood of compromised brain oxygen (PbtO2 < 20 mm Hg) was associated with a decrease in pentobarbital dose after controlling for ICP and other physiological parameters (P < 0.001). In the remaining 3 patients, pentobarbital was associated with lower PbtO2 levels. These patients had higher ICP, lower CPP, and later initiation of barbiturates compared with patients whose PbtO2 increased. CONCLUSION: Our preliminary findings suggest that pentobarbital administered for intractable intracranial hypertension is associated with a significant and independent increase in PbtO2 in the majority of patients. However, in some patients with more compromised brain physiology, pentobarbital may have a negative effect on PbtO2, particularly if administered late. Larger studies are needed to examine the relationship between barbiturates and cerebral oxygenation in brain-injured patients with refractory intracranial hypertension and to determine whether PbtO2 responses can help guide therapy.

Prise en charge du traumatisme cranio-cérébral sévère [Update on the management of severe traumatic brain injury]

Prognosis after severe traumatic brain injury (TBI) is determined by the severity of initial injury and secondary cerebral damage. The main determinants of secondary cerebral damage are brain ischemia and oedema. Traumatic brain injury is a heterogeneous disease. Head CT-scan is essential in evaluating initial type of injury and severity of brain oedema. A standardised approach based on prevention and treatment of secondary cerebral damage is the only effective therapeutic strategy of severe TBI. We review the classification, pathophysiology and treatment of secondary cerebral damage after severe TBI and discuss the management of intracranial hypertension, cerebral perfusion pressure and brain ischemia.

Neuromonitoring after major neurosurgical procedures.

Postoperative care of major neurosurgical procedures is aimed at the prevention, detection and treatment of secondary brain injury. This consists of a series of pathological events (i.e. brain edema and intracranial hypertension, cerebral hypoxia/ischemia, brain energy dysfunction, non-convulsive seizures) that occur early after the initial insult and surgical intervention and may add further burden to primary brain injury and thus impact functional recovery. Management of secondary brain injury requires specialized neuroscience intensive care units (ICU) and continuous advanced monitoring of brain physiology. Monitoring of intracranial pressure (ICP) is a mainstay of care and is recommended by international guidelines. However, ICP monitoring alone may be insufficient to detect all episodes of secondary brain insults. Additional invasive (i.e. brain tissue PO2, cerebral microdialysis, regional cerebral blood flow) and non-invasive (i.e. transcranial doppler, near-infrared spectroscopy, EEG) brain monitoring devices might complement ICP monitoring and help clinicians to target therapeutic interventions (e.g. management of cerebral perfusion pressure, blood transfusion, glucose control) to patient-specific pathophysiology. Several independent studies demonstrate such multimodal approach may optimize patient care after major neurosurgical procedures. The aim of this review is to evaluate some of the available monitoring systems and summarize recent important data showing the clinical utility of multimodal neuromonitoring for the management of main acute neurosurgical conditions, including traumatic brain injury, subarachnoid hemorrhage and stroke.

Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study.

OBJECTIVES: To analyze the effect of tight glycemic control with the use of intensive insulin therapy on cerebral glucose metabolism in patients with severe brain injury. DESIGN: Retrospective analysis of a prospective observational cohort. SETTING: University hospital neurologic intensive care unit. PATIENTS: Twenty patients (median age 59 yrs) monitored with cerebral microdialysis as part of their clinical care. INTERVENTIONS: Intensive insulin therapy (systemic glucose target: 4.4-6.7 mmol/L [80-120 mg/dL]). MEASUREMENTS AND MAIN RESULTS: Brain tissue markers of glucose metabolism (cerebral microdialysis glucose and lactate/pyruvate ratio) and systemic glucose were collected hourly. Systemic glucose levels were categorized as within the target "tight" (4.4-6.7 mmol/L [80-120 mg/dL]) vs. "intermediate" (6.8-10.0 mmol/L [121-180 mg/dL]) range. Brain energy crisis was defined as a cerebral microdialysis glucose <0.7 mmol/L with a lactate/pyruvate ratio >40. We analyzed 2131 cerebral microdialysis samples: tight systemic glucose levels were associated with a greater prevalence of low cerebral microdialysis glucose (65% vs. 36%, p < 0.01) and brain energy crisis (25% vs.17%, p < 0.01) than intermediate levels. Using multivariable analysis, and adjusting for intracranial pressure and cerebral perfusion pressure, systemic glucose concentration (adjusted odds ratio 1.23, 95% confidence interval [CI] 1.10-1.37, for each 1 mmol/L decrease, p < 0.001) and insulin dose (adjusted odds ratio 1.10, 95% CI 1.04-1.17, for each 1 U/hr increase, p = 0.02) independently predicted brain energy crisis. Cerebral microdialysis glucose was lower in nonsurvivors than in survivors (0.46 +/- 0.23 vs. 1.04 +/- 0.56 mmol/L, p < 0.05). Brain energy crisis was associated with increased mortality at hospital discharge (adjusted odds ratio 7.36, 95% CI 1.37-39.51, p = 0.02). CONCLUSIONS: In patients with severe brain injury, tight systemic glucose control is associated with reduced cerebral extracellular glucose availability and increased prevalence of brain energy crisis, which in turn correlates with increased mortality. Intensive insulin therapy may impair cerebral glucose metabolism after severe brain injury.

