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The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic-ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI., (© 2023. The Author(s).)

Importance: Brain injury biomarkers released into circulation from the injured neurovascular unit are important prognostic tools in patients with cardiac arrest who develop hypoxic ischemic brain injury (HIBI) after return of spontaneous circulation (ROSC)., Objective: To assess the neuroprognostic utility of bloodborne brain injury biomarkers in patients with cardiac arrest with HIBI., Data Sources: Studies in electronic databases from inception to September 15, 2021. These databases included MEDLINE, Embase, Evidence-Based Medicine Reviews, CINAHL, Cochrane Database of Systematic Reviews, and the World Health Organization Global Health Library., Study Selection: Articles included in this systmatic review and meta-analysis were independently assessed by 2 reviewers. We included studies that investigated neuron-specific enolase, S100 calcium-binding protein β, glial fibrillary acidic protein, neurofilament light, tau, or ubiquitin carboxyl hydrolase L1 in patients with cardiac arrest aged 18 years and older for neurologic prognostication. We excluded studies that did not (1) dichotomize neurologic outcome as favorable vs unfavorable, (2) specify the timing of blood sampling or outcome determination, or (3) report diagnostic test accuracy or biomarker concentration., Data Extraction and Synthesis: Data on the study design, inclusion and exclusion criteria, brain biomarkers levels, diagnostic test accuracy, and neurologic outcome were recorded. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline., Main Outcomes and Measures: Summary receiver operating characteristic curve analysis was used to calculate the area under the curve, sensitivity, specificity, and optimal thresholds for each biomarker. Risk of bias and concerns of applicability were assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool., Results: We identified 2953 studies, of which 86 studies with 10 567 patients (7777 men [73.6] and 2790 women [26.4]; pooled mean [SD] age, 62.8 [10.2] years) were included. Biomarker analysis at 48 hours after ROSC demonstrated that neurofilament light had the highest predictive value for unfavorable neurologic outcome, with an area under the curve of 0.92 (95% CI, 0.84-0.97). Subgroup analyses of patients treated with targeted temperature management and those who specifically had an out-of-hospital cardiac arrest showed similar results (targeted temperature management, 0.92 [95% CI, 0.86-0.95] and out-of-hospital cardiac arrest, 0.93 [95% CI, 0.86-0.97])., Conclusions and Relevance: Neurofilament light, which reflects white matter damage and axonal injury, yielded the highest accuracy in predicting neurologic outcome in patients with HIBI at 48 hours after ROSC., Trial Registration: PROSPERO Identifier: CRD42020157366.

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Purpose: Following return of spontaneous circulation after cardiac arrest, hypoxic ischemic brain injury is the primary cause of mortality and disability. Goal-directed care using invasive multimodal neuromonitoring has emerged as a possible resuscitation strategy. We evaluated whether goal-directed care was associated with improved neurologic outcome in hypoxic ischemic brain injury patients after cardiac arrest., Design: Retrospective, single-center, matched observational cohort study., Setting: Quaternary academic medical center., Patients: Adult patients admitted to the ICU following return of spontaneous circulation postcardiac arrest with clinical evidence of hypoxic ischemic brain injury defined as greater than or equal to 10 minutes of cardiac arrest with an unconfounded postresuscitation Glasgow Coma Scale of less than or equal to 8., Interventions: We compared patients who underwent goal-directed care using invasive neuromonitoring with those treated with standard of care (using both total and matched groups)., Measurements and Main Results: Goal-directed care patients were matched 1:1 to standard of care patients using propensity scores and exact matching. The primary outcome was a 6-month favorable neurologic outcome (Cerebral Performance Category of 1 or 2). We included 65 patients, of whom 21 received goal-directed care and 44 patients received standard of care. The median age was 50 (interquartile range, 35-61), 48 (74%) were male, and seven (11%) had shockable rhythms. Favorable neurologic outcome at 6 months was significantly greater in the goal-directed care group (n = 9/21 [43%]) compared with the matched (n = 2/21 [10%], p = 0.016) and total (n = 8/44 [18%], p = 0.034) standard of care groups. Goal-directed care group patients had higher mean arterial pressure (p < 0.001 vs total; p = 0.0060 vs matched) and lower temperature (p = 0.007 vs total; p = 0.041 vs matched)., Conclusions: In this preliminary study of patients with hypoxic ischemic brain injury postcardiac arrest, goal-directed care guided by invasive neuromonitoring was associated with a 6-month favorable neurologic outcome (Cerebral Performance Category 1 or 2) versus standard of care. Significant work is required to confirm this finding in a prospectively designed study., Competing Interests: Dr. Sekhon is also supported by the Vancouver Coastal Health Research Institute Clinician Scientist Award. Dr. Griesdale is supported through a Health Professional-Investigator Award from the Michael Smith Foundation for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

