Lewis Adams

An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea

BACKGROUND Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases. Since the ATS published a consensus statement on dyspnea in 1999, there has been enormous growth in knowledge about the neurophysiology of dyspnea and increasing interest in dyspnea as a patient-reported outcome. PURPOSE The purpose of this document is to update the 1999 ATS Consensus Statement on dyspnea. METHODS An interdisciplinary committee of experts representing ATS assemblies on Nursing, Clinical Problems, Sleep and Respiratory Neurobiology, Pulmonary Rehabilitation, and Behavioral Science determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant expertise. The final content of this statement was agreed upon by all members. RESULTS Progress has been made in clarifying mechanisms underlying several qualitatively and mechanistically distinct breathing sensations. Brain imaging studies have consistently shown dyspnea stimuli to be correlated with activation of cortico-limbic areas involved with interoception and nociception. Endogenous and exogenous opioids may modulate perception of dyspnea. Instruments for measuring dyspnea are often poorly characterized; a framework is proposed for more consistent identification of measurement domains. CONCLUSIONS Progress in treatment of dyspnea has not matched progress in elucidating underlying mechanisms. There is a critical need for interdisciplinary translational research to connect dyspnea mechanisms with clinical treatment and to validate dyspnea measures as patient-reported outcomes for clinical trials.

Breathlessness in humans activates insular cortex.

Dyspnea (shortness of breath, breathlessness) is a major and disabling symptom of heart and lung disease. The representation of dyspnea in the cerebral cortex is unknown. In the first study designed to explore the central neural structures underlying perception of dyspnea, we evoked the perception of severe ‘air hunger’ in healthy subjects by restraining ventilation below spontaneous levels while holding arterial oxygen and carbon dioxide levels constant. PET revealed that air hunger activated the insular cortex. The insula is a limbic structure also activated by visceral stimuli, temperature, taste, nausea and pain. Like dyspnea, such perceptions underlie behaviors essential to homeostasis and survival.

Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans

1 Positron emission tomography (PET) was used to identify the neuroanatomical correlates underlying ‘central command’ during imagination of exercise under hypnosis, in order to uncouple central command from peripheral feedback. 2 Three cognitive conditions were used: condition I, imagination of freewheeling downhill on a bicycle (no change in heart rate, HR, or ventilation, V̇I): condition II, imagination of exercise, cycling uphill (increased HR by 12 % and V̇I by 30 % of the actual exercise response): condition III, volitionally driven hyperventilation to match that achieved in condition II (no change in HR). 3 Subtraction methodology created contrast A (II minus I) highlighting cerebral areas involved in the imagination of exercise and contrast B (III minus I) highlighting areas activated in the direct volitional control of breathing (n= 4 for both; 8 scans per subject). End‐tidal PCO2 (PET,CO2) was held constant throughout PET scanning. 4 In contrast A, significant activations were seen in the right dorso‐lateral prefrontal cortex, supplementary motor areas (SMA), the right premotor area (PMA), superolateral sensorimotor areas, thalamus, and bilaterally in the cerebellum. In contrast B, significant activations were present in the SMA and in lateral sensorimotor cortical areas. The SMA/PMA, dorso‐lateral prefrontal cortex and the cerebellum are concerned with volitional/motor control, including that of the respiratory muscles. 5 The neuroanatomical areas activated suggest that a significant component of the respiratory response to ‘exercise’, in the absence of both movement feedback and an increase in CO2 production, can be generated by what appears to be a behavioural response.

Evidence for limbic system activation during CO2-stimulated breathing in man.

1. The role of supra‐brainstem structures in the ventilatory response to inhaled CO2 is unknown. The present study uses positron emission tomography (PET), with infusion of H2(15)O, to measure changes in relative regional cerebral blood flow (rCBF) in order to identify sites of increased neuronal activation during CO2‐stimulated breathing (CO2‐SB) in awake man. 2. Five male volunteers were scanned during CO2‐SB (mean +/‐ S.E.M.; end‐tidal PCO2, 50.3 +/‐ 1.7 mmHg; respiratory frequency, 16.4 +/‐ 2.7 min‐1; tidal volume, 1.8 +/‐ 0.2 l). As control, scans were performed during ‘passive’ isocapnic (elevated fraction of inspired CO2) positive pressure ventilation (end‐tidal PCO2, 38.4 +/‐ 1.0 mmHg; respiratory frequency, 15.5 +/‐ 2.2 min‐1; tidal volume, 1.6 +/‐ 0.2 l). With CO2‐SB, all subjects reported dyspnoea. 3. The anatomical locations of the increases in relative rCBF (CO2‐SB versus control) were obtained using magnetic resonance imaging. 4. Group analysis identified neuronal activation within the upper brainstem, midbrain and hypothalamus, thalamus, hippocampus and parahippocampus, fusiform gyrus, cingulate area, insula, frontal cortex, temporo‐occipital cortex and parietal cortex. No neuronal activation was seen within the primary motor cortex (at sites previously shown to be associated with volitional breathing). 5. These results suggest neuronal activation within the limbic system; this activation may be important in the sensory and/or motor respiratory responses to hypercapnia in awake man.

