Microvascular reperfusion during endovascular therapy: the balance of supply and demand.

BACKGROUND: Endovascular therapy (EVT) has revolutionized the treatment of acute stroke, but large vessel recanalization does not always result in tissue-level reperfusion. Cerebral blood flow (CBF) is not routinely monitored during EVT. We aimed to leverage diffuse correlation spectroscopy (DCS), a novel transcranial optical imaging technique, to assess the relationship between microvascular CBF and post-EVT outcomes. METHODS: Frontal lobe CBF was monitored by DCS in 40 patients undergoing EVT. Baseline CBF deficit was calculated as the percentage of CBF impairment on pre-EVT CT perfusion. Microvascular reperfusion was calculated as the percentage increase in DCS-derived CBF that occurred with recanalization. The adequacy of reperfusion was defined by persistent CBF deficit, calculated as: baseline CBF deficit - microvascular reperfusion. A good functional outcome was defined as 90-day modified Rankin Scale score ≤2. RESULTS: Thirty-six of 40 patients achieved successful recanalization, in whom microvascular reperfusion in itself was not associated with infarct volume or functional outcome. However, patients with good functional outcomes had a smaller persistent CBF deficit (median 1% (IQR -11%-16%)) than patients with poor outcomes (median 28% (IQR 2-50%)) (p=0.02). Smaller persistent CBF deficit was also associated with smaller infarct volume (p=0.004). Multivariate models confirmed that persistent CBF deficit was independently associated with infarct volume and functional outcome. CONCLUSIONS: CBF augmentation alone does not predict post-EVT outcomes, but when microvascular reperfusion closely matches the baseline CBF deficit, patients experience favorable clinical and radiographic outcomes. By recognizing inadequate reperfusion, bedside CBF monitoring may provide opportunities to personalize post-EVT care aimed at CBF optimization.

Overview of Hypothermia, Its Role in Neuroprotection, and the Application of Prophylactic Hypothermia in Traumatic Brain Injury.

The current standard of practice is to maintain normothermia in traumatic brain injury (TBI) patients despite the theoretical benefits of hypothermia and numerous animal studies with promising results. While targeted temperature management or induced hypothermia to support neurological function is recommended for a select patient population postcardiac arrest, similar guidelines have not been instituted for TBI. In this review, we will examine the pathophysiology of TBI and discuss the benefits and risks of induced hypothermia in this patient population. In addition, we provide an overview of the largest randomized controlled trials testing-induced hypothermia. Our literature review on hypothermia returned a myriad of studies and trials, many of which have inconclusive results. The aim of this review was to recognize the effects of hypothermia, summarize the latest trials, address the inconsistencies, and discuss future directions for the study of hypothermia in TBI.

Comparison of optical measurements of critical closing pressure acquired before and during induced ventricular arrhythmia in adults.

Significance: The critical closing pressure (CrCP) of cerebral circulation, as measured by diffuse correlation spectroscopy (DCS), is a promising biomarker of intracranial hypertension. However, CrCP techniques using DCS have not been assessed in gold standard experiments. Aim: CrCP is typically calculated by examining the variation of cerebral blood flow (CBF) during the cardiac cycle (with normal sinus rhythm). We compare this typical CrCP measurement with a gold standard obtained during the drops in arterial blood pressure (ABP) caused by rapid ventricular pacing (RVP) in patients undergoing invasive electrophysiologic procedures. Approach: Adults receiving electrophysiology procedures with planned ablation were enrolled for DCS CBF monitoring. CrCP was calculated from CBF and ABP data by three methods: (1) linear extrapolation of data during RVP ( CrCP RVP ; the gold standard); (2) linear extrapolation of data during regular heartbeats ( CrCP Linear ); and (3) fundamental harmonic Fourier filtering of data during regular heartbeats ( CrCP Fourier ). Results: CBF monitoring was performed prior to and during 55 episodes of RVP in five adults. CrCP RVP and CrCP Fourier demonstrated agreement ( R = 0.66 , slope = 1.05 (95%CI, 0.72 to 1.38). Agreement between CrCP RVP and CrCP Linear was worse; CrCP Linear was 8.2 ± 5.9 mmHg higher than CrCP RVP (mean ± SD; p < 0.001 ). Conclusions: Our results suggest that DCS-measured CrCP can be accurately acquired during normal sinus rhythm.

Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b.

BACKGROUND: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms. METHODS: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30-32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-d-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice. RESULTS: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours. CONCLUSIONS: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk.

Standardization of Neuroanesthesia Education: Need of the Hour and the Way Forward.

PURPOSE OF REVIEW: This review illustrates the evolution and progress with standardization of fellowship education in neuroanesthesiology. It provides a structured discussion around the need for curricula and framework which individual training programs in neuroanesthesiology can use to meet defined educational standards thus meeting criteria for accreditation. RECENT FINDINGS: Neuroanesthesiology training has traditionally been heterogenous around the world but international efforts from the community of neuroanesthesiology have culminated in the development of an international council for perioperative training in neuroscience in anesthesiology(ICPNT). This serves not only as an accrediting body but also creates a platform through their neuroanesthesia program relations committee for collaboration and engagement between various training programs internationally, increasing the educational standards of the individual programs and collectively increasing the overall level of standards for neuroanesthesia training. Standardized curriculum and competency-based assessments and milestones would help with narrowing the focus to quality education in neuroanesthesiology. SUMMARY: Structured training around the three pillars of neuroanesthesiology with concomitant accreditation is expected to lead to higher education standards with better patient care. The SNACC created milestones for neuroanesthesiology training during residency and the ICPNT can now use this as a foundation for fellowship training. Having a council to accredit and standardize will likely become indispensable in creating a set path for training in neuroanesthesiology. Additionally, the flexibility built in due to the international nature would allow modified and variable pathways depending upon individual capabilities and interests. The path forward will include widespread adoption of standardization supporting the overarching goal of excellent patient outcomes around the world.

Cerebrovascular pressure reactivity and intracranial pressure are associated with neurologic outcome after hypoxic-ischemic brain injury.

AIM: We evaluated the association of physiological parameters measured by intracranial multimodality neuromonitoring with neurologic outcome in a consecutive series of patients with hypoxic-ischemic brain injury (HIBI). METHODS: We retrospectively identified all patients with HIBI who underwent combined invasive intracranial pressure (ICP) and brain tissue oxygen (PbtO2) monitoring over a 3 year period. Cerebrovascular pressure reactivity index (PRx) was calculated continuously as a surrogate of cerebral autoregulation. Favorable outcome was defined as recovery of consciousness (Glasgow Coma Scale motor score = 6). Differences in mean ICP, PRx and PbtO2 for the entire monitoring period across outcomes were measured. Logistic regression and area under receiver operating characteristic (AUROC) curve were used to assess the association of each monitoring parameter with neurologic outcome. RESULTS: We analyzed data from 36 patients. Most (89%) had an antecedent sudden cardiac arrest. Favorable outcome occurred in 8 (22%) patients. ICP and PRx were higher in patients with unfavorable outcome (ICP: 26 ±â€¯4.1 mmHg vs 7.5 ±â€¯2 mmHg, p = 0.0002; PRx: 0.51 ±â€¯0.05 vs 0.11 ±â€¯0.05, p < 0.0001). There was no significant difference in PbtO2 between groups (unfavorable: 20 ±â€¯2.4 mmHg vs favorable: 25 ±â€¯1.5 mmHg, p = 0.12). Both ICP (AUROC 0.84, 95%CI 0.72-0.98, p = 0.003) and PRx (AUROC 0.94, 95%CI 0.85-1, p = 0.0002) discriminated between favorable and unfavorable outcome, in contrast to PbtO2, (AUROC 0.59, 95%CI 0.39-0.78, p = 0.52). ICP > 15 mmHg, PRx > 0.2, and PbtO2 < 18 mmHg had sensitivity/specificity of 68%/100%, 89%/88%, and 40%/100% respectively for discriminating outcomes. CONCLUSION: Cerebrovascular pressure reactivity and intracranial pressure appear to be associated with neurologic outcome in patients with HIBI.