The use of cerebral autoregulation monitoring to identify patient-specific optimal mean arterial pressure (MAP OPT ) has emerged as a technique to augment cerebral oxygen delivery in post-cardiac arrest patients. Our systematic review aims to determine (a) the average MAP OPT in these patients, (b) the feasibility of identifying MAP OPT , (c) the brain tissue oxygenation levels when MAP is within proximity to the MAP OPT and (d) the relationship between neurological outcome and MAP OPT -targeted resuscitation strategies. We carried out this review in accordance with the PRISMA guidelines. We included all studies that used cerebral autoregulation to determine MAP OPT in adult patients (> 16 years old) who achieved return of spontaneous circulation (ROSC) following cardiac arrest. All studies had to include our primary outcome of MAP OPT . We excluded studies where the patients had any history of traumatic brain injury, ischemic stroke or intracranial hemorrhage. We identified six studies with 181 patients. There was wide variability in cerebral autoregulation monitoring methods, length of monitoring, calculation and reporting of MAP OPT . Amongst all studies, the median or mean MAP OPT was consistently above 65 mmHg (range 70-114 mmHg). Definitions of feasibility varied among studies and were difficult to summarize. Only one study noted that brain tissue oxygenation increased as patients' MAP approached MAP OPT . There was no consistent association between targeting MAP OPT and improved neurological outcome. There is considerable heterogeneity in MAP OPT due to differences in monitoring methods of autoregulation. Further research is needed to assess the clinical utility of MAP OPT -guided strategies on decreasing secondary injury and improving neurological outcomes after ROSC.

Objectives: We sought to characterize 1) the difference in the diffusion gradient of cellular oxygen delivery and 2) the presence of diffusion limitation physiology in hypoxic-ischemic brain injury patients with brain hypoxia, as defined by parenchymal brain tissue oxygen tension less than 20 mm Hg versus normoxia (brain tissue oxygen tension > 20 mm Hg)., Design: Post hoc subanalysis of a prospective study in hypoxic-ischemic brain injury patients dichotomized into those with brain hypoxia versus normoxia., Setting: Quaternary ICU., Patients: Fourteen adult hypoxic-ischemic brain injury patients after cardiac arrest., Interventions: Patients underwent monitoring with brain oxygen tension, intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and jugular venous bulb oxygen saturation. Data were recorded in real time at 300Hz into the ICM+ monitoring software (Cambridge University Enterprises, Cambridge, United Kingdom). Simultaneous arterial and jugular venous bulb blood gas samples were recorded prospectively., Measurements and Main Results: Both the normoxia and hypoxia groups consisted of seven patients. In the normoxia group, the mean brain tissue oxygen tension, jugular venous bulb oxygen tension, and cerebral perfusion pressure were 29 mm Hg (SD, 9), 45 mm Hg (SD, 9), and 80 mm Hg (SD, 7), respectively. In the hypoxia group, the mean brain tissue oxygen tension, jugular venous bulb oxygen to brain tissue oxygen tension gradient, and cerebral perfusion pressure were 14 mm Hg (SD, 4), 53 mm Hg (SD, 8), and 72 mm Hg (SD, 6), respectively. There were significant differences in the jugular venous bulb oxygen tension-brain oxygen tension gradient (16 mm Hg [sd, 6] vs 39 mm Hg SD, 11]; p < 0.001) and in the relationship of jugular venous bulb oxygen tension-brain oxygen tension gradient to cerebral perfusion pressure (p = 0.004) when comparing normoxia to hypoxia. Each 1 mm Hg increase in cerebral perfusion pressure led to a decrease in the jugular venous bulb oxygen tension-brain oxygen tension gradient by 0.36 mm Hg (95% CI, -0.54 to 0.18; p < 0.001) in the normoxia group, but no such relation was demonstrable in the hypoxia group., Conclusions: In hypoxic-ischemic brain injury patients with brain hypoxia, there is an elevation in the jugular venous bulb oxygen tension-brain oxygen tension gradient, which is not modulated by changes in cerebral perfusion pressure.

