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1.
Stat Med ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38885949

ABSTRACT

Emergency medical diseases (EMDs) are the leading cause of death worldwide. A time-to-death analysis is needed to accurately identify the risks and describe the pattern of an EMD because the mortality rate can peak early and then decline. Dose-ranging Phase II clinical trials are essential for developing new therapies for EMDs. However, most dose-finding trials do not analyze mortality as a time-to-event endpoint. We propose three Bayesian dose-response time-to-event models for a secondary mortality analysis of a clinical trial: a two-group (active treatment vs control) model, a three-parameter sigmoid EMAX model, and a hierarchical EMAX model. The study also incorporates one specific active treatment as an active comparator in constructing three new models. We evaluated the performance of these six models and a very popular independent model using simulated data motivated by a randomized Phase II clinical trial focused on identifying the most effective hyperbaric oxygen dose to achieve favorable functional outcomes in patients with severe traumatic brain injury. The results show that the three-group, EMAX, and EMAX model with an active comparator produce the smallest averaged mean squared errors and smallest mean absolute biases. We provide a new approach for time-to-event analysis in early-phase dose-ranging clinical trials for EMDs. The EMAX model with an active comparator can provide valuable insights into the mortality analysis of new EMDs or other conditions that have changing risks over time. The restricted mean survival time, a function of the model's hazards, is recommended for displaying treatment effects for EMD research.

2.
Stat Med ; 42(25): 4582-4601, 2023 11 10.
Article in English | MEDLINE | ID: mdl-37599009

ABSTRACT

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.


Subject(s)
Brain Injuries, Traumatic , Humans , Bayes Theorem , Brain Injuries, Traumatic/therapy , Glasgow Outcome Scale , Probability , Prognosis , Clinical Trials as Topic
3.
J Neurotrauma ; 37(24): 2674-2679, 2020 12 15.
Article in English | MEDLINE | ID: mdl-32664792

ABSTRACT

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.


Subject(s)
Brain Injuries, Traumatic , Glasgow Outcome Scale , Outcome Assessment, Health Care , Clinical Trials as Topic , Humans
4.
Stat Med ; 38(17): 3123-3138, 2019 07 30.
Article in English | MEDLINE | ID: mdl-31070807

ABSTRACT

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example.


Subject(s)
Clinical Trials, Phase II as Topic , Dose-Response Relationship, Drug , Hyperbaric Oxygenation , Models, Statistical , Randomized Controlled Trials as Topic , Research Design , Bayes Theorem , Humans , Multicenter Studies as Topic , Prospective Studies
5.
J Neurotrauma ; 36(7): 1099-1105, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30014758

ABSTRACT

Mild traumatic brain injury (mTBI) is a significant cause of disability, especially when symptoms become chronic. This chronicity is often linked to oculomotor dysfunction (OMD). To our knowledge, this is the first prospective study to localize aberrations in brain function between mTBI cohorts, by comparing patients with mTBI with OMD with an mTBI control group without OMD, using task and resting-state functional magnetic resonance imaging (fMRI). Ten subjects with mTBI who had OMD (OMD group) were compared with nine subjects with mTBI who had no findings of OMD (control group). These groups were determined by a developmental optometrist using objective testing for OMD. The (convergence) task fMRI data demonstrated significantly decreased brain activity, measured as decreases in the blood oxygen level dependent (BOLD) signal, in the OMD group compared with the control group in three brain regions: the left posterior lingual gyrus, the bilateral anterior lingual gyrus and cuneus, and the parahippocampal gyrus. When doing a seed-based resting state fMRI analysis in the lingual/parahippocampal region, a large cluster covering the left middle frontal gyrus and the dorsolateral pre-frontal cortex (Brodmann areas 9 and 10), with decreased functional correlation in the OMD group, was identified. Together these observations provide evidence for neural networks of interactions involving the control of eye movement for visual processing, reading comprehension, spatial localization and navigation, and spatial working memory that appear to be decreased in mTBI patients with OMD compared with mTBI patients without OMD. The clinical symptomatology associated with post-traumatic OMD correlates well with these MRI findings.


