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.

High-level quadriplegics perceive lung volume change.

We tested the ability of tracheostomized, high-level quadriplegics to detect changes in ventilator-delivered tidal volume. Single breaths larger or smaller than control breaths were delivered, and the subjects indicated which breath was altered in a forced-choice procedure that minimizes the effect of subject bias. Quadriplegic patients detected changes in tidal volume of as little as 100 ml. Their ability to detect changes was comparable to that of a group of normal subjects similarly tested. These quadriplegic patients had little or no somatic sensation below the neck, and airways above the tracheostomy were not exposed to the stimulus. The quadriplegics consistently and emphatically reported that the sensation used in volume discrimination arose within the chest.

Gas exchange across avian eggshells oscillates in phase with heartbeat.

Rahn et al. (J. Appl. Physiol. 69: 1546-1548, 1990) showed that the gas pressure in a plethysmograph containing an intact egg oscillates in phase with electrocardiogram (ECG) and that this pressure variation could be used as a noninvasive way to determine the heart rate of an avian embryo. One possible mechanism to account for the pressure oscillation is the mechanical movement of the embryonic heart, which leads to volume shifts of gas within the plethysmograph. Another possibility is that the oscillation of gas pressure with heartbeat is pulsatile gas exchange resulting from pulsatile blood flow. If gas exchange were transiently stopped, a pressure signal dependent on gas exchange should disappear, while a pressure signal dependent on cardiovascular motion should persist. Using a number of late-age hen eggs (at days 15-20 of incubation), we tested these hypotheses by suddenly changing the gas composition surrounding an egg and measuring the effect of the pressure oscillation. We found that 1) after 5% CO2-95% N2 was flushed into the plethysmograph (presumably halting gas exchange), pressure oscillations went almost to zero and the ECG signal remained; after air was flushed back to the plethysmograph, the pressure signal returned to control level; 2) after 20% CO2-20% O2-60% N2 was flushed into the plethysmograph (presumably increasing net gas exchange), the pressure signal increased 2.5-fold compared with that in air; and 3) after 1% CO2-99% N2 was flushed into the plethysmograph (presumably reversing gas exchange), the oscillation pressure decreased to one-fourth of that in air and the phase of pressure relative to ECG reversed compared with the phase in air.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex compensation of voluntary inspiration when immersion changes diaphragm length.

When immersion alters inspiratory muscle operating lengths, spontaneously breathing humans maintain a constant tidal volume by reflex adjustment of inspiratory muscle activation (Reid et al. J. Appl. Physiol. 58: 1136-1142, 1985). We term this the operational length compensation reflex. The present experiment demonstrates that similar adjustments occur during voluntary respiratory maneuvers. Each of seven naive subjects sat in a tank with water at hip level. We trained them to reproduce an inspired volume (+/- 10%) at constant inspiratory duration. They received verbal feedback during training but not during the experiment. We measured surface electromyograms (EMGs) of diaphragm and intercostal muscles and tidal volume. After the subjects were trained, we made repeated measurements of 10 trained breaths with water at the hip and then again after raising water level to the xiphoid (which decreases lung volume and increases operating length of the diaphragm). In 30 of 42 trials there was a substantial fall in peak diaphragm EMG. In 10 trials this was sufficient to prevent any change in tidal volume. Inspiratory flow was more closely regulated than tidal volume. Subjects were not aware of making adjustments in drive.

Locomotion in men has no appreciable mechanical effect on breathing.

It has been suggested that the act of taking a stride produces substantial respiratory volume displacement and that this assists the respiratory muscles during locomotion. We measured the flow at the mouth associated with stride in walking and running humans and found it to be 1-2% of respiratory tidal volume, which is too small to make an appreciable contribution to pulmonary ventilation.

Passive mechanics of upright human chest wall during immersion from hips to neck.

