Changes In End-tidal CO2 Research Articles

Worse arterial pressure reservoir capacity is associated with exacerbated hemodynamic response to capnogram changes and more labile intraoperative cardiopulmonary-metabolic coupling

Abstract Background The apparent promise of capnography as a cardiac monitor based on the coupled cardiopulmonary response to metabolic changes remains hampered by inconsistent results in studies investigating previous correlations between hemodynamics (e.g.cardiac output) and end-tidal CO2 (EtCO2).(1,2,3) Excess pressure (Pexcess), a dynamic sub-component of pressure waveform representing pressure beyond buffering capacity (reservoir pressure) of elastic large arteries, strongly correlates with aortic flow in humans, suggesting the Pexcess as a promising tool for non-invasive hemodynamic monitoring.(4,5) Purpose We aimed to clarify potential cofounders and pathophysiological mechanisms modifying the EtCO2-arterial hemodynamic coupling, by analysing the intra-operative temporal relations of paired reservoir-excess and capnogram parameters Methods In 190 patients with normal pre-operative pulmonary function tests who underwent non-cardiac surgery, simultaneous capnogram and intra-arterial pressure signals were analysed off-line. Signal windows (>2 minutes) of maximum and minimum mean arterial pressure were autoidentified, the capnogram and pressure signals were averaged into a single representative cycle, to extract reservoir-excess pressure and capnogram parameters (EtCO2, expiratory slope, alpha slope, and plateau slope) accordingly.(6,7) Arterial reservoir capacity (ARC) was defined as Preservoir/Pexcess, which was used to stratify patients into quartiles. Relationships between maximum changes in capnogram and pressure parameters were analysed (Figure 1). Results The ΔEtCO2 and ΔPa mean were correlated significantly in all groups. In patients with the highest ARC (Q4), Pexcess remained unaltered in response to ΔEtCO2 (r:0.095 p:0.545), unlike other subgroups with significant positive correlations. In Q4 (the highest ARC group), the increment in Preservoir was the main cause of ΔPa in relation to ΔEtCO2. In contrast, the ΔEtCO2 - ∆Pexcess relationship was most pronounced in the group with the poorest ARC (r:0.634 p:0.005), underlying the significance of the pressure reservoir behaviour as a determinant of metabolic oscillations in arterial hemodynamics, even though the changes in ΔEtCO2 were equivalent.(Figure 2) Conclusion(s) Worse arterial pressure reserve capacity is associated with an exacerbated hemodynamic response to capnogram changes and a more labile cardiopulmonary-metabolic coupling, characterised by a pronounced increase in excess pressure in response to increased EtCO2 in patients with low ARC. Substantial Pa alterations accompanying EtCO2 changes had opposite drivers in low and high ARC groups (predominant augmentation of Preservoir vs Pexcess). Utilisation of the capnogram for cardiac hemodynamic monitoring is substantially affected by ARC, hence it should be considered while developing capnogram-based monitoring indices.Figure 1.Methodology and example casesFigure 2.Main results

The risk of intraoperative venous air embolism from neurosurgical procedures performed in the lounging position: an in-depth analysis of detection, management, and outcomes of 1000 consecutive cases

OBJECTIVE The overall benefit of employing a sitting/semisitting position for neurosurgical procedures remains under criticism due to concerns for additional risk, especially the risk of intraoperative venous air embolism (VAE). The aim of this single-center cohort study was to evaluate the frequency and severity of VAEs and associated complications in patients undergoing neurosurgery in the lounging position. METHODS From 2010 to 2020, 1000 patients, including 172 patients with a patent foramen ovale, underwent surgery in the lounging position for different neurosurgical pathologies. All patients were monitored intraoperatively using continuous transesophageal echocardiography (TEE). The anesthesia team documented any observed incidences of VAEs and scored their severity according to the Tuebingen classification system (TCS) for VAE (TCS-VAE). The patients’ clinical condition, radiological findings, and hospital course were subsequently analyzed to assess complications in a retrospective analysis of prospectively collected data. RESULTS In the cohort of 1000 patients, 5 underwent cervical spine surgery and 995 underwent suboccipital craniotomy. VAE was detected by TEE in 51.4% (95% CI 48.4%–54.5%) of patients, with synchronous changes in end-tidal CO2 (grade 2–5 TCS-VAE) noted in 10.2% (95% CI 8.3%–12.3%). None of the patients presented with hemodynamic instability (grade 5 TCS-VAE). Patients with high-grade VAEs were significantly older (p = 0.02) and had lower BMIs (p = 0.001) than the respective mean value of the cohort. VAE grade was not associated with any of the outcome measures such as Karnofsky Performance Scale score, duration of ventilation, length of intensive care unit stay, and length of hospital stay. Postoperative acute respiratory distress syndrome (ARDS) was diagnosed in 0.3% (95% CI 0.0%–0.7%, n = 3) of all cases, and ARDS was associated with perioperative VAE grade (p = 0.001). No patient suffered a new permanent neurological deficit due to a paradoxical VAE. CONCLUSIONS In this large cohort, the risk of an intraoperative VAE during neurosurgery in the lounging position was assessed, and contrary to the general perception in the field, no permanent sequelae or fatal adverse events attributable to VAEs were observed. Furthermore, the overall incidence of ARDS was very low. This study clearly establishes that experienced interdisciplinary teams can safely use the lounging position for neurosurgical procedures.

