Bispectral Index Changes Following Boluses of Commonly Used Intravenous Medications During Volatile Anesthesia Identified From Retrospective Data.

BACKGROUND: Although patients are commonly monitored for depth of anesthesia, it is unclear to what extent administration of intravenous anesthetic medications may affect calculated bispectral (BIS) index values under general anesthesia. METHODS: In a retrospective analysis of electronic anesthesia records from an academic medical center, we examined BIS index changes associated with 14 different intravenous medications, as administered in routine practice, during volatile-based anesthesia using a novel screening approach. Discrete-time windows were identified in which only a single drug bolus was administered, and subsequent changes in the BIS index, concentration of volatile anesthetic, and arterial pressure were analyzed. Our primary outcome was change in BIS index, following drug administration. Adjusted 95% confidence intervals were compared to predetermined thresholds for clinical significance. Secondary sensitivity analyses examined the same outcomes, with available data separated according to differences in baseline volatile anesthetic concentrations, doses of the administered medications, and length of time window. RESULTS: The study cohort was comprised of data from 20,170 distinct cases, 54.7% of patients were men, with a median age of 55. In the primary analysis, ketamine at a median dose of 20 mg was associated with a median (confidence limits) increase in BIS index of 3.8 (2.5-5.0). Midazolam (median dose 2 mg) was associated with a median decrease in BIS index of 3.0 (1.5-4.5). Neither of these drug administrations occurred during time periods associated with changes in volatile anesthetic concentration. Analysis for dexmedetomidine was confounded by concomitant decreases in volatile anesthetic concentration. No other medication analyzed, including propofol and common opioids, was associated with a significant change in BIS index. Secondary analyses revealed that similar BIS index changes occurred when midazolam and ketamine were administered at different volatile anesthetic concentrations and different doses, and these changes persisted 11 to 20 minutes postadministration. CONCLUSIONS: Modest, but persistent changes in BIS index occurred following doses of ketamine (increase) and midazolam (decrease) during periods of stable volatile anesthetic administration.

Characterization of oscillations in the brain and cerebrospinal fluid using ultra-high field magnetic resonance imaging.

Development of innovative non-invasive neuroimaging methods and biomarkers are critical for studying brain disease. In this work, we have developed a methodology to characterize the frequency responses and spatial localization of oscillations and movements of cerebrospinal fluid (CSF) flow in the human brain. Using 7 Tesla human MRI and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture CSF oscillations and movements. Physiological data was simultaneously collected and correlated with the 7T MR data. The primary components of CSF oscillations were identified using spectral analysis (with frequency bands identified around 0.3Hz, 1.2Hz and 2.4Hz) and were mapped spatially and temporally onto the MR image domain and temporally onto the physiological domain. The developed methodology shows a good consistency and repeatability (standard deviation of 0.052 and 0.078 for 0.3Hz and 1.2Hz bands respectively) in-vivo for potential brain dynamics and CSF flow and clearance studies.

Brain connectivity under light sedation with midazolam and ketamine during task performance and the periodic experience of pain: Examining concordance between different approaches for seed-based connectivity analysis.

This work focused on functional connectivity changes under midazolam and ketamine sedation during performance of a memory task, with the periodic experience of pain. To maximize ability to compare to previous and future work, we performed secondary region of interest (ROI)-to-ROI functional connectivity analyses on these data, using two granularities of scale for ROIs. These findings are compared to the results of a previous seed-to-voxel analysis methodology, employed in the primary analysis. Healthy adult volunteers participated in this randomized crossover 3 T functional MRI study under no drug, followed by subanesthetic doses of midazolam or ketamine achieving minimal sedation. Periodic painful stimulation was delivered while subjects repeatedly performed a memory-encoding task. Atlas-based and network-level ROIs were used from within Conn Toolbox (ver 18). Timing of experimental task events was regressed from the data to assess drug-induced changes in background connectivity, using ROI-to-ROI methodology. Compared to saline, ROI-to-ROI connectivity changes under ketamine did not survive correction for multiple comparisons, thus data presented is from 16 subjects in a paired analysis between saline and midazolam. In both ROI-to-ROI analyses, the predominant direction of change was towards increased connectivity under midazolam, compared to saline. These connectivity increases occurred between functionally-distinct brain areas, with a posterior-predominant spatial distribution that included many long-range connectivity changes. During performance of an experimental task that involved periodic painful stimulation, compared to saline, low-dose midazolam was associated with robust increases in functional connectivity. This finding was concordant across different seed-based analyses for midazolam, but not ketamine. The neuroimaging drug trial from which this data was drawn was pre-registered (NCT-02515890) prior to enrollment of the first subject.