Four years later: a clinical update on latanoprost.

PURPOSE: Almost five years have elapsed since the introduction of latanoprost on several markets and considering the large number of publications dealing with it, the authors felt that it was worth re-evaluating the drug. METHODS: The criterion used to select trials for inclusion in the review was: all articles mentioning the drug in common electronic data-bases; these were then screened and considered, on the basis of methodological quality. RESULTS: Experimental data suggest that latanoprost acts by remodeling the extracellular matrix in the ciliary muscle, thus increasing the flow of aqueous humor through the ciliary muscle bundles of the uveoscleral pathway. POAG: Latanoprost persistently improves the pulsatile ocular blood flow in primary open angle glaucoma (POAG). Recent trials confirmed the greater IOP-lowering efficacy of latanoprost vs. timolol, dorzolamide, brimonidine and unoprostone. Trials lasting up to 24 months showed that latanoprost is effective in long-term treatment of POAG and ocular hypertension (OH), with no signs of loss of efficacy when compared to timolol or dorzolamide. Latanoprost provides better control of circadian IOP. Non-responders to beta-blockers should preferably be switched to latanoprost monotherapy before a combination therapy is started. The possibility of a fixed combination of latanoprost and timolol has been explored, with promising results. NTG: Latanoprost is effective in normal tension glaucoma (NTG), lowering IOP, improving pulsatile ocular blood flow and increasing ocular perfusion pressure. OTHER GLAUCOMAS: Latanoprost may provide effective IOP control in angle-closure glaucoma after iridectomy, in pigmentary glaucoma, glaucoma after cataract extraction and steroid-induced glaucoma. However, latanoprost was effective in only a minority of pediatric cases of glaucoma and is contraindicated in all forms of uveitic glaucoma. SAFETY: In the articles reviewed, new or duration-related adverse events were reported.

Transcranial Doppler Pulsatility Index: What it is and What it Isn't.

BACKGROUND: Transcranial Doppler (TCD) pulsatility index (PI) has traditionally been interpreted as a descriptor of distal cerebrovascular resistance (CVR). We sought to evaluate the relationship between PI and CVR in situations, where CVR increases (mild hypocapnia) and decreases (plateau waves of intracranial pressure-ICP). METHODS: Recordings from patients with head-injury undergoing monitoring of arterial blood pressure (ABP), ICP, cerebral perfusion pressure (CPP), and TCD assessed cerebral blood flow velocities (FV) were analyzed. The Gosling pulsatility index (PI) was compared between baseline and ICP plateau waves (n = 20 patients) or short term (30-60 min) hypocapnia (n = 31). In addition, a modeling study was conducted with the "spectral" PI (calculated using fundamental harmonic of FV) resulting in a theoretical formula expressing the dependence of PI on balance of cerebrovascular impedances. RESULTS: PI increased significantly (p < 0.001) while CVR decreased (p < 0.001) during plateau waves. During hypocapnia PI and CVR increased (p < 0.001). The modeling formula explained more than 65% of the variability of Gosling PI and 90% of the variability of the "spectral" PI (R = 0.81 and R = 0.95, respectively). CONCLUSION: TCD pulsatility index can be easily and quickly assessed but is usually misinterpreted as a descriptor of CVR. The mathematical model presents a complex relationship between PI and multiple haemodynamic variables.