Subject(s)
Brain Concussion/diagnostic imaging , Brain/diagnostic imaging , Ocular Motility Disorders/diagnostic imaging , Adult , Brain Concussion/complications , Brain Concussion/physiopathology , Eye Movements/physiology , Female , Functional Neuroimaging , Humans , Magnetic Resonance Imaging , Male , Neuropsychological Tests , Ocular Motility Disorders/etiology , Ocular Motility Disorders/physiopathology , Prospective Studies , Spatial Navigation/physiology
6.
Pharm Stat ; 15(5): 396-404, 2016 09.
Article in English | MEDLINE | ID: mdl-27306921

ABSTRACT

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd.


Subject(s)
Brain Injuries/therapy , Clinical Trials, Phase II as Topic/statistics & numerical data , Hyperbaric Oxygenation/statistics & numerical data , Models, Statistical , Causality , Clinical Trials, Phase II as Topic/methods , Humans , Longitudinal Studies , Random Allocation
7.
Neurosurgery ; 74(5): 553-9; discussion 559-60, 2014 May.
Article in English | MEDLINE | ID: mdl-24521612

ABSTRACT

Neurosurgery began as a distinct discipline at the University of Minnesota in 1937 with the appointment of William Peyton as head of the division. Under the leadership of Peyton, Lyle French, and Shelley Chou, the Department rose to national prominence. Substantial contributions included the introduction of dexamethasone to the practice of neurosurgery by Galicich and French, early procedures for the transthoracic correction of spinal deformity, important contributions to the understanding of brain death, the early laboratory work that led to the development of nimodopine, one of the first intraoperative magnetic resonance imaging facilities in the United States (1996), and the training of many academic neurosurgeons and department chairmen. The challenges of managed care and more recent changes in the health care system have been met, and the Department is a thriving clinical, educational, and research center for 21st-century neurosurgery.


Subject(s)
Faculty, Medical/history , Hospitals, University/history , Neurosurgery/history , Biomedical Research/history , Delivery of Health Care, Integrated/history , Education, Medical/history , History, 20th Century , History, 21st Century , Minnesota , Neurosurgical Procedures/history , Surgery Department, Hospital/history
8.
J Neurosurg ; 118(6): 1317-28, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23510092

ABSTRACT

OBJECT: Preclinical and clinical investigations indicate that the positive effect of hyperbaric oxygen (HBO2) for severe traumatic brain injury (TBI) occurs after rather than during treatment. The brain appears better able to use baseline O2 levels following HBO2 treatments. In this study, the authors evaluate the combination of HBO2 and normobaric hyperoxia (NBH) as a single treatment. METHODS: Forty-two patients who sustained severe TBI (mean Glasgow Coma Scale [GCS] score 5.7) were prospectively randomized within 24 hours of injury to either: 1) combined HBO2/NBH (60 minutes of HBO2 at 1.5 atmospheres absolute [ATA] followed by NBH, 3 hours of 100% fraction of inspired oxygen [FiO2] at 1.0 ATA) or 2) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Intracranial pressure, surrogate markers for cerebral metabolism, and O2 toxicity were monitored. Clinical outcome was assessed at 6 months using the sliding dichotomized Glasgow Outcome Scale (GOS) score. Mixed-effects linear modeling was used to statistically test differences between the treatment and control groups. Functional outcome and mortality rates were compared using chi-square tests. RESULTS: There were no significant differences in demographic characteristics between the 2 groups. In comparison with values in the control group, brain tissue partial pressure of O2 (PO2) levels were significantly increased during and following combined HBO2/NBH treatments in both the noninjured and pericontusional brain (p < 0.0001). Microdialysate lactate/pyruvate ratios were significantly decreased in the noninjured brain in the combined HBO2/NBH group as compared with controls (p < 0.0078). The combined HBO2/NBH group's intracranial pressure values were significantly lower than those of the control group during treatment, and the improvement continued until the next treatment session (p < 0.0006). The combined HBO2/NBH group's levels of microdialysate glycerol were significantly lower than those of the control group in both noninjured and pericontusional brain (p < 0.001). The combined HBO2/NBH group's level of CSF F2-isoprostane was decreased at 6 hours after treatment as compared with that of controls, but the difference did not quite reach statistical significance (p = 0.0692). There was an absolute 26% reduction in mortality for the combined HBO2/NBH group (p = 0.048) and an absolute 36% improvement in favorable outcome using the sliding dichotomized GOS (p = 0.024) as compared with the control group. CONCLUSIONS: In this Phase II clinical trial, in comparison with standard care (control treatment) combined HBO2/NBH treatments significantly improved markers of oxidative metabolism in relatively uninjured brain as well as pericontusional tissue, reduced intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. There was significant reduction in mortality and improved favorable outcome as measured by GOS. The combination of HBO2 and NBH therapy appears to have potential therapeutic efficacy as compared with the 2 treatments in isolation. CLINICAL TRIAL REGISTRATION NO.: NCT00170352 (ClinicalTrials.gov).


