Epidural electrical stimulation of the cervical spinal cord opposes opioid-induced respiratory depression.

Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid-induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90 s at 5 or 30 Hz during complete (OFF-State) or partial suppression (ON-State) of respiration induced by remifentanil. During the ON-State, 30 Hz EES at C4 and 5 Hz EES at C3/4 increased tidal volume and decreased the end-tidal carbon dioxide level compared to pre-stimulation control levels. EES of 5 Hz at C5 and C7 increased respiratory frequency compared to pre-stimulation control levels. In the OFF-State, 30 Hz cervical EES at C3/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3/4, C6 and C7) compared to a region non-responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions. KEY POINTS: Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA-approved method to manage chronic pain. We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low-dose remifentanil that suppressed respiration (ON-State) or high-dose remifentanil that completely inhibited breathing (OFF-State) during the course of cervical surgery. Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30 Hz) and the cervical level stimulated (C2-C7). Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF-State, suggesting that cervical EES reversed the opioid-induced respiratory depression. These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids.

Early brain biomarkers of post-traumatic seizures: initial report of the multicentre epilepsy bioinformatics study for antiepileptogenic therapy (EpiBioS4Rx) prospective study.

BACKGROUND: Traumatic brain injury (TBI) causes early seizures and is the leading cause of post-traumatic epilepsy. We prospectively assessed structural imaging biomarkers differentiating patients who develop seizures secondary to TBI from patients who do not. DESIGN: Multicentre prospective cohort study starting in 2018. Imaging data are acquired around day 14 post-injury, detection of seizure events occurred early (within 1 week) and late (up to 90 days post-TBI). RESULTS: From a sample of 96 patients surviving moderate-to-severe TBI, we performed shape analysis of local volume deficits in subcortical areas (analysable sample: 57 patients; 35 no seizure, 14 early, 8 late) and cortical ribbon thinning (analysable sample: 46 patients; 29 no seizure, 10 early, 7 late). Right hippocampal volume deficit and inferior temporal cortex thinning demonstrated a significant effect across groups. Additionally, the degree of left frontal and temporal pole thinning, and clinical score at the time of the MRI, could differentiate patients experiencing early seizures from patients not experiencing them with 89% accuracy. CONCLUSIONS AND RELEVANCE: Although this is an initial report, these data show that specific areas of localised volume deficit, as visible on routine imaging data, are associated with the emergence of seizures after TBI.

Improving transparency and scientific rigor in academic publishing.

Progress in basic and clinical research is slowed when researchers fail to provide a complete and accurate report of how a study was designed, executed, and the results analyzed. Publishing rigorous scientific research involves a full description of the methods, materials, procedures, and outcomes. Investigators may fail to provide a complete description of how their study was designed and executed because they may not know how to accurately report the information or the mechanisms are not in place to facilitate transparent reporting. Here, we provide an overview of how authors can write manuscripts in a transparent and thorough manner. We introduce a set of reporting criteria that can be used for publishing, including recommendations on reporting the experimental design and statistical approaches. We also discuss how to accurately visualize the results and provide recommendations for peer reviewers to enhance rigor and transparency. Incorporating transparency practices into research manuscripts will significantly improve the reproducibility of the results by independent laboratories.

Acute glucose and lactate metabolism are associated with cognitive recovery following traumatic brain injury.

