Blunted perception of breathlessness in three cases of low grade insular-glioma.

Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5 mmHg above baseline (38.5 ± 5.7 mmHg), whilst ventilation was constrained (10.7 ± 2.3 L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8 ± 2 vs. 11 ± 4 %VAS/mmHg; p = 0.004), but similar threshold (40.5 ± 3.9 vs. 43.2 ± 5.1 mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.

Symptom experiences in hypertension: a mixed methods systematic review.

AIM: Understanding patients' hypertension (HTN) symptoms can assist healthcare professionals' awareness of individual, cultural, and behavioral responses and improve diagnostic accuracy to optimize treatment. The purpose of this review was to evaluate and synthesize current literature exploring HTN symptoms. METHODS: Databases searched included MEDLINE (PubMed), CINAHL (EBSCO), Scopus, and Web of Science from January 2010 to January 2022. The search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The McMaster critical review forms were used to determine the quality of both qualitative and quantitative articles. Synthesis of the data was guided by the Joanna Briggs Institute Convergent Integrated Approach to Mixed Study Systematic Reviews. RESULTS: In total, 41 articles were included, nine qualitative studies and 32 quantitative. The quality of the articles varied. Symptoms included commonly reported symptoms and some less prevalent, including some reporting absence of symptoms. Factors that affected symptoms included culture, beliefs, psychosocial factors, and knowledge. We also found that there may be a bidirectional relationship between symptoms and behaviors that may lead to self-management. CONCLUSION: HTN is common and symptoms are frequently reported. HTN management is related to multiple factors. Symptoms continue in a number of individuals after initial diagnosis. Evaluating symptoms after initial diagnosis may help to optimally manage and meet blood pressure guidelines.

Feasibility and accuracy of the 40-steps desaturation test to determine outcomes in a cohort of patients presenting to hospital with and without COVID-19.

Desaturation on exercise has been suggested as a predictive feature for deterioration in COVID-19. The objective of this paper was to determine the feasibility and validity for the 40-steps desaturation test.A prospective observational cohort study was undertaken in patients assessed in hospital prior to discharge. One-hundred and fifty-two participants were screened between November 2020 and February 2021, and 64 were recruited to perform a 40-steps desaturation test. Patients who were able to perform the test were younger and less frail. Four patients were readmitted to hospital and one patient deteriorated within 30 days but no patient died.The majority of patients showed little change in saturations during the test, even with pre-existing respiratory pathology. Change in saturations, respiratory rate, heart rate and breathlessness were not predictive of death or readmission to hospital within 30 days. Of 13 patients who had a desaturation of 3% or more during exercise, none was readmitted to hospital within 30 days.Not enough patients with COVID-19 could be recruited to the study to provide evidence for the safety of the test in this patient group.The 40-steps desaturation test requires further evaluation to assess clinical utility.

Differential responses to breath-holding, voluntary deep breathing and hypercapnia in left and right dorsal anterior cingulate.

NEW FINDINGS: What is the central question of this study? What is the role of dorsal anterior cingulate cortex (ACC) in respiration control in humans? What is the main finding and its importance? Direct evidence is provided for a role of the ACC in respiratory control in humans. The neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC. ABSTRACT: The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.

Low-level carbon monoxide exposure affects BOLD fMRI response.

Blood oxygen level dependent (BOLD) fMRI is a common technique for measuring brain activation that could be affected by low-level carbon monoxide (CO) exposure from, e.g. smoking. This study aimed to probe the vulnerability of BOLD fMRI to CO and determine whether it may constitute a significant neuroimaging confound. Low-level (6 ppm exhaled) CO effects on BOLD response were assessed in 12 healthy never-smokers on two separate experimental days (CO and air control). fMRI tasks were breath-holds (hypercapnia), visual stimulation and fingertapping. BOLD fMRI response was lower during breath holds, visual stimulation and fingertapping in the CO protocol compared to the air control protocol. Behavioural and physiological measures remained unchanged. We conclude that BOLD fMRI might be vulnerable to changes in baseline CO, and suggest exercising caution when imaging populations exposed to elevated CO levels. Further work is required to fully elucidate the impact on CO on fMRI and its underlying mechanisms.

The pedunculopontine region and breathing in Parkinson's disease.