Subject(s)
Brain Injuries/therapy , Brain/metabolism , Hyperbaric Oxygenation/methods , Intracranial Pressure/physiology , Oxygen/toxicity , Oxygen/therapeutic use , Severity of Illness Index , Adult , Biomarkers/metabolism , Brain Injuries/metabolism , Brain Injuries/physiopathology , Combined Modality Therapy , Female , Glasgow Outcome Scale , Humans , Intracranial Hypertension/epidemiology , Linear Models , Male , Oxygen/metabolism , Prospective Studies , Risk Factors , Treatment Outcome
10.
Neurocrit Care ; 17(2): 204-10, 2012 Oct.
Article in English | MEDLINE | ID: mdl-21725694

ABSTRACT

BACKGROUND: Osmotherapy has been the cornerstone in the management of patients with elevated intracranial pressure (ICP) following traumatic brain injury (TBI). Several studies have demonstrated that hypertonic saline (HTS) is a safe and effective osmotherapy agent. This study evaluated the effectiveness of HTS in reducing intracranial hypertension in the presence of a wide range of serum and cerebrospinal fluid (CSF) osmolalities. METHODS: Forty-two doses of 23.4% saline boluses for treatment of refractory intracranial hypertension were reviewed retrospectively. Thirty milliliters of 23.4% NaCl was infused over 15 min for intracranial hypertension, defined as ICP >20 mmHg. The CSF and serum osmolalities from frozen stored samples were measured with an osmometer. The values of serum sodium, hourly ICP, blood urea nitrogen (BUN), and creatinine were obtained directly from the medical records. RESULTS: The serum and CSF osmolalities correlated very closely to serum sodium (r > 0.9, P < 0.0001). The reduction in ICP from the baseline (measured from either the mean ICP or the lowest ICP measurement in the first 6 h after bolus HTS treatment) was statistically significant regardless of serum osmolality. The mean reduction from baseline to follow-up values was 8.8 mm Hg (P < 0.0001). The decrease in ICP was as evident with serum osmolalities >320 as it was at ≤320. CONCLUSION: This study demonstrates that 23.4% HTS bolus is effective for the reduction of elevated ICP in patients with severe TBI even in the presence of high serum and CSF osmolalities.


Subject(s)
Brain Injuries/complications , Fluid Therapy/methods , Intracranial Hypertension/therapy , Saline Solution, Hypertonic/therapeutic use , Adolescent , Adult , Aged , Cerebrospinal Fluid/chemistry , Female , Humans , Intracranial Hypertension/complications , Male , Middle Aged , Osmolar Concentration , Retrospective Studies , Serum/chemistry , Sodium/blood , Sodium/cerebrospinal fluid
11.
J Neurotrauma ; 28(1): 135-42, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21121814

ABSTRACT

The purpose of this study was to explore a novel treatment involving removal of free water from ventricular cerebrospinal fluid (CSF) for the reduction of cerebra]l edema. The hypothesis is that removal of free water from the CSF will increase the osmolarity of the CSF, which will favor movement of tissue-bound water into the ventricles, where the water can be removed. Reductive ventricular osmotherapy (RVOT) was tested in a flowing solution of artificial CSF (aCSF) with two end-points: (1) the effect of RVOT on osmolarity of the CSF, and (2) the effect of RVOT on water content of ex vivo cerebral tissue. RVOT catheters are made up of membranes permeable only to water vapor. When a sweep gas is drawn through the catheter, free water in the form of water vapor is removed from the solution. With RVOT treatment, aCSF osmolarity increased from a baseline osmolarity of 318.8 ± 0.8 mOsm/L to 339.0 ± 3.3 mOsm/L (mean ± standard deviation) within 2 h. After 10 h of treatment, aCSF osmolarity approached an asymptote at 344.0 ± 4.2 mOsm/L, which was significantly greater than control aCSF osmolarity (p <<0.001 by t-test, n = 8). Water content at the end of 6 h of circulating aCSF exposure was 6.4 ± 0.9 g H2O (g dry wt)⁻¹ in controls, compared to 6.1 ± 0.7 g H2O (g dry wt)⁻ after 6 h of RVOT treatment of aCSF (p = 0.02, n = 24). The results support the potential of RVOT as a treatment for cerebral edema and intracranial hypertension.