Traumatic brain injury (TBI) is associated with acute cerebral metabolic crisis (ACMC). ACMC-related atrophy appears to be prominent in frontal and temporal lobes following moderate-to-severe TBI. This atrophy is correlated with poorer cognitive outcomes in TBI. The current study investigated ability of acute glucose and lactate metabolism to predict long-term recovery of frontal-temporal cognitive function in participants with moderate-to-severe TBI. Cerebral metabolic rate of glucose and lactate were measured by the Kety-Schmidt method on days 0-7 post-injury. Indices of frontal-temporal cognitive processing were calculated for six months post-injury; 12 months post-injury; and recovery (the difference between the six- and 12-month scores). Glucose and lactate metabolism were included in separate regression models, as they were highly intercorrelated. Also, glucose and lactate values were centered and averaged and included in a final regression model. Models for the prediction frontal-temporal cognition at six and 12 months post-injury were not significant. However, average glucose and lactate metabolism predicted recovery of frontal-temporal cognition, accounting for 23% and 22% of the variance, respectively. Also, maximum glucose metabolism, but not maximum lactate metabolism, was an inverse predictor in the recovery of frontal-temporal cognition, accounting for 23% of the variance. Finally, the average of glucose and lactate metabolism predicted frontal-temporal cognitive recovery, accounting for 22% of the variance. These data indicate that acute glucose and lactate metabolism both support cognitive recovery from TBI. Also, our data suggest that control of endogenous fuels and/or supplementation with exogenous fuels may have therapeutic potential for cognitive recovery from TBI.

Influence of Glycemic Control on Endogenous Circulating Ketone Concentrations in Adults Following Traumatic Brain Injury.

BACKGROUND: The objective was to investigate the impact of targeting tight glycemic control (4.4-6.1 mM) on endogenous ketogenesis in severely head-injured adults. METHODS: The data were prospectively collected during a randomized, within-patient crossover study comparing tight to loose glycemic control, defined as 6.7-8.3 mM. Blood was collected periodically during both tight and loose glycemic control epochs. Post hoc analysis of insulin dose and total nutritional provision was performed. RESULTS: Fifteen patients completed the crossover study. Total ketones were increased 81 µM ([38 135], p < 0.001) when blood glucose was targeted to tight (4.4-6.1 mM) compared with loose glycemic control (6.7-8.3 mM), corresponding to a 60 % increase. There was a significant decrease in total nutritional provisions (p = 0.006) and a significant increase in insulin dose (p = 0.008). CONCLUSIONS: Permissive underfeeding was tolerated when targeting tight glycemic control, but total nutritional support is an important factor when treating hyperglycemia.

Therapeutic intravascular normothermia reduces the burden of metabolic crisis.

BACKGROUND: We aim to investigate whether therapeutic-induced normothermia (TIN) ≤ 37.5 °C, by means of intravascular cooling devices is more efficacious than standard medical therapy (MED) in alleviating metabolic crisis (MC) acutely following traumatic brain injury (TBI). METHODS: We retrospectively analyzed data from 62 patients with severe TBI, GCS ≤ 8. We divided the cohort into two groups. (1) Patients who had temperature controlled via standard medical therapies (n = 52), (2) TIN group (n = 10). For each group, we analyzed the percent time spent in normothermia, and in MC. Furthermore, we focused the investigation on pre-TIN versus post-TIN comparing temp, intracranial pressure (ICP), sedation, and MC before and after intravascular cooling. RESULTS: TIN patients had a better temperature control than MED group (60.72 ± 19.53 vs 69.75 ± 24.98 %, p < 0.001) and spent shorter time in MC (22.60 ± 20.45 vs 32.17 ± 27.25 %, p < 0.001). Temperature control was associated with reduced incidence of MC in TIN (OR 0.51, CI 0.38-0.67, p < 0.001, p < 0.001) but not in MED (OR 0.97, CI 0.87-1.1, p = 0.63). Within TIN group analysis, following TIN both temperature and incidence of MC improved from 37.62 ± 0.34 versus 36.69 ± 0.90 °C (p < 0.005) and 41.95 ± 27.74 % before to 8.35 ± 9.78 % (p = 0.005) after, respectively. ICP was well controlled both before and after intravascular cooling (13.07 vs 15.83 mmHg, p = 0.20). CONCLUSION: Therapeutic normothermia, using intravascular cooling, results in a reduction in the burden of MC. This differential effect occurs despite equivalent control of ICP in both TIN and MED treatments. These results demonstrate proof of concept of normothermia, when applied in a controlled manner, being neuroprotective.

