Effect of respiratory apparatus on respiration

A mouthpiece plus noseclip (MP + NC) is frequently used in performing measurements of breathing patterns. Although the effects the apparatus exerts on breathing patterns have been studied, the mechanism of the changes it causes remains unclear. The current study examines the effects on respiratory patterns of a standard (17-mm-diam) MP + NC during room air (RA) breathing and the administration of 2 and 4% CO2 in normal volunteers and in patients 2-4 days after abdominal operation. When compared with values obtained with a noninvasive canopy system, the MP + NC induced increases in minute ventilation (VE), tidal volume (VT), and mean inspiratory flow (VT/TI), but not frequency (f) or inspiratory duty cycle, during both RA and CO2 administration. The percentage increase in VE, VT, and VT/TI caused by the MP + NC decreased as the concentration of CO2 increased. During RA breathing, the application of noseclip alone resulted in a decrease in f and an increase in VT, but VE and VT/TI were unchanged. The changes were attenuated during the administration of 2 and 4% CO2. Reducing the diameter of the mouthpiece to 9 mm abolished the alterations in breathing pattern observed with the larger (17-mm) diameter MP.     

Human breathing patterns on mouthpiece or face mask during air, CO2, or low O2

Steady-state breathing patterns on mouthpiece and noseclip (MP) and face mask (MASK) during air and chemostimulated breathing were obtained from pneumotachometer flow. On air, all 10 subjects decreased frequency (f) and increased tidal volume (VT) on MP relative to that on MASK without changing ventilation (VE), mean inspiratory flow (VT/TI), or mean expiratory flow (VT/TE). On elevated CO2 and low O2, MP exaggerated the increase in VE, f, and VT/TE due to profoundly shortened TE. On elevated CO2, MASK exaggerated VT increase with little change in f. Increased VE and VT/TI were thus due to increased VT. During low O2 on MASK, both VT and f increased. During isocapnia, shortened TE accounted for increased f; during hypocapnia, increased f was related primarily to shortened TI. Thus the choice of a mouthpiece or face mask differentially alters breathing pattern on air and all components of ventilatory responses to chemostimuli. In addition, breathing apparatus effects are not a simple consequence of a shift from oronasal to oral breathing, since a noseclip under the mask did not change breathing pattern from that on mask alone.     

Postnatal maturation of ventilation and breathing pattern in kittens: influence of sleep

Ventilation and breathing pattern were studied in kittens at 1, 2, 3, 4, and 8 wk of life during quiet wakefulness (W), quiet sleep (QS), and active sleep (AS) with the barometric method. Tidal volume (VT), respiratory frequency (f), ventilation (VE), inspiratory time (TI), expiratory time (TE), mean inspiratory flow (VT/TI), and respiratory "duty cycle" (TI/TT) were measured. VT, VE, TI, TE, and VT/TI increased; f decreased and TI/TT remained constant during postnatal development in wakefulness and in both sleep states. No significant difference was observed between AS and QS for all the ventilatory parameters except TI/TT, which was greater in QS than in AS at 2 wk. VE was larger in W than in both AS and QS at all ages. This was mainly due to a greater f, TI/TT remaining constant. VT/TI, which represents an index of the central inspiratory activity, was larger in W than in sleep, VT not being significantly different whatever the stage of consciousness. The results of this study show that in the kitten 1) unlike in the adult cat, ventilation and breathing pattern are similar in QS and in AS; 2) in sleep, the central inspiratory drive appears to be independent of the type of sleep; and 3) in wakefulness, the increase of the central inspiratory activity could be related to important excitatory inputs.     

Ventilatory response during CO2 inhalation after airway anesthesia with lidocaine

Airway anesthesia with inhaled aerosolized lidocaine has been associated with increases in minute ventilation (VE) and mean inspiratory flow rate (VT/TI) during CO2 inhalation. However, it is unclear whether these increases are local effects of the anesthesia or systemic effects of absorbed and circulating lidocaine. To evaluate this 20 normal subjects were treated on separate days with aerosolized lidocaine, intravenous lidocaine, aerosolized control solution, or intravenous control solution, and the effects of each treatment on VE and VT/TI were determined and compared during room-air breathing and inhalation of 5% CO2-95% O2. None of the treatments altered VE or VT/TI during room-air breathing. Aerosolized lidocaine produced small (5.9-6.0%) increases in VE and VT/TI during CO2 inhalation, but these effects were not present after intravenous lidocaine despite equivalent lidocaine blood levels. We concluded that the increases in VE and VT/TI after aerosolized lidocaine were local effects of airway anesthesia rather than systemic effects of absorbed and circulating lidocaine.     

