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.

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.

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.

An Immersive Virtual Reality Intervention for Preoperative Anxiety and Distress Among Adults Undergoing Oncological Surgery: Protocol for a 3-Phase Development and Feasibility Trial.

BACKGROUND: Preoperative state anxiety (PSA) is distress and anxiety directly associated with perioperative events. PSA is associated with negative postoperative outcomes such as longer hospital length of stay, increased pain and opioid use, and higher rates of rehospitalization. Psychological prehabilitation, such as education, exposure to hospital environments, and relaxation strategies, has been shown to mitigate PSA; however, there are limited skilled personnel to deliver such interventions in clinical practice. Immersive virtual reality (VR) has the potential for greater accessibility and enhanced integration into an immersive and interactive experience. VR is rarely used in the preoperative setting, but similar forms of stress inoculation training involving exposure to stressful events have improved psychological preparation in contexts such as military deployment. OBJECTIVE: This study seeks to develop and investigate a targeted PSA intervention in patients undergoing oncological surgery using a single preoperative VR exposure. The primary objectives are to (1) develop a novel VR program for patients undergoing oncological surgery with general anesthesia; (2) assess the feasibility, including acceptability, of a single exposure to this intervention; (3) assess the feasibility, including acceptability, of outcome measures of PSA; and (4) use these results to refine the VR content and outcome measures for a larger trial. A secondary objective is to preliminarily assess the clinical utility of the intervention for PSA. METHODS: This study comprises 3 phases. Phase 1 (completed) involved the development of a VR prototype targeting PSA, using multidisciplinary iterative input. Phase 2 (data collection completed) involves examining the feasibility aspects of the VR intervention. This randomized feasibility trial involves assessing the novel VR preoperative intervention compared to a VR control (ie, nature trek) condition and a treatment-as-usual group among patients undergoing breast cancer surgery. Phase 3 will involve refining the prototype based on feasibility findings and input from people with lived experience for a future clinical trial, using focus groups with participants from phase 2. RESULTS: This study was funded in March 2019. Phase 1 was completed in April 2020. Phase 2 data collection was completed in January 2024 and data analysis is ongoing. Focus groups were completed in February 2024. Both the feasibility study and focus groups will contribute to further refinement of the initial VR prototype (phase 3), with the final simulation to be completed by mid-2024. CONCLUSIONS: The findings from this work will contribute to the limited body of research examining feasible and broadly accessible interventions for PSA. Knowledge gained from this research will contribute to the final development of a novel VR intervention to be tested in a large population of patients with cancer before surgery in a randomized clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04544618; https://www.clinicaltrials.gov/study/NCT04544618. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55692.

Cerebral oxygen desaturation during one-lung ventilation: correlation with hemodynamic variables.

PURPOSE: Cerebral desaturation occurs frequently in patients undergoing one-lung ventilation for thoracic surgery. The mechanism of this desaturation is unclear regarding its etiology. The objective of this study was to investigate whether or not decreases in cerebral oxygen saturation associated with one-lung ventilation were a consequence of decreased cardiac output. METHODS: A blinded observational study was conducted in 23 patients undergoing one-lung ventilation with thoracic surgery. Eighteen patients completed the study. Cerebral oxygen saturation was monitored using near-infrared spectroscopy (FORE-SIGHT(®) monitor). Invasive blood pressure was monitored and hemodynamic variables were interrogated using the FloTrac(®) system. Anesthesia was maintained with sevoflurane with a F(i)O(2) of 1.0. Post-hoc analysis involved a comparison between baseline and integrated changes in cerebral saturation, heart rate, stroke index, cardiac index, and stroke volume variability. RESULTS: All patients showed cerebral desaturation from a baseline of two-lung ventilation in the lateral decubitus position following institution of one-lung ventilation. The cardiac index was stable at these times, but with one-lung ventilation, the heart rate decreased and the stroke index increased to maintain a stable product. The integral of heart rate × time was inversely correlated with the integral of cerebral desaturation × time (linear regression analysis; P = 0.02; (df) = 16)). CONCLUSIONS: Cerebral oxygen desaturation was universal during one-lung ventilation in this study. There was no correlation between cerebral desaturation and cardiac output or other hemodynamic variables.