OBJECTIVE: Respiratory abnormalities such as upper airway obstruction are common in Parkinson's disease (PD) and are an important cause of mortality and morbidity. We tested the effect of pedunculopontine region (PPNr) stimulation on respiratory maneuvers in human participants with PD, and separately recorded PPNr neural activity reflected in the local field potential (LFP) during these maneuvers. METHODS: Nine patients with deep brain stimulation electrodes in PPNr, and seven in globus pallidus interna (GPi) were studied during trials of maximal inspiration followed by forced expiration with stimulation OFF and ON. Local field potentials (LFPs) were recorded in the unstimulated condition. RESULTS: PEFR increased from 6.41 ± 0.63 L/sec in the OFF stimulation state to 7.5 L ± 0.65 L/sec in the ON stimulation state (z = -2.666, df = 8, P = 0.024). Percentage improvement in PEFR was strongly correlated with proximity of the stimulated electrode contact to the mesencephalic locomotor region in the rostral PPN (r = 0.814, n = 9, P = 0.008). Mean PPNr LFP power increased within the alpha band (7-11 Hz) during forced respiratory maneuvers (1.63 ± 0.16 µV2/Hz) compared to resting breathing (0.77 ± 0.16 µV2/Hz; z = -2.197, df = 6, P = 0.028). No changes in alpha activity or spirometric indices were seen with GPi recording or stimulation. Percentage improvement in PEFR was strongly positively correlated with increase in alpha power (r = 0.653, n = 14 (7 PPNr patients recorded bilaterally), P = 0.0096). INTERPRETATION: PPNr stimulation in PD improves indices of upper airway function. Increased alpha-band activity is seen within the PPNr during forced respiratory maneuvers. Our findings suggest a link between the PPNr and respiratory performance in PD.

Inhaled furosemide for relief of air hunger versus sense of breathing effort: a randomized controlled trial.

BACKGROUND: Inhaled furosemide offers a potentially novel treatment for dyspnoea, which may reflect modulation of pulmonary stretch receptor feedback to the brain. Specificity of relief is unclear because different neural pathways may account for different components of clinical dyspnoea. Our objective was to evaluate if inhaled furosemide relieves the air hunger component (uncomfortable urge to breathe) but not the sense of breathing work/effort of dyspnoea. METHODS: A randomised, double blind, placebo-controlled crossover trial in 16 healthy volunteers studied in a university research laboratory. Each participant received 3 mist inhalations (either 40 mg furosemide or 4 ml saline) separated by 30-60 min on 2 test days. Each participant was randomised to mist order 'furosemide-saline-furosemide' (n- = 8) or 'saline-furosemide-saline' (n = 8) on both days. One day involved hypercapnic air hunger tests (mean ± SD PCO2 = 50 ± 3.7 mmHg; constrained ventilation = 9 ± 1.5 L/min), the other involved work/effort tests with targeted ventilation (17 ± 3.1 L/min) and external resistive load (20cmH2O/L/s). Primary outcome was ratings of air hunger or work/effort every 15 s on a visual analogue scale. During saline inhalations, 1.5 mg furosemide was infused intravenously to match the expected systemic absorption from the lungs when furosemide is inhaled. Corresponding infusions of saline during furosemide inhalations maintained procedural blinding. Average visual analogue scale ratings (%full scale) during the last minute of air hunger or work/effort stimuli were analysed using Linear Mixed Methods. RESULTS: Data from all 16 participants were analysed. Inhaled furosemide relative to inhaled saline significantly improved visual analogues scale ratings of air hunger (Least Squares Mean ± SE - 9.7 ± 2%; p = 0.0015) but not work/effort (+ 1.6 ± 2%; p = 0.903). There were no significant adverse events. CONCLUSIONS: Inhaled furosemide was effective at relieving laboratory induced air hunger but not work/effort in healthy adults; this is consistent with the notion that modulation of pulmonary stretch receptor feedback by inhaled furosemide leads to dyspnoea relief that is specific to air hunger, the most unpleasant quality of dyspnoea. FUNDING: Oxford Brookes University Central Research Fund. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02881866 . Retrospectively registered on 29th August 2018.

The time-course of cortico-limbic neural responses to air hunger.

Several studies have mapped brain regions associated with acute dyspnea perception. However, the time-course of brain activity during sustained dyspnea is unknown. Our objective was to determine the time-course of neural activity when dyspnea is sustained. Eight healthy subjects underwent brain blood oxygen level dependent functional magnetic imaging (BOLD-fMRI) during mechanical ventilation with constant mild hypercapnia (∼ 45 mm Hg). Subjects rated dyspnea (air hunger) via visual analog scale (VAS). Tidal volume (V(T)) was alternated every 90 s between high VT (0.96 ± 0.23 L) that provided respiratory comfort (12 ± 6% full scale) and low V(T) (0.48 ± 0.08 L) which evoked air hunger (56 ± 11% full scale). BOLD signal was extracted from a priori brain regions and combined with VAS data to determine air hunger related neural time-course. Air hunger onset was associated with BOLD signal increases that followed two distinct temporal profiles within sub-regions of the anterior insula, anterior cingulate and prefrontal cortices (cortico-limbic circuitry): (1) fast, BOLD signal peak <30s and (2) slow, BOLD signal peak >40s. BOLD signal during air hunger offset followed fast and slow temporal profiles symmetrical, but inverse (signal decreases) to the time-courses of air hunger onset. We conclude that differential cortico-limbic circuit elements have unique contributions to dyspnea sensation over time. We suggest that previously unidentified sub-regions are responsible for either the acute awareness or maintenance of dyspnea. These data enhance interpretation of previous studies and inform hypotheses for future dyspnea research.

Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety.

Based on the neurophysiology of dyspnoea and the distribution of cannabinoid receptors within the central nervous system, we hypothesize that the unpleasantness of breathlessness will be ameliorated in humans by cannabinoids, without respiratory depression. Five normal and four chronic obstructive pulmonary disease (COPD) subjects entered a double blind, randomized, placebo-controlled crossover study with two test days. Subjects received sublingual cannabis extract or placebo. A maximum of 10.8 mg tetrahydrocannabinol and 10 mg cannabidiol were given. Breathlessness was simulated using fixed carbon dioxide loads. Measurements taken were of breathlessness (visual analogue scale [VAS] and breathlessness descriptors), mood and activation, end-tidal carbon dioxide tension and ventilatory parameters. These were measured at baseline and 2 hours post placebo and drug administration. Normal and COPD subjects showed no differences in breathlessness VAS scores and respiratory measurements before and after placebo or drug. After drug administration, COPD subjects picked 'air hunger' breathlessness descriptors less frequently compared to placebo. We have shown that breathlessness descriptors may detect an amelioration of the unpleasantness of breathlessness by cannabinoids without a change in conventional breathlessness ratings (VAS). A stimulus more specific for air hunger may be needed to demonstrate directly a drug effect on breathlessness. However, this study shows that the inclusion of respiratory descriptors may contribute to the assessment of drug effects on breathlessness.

Dyspnea-12 is a valid and reliable measure of breathlessness in patients with interstitial lung disease.

OBJECTIVE: In this study, we aimed to determine the validity and reliability of the Dyspnea-12 questionnaire (D-12) for the assessment of breathlessness in patients with interstitial lung disease (ILD). METHODS: A total of 101 patients with ILD completed the D-12 (scale range, 0-36, with a high score indicating worse dyspnea), Medical Research Council (MRC) dyspnea scale, St. George Respiratory Questionnaire (SGRQ), and Hospital Anxiety and Depression Scale (HADS) at baseline, and 84 patients completed the D-12 and a global health transition score at follow-up 2 weeks later. D-12 psychometric properties, including floor and ceiling effects, internal consistency, test-retest reliability, and construct validity were examined. RESULTS: The D-12 showed good internal consistency (Cronbach α, 0.93) and repeatability (intraclass correlation coefficient, 0.94). Its scores were significantly associated with MRC grade (r = 0.59; P < .001), SGRQ (symptoms, r = 0.57; activities, r = 0.78; impacts, r = 0.75; total, r = 0.79; P < .001). Factor analysis confirmed the previously determined structure of the D-12 in this patient group. CONCLUSION: In patients with ILD, the D-12, a patient-reported measure of dyspnea severity that requires no reference to activity, is a reliable and valid instrument. It is short, simple to complete, and easy to score.

Pharmacological treatment of refractory breathlessness.

Refractory breathlessness is one of the most common and devastating symptoms of advanced cardiorespiratory disease, both malignant and nonmalignant. In spite of increased interest in research in the last 20 years, there have been few significant advances in the palliation of this distressing condition. The most successful palliative regimens for breathlessness always include pharmacological and nonpharmacological interventions used concurrently. When patients are active, nonpharmacological treatments (e.g., exercise) are the most effective. As the patient becomes more breathless, eventually becoming breathless at rest, pharmacological treatments become more important. Opioids have the most extensive evidence base to guide their use. Other pharmacological interventions may act partly by helping breathlessness (by mechanisms still uncertain) or by treating concomitant precipitating and exacerbating conditions, such as depression and anxiety. A specific treatment to palliate breathlessness remains elusive. The neurophysiological substrate of breathlessness perception is still relatively poorly understood and not well reproduced in animal models. Research using functional MRI and other imaging, with more precise clinical trial methods, may help to bring significant advances. In the next 5 years, novel approaches to delivering opioids may be developed, the effective use of inhaled furosemide may be elucidated and the place of antidepressants and anxiolytics will become clearer. A role for cannabinoids may emerge. New drugs may be developed as our understanding of neurophysiology grows.

