Robert B. Banzett

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.

The Affective Dimension of Laboratory Dyspnea Air Hunger Is More Unpleasant than Work/Effort

RATIONALE It is hypothesized that the affective dimension of dyspnea (unpleasantness, emotional response) is not strictly dependent on the intensity of dyspnea. OBJECTIVES We tested the hypothesis that the ratio of immediate unpleasantness (A(1)) to sensory intensity (SI) varies depending on the type of dyspnea. METHODS Twelve healthy subjects experienced three stimuli: stimulus 1: maximal eucapnic voluntary hyperpnea against inspiratory resistance, requiring 15 times the work of resting breathing; stimulus 2: Pet(CO(2)) 6.1 mm Hg above resting with ventilation restricted to less than spontaneous breathing; stimulus 3: Pet(CO(2)) 7.7 mm Hg above resting with ventilation further restricted. After each trial, subjects rated SI, A(1), and qualities of dyspnea on the Multidimensional Dyspnea Profile (MDP), a comprehensive instrument tested here for the first time. MEASUREMENTS AND MAIN RESULTS Stimulus 1 was always limited by subjects failing to meet a higher ventilation target; none signaled severe discomfort. This evoked work and effort sensations, with relatively low unpleasantness (mean A(1)/SI = 0.64). Stimulus 2, titrated to produce dyspnea ratings similar to those subjects gave during stimulus 1, evoked air hunger and produced significantly greater unpleasantness (mean A(1)/SI = 0.95). Stimulus 3, increased until air hunger was intolerable, evoked the highest intensity and unpleasantness ratings and high unpleasantness ratio (mean A(1)/SI = 1.09). When asked which they would prefer to repeat, all subjects chose stimulus 1. CONCLUSIONS (1) Maximal respiratory work is less unpleasant than moderately intense air hunger in this brief test; (2) unpleasantness of dyspnea can vary independently from perceived intensity, consistent with the prevailing model of pain; (3) separate dimensions of dyspnea can be measured with the MDP.

Ventilatory responses to exercise in humans lacking ventilatory chemosensitivity.

1. In healthy humans during aerobic exercise ventilation increases and mean arterial PCO2 usually remains constant over a wide range of CO2 production. 2. Congenital central hypoventilation syndrome (CCHS) is associated with ineffective chemoreceptor regulation of breathing and severe hypoventilation during sleep (requiring mechanical ventilation) reflecting abnormalities in the brainstem respiratory complex or its chemoreceptor input. Such patients can have adequate spontaneous ventilation during resting wakefulness and participate in normal activities. 3. If children with CCHS have normal ventilatory responses to exercise then chemoreceptors are not necessary for this ventilatory response or the resultant control of Pa,CO2 during exercise. We studied five children with CCHS (aged 8‐17 years) with abnormally low ventilatory responses to steady‐state increased end‐tidal PCO2 (< 9 ml min‐1 kg‐1 mmHg‐1) and five age‐matched controls. 4. Depth and rate of breathing, end‐tidal PCO2, end‐tidal PO2, CO2 production, O2 utilization and heart rate were monitored during the following conditions: whilst subjects stood at rest; following the onset of treadmill exercise (4 m.p.h.); during steady‐state exercise (4 m.p.h.); during an incremental maximal exercise test; and during recovery from exercise. 5. There were no significant differences in the ventilatory responses between CCHS subjects and controls during the onset of treadmill exercise, in the dynamic response in achieving the steady‐state exercise, during steady‐state exercise, in the recovery from steady‐state exercise, or during incremental exercise (up to the point of presumed blood lactate accumulation, as indicated by gas exchange criteria). There was a very small mean increase in PCO2 in both groups during steady‐state exercise (controls 1.4 mmHg; CCHS 2.2 mmHg). 6. The only differences which emerged between groups were (i) slightly more variability in PCO2 in the CCHS group during steady‐state exercise, and (ii) the CCHS subjects did not hyperventilate, as the controls did, at exercise levels above the point of presumed blood lactate accumulation. 7. Breath‐by‐breath coefficient of variation of ventilation was significantly reduced in both groups during steady‐state exercise compared to rest. There were no differences between groups in either state. 8. We conclude that chemoreceptors are not necessary for an appropriate ventilatory response to aerobic exercise. Hence, other stimuli, such as afferent information from the exercising limbs or signals related to activation of the motor cortex, can increase alveolar ventilation in close proportion to CO2 production. 9. The lack of hyperventilatory response to blood lactate accumulation during heavy exercise provides good evidence that these CCHS patients have ineffective peripheral chemoreception.

Intrapulmonary chemoreceptors in Gallus domesticus: Adequate stimulus and functional localization

Abstract Experiments were performed in anesthetized chickens in order to determine functional characteristics and localization of intrapulmonary chemoreceptors. Each lung of the bird was separately unidirectionally ventilated with controlled gas mixtures at controlled flow rates; pulmonary blood flow to one lung could be occluded. Action potentials in vagal afferents from the receptors as well as ventilatory responses to stimulation of the receptors were recorded. Main findings include: (a) Presence of two groups of afferent fibers carrying activity from intrapulmonary chemoreceptors, one in the vagus, the other in the cardiac sympathetic nerve, (b) Intrapulmonary chemoreceptors show high sensitivity to CO 2 concentration in lung gas and blood; they show little sensitivity to arterial pH, to most drugs which stimulate arterial chemoreceptors, to mild mechanical distortion of the lung, or to substances in bronchial arterial blood, (c) The receptors are located in the parabronchi. It is suggested that physiological processes monitored by intrapulmonary CO 2 receptors are those which modify parabronchial P CO 2 , i.e. ventilation, venous CO 2 load, and mixed venous P CO 2 .

