Prognostic value of near-infrared spectroscopy regional oxygen saturation and cerebrovascular reactivity index in acute traumatic neural injury: a CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Cohort Study.

BACKGROUND: Near-infrared spectroscopy regional cerebral oxygen saturation (rSO2) has gained interest as a raw parameter and as a basis for measuring cerebrovascular reactivity (CVR) due to its noninvasive nature and high spatial resolution. However, the prognostic utility of these parameters has not yet been determined. This study aimed to identify threshold values of rSO2 and rSO2-based CVR at which outcomes worsened following traumatic brain injury (TBI). METHODS: A retrospective multi-institutional cohort study was performed. The cohort included TBI patients treated in four adult intensive care units (ICU). The cerebral oxygen indices, COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and arterial blood pressure) were calculated for each patient. Grand mean thresholds along with exposure-based thresholds were determined utilizing sequential chi-squared analysis and univariate logistic regression, respectively. RESULTS: In the cohort of 129 patients, there was no identifiable threshold for raw rSO2 at which outcomes were found to worsen. For both COx and COx_a, an optimal grand mean threshold value of 0.2 was identified for both survival and favorable outcomes, while percent time above - 0.05 was uniformly found to have the best discriminative value. CONCLUSIONS: In this multi-institutional cohort study, raw rSO2was found to contain no significant prognostic information. However, rSO2-based indices of CVR, COx and COx_a, were found to have a uniform grand mean threshold of 0.2 and exposure-based threshold of - 0.05, above which clinical outcomes markedly worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.

Cerebral physiologic insult burden in acute traumatic neural injury: a Canadian High Resolution-TBI (CAHR-TBI) descriptive analysis.

BACKGROUND: Over the recent decades, continuous multi-modal monitoring of cerebral physiology has gained increasing interest for its potential to help minimize secondary brain injury following moderate-to-severe acute traumatic neural injury (also termed traumatic brain injury; TBI). Despite this heightened interest, there has yet to be a comprehensive evaluation of the effects of derangements in multimodal cerebral physiology on global cerebral physiologic insult burden. In this study, we offer a multi-center descriptive analysis of the associations between deranged cerebral physiology and cerebral physiologic insult burden. METHODS: Using data from the Canadian High-Resolution TBI (CAHR-TBI) Research Collaborative, a total of 369 complete patient datasets were acquired for the purposes of this study. For various cerebral physiologic metrics, patients were trichotomized into low, intermediate, and high cohorts based on mean values. Jonckheere-Terpstra testing was then used to assess for directional relationships between these cerebral physiologic metrics and various measures of cerebral physiologic insult burden. Contour plots were then created to illustrate the impact of preserved vs impaired cerebrovascular reactivity on these relationships. RESULTS: It was found that elevated intracranial pressure (ICP) was associated with more time spent with cerebral perfusion pressure (CPP) < 60 mmHg and more time with impaired cerebrovascular reactivity. Low CPP was associated with more time spent with ICP > 20 or 22 mmHg and more time spent with impaired cerebrovascular reactivity. Elevated cerebrovascular reactivity indices were associated with more time spent with CPP < 60 mmHg as well as ICP > 20 or 22 mmHg. Low brain tissue oxygenation (PbtO2) only demonstrated a significant association with more time spent with CPP < 60 mmHg. Low regional oxygen saturation (rSO2) failed to produce a statistically significant association with any particular measure of cerebral physiologic insult burden. CONCLUSIONS: Mean ICP, CPP and, cerebrovascular reactivity values demonstrate statistically significant associations with global cerebral physiologic insult burden; however, it is uncertain whether measures of oxygen delivery provide any significant insight into such insult burden.

Primary and metastatic glioblastoma of the spine in the pediatric population: a systematic review.