Physiological Signatures of Brain Death Uncovered by Intracranial Multimodal Neuromonitoring.

BACKGROUND: The physiological and neurochemical changes that accompany brain death are not well described. MATERIALS AND METHODS: A retrospective observational study of patients with acute brain injury who underwent intracranial multimodality neuromonitoring between October 2015 and June 2018. Patients were included for analysis either if brain death was diagnosed or refractory intracranial hypertension with persistent equalization of intracranial pressure (ICP) and mean arterial pressure (MAP) developed. RESULTS: Of 114 patients who underwent invasive neuromonitoring, 11 cases with MAP/ICP equalization were identified. Of those, 9 were declared brain dead based on accepted national and institutional criteria. An additional 2 cases with MAP/ICP equalization who died after withdrawal of life-sustaining therapies were identified. Of the 11 identified patients, 10 had continuous monitoring data available for analysis. Cerebral microdialysis data were available for 4 patients.In the 10 cases with available continuous data, ICP/MAP equalization was associated with marked reduction of cerebral blood flow and brain tissue oxygen tension to near zero levels as well as a significant decrease in brain temperature compared with body temperature. In the 4 patients with microdialysis monitoring, ICP/MAP equalization resulted in a near complete depletion of cerebral glucose and pyruvate, as well as a marked rise in cerebral glycerol. Finally, ICP/MAP equalization was accompanied by complete loss of cerebrovascular pressure reactivity, decrease in intracranial pulse pressure, and a paradoxical improvement of ICP waveform morphology. CONCLUSIONS: A characteristic set of changes in cerebrovascular physiology and neurochemistry occurs during brain death. These changes can be identified by intracranial neuromonitoring.

Anesthetic Management of Endovascular Treatment of Acute Ischemic Stroke During COVID-19 Pandemic: Consensus Statement From Society for Neuroscience in Anesthesiology & Critical Care (SNACC): Endorsed by Society of Vascular & Interventional Neurology (SVIN), Society of NeuroInterventional Surgery (SNIS), Neurocritical Care Society (NCS), European Society of Minimally Invasive Neurological Therapy (ESMINT) and American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) Cerebrovascular Section.

The pandemic of coronavirus disease 2019 (COVID-19) has unique implications for the anesthetic management of endovascular therapy for acute ischemic stroke. The Society for Neuroscience in Anesthesiology and Critical Care appointed a task force to provide timely, consensus-based expert recommendations using available evidence for the safe and effective anesthetic management of endovascular therapy for acute ischemic stroke during the COVID-19 pandemic. The goal of this consensus statement is to provide recommendations for anesthetic management considering the following (and they are): (1) optimal neurological outcomes for patients; (2) minimizing the risk for health care professionals, and (3) facilitating judicious use of resources while accounting for existing variability in care. It provides a framework for selecting the optimal anesthetic technique (general anesthesia or monitored anesthesia care) for a given patient and offers suggestions for best practices for anesthesia care during the pandemic. Institutions and health care providers are encouraged to adapt these recommendations to best suit local needs, considering existing practice standards and resource availability to ensure safety of patients and providers.

Quantification of cerebral blood flow in adults by contrast-enhanced near-infrared spectroscopy: Validation against MRI.

