Inflammatory Process in the Pathobiology of Secondary Damage After Traumatic Brain Injury

Abstract BACKGROUND Increased intracranial pressure (ICP) causes secondary damage in traumatic brain injury (TBI), and intracranial hemorrhage (ICH). Current methods of ICP monitoring require surgery and carry risks of complications. OBJECTIVE To validate a new instrument for noninvasive ICP measurement by comparing values obtained from noninvasive measurements to those from commercial implantable devices through this pilot study. METHODS The ophthalmic artery (OA) served as a natural ICP sensor. ICP measurements obtained using noninvasive, self-calibrating device utilizing Doppler ultrasound to evaluate OA flow were compared to standard implantable ICP measurement probes. RESULTS A total of 78 simultaneous, paired, invasive, and noninvasive ICP measurements were obtained in 11 ICU patients over a 17-mo period with the diagnosis of TBI, SAH, or ICH. A total of 24 paired data points were initially excluded because of questions about data independence. Analysis of variance was performed first on the 54 remaining data points and then on the entire set of 78 data points. There was no difference between the 2 groups nor was there any correlation between type of sensor and the patient (F[10, 43] = 1.516, P = .167), or the accuracy and precision of noninvasive ICP measurements (F[1, 43] = 0.511, P = .479). Accuracy was [−1.130; 0.539] mm Hg (CL = 95%). Patient-specific calibration was not needed. Standard deviation (precision) was [1.632; 2.396] mm Hg (CL = 95%). No adverse events were encountered. CONCLUSION This pilot study revealed no significant differences between invasive and noninvasive ICP measurements (P < .05), suggesting that noninvasive ICP measurements obtained by this method are comparable and reliable.

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Mitochondria-Targeted Antioxidants as Potential Therapy for the Treatment of Traumatic Brain Injury

Antioxidants ◽

10.3390/antiox8050124 ◽

2019 ◽

Vol 8 (5) ◽

pp. 124 ◽

Cited By ~ 7

Author(s):

Elena V. Stelmashook ◽

Nickolay K. Isaev ◽

Elisaveta E. Genrikhs ◽

Svetlana V. Novikova

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cortical Lesion ◽

Lesion Volume ◽

Negative Effects ◽

Behavioral Deficits ◽

Secondary Damage ◽

Long Time ◽

The Brain ◽

Brain Water

The aim of this article is to review the publications describing the use of mitochondria-targeted antioxidant therapy after traumatic brain injury (TBI). Recent works demonstrated that mitochondria-targeted antioxidants are very effective in reducing the negative effects associated with the development of secondary damage caused by TBI. Using various animal models of TBI, mitochondria-targeted antioxidants were shown to prevent cardiolipin oxidation in the brain and neuronal death, as well as to markedly reduce behavioral deficits and cortical lesion volume, brain water content, and DNA damage. In the future, not only a more detailed study of the mechanisms of action of various types of such antioxidants needs to be conducted, but also their therapeutic values and toxicological properties are to be determined. Moreover, the optimal therapeutic effect needs to be achieved in the shortest time possible from the onset of damage to the nervous tissue, since secondary brain damage in humans can develop for a long time, days and even months, depending on the severity of the damage.

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Quinolinic Acid is Increased in CSF and Associated with Mortality after Traumatic Brain Injury in Humans

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199806000-00002 ◽

1998 ◽

Vol 18 (6) ◽

pp. 610-615 ◽

Cited By ~ 48

Author(s):

Elizabeth H. Sinz ◽

Patrick M. Kochanek ◽

Melvyn P. Heyes ◽

Stephen R. Wisniewski ◽

Michael J. Bell ◽

...

Keyword(s):

Mass Spectrometry ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Acid Concentration ◽

Quinolinic Acid ◽

Multivariate Analyses ◽

Normal Values ◽

Injury Mortality ◽

Secondary Damage ◽

Ventricular Catheters

We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-d-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF ( n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32°C) or normothermia (37°C) treatments for 24 hours. Oth-erwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 ± 128 nmol/L (mean ± SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5-to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid ( P < 0.00001), and quinolinic acid was higher in patients who died than in survivors ( P = 0.003). Age, gender, GCS, and treatment (32°C versus 37°C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.