Quantitative computed tomography in porcine lung injury with variable versus conventional ventilation: recruitment and surfactant replacement.

OBJECTIVES: Biologically variable ventilation improves lung function in acute respiratory distress models. If enhanced recruitment is responsible for these results, then biologically variable ventilation might promote distribution of exogenous surfactant to nonaerated areas. Our objectives were to confirm model predictions of enhanced recruitment with biologically variable ventilation using computed tomography and to determine whether surfactant replacement with biologically variable ventilation provides additional benefit in a porcine oleic acid injury model. DESIGN: Prospective, randomized, controlled experimental animal investigation. SETTING: University research laboratory. SUBJECTS: Domestic pigs. INTERVENTIONS: Standardized oleic acid lung injury in pigs randomized to conventional mechanical ventilation or biologically variable ventilation with or without green dye labeled surfactant replacement. MEASUREMENTS AND MAIN RESULTS: Computed tomography-derived total and regional masses and volumes were determined at injury and after 4 hrs of ventilation at the same average low tidal volume and minute ventilation. Hemodynamics, gas exchange, and lung mechanics were determined hourly. Surfactant distribution was determined in postmortem cut lung sections. Biologically variable ventilation alone resulted in 7% recruitment of nonaerated regions (p < .03) and 15% recruitment of nonaerated and poorly aerated regions combined (p < .04). Total and normally aerated regional volumes increased significantly with biologically variable ventilation, biologically variable ventilation with surfactant replacement, and conventional mechanical ventilation with surfactant replacement, while poorly and nonaerated regions decreased after 4 hrs of ventilation with biologically variable ventilation alone (p < .01). Biologically variable ventilation showed the greatest improvement (p < .003, biologically variable ventilation vs. all other groups). Hyperaerated regional gas volume increased significantly with biologically variable ventilation, biologically variable ventilation with surfactant replacement, and conventional mechanical ventilation with surfactant replacement. Biologically variable ventilation was associated with restoration of respiratory compliance to preinjury levels and significantly greater improvements in gas exchange at lower peak airway pressures compared to all other groups. Paradoxically, gas exchange and lung mechanics were impaired to a greater extent initially with biologically variable ventilation with surfactant replacement. Peak airway pressure was greater in surfactant-treated animals with either ventilation mode. Surfactant was distributed to the more caudal/injured lung sections with biologically variable ventilation. CONCLUSIONS: Quantitative computed tomography analysis confirms lung recruitment with biologically variable ventilation in a porcine oleic acid injury model. Surfactant replacement with biologically variable ventilation provided no additional recruitment benefit and may in fact be harmful.

Resolution of pulmonary edema with variable mechanical ventilation in a porcine model of acute lung injury.