We have determined the mechanical effects of immersion to the neck on the passive chest wall of seated upright humans. Repeated measurements were made at relaxed end expiration on four subjects. Changes in relaxed chest wall configuration were measured using magnetometers. Gastric and esophageal pressures were measured with balloon-tipped catheters in three subjects; from these, transdiaphragmatic pressure was calculated. Transabdominal pressure was estimated using a fluid-filled, open-tipped catheter referenced to the abdomen's exterior vertical surface. We found that immersion progressively reduced mean transabdominal pressure to near zero and that the relaxed abdominal wall was moved inward 3-4 cm. The viscera were displaced upward into the thorax, gastric pressure increased by 20 cmH2O, and transdiaphragmatic pressure decreased by 10-15 cmH2O. This lengthened the diaphragm, elevating the diaphragmatic dome 3-4 cm. Esophageal pressure became progressively more positive throughout immersion, increasing by 8 cmH2O. The relaxed rib cage was elevated and expanded by raising water from hips to lower sternum; this passively shortened the inspiratory intercostals and the accessory muscles of inspiration. Deeper immersion distorted the thorax markedly: the upper rib cage was forced inward while lower rib cage shape was not systematically altered and the rib cage remained elevated. Such distortion may have passively lengthened or shortened the inspiratory muscles of the rib cage, depending on their location. We conclude that the nonuniform forcing produced by immersion provides unique insights into the mechanical characteristics of the abdomen and rib cage, that immersion-induced length changes differ among the inspiratory muscles according to their locations and the depth of immersion, and that such length changes may have implications for patients with inspiratory muscle deficits.

Reflex compensation of spontaneous breathing when immersion changes diaphragm length.

We measured tidal volume (VT), chest wall dimensions, end-tidal PCO2, and respiratory muscle electromyograms as seated subjects were immersed in water. We studied nine spontaneously breathing subjects; five were uninformed. Raising the water to xiphoid level pushed the abdomen in and expanded the rib cage at end expiration. This increased the diaphragm's operating length, giving it a contractile advantage, and shortened the inspiratory intercostals, giving them a contractile disadvantage. Peak inspiratory activities of both muscle groups decreased; inspiratory time (TI), respiratory frequency (f), and VT were unchanged. The experiments thus demonstrated operational length compensation during immersion and further showed that inspiratory muscle activation is not adjusted locally, according to changes in each muscle's length, but rather that the response is global. Xiphoid-to-shoulder immersion was less easily interpreted, since both rib cage and abdomen were compressed, lengthening both inspiratory muscles. Our subjects continued to maintain VT, f, and TI. Peak inspiratory activities of both muscles were further reduced. We do not attribute the change in inspiratory muscle activation to altered chemical drive or to voluntary response. Rather, the response appears to be a mechanoreceptive reflex that employs afferent information from the lungs or diaphragm to adjust all inspiratory muscle activities.

Pulmonary afferent activity during high-frequency ventilation at constant mean lung volume.

We recorded the responses of 21 slowly adapting pulmonary stretch receptors (PSRs) and 8 rapidly adapting pulmonary stretch receptors (RARs) from the vagi of anesthetized open-chest dogs to high-frequency ventilation (HFV) at 15 Hz, at constant mean end-expiratory lung volume, and constant end-tidal PCO2. HFV applied in this way has been shown to prolong expiration. The responses of pulmonary afferents during HFV at constant mean volume have not been described. In the present experiments, receptor discharge during HFV was compared with that during the end-expiratory pause of normal-frequency ventilation. Average PSR discharge increased when HFV was applied, although not all PSRs exhibited increases. RARs were generally silent during normal and high-frequency ventilation at functional residual capacity and above. However, at low lung volumes, RAR discharge increased greatly when HFV was applied. We conclude that PSR discharge is increased during HFV in the absence of increased lung volume and that increases in PSR discharge during HFV are sufficient to explain the reflex that prolongs expiration in dogs.

Simple contrivance "clamps" end-tidal PCO(2) and PO(2) despite rapid changes in ventilation.

The device described in this study uses functionally variable dead space to keep effective alveolar ventilation constant. It is capable of maintaining end-tidal PCO(2) and PO(2) within +/-1 Torr of the set value in the face of increases in breathing above the baseline level. The set level of end-tidal PCO(2) or PO(2) can be independently varied by altering the concentration in fresh gas flow. The device comprises a tee at the mouthpiece, with one inlet providing a limited supply of fresh gas flow and the other providing reinspired alveolar gas when ventilation exceeds fresh gas flow. Because the device does not depend on measurement and correction of end-tidal or arterial gas levels, the response of the device is essentially instantaneous, avoiding the instability of negative feedback systems having significant delay. This contrivance provides a simple means of holding arterial blood gases constant in the face of spontaneous changes in breathing (above a minimum alveolar ventilation), which is useful in respiratory experiments, as well as in functional brain imaging where blood gas changes can confound interpretation by influencing cerebral blood flow.