Pediatric glioblastoma multiforme (GBM) involving the spine is an aggressive tumor with a poor quality of life for patients. Despite this, there is only a limited number of reports describing the outcomes of pediatric spinal GBMs, both as primary spinal GBMs and metastases from an intracranial tumor. Here, we performed an individual patient meta-analysis to characterize factors affecting prognosis of pediatric spinal GBM. MEDLINE, Embase, and the Cochrane databases were searched for published studies on GBMs involving the spine in pediatric patients (age ≤ 21 years old). Factors associated with the survival were assessed with multi-factor ANOVAs, Cox hazard regression, and Kaplan-Meier analyses. We extracted data on 61 patients with spinal GBM from 40 studies that met inclusion criteria. Median survival was significantly longer in the primary spinal GBM compared that those with metastatic GBM (11 vs 3 months, p < 0.001). However, median survival of metastatic GBM patients was 10 months following diagnosis of their primary brain tumor, which was not different from that of primary spinal GBM patients (p = 0.457). Among primary spinal GBM patients, chemotherapy (hazard ratio (HR) = 0.255 [0.106-0.615], p = 0.013) and extent of resection (HR = 0.582 [0.374-0.905], p = 0.016) conferred a significant survival benefit. Younger age (less than 14 years) was associated with longer survival in patients treated with chemotherapy than those who did not undergo chemotherapy (ß = - 1.12, 95% CI [- 2.20, - 0.03], p < 0.05). In conclusion, survival after presentation of metastases from intracranial GBM is poor in the pediatric population. In patients with metastatic GBM, chemotherapy may have provided the most benefit in young patients, and its efficacy might have an association with extent of surgical resection.

The CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Research Collaborative.

In traumatic brain injury (TBI), future integration of multimodal monitoring of cerebral physiology and high-frequency signal processing techniques, with advanced neuroimaging, proteomic and genomic analysis, provides an opportunity to explore the molecular pathways involved in various aspects of cerebral physiologic dysfunction in vivo. The main issue with early and rapid discovery in this field of personalized medicine is the expertise and complexity of data involved. This brief communication highlights the CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Research Collaborative, which has been formed from centers with specific expertise in the area of high-frequency physiologic monitoring/processing, and outlines its objectives.

Consensus statement from the International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury : Consensus statement.

BACKGROUND: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries. RESULTS: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval. CONCLUSIONS: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction.

Continuous Assessment of "Optimal" Cerebral Perfusion Pressure in Traumatic Brain Injury: A Cohort Study of Feasibility, Reliability, and Relation to Outcome.

BACKGROUND: Guidelines recommend maintaining cerebral perfusion pressure (CPP) between 60 and 70 mmHg in patients with severe traumatic brain injury (TBI), but acknowledge that optimal CPP may vary depending on cerebral blood flow autoregulation. Previous retrospective studies suggest that targeting CPP where the pressure reactivity index (PRx) is optimized (CPPopt) may be associated with improved recovery. METHODS: We performed a retrospective cohort study involving TBI patients who underwent PRx monitoring to assess issues of feasibility relevant to future interventional studies: (1) the proportion of time that CPPopt could be detected; (2) inter-observer variability in CPPopt determination; and (3) agreement between manual and automated CPPopt estimates. CPPopt was determined for consecutive 6-h epochs during the first week following TBI. Sixty PRx-CPP tracings were randomly selected and independently reviewed by six critical care professionals. We also assessed whether greater deviation between actual CPP and CPPopt (ΔCPP) was associated with poor outcomes using multivariable models. RESULTS: In 71 patients, CPPopt could be manually determined in 985 of 1173 (84%) epochs. Inter-observer agreement for detectability was moderate (kappa 0.46, 0.23-0.68). In cases where there was consensus that it could be determined, agreement for the specific CPPopt value was excellent (weighted kappa 0.96, 0.91-1.00). Automated CPPopt was within 5 mmHg of manually determined CPPopt in 93% of epochs. Lower PRx was predictive of better recovery, but there was no association between ΔCPP and outcome. Percentage time spent below CPPopt increased over time among patients with poor outcomes (p = 0.03). This effect was magnified in patients with impaired autoregulation (defined as PRx > 0.2; p = 0.003). CONCLUSION: Prospective interventional clinical trials with regular determination of CPPopt and corresponding adjustment of CPP goals are feasible, but measures to maximize consistency in CPPopt determination are necessary. Although we could not confirm a clear association between ΔCPP and outcome, time spent below CPPopt may be particularly harmful, especially when autoregulation is impaired.

