Preoperative Virtual Reality to Expose Patients With Breast Cancer to the Operating Room Environment: Feasibility and Pilot Case Series Study.

BACKGROUND: Clinically elevated preoperative distress and anxiety are common among patients undergoing cancer surgery. Preoperative interventions have been developed to mitigate this distress and anxiety but are inconsistent in efficacy and feasibility for broad implementation. OBJECTIVE: This preliminary pilot study aims to assess the feasibility and utility of a newly developed virtual reality (VR) intervention to expose patients awaiting breast cancer surgery to the operating room environment and a simulation of anesthetic induction. METHODS: Patients undergoing breast cancer surgery (N=7) were assigned to the VR intervention or control (treatment as usual) group and completed self-report measures of distress and anxiety before surgery, on the day of surgery, and after surgery (5 and 30 d postoperatively). Those in the intervention group trialed the VR simulation 1 to 2 weeks preoperatively and provided qualitative and quantitative feedback. We assessed the feasibility of recruitment capability and study design and evaluated participants' impressions of the intervention using self-report rating scales and open-ended questions. We also descriptively examined distress and anxiety levels throughout the duration of the study. RESULTS: Recruitment occurred between December 2021 and December 2022 and progressed slowly (rate: 1 participant/7 wk on average; some hesitancy because of stress and being overwhelmed). All participants who consented to participate completed the entire study. All participants were female and aged 56 (SD 10.56) years on average. In total, 57% (4/7) of the participants were assigned to the intervention group. On average, intervention participants spent 12 minutes engaged in the VR simulation. In general, the intervention was rated favorably (eg, clear information, enjoyable, and attractive presentation; mean% agreement 95.00-96.25, SD 4.79-10.00) and as helpful (mean% agreement 87.50, SD 25.00). Participants described the intervention as realistic (eg, "It was realistic to my past surgical experiences"), impacting their degree of preparedness and expectations for surgery (eg, "The sounds and sights and procedures give you a test run; they prepare you for the actual day"), and having a calming or relaxing effect (eg, "You feel more relaxed for the surgery"). CONCLUSIONS: This preoperative VR intervention demonstrated preliminary feasibility among a sample of patients undergoing breast cancer surgery. Results and participant feedback will inform modifications to the VR intervention and the study design of a large-scale randomized controlled trial to examine the efficacy of this intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04544618; https://clinicaltrials.gov/study/NCT04544618.

Differential regional cerebrovascular reactivity to end-tidal gas combinations commonly seen during anaesthesia: A blood oxygenation level-dependent MRI observational study in awake adult subjects.

BACKGROUND: Regional cerebrovascular reactivity (rCVR) is highly variable in the human brain as measured by blood oxygenation level-dependent (BOLD) MRI to changes in both end-tidal CO 2 and O 2 . OBJECTIVES: We examined awake participants under carefully controlled end-tidal gas concentrations to assess how regional CVR changes may present with end-tidal gas changes seen commonly with anaesthesia. DESIGN: Observational study. SETTING: Tertiary care centre, Winnipeg, Canada. The imaging for the study occurred in 2019. SUBJECTS: Twelve healthy adult subjects. INTERVENTIONS: Cerebral BOLD response was studied under two end-tidal gas paradigms. First end-tidal oxygen (ETO 2 ) maintained stable whereas ETCO 2 increased incrementally from hypocapnia to hypercapnia (CO 2 ramp); second ETCO 2 maintained stable whereas ETO 2 increased from normoxia to hyperoxia (O 2 ramp). BOLD images were modeled with end-tidal gas sequences split into two equal segments to examine regional CVR. MAIN OUTCOME MEASURES: The voxel distribution comparing hypocapnia to mild hypercapnia and mild hyperoxia (mean F I O 2  = 0.3) to marked hyperoxia (mean F I O 2  = 0.7) were compared in a paired fashion ( P  < 0.005 to reach threshold for voxel display). Additionally, type analysis was conducted on CO 2 ramp data. This stratifies the BOLD response to the CO 2 ramp into four categories of CVR slope based on segmentation (type A; +/+slope: normal response, type B +/-, type C -/-: intracranial steal, type D -/+.) Types B to D represent altered responses to the CO 2 stimulus. RESULTS: Differential regional responsiveness was seen for both end-tidal gases. Hypocapnic regional CVR was more marked than hypercapnic CVR in 0.3% of voxels examined ( P  < 0.005, paired comparison); the converse occurred in 2.3% of voxels. For O 2 , mild hyperoxia had more marked CVR in 0.2% of voxels compared with greater hyperoxia; the converse occurred in 0.5% of voxels. All subjects had altered regional CO 2 response based on Type Analysis ranging from 4 ±â€Š2 to 7 ±â€Š3% of voxels. CONCLUSION: In awake subjects, regional differences and abnormalities in CVR were observed with changes in end-tidal gases common during the conduct of anaesthesia. On the basis of these findings, consideration could be given to minimising regional CVR fluctuations in patients-at-risk of neurological complications by tighter control of end-tidal gases near the individual's resting values.