The purpose of this study was to assess the accuracy of absolute cerebral blood flow (CBF) measurements obtained by dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) using indocyanine green as a perfusion contrast agent. For validation, CBF was measured independently using the MRI perfusion method arterial spin labeling (ASL). Data were acquired at two sites and under two flow conditions (normocapnia and hypercapnia). Depth sensitivity was enhanced using time-resolved detection, which was demonstrated in a separate set of experiments using a tourniquet to temporally impede scalp blood flow. A strong correlation between CBF measurements from ASL and DCE-NIRS was observed (slope = 0.99 ± 0.08, y-intercept = -1.7 ± 7.4 mL/100 g/min, and R2 = 0.88). Mean difference between the two techniques was 1.9 mL/100 g/min (95% confidence interval ranged from -15 to 19 mL/100g/min and the mean ASL CBF was 75.4 mL/100 g/min). Error analysis showed that structural information and baseline absorption coefficient were needed for optimal CBF reconstruction with DCE-NIRS. This study demonstrated that DCE-NIRS is sensitive to blood flow in the adult brain and can provide accurate CBF measurements with the appropriate modeling techniques.

Defining a Taxonomy of Intracranial Hypertension: Is ICP More Than Just a Number?

Intracranial pressure (ICP) monitoring and control is a cornerstone of neuroanesthesia and neurocritical care. However, because elevated ICP can be due to multiple pathophysiological processes, its interpretation is not straightforward. We propose a formal taxonomy of intracranial hypertension, which defines ICP elevations into 3 major pathophysiological subsets: increased cerebral blood volume, masses and edema, and hydrocephalus. (1) Increased cerebral blood volume increases ICP and arises secondary to arterial or venous hypervolemia. Arterial hypervolemia is produced by autoregulated or dysregulated vasodilation, both of which are importantly and disparately affected by systemic blood pressure. Dysregulated vasodilation tends to be worsened by arterial hypertension. In contrast, autoregulated vasodilation contributes to intracranial hypertension during decreases in cerebral perfusion pressure that occur within the normal range of cerebral autoregulation. Venous hypervolemia is produced by Starling resistor outflow obstruction, venous occlusion, and very high extracranial venous pressure. Starling resistor outflow obstruction tends to arise when cerebrospinal fluid pressure causes venous compression to thus increase tissue pressure and worsen tissue edema (and ICP elevation), producing a positive feedback ICP cycle. (2) Masses and edema are conditions that increase brain tissue volume and ICP, causing both vascular compression and decrease in cerebral perfusion pressure leading to oligemia. Brain edema is either vasogenic or cytotoxic, each with disparate causes and often linked to cerebral blood flow or blood volume abnormalities. Masses may arise from hematoma or neoplasia. (3) Hydrocephalus can also increase ICP, and is either communicating or noncommunicating. Further research is warranted to ascertain whether ICP therapy should be tailored to these physiological subsets of intracranial hypertension.

Transcranial Optical Monitoring of Cerebral Hemodynamics in Acute Stroke Patients during Mechanical Thrombectomy.

INTRODUCTION: Mechanical thrombectomy is revolutionizing treatment of acute stroke due to large vessel occlusion (LVO). Unfortunately, use of the modified Thrombolysis in Cerebral Infarction score (mTICI) to characterize recanalization of the cerebral vasculature does not address microvascular perfusion of the distal parenchyma, nor provide more than a vascular "snapshot." Thus, little is known about tissue-level hemodynamic consequences of LVO recanalization. Diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) are promising methods for continuous, noninvasive, contrast-free transcranial monitoring of cerebral microvasculature. METHODS: Here, we use a combined DCS/DOS system to monitor frontal lobe hemodynamic changes during endovascular treatment of 2 patients with ischemic stroke due to internal carotid artery (ICA) occlusions. RESULTS AND DISCUSSION: The monitoring instrument identified a recanalization-induced increase in ipsilateral cerebral blood flow (CBF) with little or no concurrent change in contralateral CBF and extracerebral blood flow. The results suggest that diffuse optical monitoring is sensitive to intracerebral hemodynamics in patients with ICA occlusion and can measure microvascular responses to mechanical thrombectomy.

Detection of Brain Hypoxia Based on Noninvasive Optical Monitoring of Cerebral Blood Flow with Diffuse Correlation Spectroscopy.