Subject(s)
Brain Edema/therapy , Cerebral Ventricles/chemistry , Cerebral Ventricles/metabolism , Cerebrospinal Fluid/chemistry , Osmosis/physiology , Water/chemistry , Animals , Brain Chemistry , Osmolar Concentration , Sheep
12.
J Neurosurg ; 112(5): 1080-94, 2010 May.
Article in English | MEDLINE | ID: mdl-19852540

ABSTRACT

OBJECT: Oxygen delivered in supraphysiological amounts is currently under investigation as a therapy for severe traumatic brain injury (TBI). Hyperoxia can be delivered to the brain under normobaric as well as hyperbaric conditions. In this study the authors directly compare hyperbaric oxygen (HBO2) and normobaric hyperoxia (NBH) treatment effects. METHODS: Sixty-nine patients who had sustained severe TBIs (mean Glasgow Coma Scale Score 5.8) were prospectively randomized to 1 of 3 groups within 24 hours of injury: 1) HBO2, 60 minutes of HBO(2) at 1.5 ATA; 2) NBH, 3 hours of 100% fraction of inspired oxygen at 1 ATA; and 3) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Brain tissue PO(2), microdialysis, and intracranial pressure were continuously monitored. Cerebral blood flow (CBF), arteriovenous differences in oxygen, cerebral metabolic rate of oxygen (CMRO2), CSF lactate and F2-isoprostane concentrations, and bronchial alveolar lavage (BAL) fluid interleukin (IL)-8 and IL-6 assays were obtained pretreatment and 1 and 6 hours posttreatment. Mixed-effects linear modeling was used to statistically test differences among the treatment arms as well as changes from pretreatment to posttreatment. RESULTS: In comparison with values in the control group, the brain tissue PO2 levels were significantly increased during treatment in both the HBO2 (mean +/- SEM, 223 +/- 29 mm Hg) and NBH (86 +/- 12 mm Hg) groups (p < 0.0001) and following HBO2 until the next treatment session (p = 0.003). Hyperbaric O2 significantly increased CBF and CMRO2 for 6 hours (p < or = 0.01). Cerebrospinal fluid lactate concentrations decreased posttreatment in both the HBO2 and NBH groups (p < 0.05). The dialysate lactate levels in patients who had received HBO2 decreased for 5 hours posttreatment (p = 0.017). Microdialysis lactate/pyruvate (L/P) ratios were significantly decreased posttreatment in both HBO2 and NBH groups (p < 0.05). Cerebral blood flow, CMRO2, microdialysate lactate, and the L/P ratio had significantly greater improvement when a brain tissue PO2 > or = 200 mm Hg was achieved during treatment (p < 0.01). Intracranial pressure was significantly lower after HBO2 until the next treatment session (p < 0.001) in comparison with levels in the control group. The treatment effect persisted over all 3 days. No increase was seen in the CSF F2-isoprostane levels, microdialysate glycerol, and BAL inflammatory markers, which were used to monitor potential O2 toxicity. CONCLUSIONS: Hyperbaric O2 has a more robust posttreatment effect than NBH on oxidative cerebral metabolism related to its ability to produce a brain tissue PO2 > or = 200 mm Hg. However, it appears that O2 treatment for severe TBI is not an all or nothing phenomenon but represents a graduated effect. No signs of pulmonary or cerebral O2 toxicity were present.


Subject(s)
Brain Injuries/metabolism , Brain Injuries/therapy , Hyperbaric Oxygenation/methods , Hyperoxia/diagnosis , Intracranial Hypertension/diagnosis , Intracranial Hypertension/metabolism , Oxygen/adverse effects , Biomarkers , Bronchoalveolar Lavage , Cerebrovascular Circulation/physiology , Drug Administration Schedule , Humans , Mitochondria/metabolism , Oxygen/administration & dosage , Oxygen Consumption , Prospective Studies , Severity of Illness Index
13.
Neurosurgery ; 65(6): 1035-41; discussion 1041-2, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19934962