Differential regional cerebral blood flow reactivity to alterations in end-tidal gases in healthy volunteers.

PURPOSE: Anesthesia is associated with alterations in end-tidal (ET) respiratory gases from the awake state. These alterations result in marked vasoactive changes in regional cerebral blood flow (rCBF). Altered regional cerebrovascular reactivity (rCVR) is linked to neurologic dysfunction. We examined these differences in reactivity from prior work by focusing on the ratio of vasoconstriction with hyperoxia/hypocapnia (HO/hc):vasodilation with hypercapnia (HC) using magnetic resonance imaging pseudo-continuous arterial spin labelling (pCASL) to measure rCBF and compare rCVR The distribution and magnitude of these ratios could provide insights into rCBF during clinical anesthesia and inform future research into the origins of postoperative delirium (POD). METHODS: Ten healthy subjects underwent cerebral blood flow (CBF) studies using pCASL with computer-controlled delivery of ET gases to assess flow effects of hyperoxia, hypercapnia, and hyperoxia/hypocapnia as part of a larger study into cerebrovascular reactivity. The vasoconstrictor stimulus was compared with the vasodilator stimulus by the ratio HO/hc:HC. RESULTS: Hyperoxia minimally decreased whole brain CBF by - 0.6%/100 mm Hg increase in ETO2. Hypercapnia increased CBF by +4.6%/mm Hg carbon dioxide (CO2) and with HO/hc CBF decreased by - 5.1%/mm Hg CO2. The brain exhibited markedly different rCVR-regional HO/hc:HC ratios varied from 7.2:1 (greater response to vasoconstriction) to 0.49:1 (greater response to vasodilation). Many of the ratios greater than 1, where vasoconstriction predominated, were seen in regions associated with memory, cognition, and executive function, including the entorhinal cortex, hippocampus, parahippocampus, and dorsolateral prefrontal cortex. CONCLUSIONS: In awake humans, marked rCBF changes occurred with alterations in ET respiratory gases common under anesthesia. Such heterogeneous reactivity may be relevant to future studies to identify those at risk of POD.

