Influence of lung volume on phrenic, hypoglossal and mylohyoid nerve activities

In decerebrate, paralyzed cats, ventilated by a servo-respirator in accordance with phrenic nerve activity, we examined the influence of lung volume on the activities of the phrenic, hypoglossal and mylohyoid nerves. When lung inflation was briefly withheld, the durations of inspiration (TI) and expiration (TE) and the activities of all three nerves increased. The relative increase in hypoglossal activity greatly exceeded that of phrenic activity and was apparent earlier in the course of inspiration. This hypoglossal response was enhanced by hypercapnia and isocapnic hypoxia. The responses of mylohyoid activity were quite variable: withholding lung inflation augmented inspiratory activity in some cats, but expiratory discharge in others. Sustained increases in end-expiratory lung volume were induced by application of 3-4 cm H2O of positive end-expiratory pressure (PEEP). Steady-state PEEP did not influence nerve activities or the breathing pattern. Bilateral vagotomy increased TI, TE, and the activities of all three nerves. No response to withoholding lung inflation could be discerned after vagal section. The results provide further definition of the influence of vagally mediated, lung volume dependent reflexes on the control of upper airway muscles. These reflexes are well suited to relieve or prevent upper airway obstruction.     

Hypoglossal motoneuron responses to pulmonary and superior laryngeal afferent inputs

In decerebrate, paralyzed cats ventilated with a cycle-triggered pump, the inspiratory discharges of the hypoglossal (whole nerve or single fibers), phrenic, and recurrent laryngeal nerves were compared, and the effects of pulmonary and superior laryngeal afferent inputs were observed. During lung inflations in phase with neural inspiration, hypoglossal and recurrent laryngeal activities differed from phrenic with respect to (a) burst onset times: both preceded the phrenic; (b) overall pattern: phrenic, augmenting; hypoglossal, decrementing; recurrent laryngeal, plateau-like. When inflation was withheld, the phrenic pattern was not markedly changed, but both hypoglossal and recurrent laryngeal became augmenting; the marked increase of hypoglossal activity (both whole nerve and single fiber) indicated strong inhibition by lung afferents. Superior laryngeal electrical stimulation evoked excitation of the contralateral phrenic (latency 4.1 msec) and the ipsilateral whole hypoglossal (latency 5.3 msec), followed by bilateral inhibitions (durations 20-30 msec); most hypoglossal fibers showed only inhibition. We conclude that, although both hypoglossal and phrenic outputs are driven by the inspiratory pattern generator(s), their promotor systems differ with respect to influences from central and peripheral inputs.     

The mechanism of rapid shallow breathing due to histamine and phenyldiguanide in cats and rabbits

In anaesthetized cats and rabbits we analyzed the rapid shallow breathing following exposure to histamine aerosol (mainly an irritant receptor stimulant) and i.v. injection of phenyldiguanide (mainly a J receptor stimulant). Both drugs caused a marked leftward displacement of the tidal volume (VT) vs inspiratory time (TI) relationship (Hering-Breuer threshold curve) without a corresponding increase in inspiratory flow rate so that inspiration was cut off at a lower VT and TI. The leftward displacement of the VT vs TI relationship occurred with a great shortening of the duration of inspiration during occluded breaths (T0I) accompanied by a shortening of the expiratory phase (T0E). These parameters monitored the central respiratory rhythm in absence of the phasic lung volume related vagal loop. It is suggested that the increased central respiratory frequency was due to the augmented firing of fibers from stimulated irritant and J receptors. Stimulation of these endings also caused the TE vs TI relationship to become steeper in cats and to be displaced downwards in rabbits.     

The effects of passive CO2 removal on breathing pattern in humans

To determine the effects of nonventilatory CO2 transfer on breathing pattern, we monitored breathing in 7 patients with renal failure undergoing hemodialysis. A respiratory inductance plethysmograph was used to record ventilation before and during dialysis. The duration of inspiration (TI), the duration of each breath (TTot) and the duty cycle (TI/TTot) did not differ for the pre-dialysis and the dialysis periods. In contrast, for each patient the mean tidal volume (VT) fell significantly during dialysis (p less than 0.05), accounting for the reduction in minute ventilation (p less than 0.005). The mean inspiratory flow rate (VT/TI) also fell (p less than 0.01), demonstrating that nonventilatory CO2 loss via the dialysis bath is associated with reduced respiratory drive.     