Assessing Common Content and Responsiveness of the QoR-15 and the SF-8 in the Context of Recovery from Regional Anesthesia for Joint Replacement.

PURPOSE: There is no consensus regarding how best to measure postoperative quality of recovery after anesthesia/surgery (e.g., using 24-hour survey instruments) in veterans or active military. Our goals were to (1) describe health-related quality-of-life (HRQoL) and recovery across time in veterans, (2) examine the commonality between the quality of recovery (QoR-15) and short-form (SF) surveys (including the SF-8, 24-hour version), and (3) examine the responsiveness of these surveys. MATERIALS AND METHODS: This study was approved by the Institutional Review Boards from the University of Pittsburgh, the VA Pittsburgh, and the Human Research Protection Office of the Department of Defense. Secondary analyses of data were executed based on a randomized trial dataset of knee/hip arthroplasty patients, the study having recruited 135 total veterans. QoR-15 and HRQoL SF surveys were completed and self-reported before surgery (pre-op), on postoperative day 2 (PO-D2), and 6 weeks postoperatively. Descriptive statistics were used to examine scores across time. Common content was examined using Pearson's r. Responsiveness was examined using distribution-based methods. RESULTS: Average veteran age was 67 year, 89% were male, 88% white, and average body mass index was 33 kg∙m-2. QoR-15 scores declined from pre-op to PO-D2 but were higher than pre-op at 6 weeks. SF physical component summary (PCS) scores were low both pre-op and PO-D2, but were elevated over baseline at 6 weeks. SF mental component summary (MCS) scores declined from baseline to PO-D2 but were higher than pre-op at 6 weeks. Associations of the QoR-15 total score and PCS/MCS were medium/large and statistically significant at P ≤ .01. Both instruments were responsive to changes. CONCLUSION: QoR-15 and SF-8 have high content commonality and performed similarly in veterans across time. SF-8 has added benefits of (1) brevity, (2) assessment of physical and mental health components, and (3) being normed to the general population. The SF-8, if used without the QoR-15 in tandem in future study of anesthesia-related outcomes, would need to be supplemented by separate questions addressing postoperative nausea/vomiting (a frequent outcome after anesthesia that is relevant to same-day and next-day mobilization after elective joint replacement surgery).

Validity of the Modified Defense and Veterans Pain Rating Scale Supplemented With Items Germane to Total Joint Replacement: Secondary Analysis From a Randomized Trial.

INTRODUCTION: Valid measures of pain are helpful to adjust treatment plans in real time after total joint replacement (TJR). We enhanced the existing Defense and Veterans Pain Rating Scale (DVPRS) with items related to pain at rest and movement, in specific reference to operative and nonoperative joints, creating the TJR-DVPRS. This manuscript is presented to validate the modified survey instrument. The aims of this psychometric study were to evaluate (1) the latent structure of the TJR-DVPRS, (2) the relationships among the pain dimensions represented on the TJR-DVPRS and the reference-standard Short-Form McGill Pain Questionnaire (version 2, SF-MPQ-2), and (3) the responsiveness of these two measures before and after TJR. MATERIALS AND METHODS: This report involves a secondary analysis of pain surveys from 135 veterans undergoing TJR at one center who participated in a randomized trial. The study was approved by the institutional review boards from participating institutions. The TJR-DVPRS and SF-MPQ-2 were completed preoperatively, during postoperative day 1, and 6 weeks post-surgery. Standard psychometric evaluations included correlations, principal component analysis, and internal consistency of survey items and subscales, using preoperative baseline data as a frame of reference. Responsiveness analysis included assessing both effect size and thresholds of clinically important change for survey subscales using data from all three time points. RESULTS: Two reliable subscales were identified for the TJR-DVPRS, one including items about pain intensity and interference related to the operative joint (Cronbach's α = .809) and the other including two pain items on the nonoperative joint. Combining the subscales indicated a two-factor solution: The first valid factor entailed the four subscales of the SF-MPQ-2 and the TJR-DVPRS operative joint subscales, indicating that these subscales validly represent the same pain dimension. The second valid factor entailed the TJR-DVPRS subscale addressing the nonoperative joint. Responsiveness analysis following accepted psychometric methods demonstrated significant decreases in pain from the preoperative period to 6 weeks postoperatively for all subscales. The TJR-DVPRS and SF-MPQ-2 subscales were similarly responsive, except for the SF-MPQ-2 neuropathic and TJR-DVPRS nonoperative joint subscales, which were minimally responsive during the preoperative to 6-week period. CONCLUSIONS: The TJR-DVPRS is valid for use among veterans undergoing TJR and poses significantly less respondent burden than does the SF-MPQ-2. The brevity and ease of use of the TJR-DVPRS make it a practical tool for use during surgical recovery to monitor pain intensity at rest and with movement in the operative joint, and to assess pain interference with activity, sleep, and mood. The TJR-DVPRS is at least as responsive as the SF-MPQ-2, but the SF-MPQ-2 neuropathic and TJR-DVPRS nonoperative joint subscales were minimally responsive. Limitations of this study include the small sample size, under-representation of women (which would be expected in the veteran population), and using only veterans. Future validations studies should include civilians and active military TJR patients.