RéSUMé: OBJECTIF: L'anesthésie est associée à des altérations des gaz respiratoires télé-expiratoires par rapport à l'état d'éveil. Ces altérations entraînent des changements vasoactifs marqués dans le débit sanguin cérébral régional (DSCR). Une altération de la réactivité cérébrovasculaire régionale (rCVR) est liée au dysfonctionnement neurologique. Nous avons examiné ces différences de réactivité dans des études antérieures en nous concentrant sur le rapport entre la vasoconstriction et l'hyperoxie/hypocapnie (HO/hc):vasodilatation et l'hypercapnie (HC), en utilisant une technique d'imagerie par résonance magnétique dite pCASL (pour pseudo-continuous arterial spin labelling) pour mesurer le DSCR et comparer la rCVR. La distribution et l'ampleur de ces rapports pourraient fournir des renseignements concernant le DSCR pendant l'anesthésie clinique et éclairer la recherche future sur les origines du delirium postopératoire (DPO). MéTHODE: Dix volontaires sains ont subi des études de débit sanguin cérébral (DSC) à l'aide d'une pCASL avec un contrôle géré par ordinateur des gaz télé-expiratoires pour évaluer les effets sur le débit de l'hyperoxie, de l'hypercapnie, et de l'hyperoxie/hypocapnie dans le cadre d'une plus grande étude sur la réactivité cérébrovasculaire. Le stimulus vasoconstricteur a été comparé au stimulus vasodilatateur par le rapport de HO/hc:HC. RéSULTATS: L'hyperoxie a diminué de façon minimale le DSC du cerveau entier de − 0,6 %/100 mmHg en ETO2. L'hypercapnie a augmenté le DSC de +4,6 %/mmHg de dioxyde de carbone (CO2) et avec le HO/hc, le DSC a diminué de − 5,1 %/mmHg CO2. Le cerveau a exhibé une rCVR nettement différente ­-les rapports régionaux HO/hc:HC allaient de 7.2:1 (plus grande réponse à la vasoconstriction) à 0.49:1 (plus grande réponse à la vasodilatation). Beaucoup des rapports supérieurs à 1, où la vasoconstriction était prédominante, ont été observés dans les régions associées à la mémoire, à la cognition et à la fonction exécutive, y compris le cortex entorhinal, l'hippocampe, le parahippocampe et le cortex préfrontal dorsolatéral. CONCLUSION: Chez une personne éveillée, des changements marqués de DSCR se sont produits lors des changements dans les gaz respiratoires télé-expiratoires survenant communément sous anesthésie. Une telle réactivité hétérogène pourrait être pertinente pour les études futures afin d'identifier les personnes à risque de DPO.

The Incidence and Magnitude of Cerebral Desaturation in Traumatic Brain Injury: An Observational Cohort Study.

BACKGROUND: Cerebral ischemia in patients with traumatic brain injury (TBI) may propagate secondary neurological injury. Episodes of cerebral ischemia can be revealed through the use of cerebral oximetry monitoring. The objective of this study was to determine the incidence and severity of regional cerebral oxygen (rSO2) desaturation (rSO2<65%) in patients with severe TBI. Secondary outcomes included changes in other monitoring parameters associated with cerebral desaturation. MATERIALS AND METHODS: In this single-center prospective observational cohort study, cerebral oximetry data were collected continuously for up to 72 hours in 18 adult patients with a diagnosis of severe nonpenetrating TBI who were being mechanically ventilated and undergoing intracranial pressure (ICP) monitoring an in intensive care unit in Canada. Mean arterial pressure (MAP), ICP, and cerebral perfusion pressure were collected at 5-minute intervals during the study period. RESULTS: Twelve of 18 (67%) patients experienced an episode of cerebral desaturation. The median (interquartile range) nadir rSO2 was 57% (51% to 62%). The duration of desaturation was 265 (57 to 1277) minutes or 8.1% (2.6% to 26.0%) of recording time. In all patients, a linear regression analysis of the area under threshold of 65% for rSO2 was moderately correlated with the area above an ICP threshold of 20 mm Hg (R2=0.52; P<0.01). Similarly, there was a modest correlation between rSO2 and MAP (R2=0.41; P<0.01). These relationships also held true for those patients who experienced cerebral desaturation. Patients having episodes of ICP >20 mm Hg were 6 times more likely to have a cerebral desaturation (relative risk: 6.0; 95% confidence interval: 1.3-34.7). CONCLUSIONS: Cerebral desaturations occur frequently in patients with severe TBI, and their duration can be protracted. Episodes of desaturation were moderately correlated with increased ICP and decreased MAP.

Magnetic Resonance Imaging Biomarkers of Brain Connectivity in Predicting Outcome after Mild Traumatic Brain Injury: A Systematic Review.