Dynamic cerebral autoregulation during repeated handgrip exercise: comparisons with spontaneous rest and sit-stand maneuvers.

Induced arterial pressure oscillation may improve the assessment of dynamic cerebral autoregulation (dCA) with transfer function analysis (TFA). This study investigated dCA during repeated handgrip exercise (RHE) compared with spontaneous rest and sit-stand maneuvers (SSM), often used in cerebrovascular research. After a 5-min rest, 20 healthy young adults (10 women and 10 men) underwent 5 min of RHE (30% maximal voluntary contraction) and SSM at 0.05 Hz and 0.10 Hz each in random order. Power spectral density (PSD) and TFA gain, phase, coherence of mean arterial pressure (MAP), and blood velocity in the middle cerebral artery (MCAvmean) were measured in very low (VLF: 0.02-0.07 Hz) and low (LF: 0.07-0.20 Hz) frequencies. End-tidal CO2 (EtCO2) was continuously recorded throughout data collection. Compared with rest, RHE increased the PSD of MAP and MCAvmean in VLF (444% and 273%, respectively) and LF (1,571% and 1,765%, respectively) (all P < 0.001). Coherence increased during RHE (VLF: 131%, LF: 128%) and SSM (VLF: 166%, LF: 136%) compared with rest (all P < 0.05). TFA gain and phase were similar between RHE and rest, but VLF gain was higher, whereas VLF and LF phases were lower during SSM than RHE (all P < 0.05). EtCO2 was higher during SSM than rest and RHE (both P < 0.05), with the individual EtCO2 changes positively correlated with VLF gain (r = 0.538, P < 0.001). These results indicate that RHE significantly increases arterial pressure oscillation and TFA coherence and may improve dCA assessment in individuals unable to perform repeated postural changes.NEW & NOTEWORTHY This is the first study investigating dynamic cerebral autoregulation (dCA) during light-intensity repeated handgrip exercise (RHE) compared with rest and sit-stand maneuvers (SSM) using transfer function analysis (TFA). Compared with rest, RHE significantly increased oscillations of arterial blood pressure and cerebral blood velocity and coherence, whereas SSM exhibited the highest oscillations and coherence. These findings suggest that RHE may serve as an alternative method for assessing dCA in individuals unable to perform repeated postural changes.

Cerebral blood flow and end-tidal CO2 predict lightheadedness during head-up tilt in patients with orthostatic intolerance.

Orthostatic intolerance (OI) is a common problem. Reliable markers of OI are missing, as orthostatic blood pressure and heart rate poorly correlate with orthostatic symptoms. The objective of this study was to assess the relationship between orthostatic lightheadedness and cerebral blood flow. In this retrospective study patients with OI were evaluated at the Autonomic Laboratory of the Department of Neurology, Brigham and Women's Faulkner Hospital, Boston. The 10-minute head-up tilt test was performed as a part of autonomic testing. Orthostatic lightheadedness was evaluated at every minute of the head-up tilt. Heart rate, blood pressure, capnography, and cerebral blood flow velocity (CBFv) in the middle cerebral artery using transcranial Doppler were measured. Repeated-measures design with a linear mixed-effects model was used to evaluate the relationship between orthostatic lightheadedness and hemodynamic variables. Correlation analyses were done by calculating Pearson's coefficient. Twenty-two patients with OI were compared to nineteen controls. Orthostatic CBFv and end-tidal CO2 decreased in OI patients compared to controls (p < 0.001) and predicted orthostatic lightheadedness. Orthostatic heart rate and blood pressure failed to predict orthostatic lightheadedness. The lightheadedness threshold, which marked the onset of lightheadedness, was equal to an average systolic CBFv decrease of 18.92% and end-tidal CO2 of 12.82%. The intensity of lightheadedness was proportional to the CBFv and end-tidal CO2 decline. Orthostatic lightheadedness correlated with systolic CBFv (r=-0.6, p < 0.001) and end-tidal CO2 (r=-0.33, p < 0.001) decline. In conclusion, orthostatic CBFv and end-tidal CO2 changes predict orthostatic lightheadedness and can be used as objective markers of OI.