Variability of resting respiratory drive and timing in healthy subjects

Studies of breathing pattern have focused primarily on changes in the mean values of the breathing pattern components, whereas there has been minimal investigation of breath-to-breath variability, which should provide information on the constancy with which respiration is controlled. In this study we examined the variability of breathing pattern both on a breath-to-breath and day-to-day basis by calculating the coefficient of variation (i.e., the standard deviation expressed as a percentage of the mean). By examining breath-to-breath data, we found that the coefficients of variation of tidal volume (VT) and fractional inspiratory time (TI/TT, an index of timing) obtained with an inductive plethysmograph and spirometer were within 1% of each other. Examination of breath-to-breath variability in breathing pattern over a 15-min period in 65 subjects revealed large coefficients of variation, indicating the need to base calculations on a relatively large number of breaths. Less breath-to-breath variability was observed in respiratory frequency [f, 20.8 +/- 11.5% (SD)] and TI/TT (17.9 +/- 6.5%) than in VT (33 +/- 14.9%) and mean inspiratory flow (VT/TI, an index of drive; 31.6 +/- 12.6%; P less than 0.0001). Older subjects (60-81 yr) displayed greater breath-to-breath variability than young subjects (21-50 yr). Use of a mouthpiece did not affect the degree of variability.(ABSTRACT TRUNCATED AT 250 WORDS)     

Breathing pattern during exercise in young black and Caucasian subjects

Lung volumes in sex-, age-, height-, and weight-matched Black subjects are 10-15% lower than those in Caucasians. To determine whether this decreased lung volume affected the ventilatory adaptation to exercise, minute ventilation (VE), its components, frequency (f) and tidal volume (VT), and breathing pattern were observed during incremental cycle-ergometer exercise. Eighteen Caucasian (age 8-30 yr) and 14 Black (age 8-25 yr) subjects were studied. Vital capacity (VC) was lower (P less than 0.001) in the Black subjects [90.6 +/- 8.6 (SD) vs. 112.9 +/- 9.9% predicted], whereas functional residual capacity/total lung capacity was higher (P less than 0.05). VE, mixed expired O2 and CO2, VT, f, and inspiratory (TI), expiratory (TE), and total respiratory cycle (TT) duration were measured during the last 30 s of each 2-min load. Statistical comparisons with increasing power output were made at rest and from 0.6 to 2.4 W/kg in 0.3-W/kg increments. VE was higher in Blacks at all work loads and reached significance (P less than 0.05) at 0.6 and 1.5 W/kg. VE/VO2 was also higher throughout exercise, reaching significance (P less than 0.01) at 1.2, 1.5, and 1.8 W/kg. The Black subjects attained any given level of VE with a higher f (P less than 0.001) and lower VT. TI and TE were shortened proportionately so that TI/TT was not different. Differences in lung volume and the ventilatory response to exercise in these Black and Caucasian subjects suggest differences in the respiratory pressure-volume relationships or that the Black subjects may breathe higher on their pressure-volume curve.     

Effects of inspiratory resistive load on respiratory control in hypercapnia and exercise

Eight healthy young men underwent two separate steady-state incremental exercise runs within the aerobic range on a treadmill with alternating periods of breathing with no load (NL) and with an inspiratory resistive load (IRL) of approximately 12 cmH2O.1-1.s. End-tidal PCO2 was maintained constant throughout each run at the eucapnic or a constant hypercapnic level by adding 0-5% CO2 to the inspired O2. Hypercapnia caused a steepening, as well as upward shift, relative to the corresponding eucapnic ventilation-CO2 output (VE - VCO2) relationship in NL and IRL. Compared with NL, the VE - VCO2 slope was depressed by IRL, more so in hypercapnic [-19.0 +/- 3.4 (SE) %] than in eucapnic exercise (-6.0 +/- 2.0%), despite a similar increase in the slope of the occlusion pressure at 100 ms - VCO2 (P100 - VCO2) relationship under both conditions. The steady-state hypercapnic ventilatory response at rest was markedly depressed by IRL (-22.6 +/- 7.5%), with little increase in P100 response. For a given inspiratory load, breathing pattern responses to separate or combined hypercapnia and exercise were similar. During IRL, VE was achieved by a greater tidal volume (VT) and inspiratory duty cycle (TI/TT) along with a lower mean inspiratory flow (VT/TI). The increase in TI/TT was solely because of a prolongation of inspiratory time (TI) with little change in expiratory duration for any given VT. The ventilatory and breathing pattern responses to IRL during CO2 inhalation and exercise are in favor of conservation of respiratory work.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phonospirometry for noninvasive measurement of ventilation: methodology and preliminary results.