The pituitary stalk effect: is it a passing phenomenon?

Most patients with large pituitary tumors do not exhibit hyperprolactinemia as a result of pituitary lactotroph disinhibition (stalk effect). Studies have demonstrated that increased intrasellar pressure is associated with both "stalk effect" hyperprolactinemia and pituitary insufficiency. Our primary hypothesis was that, despite continued disinhibition, lactotroph failure is responsible for normoprolactinemia in patients with large macroadenomas. As a corollary, we proposed that the hyperprolactinemia phase, which presumably would precede the insufficiency/normoprolactinemic state, would more likely be discovered in premenopausal females and go unnoticed in males. Prospective, consecutive surgical series of 98 patients of clinically nonfunctional pituitary adenomas. Lactotroph insufficiency was inferred by the coexistence of insufficiency in another pituitary axis. The existence of pre-operative lactotroph disinhibition was inferred based on comparison of pre- versus post-operative prolactin levels. 87 % of patients with tumor size >20 mm and normoprolactinemia had pituitary insufficiency. Pre-operative prolactin in patients with pituitary insufficiency were lower than those with intact pituitary function. Prolactin levels dropped in nearly all patients, including patients with normoprolactinemia pre-operatively. Premenopausal women had smaller tumors and higher pre-operative prolactin levels compared to males. No premenopausal female exhibited evidence of pituitary insufficiency. Our study provides suggestive evidence that the "stalk effect" pathophysiology is the norm rather than the exception, and that the finding of normoprolactinemia in a patient with a large macroadenoma is likely a consequence of lactotroph insufficiency. In males, the hyperprolactinemia window is more likely to be missed clinically due to an absence of prolactin-related symptoms.

Association of Premorbid Anxiety and Depression Symptoms in Concussion Recovery in Collegiate Student-Athletes.

BACKGROUND: Mental health disorders are linked to prolonged concussion symptoms. However, the association of premorbid anxiety/depression symptoms with postconcussion return-to-play timelines and total symptom burden is unclear. OBJECTIVE: To examine the association of self-reported premorbid anxiety/depression symptoms in collegiate student-athletes with (1) recovery times until asymptomatic, (2) return-to-play, and (3) postconcussion symptom burden. STUDY DESIGN: Athletes in the Concussion Assessment, Research and Education Consortium completed baseline concussion assessments (Sport Concussion Assessment Tool [SCAT3] and Brief Symptom Inventory-18 [BSI-18]). Athletes were tested postinjury at <6 hours, 24 to 48 hours, time of asymptomatic and start of return-to-play protocol, unrestricted return-to-play, and 6 months after injury. Injured athletes were categorized into 4 groups based on BSI-18 scores: (1) B-ANX, elevated anxiety symptoms only; (2) B-DEP, elevated depression symptoms only; (3) B-ANX&DEP, elevated anxiety and depression symptoms; and (4) B-NEITHER, no elevated anxiety or depression symptoms. Relationship between age, sex, BSI-18 group, SCAT3 total symptom and severity scores, and time to asymptomatic status and return-to-play was assessed with Pearson's chi-squared test and robust analysis of variance. LEVEL OF EVIDENCE: Level 3. RESULTS: Among 1329 athletes with 1352 concussions, no respondents had a self-reported premorbid diagnosis of anxiety/depression. There was no difference in time until asymptomatic or time until return-to-play between BSI-18 groups (P = 0.15 and P = 0.11, respectively). B-ANX, B-DEP, and B-ANX&DEP groups did not have higher total symptom or severity scores postinjury compared with the B-NEITHER group. CONCLUSION: Baseline anxiety/depression symptoms in collegiate student-athletes without a mental health diagnosis are not associated with longer recovery times until asymptomatic, longer time to return-to-play, or higher postconcussion total symptom and severity scores compared with athletes without baseline symptoms. CLINICAL RELEVANCE: Anxiety and depression symptoms without a clear mental health diagnosis should be considered differently from other comorbidities when discussing prolonged recovery in collegiate student-athletes.

Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response.

BACKGROUND: Rasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy. METHODS: Quantitative polymerase chain reactions measured the relative expression of 84 genes related to inflammation and autoimmunity in 12 RE specimens and in the reference group of 12 CD surgical specimens. Data were analyzed by consensus clustering using the entire dataset, and by pairwise comparison of gene expression levels between the RE and CD cohorts using the Harrell-Davis distribution-free quantile estimator method. RESULTS: Consensus clustering identified six RE cases that were clearly distinguished from the CD cases and from other RE cases. Pairwise comparison showed that seven mRNAs encoding interferon-γ, CCL5, CCL22, CCL23, CXCL9, CXCL10, and Fas ligand were higher in the RE specimens compared with the CD specimens, whereas the mRNA encoding hypoxanthine-guanine phosphoribosyltransferase was reduced. Interferon-γ, CXCL5, CXCL9 and CXCL10 mRNA levels negatively correlated with time from seizure onset to surgery (P <0.05), whereas CCL23 and Fas ligand transcript levels positively correlated with the degree of tissue destruction and inflammation, respectively (P <0.05), as determined from magnetic resonance imaging (MRI) T2 and FLAIR images. Accumulation of CD4+ lymphocytes in leptomeninges and perivascular spaces was a prominent feature in RE specimens resected within a year of seizure onset. CONCLUSIONS: Active disease is characterized by a Th1 immune response that appears to involve both CD8+ and CD4+ T cells. Our findings suggest therapeutic intervention targeting specific chemokine/chemokine receptors may be useful in early stage RE.

Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort.

PURPOSE: Traumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video-EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS. METHODS: Eighty-seven consecutive, unselected (mild - severe), acute TBI patients requiring pediatric intensive care unit (PICU) admission at two academic centers were monitored prospectively with cEEG per established clinical TBI protocols. Clinical and subclinical seizures and status epilepticus (SE, clinical and subclinical) were assessed for their relation to clinical risk factors and short-term outcome measures. KEY FINDINGS: Of all patients, 42.5% (37/87) had seizures. Younger age (p = 0.002) and injury mechanism (abusive head trauma - AHT, p < 0.001) were significant risk factors. Subclinical seizures occurred in 16.1% (14/87), while 6.9% (6/87) had only subclinical seizures. Risk factors for subclinical seizures included younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p < 0.001). SE occurred in 18.4% (16/87) with risk factors including younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p = 0.002). Subclinical SE was detected in 13.8% (12/87) with significant risk factors including younger age (p < 0.001), AHT (p = 0.001), and intraaxial bleed (p = 0.004). Subclinical seizures were associated with lower discharge King's Outcome Scale for Childhood Head Injury (KOSCHI) score (p = 0.002). SE and subclinical SE were associated with increased hospital length of stay (p = 0.017 and p = 0.041, respectively) and lower hospital discharge KOSCHI (p = 0.007 and p = 0.040, respectively). SIGNIFICANCE: cEEG monitoring significantly improves detection of seizures/SE and is the only way to detect subclinical seizures/SE. cEEG may be indicated after pediatric TBI, particularly in younger children, AHT cases, and those with intraaxial blood on computerized tomography (CT).

Prevalence of epileptic and nonepileptic events after pediatric traumatic brain injury.

Though posttraumatic epilepsy (PTE) is a prominent sequela of traumatic brain injury (TBI), other nonepileptic phenomena also warrant consideration. Within two UCLA pediatric TBI cohorts, we categorized five spell types: 1) PTE; 2) Epilepsy with other potential etiologies (cortical dysplasia, primary generalized); 3) Psychopathology; 4) Behavior misinterpreted as seizures; and 5) Other neurologic events. The two cohort subsets differed slightly in injury severity, but they were otherwise similar. Overall, PTE occurred in 40%, other epilepsy etiologies in 14%, and nonepileptic spells collectively in 46%. Among children with spells, PTE was associated with severe TBI (p=0.001), whereas psychopathology (p=0.014) and epilepsy with other etiologies (p=0.006) were associated with milder TBI severity. Posttraumatic epilepsy (p=0.002) and misinterpreted behavior (p=0.049) occurred with younger injury age. Psychopathology (p=0.020) and other neurologic events (p=0.002) occurred with older injury age. In evaluating possible PTE, clinicians should maintain a broad differential diagnosis to prevent misdiagnosis and inappropriate treatment.