Neutral auditory words immediately followed by painful electric shock may show reduced next-day recollection.

In this study, we investigated the effect of experimentally delivered acute pain on memory. Twenty-five participants participated in experimental sessions on consecutive days. The first session involved a categorization task to encourage memory encoding. There were two conditions, presented in randomized order, in which participants listened to a series of words, which were repeated three times. In one condition, one-third of the word items were immediately followed by a painful electrical shock. This word-shock pairing was consistent across repetition and the pain-paired items were presented unpredictably. In the other condition, all word items were not associated with pain. Response times over these repeated presentations were assessed for differences. Explicit memory was tested the following day, employing a Remember-Know assessment of word recognition, with no shocks employed. We found evidence that recollection may be reduced for pain-paired words, as the proportion of correct Remember responses (out of total correct responses) was significantly lower. There were no significant reductions in memory for non-pain items that followed painful stimulation after a period of several seconds. Consistent with the experience of pain consuming working memory resources, we theorize that painful shocks interrupt memory encoding for the immediately preceding experimental items, due to a shift in attention away from the word item.

Comparison of test-retest reliability of BOLD and pCASL fMRI in a two-center study.

BACKGROUND: The establishment of test-retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BOLD) fMRI data acquired across two different scanners in a sample of healthy adults. While single site/single scanner studies have shown acceptable repeatability, TRR of both in a practical multisite study occurring in two facilities spread out across the country with weeks to months between scans is critically needed. METHODS: Ten subjects were imaged with similar 3 T MRI scanners at the University of Pittsburgh and Massachusetts General Hospital. Finger-tapping and Resting-state data were acquired for both techniques. Analysis of the resting state data for functional connectivity was performed with the Functional Connectivity Toolbox, while analysis of the finger tapping data was accomplished with FSL. pCASL Blood flow data was generated using AST Toolbox. Activated areas and networks were identified via pre-defined atlases and dual-regression techniques. Analysis for TRR was conducted by comparing pCASL and BOLD images in terms of Intraclass correlation coefficients, Dice Similarity Coefficients, and repeated measures ANOVA. RESULTS: Both BOLD and pCASL scans showed strong activation and correlation between the two locations for the finger tapping tasks. Functional connectivity analyses identified elements of the default mode network in all resting scans at both locations. Multivariate repeated measures ANOVA showed significant variability between subjects, but no significant variability for location. Global CBF was very similar between the two scanning locations, and repeated measures ANOVA showed no significant differences between the two scanning locations. CONCLUSIONS: The results of this study show that when similar scanner hardware and software is coupled with identical data analysis protocols, consistent and reproducible functional brain images can be acquired across sites. The variability seen in the activation maps is greater for pCASL versus BOLD images, as expected, however groups maps are remarkably similar despite the low number of subjects. This demonstrates that multi-site fMRI studies of task-based and resting state brain activity is feasible.