Does hypercapnia-induced cerebral vasodilation modulate the hemodynamic response to neural activation?

Increases in cerebral blood flow produced by vasoactive agents will increase blood oxygen level-dependent (BOLD) MRI signal intensity. The effects of such vasodilation on activation-related signal changes are incompletely characterized. The two signal changes may be simply additive or there may be more a complex interaction. To investigate this, BOLD MRI was performed in four normal male subjects using T2*-weighted echo planar imaging; brain volumes were acquired every 6.2 s, using a Siemens VISION scanner operating at 2 Tesla; each volume consisted of 64 sequential transverse slices (64 x 64 pixels per slice, 3 x 3 x 3 mm). Sixteen periods of visual stimulation were produced using a flickering checkerboard (8 Hz, 31 s On/31 s Off); this was coupled with five periods of hypercapnia (4% inspired CO(2), 62 s On/124 s Off). Data were analyzed using SPM96. Mean signal intensity, calculated globally for the whole brain, closely mirrored changes in the partial pressure of end-tidal CO(2) (PCO(2)), and hypercapnia was associated with widespread significant signal increases (P < 0.001), predominantly within grey matter. As expected, the visual stimulation produced significant signal changes within the occipital cortex (P < 0.001). Within the occipital cortex, no significant interactions (P > 0.001) between the effects of the visual stimulation and PCO(2) were present. The increases in PCO(2) imposed dynamically in the present study would increase cerebral blood flow by between 25 and 40%, an increase within the physiological range and comparable to that induced by neural activation. With this flow change the effects of vasodilation, on an activation-related signal change, are simply additive.

Imagination of dynamic exercise produced ventilatory responses which were more apparent in competitive sportsmen.

1. The cardiorespiratory response to imagination of previously performed treadmill exercise was measured in six competitive sportsmen and six non‐athletic males. This was compared with the response to a control task (imaging letters) and a task not involving imagination (‘treadmill sound only’). 2. In athletes, imagined exercise produced increases in ventilation which varied within and between subjects. The mean maximal increase (11.71 min‐1) was approximately 20% of the ventilatory response to actual exercise. This was primarily due to treadmill speed‐related increases in respiratory frequency (mean maximal increase, 14.8 breaths min‐1) and resulted in significant reductions in end‐tidal PCO2 (mean maximal fall, 7 mmHg). These effects were greater (P < 0.01) than any observed during the control tasks. 3. Changes in heart rate (mean increase, 12 beats min‐1) were not significantly different from those observed during the control tasks (P > 0.2). 4. In non‐athletes, imagination of exercise produced no changes in cardiorespiratory variables. No significant differences were detected in subjective assessments of movement imagery ability between athletes and non‐athletes (P = 0.17). 5. This study demonstrates that ventilatory effects, when observed, are specific to imagination of exercise. The greater likelihood of generating ventilatory responses in highly trained athletes, experienced in ‘rhythmic’ sports, may be related to awareness of breathing and its role in exercise imagination strategy. A volitional component of the response cannot be discounted.

Reference values and prediction equations for normal lung function in a non-smoking white urban population.

Prediction equations for normal lung function have been derived from tests on 179 healthy, non-smoking, white urban dwellers. The subjects, 96 women (height 1.46-1.77 m) and 83 men (height 1.61-1.96 m) aged 18-86 years, underwent measurements of spirometric flow and volume, multi-breath helium dilution lung volumes, and single breath carbon monoxide transfer factor and the single breath nitrogen washout test. Regression analysis using height, age, and weight as independent variables was used to provide predicted values for both sexes. Correlation coefficients were similar to those found in previous studies but normal ranges for spirometic measurements were narrower than in many previous studies, and spirometric flow and volume measurements were higher than those obtained in studies that included cigarette smokers, reflecting our more stringent criteria for selecting subjects and the newer standardised technical methods adopted. Multi-breath helium dilution values for total lung capacity were similar to those found in previous studies but the inspiratory vital capacity was larger and the residual volume reduced. Values for carbon monoxide transfer factor and the single breath nitrogen washout did not differ significantly from existing values. A complete set of lung function reference values and prediction equations for both sexes has been derived from a single population. The exclusion of cigarette smokers and subjects with respiratory symptoms has produced values that should have a greater sensitivity in the detection of mild lung disease.