Inhibitory and excitatory effects on respiration by phrenic nerve afferent stimulation in cats

Respiratory effects of electrical stimulation of phrenic nerve afferents were studied in anesthetized cats, either spontaneously breathing or paralyzed and ventilated. The type of phrenic afferent fibers activated was controlled by recording the evoked action potentials from dorsal root fibers. In both preparations, stimulation at a strength sufficient to activate small diameter myelinated phrenic nerve afferents induced a biphasic response. The first phase lasted a few respiratory cycles and was inhibitory and consisted of a decrease in tidal volume (VT) or phrenic activity (NA), inspiratory time (TI), respiratory duty cycle (TI/Ttot) and instantaneous ventilation (VE) or minute phrenic activity (NMA). Expiratory time (TE) increased and breathing frequency (f) and mean inspiratory flow (VT/TI) or mean inspiratory neural activity (NA/TI) did not change. This short-term response was suppressed in animals pretreated with bicuculline. The second phase was a long-term excitation in which VT or NA, f, VE or NMA and VT/TI increased whereas both TI and TI/Ttot decreased and TE did not change. Unlike published data, our results suggest that small-diameter myelinated phrenic nerve afferents are involved in these responses. These phrenic fibers, like afferents from other muscles, affect respiratory output and may play a role in the control of breathing.     

A comparative analysis of contractile characteristics of the diaphragm and of respiratory system mechanics

The mean inspiratory flow rate (VT/TI) is used as an index of central respiratory 'drive', and, at rest, it varies interspecifically in proportion to body weight (BW) raised to the 0.74 power (Boggs and Tenney, 1984). VT/TI is determined by the level of central neural respiratory output, the velocity of contraction of respiratory muscles, and the mechanical characteristics of the respiratory system. We have examined the last two factors in 13 species ranging in weight from 0.025 to 515 kg. We determined the 'effective' inspiratory mechanical characteristics of the respiratory system (time constant, resistance, and compliance) and the time course of diaphragmatic contraction during bilateral supramaximal phrenic nerve stimulation in anesthetized animals. We also measured passive expiratory mechanical variables and made morphometric measurements of the diaphragm. We found that VT/TI during phrenic nerve stimulation was proportional to BW0.82. The 'effective' respiratory time constant (tau'rs) and passive expiratory time constant (tau rs) scaled in proportion to body weight with nearly similar exponents: tau'rs alpha BW0.26 and tau rs alpha BW0.21. In addition, the time constant of diaphragmatic contraction (tau mc) was proportional to BW0.20. Inspiratory time is proportional to tau'rs and tau mc, and tidal volume during stimulation was almost directly proportional to body weight. Thus, interspecific changes in VT/TI during stimulation were related to interspecific changes in the mechanical characteristics of the respiratory system and the velocity of muscular contraction. We conclude that interspecific changes in VT/TI need not reflect interspecific variation in central respiratory drive under resting conditions. We found that diaphragm weight and volume and diaphragm muscle thickness were geometrically similar in all species studied. Inspiratory pressure is an interspecific constant; therefore, by the Law of Laplace, smaller animals must develop greater tension per unit of muscle mass.     

Respiratory response to positive and negative inspiratory pressure in humans.

To investigate the effect of positive or negative inspiratory pressure on respiration, eight subjects breathed, either without or with added external dead space (VD, 600 ml), through either added inspiratory laminar flow resistances (RES; peak inspiratory airway pressure, Pinsp, down to -9 cmH2O) or with inspiratory pressure support (IPS; Pinsp up to +10 cmH2O). IPS, triggered by the subject's inspiratory effort, provided positive airway pressure throughout inspiration, but allowed for attainment of the subject's own respiratory pattern. The following main results were obtained with IPS or RES relative to the control (no IPS, no RES): (1) with VD, IPS led to small, but significant, increases in tidal volume (VT), respiratory frequency (fR) and ventilation (VE), with no changes in inspiratory time (TI) or duty cycle (TI/TT). Mean inspiratory flow (VT/TI) increased, and mouth occlusion pressure 0.1 sec after onset of inspiration (P0.1) decreased significantly with IPS. The changes during RES were essentially in the opposite direction; (2) without VD, similar, but smaller effects were observed, and only the changes in VT/TI and P0.1 during IPS were significant; (3) highly significant decreases were observed during IPS in end-tidal PCO2 (PETCO2); on the average from 39.6 to 29.2 Torr without VD, and from 45.7 to 39.3 Torr with VD breathing. A small, but significant decrease in PETCO2 occurred also during RES with VD. We conclude that while resistive loading is nearly completely compensated with but small changes in PETCO2, inspiratory pressure support leads to marked hyperventilation, which is not effectively counteracted by central timing commands.     