Brain multimodality monitoring: an update.

PURPOSE OF REVIEW: An important goal of neurocritical care is the management of secondary brain injury (SBI), that is pathological events occurring after primary insult that add further burden to outcome. Brain oedema, cerebral ischemia, energy dysfunction, seizures and systemic insults are the main components of SBI. We here review recent data showing the clinical utility of brain multimodality monitoring (BMM) for the management of SBI. RECENT FINDINGS: Despite being recommended by international guidelines, standard intracranial pressure (ICP) monitoring may be insufficient to detect all episodes of SBI. ICP monitoring, combined with brain oxygen (PbtO(2)), cerebral microdialysis and regional cerebral blood flow, might help to target therapy (e.g. management of cerebral perfusion pressure, blood transfusion, glucose control) to patient-specific pathophysiology. Physiological parameters derived from BMM, including PbtO(2) and microdialysis lactate/pyruvate ratio, correlate with outcome and have recently been incorporated into neurocritical care guidelines. Advanced intracranial devices can be complemented by quantitative electroencephalography to monitor changes of brain function and nonconvulsive seizures. SUMMARY: BMM offers an on-line comprehensive scrutiny of the injured brain and is increasingly used for the management of SBI. Integration of monitored data using new informatics tools may help optimize therapy of brain-injured patients and quality of care.

A prospective, randomized, and controlled study of fluid management in children with severe head injury: lactated Ringer's solution versus hypertonic saline.

OBJECTIVES: Resuscitation in severe head injury may be detrimental when given with hypotonic fluids. We evaluated the effects of lactated Ringer's solution (sodium 131 mmol/L, 277 mOsm/L) compared with hypertonic saline (sodium 268 mmol/L, 598 mOsm/L) in severely head-injured children over the first 3 days after injury. DESIGN: An open, randomized, and prospective study. SETTING: A 16-bed pediatric intensive care unit (ICU) (level III) at a university children's hospital. PATIENTS: A total of 35 consecutive children with head injury. INTERVENTIONS: Thirty-two children with Glasgow Coma Scores of <8 were randomly assigned to receive either lactated Ringer's solution (group 1) or hypertonic saline (group 2). Routine care was standardized, and included the following: head positioning at 30 degrees; normothermia (96.8 degrees to 98.6 degrees F [36 degrees to 37 degrees C]); analgesia and sedation with morphine (10 to 30 microg/kg/hr), midazolam (0.2 to 0.3 mg/kg/hr), and phenobarbital; volume-controlled ventilation (PaCO2 of 26.3 to 30 torr [3.5 to 4 kPa]); and optimal oxygenation (PaO2 of 90 to 105 torr [12 to 14 kPa], oxygen saturation of >92%, and hematocrit of >0.30). MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure (ICP) were monitored continuously and documented hourly and at every intervention. The means of every 4-hr period were calculated and serum sodium concentrations were measured at the same time. An ICP of 15 mm Hg was treated with a predefined sequence of interventions, and complications were documented. There was no difference with respect to age, male/female ratio, or initial Glasgow Coma Score. In both groups, there was an inverse correlation between serum sodium concentration and ICP (group 1: r = -.13, r2 = .02, p < .03; group 2: r = -.29, r2 = .08, p < .001) that disappeared in group 1 and increased in group 2 (group 1: r = -.08, r2 = .01, NS; group 2: r = -.35, r2 =.12, p < .001). Correlation between serum sodium concentration and cerebral perfusion pressure (CPP) became significant in group 2 after 8 hrs of treatment (r = .2, r2 = .04, p = .002). Over time, ICP and CPP did not significantly differ between the groups. However, to keep ICP at <15 mm Hg, group 2 patients required significantly fewer interventions (p < .02). Group 1 patients received less sodium (8.0 +/- 4.5 vs. 11.5 +/- 5.0 mmol/kg/day, p = .05) and more fluid on day 1 (2850 +/- 1480 vs. 2180 +/- 770 mL/m2, p = .05). They also had a higher frequency of acute respiratory distress syndrome (four vs. 0 patients, p = .1) and more than two complications (six vs. 1 patient, p = .09). Group 2 patients had significantly shorter ICU stay times (11.6 +/- 6.1 vs. 8.0 +/- 2.4 days; p = .04) and shorter mechanical ventilation times (9.5 +/- 6.0 vs. 6.9 +/- 2.2 days; p = .1). The survival rate and duration of hospital stay were similar in both groups. CONCLUSIONS: Treatment of severe head injury with hypertonic saline is superior to that treatment with lactated Ringer's solution. An increase in serum sodium concentrations significantly correlates with lower ICP and higher CPP. Children treated with hypertonic saline require fewer interventions, have fewer complications, and stay a shorter time in the ICU.