Cardiorespiratory variables and sensation during stimulation of the left vagus in patients with epilepsy.

We studied physiological and sensory effects of left cervical vagal stimulation in six adult patients receiving this stimulation as adjunctive therapy for intractable epilepsy. Stimulus strength varied among subjects from 0.1 to 2.1 microCoulomb (microC) per pulse, delivered in trains of 30-45 s at frequencies from 20 to 30 Hz; these stimulation parameters were standard in a North American study. The stimulation produced no systematic changes in ECG, arterial pressure, breathing frequency tidal volume or end-expiratory volume. Five subjects experienced hoarseness during stimulation. Three subjects with high stimulus strength (0.9-2.1 microC) recalled shortness of breath during stimulation when exercising; these sensations were seldom present during stimulation at rest. No subjects reported the thoracic burning sensation or cough previously reported with chemical stimulation of pulmonary C fibers. Four of six subjects (all those receiving stimuli at or above 0.6 microC) experienced a substantial reduction in monthly seizure occurrence at the settings used in our studies. Although animal models of epilepsy suggest that C fibers are the most important fibers mediating the anti-seizure effect of vagal stimulation, our present findings suggest that the therapeutic stimulus activated A fibers (evidenced by laryngeal effects) but was not strong enough to activate B or C fibers.

Multidimensional Dyspnea Profile: an instrument for clinical and laboratory research

There is growing awareness that dyspnoea, like pain, is a multidimensional experience, but measurement instruments have not kept pace. The Multidimensional Dyspnea Profile (MDP) assesses overall breathing discomfort, sensory qualities, and emotional responses in laboratory and clinical settings. Here we provide the MDP, review published evidence regarding its measurement properties and discuss its use and interpretation. The MDP assesses dyspnoea during a specific time or a particular activity (focus period) and is designed to examine individual items that are theoretically aligned with separate mechanisms. In contrast, other multidimensional dyspnoea scales assess recalled recent dyspnoea over a period of days using aggregate scores. Previous psychophysical and psychometric studies using the MDP show that: 1) subjects exposed to different laboratory stimuli could discriminate between air hunger and work/effort sensation, and found air hunger more unpleasant; 2) the MDP immediate unpleasantness scale (A1) was convergent with common dyspnoea scales; 3) in emergency department patients, two domains were distinguished (immediate perception, emotional response); 4) test–retest reliability over hours was high; 5) the instrument responded to opioid treatment of experimental dyspnoea and to clinical improvement; 6) convergent validity with common instruments was good; and 7) items responded differently from one another as predicted for multiple dimensions. The Multidimensional Dyspnea Profile provides a unified, reliable instrument for both clinical and laboratory research http://ow.ly/Ix8ic

II. Effect of CO2 on afferent vagal endings in the canine lung

We have attempted to identify the afferent endings responsible for the pulmonary-CO2 ventilatory reflex. We recorded afferent vagal impulses arising from the left lung in anesthetized dogs with separately ventilated lungs. When the left pulmonary artery was occluded, left lung PCO2 fell to 3 mm Hg and slowly-adapting pulmonary stretch receptor activity increased 46%. Firing declined to its original intensity when left lung PCO2 was raised in steps by administration of CO2, firing decreasing most between 2 and 19 mm Hg, and least between 30 and 50 mm Hg. Irritant receptor activity also increased (from 2.8 to 7.4 impulses/sec) after pulmonary arterial occlusion, the effect being reversed by administration of CO2. These procedures caused trivial changes in pulmonary and bronchial C-fiber activity. Effects on both slowly-adapting stretch receptors and irritant receptors appeared to result from a direct action of CO2 on the endings themselves, rather than from mechanical changes in the lung. Changes in slowly-adapting stretch receptor activity provide an adequate explanation for the pulmonary-CO2 ventilatory reflex, the relationship between impulse frequency and lung PCO2 suggesting that these afferents may have a role in limiting CO2 loss under conditions causing hypocapnia, but be less effective in stimulating breathing during hypercapnia.

Reliability and Validity of the Multidimensional Dyspnea Profile

BACKGROUND Most measures of dyspnea assess a single aspect (intensity or distress) of the symptom. We developed the Multidimensional Dyspnea Profile (MDP) to measure qualities and intensities of the sensory dimension and components of the affective dimension. The MDP is not indexed to a particular activity and can be applied at rest, during exertion, or during clinical care. We report on the development and testing of the MDP in patients with a variety of acute and chronic cardiopulmonary conditions. METHODS One hundred fifty-one adults admitted to the ED with breathing symptoms completed the MDP three times in the ED, twice at least 1 h apart (T1, T2), and near discharge from the ED (T3). Measures were repeated in 68 patients twice in a follow-up session 4 to 6 weeks later (T4-T5). The ED sample was 56% men with a mean age of 53 ± 15 years; the follow-up sample was similar. RESULTS Factor analysis resulted in a two-factor solution with a total explained variance of 63%, 74%, and 72% at T1, T2, and T3, respectively. One domain related to primary sensory qualities and immediate unpleasantness, and the second encompassed emotional response. For the two domains, Cronbach α ranged from 0.82 to 0.95, and the intraclass correlation coefficient ranged from 0.91 to 0.98. Repeated-measures analysis was significant for change (T1, T3, T4), showing responsiveness to change in MDP domains with treatment (F([2,66]) = 19.67, P > .001). CONCLUSIONS These analyses support the reliability, validity, and responsiveness to clinical change of the MDP with two domains in an acute care and follow-up setting.

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.