Influenza D Virus in Cattle, Ireland.

We detected influenza D virus in 18 nasal swab samples from cattle in Ireland that were clinically diagnosed with respiratory disease. Specimens were obtained from archived samples received for routine diagnosis during 2014-2016. Sequencing showed that viruses from Ireland clustered with virus sequences obtained in Europe within the D/swine/OK/1334/2011 clade.

A survey of free-ranging deer in Ireland for serological evidence of exposure to bovine viral diarrhoea virus, bovine herpes virus-1, bluetongue virus and Schmallenberg virus.

BACKGROUND: Deer are an important wildlife species in both the Republic of Ireland and Northern Ireland having colonised most regions across the island of Ireland. In comparison to cattle and sheep which represent the main farmed ruminant species on the island, there is a lack of data concerning their exposure, as measured by the presence of antibodies, to important viral pathogens of ruminants. A study was therefore undertaken to investigate the seroprevalence of wild deer to four viruses, namely bovine viral diarrhoea virus (BVDV), bovine herpesvirus-1 (BoHV-1), Schmallenberg virus (SBV) and bluetongue virus (BTV). RESULTS: Two panels of sera were assembled; Panel 1 comprised 259 samples (202 collected in the Republic of Ireland and 57 in Northern Ireland) between 2013 and 2015, while Panel 2 comprised 131 samples collected in the Republic of Ireland between 2014 and 2015. Overall sika deer (Cervus nippon) were sampled most commonly (54.8%), followed by fallow deer (Dama dama) (35.3%), with red deer (Cervus elaphus) (4.3%) and hybrid species (0.3%) sampled less frequently, with the species not being recorded for the remaining 5.3% of deer sampled. Age was not recorded for 96 of the 390 deer sampled. 196 of the remainder were adults, while 68 and 30 were yearlings and calves, respectively. Using commercially available enzyme-linked immunosorbent assays, true prevalence and 95% confidence intervals were calculated as 9.9%, (6.8-13.0% CI), SBV; 1.5% (0.1-3.0% CI), BoHV-1; 0.0%, 0-1.7% CI), BVDV; and 0.0%, (0.01-0.10% CI), BTV. CONCLUSIONS: The results indicate a very low seroprevalence for both BVDV and BoHV-1 in the wild deer tested within the study and, are consistent with a very low prevalence in Ireland. While serological cross-reaction with cervid herpesviruses cannot be excluded, the results in both cases suggest that the presence of these viruses in deer is not a significant risk to their control and eradication from the cattle population. This is important given the ongoing programme to eradicate BVDV in Ireland and deliberations on a national eradication programme for BoHV-1. The SBV results show consistency with those reported from cattle and sheep on the island of Ireland, while the BTV results are consistent with this virus remaining exotic to Ireland. The results provide a baseline against which future surveys of either wild or farmed/captive deer populations can be compared.