Respiratory-modulated activities of motor units of the facial nerve

The purpose of this work was to characterize the influence of activity of vagal pulmonary receptors upon the discharge pattern of motor units of the facial nerve. Decerebrate and paralyzed cats were ventilated with a servo-respirator which produced pulmonary inflations in parallel with activity of the phrenic nerve. At normocapnia, facial units discharged phasically during neural inspiration, expiration or across both phases or discharged tonically throughout the respiratory cycle. When pulmonary inflation was withheld, the tonic discharge of some units became phasic; others changed the pattern of phasic discharge. In hypercapnia, the number of tonic fiber activities increased and, again, some phasic discharge patterns were altered. Withholding inflation caused similar alterations as in normocapnia. Activities of facial fibers in vagotomized animals differed in that no tonic activities were recorded, and no change in phasic discharge patterns was induced by hypercapnia. We conclude that afferents from pulmonary stretch receptors influence ventilatory activity throughout the entire respiratory cycle. The concept is discussed that the tonic, as well as phasic discharge of these receptors, is important for the regulation of activity of motoneurons to upper airway muscles.     

Effect of posture on ventilation and breathing pattern during room air breathing at rest

We measured minute ventilation (VE), tidal volume (VT), mean inspiratory flow (VT/TI), and occlusion pressure (P.1) in 10 resting subjects breathing room air, in sitting, supine, right and left lateral positions, and compared them with corresponding data on static lung compliance [Cst(l)], dynamic lung compliance [Cdyn(l)], and pulmonary flow resistance [R(l)]. Highest values for VT, VE, VT/TI, P.1, and effective inspiratory impedance [P.1/(VT/Ti)] were observed in the supine posture. Values for P.1 and P.1/(VT/TI in lateral decubitus were intermediate to those obtained when seated and supine. While the increases in P.1 and P.1/(VT/TI) in recumbent postures were qualitatively similar to the decrease in Cdyn(l) and increase in R(l), there was no significant correlation between them, probably reflecting the complex relationship between P.1/(VT/TI) and lung compliance and resistance, as the former, in addition to lung mechanics, also depends on the shape of the inspiratory driving pressure wave, the active inspiratory impedance, the mechanics of the chest wall, and the duration of inspiration.     

Effects of end-expired pressure on phrenic output in servo-ventilated dogs

The pattern of breathing induced by increases in end-expired lung volume (EEVL) was determined in 9 anesthetized dogs. The pulmonary and systemic circulations were separately pump-perfused and the lungs were ventilated with a servo-ventilator actuated from the phrenic neurogram. EEVL was increased as a continuous ramp by slowly raising end-expired transpulmonary pressure from 1.5 to 12 cm H2O. Tidal volume (VT), inspiratory time (TI), and expiratory time (TE) were measured at vagal temperatures of 39 degrees C and 7 degrees C and following vagotomy. At a vagal temperature of 39 degrees C, increasing EEVL produced significant reductions in VT and TI while greatly prolonging TE. Vagal cooling to 7 degrees C, substantially altered the reflex response to increased EEVL. At 7 degrees C, VT decreased as EEVL increased, but the reduction was not so pronounced as at 39 degrees C. In addition, both TI and TE shortened. Increasing EEVL following vagotomy had no consistent effects on breathing pattern. We conclude that increasing EEVL stimulates tachypneic promoting pulmonary afferent nerves, most likely pulmonary C-fibers, but at normal vagal temperature their effect is masked by the stronger reflex inhibition of slowly adapting pulmonary stretch receptors.     