End-tidal carbon dioxide after sodium bicarbonate infusion during mechanical ventilation or ongoing cardiopulmonary resuscitation

PurposeEnd-tidal CO2 is used to monitor the ventilation status or hemodynamic efficacy during mechanical ventilation or cardiopulmonary resuscitation (CPR), and it may be affected by various factors including sodium bicarbonate administration. This study investigated changes in end-tidal CO2 after sodium bicarbonate administration. Materials and methodsThis single-center, prospective observational study included adult patients who received sodium bicarbonate during mechanical ventilation or CPR. End-tidal CO2 elevation was defined as an increase of ≥20% from the baseline end-tidal CO2 value. The time to initial increase (lag time, Tlag), time to peak (Tpeak), and duration of the end-tidal CO2 rise (Tduration) were compared between the patients with spontaneous circulation (SC group) and those with ongoing resuscitation (CPR group). ResultsThirty-three patients, (SC group, n = 25; CPR group, n = 8), were included. Compared with the baseline value, the median values of peak end-tidal CO2 after sodium bicarbonate injection increased by 100% (from 21 to 41 mmHg) in all patients, 89.5% (from 21 to 39 mmHg) in the SC group, and 160.2% (from 15 to 41 mmHg) in the CPR group. The median Tlag was 17 s (IQR: 12–21) and the median Tpeak was 35 s (IQR: 27–52). The median Tduration was 420 s (IQR: 90–639). The median Tlag, Tpeak, and Tduration were not significantly different between the groups. Tduration was associated with the amount of sodium bicarbonate for SC group (correlation coefficient: 0.531, p = 0.006). ConclusionThe administration of sodium bicarbonate may lead to a substantial increase in end-tidal CO2 for several minutes in patients with spontaneous circulation and in patients with ongoing CPR. After intravenous administration of sodium bicarbonate, the use of end-tidal CO2 pressure as a physiological indicator may be limited.

Abstract 17121: Elevated Aortic Stiffness and Impairments in Cerebrovascular Regulation in Cancer Survivorship

Background: Approximately 46% of cancer survivors report cognitive impairments across many types of cancer, which has been associated with anti-cancer therapy and often results in reduced quality of life. Pre-clinical studies suggest that predictors of cognitive decline may involve vascular dysfunction. We aimed to characterize local (cerebrovascular reactivity and cerebral autoregulation) and global (aortic arch stiffness) vascular regulation in cancer survivorship. Methods: Cerebral autoregulation was determined using Mx, a moving 10s-windowed correlation between finger plethysmography-derived blood pressure and cerebral blood velocity of the middle cerebral artery. Higher Mx values represent pressure-passive cerebral blood flow, indicating poor cerebral autoregulation. In addition, cerebral blood velocity, blood pressure, and end-tidal CO 2 were collected during a rebreathing task. MAP was used to calculate an index of cerebrovascular conductance (CVCi). Cerebrovascular reactivity was calculated as the change in cerebral blood velocity or CVCi over the change in end-tidal CO 2 . Aortic arch stiffness, as pulse wave velocity (aaPWV), was calculated from ultrasound scans of the aortic valve and the descending aorta. Differences between groups were assessed with Mann-Whitney tests. Results: Eleven women were recruited (5 controls and 6 cancer survivors who had received treatment). Cancer types included melanoma, lymphoma, and breast cancer. Age and resting MAP were similar between groups. Mx values were higher in cancer survivors (-0.13 ± 0.14 vs. 0.14 ± 0.11, p &lt; 0.05). Cerebrovascular reactivity, both absolute (2.8 ± 1.1 vs. 1.6 ± 0.8, p = 0.05) and as CVCi (16.8 ± 2.4 vs. 2.3 ± 9.4, p &lt; 0.05), were lower in cancer survivors. aaPWV was higher in cancer survivors (2.7 ± 0.8 vs. 3.8 ± 0.6, p &lt; 0.05). Across the entire study sample, aaPWV trended towards an association only with absolute cerebrovascular reactivity (Spearman r = -0.6, p = 0.054). Conclusion: Aortic stiffness was elevated and both cerebrovascular regulatory functions were impaired in cancer survivors compared to healthy controls. Present findings highlight the importance of monitoring cerebral and global vascular function in cancer survivors at high-risk for cognitive decline.

Abstract 14917: The Influence of Coronary Artery Disease on Cerebrovascular Reactivity and Cognitive Function

Introduction: Patients with coronary artery disease (CAD) are at increased risk of cognitive decline. A proposed mechanism is cerebral hypoperfusion related to vascular dysfunction and impaired cerebral blood flow regulation Hypothesis: Patients with CAD will have lower cerebrovascular function than age- and sex-matched controls, assessed as reactivity to a vasodilatory carbon dioxide (CO 2 ) stimulus. Methods: Adults 40-70years old with CAD were recruited on enrollment to a cardiac rehabilitation program following a cardiac event or hospitalization. Age and sex-matched adults without known disease or cardiovascular risk factors were recruited as healthy controls. Cognitive function was assessed by the Fluid Composite of the NIH Cognition Toolbox. Following a familiarization visit, participants underwent a stepped CO 2 protocol (room air, 2% CO 2 , 4% CO 2 , 6% CO 2 ) while continuously measuring middle cerebral artery velocity (MCAv) using transcranial doppler ultrasound, mean arterial pressure (MAP), ventilation (VE), and end-tidal CO 2 . Cerebrovascular conductance (CVCi) was calculated as MCAv/MAP. Cerebrovascular reactivity was calculated as the linear regression slope of CVCi against the change in end-tidal CO 2 . The reactivity of MAP and VE (or chemosensitivity) were also calculated. Results: 19 patients with CAD and 10 healthy controls were recruited ( Table 1 ). Compared with controls, patients with CAD had a 2-fold lower cerebrovascular reactivity (p=0.003), higher MAP reactivity (p&lt;0.05), and a trend towards higher chemosensitivity (p&lt;0.1) ( Table 2 ). There were no group differences in resting CVCi or cognition ( Table 2 ). After adjustment for age and sex, lower cerebrovascular reactivity was associated with lower peak oxygen uptake, diabetes, and smoking history ( Table 3 ). Conclusions: Compared with healthy controls, we report that patients with CAD have significantly lower cerebrovascular function, with no differences in cognitive function.