Metabolomic analysis of cerebral spinal fluid from patients with severe brain injury.

Proton nuclear magnetic resonance (H-NMR) spectroscopic analysis of cerebral spinal fluid provides a quick, non-invasive modality for evaluating the metabolic activity of brain-injured patients. In a prospective study, we compared the CSF of 44 TBI patients and 13 non-injured control subjects. CSF was screened for ten parameters: ß-glucose (Glu), lactate (Lac), propylene glycol (PG), glutamine (Gln), alanine (Ala), α-glucose (A-Glu), pyruvate (PYR), creatine (Cr), creatinine (Crt), and acetate (Ace). Using mixed effects measures, we discovered statistically significant differences between control and trauma concentrations (mM). TBI patients had significantly higher concentrations of PG, while statistical trends existed for lactate, glutamine, and creatine. TBI patients had a significantly decreased concentration of total creatinine. There were no significant differences between TBI patients and non-injured controls regarding ß- or α-glucose, alanine, pyruvate or acetate. Correlational analysis between metabolites revealed that the strongest significant correlations in non-injured subjects were between ß- and α-glucose (r = 0.74), creatinine and pyruvate (r = 0.74), alanine and creatine (r = 0.62), and glutamine and α-glucose (r = 0.60). For TBI patients, the strongest significant correlations were between lactate and α-glucose (r = 0.54), lactate and alanine (r = 0.53), and α-glucose and alanine (r = 0.48). The GLM and multimodel inference indicated that the combined metabolites of PG, glutamine, α-glucose, and creatinine were the strongest predictors for CMRO2, ICP, and GOSe. By analyzing the CSF of patients with TBI, our goal was to create a metabolomic fingerprint for brain injury.

Tight glycemic control increases metabolic distress in traumatic brain injury: a randomized controlled within-subjects trial.

OBJECTIVE: To determine the effects of tight glycemic control on brain metabolism after traumatic brain injury using brain positron emission tomography and microdialysis. DESIGN: Single-center, randomized controlled within-subject crossover observational trial. SETTING: Academic intensive care unit. METHODS: We performed a prospective, unblinded randomized controlled within-subject crossover trial of tight (80-110 mg/dL) vs. loose (120-150 mg/dL) glycemic control in patients with severe traumatic brain injury to determine the effects of glycemic control on brain glucose metabolism, as measured by [18F] deoxy-D-glucose brain positron emission tomography. Brain microdialysis was done simultaneously. MEASUREMENTS AND MAIN RESULTS: Thirteen severely injured traumatic brain injury patients underwent the study between 3 and 8 days (mean 4.8 days) after traumatic brain injury. In ten of these subjects, global brain and gray matter tissues demonstrated higher glucose metabolic rates while glucose was under tight control as compared with loose control (3.2 ± 0.6 vs. 2.4 + 0.4, p = .02 [whole brain] and 3.8 ± 1.4 vs. 2.9 ± 0.8, p = .05 [gray matter]). However, the responses were heterogeneous with pericontusional tissue demonstrating the least state-dependent change. Cerebral microdialysis demonstrated more frequent critical reductions in glucose (p = .02) and elevations of lactate/pyruvate ratio (p = .03) during tight glycemic control. CONCLUSION: Tight glycemic control results in increased global glucose uptake and an increased cerebral metabolic crisis after traumatic brain injury. The mechanisms leading to the enhancement of metabolic crisis are unclear, but delivery of more glucose through mild hyperglycemia may be necessary after traumatic brain injury.