ABSTRACT

OBJECTIVE: Hypertonic saline is emerging as a potentially effective single osmotic agent for control of acute elevations in intracranial pressure (ICP) caused by severe traumatic brain injury. This study examines its effect on ICP, cerebral perfusion pressure (CPP), and brain tissue oxygen tension (PbtO2). METHODS: Twenty-five consecutive patients with severe traumatic brain injury who were treated with 23.4% NaCl for elevated ICP were evaluated. Bolt catheter probes were placed in the noninjured hemisphere, and hourly ICP, mean arterial pressure, CPP, and PbtO2 values were recorded. Thirty milliliters of 23.4% NaCl was infused over 15 minutes for intracranial hypertension, defined as ICP greater than 20 mm Hg. Twenty-one male patients and 4 female patients aged 16 to 64 years were included. The mean presenting Glasgow Coma Scale score was 5.7. RESULTS: Mean pretreatment values included an ICP level of 25.9 mm Hg and a PbtO2 value of 32 mm Hg. The posttreatment ICP level was decreased by a mean of 8.3 mm Hg (P < 0.0001), and there was an improvement in PbtO2 of 3.1 mm Hg (P < 0.01). ICP of more than 31 mm Hg decreased by 14.2 mm Hg. Pretreatment CPP values of less than 70 mm Hg increased by a mean of 6 mm Hg (P < 0.0001). No complications occurred from this treatment, with the exception of electrolyte and chemistry abnormalities. At 6 months postinjury, the mortality rate was 28%, with 48% of patients achieving a favorable outcome by the dichotomized Glasgow Outcome Scale. CONCLUSION: Hypertonic saline as a single osmotic agent decreased ICP while improving CPP and PbtO2 in patients with severe traumatic brain injury. Patients with higher baseline ICP and lower CPP levels responded to hypertonic saline more significantly.


Subject(s)
Brain Injuries , Brain/metabolism , Cerebrovascular Circulation/drug effects , Intracranial Pressure/drug effects , Oxygen/metabolism , Saline Solution, Hypertonic/pharmacology , Saline Solution, Hypertonic/therapeutic use , Adolescent , Adult , Blood Pressure/drug effects , Brain Injuries/drug therapy , Brain Injuries/metabolism , Brain Injuries/pathology , Female , Glasgow Coma Scale , Humans , Male , Middle Aged , Time Factors , Tomography Scanners, X-Ray Computed , Young Adult
15.
J Neurosurg ; 106(4): 687-94, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17432723

ABSTRACT

OBJECT: Hyperbaric oxygen (HBO2) has been shown to improve outcome after severe traumatic brain injury, but its underlying mechanisms are unknown. Following lateral fluid-percussion injury (FPI), the authors tested the effects of HBO2 treatment as well as enhanced normobaric oxygenation on mitochondrial function, as measured by both cognitive recovery and cellular adenosine triphosphate (ATP) levels. METHODS: Adult male Sprague-Dawley rats were subjected to moderate lateral FPI or sham injury and were allocated to one of four treatment groups: 1) FPI treated with 4 hours of normobaric 30% O2; 2) FPI treated with 4 hours of normobaric 100% O2; 3) FPI treated with 1 hour of HBO2 plus 3 hours of normobaric 100% O2; and 4) sham-injured treated with normobaric 30% O2. Cognitive outcome was assessed using the Morris water maze (MWM) on Days 11 to 15 after injury. Animals were then killed 21 days postinjury to assess hippocampal neuronal loss. Adenosine triphosphate was extracted from the neocortex and measured using high-performance liquid chromatography. The results showed that injured animals treated with HBO2 or normobaric 100% O2 alone had significantly higher levels of cerebral ATP as compared with animals treated using normobaric 30% O2 (p < or = 0.05). The injured animals treated with HBO2 had significant improvements in cognitive recovery, as characterized by a shorter latency in MWM performance (p < or = 0.05), and decreased neuronal loss in the CA2/3 and hilar regions as compared with those treated with 30% or 100% O2, (p < or = 0.05). CONCLUSIONS: Both hyperbaric and normobaric hyperoxia increased cerebral ATP levels after lateral FPI. In addition, HBO2 treatment improved cognitive recovery and reduced hippocampal neuronal cell loss after brain injury in the rat.