Cerebrovascular reactivity measurements using 3T BOLD MRI and a fixed inhaled CO2 gas challenge: Repeatability and impact of processing strategy.

Introduction: Cerebrovascular reactivity (CVR) measurements using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) are commonly used to assess the health of cerebral blood vessels, including in patients with cerebrovascular diseases; however, evidence and consensus regarding reliability and optimal processing are lacking. We aimed to assess the repeatability, accuracy and precision of voxel- and region-based CVR measurements at 3 T using a fixed inhaled (FI) CO2 stimulus in a healthy cohort. Methods: We simulated the effect of noise, delay constraints and voxel- versus region-based analysis on CVR parameters. Results were verified in 15 healthy volunteers (28.1±5.5years, female: 53%) with a test-retest MRI experiment consisting of two CVR scans. CVR magnitude and delay in grey matter (GM) and white matter were computed for both analyses assuming a linear relationship between the BOLD signal and time-shifted end-tidal CO2 (EtCO2) profile. Results: Test-retest repeatability was high [mean (95% CI) inter-scan difference: -0.01 (-0.03, -0.00) %/mmHg for GM CVR magnitude; -0.3 (-1.2,0.6) s for GM CVR delay], but we detected a small systematic reduction in CVR magnitude at scan 2 versus scan 1, accompanied by a greater EtCO2 change [±1.0 (0.4,1.5) mmHg] and lower heart rate [-5.5 (-8.6,-2.4] bpm]. CVR magnitude estimates were higher for voxel- versus region-based analysis [difference in GM: ±0.02 (0.01,0.03) %/mmHg]. Findings were supported by simulation results, predicting a positive bias for voxel-based CVR estimates dependent on temporal contrast-to-noise ratio and delay fitting constraints and an underestimation for region-based CVR estimates. Discussion: BOLD CVR measurements using FI stimulus have good within-day repeatability in healthy volunteers. However, measurements may be influenced by physiological effects and the analysis protocol. Voxel-based analyses should be undertaken with care due to potential for systematic bias; region-based analyses are more reliable in such cases.

Menstrual phase influences cerebrovascular responsiveness in females but may not affect sex differences.

Background and aims: Sex differences in the rate and occurrence of cerebrovascular diseases (e.g., stroke) indicate a role for female sex hormones (i.e., oestrogen and progesterone) in cerebrovascular function and regulation. However, it remains unclear how cerebrovascular function differs between the sexes, and between distinct phases of the menstrual cycle. This study aimed to compare cerebrovascular-CO2 responsiveness in 1) females during the early follicular (EF), ovulatory (O) and mid-luteal (ML) phases of their menstrual cycle; and 2) males compared to females during phases of lower oestrogen (EF) and higher oestrogen (O). Methods: Eleven females (25 ± 5years) complete experimental sessions in the EF (n = 11), O (n = 9) and ML (n = 11) phases of the menstrual cycle. Nine males (22 ± 3years) completed two experimental sessions, approximately 2weeks apart for comparison to females. Middle and posterior cerebral artery velocity (MCAv, PCAv) was measured at rest, during two stages of hypercapnia (2% and 5% CO2 inhalation) and hypocapnia (voluntary hyperventilation to an end-tidal CO2 of 30 and 24mmHg). The linear slope of the cerebral blood velocity response to changes in end-tidal CO2 was calculated to measure cerebrovascular-CO2 responsiveness.. Results: In females, MCAv-CO2 responsiveness to hypocapnia was lower during EF (-.78 ± .45cm/s/mmHg) when compared to the O phase (-1.17 ± .52cm/s/mmHg; p < .05) and the ML phase (-1.30 ± .82; p < .05). MCAv-CO2 responsiveness to hypercapnia and hypo-to-hypercapnia, and PCAv-CO2 responsiveness across the CO2 range were similar between menstrual phases (p ≥ .20). MCAv-CO2 responsiveness to hypo-to hypercapnia was greater in females compared to males (3.12 ± .91cm/s/mmHg vs. 2.31 ± .46cm/s/mmHg; p = .03), irrespective of menstrual phase (EF or O). Conclusion: Females during O and ML phases have an enhanced vasoconstrictive capacity of the MCA compared to the EF phase. Additionally, biological sex differences can influence cerebrovascular-CO2 responsiveness, dependent on the insonated vessel.