BACKGROUND: Diffuse correlation spectroscopy (DCS) noninvasively permits continuous, quantitative, bedside measurements of cerebral blood flow (CBF). To test whether optical monitoring (OM) can detect decrements in CBF producing cerebral hypoxia, we applied the OM technique continuously to probe brain-injured patients who also had invasive brain tissue oxygen (PbO2) monitors. METHODS: Comatose patients with a Glasgow Coma Score (GCS) < 8) were enrolled in an IRB-approved protocol after obtaining informed consent from the legally authorized representative. Patients underwent 6-8 h of daily monitoring. Brain PbO2 was measured with a Clark electrode. Absolute CBF was monitored with DCS, calibrated by perfusion measurements based on intravenous indocyanine green bolus administration. Variation of optical CBF and mean arterial pressure (MAP) from baseline was measured during periods of brain hypoxia (defined as a drop in PbO2 below 19 mmHg for more than 6 min from baseline (PbO2 > 21 mmHg). In a secondary analysis, we compared optical CBF and MAP during randomly selected 12-min periods of "normal" (> 21 mmHg) and "low" (< 19 mmHg) PbO2. Receiver operator characteristic (ROC) and logistic regression analysis were employed to assess the utility of optical CBF, MAP, and the two-variable combination, for discrimination of brain hypoxia from normal brain oxygen tension. RESULTS: Seven patients were enrolled and monitored for a total of 17 days. Baseline-normalized MAP and CBF significantly decreased during brain hypoxia events (p < 0.05). Through use of randomly selected, temporally sparse windows of low and high PbO2, we observed that both MAP and optical CBF discriminated between periods of brain hypoxia and normal brain oxygen tension (ROC AUC 0.761, 0.762, respectively). Further, combining these variables using logistic regression analysis markedly improved the ability to distinguish low- and high-PbO2 epochs (AUC 0.876). CONCLUSIONS: The data suggest optical techniques may be able to provide continuous individualized CBF measurement to indicate occurrence of brain hypoxia and guide brain-directed therapy.

Noninvasive continuous optical monitoring of absolute cerebral blood flow in critically ill adults.

We investigate a scheme for noninvasive continuous monitoring of absolute cerebral blood flow (CBF) in adult human patients based on a combination of time-resolved dynamic contrast-enhanced near-infrared spectroscopy (DCE-NIRS) and diffuse correlation spectroscopy (DCS) with semi-infinite head model of photon propogation. Continuous CBF is obtained via calibration of the DCS blood flow index (BFI) with absolute CBF obtained by intermittent intravenous injections of the optical contrast agent indocyanine green. A calibration coefficient ( γ ) for the CBF is thus determined, permitting conversion of DCS BFI to absolute blood flow units at all other times. A study of patients with acute brain injury ( N = 7 ) is carried out to ascertain the stability of γ . The patient-averaged DCS calibration coefficient across multiple monitoring days and multiple patients was determined, and good agreement between the two calibration coefficients measured at different times during single monitoring days was found. The patient-averaged calibration coefficient of 1.24 × 10 9 ( mL / 100 g / min ) / ( cm 2 / s ) was applied to previously measured DCS BFI from similar brain-injured patients; in this case, absolute CBF was underestimated compared with XeCT, an effect we show is primarily due to use of semi-infinite homogeneous models of the head.

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

INTRODUCTION: Patients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium. METHODS: Ninety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism. RESULTS: Genotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050. CONCLUSION: This observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments.

Connecting the dots: an association between opioids and acute hippocampal injury.

Acute hippocampal injury represents a relatively rare cause of amnesia. Interestingly however, between 2012 and 2017, 18 patients were reported at hospitals in Massachusetts with sudden-onset amnesia in the setting of complete diffusion-weighted hyperintensity of both hippocampi on magnetic resonance imaging. Notably, 17 of the 18 patients tested positive for opioids or had a recorded history of opioid use. This observation suggests an association between opioids and acute hippocampal injury. With particular attention to the Massachusetts cluster and data on fentanyl and its congeners, the epidemiological and pathophysiological evidence that supports this hypothesis is presented, as are potential underlying mechanisms.