We measured tracheal flow from tracheal sounds to estimate tidal volume, minute ventilation (VI), respiratory frequency, mean inspiratory flow (VT/TI), and duty cycle (TI/Ttot). In 11 normal subjects, 3 patients with unstable airway obstruction, and 3 stable asthmatic patients, we measured tracheal sounds and flow twice: first to derive flow-sound relationships and second to obtain flow-volume relationships from the sound signal. The flow-volume relationship was compared with pneumotach-derived volume. When subjects were seated, facing forward and with neck rotation, flexion, and standing, flow-volume relationship was within 15% of pneumotach-derived volume. Error increased with neck extension and while supine. We then measured ventilation without mouthpiece or nose clip from tracheal sounds during quiet breathing for up to 30 min. Normal results +/- SD revealed tidal volume = 0.37 +/- 0.065 liter, respiratory frequency = 19.3 +/- 3.5 breaths/min, VI = 6.9 +/- 1.2 l/min, VT/TI = 0.31 +/- 0.06 l/s, and TI/Ttot = 0.37 +/- 0.04. Unstable airway obstruction had large VI due to increased VT/TI. With the exception of TI/Ttot, variations in ventilatory parameters were closer to log normal than normal distributions and tended to be greater in patients. We conclude that phonospirometry measures ventilation reasonably accurately without mouthpiece, nose clip, or rigid postural constraints.     

Effect of hilar nerve denervation on breathing and arterial PCO2 during CO2 inhalation

We determined the effects of denervating the hilar branches (HND) of the vagus nerves on breathing and arterial PCO2 (PaCO2) in awake ponies during eupnea and when inspired PCO2 (PICO2) was increased to 14, 28, and 42 Torr. In five carotid chemoreceptor-intact ponies, breathing frequency (f) was less, whereas tidal volume (VT), inspiratory time (TI), and ratio of TI to total cycle time (TT) were greater 2-4 wk after HND than before HND. HND per se did not significantly affect PaCO2 at any level of PICO2, and the minute ventilation (VE)-PaCO2 response curve was not significantly altered by HND. Finally, the attenuation of a thermal tachypnea by elevated PICO2 was not altered by HND. Accordingly, in carotid chemoreceptor-intact ponies, the only HND effect on breathing was the change in pattern classically observed with attenuated lung volume feedback. There was no evidence suggestive of a PCO2-H+ sensory mechanism influencing VE, f, VT, or PaCO2. In ponies that had the carotid chemoreceptors denervated (CBD) 3 yr earlier, HND also decreased f, increased VT, TI, and TT, but did not alter the slope of the VE-PaCO2 response curve. However, at all levels of elevated PICO2, the arterial hypercapnia that had persistently been attenuated, since CBD was restored to normal by HND. The data suggest that during CO2 inhalation in CBD ponies a hilar-innervated mechanism influences PaCO2 by reducing physiological dead space to increase alveolar ventilation.     

Pattern of breathing in the rat.

The basic ventilation values - tidal volume (VT), breathing frequency (f), minute ventilation (VE) and the duration of inspiration (TI) and expiration (TE) -- were determined in adult male rats. The range of these values is given and the pattern of breathing is defined as the relationship between VE and VT, which in the rat is linear throughout its entire range. The role of TI and TE in changing f in the rat were evaluated. The breathing pattern of the rat was compared with data for the rabbit and man, using percentual expression of the basic values. A shift of the breathing pattern to higher f values was observed in rats with experimental lung diseases. In these rats, the inhalation of 100% O2 shifted the pattern of breathing markedly to lower VE values, though not to values comparable with the controls. Bilateral cervical vagotomy was followed by a pronouced decrease in f, an increase in VT and T1 persisted even after vagotomy, however; it can be assumed that this relationship is effected either by means of receptors in the chest muscles, or by the direct action of CO2 which is used to stimulate breathing, on the bulbopontine pacemaker.     