Change in End-Tidal Co2 After Mini-Fluid Challenge to Determine Fluid Responsiveness.

Single-center prospective study. Patients were enrolled from 2019 to 2021 from the medical ICU within a single academic hospital. Thirty-eight patients with paired measurements of fluid responsiveness as determined by bioreactance who were admitted to the ICU with a diagnosis of distributive shock and on mechanical ventilation. Stroke volume index (SVI), cardiac index, heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and ETco2 were measured before and after completion of a mini-fluid challenge. Test characteristics of change in ETco2 (ΔETco2) greater than or equal to 2 after mini-fluid challenge to determine fluid responsiveness were calculated with percentage change in SVI greater than or equal to 10% used as the reference standard. The sensitivity and specificity of a ΔETco2 greater than or equal to 2 mm Hg as a predictor of a change in SVI greater than or equal to 10% following a mini-fluid challenge were 20.0% and 91.3%, respectively. The area under the receiver operating characteristic curve was 0.62. A ΔETco2 greater than or equal to 2 mm Hg after mini-fluid challenge has limited test performance for determining fluid responsiveness in intubated patients with distributive shock.

Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits.

Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury. The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2. Elevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19). Findings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.

Comparison of nasal intermittent positive pressure ventilation and bubble CPAP with an in-line high-frequency interrupter in a premature infant lung model.

Noninvasive ventilation has become a staple in the care of premature infants. However, failure rates continue to be high in this population. Modifications to noninvasive support, such as nasal intermittent positive pressure ventilation (NIPPV), are used clinically to reduce such failure. Previous in vitro studies have shown improved CO2 clearance when superimposing high-frequency oscillations onto bubblecontinuous positive airway pressure(BCPAP). To compare the CO2 clearance of NIPPV to BCPAP with an in-line high-frequency interrupter (HFI) in a premature infant lung model. A premature infant lung model was connected to either a Dräger VN500 for delivery of NIPPV or a BCPAP device with superimposed high-frequency oscillations generated by an in-line HFI. Change in end-tidal CO2 (ETCO2 ) and mean airway pressure at the simulated trachea were measured and compared for both noninvasive modalities. Superimposing HF oscillations onto BCPAP with an in-line HFI resulted in improved CO2 clearance relative to BCPAP alone for all tested oscillation frequencies at all CPAP levels (p < 0.001). NIPPV also resulted in improved CO2 clearance relative to nasal CPAP (NCPAP) alone (p < 0.001). Among the tested settings, BCPAP with an in-line HFI resulted in decreased ETCO2 relative to BCPAP ranging from -14% to -36%, while NIPPV resulted in decreased ETCO2 relative to NCPAP ranging from -2% to -12%. Superimposing high-frequency oscillations onto BCPAP using a novel in-line HFI was found to be more effective at clearing CO2 than NIPPV in a premature infant lung model.

The Influence of Sleep Duration on Cerebrovascular Reactivity

The impaired ability of the cerebrovasculature to dilate in response to a vasoactive stimulus (i.e., cerebrovascular reactivity, CVR) is associated with an increased risk of cognitive impairment. The association between sleep duration and dementia risk is “U‐shaped”, where adults who achieve seven hours of sleep have the lowest risk of cognitive impairment, compared to adults who achieve greater than or less than seven hours of sleep. In otherwise healthy adults, poor sleep quality and duration impairs peripheral vascular function, but its effect on CVR in generally healthy adults has remained largely been unexplored. The purpose of this study was to assess the relation between subjective sleep quality and CVR in healthy adults. Because the relation between sleep duration and cognitive impairment is an inverted U‐shape, we hypothesized that CVR would be lower in adults who slept longer than or shorter than the recommended 7‐8 hours of sleep. Data from thirty‐five individuals across the adult lifespan (21 males / 14 females, age: 44 ± 17 years; BMI: 26.8 ± 4.8 kg/m2; blood pressure, BP: 114 ± 12 / 71 ± 10 mmHg; heart rate, HR: 62 ± 8 bpm) were included in this analysis. CVR was assessed by measuring the change in middle cerebral artery blood flow velocity (MCAv) at baseline and following a 3‐minute hypercapnic stimulus (+9 mmHg increase in the end‐tidal partial pressure of CO2) using transcranial Doppler ultrasound. MCAv was normalized to beat‐to‐beat BP (MCACVC), and CVR was calculated as the percentage change in MCACVC and normalized to the absolute change in end‐tidal CO2.Sleep duration was negatively predictive of lower CVR (R2=0.17, β1± SE = ‐0.45 ± 0.18 %/mmHg/hour, P=0.014). A correlation matrix was performed to determine if any variables other than sleep duration (e.g., age, sex, etc) might also impact CVR. Age (P=0.53), BMI (P=0.93), systolic BP (P=0.22), diastolic BP (P=0.84), HR (P=0.071), and mean arterial pressure (P=0.57) were not associated with CVR. Only sex was significantly associated with CVR (R= ‐0.36, P=0.036), where men had augmented CVR compared to women (2.20 ± 0.73 %/mmHg vs. 1.59 ± 0.93 %/mmHg, P=0.036). Importantly, sex (β1± SE= ‐0.18 ± 0.27 %/mmHg, P=0.51) did not influence the relation between CVR (β1± SE= ‐0.41 ± 0.16 %/mmHg/hour, P=0.013) and sleep duration (model adjusted for sex: R2= 0.17, P=0.042). In conclusion, longer sleep duration was independently associated with lower CVR in healthy adults. Future studies should include more individuals with shorter sleep duration to test the possibility of an inverted U‐shaped association with CVR.