The International Incidence of Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Understanding the epidemiology of traumatic brain injury (TBI) is essential to shape public health policy, implement prevention strategies, and justify allocation of resources toward research, education, and rehabilitation in TBI. There is not, to our knowledge, a systematic review of population-based studies addressing the epidemiology of TBI that includes all subtypes. We performed a comprehensive systematic review and meta-analysis of the worldwide incidence of TBI. METHODS: A search was conducted on May 23, 2014, in Medline and EMBASE according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Abstracts were screened independently and in duplicate to identify original research. Study quality and ascertainment bias were assessed in duplicate using a previously published tool. Demographic data and incidence estimates from each study were recorded, along with stratification by age, gender, year of data collection, and severity. RESULTS: The search strategy yielded 4944 citations. Two hundred and sixteen articles met criteria for full-text review; 144 were excluded. Hand searching resulted in ten additional articles. Eighty-two studies met all eligibility criteria. The pooled annual incidence proportion for all ages was 295 per 100,000 (95% confidence interval: 274-317). The pooled incidence rate for all ages was 349 (95% confidence interval: 96.2-1266) per 100,000 person-years. Incidence proportion and incidence rate were examined to see if associated with age, sex, country, or severity. CONCLUSIONS: We conclude that most TBIs are mild and most TBIs occur in males among the adult population. The incidence of TBI varies widely by ages and between countries. Despite being an important medical, economic, and social problem, the global epidemiology of TBI is still not well-characterized in the current literature. Understanding the incidence of TBI, particularly mild TBI, remains challenging because of nonstandardized reporting among neuroepidemiological studies.

Decompressive Craniectomy in Patients with Traumatic Brain Injury: Are the Usual Indications Congruent with Those Evaluated in Clinical Trials?

BACKGROUND: In patients with traumatic brain injury (TBI), multicenter randomized controlled trials have assessed decompressive craniectomy (DC) exclusively as treatment for refractory elevation of intracranial pressure (ICP). DC reliably lowers ICP but does not necessarily improve outcomes. However, some patients undergo DC as treatment for impending or established transtentorial herniation, irrespective of ICP. METHODS: We performed a population-based cohort study assessing consecutive patients with moderate-severe TBI. Indications for DC were compared with enrollment criteria for the DECRA and RESCUE-ICP trials. RESULTS: Of 644 consecutive patients, 51 (8 %) were treated with DC. All patients undergoing DC had compressed basal cisterns, 82 % had at least temporary preoperative loss of ≥1 pupillary light reflex (PLR), and 80 % had >5 mm of midline shift. Most DC procedures (67 %) were "primary," having been performed concomitantly with evacuation of a space-occupying lesion. ICP measurements influenced the decision to perform DC in 18 % of patients. Only 10 and 16 % of patients, respectively, would have been eligible for the DECRA and RESCUE-ICP trials. DC improved basal cistern compression in 76 %, and midline shift in 94 % of patients. Among patients with ≥1 absent PLR at admission, DC was associated with lower mortality (46 vs. 68 %, p = 0.03), especially when the admission Marshall CT score was 3-4 (p = 0.0005). No patients treated with DC progressed to brain death. Variables predictive of poor outcome following DC included loss of PLR(s), poor motor score, midline shift ≥11 mm, and development of perioperative cerebral infarcts. CONCLUSIONS: DC is most often performed for clinical and radiographic evidence of herniation, rather than for refractory ICP elevation. Results of previously completed randomized trials do not directly apply to a large proportion of patients undergoing DC in practice.

Lactate storm marks cerebral metabolism following brain trauma.

Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling. Glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. The origin and role of lactate in severe traumatic brain injury (TBI) remains controversial. Using a modified weight drop model of severe TBI and magnetic resonance (MR) spectroscopy with infusion of (13)C-labeled glucose, lactate, and acetate, the present study investigated the possibility that neuronal-glial metabolism is uncoupled following severe TBI. Histopathology of the model showed severe brain injury with subarachnoid and hemorrhage together with glial cell activation and positive staining for Tau at 90 min post-trauma. High resolution MR spectroscopy of brain metabolites revealed significant labeling of lactate at C-3 and C-2 irrespective of the infused substrates. Increased (13)C-labeled lactate in all study groups in the absence of ischemia implied activated astrocytic glycolysis and production of lactate with failure of neuronal uptake (i.e. a loss of glial sensing for glutamate). The early increase in extracellular lactate in severe TBI with the injured neurons rendered unable to pick it up probably contributes to a rapid progression toward irreversible injury and pan-necrosis. Hence, a method to detect and scavenge the excess extracellular lactate on site or early following severe TBI may be a potential primary therapeutic measure.

Intracranial Pressure-Derived Cerebrovascular Reactivity Indices and Their Critical Thresholds: A Canadian High Resolution-Traumatic Brain Injury Validation Study.