Introduction: In hypoxic ischemic brain injury (HIBI), increased intracranial pressure (ICP) can ensue from cerebral edema stemming from cytotoxic and vasogenic mechanisms. Downstream sequelae of restricted cerebral blood flow lead to neurologic braindeath. There is limited data characterizing the temporal trends and patterns of ICP and compliance in human HIBI patients., Methods: Patients underwent invasive ICP monitoring with a parenchymal probe (Camino) and were managed with a tier-based management algorithm for elevated ICP. Data pertaining to mean arterial pressure (MAP), ICP, brain tissue oxygenation (PbtO 2 ), end tidal carbon dioxide (ETCO 2 ), core body temperature and RAP (moving correlation coefficient between mean ICP and its mean pulse amplitude) as a measure of intracranial compliance were recorded in the ICM + software. Data pertaining to ICP lowering interventions was also collected., Results: Ten patients were included with a median age of 47 (range 20-71) and seven were male (7/10). The mean ICP was 14 mmHg (SD 11) and time of ICP> 20 mmHg was 22% (range 0-100). The mean MAP, ETCO 2 and temperature were 89 mmHg (SD 13), 31 mmHg (SD 7), 35.7 °C (SD 0.9), respectively. The mean RAP was 0.58 (SD 0.34) and time of RAP > 0.4 was 78% (range 57-97). There were no significant relationships between ETCO 2 and temperature with ICP., Conclusions: In our cohort, HIBI was characterized by normal ICP but with limited intracranial compliance. However, significant in between patient heterogeneity exists with respect to temporal patterns of intracranial pressure - volume relationships in HIBI., Trial Registration: clinicaltrials.gov (NCT03609333)., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Objectives: In patients at risk of hypoxic ischemic brain injury following cardiac arrest, we sought to: 1) characterize brain oxygenation and determine the prevalence of brain hypoxia, 2) characterize autoregulation using the pressure reactivity index and identify the optimal mean arterial pressure, and 3) assess the relationship between optimal mean arterial pressure and brain tissue oxygenation., Design: Prospective interventional study., Setting: Quaternary ICU., Patients: Adult patients with return of spontaneous circulation greater than 10 minutes and a postresuscitation Glasgow Coma Scale score under 9 within 72 hours of cardiac arrest., Interventions: All patients underwent multimodal neuromonitoring which included: 1) brain tissue oxygenation, 2) intracranial pressure, 3) jugular venous continuous oximetry, 4) regional saturation of oxygen using near-infrared spectroscopy, and 5) pressure reactivity index-based determination of optimal mean arterial pressure, lower and upper limit of autoregulation. We additionally collected mean arterial pressure, end-tidal CO2, and temperature. All data were captured at 300 Hz using ICM+ (Cambridge Enterprise, Cambridge, United Kingdom) brain monitoring software., Measurements and Main Results: Ten patients (7 males) were included with a median age 47 (range 20-71) and return to spontaneous circulation 22 minutes (12-36 min). The median duration of monitoring was 47 hours (15-88 hr), and median duration from cardiac arrest to inclusion was 15 hours (6-44 hr). The mean brain tissue oxygenation was 23 mm Hg (SD 8 mm Hg), and the mean percentage of time with a brain tissue oxygenation below 20 mm Hg was 38% (6-100%). The mean pressure reactivity index was 0.23 (0.27), and the percentage of time with a pressure reactivity index greater than 0.3 was 50% (12-91%). The mean optimal mean arterial pressure, lower and upper of autoregulation were 89 mm Hg (11), 82 mm Hg (8), and 96 mm Hg (9), respectively. There was marked between-patient variability in the relationship between mean arterial pressure and indices of brain oxygenation. As the patients' actual mean arterial pressure approached optimal mean arterial pressure, brain tissue oxygenation increased (p < 0.001). This positive relationship did not persist when the actual mean arterial pressure was above optimal mean arterial pressure., Conclusions: Episodes of brain hypoxia in hypoxic ischemic brain injury are frequent, and perfusion within proximity of optimal mean arterial pressure is associated with increased brain tissue oxygenation. Pressure reactivity index can yield optimal mean arterial pressure, lower and upper limit of autoregulation in patients following cardiac arrest.