Normal BOLD Response to a Step CO2 Stimulus After Correction for Partial Volume Averaging.

Cerebrovascular reactivity (CVR) is defined as the change in cerebral blood flow induced by a change in a vasoactive stimulus. CVR using BOLD MRI in combination with changes in end-tidal CO2 is a very useful method for assessing vascular performance. In recent years, this technique has benefited from an advanced gas delivery method where end-tidal CO2 can be targeted, measured very precisely, and validated against arterial blood gas sampling (Ito et al., 2008). This has enabled more precise comparison of an individual patient against a normative atlas of healthy subjects. However, expected control ranges for CVR metrics have not been reported in the literature. In this work, we calculate and report the range of control values for the magnitude (mCVR), the steady state amplitude (ssCVR), and the speed (TAU) of the BOLD response to a standard step stimulus, as well as the time delay (TD) as observed in a cohort of 45 healthy controls. These CVR metrics maps were corrected for partial volume averaging for brain tissue types using a linear regression method to enable more accurate quantitation of CVR metrics. In brief, this method uses adjacent voxel CVR metrics in combination with their tissue composition to write the corresponding set of linear equations for estimating CVR metrics of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). After partial volume correction, mCVR and ssCVR increase as expected in gray matter, respectively, by 25 and 19%, and decrease as expected in white matter by 33 and 13%. In contrast, TAU and TD decrease in gray matter by 33 and 13%. TAU increase in white matter by 24%, but TD surprisingly decreased by 9%. This correction enables more accurate voxel-wise tissue composition providing greater precision when reporting gray and white matter CVR values.

Association between platelet inhibition in the blood and cerebrovascular function in healthy young and older adults

Platelet activation may contribute to age-related cerebrovascular dysfunction by interacting with the endothelial cells that regulate the response to vasodilatory stimuli. The purpose of this study was to evaluate the relationship between a platelet inhibitor, prostacyclin, and cerebrovascular function in healthy young and older adults before and after cyclooxygenase inhibition. We hypothesized that higher levels of prostacyclin would be positively associated with cerebrovascular function. Healthy young (n=36; 25 ± 4 yrs; 19 women, 17 men) and older (n=12; 62 ± 2 yrs; 8 women, 4 men) adults who were not taking daily aspirin participated in the study. Prostacyclin was determined by levels of 6-keto-PGF1α in the blood. On a separate study visit, cerebrovascular function was assessed by cerebrovascular reactivity (CVR) to hypercapnia in the middle cerebral artery before (CON) and 90 minutes after cyclooxygenase inhibition with indomethacin (INDO) at 1.2 mg/kg. Participants were instrumented with a transcranial Doppler ultrasound which continuously recorded middle cerebral artery velocity, a nasal cannula to measure end-tidal CO2, a finger blood pressure cuff to measure beat-by-beat blood pressure, and a mask with a one-way valve to prevent rebreathing. CVR was calculated as the slope of the relationship between middle cerebral artery velocity and the change in end-tidal CO2 during stepwise elevations in CO2. The associations between prostacyclin and CVR were analyzed using Pearson's Product-Moment correlations. In young adults, there were no associations between prostacyclin and CVR during CON (r = 0.11, p = 0.54) or INDO (r = 0.15, p = 0.39). In older adults, there was a trend for an association between prostacyclin and CVR during CON (r = 0.52, p = 0.08), but no association during INDO (r = -0.41, p = 0.18). We also evaluated the relationship between prostacyclin and the change in CVR between conditions. We found no association in young adults (r = 0.15, p = 0.37); however, in older adults, those with higher baseline prostacyclin levels demonstrated a greater change in CVR (r = 0.69, p = 0.01). In conclusion, there was a trend for a positive association between platelet inhibition and cerebrovascular function in older adults. Furthermore, older adults may rely more on cyclooxygenase products to mediate CVR. Future studies could evaluate how platelet activation may contribute to age-related changes in cerebrovascular function.

Comparisons of the Nonlinear Relationship of Cerebral Blood Flow Response and Cerebral Vasomotor Reactivity to Carbon Dioxide under Hyperventilation between Postural Orthostatic Tachycardia Syndrome Patients and Healthy Subjects.