Subject(s)
Brain Injuries/therapy , Cognition/physiology , Hyperbaric Oxygenation , Mitochondria/physiology , Adenosine Triphosphate/metabolism , Animals , Brain Injuries/metabolism , Brain Injuries/psychology , Chromatography, High Pressure Liquid , Free Radicals/metabolism , Hippocampus/pathology , Male , Maze Learning , Rats , Rats, Sprague-Dawley , Recovery of Function/physiology
16.
Neurol Res ; 29(2): 162-72, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17439701

ABSTRACT

OBJECTIVES: This critical literature review examines historical and current investigations on the efficacy and mechanisms of hyperbaric oxygen (HBO) treatment in traumatic brain injury (TBI). Potential safety risks and oxygen toxicity, as well as HBO's future potential, are also discussed. METHODS: Directed literature review. RESULTS: Historically, cerebral vasoconstriction and increased oxygen availability were seen as the primary mechanisms of HBO in TBI. HBO now appears to be improving cerebral aerobic metabolism at a cellular level, namely, by enhancing damaged mitochondrial recovery. HBO given at the ideal treatment paradigm, 1.5 ATA for 60 minutes, does not appear to produce oxygen toxicity and is relatively safe. DISCUSSION: The use of HBO in TBI remains controversial. Growing evidence, however, shows that HBO may be a potential treatment for patients with severe brain injury. Further investigations, including a multicenter prospective randomized clinical trial, will be required to definitively define the role of HBO in severe TBI.


Subject(s)
Brain Injuries/physiopathology , Brain Injuries/therapy , Hyperbaric Oxygenation/standards , Hyperbaric Oxygenation/trends , Hypoxia-Ischemia, Brain/physiopathology , Hypoxia-Ischemia, Brain/therapy , Animals , Brain/blood supply , Brain/metabolism , Brain/physiopathology , Cerebrovascular Circulation/physiology , Clinical Trials as Topic/statistics & numerical data , Disease Models, Animal , Humans , Hyperbaric Oxygenation/adverse effects , Hypoxia-Ischemia, Brain/etiology , Oxygen Consumption/physiology , Treatment Outcome
18.
J Neurosurg ; 101(3): 499-504, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15352608

ABSTRACT

OBJECT: In the current study, the authors examined the effects of hyperbaric O2 (HBO) following fluid-percussion brain injury and its implications on brain tissue oxygenation (PO2) and O2 consumption (VO2) and mitochondrial function (redox potential). METHODS: Cerebral tissue PO2 was measured following induction of a lateral fluid-percussion brain injury in rats. Hyperbaric O2 treatment (100% O2 at 1.5 ata) significantly increased brain tissue PO2 in both injured and sham-injured animals. For VO2 and redox potential experiments, animals were treated using 30% O2 or HBO therapy for 1 or 4 hours (that is, 4 hours 30% O2 or 1 hour HBO and 3 hours 100% O2). Microrespirometer measurements of VO2 demonstrated significant increases following HBO treatment in both injured and sham-injured animals when compared with animals that underwent 30% O2 treatment. Mitochondrial redox potential, as measured by Alamar blue fluorescence, demonstrated injury-induced reductions at 1 hour postinjury. These reductions were partially reversed at 4 hours postinjury in animals treated with 30% O2 and completely reversed at 4 hours postinjury in animals on HBO therapy when compared with animals treated for only 1 hour. CONCLUSIONS: Analysis of data in the current study demonstrates that HBO significantly increases brain tissue PO2 after injury. Nonetheless, treatment with HBO was insufficient to overcome injury-induced reductions in mitochondrial redox potential at 1 hour postinjury but was able to restore redox potential by 4 hours postinjury. Furthermore, HBO induced an increase in VO2 in both injured and sham-injured animals. Taken together, these data demonstrate that mitochondrial function is depressed by injury and that the recovery of aerobic metabolic function may be enhanced by treatment with HBO.


Subject(s)
Brain Concussion/physiopathology , Dominance, Cerebral/physiology , Energy Metabolism/physiology , Hyperbaric Oxygenation , Mitochondria/physiology , Oxygen Consumption/physiology , Animals , Brain Ischemia/physiopathology , Cerebral Cortex/injuries , Cerebral Cortex/physiopathology , Male , Oxidation-Reduction , Oximetry , Rats , Rats, Sprague-Dawley
19.
J Neurosurg ; 99(6): 1111-2; author reply 1112-3, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14705746
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