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Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury., (Copyright © 2024. Published by Elsevier B.V.)

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).)

Following resuscitation from cardiac arrest, hypoxic ischemic brain injury (HIBI) ensues, which is the primary determinant of adverse outcome. The pathophysiology of HIBI can be compartmentalized into primary and secondary injury, resulting from cerebral ischemia during cardiac arrest and reperfusion following successful resuscitation, respectively. During the secondary injury phase, increased attention has been directed towards the optimization of cerebral oxygen delivery to prevent additive injury to the brain. During this phase, cerebral hemodynamics are characterized by early hyperemia following resuscitation and then a protracted phase of cerebral hypoperfusion termed "no-reflow" during which additional hypoxic-ischemic injury can occur. As such, identification of therapeutic strategies to optimize cerebral delivery of oxygen is at the forefront of HIBI research. Unfortunately, randomized control trials investigating the manipulation of arterial carbon dioxide tension and mean arterial pressure augmentation as methods to potentially improve cerebral oxygen delivery have shown no impact on clinical outcomes. Emerging literature suggests differential patient-specific phenotypes may exist in patients with HIBI. The potential to personalize therapeutic strategies in the critical care setting based upon patient-specific pathophysiology presents an attractive strategy to improve HIBI outcomes. Herein, we review the cerebral hemodynamic pathophysiology of HIBI, discuss patient phenotypes as it pertains to personalizing care, as well as suggest future directions.

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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.

Introduction: Invasive monitoring of cerebral autoregulation using the pressure reactivity index (PRx) allows for the determination of optimal mean arterial pressure (MAP OPT ) in hypoxic ischemic brain injury (HIBI) patients following cardiac arrest. However, the utility of non-invasive surrogates to determine MAP OPT has not been addressed. We aimed to determine the agreement between PRx-derived MAP OPT versus MAP OPT determined by the near-infrared spectroscopy (NIRS) based cerebral oximetry index (COx)., Methods: Ten HIBI patients were enrolled. PRx-derived MAP OPT , lower (LLA) and upper limits of autoregulation (ULA) were compared against COx-derived MAP OPT , LLA and ULA. Multimodal neuromonitoring included mean arterial pressure, intracranial pressure, brain tissue oxygenation, jugular venous oxygen saturation, and NIRS-derived regional cerebral oxygen saturation., Results: Repeated measures Bland-Altman plots demonstrated limited agreement between MAP OPT derived from COx and PRx (mean bias: 1.4 mmHg; upper limit of agreement: 25.9 mmHg; lower limit of agreement: -23.0 mmHg). Similarly, there was limited agreement between the absolute values of PRx and COx. Mean bias was 0.26 and the upper and lower limits of agreement were 1.05 and -0.53, respectively. Systematic bias was apparent, whereby at low PRx values COx overestimated PRx and at high PRx values, COx underestimated PRx. COx was limited in its ability to determine impaired autoregulation defined by PRx (receiver operator characteristic area under the curve was 0.488)., Conclusion: Collectively, we demonstrate that COx-based determination of MAP OPT lacks agreement with MAP OPT derived from PRx. Further research must be done to evaluate the physiologic and clinical efficacy of PRx derived MAP OPT in HIBI., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.)

Secondary injury is a major determinant of outcome in hypoxic ischemic brain injury (HIBI) after cardiac arrest and may be mitigated by optimizing cerebral oxygen delivery (CDO 2 ). CDO 2 is determined by cerebral blood flow (CBF), which is dependent upon mean arterial pressure (MAP). In health, CBF remains constant over the MAP range through cerebral autoregulation. In HIBI, the zone of intact cerebral autoregulation is narrowed and varies for each patient. Maintaining MAP within the intact autoregulation zone may mitigate ischemia, hyperemia and secondary injury. The optimal MAP in individual patients can be determined using real time autoregulation monitoring techniques.

Objective: Optic nerve sheath diameter (ONSD) measured on a head computed tomography (CT) has been suggested as a potential prognostic factor for poor neurological outcome after cardiac arrest. We performed a single centre retrospective cohort analysis to further investigate this relationship., Methods: All patients >18 years of age admitted to St. Paul's Hospital in Vancouver, Canada who survived a cardiac arrest and had a CT scan of the head within 48 hours were included in the analysis., Results: A total of 72 patients met inclusion criteria for the study; 54 (75.0%) of the patients had a poor neurological outcome, whereas 18 (25.0%) patients were discharged from the hospital with a good outcome. A CT head was obtained for patients in the good outcome group in a mean time of 9.3 hours (SD 10.0) compared to 10.2 hours (SD 11.2) for the poor outcome group (p=0.75). There was no difference in average ONSD observed between the two outcome groups (6.66 mm SD 0.78 v. 6.60 mm SD 0.82, p=0.77). Multiple logistic regression failed to show any association between ONSD and neurological outcome when adjusted for all other covariates (OR 1.32 95% CI 0.40-4.34, p=0.65). Setting an ONSD threshold of >8 mm (OR 2.32, 95% CI 0.14-39.40, p=0.55) or >7 mm (OR 0.28, 95% CI 0.03-2.77, p=0.28) also failed to show any association on neurological outcome., Conclusion: There was no observed difference in ONSD between those with a good neurological outcome and those with a poor outcome. ONSD was not an independent predictor of poor neurological outcome.

Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.

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.)

Introduction: Prospectively assess cerebral autoregulation and optimal mean arterial pressure (MAPOPT) using the dynamic relationship between MAP and regional saturation of oxygen (rSO2) using near-infrared spectroscopy., Methods: Feasibility study of twenty patients admitted to the intensive care unit following a cardiac arrest. All patients underwent continuous rSO2 monitoring using the INVOS(®) cerebral oximeter. ICM+(®) brain monitoring software calculates the cerebral oximetry index (COx) in real-time which is a moving Pearson correlation coefficient between 30 consecutive, 10-s averaged values of MAP and correspond rSO2 signals. When rSO2 increases with increasing MAP (COx ≥0.3), cerebral autoregulation is dysfunctional. Conversely, when rSO2 remains constant or decreases with increasing MAP (COx <0.3), autoregulation is preserved. ICM+(®) fits a U-shaped curve through the COx values plotted vs. MAP. The MAPOPT is nadir of this curve., Results: The median age was 59 years (IQR 54-67) and 7 of 20 were female. The cardiac arrest was caused by myocardial infarction in 12 (60%) patients. Nineteen arrests were witnessed and return of spontaneous circulation occurred in a median of 15.5min (IQR 8-33). Patients underwent a median of 30h (IQR 23-46) of monitoring. COx curves and MAPOPT were generated in all patients. The mean overall MAP and MAPOPT were 76mmHg (SD 10) and 76mmHg (SD 7), respectively. MAP was outside of 5mmHg from MAPOPT in 50% (SD 15) of the time. Out of the 7672 5-min averaged COx measurements, 1182 (15%) were at 0.3 or above, indicating absence of autoregulation. Multivariable polynomial fractional regression demonstrated an increase in COx with increasing temperature (P=0.008)., Conclusions: We demonstrated the feasibility to determine a MAPOPT using cerebral oximetry in patients after cardiac arrest., (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.)