Postural orthostatic tachycardia syndrome (POTS) typically occurs in youths, and early accurate POTS diagnosis is challenging. A recent hypothesis suggests that upright cognitive impairment in POTS occurs because reduced cerebral blood flow velocity (CBFV) and cerebrovascular response to carbon dioxide (CO2) are nonlinear during transient changes in end-tidal CO2 (PETCO2). This novel study aimed to reveal the interaction between cerebral autoregulation and ventilatory control in POTS patients by using tilt table and hyperventilation to alter the CO2 tension between 10 and 30 mmHg. The cerebral blood flow velocity (CBFV), partial pressure of end-tidal carbon dioxide (PETCO2), and other cardiopulmonary signals were recorded for POTS patients and two healthy groups including those aged >45 years (Healthy-Elder) and aged <45 years (Healthy-Youth) throughout the experiment. Two nonlinear regression functions, Models I and II, were applied to evaluate their CBFV-PETCO2 relationship and cerebral vasomotor reactivity (CVMR). Among the estimated parameters, the curve-fitting Model I for CBFV and CVMR responses to CO2 for POTS patients demonstrated an observable dissimilarity in CBFVmax (p = 0.011), mid-PETCO2 (p = 0.013), and PETCO2 range (p = 0.023) compared with those of Healthy-Youth and in CBFVmax (p = 0.015) and CVMRmax compared with those of Healthy-Elder. With curve-fitting Model II for POTS patients, the fit parameters of curvilinear (p = 0.036) and PETCO2 level (p = 0.033) displayed significant difference in comparison with Healthy-Youth parameters; range of change (p = 0.042), PETCO2 level, and CBFVmax also displayed a significant difference in comparison with Healthy-Elder parameters. The results of this study contribute toward developing an early accurate diagnosis of impaired CBFV responses to CO2 for POTS patients.

Assessment of High Flow Nasal Cannula Oxygenation in Endobronchial Ultrasound Bronchoscopy

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely implemented in evaluating mediastinal disease. EBUS-TBNA is performed with low flow oxygen systems or general anesthesia. Little data exist on use of high flow nasal cannula (HFNC) in EBUS-TBNA. This was a single center parallel group randomized controlled trial comparing oxygenation through HFNC (Optiflow) against nasal prongs during EBUS. The primary end-point was the drop in oxygen saturations from procedure commencement, recorded by pulse oximetry, to the lowest level during EBUS-TBNA. Secondary end-points included changes in venous blood carbon dioxide, lowest oxygen saturation, changes in end-tidal CO2 during the procedure, intubation within 8 hours of the procedure and patient experience reported on a visual analog scale. We randomized 20 patients to each study arm. The primary outcome of oxygen desaturation during the procedure was statistically significant with a difference of 7.7 percentage points (95% confidence interval, 4.91-10.49, P<0.001). The secondary outcome measure of lowest oxygen saturation was also statistically significant with a difference of -9.2 (95% confidence interval, -11.96 to -6.44, P<0.001). There was no difference in safety outcomes, visual analog scale score or in their willingness to return for repeat procedure. This single institution study in a university, tertiary referral center confirms that EBUS-TBNA performed with HFNC is associated with a statistically significant lower drop in oxygen saturation. Additional studies are needed to assess if this translates into improved clinical outcomes postprocedure.

Diagnostic utility of sub-maximum cardiopulmonary exercise testing in the ambulatory setting for heart failure with preserved ejection fraction.

Pulmonary hypertension is commonly associated with heart failure with preserved ejection fraction. In heart failure with preserved ejection fraction, the elevated left-sided filling pressures result in isolated post-capillary pulmonary hypertension or combined pre- and post-capillary pulmonary hypertension. Although right heart catheterization is the gold standard for diagnosis, it is an invasive test with associated risks. The ability of sub-maximum cardiopulmonary exercise test as an adjunct diagnostic tool in pulmonary hypertension-associated heart failure with preserved ejection fraction is not known. Forty-six patients with heart failure with preserved ejection fraction and pulmonary hypertension (27 patients with combined pre- and post-capillary pulmonary hypertension and 19 patients with isolated post-capillary pulmonary hypertension) underwent sub-maximum cardiopulmonary exercise test followed by right heart catheterization. The study also included 18 age- and gender-matched control subjects. Several sub-maximum gas exchange parameters were examined to determine the ability of sub-maximum cardiopulmonary exercise test to distinguish between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Conventional echocardiogram measures did not distinguish between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Compared to isolated post-capillary pulmonary hypertension, combined pre- and post-capillary pulmonary hypertension had greater ventilatory equivalent for carbon dioxide (VE/VCO2) slope, reduced delta end-tidal CO2 change during exercise, reduced oxygen uptake efficiency slope, and reduced gas exchange determined pulmonary vascular capacitance. The latter was significantly associated with right heart catheterization determined pulmonary artery compliance (r = 0.5; p = 0.0004). On univariate analysis, sub-maximum VE/VCO2, delta end-tidal carbon dioxide, and gas exchange determined pulmonary vascular capacitance emerged as independent predictors of the extrapolated maximum oxygen uptake (%predicted) (β-coefficient values of –7.32, 95% CI: –13.3 – (–1.32), p = 0.01; 8.01, 95% CI: 1.96–14.05, p = 0.01; 8.78, 95% CI: 2.26–15.29, p = 0.01, respectively). Sub-maximum gas exchange parameters obtained during cardiopulmonary exercise test in an ambulatory setting allows for discrimination between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Additionally, sub-maximum cardiopulmonary exercise test derived VE/VCO2, delta end-tidal carbon dioxide, and gas exchange determined pulmonary vascular capacitance influences aerobic capacity in heart failure with preserved ejection fraction.