Realising the potential of functional imaging to reveal brain changes after anaesthesia and surgery.

We highlight the ability of functional brain imaging to detect changes in human brain function, even when changes are not seen in cognitive testing. These imaging changes are plausible as they correlate with known activity changes in carriers of APOE4, a genetic variant associated with increased risk for Alzheimer's disease. However, to realise the potential of functional imaging for perioperative neurocognitive disorders, collaborations similar to the Alzheimer's Disease Neuroimaging Initiative (ADNI) with open data sharing will be required. For the practicing anaesthesiologist, we believe that postoperative cognitive issues are important topics to discuss during the informed consent process.

Day-One Pain Reductions After Hip and Knee Replacement When Buprenorphine-Clonidine-Dexamethasone Is Added to Bupivacaine Nerve/Plexus Blocks: A Randomized Clinical Trial.

OBJECTIVE: To compare pain outcome reports of patients undergoing hip or knee replacement who received single-injection nerve/plexus blocks with plain bupivacaine (BPV) with those of patients who received injections of buprenorphine-clonidine-dexamethasone (BCD) admixed with BPV. DESIGN: Prospective, parallel-arm, randomized, double-blind trial. SETTING: A single veterans' hospital. SUBJECTS: Ninety-eight veterans scheduled for total hip or knee replacement surgery with spinal as the primary anesthetic. METHODS: Participants were randomized to BPV-BCD or plain BPV groups. They underwent nerve/plexus blocks in the L2-L4 and L4-S3 distributions in advance of joint replacement surgery. The primary outcome was change in pain from baseline during the postoperative day, as assessed by the total pain score on the short-form McGill Pain Questionnaire-v2 (SF-MPQ-2). Secondary outcomes were pain during movement, pain interference, range of motion, mobility, and quality of recovery. RESULTS: On postoperative day one, the SF-MPQ-2 total score for the BPV-BCD group demonstrated greater pain reduction than that of the plain BPV group (mean difference 1.8 points, 95% confidence interval 0.6 to 3.0, P = 0.003). The BPV-BCD group also had larger reductions in pain during movement in the surgical joint and less pain interference, along with increased range of hip and knee flexion, compared with the plain BPV group. Outcomes of mobility and quality of recovery were not different between groups. CONCLUSIONS: Preoperative BPV-BCD blocks in the L2-L4 and L4-S3 nerve distributions for hip and knee replacements led to less pain on postoperative day one and increased knee and hip range of motion, compared with plain BPV blocks. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02891798.

Midazolam and Ketamine Produce Distinct Neural Changes in Memory, Pain, and Fear Networks during Pain.

BACKGROUND: Despite the well-known clinical effects of midazolam and ketamine, including sedation and memory impairment, the neural mechanisms of these distinct drugs in humans are incompletely understood. The authors hypothesized that both drugs would decrease recollection memory, task-related brain activity, and long-range connectivity between components of the brain systems for memory encoding, pain processing, and fear learning. METHODS: In this randomized within-subject crossover study of 26 healthy adults, the authors used behavioral measures and functional magnetic resonance imaging to study these two anesthetics, at sedative doses, in an experimental memory paradigm using periodic pain. The primary outcome, recollection memory performance, was quantified with d' (a difference of z scores between successful recognition versus false identifications). Secondary outcomes were familiarity memory performance, serial task response times, task-related brain responses, and underlying brain connectivity from 17 preselected anatomical seed regions. All measures were determined under saline and steady-state concentrations of the drugs. RESULTS: Recollection memory was reduced under midazolam (median [95% CI], d' = 0.73 [0.43 to 1.02]) compared with saline (d' = 1.78 [1.61 to 1.96]) and ketamine (d' = 1.55 [1.12 to 1.97]; P < 0.0001). Task-related brain activity was detected under saline in areas involved in memory, pain, and fear, particularly the hippocampus, insula, and amygdala. Compared with saline, midazolam increased functional connectivity to 20 brain areas and decreased to 8, from seed regions in the precuneus, posterior cingulate, and left insula. Compared with saline, ketamine decreased connectivity to 17 brain areas and increased to 2, from 8 seed regions including the hippocampus, parahippocampus, amygdala, and anterior and primary somatosensory cortex. CONCLUSIONS: Painful stimulation during light sedation with midazolam, but not ketamine, can be accompanied by increased coherence in brain connectivity, even though details are less likely to be recollected as explicit memories.