Current neurointensive care guidelines recommend intracranial pressure (ICP) and cerebral perfusion pressure (CPP) centered management for moderate-severe traumatic brain injury (TBI) because of their demonstrated associations with patient outcome. Cerebrovascular reactivity metrics, such as the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC index, have also demonstrated significant prognostic capabilities with regard to outcome. However, critical thresholds for cerebrovascular reactivity indices have only been identified in two studies conducted at the same center. In this study, we aim to determine the critical thresholds of these metrics by leveraging a unique multi-center database. The study included a total of 354 patients from the CAnadian High-Resolution TBI (CAHR-TBI) Research Collaborative. Based on 6-month Glasgow Outcome Scores, patients were dichotomized into alive versus dead and favorable versus unfavorable. Chi-square values were then computed for incrementally increasing values of each physiological parameter of interest against outcome. The values that generated the greatest chi-squares for each parameter were considered to be the thresholds with the greatest outcome discriminatory capacity. To confirm that the identified thresholds provide prognostic utility, univariate and multivariable logistical regression analyses were performed adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. Through the chi-square analysis, a lower limit CPP threshold of 60 mm Hg and ICP thresholds of 18 mm Hg and 22 mm Hg were identified for both survival and favorable outcome predictions. For the cerebrovascular reactivity metrics, different thresholds were identified for the two outcome dichotomizations. For survival prediction, thresholds of 0.35, 0.25, and 0 were identified for PRx, PAx, and RAC, respectively. For favorable outcome prediction, thresholds of 0.325, 0.20, and 0.05 were found. Univariate logistical regression analysis demonstrated that the time spent above/below thresholds were associated with outcome. Further, multivariable logistical regression analysis found that percent time above/below the identified thresholds added additional variance to the IMPACT core model for predicting both survival and favorable outcome. In this study, we were able to validate the results of the previous two works as well as to reaffirm the ICP and CPP guidelines from the Brain Trauma Foundation (BTF) and the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

Temporal Statistical Relationship between Regional Cerebral Oxygen Saturation (rSO2) and Brain Tissue Oxygen Tension (PbtO2) in Moderate-to-Severe Traumatic Brain Injury: A Canadian High Resolution-TBI (CAHR-TBI) Cohort Study.

Brain tissue oxygen tension (PbtO2) has emerged as a cerebral monitoring modality following traumatic brain injury (TBI). Near-infrared spectroscopy (NIRS)-based regional cerebral oxygen saturation (rSO2) can non-invasively examine cerebral oxygen content and has the potential for high spatial resolution. Past studies examining the relationship between PbtO2 and NIRS-based parameters have had conflicting results with varying degrees of correlation. Understanding this relationship will help guide multimodal monitoring practices and impact patient care. The aim of this study is to examine the relationship between PbtO2 and rSO2 in a cohort of TBI patients by leveraging contemporary statistical methods. A multi-institutional retrospective cohort study of prospectively collected data was performed. Moderate-to-severe adult TBI patients were included with concurrent rSO2 and PbtO2 monitoring during their stay in the intensive care unit (ICU). The high-resolution data were analyzed utilizing time series techniques to examine signal stationarity as well as the cross-correlation relationship between the change in PbtO2 and the change in rSO2 signals. Finally, modeling of the change in PbtO2 by the change in rSO2 was attempted utilizing linear methods that account for the autocorrelative nature of the data signals. A total of 20 subjects were included in the study. Cross-correlative analysis found that changes in PbtO2 were most significantly correlated with changes in rSO2 one minute earlier. Through mixed-effects and time series modeling of parameters, changes in rSO2 were found to often have a statistically significant linear relationship with changes in PbtO2 that occurred a minute later. However, changes in rSO2 were inadequate to predict changes in PbtO2. In this study, changes in PbtO2 were found to correlate most with changes in rSO2 approximately one minute earlier. While changes in rSO2 were found to contain information about future changes in PbtO2, they were not found to adequately model them. This strengthens the body of literature indicating that NIRS-based rSO2 is not an adequate substitute for PbtO2 in the management of TBI.