There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain connectivity from resting-state functional (rs-fMRI) and diffusion tensor imaging (DTI) to aid in the diagnosis and management of patients with mild traumatic brain injury (mTBI). To determine whether early MRI biomarkers of brain connectivity are useful in predicting outcome after mTBI, we conducted a systematic review using the following inclusion criteria: 1) patients aged >16 years with mTBI, 2) MRI performed during the first month post-injury, 3) outcome measure available, 4) control group, and 5) original article published in a peer-reviewed journal. Of the 1351 citations identified, 14 studies met inclusion criteria (5 rs-fMRI and 10 DTI; 680 patients with mTBI vs. 436 controls) including those where MRI was performed from <12 h to 1 month post-injury. The most common clinical outcome measure used in these studies was symptom burden using the Rivermead Post-Concussion Questionnaire. The most frequently studied brain connectivity MRI biomarkers were global functional connectivity, default-mode network, and fractional anisotropy (FA). Despite the scant evidence and considerable methodological heterogeneity observed among studies, we conclude that brain connectivity MRI biomarkers obtained within 1 month of injury may be potentially useful in predicting outcome in mTBI. Further longitudinal studies are needed to evaluate the effect of mTBI on MRI-based brain connectivity biomarkers and examine how incorporation of these tests can inform the clinical care of individual mTBI patients.

Brain BOLD MRI O2 and CO2 stress testing: implications for perioperative neurocognitive disorder following surgery.

BACKGROUND: Mechanical ventilation to alter and improve respiratory gases is a fundamental feature of critical care and intraoperative anesthesia management. The range of inspired O2 and expired CO2 during patient management can significantly deviate from values in the healthy awake state. It has long been appreciated that hyperoxia can have deleterious effects on organs, especially the lung and retina. Recent work shows intraoperative end-tidal (ET) CO2 management influences the incidence of perioperative neurocognitive disorder (POND). The interaction of O2 and CO2 on cerebral blood flow (CBF) and oxygenation with alterations common in the critical care and operating room environments has not been well studied. METHODS: We examine the effects of controlled alterations in both ET O2 and CO2 on cerebral blood flow (CBF) in awake adults using blood oxygenation level-dependent (BOLD) and pseudo-continuous arterial spin labeling (pCASL) MRI. Twelve healthy adults had BOLD and CBF responses measured to alterations in ET CO2 and O2 in various combinations commonly observed during anesthesia. RESULTS: Dynamic alterations in regional BOLD and CBF were seen in all subjects with expected and inverse brain voxel responses to both stimuli. These effects were incremental and rapid (within seconds). The most dramatic effects were seen with combined hyperoxia and hypocapnia. Inverse responses increased with age suggesting greater risk. CONCLUSIONS: Human CBF responds dramatically to alterations in ET gas tensions commonly seen during anesthesia and in critical care. Such alterations may contribute to delirium following surgery and under certain circumstances in the critical care environment. TRIAL REGISTRATION: ClincialTrials.gov NCT02126215 for some components of the study. First registered April 29, 2014.

End-Tidal Hypocapnia Under Anesthesia Predicts Postoperative Delirium.