The linear relationship between transcranial Doppler pulsatility indices and intracranial pressure is influenced by traumatic brain injury and vasospasm.

The pulsatility index (PI) and the intracranial -pressure (ICP) may or may not be correlated; the evidence to date differs widely. A study of multiple measures of PI and the corresponding ICP in patients with severe traumatic brain injury (TBI) showed that some of the relationships were moderately strong when calculated as conventional Pearson correlation coefficients. However, that method makes no adjustment of any kind for statistical outliers in the data. With the TBI patients demonstrating a large fraction of skewed measurements, a set of robust correlations were calculated that demonstrated that the apparent relationships between PI and ICP were entirely attributable to the statistical outliers. We conclude that the fundamental relationship of PI to ICP is weakly positive at best.

Early cerebral metabolic crisis after TBI influences outcome despite adequate hemodynamic resuscitation.

BACKGROUND: Optimal resuscitation after traumatic brain injury (TBI) remains uncertain. We hypothesize that cerebral metabolic crisis is frequent despite adequate resuscitation of the TBI patient and that metabolic crisis negatively influences outcome. METHODS: We assessed the effectiveness of a standardized trauma resuscitation protocol in 89 patients with moderate to severe TBI, and determined the frequency of adequate resuscitation. Prospective hourly values of heart rate, blood pressure, pulse oximetry, intracranial pressure (ICP), respiratory rate, jugular venous oximetry, and brain extracellular values of glucose, lactate, pyruvate, glycerol, and glutamate were obtained. The incidence during the initial 72 h after injury of low brain glucose <0.8 mmol/L, elevated lactate/pyruvate ratio (LPR) >25, and metabolic crisis, defined as the simultaneous occurrence of both low glucose and high LPR, were determined for the group. RESULTS: 5 patients were inadequately resuscitated and eight patients had intractable ICP. In patients with successful resuscitation and controlled ICP (n = 76), within 72 h of trauma, 76% had low glucose, 93% had elevated LPR, and 74% were in metabolic crisis. The duration of metabolic crisis was longer in those patients with unfavorable (GOSe ≤ 6) versus favorable (GOSe ≥ 7) outcome at 6 months (P = 0.011). In four multivariate models the burden of metabolic crisis was a powerful independent predictor of poor outcome. CONCLUSIONS: Metabolic crisis occurs frequently after TBI despite adequate resuscitation and controlled ICP, and is a strong independent predictor of poor outcome at 6 months.

Monitoring the conjunctiva for carbon dioxide and oxygen tensions and pH during cardiopulmonary bypass.

The purpose of this study was to measure, for the first time, multiple physiologic parameters of perfusion (pH, PCO2, PO2, and temperature) from the conjunctiva of adult patients during cardiopulmonary bypass while undergoing cardiothoracic surgery. Ten patients who underwent either intracardiac valve repair, atrial septal defect repair, or coronary artery bypass graft surgery had placement of a sensor which directly measured pH, PCO2, PO2, and temperature from the conjunctiva. Data were stratified into seven phases (0-5 minutes prior to bypass; 0-5, 6-10, and 11-15 minutes after initiation of bypass; 0-5 minutes prior to conclusion of bypass; and 0-5 and 6-10 minutes after bypass) and analyzed using a mixed model analysis.The change in conjunctival pH over the course of measurement was not statistically significant (p = .56). The PCO2 level followed a quadratic pattern, decreasing from a mean pre-bypass level of 37.7 mmHg at baseline prior to the initiation of cardiopulmonary bypass to a nadir of 33.2 mmHg, then increasing to a high of 39.4 mmHg at 6-10 minutes post bypass (p < .01). The PO2 declined from a mean pre-bypass level of 79.5 mmHg to 31.3 mmHg by 6-10 minutes post bypass and even post-bypass, it never returned to baseline values (p < .01). Temperature followed a pattern similar to PCO2 by returning to baseline levels as the patient was re-warmed following bypass (p < .01). There was no evidence of any eye injury or inflammation following the removal of the sensor. In the subjects studied, the conjunctival sensor yielded reproducible measurements during the various phases of cardiopulmonary bypass without ocular injury. Further study is necessary to determine the role of conjunctival measurements in critical settings.