Aim: Increased intracranial pressure (ICP) in hypoxic ischaemic brain injury (HIBI) can cause secondary ischaemic brain injury and culminate in brain death. Invasive ICP monitoring is limited by associated risks in HIBI patients. We sought to evaluate the agreement between invasive ICP measurements and non-invasive estimators of ICP (nICP) in HIBI patients., Methods: Eligible consecutive adult (age>18) cardiac arrest patients with HIBI were included as part of a single centre prospective interventional study. Invasive ICP monitoring and nICP measurements were undertaken using: a) transcranial Doppler ultrasonography (TCD), b) optic nerve sheet diameter ultrasound (ONSD) and c) jugular venous bulb pressure (JVP). Multiple measurements applied in linear mixed-effects models were considered to obtain the correlation coefficient between ICP and nICP as well as their predictive abilities to detect intracranial hypertension (ICP≥20mm Hg)., Results: Eleven patients were included (median age of 47 [range 20-71], 8 males and 3 females). There was a linear relationship between ICP and nICP with ONSD (R=0.53 [p<0.0001]), JVP (R=0.38 [p<0.001]) and TCD (R=0.30 [p<0.01]). The ability to predict intracranial hypertension was highest for ONSD and TCD (area under the receiver operating curve (AUC)=0.96 [95% CI: 0.90-1.00] and AUC=0.91 [95% CI: 0.83-1.00], respectively). JVP presented the weakest prediction ability (AUC=0.75 [95% CI: 0.56-0.94])., Conclusions: ONSD and TCD methods demonstrated agreement with invasively-monitored ICP, suggesting their potential roles in the detection of intracranial hypertension in HIBI after cardiac arrest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: To examine the relationship between daily mean hemoglobin concentration and neurological outcome in hypoxic ischemic brain injury (HIBI) following cardiac arrest., Methods: We conducted a single center retrospective observational study using a database of HIBI patients between March 2009 and December 2014. We included all adults admitted to the intensive care unit following an in-hospital or out-of-hospital cardiac arrest. The primary outcome was neurological outcome measured by the Cerebral Performance Category (CPC) at hospital discharge. Multivariable logistic regression was used to analyze the association of mean hemoglobin concentration over 48h and 7 days after the onset of HIBI and discharge CPC. Favorable and unfavorable neurological outcome was dichotomized for a discharge CPC 1-2 vs 3-5, respectively., Results: 118 patients were included in the analysis. Patients with a favorable neurological outcome had higher mean 7-day hemoglobin (115g/L vs 107g/L; p=0.05) compared to those with unfavorable outcome. Multivariate logistic regression controlling for age, time to return of spontaneous circulation and blood transfusion demonstrated that lower mean 48-h hemoglobin concentration was associated with unfavorable outcome (OR 0.69 per 10 unit change in Hgb, 95% CI 0.54-0.88, p<0.01). A repeated analysis using mean Hgb for the first 7 days yielded similar results for unfavorable outcome (OR 0.75 per 10 unit change in Hgb, 95% CI 0.57-0.97, p=0.03)., Conclusions: Lower mean hemoglobin concentration in the first 48h and 7 days following HIBI is associated with a higher odds of unfavorable outcome at hospital discharge. Further study to examine this association is warranted., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Hypoxic ischaemic brain injury (HIBI) is a major cause of disability after cardiac arrest. HIBI leads to impaired cerebral autoregulation such that adequate cerebral perfusion becomes critically dependent on blood pressure. However, the optimal blood pressure after cardiac arrest remains unclear. Therefore, we conducted a systematic review to investigate the association between blood pressure and neurologic outcome patients after cardiac arrest., Methods: We systematically searched MEDLINE, EMBASE, conference abstracts and article references to identify randomized and observational studies investigating the relationship between blood pressure and neurologic outcome. We included studies that reported adjusted point estimates for the relationship between blood pressure and neurologic status in adult patients after cardiac arrest., Results: We included 9 studies with a total of 13,150 patients. Three studies included only patients with an out-of-hospital cardiac arrest. There was marked between-study heterogeneity with respect to blood pressure definition (MAP vs. systolic), exposure duration and modelling (dichotomous vs. continuous). All studies examined either mortality or neurological status as an outcome. Seven of nine studies demonstrated that higher blood pressure was associated with improved outcomes either by an association between higher MAP and good neurologic outcome or the presence of hypotension and increased odds of mortality., Conclusions: The included studies suggest improved neurologic outcomes are associated with higher blood pressures in patients after cardiac arrest. This study highlights a need for further research to define the optimal management of blood pressure in this population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)