Background: Postoperative delirium (POD) might be associated with anesthetic management, but research has focused on choice or dosage of anesthetic drugs. We examined potential contributions of intraoperative ventilatory and hemodynamic management to POD. Methods: This was a sub-study of the ENGAGES-Canada trial (NCT02692300) involving non-cardiac surgery patients enrolled in Winnipeg, Canada. Patients received preoperative psychiatric and cognitive assessments, and intraoperatively underwent high-fidelity data collection of blood pressure, end-tidal respiratory gases and anesthetic agent concentration. POD was assessed by peak and mean POD scores using the Confusion Assessment Method-Severity (CAM-S) tool. Bivariate and multiple linear regression models were constructed controlling for age, psychiatric illness, and cognitive dysfunction in the examination of deviations in intraoperative end-tidal carbon dioxide (areas over (AOC) and under the curve (AUC)) on POD severity scores. Results: A total of 101 subjects [69 (6) years of age] were studied; 89 had comprehensive intraoperative hemodynamic and end-tidal gas measurements (data recorded at 1 Hz). The incidence of POD was 11.9% (12/101). Age, cognitive dysfunction, anxiety, depression, and intraoperative end-tidal CO2 (AUC) were significant correlates of POD severity. In the multiple regression model, cognitive dysfunction and AUC end-tidal CO2 (0.67 kPa below median intra-operative value) were the only independent significant predictors across both POD severity (mean and peak) scores. There was no association between cumulative anesthetic agent exposure and POD. Conclusions: POD was associated with intraoperative ventilatory management, reflected by low end-tidal CO2 concentrations, but not with cumulative anesthetic drug exposure. These findings suggest that maintenance of intraoperative normocapnia might benefit patients at risk of POD.

Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions.

Evidence of anesthetic neurotoxicity is unequivocal when studied in animal models. These findings have translated poorly to the clinical domain when equated to postoperative delirium (POD) in adults and postoperative cognitive dysfunction (POCD) in either children or the elderly. In this perspective, we examine various reasons for the differences between animal modeling of neurotoxicity and the clinical situation of POD and POCD and make suggestions as to potential directions for ongoing research. We hypothesize that the animal anesthetic neurotoxicity models are limited, in part, due to failed scaling correction of physiological time. We posit that important insights into POCD in children and adults may be gleaned from studies in adults examining alterations in perioperative management designed to limit POD. In this way, POD may be more useful as the proxy for POCD rather than neuronal dropout or behavioral abnormalities that have been used in animal models but which may not be proxies for the human condition. We argue that it is time to move beyond animal models of neurotoxicity to directly examine these problems in well-conducted clinical trials with comprehensive preoperative neuropsychometric and psychiatric testing, high fidelity intraoperative monitoring of physiological parameters during the anesthetic course and postoperative assessment of subthreshold and full classification of POD. In this manner, we can "model ourselves" to better understand these important and poorly understood conditions.

Patient-Specific Alterations in CO2 Cerebrovascular Responsiveness in Acute and Sub-Acute Sports-Related Concussion.

BACKGROUND: Preliminary studies suggest that sports-related concussion (SRC) is associated with alterations in cerebral blood flow (CBF) regulation. Here, we use advanced magnetic resonance imaging (MRI) techniques to measure CBF and cerebrovascular responsiveness (CVR) in individual SRC patients and healthy control subjects. METHODS: 15 SRC patients (mean age = 16.3, range 14-20 years) and 27 healthy control subjects (mean age = 17.6, range 13-21 years) underwent anatomical MRI, pseudo-continuous arterial spin labeling (pCASL) MRI and model-based prospective end-tidal targeting (MPET) of CO2 during blood oxygenation level-dependent (BOLD) MRI. Group differences in global mean resting CBF were examined. Voxel-by-voxel group and individual differences in regional CVR were examined using statistical parametric mapping (SPM). Leave-one-out receiver operating characteristic curve analysis was used to evaluate the utility of brain MRI CO2 stress testing biomarkers to correctly discriminate between SRC patients and healthy control subjects. RESULTS: All studies were tolerated with no complications. Traumatic structural findings were identified in one SRC patient. No significant group differences in global mean resting CBF were observed. There were no significant differences in the CO2 stimulus and O2 targeting during BOLD MRI. Significant group and patient-specific differences in CVR were observed with SRC patients demonstrating a predominant pattern of increased CVR. Leave-one-out ROC analysis for voxels demonstrating a significant increase in CVR was found to reliably discriminate between SRC patients and healthy control subjects (AUC of 0.879, p = 0.0001). The optimal cutoff for increased CVR declarative for SRC was 1,899 voxels resulting in a sensitivity of 0.867 and a specificity of 0.778 for this specific ROC analysis. There was no correlation between abnormal voxel counts and Postconcussion Symptom Scale scores among SRC patients. CONCLUSION: Acute and subacute SRCs are associated with alterations in CVR that can be reliably detected by brain MRI CO2 stress testing in individual patients.