Time course of air hunger mirrors the biphasic ventilatory response to hypoxia.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive ("corollary discharge") to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 +/- 1.4 l/min; end-tidal Pco(2) = 37 +/- 2 Torr; end-tidal Po(2) = 45 +/- 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by "urge to breathe" was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r(2) = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min(-1) and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min(-1) and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of approximately 30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.

Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans.

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via "corollary discharge" to higher centers; absence of dyspnea during low inspired Po(2) may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po(2) = 60-40 Torr) and hypercapnic hyperoxia (end-tidal Pco(2) = 40-50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, "matched" by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. "Air hunger" was rated every 30 s on a visual analog scale. Air hunger-Pet(O(2)) curves rose sharply at Pet(O(2)) <50 Torr. Air hunger was not different between matched stimuli (P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.

Air hunger induced by acute increase in PCO2 adapts to chronic elevation of PCO2 in ventilated humans.

Brief increases in arterial PCO2 (PaCO2) (lasting several minutes) produce a sensation of respiratory discomfort (air hunger). It is not known whether air hunger adapts to chronic changes in PaCO2. This study tested whether the level of end-tidal PCO2 (PETCO2) required to evoke air hunger would increase with chronic elevation of PETCO2 (lasting several days). Four ventilator-dependent subjects participated in a 2-wk study during which they were ventilated with air (placebo) or air rich in CO2 (CO2 exposure). Average resting PETCO2 during control periods was 25 Torr (typical for such patients); PETCO2 was 15 Torr higher during CO2 exposure. Ventilation and arterial PO2 did not differ between conditions. Periodically, we performed tests in which subjects rated the intensity of air hunger induced by brief increases in PETCO2. The increase in PETCO2 required to elicit a given air hunger rating during CO2 exposure also increased by approximately 15 Torr. That is, subjects' sensation of air hunger fully adapted to the chronic increase in PETCO2. Arterial pH did not fully return to control values during CO2 exposure. Accommodation in the chemoreceptors and neural pathways that subserve air hunger sensation may explain the adaptation of air hunger.

A simple and reliable method to calibrate respiratory magnetometers and Respitrace.

We present a simple and reliable method to calibrate respiratory magnetometers and Respitrace to infer respiratory volume changes. As in earlier methods, we assume two degrees of freedom in the chest wall and that volume displacement depends linearly on surface motion at the rib cage and abdomen. Because the area of the rib cage is larger, a given motion of its surface produces a greater lung volume change; therefore, the rib cage motion signal is given a larger gain before the two signals are added to estimate volume. In contrast to earlier methods, we use a "standard ratio" to weight relative gains of the rib cage and abdominal signals for all subjects rather than determining a gain ratio for each individual subject. Our procedure does not require subjects to perform the sometimes difficult isovolume maneuvers used in the calibration method of Konno and Mead (J. Appl. Physiol. 22: 407-422, 1967), does not require statistical computation used in the multiple-breath linear regression method, and does not produce the occasional substantial errors in gain ratio that may occur with the other methods. When magnetometers are used, the standard ratio is 4:1 (rib cage-to-abdomen); when Respitrace is used, the standard ratio is 2:1. In 11 subjects, calibration with standard ratios was as accurate as the isovolume and linear regression techniques. Accuracy during normal breathing was nearly always within 10% (median 2%), but occasional large errors occurred with both instruments.

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.

Mechanical chest-wall vibration does not relieve air hunger.

Mechanical vibration of the chest wall can reduce dyspnea. It is unclear which sensations of respiratory discomfort are modulated by vibration (work/effort, air hunger, tightness). We performed two experiments to test whether vibration modifies air hunger: Experiment 1-eight adults performed six breath holds and rated their uncomfortable 'urge to breathe.' Vibration was applied separately at four chest-wall and two control sites, using two amplitudes. Breath-hold duration and ratings were unchanged by vibration at any site or amplitude. Experiment 2-nine adults were mechanically ventilated (mean 8.73 L/min) at constant hypercapnia (mean 48 mmHg) to produce mild to moderate ratings of air hunger (mean 37% of scale) with minimal respiratory muscle work. Vibration at 2nd or 3rd intercostal spaces during either inspiration or expiration did not change air hunger compared to triceps vibration. These experiments demonstrated that vibration does not relieve air hunger; we postulate that the effect of vibration is specific to the form of dyspnea.

Competition between gas exchange and speech production in ventilated subjects.