Accelerated brain aging in chronic low back pain.

Chronic low back pain (CLBP) is a leading cause of disability and is associated with neurodegenerative changes in brain structure. These changes lead to impairments in cognitive function and are consistent with those seen in aging, suggesting an accelerated aging pattern. In this study we assessed this using machine-learning estimated brain age (BA) as a holistic metric of morphometric changes associated with aging. Structural imaging data from 31 non-depressed CLBP patients and 32 healthy controls from the Pain and Interoception Imaging Network were included. Using our previously developed algorithm, we estimated BA per individual based on grey matter density. We then conducted multivariable linear modeling for effects of group, chronological age, and their interaction on BA. We also performed two voxel-wise analyses comparing grey matter density between CLBP and control individuals and the association between gray matter density and BA. There was an interaction between CLBP and greater chronological age on BA such that the discrepancy in BA between healthy and CLBP individuals was greater for older individuals. In CLBP individuals, BA was not associated with sex, current level of pain, duration of CLBP, or mild to moderate depressive symptoms. CLBP individuals had lower cerebellar grey matter density compared to healthy individuals. Brain age was associated with lower gray matter density in numerous brain regions. CLBP was associated with greater BA, which was more profound in later life. BA as a holistic metric was sensitive to differences in gray matter density in numerous regions which eluded direct comparison between groups.

Extended Perineural Analgesia After Hip and Knee Replacement When Buprenorphine-Clonidine-Dexamethasone Is Added to Bupivacaine: Preliminary Report from a Randomized Clinical Trial.

OBJECTIVE: We tested the hypothesis that buprenorphine-clonidine-dexamethasone (BCD) extends perineural analgesia compared with plain bupivacaine (BPV) nerve blocks used for hip and knee replacement surgery. DESIGN: Prospective, parallel-arms, randomized, double-blind trial. SETTING: A single veterans' hospital. SUBJECTS: Seventy-eight veterans scheduled for total hip or knee replacement with plans for spinal as the primary anesthetic. METHODS: Participants underwent nerve/plexus blocks at L2-L4 and L4-S3 in advance of hip or knee joint replacement surgery. Patients were randomized to receive BPV-BCD or plain BPV in a 4:1 allocation ratio. Patients answered four block duration questions (listed below). Time differences between treatments were analyzed using the t test. RESULTS: Significant (P < 0.001) prolongation of the time parameters was reported by patients after the BPV-BCD blocks (N = 62) vs plain BPV (N = 16). The time until start of postoperative pain was 26 vs 11 hours (mean difference = 15 hours, 95% CI = 8 to 21). The time until no pain relief from the blocks was 32 vs 15 hours (mean difference = 17 hours, 95% CI = 10 to 24). The time until the numbness wore off was 37 vs 21 hours (mean difference = 16 hours, 95% CI = 8 to 23). The time until the worst postoperative pain was 39 vs 20 hours (mean difference = 19 hours, 95% CI = 11 to 27). CONCLUSIONS: BPV-BCD provided 26-39 hours of perineural analgesia in the L2-L4 and L4-S3 nerve distributions after hip/knee replacement surgery, compared with 11-21 hours for plain BPV.

Retrospective analysis of cases of intraoperative awareness in a large multi-hospital health system reported in the early postoperative period.

BACKGROUND: Awareness with recall under general anesthesia remains a rare but important issue that warrants further study. METHODS: We present a series of seven cases of awareness that were identified from provider-reported adverse event data from the electronic anesthesia records of 647,000 general anesthetics. RESULTS: The low number of identified cases suggests an under-reporting bias. Themes that emerge from this small series can serve as important reminders to anesthesia providers to ensure delivery of an adequate anesthetic for each patient. Commonalities between a majority of our identified anesthetic awareness cases include: obesity, use of total intravenous anesthesia, use of neuromuscular blockade, and either a lack of processed electroencephalogram (EEG) monitoring or documented high depth of consciousness index values. An interesting phenomenon was observed in one case, where adequately-dosed anesthesia was delivered without technical issue, processed EEG monitoring was employed, and the index value suggested an adequate depth of consciousness throughout the case. CONCLUSIONS: Provider-reported adverse event data in the immediate post-operative period are likely insensitive for detecting cases of intraoperative awareness. Though causation cannot firmly be established from our data, themes identified in this series of cases of awareness with recall under general anesthesia provide important reminders for anesthesia providers to maintain vigilance in monitoring depth and dose of anesthesia, particularly with total intravenous anesthesia.