The etiology and management of intractable breathlessness in patients with advanced cancer: a systematic review of pharmacological therapy.

Intractable breathlessness is a common, devastating symptom of advanced cancer causing distress and isolation for patients and families. In advanced cancer, breathlessness is complex and usually multifactorial and its severity unrelated to measurable pulmonary function or disease status. Therapeutic advances in the clinical management of dyspnea are limited and it remains difficult to treat successfully. There is growing interest in the palliation of breathlessness, and recent work has shown that a systematic, evidence-based approach by a committed multidisciplinary team can improve lives considerably. Where such care is lacking it may be owing to therapeutic nihilism in clinicians untrained in the management of chronic breathlessness and unaware that there are options other than endurance. Optimum management involves pharmacological treatment (principally opioids, occasionally oxygen and anxiolytics) and nonpharmacological interventions (including use of a fan, a tailor-made exercise program, and psychoeducational support for patient and family) with the use of parenteral opioids and sedation at the end of life when appropriate. Effective care centers on the patient's needs and goals. Priorities in breathlessness research include studies on: neuroimaging, the effectiveness of new interventions, the efficacy, safety, and dosing regimens of opioids, the contribution of deconditioning, and the effect of preventing or reversing breathlessness.

Effect of inhaled furosemide on air hunger induced in healthy humans.

Recent evidence suggests that inhaled furosemide relieves dyspnoea in patients and in normal subjects made dyspnoeic by external resistive loads combined with added dead-space. Furosemide sensitizes lung inflation receptors in rats, and lung inflation reduces air hunger in humans. We therefore hypothesised that inhaled furosemide acts on the air hunger component of dyspnoea. Ten subjects inhaled aerosolized furosemide (40 mg) or placebo in randomised, double blind, crossover experiments. Air hunger was induced by hypercapnia (50+/-2 mmHg) during constrained ventilation (8+/-0.9 L/min) before and after treatment, and rated by subjects using a 100 mm visual analogue scale. Subjects described a sensation of air hunger with little or no work/effort of breathing. Hypercapnia generated less air hunger in the first trial at 23+/-3 min after start of furosemide treatment (58+/-11% to 39+/-14% full scale); the effect varied substantially among subjects. The mean treatment effect, accounting for placebo, was 13% of full scale (P=0.052). We conclude that 40 mg of inhaled furosemide partially relieves air hunger within 1h and is accompanied by substantial diuresis.

Measurement of dyspnea: word labeled visual analog scale vs. verbal ordinal scale.

We previously used a verbal ordinal rating scale to measure dyspnea. That scale was easy for subjects to use and the words provided consistency in ratings. We have recently developed a word labeled visual analog scale (LVAS) with labels placed by the subjects, retaining the advantages of a verbal scale while offering a continuous scale that generates parametric data. In a retrospective meta-analysis of data from 43 subjects, individuals differed little in their placement of words on the 100 mm LVAS (mean+/-S.D. for slight=20+/-2.5 mm, moderate=50+/-5 mm and severe=80+/-6 mm) and ratings were distributed uniformly along the scale. A significant stimulus-response correlation was obtained for both the LVAS (r(2)=0.98) and for the verbal ordinal scale (Spearman r=0.94). The resolution of the two scales differed only slightly. With meaningful verbal anchors, well-defined end-points, and clear instructions about the specific sensation to be rated, both scales provide valid measures of dyspnea.

"Tightness" sensation of asthma does not arise from the work of breathing.

Asthma evokes several uncomfortable sensations including increased "effort to breathe" and chest "tightness." We have tested the hypotheses that "effort" and "tightness" are due to perception of increased work performed by the respiratory muscles. Bronchoconstriction was induced by inhaled methacholine in 15 subjects with mild asthma (FEV(1)/FVC baseline = 81.9% +/- 5.8; bronchoconstriction = 64.0% +/- 8.6). To relieve the work of breathing, and thereby minimize activation of respiratory muscle afferents and motor command, subjects were mechanically ventilated. Subjects separately rated effort to breathe and tightness during mechanical ventilation and during spontaneous breathing. Bronchoconstriction produced elevated end-expiratory lung volume (279 +/- 62 ml); in a control study, end-expiratory lung volume was increased equally in the absence of bronchoconstriction by increasing end-expiratory pressure. During bronchoconstriction, ratings of effort were greater during spontaneous breathing than during mechanical ventilation (p < 0.05). Ratings of tightness were unchanged by the absence of respiratory muscle activity (p = 0.12). Hyperinflation alone did not produce tightness or effort. We conclude that tightness is not related to the increase in respiratory work during bronchoconstriction.