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Cerebral tissue PO2 and SjvO2 changes during moderate hyperventilation in patients with severe traumatic brain injury

Journal of Neurosurgery ◽

10.3171/jns.2002.96.1.0097 ◽

2002 ◽

Vol 96 (1) ◽

pp. 97-102 ◽

Cited By ~ 91

Author(s):

Roberto Imberti ◽

Guido Bellinzona ◽

Martin Langer

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Tissue ◽

Severe Traumatic Brain Injury ◽

Cerebral Perfusion ◽

Content Type ◽

Secondary Damage ◽

Tissue Po2 ◽

Two Parameters ◽

Fine Print

Object. The aim of this study was to investigate the effects of moderate hyperventilation on intracranial pressure (ICP), jugular venous oxygen saturation ([SjvO2], an index of global cerebral perfusion), and brain tissue PO2 (an index of local cerebral perfusion). Methods. Ninety-four tests consisting of 20-minute periods of moderate hyperventilation (27–32 mm Hg) were performed on different days in 36 patients with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8). Moderate hyperventilation resulted in a significant reduction in average ICP, but in seven tests performed in five patients it was ineffective. The response of SjvO2 and brain tissue PO2 to CO2 changes was widely variable and unpredictable. After 20 minutes of moderate hyperventilation in most tests (79.8%), both SjvO2 and brain tissue PO2 values remained above the lower limits of normality (50% and 10 mm Hg, respectively). In contrast, in 15 tests performed in six patients (16.6% of the studied population) brain tissue PO2 decreased below 10 mm Hg although the corresponding SjvO2 values were greater than 50%. The reduction of brain tissue PO2 below 10 mm Hg was favored by the low prehyperventilation values (10 tests), higher CO2 reactivity, and, possibly, by lower prehyperventilation values of cerebral perfusion pressure. In five of those 15 tests, the prehyperventilation values of SjvO2 were greater than 70%, a condition of relative hyperemia. The SjvO2 decreased below 50% in four tests; the corresponding brain tissue PO2 values were less than 10 mm Hg in three of those tests, whereas in the fourth, the jugular venous O2 desaturation was not detected by brain tissue PO2. The analysis of the simultaneous relative changes (prehyperventilation — posthyperventilation) of SjvO2 and brain tissue PO2 showed that in most tests (75.5%) there was a reduction of both SjvO2 and brain tissue PO2. In two tests moderate hyperventilation resulted in an increase of both SjvO2 and brain tissue PO2. In the remaining 17 tests a redistribution of the cerebral blood flow was observed, leading to changes in SjvO2 and brain tissue PO2 in opposite directions. Conclusions. Hyperventilation, even if moderate, can frequently result in harmful local reductions of cerebral perfusion that cannot be detected by assessing SjvO2. Therefore, hyperventilation should be used with caution and should not be considered safe. This study confirms that SjvO2 and brain tissue PO2 are two parameters that provide complementary information on brain oxygenation that is useful to reduce the risk of secondary damage. Changes in SjvO2 and brain tissue PO2 in opposite directions indicate that data obtained from brain tissue PO2 monitoring cannot be extrapolated to evaluate the global cerebral perfusion.

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The Role of Neuroimaging in Assessing Neuropsychological Deficits following Traumatic Brain Injury

The Journal of Psychiatry & Law ◽

10.1177/009318531103900403 ◽

2011 ◽

Vol 39 (4) ◽

pp. 537-566 ◽

Cited By ~ 1

Author(s):

Benjamin J. Hayempour ◽

Susan E. Rushing ◽

Abass Alavi

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Damage ◽

Brain Injuries ◽

Neuropsychological Deficits ◽

Prognostic Information ◽

Specific Identification ◽

Secondary Damage ◽

Neuroimaging Techniques

Neuroimaging enables highly accurate and specific identification of treatable brain injuries for the purposes of preventing secondary damage as well as providing useful prognostic information. This article addresses the range of currently employed neuroimaging techniques and their utility in assessing legal claims involving the presence of brain damage.

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Increased S-Nitrosothiols and S-Nitrosoalbumin in Cerebrospinal Fluid after Severe Traumatic Brain Injury in Infants and Children: Indirect Association with Intracranial Pressure

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000040399.30600.e3 ◽

2003 ◽

Vol 23 (1) ◽

pp. 51-61 ◽

Cited By ~ 20

Author(s):

Hülya Bayir ◽

Patrick M. Kochanek ◽

Shang-Xi Liu ◽

Antonio Arroyo ◽

Anatoly Osipov ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cerebrospinal Fluid ◽