Responses of early and late onset phrenic motoneurons to lung inflation

In anesthetized or decerebrate cats that were paralyzed and ventilated with a cycle-triggered pump, we produced changes in activity of the whole phrenic nerve and of individual phrenic motoneurons (fibers or cells in the spinal cord) by withholding lung inflation during the inspiratory (I) phase. The neurons were classified into early- and late-onset types (discharge onset less or greater than 80 msec, respectively, after whole phrenic onset). Both unit and whole phrenic activity exhibited a variety of responses to inflation (excitation, depression, or no effect); but there were no consistent differences between responses of early- and late-onset neurons. The distribution of responses was quite different from that of dorsal respiratory group (DRG) I neurons (Cohen and Feldman, 1984); in particular there was no group of phrenic neurons corresponding to the late-onset I-beta neurons (I neurons excited by inflation). We conclude that the inputs to late-onset phrenic neurons are not predominantly or exclusively from late-onset DRG neurons.     

Fog-induced respiratory responses are attenuated by nedocromil sodium in humans

Fog inhalation induces cough and bronchoconstriction in patients with asthma, but only cough in normal subjects; whether it also influences the pattern of breathing is unclear. Nedocromil sodium (NCS) inhibits the cough response to inhalation of several pharmacological agents but its effects on fog-induced cough and changes in the pattern of breathing are unknown. We evaluated the effects of no drug, placebo, and 4- and 8-mg NCS administration on the cough threshold and changes in the pattern of breathing during fog inhalation in 14 healthy subjects. Measurements of tidal volume (VT), duration of inspiratory and expiratory times (TI and TE, respectively), total duration of the respiratory cycle (TT), mean inspiratory flow (VT/TI), duty cycle (TI/TT), respiratory frequency (f, 60/TT), and inspiratory minute ventilation (V I) were obtained by inductive plethysmography. Median cough threshold values were unaffected by placebo, but were increased (p < 0.01) by both NCS doses. In no-drug and placebo trials, inhalation of the threshold fog concentration caused increases in both VT/TI and V I (p always < 0.05) due to selective increases (p < 0.01) in VT. These changes were markedly attenuated by both NCS doses administration. Thus, fog induces coughing and increases in VT, VT/ TI, and V I in healthy subjects; NCS possesses antitussive effects and attenuates fog-induced changes in the pattern of breathing, possibly through inhibition of rapidly adapting "irritant" receptors.     

Influence of lung volume on sympathetic nerve discharge in normal humans

The purpose of this study was to determine the influence of tidal volume, breathing pattern, and beginning lung volume on the modulation of efferent, muscle sympathetic nerve activity (MSNA) in humans. In seven supine, healthy subjects, we measured MSNA (microneurography of the right peroneal nerve) and beat to beat arterial blood pressure during 1) low-frequency breathing (fb = 12 breaths/min) at tidal volumes (VT) of 30% (control), 50%, and 70% of inspiratory capacity and with inspiratory time-to-total breath time ratios (TI/TTOT) of 0.3-0.5 (control), less than 0.3, and greater than 0.5; and 2) simulated exercise hyperpnea (fb = 40 breaths/min; VT = 60-70% inspiratory capacity; minute ventilation, approximately 90 1). To optimize our ability to discern modulatory effects, breathing was performed during three conditions of heightened MSNA: nonhypotensive (less than 20 mm Hg) lower-body negative pressure, isometric handgrip exercise, and posthandgrip vascular occlusion (ischemia). PETCO2 was maintained at normal levels by adjusting the FICO2. Within-breath modulation of MSNA was observed during control tidal breathing with approximately 65% of the burst frequency occurring during the expiratory phase. Deep, low-frequency breathing potentiated this modulatory influence (p less than 0.05 versus control) and produced near-complete sympathoinhibition from onset-mid inspiration to early-mid expiration. Increasing (slow inspiration) and decreasing (fast inspiration) TI/TTOT shifted the onset of sympathoinhibition occurring later (greater change in volume) and earlier (less change in volume) during inspiration, respectively. In two subjects who performed deep breathing from an elevated beginning lung volume, the sympathoinhibition was observed earlier in the inspiratory period and with less change in volume compared with control. These within-breath modulatory effects did not appear to be due solely to changes in arterial pressure. Sustained low- or high ("exerciselike")-frequency deep breathing did not alter total minute MSNA compared with control breathing. These results demonstrate that the depth and pattern of breathing, and possibly the starting lung volume, exert marked influences on the within-breath modulation of MSNA in humans. Our findings also suggest that these modulatory effects may be mediated, at least in part, by pulmonary stretch reflexes.     

Properties of inspiratory termination by superior laryngeal and vagal stimulation.