Impact of Chronological Age and Biological Sex on Cerebrovascular Reactivity in Moderate/Severe Traumatic Brain Injury: A CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Study.

Impaired cerebrovascular reactivity has emerged as an important associate with poor long-term outcome after moderate/severe traumatic brain injury (TBI). However, our understanding of what drives or modulates the degree of impaired cerebrovascular function remains poor. Age and biological sex remain important modifiers of cerebrovascular function in health and disease, yet their impact on cerebrovascular reactivity after TBI remains unclear. The aim of this study was to explore subgroup responses based on age and biological sex on cerebral physiology. Data from 283 TBI patients from the CAnadian High Resolution TBI (CAHR-TBI) Research Collaborative were evaluated. Cerebrovascular reactivity was determined using high-frequency cerebral physiology for the derivation of three intracranial pressure (ICP)-based indices: 1) pressure reactivity index (PRx)-correlation between ICP and mean arterial pressure (MAP); 2) pulse amplitude index (PAx)-correlation between pulse amplitude of ICP (AMP) and MAP; and 3) RAC-correlation between AMP and cerebral perfusion pressure (CPP). Insult burden (% time above clinically defined thresholds) were calculated for these indices. These cerebral physiology indices were studied for their relationship with age via linear regression, age trichotomization (< 40, 40 - 60, > 60), and decades of age (< 30, 30-39, 40-49, 50-59, 60-69, > 69) schemes. Similarly, differences based on biological sex were assessed. A statistically significant positive linear correlation was found between PAx, RAC, and age. In corollary, a statistically significant relationship was found between increasing age on trichotomized and decades of age analysis with PAx and RAC measures. PRx failed to demonstrate such relationships to advancing age. There was no clear difference in cerebrovascular reactivity profiles between biological sex categories. These findings suggest that AMP-based cerebrovascular reactivity indices may be better positioned to detect impairment in TBI patients with advancing age. Further investigation into the utility of PAx and RAC is required, as they may prove useful for certain subgroups of patients.

High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

Cerebrovascular pressure reactivity and brain tissue oxygen monitoring provide complementary information regarding the lower and upper limits of cerebral blood flow control in traumatic brain injury: a CAnadian High Resolution-TBI (CAHR-TBI) cohort study.

BACKGROUND: Brain tissue oxygen tension (PbtO2) and cerebrovascular pressure reactivity monitoring have emerged as potential modalities to individualize care in moderate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO2 and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity. METHODS: A retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pressure (ICP), arterial blood pressure (ABP), and PbtO2 monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx). RESULTS: A total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact. CONCLUSIONS: In this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO2 seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF.

Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials.

OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury. DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles. STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury. DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results. DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure. CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.

The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study.

Energy metabolism in the human brain is not fully understood. Classically, glucose is regarded as the major energy substrate. However, lactate (conventionally a product of anaerobic metabolism) has been proposed to act as an energy source, yet whether this occurs in man is not known. Here we show that the human brain can indeed utilize lactate as an energy source via the tricarboxylic acid cycle. We used a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C substrates into the brain and recover (13)C metabolites from the brain, and high-resolution (13)C nuclear magnetic resonance. Microdialysis catheters were placed in the vicinity of focal lesions and in relatively less injured regions of brain, in patients with traumatic brain injury. Infusion with 2-(13)C-acetate or 3-(13)C-lactate produced (13)C signals for glutamine C4, C3 and C2, indicating tricarboxylic acid cycle operation followed by conversion of glutamate to glutamine. This is the first direct demonstration of brain utilization of lactate as an energy source in humans.

Phosphorus spectroscopy in acute TBI demonstrates metabolic changes that relate to outcome in the presence of normal structural MRI.

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-based in vivo phosphorus magnetic resonance spectroscopy (31P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm3 voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. 31P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.