Competition between airflow requirements for speaking and gas exchange occurs in ventilator-dependent tracheotomized subjects who can 'steal' air from alveolar ventilation during the ventilator's inflation phase to produce sound. We wondered whether these subjects adopted strategies to minimize hypoventilation when speaking, particularly when ventilatory drive and respiratory discomfort are increased by hypercapnia. We recorded speech and ventilatory and speaking volumes in five ventilated subjects during reading and extemporaneous speech. All subjects spoke during the ventilator's inflation (and expiratory) phase, losing approximately 15% of their inspired tidal volume. During induced hypercapnia (15 mmHg increase in PetCO2) which caused shortness of breath, all subjects could still speak adequately. Two subjects 'adapted' to hypercapnia by reducing the air used for speaking during inflation. In contrast, one subject reacted, as normal subjects do, by increasing the airflow per syllable (a mal-adaptive strategy in ventilated subjects). These changes were modest despite the strong hypercapnic stimulus.

What do fully paralyzed awake humans feel when they attempt to move?

Subjects are able to judge the strength of muscle contraction. In theory, the force of muscular exertion could be perceived either from mechanoreceptor afferents or from knowledge of central motor command (corollary discharge). Sensations of great effort or exerted force have been described by subjects when their limbs were weakened by fatigue or partial paralysis. This has been taken as evidence that effort sensations arise from central motor commands rather than from mechanoreceptor afferent signals produced by muscle contraction. To differentiate between these possibilities, we used neuromuscular block to completely paralyze four waking subjects and required them to attempt maximal contraction of inspiratory muscles and of hand muscles. They were questioned after recovery about what their sensations were when attempting these contractions. None described the sensations of exerted force, great effort, or heaviness, which would have been expected if motor commands alone were the source of these sensations. The contradiction between our findings and those previously reported suggests that the specific neural mechanisms for effort sensations must be reexamined.

Tidal volume perception in a C1-C2 tetraplegic subject is blocked by airway anesthesia.

We administered lidocaine aerosol intratracheal anesthesia to a ventilator-dependent, tracheostomized C1-C2 tetraplegic subject to determine its effect on her ability to detect small changes in tidal volume. A psychophysical test of volume detection was given before and immediately after a 20 percent lidocaine aerosol was delivered through the subject's cuffed tracheostomy tube. On each of three occasions, she reliably (p < .001) detected changes in tidal volume during a control period; on two of these occasions she could not detect the same volume after inhaling the anesthetic. On one occasion the anesthetic had no effect on volume perception, possibly because copious airway secretions interfered with lidocaine uptake. Subject-blinded control tests with saline aerosol inhalation did not affect detection. We concluded that this subject's tidal volume perception depended on mechanoreceptors in the lungs and thoracic airways and that local anesthetic interrupted these sensory signals when airway secretions were not excessive.

The experience of complete neuromuscular blockade in awake humans.

STUDY OBJECTIVE: To describe the subjective experience and the physiologic effects of endotracheal intubation and complete neuromuscular block in unsedated humans. SETTING: Metropolitan V.A. Hospital. PATIENTS: 4 healthy, unsedated volunteers. INTERVENTIONS: Subjects' tracheas were intubated using topical anesthesia, then subjects were completely paralyzed with vecuronium and mechanically ventilated at various end-tidal partial pressure of carbon dioxide (PETCO2) levels, all without sedation. MEASUREMENTS AND MAIN RESULTS: Heart rate (HR), blood pressure, oxygen saturation by pulse oximeter (SpO2), and PETCO2 were measured. Subjects' verbatim descriptions of their experiences and answers to systematic questions were recorded after the experiments. All subjects reported that tracheal intubation was a very unpleasant experience. None of the subjects found paralysis itself to be distressing, and it did not affect mentation. Subjects felt breathless when PETCO2 was even slightly elevated. HR was increased by intubation, but not by paralysis. All subjects reported sore throat, muscle aches, fever, and fatigue lasting up to 24 hours after the experiment. One subject experienced nausea and vomiting. Another subject experienced a sore throat that persisted for weeks due to a vocal cord ulcer, which resolved spontaneously. All subjects' SpO2 levels after the experiment were below their pre-experiment baselines. CONCLUSIONS: Our findings suggest that paralysis of healthy, knowledgeable, and psychologically well-prepared subjects for experimental purposes is feasible but may result in unpleasant, self-limiting after effects. Further, we conclude that, in any case of awake paralysis, close attention should be paid to arterial PCO2, adequate sedation and analgesia, minimization of pain during procedures, psychological support, and maintenance of communication when possible.