Monitoring of brain and systemic oxygenation in neurocritical care patients.

Maintenance of adequate oxygenation is a mainstay of intensive care, however, recommendations on the safety, accuracy, and the potential clinical utility of invasive and non-invasive tools to monitor brain and systemic oxygenation in neurocritical care are lacking. A literature search was conducted for English language articles describing bedside brain and systemic oxygen monitoring in neurocritical care patients from 1980 to August 2013. Imaging techniques e.g., PET are not considered. A total of 281 studies were included, the majority described patients with traumatic brain injury (TBI). All tools for oxygen monitoring are safe. Parenchymal brain oxygen (PbtO2) monitoring is accurate to detect brain hypoxia, and it is recommended to titrate individual targets of cerebral perfusion pressure (CPP), ventilator parameters (PaCO2, PaO2), and transfusion, and to manage intracranial hypertension, in combination with ICP monitoring. SjvO2 is less accurate than PbtO2. Given limited data, NIRS is not recommended at present for adult patients who require neurocritical care. Systemic monitoring of oxygen (PaO2, SaO2, SpO2) and CO2 (PaCO2, end-tidal CO2) is recommended in patients who require neurocritical care.

Normobaric Hyperoxia is Associated with Increased Cerebral Excitotoxicity After Severe Traumatic Brain Injury.

BACKGROUND: Normobaric oxygen therapy is frequently applied in neurocritical care, however, whether supplemental FiO2 has beneficial cerebral effects is still controversial. We examined in patients with severe traumatic brain injury (TBI) the effect of incremental FiO2 on cerebral excitotoxicity, quantified by cerebral microdialysis (CMD) glutamate. METHODS: This was a retrospective analysis of a database of severe TBI patients monitored with CMD and brain tissue oxygen (PbtO2). The relationship of FiO2-categorized into four separate ranges (<40, 41-60, 61-80, and >80 %)-with CMD glutamate was examined using ANOVA with Tukey's post hoc test. RESULTS: A total of 1,130 CMD samples from 36 patients-monitored for a median of 4 days-were examined. After adjusting for brain (PbtO2, intracranial pressure, cerebral perfusion pressure, lactate/pyruvate ratio, Marshall CT score) and systemic (PaCO2, PaO2, hemoglobin, APACHE score) covariates, high FiO2 was associated with a progressive increase in CMD glutamate [8.8 (95 % confidence interval 7.4-10.2) µmol/L at FiO2 < 40 % vs. 12.8 (10.9-14.7) µmol/L at 41-60 % FiO2, 19.3 (15.6-23) µmol/L at 61-80 % FiO2, and 22.6 (16.7-28.5) µmol/L at FiO2 > 80 %; multivariate-adjusted p < 0.05]. The threshold of FiO2-related increase in CMD glutamate was lower for samples with normal versus low PbtO2 < 20 mmHg (FiO2 > 40 % vs. FiO2 > 60 %). Hyperoxia (PaO2 > 150 mmHg) was also associated with increased CMD glutamate (adjusted p < 0.001). CONCLUSIONS: Incremental normobaric FiO2 levels were associated with increased cerebral excitotoxicity in patients with severe TBI, independent from PbtO2 and other important cerebral and systemic determinants. These data suggest that supra-normal oxygen may aggravate secondary brain damage after severe TBI.