Electrical stimulation of two respiratory afferent nerves, the vagus and the internal branch of the superior laryngeal, was used to terminate inspiration. The short latency responses of phrenic motoneurones to these stimuli were studied to determine if inspiratory termination was preceded by a characteristic phrenic motoneurone discharge pattern, reflecting changes in brainstem inspiratory neurone discharge and inspiratory terminating mechanisms. Stimulus trains of sufficient intensity delivered to the superior laryngeal nerve terminated inspiration within 50 ms and were preceded by a stereotyped pattern of phrenic motoneurone discharge. This consisted of a short latency (disynaptic), predominantly contralateral excitation in response to the first shock of the train, followed by a marked and long lasting inhibition. In contrast, vagal stimulation typically terminated inspiration hundreds of milliseconds after the onset of the stimulus train and was not preceded by a stereotyped pattern of phrenic motoneurone responses to single shocks. Transient short latency responses were obtained but were extremely small, requiring considerable excitation followed by a moderate bilateral depression of activity. Inspiration could be terminated with or without the presence of these short latency responses. These results indicate that superior laryngeal and vagal (presumably pulmonary stretch receptor) afferents have different projections to brainstem inspiratory neurones and may exert their effects on inspiratory duration through different, but as yet undefined, neural mechanisms.     

Breathing pattern and occlusion pressure during exercise in pre- and peripubertal swimmers

In two groups of young swimmers (prepubertal stage: group A; peripubertal stage: group B), the ventilatory response to graded exercise work with a cycle ergometer was studied. Ventilatory variables (ventilation, VE, tidal volume, VT, respiratory frequency,f, ratio between inspiratory period and total breath duration, TI/TTOT, and mean inspiratory flow, VT/TI) as well as mouth occlusion pressure measured at 100 msec (P0.1), effective impedance of the respiratory system (P0.1/VT/TI), inspiratory power for breathing (W) and O2 uptake (VO2) were measured during the third minute of each work load. At the same level of exercise both groups showed identical values of VT/TI, but VE was higher in group A individuals. This resulted from higher values of respiratory frequency with higher TI/TTOT ratios. P0.1, P0.1(VT/TI) and W were also much higher during work load in group A than in peripubertal subjects. When the above results were related to the same percentage of VO2 max, P0.1, W, respiratory frequency and duty cycle did not differ within both groups. However, VE, VT and VT/TI were lower in group A subjects with a higher P0.1/(VT/TI) ratio. Further corrections of VT, VT/TI and P0.1/(VT/TI) ratios by body weight cancelled all these differences. In conclusion, our results strongly suggest that biometric factors only determined interindividual differences in ventilatory response to exercise in prepubertal and peripubertal swimmers.     

Individuality of breathing patterns in adults assessed over time

Sixteen healthy adult subjects underwent two studies separated by 4-5 years to test whether their resting pattern of breathing was reproducible over time. From breath-by-breath analysis of airflow, measured with a pneumotachometer, the pattern of breathing was quantified in terms of individual respiratory variables; inspiratory time (TI), expiratory time (TE), total breath duration (TTOT), tidal volume (VT), VT/TI, TI/TTOT, and by taking TI, TE and VT all together (TRIAD). Also, the shape of the entire airflow profile was quantified by harmonic analysis (ASTER). A statistical analysis was designed to compare differences between the 1st and the 2nd recording within individuals with those differences observed between random pairs of recordings from the two studies in the same 16 individuals. It was found that all variables were significantly more similar within-individuals than between-individuals; this is best demonstrated when considering the ASTER and/or the TRIAD. It was concluded that the individuality of breathing pattern is maintained over a long period despite changes in smoking habit, weight, mild respiratory diseases, and other changes which occurred between the two studies in our subjects.     

Effect of intermittent mandatory ventilation on respiratory drive and timing

Seven patients receiving chronic ventilatory support were studied to better define the effects of intermittent mandatory ventilation (IMV) on the control and timing of spontaneous breathing between mandatory breaths. Each of these patients could sustain adequate spontaneous ventilation, as reflected by stable end-tidal carbon dioxide concentration (FETCO2), and arterial oxygen saturation (SO2) during periods of unassisted ventilation of sufficient duration to allow study. Inspiratory time (TI), respiratory cycle duration (Ttot), tidal volume (VT), and tracheal occlusion pressure (P0.1) were measured as IMV rate was progressively reduced. Respiratory timing was unaltered by decreasing IMV frequency; however, VT increased progressively. The P0.1 and mean inspiratory flow rate (VT/TI) also increased with each decrease in IMV rate, whereas FETCO2 and arterial SO2 remained constant. Thus, in these stable but ventilator-dependent patients, IMV did not alter respiratory timing or chemical stimuli, but it did alter respiratory drive as measured by VT/TI and P0.1.     