Brain Injury ◽

Intracranial Pressure ◽

Fold Increase ◽

Infants And Children ◽

No Production ◽

Secondary Damage ◽

Severe Tbi ◽

Pediatric Tbi

Nitric oxide (NO) is implicated in both secondary damage and recovery after traumatic brain injury (TBI). Transfer of NO groups to cysteine sulfhydryls on proteins produces S-nitrosothiols (RSNO). S-nitrosothiols may be neuroprotective after TBI by nitrosylation of N-methyl-D-aspartate receptor and caspases. S-nitrosothiols release NO on decomposition for which endogenous reductants (i.e., ascorbate) are essential, and ascorbate is depleted in cerebrospinal fluid (CSF) after pediatric TBI. This study examined the presence and decomposition of RSNO in CSF and the association between CSF RSNO level and physiologic parameters after severe TBI. Cerebrospinal fluid samples (n = 72) were obtained from 18 infants and children on days 1 to 3 after severe TBI (Glasgow Coma Scale score < 8) and 18 controls. Cerebrospinal fluid RSNO levels assessed by fluorometric assay peaked on day 3 versus control (1.42 ± 0.11 μmol/L vs. 0.86 ± 0.04, P < 0.05). S-nitrosoalbumin levels were also higher after TBI (n = 8, 0.99 ± 0.09 μmol/L on day 3 vs. n = 6, 0.42 ± 0.02 in controls, P < 0.05). S-nitrosoalbumin decomposition was decreased after TBI. Multivariate analysis showed an inverse relation between CSF RSNO and intracranial pressure and a direct relation with barbiturate treatment. Using a novel assay, the presence of RSNO and S-nitrosoalbumin in human CSF, an ∼1.7-fold increase after TBI, and an association with low intracranial pressure are reported, supporting a possible neuroprotective role for RSNO. The increase in RSNO may result from increased NO production and/or decreased RSNO decomposition.

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Endogenous Melatonin Increases in Cerebrospinal Fluid of Patients after Severe Traumatic Brain Injury and Correlates with Oxidative Stress and Metabolic Disarray

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600603 ◽

2008 ◽

Vol 28 (4) ◽

pp. 684-696 ◽

Cited By ~ 60

Author(s):

Marc A Seifman ◽

Alexios A Adamides ◽

Phuong N Nguyen ◽

Shirley A Vallance ◽

David James Cooper ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Cerebrospinal Fluid ◽

Brain Injury ◽

Severe Traumatic Brain Injury ◽

Serum Levels ◽

Serum Samples ◽

Secondary Damage ◽

Metabolic Disarray ◽

Melatonin Production

Oxidative stress plays a significant role in secondary damage after severe traumatic brain injury (TBI); and melatonin exhibits both direct and indirect antioxidant effects. Melatonin deficiency is deleterious in TBI animal models, and its administration confers neuroprotection, reducing cerebral oedema, and improving neurobehavioural outcome. This study aimed to measure the endogenous cerebrospinal fluid (CSF) and serum melatonin levels post-TBI in humans and to identify relationships with markers of oxidative stress via 8-isoprostaglandin-F2α (isoprostane), brain metabolism and neurologic outcome. Cerebrospinal fluid and serum samples of 39 TBI patients were assessed for melatonin, isoprostane, and various metabolites. Cerebrospinal fluid but not serum melatonin levels were markedly elevated (7.28±0.92 versus 1.47±0.35 pg/mL, P<0.0005). Isoprostane levels also increased in both CSF (127.62±16.85 versus 18.28±4.88 pg/mL, P<0.0005) and serum (562.46±50.78 versus 126.15±40.08 pg/mL ( P<0.0005). A strong correlation between CSF melatonin and CSF isoprostane on day 1 after injury ( r=0.563, P=0.002) suggests that melatonin production increases in conjunction with lipid peroxidation in TBI. Relationships between CSF melatonin and pyruvate ( r=0.369, P=0.049) and glutamate ( r=0.373, P=0.046) indicate that melatonin production increases with metabolic disarray. In conclusion, endogenous CSF melatonin levels increase after TBI, whereas serum levels do not. This elevation is likely to represent a response to oxidative stress and metabolic disarray, although further studies are required to elucidate these relationships.

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Is erythropoietin a worthy candidate for traumatic brain injury or are we heading the wrong way?

F1000Research ◽

10.12688/f1000research.8723.1 ◽

2016 ◽

Vol 5 ◽

pp. 911 ◽

Cited By ~ 2

Author(s):

Giovanni Grasso ◽

Concetta Alafaci ◽

Pietro Ghezzi

Keyword(s):

Clinical Trial ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Modern Society ◽

Therapeutic Strategies ◽

Solid Base ◽

Preclinical Studies ◽

Promising Candidate ◽

Secondary Damage ◽

Recent Clinical Trial

Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of these observations, further investigations are needed to resolve doubts on EPO effectiveness in order to provide a more solid base for tailoring conclusive clinical trials.

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