A Novel Stress-Diathesis Model to Predict Risk of Post-operative Delirium: Implications for Intra-operative Management.

Introduction: Risk assessment for post-operative delirium (POD) is poorly developed. Improved metrics could greatly facilitate peri-operative care as costs associated with POD are staggering. In this preliminary study, we develop a novel stress-diathesis model based on comprehensive pre-operative psychiatric and neuropsychological testing, a blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) carbon dioxide (CO2) stress test, and high fidelity measures of intra-operative parameters that may interact facilitating POD. Methods: The study was approved by the ethics board at the University of Manitoba and registered at clinicaltrials.gov as NCT02126215. Twelve patients were studied. Pre-operative psychiatric symptom measures and neuropsychological testing preceded MRI featuring a BOLD MRI CO2 stress test whereby BOLD scans were conducted while exposing participants to a rigorously controlled CO2 stimulus. During surgery the patient had hemodynamics and end-tidal gases downloaded at 0.5 hz. Post-operatively, the presence of POD and POD severity was comprehensively assessed using the Confusion Assessment Measure -Severity (CAM-S) scoring instrument on days 0 (surgery) through post-operative day 5, and patients were followed up at least 1 month post-operatively. Results: Six of 12 patients had no evidence of POD (non-POD). Three patients had POD and 3 had clinically significant confusional states (referred as subthreshold POD; ST-POD) (score ≥ 5/19 on the CAM-S). Average severity for delirium was 1.3 in the non-POD group, 3.2 in ST-POD, and 6.1 in POD (F-statistic = 15.4, p < 0.001). Depressive symptoms, and cognitive measures of semantic fluency and executive functioning/processing speed were significantly associated with POD. Second level analysis revealed an increased inverse BOLD responsiveness to CO2 pre-operatively in ST-POD and marked increase in the POD groups when compared to the non-POD group. An association was also noted for the patient population to manifest leucoaraiosis as assessed with advanced neuroimaging techniques. Results provide preliminary support for the interacting of diatheses (vulnerabilities) and intra-operative stressors on the POD phenotype. Conclusions: The stress-diathesis model has the potential to aid in risk assessment for POD. Based on these initial findings, we make some recommendations for intra-operative management for patients at risk of POD.

Longitudinal Brain Magnetic Resonance Imaging CO2 Stress Testing in Individual Adolescent Sports-Related Concussion Patients: A Pilot Study.

BACKGROUND: Advanced neuroimaging studies in concussion have been limited to detecting group differences between concussion patients and healthy controls. In this small pilot study, we used brain magnetic resonance imaging (MRI) CO2 stress testing to longitudinally assess cerebrovascular responsiveness (CVR) in individual sports-related concussion (SRC) patients. METHODS: Six SRC patients (three males and three females; mean age = 15.7, range = 15-17 years) underwent longitudinal brain MRI CO2 stress testing using blood oxygen level-dependent (BOLD) MRI and model-based prospective end-tidal CO2 targeting under isoxic conditions. First-level and second-level comparisons were undertaken using statistical parametric mapping (SPM) to score the scans and compare them to an atlas of 24 healthy control subjects. RESULTS: All tests were well tolerated and without any serious adverse events. Anatomical MRI was normal in all study participants. The CO2 stimulus was consistent between the SRC patients and control subjects and within SRC patients across the longitudinal study. Individual SRC patients demonstrated both quantitative and qualitative patient-specific alterations in CVR (p < 0.005) that correlated strongly with clinical findings, and that persisted beyond clinical recovery. CONCLUSION: Standardized brain MRI CO2 stress testing is capable of providing a longitudinal assessment of CVR in individual SRC patients. Consequently, larger prospective studies are needed to examine the utility of brain MRI CO2 stress testing as a clinical tool to help guide the evaluation, classification, and longitudinal management of SRC patients.