Breathing pattern during exercise in untrained children

Breathing pattern during exercise on a cycle ergometer was studied in 18 untrained children aged from 6 to 15 years of age (9 boys, 9 girls). Oxygen uptake, tidal volume, minute ventilation, all normalized for body weight (VO2BW, VT BW, VE BW), respiratory frequency (f), inspiratory (TI) and expiratory (TE) times, ratio TI over total duration of the respiratory cycle (TI/TTOT) and mean inspiratory flow (VT BW/TI) were measured: (1) at rest (W0) and at the highest load (maximal cardiac rate) of an incremental exercise (W1); (2) in steady state conditions, at 50% of W1 (W1/2) and at 2/3 of W1 (W2/3). VO2BW, VT BW, VE BW, TI/TTOT, VT BW/TI increased significantly (P less than 0.01) from W0 to W1. Behaviour of f and TI were different from the latter parameters: f increased and TI decreased significantly from W0 to W1/2 (P less than 0.01) and from W1/2 to W2/3 (P less than 0.01) but remained similar at W2/3 and W1. We observed a relationship between VO2 BW and VT BW/TI, and between VT BW and TI/TTOT at each step of workload. We conclude that untrained children adapt the pattern of breathing during exercise, as at rest, to metabolic demand. However, the increase in f and the decrease in TI are limited at maximal workload.     

Ventilatory pressure loading at constant pulmonary FCO2 in Gallus domesticus

Seven White Leghorn roosters were unidirectionally ventilated at constant flows and CO2 concentrations. The birds were awake and stood or crouched in a plethysmograph. A servo system clamped the pressure in the air sacs at constant values from -10 to +10 cm H2O in 2 cm H2O increments. Therefore, the animals could inflate or deflate the air sacs with breathing movements without affecting intrapulmonary pressures. Decreasing air sac pressure less than atmospheric caused inspiratory duration (TI), expiratory duration (TE), total period (TTOT) and tidal volume (VR) to decrease, and the ratio, TI/TE to increase. Increasing air sac pressures to 6 cm H2O above atmospheric caused, TE to increase, TI and TI/TE to decrease and VT and TTOT to change very little. After bilateral vagotomy air sac pressure changes caused little or no changes in TI, TE, TTOT or TI/TE, but produced percentage changes in VT similar to before vagotomy. Comparison of end expiratory volumes with apneic volumes (produced by lowering CO2 in the insulfating gas) over the range of air sac pressures clamped shows: (1) chickens actively exhale at pressures as low as -10 cm H2O, and (2) the change of mean air sac volume due to imposed pressure is less during breathing than during apnea. These findings, we believe, are due to a reflex initiated by mechanoreceptors with projections in the vagus nerves.     

Entrainment of respiration in humans by periodic lung inflations. Effect of state and CO(2).

Lack of synchrony between a patient and the mechanical ventilator occurs when the respiratory rhythm of the patient fails to entrain to machine inflations. Entrainment implies a resetting of the respiratory rhythm such that a fixed temporal relationship exists between the onset of inspiratory activity and the onset of a mechanical breath. We examined the entrainment response to mechanical ventilation of normal humans over a range of machine rates during wakefulness and during isocapnic and hypercapnic NREM sleep. Wakefulness facilitated 1:1 entrainment of the respiratory rhythm to the mechanical ventilator over a wider range of machine frequencies than during NREM sleep (p < 0.001); isocapnic and hypercapnic conditions did not differ (p = 0.95). To evaluate the Hering-Breuer reflexes in the resetting of the respiratory rhythm during sleep, we examined changes in neural inspiratory time (TI) as the relationship between inspiratory efforts and onset of machine inflations changed. As inspiratory efforts extended into the machine inflation cycle, neural TI shortened. We conclude that entrainment responses of normal humans to mechanical ventilation differ depending on state, but mild increases in respiratory drive caused by CO(2) stimulation do not affect these entrainment responses. Furthermore, the changes in neural TI are consistent with observations in animal studies in which Hering-Breuer reflexes mediated entrainment.