The Ultrasound Anatomy of Nerves in the Interscalene Groove: Can We Reliably Distinguish the Nerve Structures for Needle Placement During Nerve Blocks?

In the interscalene groove, nerve structures are in close proximity and may not be visible as separate structures, increasing the risk of insertion of the needle tip within the epineurium. We evaluated whether experienced regional anesthesiologists can distinguish between nerve elements lying in close proximity on ultrasound images.Brachial plexus elements from 4 nonpreserved cadavers were arranged in a water bath. Ultrasound images of the nerve roots and trunks were taken. Regional anesthesiologists and residents were asked whether they could distinguish the nerves as 2 separate structures and if they could identify a pair of nerve roots versus a single trunk.Attending anesthesiologists reported the ability to discriminate 2 nerve structures when a 2-mm space was arranged between them in 54% of images; however, when in direct contact, this recognition was significantly lower. The residents reported a higher ability to discriminate the 2 nerves in all scenarios. In addition, the attending anesthesiologists successfully identified paired nerve roots versus nerve trunks in 70% of the images, significantly higher than chance (P = 0.01), whereas the fraction of correct resident responses was not significantly different from guessing.When nerves were placed in close proximity, experienced regional anesthesiologists had difficulty identifying them as separate structures and were incorrect nearly one-third of the time in discriminating 2 closely positioned roots versus a nerve trunk. This underscores the importance of cautious needle insertion into the interscalene groove, where nerve elements are often juxtaposed one to another.

Association of Preoperative Patient Frailty and Operative Stress With Postoperative Mortality.

Importance: Patients with frailty have higher risk for postoperative mortality and complications; however, most research has focused on small groups of high-risk procedures. The associations among frailty, operative stress, and mortality are poorly understood. Objective: To assess the association between frailty and mortality at varying levels of operative stress as measured by the Operative Stress Score, a novel measure created for this study. Design, Setting, and Participants: This retrospective cohort study included veterans in the Veterans Administration Surgical Quality Improvement Program from April 1, 2010, through March 31, 2014, who underwent a noncardiac surgical procedure at Veterans Health Administration Hospitals and had information available on vital status (whether the patient was alive or deceased) at 1 year postoperatively. A Delphi consensus method was used to stratify surgical procedures into 5 categories of physiologic stress. Exposures: Frailty as measured by the Risk Analysis Index and operative stress as measured by the Operative Stress Score. Main Outcomes and Measures: Postoperative mortality at 30, 90, and 180 days. Results: Of 432 828 unique patients (401 453 males [92.8%]; mean (SD) age, 61.0 [12.9] years), 36 579 (8.5%) were frail and 9113 (2.1%) were very frail. The 30-day mortality rate among patients who were frail and underwent the lowest-stress surgical procedures (eg, cystoscopy) was 1.55% (95% CI, 1.20%-1.97%) and among patients with frailty who underwent the moderate-stress surgical procedures (eg, laparoscopic cholecystectomy) was 5.13% (95% CI, 4.79%-5.48%); these rates exceeded the 1% mortality rate often used to define high-risk surgery. Among patients who were very frail, 30-day mortality rates were higher after the lowest-stress surgical procedures (10.34%; 95% CI, 7.73%-13.48%) and after the moderate-stress surgical procedures (18.74%; 95% CI, 17.72%-19.80%). For patients who were frail and very frail, mortality continued to increase at 90 and 180 days, reaching 43.00% (95% CI, 41.69%-44.32%) for very frail patients at 180 days after moderate-stress surgical procedures. Conclusions and Relevance: We developed a novel operative stress score to quantify physiologic stress for surgical procedures. Patients who were frail and very frail had high rates of postoperative mortality across all levels of the Operative Stress Score. These findings suggest that frailty screening should be applied universally because low- and moderate-stress procedures may be high risk among patients who are frail.