Sedation-Induced Burst Suppression Predicts Positive Outcome Following Traumatic Brain Injury.

While electroencephalogram (EEG) burst-suppression is often induced therapeutically using sedatives in the intensive care unit (ICU), there is hitherto no evidence with respect to its association to outcome in moderate-to-severe neurological patients. We examined the relationship between sedation-induced burst-suppression (SIBS) and outcome at hospital discharge and at 6-month follow up in patients surviving moderate-to-severe traumatic brain injury (TBI). For each of 32 patients recovering from coma after moderate-to-severe TBI, we measured the EEG burst suppression ratio (BSR) during periods of low responsiveness as assessed with the Glasgow Coma Scale (GCS). The maximum BSR was then used to predict the Glasgow Outcome Scale extended (GOSe) at discharge and at 6 months post-injury. A multi-model inference approach was used to assess the combination of predictors that best fit the outcome data. We found that BSR was positively associated with outcomes at 6 months (P = 0.022) but did not predict outcomes at discharge. A mediation analysis found no evidence that BSR mediates the effects of barbiturates or propofol on outcomes. Our results provide initial observational evidence that burst suppression may be neuroprotective in acute patients with TBI etiologies. SIBS may thus be useful in the ICU as a prognostic biomarker.

Distribution and volume analysis of early hemorrhagic contusions by MRI after traumatic brain injury: a preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx).

Traumatic brain injury (TBI) can produce heterogeneous injury patterns including a variety of hemorrhagic and non-hemorrhagic lesions. The impact of lesion size, location, and interaction between total number and location of contusions may influence the occurrence of seizures after TBI. We report our methodologic approach to this question in this preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). We describe lesion identification and segmentation of hemorrhagic contusions by early posttraumatic magnetic resonance imaging (MRI). We describe the preliminary methods of manual lesion segmentation in an initial cohort of 32 TBI patients from the EpiBioS4Rx cohort and the preliminary association of hemorrhagic contusion and edema location and volume to seizure incidence.

The subcortical basis of outcome and cognitive impairment in TBI: A longitudinal cohort study.

OBJECTIVE: To understand how, biologically, the acute event of traumatic brain injury gives rise to a long-term disease, we address the relationship between evolving cortical and subcortical brain damage and measures of functional outcome and cognitive functioning at 6 months after injury. METHODS: For this longitudinal analysis, clinical and MRI data were collected in a tertiary neurointensive care setting in a continuous sample of 157 patients surviving moderate to severe traumatic brain injury between 2000 and 2018. For each patient, we collected T1- and T2-weighted MRI data acutely and at the 6-month follow-up, as well as acute measures of injury severity (Glasgow Coma Scale), follow-up measures of functional impairment (Glasgow Outcome Scale-extended), and, in a subset of patients, neuropsychological measures of attention, executive functions, and episodic memory. RESULTS: In the final cohort of 113 subcortical and 92 cortical datasets that survived (blind) quality control, extensive atrophy was observed over the first 6 months after injury across the brain. However, only atrophy within subcortical regions, particularly in the left thalamus, was associated with functional outcome and neuropsychological measures of attention, executive functions, and episodic memory. Furthermore, when brought together in an analytical model, longitudinal brain measurements could distinguish good from bad outcome with 90% accuracy, whereas acute brain and clinical measurements alone could achieve only 20% accuracy. CONCLUSION: Despite great injury heterogeneity, secondary thalamic pathology is a measurable minimum common denominator mechanism directly relating biology to clinical measures of outcome and cognitive functioning, potentially linking the acute event and the longer-term disease of traumatic brain injury.