Putative cerebral cortical involvement in the ventilatory response to inhaled CO2 in conscious man.

1. The response of the diaphragm to both transcranial magnetic stimulation and electrical phrenic nerve stimulation was studied in thirteen normal subjects under conditions of either a ‘reflex’ drive to ventilation with inhaled CO2 or during volitional ventilation of similar magnitude. 2. The induced compound action potential in the diaphragm was recorded using an oesophageal electrode, and in some cases transdiaphragmatic pressure was recorded using oesophageal and gastric balloon catheters. 3. The response of the diaphragm to transcranial magnetic stimulation was invariably facilitated with volitional inspiration; there was either minimal or no response at functional residual capacity. 4. Facilitation with inspiration was also seen during a ‘reflex’ drive to ventilation with inhaled CO2 in the presumed absence of any volitional contribution to ventilation. A similar degree of facilitation was seen with voluntary ventilation of similar magnitude and pattern. 5. If the facilitation is predominantly a cortical phenomenon, then these results imply that there is a behavioural component in the previously supposed purely ‘reflex’ drive to ventilation with inhaled CO2. We also discuss the interpretation of these results if some of the facilitation occurs at the phrenic motoneurone.

The 6-minute walk test in outpatient cardiac rehabilitation: validity, reliability and responsiveness—a systematic review

BACKGROUND The 6-minute walk test (6MWT) is a common outcome measurement in cardiac rehabilitation. However, a search of the literature found no established guidelines for use of the 6MWT in cardiac rehabilitation. OBJECTIVES Systematic review of the validity, reliability and responsiveness of the 6MWT in cardiac rehabilitation. DATA SOURCES OvidMEDLINE, SPORTdiscus, EMBASE, CINAHL, Cochrane Reviews and Cochrane Clinical Trials between January 1948 and April 2011. ELIGIBILITY CRITERIA Studies using 6MWTs in subjects with coronary artery disease undergoing cardiac rehabilitation on an outpatient basis, published in English, were included. STUDY APPRAISAL AND METHODS: Quantitative and qualitative analyses were conducted, including quality assessment of methodology, meta-analysis and assessment against level of evidence criteria. RESULTS Fifteen articles met the inclusion criteria. One high-quality study was identified for reliability, six high-quality studies were identified for validity and 11 high-quality studies were identified for responsiveness. The meta-analysis found strong evidence that the 6MWT was responsive to change in clinical status following cardiac rehabilitation, with an estimated mean difference in 6-minute walk distance of 60.43m (95% confidence interval 54.57 to 66.30m; P<0.001). Qualitative analysis indicated moderate evidence for repeatability of the 6MWT in patients undergoing cardiac rehabilitation, for a 2% to 8% learning effect between repeated 6MWTs, for a relationship between peak heart rate during the 6MWT and during cycle exercise at the ventilatory threshold, and for moderate-to-high correlation between the 6-minute walk distance and maximum metabolic equivalents achieved on symptom-limited exercise tests. LIMITATIONS Few studies assessed similar aspects of validity for the 6MWT. CONCLUSION Strong evidence suggests that the 6MWT is responsive to clinical change following cardiac rehabilitation. Intra- and intertester reliability of the 6MWT and its validity in patients undergoing cardiac rehabilitation requires further research.

A bilateral cortico-bulbar network associated with breath holding in humans, determined by functional magnetic resonance imaging

Few tasks are simpler to perform than a breath hold; however, the neural basis underlying this voluntary inhibitory behaviour, which must suppress spontaneous respiratory motor output, is unknown. Here, using blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI), we investigated the neural network responsible for volitional breath holding in 8 healthy humans. BOLD images of the whole brain (156 brain volumes, voxel resolution 3x3x3 mm) were acquired every 5.2 s. All breath holds were performed for 15 s at resting expiratory lung volume when respiratory musculature was presumed to be relaxed, which ensured that the protocol highlighted the inhibitory components underlying the breath hold. An experimental paradigm was designed to dissociate the time course of the whole-brain BOLD signal from the time course of the local, neural-related BOLD signal associated with the inhibitory task. We identified a bilateral network of cortical and subcortical structures including the insula, basal ganglia, frontal cortex, parietal cortex and thalamus, which are in common with response inhibition tasks, and in addition, activity within the pons. From these results we speculate that the pons has a role in integrating information from supra-brainstem structures, and in turn it exerts an inhibitory effect on medullary respiratory neurones to inhibit breathing during breath holding.