Assessment of Dynamic Intracranial Compliance in Children with Severe Traumatic Brain Injury: Proof-of-Concept.

Background and AimsIntracranial compliance refers to the relationship between a change in intracranial volume and the resultant change in intracranial pressure (ICP). Measurement of compliance is useful in managing cardiovascular and respiratory failure; however, there are no contemporary means to assess intracranial compliance. Knowledge of intracranial compliance could complement ICP and cerebral perfusion pressure (CPP) monitoring in patients with severe traumatic brain injury (TBI) and may enable a proactive approach to ICP management. In this proof-of-concept study, we aimed to capitalize on the physiologic principles of intracranial compliance and vascular reactivity to CO2, and standard-of-care neurocritical care monitoring, to develop a method to assess dynamic intracranial compliance.MethodsContinuous ICP and end-tidal CO2 (ETCO2) data from children with severe TBI were collected after obtaining informed consent in this Institutional Review Board-approved study. An intracranial pressure-PCO2 Compliance Index (PCI) was derived by calculating the moment-to-moment correlation between change in ICP and change in ETCO2. As such, “good” compliance may be reflected by a lack of correlation between time-synched changes in ICP in response to changes in ETCO2, and “poor” compliance may be reflected by a positive correlation between changes in ICP in response to changes in ETCO2.ResultsA total of 978 h of ICP and ETCO2 data were collected and analyzed from eight patients with severe TBI. Demographic and clinical characteristics included patient age 7.1 ± 5.8 years (mean ± SD); 6/8 male; initial Glasgow Coma Scale score 3 [3–7] (median [IQR]); 6/8 had decompressive surgery; 7.1 ± 1.4 ICP monitor days; ICU length of stay (LOS) 16.1 ± 6.8 days; hospital LOS 25.9 ± 8.4 days; and survival 100%. The mean PCI for all patients throughout the monitoring period was 0.18 ± 0.04, where mean ICP was 13.7 ± 2.1 mmHg. In this cohort, PCI was observed to be consistently above 0.18 by 12 h after monitor placement. Percent time spent with PCI thresholds > 0.1, 0.2, and 0.3 were 62% [24], 38% [14], and 23% [15], respectively. The percentage of time spent with an ICP threshold > 20 mmHg was 5.1% [14.6].ConclusionsIndirect assessment of dynamic intracranial compliance in TBI patients using standard-of-care monitoring appears feasible and suggests a prolonged period of derangement out to 5 days post-injury. Further study is ongoing to determine if the PCI—a new physiologic index, complements utility of ICP and/or CPP in guiding management of patients with severe TBI.Electronic supplementary materialThe online version of this article (10.1007/s12028-020-01004-3) contains supplementary material, which is available to authorized users.

Acute exercise-related cognitive effects are not attributable to changes in end-tidal CO2 or cerebral blood velocity

Cognition, cerebral blood flow (CBF) and its major regulator (i.e., arterial CO2), increase with submaximal exercise and decline with severe exercise. These responses may depend on fitness. We investigated whether exercise-related changes in cognition are mediated in part by concomitant changes in CBF and CO2, in ten active (26 ± 3years) and ten inactive (24 ± 6years) healthy adults. Participants completed two randomised sessions; exercise and a resting CO2-control-wherein end-tidal CO2 (PETCO2) was matched between sessions and clamped across conditions at exercise-associated increases (+ 3mmHg) and hypercapnia (+ 10mmHg). Exercise comprised inclined walking at submaximal and severe intensities. CBF was indexed using right middle cerebral artery blood velocity (MCAv). Cognition (visuomotor, switching and inhibitory response time) was measured before, during, and after exercise. MCAv and its inverted-U response to exercise were comparable between groups, whereas visuomotor performance improved during submaximal exercise in the active group only (p = 0.046). Submaximal, but not severe (p = 0.33), exercise increased MCAv (p ≤ 0.03). Hypercapnia increased MCAv during the CO2-control (27 ± 12%) and during submaximal exercise (39 ± 17%; p < 0.01). Despite the acute increases in MCAv, cognition was impaired during both levels of increased PETCO2 (3-6%; p ≤ 0.04), regardless of session. Overall, resting or exercise-related changes in PETCO2 and MCAv did not associate with changes in cognition (r ≤ 0.29 ± 0.34). Fitness ([Formula: see text]O2MAX) was associated with baseline cognition (r ≥ 0.50). Acute increases in PETCO2 and MCAv were not associated with improved cognition. In fact, cognitive performance was impaired at both levels of increased PETCO2, regardless of session. Finally, fitter people were found to have better cognition.