OBJECTIVE: Resolution of the acute respiratory distress syndrome (ARDS) requires clearance of pulmonary edema. Biologically variable ventilation (BVV) strategies that improve gas exchange, lung mechanics, and inflammatory mediators in ARDS may be beneficial in this regard. We used quantitative computed tomography (CT), a single indicator thermodilution system (PiCCO®) to determine extravascular lung water (EVLW), and the change in edema protein concentration over time to compare edema clearance with BVV vs conventional mechanical ventilation (CMV) in a porcine ARDS model. METHODS: Sixteen pigs with oleic acid lung injury were randomized to four hours of ventilation with either CMV (n = 8) or BVV (n = 8) at identical low tidal volume and minute ventilation over time. Hemodynamic variables, gas exchange, lung mechanics, and PiCCO derived EVLW were determined hourly. Computed tomography images and edema fluid samples were obtained at baseline lung injury and after four hours of ventilation. Wet and dry lung weights were determined postmortem. RESULTS: At four hours with BVV, peak airway pressure was decreased significantly and lung compliance improved compared with CMV (P = 0.003; P < 0.001, respectively). Hemodynamic variables and gas exchange were not different between groups. Also at four hours, computed tomography revealed an increase in total gas volume (P = 0.001) and a decrease in total lung weight and global lung density (P = 0.005; P = 0.04 respectively) with BVV. These findings were associated with a significant increase in the gas volume of normally aerated lung regions (P < 0.001) and a decrease in the poorly and non-aerated lung regions (P = 0.001). No change in any CT parameter occurred with CMV. The lung weights derived from computed tomography correlated well with postmortem wet weights (R(2) = 0.79; P < 0.01). The decrease in PiCCO derived EVLW from injury to four hours did not differ significantly between BVV and CMV. Extravascular lung water showed no correlation with postmortem wet weights and significantly underestimated lung water. Average alveolar fluid clearance rates were positive (1.4%·hr(-1) (3%)) with BVV and negative with CMV (-2.0%·hr(-1) (4%)). CONCLUSIONS: In a comparison between BVV and CMV, computed tomography evidence suggests that BVV facilitates enhanced clearance and/or redistribution of edema fluid with improved recruitment of atelectatic and poorly aerated lung regions; no such evidence was seen with either single thermodilution measurement of EVLW or edema clearance rates. The results of computed tomography provide further evidence of the benefit of BVV over conventional ventilation in ARDS.

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.

A Promising Subject-Level Classification Model for Acute Concussion Based on Cerebrovascular Reactivity Metrics.

Concussion imaging research has primarily focused on neuronal disruption with lesser emphasis directed toward vascular dysfunction. However, blood flow metrics may be more sensitive than measures of neuronal integrity. Vascular dysfunction can be assessed by measuring cerebrovascular reactivity (CVR)-the change in cerebral blood flow per unit change in vasodilatory stimulus. CVR metrics, including speed and magnitude of flow responses to a standardized well-controlled vasoactive stimulus, are potentially useful for assessing individual subjects following concussion given that blood flow dysregulation is known to occur with traumatic brain injury. We assessed changes in CVR metrics to a standardized vasodilatory stimulus during the acute phase of concussion. Using a case control design, 20 concussed participants and 20 healthy controls (HCs) underwent CVR assessment measuring blood oxygen-level dependent (BOLD) magnetic resonance imaging using precise changes in end-tidal partial pressure of CO2 (PETCO2). Metrics were calculated for the whole brain, gray matter (GM), and white matter (WM) using sex-stratification. A leave-one-out receiver operating characteristic (ROC) analysis classified concussed from HCs based on CVR metrics. CVR magnitude was greater and speed of response faster in concussed participants relative to HCs, with WM showing higher classification accuracy compared with GM. ROC analysis for WM-CVR metrics revealed an area under the curve of 0.94 in males and 0.90 in females for speed and magnitude of response respectively. These greater than normal responses to a vasodilatory stimulus warrant further investigation to compare the predictive ability of CVR metrics against structural injury metrics for diagnosis and prognosis in acute concussion.

Lumbar cerebrospinal fluid drainage for thoracoabdominal aortic surgery: rationale and practical considerations for management.

Paraplegia remains one of the most devastating complications of thoracoabdominal aortic surgery and is associated with a significant increase in both morbidity and mortality. Modern aortic repair techniques use many modalities aimed at reducing the risk of spinal cord ischemia inherent with surgical management. One of these modalities that acts via optimizing spinal cord blood flow is lumbar cerebrospinal fluid (CSF) drainage. Either alone or in combination with other interventions, CSF drainage remains one of the most frequently used spinal cord protection techniques. Despite no definitive proof of efficacy for reducing spinal cord injury, there are compelling data supporting its use. However, the potential benefit of CSF drainage must be balanced against the risks associated with its use, including nerve injury during insertion, compressive neuraxial hematoma formation, intracranial hemorrhage due to excessive drainage, and infection. The optimal benefit to risk ratio can be achieved by understanding the rationale for its use and following practical management guidelines.