Airway anesthesia effects on hypercapnic breathing pattern in humans

Minute ventilation (VE) and breathing pattern during an abrupt increase in fractional CO2 were compared in 10 normal subjects before and after airway anesthesia. Subjects breathed 7% CO2-93% O2 for 5 min before and after inhaling aerosolized lidocaine. As a result of airway anesthesia, VE and tidal volume (VT) were greater during hypercapnia, but there was no effect on inspiratory time (TI). Therefore, airway anesthesia produced an increase in mean inspiratory flow (VT/TI) during hypercapnia. The increase in VT/TI was compatible with an increase in neuromuscular output. There was no effect of airway anesthesia on the inspiratory timing ratio or the shape and position of the curve relating VT and TI. We also compared airway resistance (Raw), thoracic gas volume, forced vital capacity, forced expired volume at 1s, and maximum midexpiratory flow rate before and after airway anesthesia. A small (0.18 cmH2O X l-1 X s) decrease in Raw occurred after airway anesthesia that did not correlate with the effect of airway anesthesia on VT/TI. We conclude that airway receptors accessible to airway anesthesia play a role in hypercapnic VE.     

Hyperpnoea and CO2 sensitivity of the respiratory centres during exercise

The aim of this study was to specify whether exercise hyperpnoea was related to the CO2 sensitivity of the respiratory centres measured during steady-state exercise of mild intensity. Thus, ventilation (VE), breathing pattern [tidal volume (VT), respiratory frequency (f), inspiratory time (TI), total time of the respiratory cycle (TTOT), VT/TI, TI/TTOT] and CO2 sensitivity of the respiratory centres determined by the rebreathing method were measured at rest (SCO2re) and during steady-state exercise (SCO2ex) of mild intensity [CO2 output (VCO2) = 20 ml.kg-1.min-1] in 11 sedentary male subjects (aged 20-34 years). The results showed that SCO2re and SCO2ex were not significantly different. During exercise, there was no correlation between VE and SCO2ex and, for the same VCO2, all subjects had very close VE values normalized for body mass (bm), regardless of their SCO2ex (VEbm0.75 = 1.44 l.min-1.kg-1 SD 0.10). A highly significant positive correlation between SCO2ex and VT (normalised for bm) (r = 0.80, P less than 0.01), TI (r = 0.77, P less than 0.01) and TTOT (r = 0.77, P less than 0.01) existed, as well as a highly significant negative correlation between SCO2ex and (normalised for bm-0.25) (r = -0.73, P less than 0.01). We conclude that the hyperpnoea during steady-state exercise of mild intensity is not related to the SCO2ex. The relationship between breathing pattern and SCO2ex suggests that the breathing pattern could influence the determination of the SCO2ex. This finding needs further investigation.     

Ventilatory response to fatiguing and nonfatiguing resistive loads in awake sheep

To study the changes in ventilation induced by inspiratory flow-resistive (IFR) loads, we applied moderate and severe IFR loads in chronically instrumented and awake sheep. We measured inspired minute ventilation (VI), ventilatory pattern [inspiratory time (TI), expiratory time (TE), respiratory cycle time (TT), tidal volume (VT), mean inspiratory flow (VT/TI), and respiratory duty cycle (TI/TT)], transdiaphragmatic pressure (Pdi), functional residual capacity (FRC), blood gas tensions, and recorded diaphragmatic electromyogram. With both moderate and severe loads, Pdi, TI, and TI/TT increased, TE, TT, VT, VT/TI, and VI decreased, and hypercapnia ensued. FRC did not change significantly with moderate loads but decreased by 30-40% with severe loads. With severe loads, arterial PCO2 (PaCO2) stabilized at approximately 60 Torr within 10-15 min and rose further to levels exceeding 80 Torr when Pdi dropped. This was associated with a lengthening in TE and a decrease in breathing frequency, VI, and TI/TT. We conclude that 1) timing and volume responses to IFR loads are not sufficient to prevent alveolar hypoventilation, 2) with severe loads the considerable increase in Pdi, TI/TT, and PaCO2 may reduce respiratory muscle endurance, and 3) the changes in ventilation associated with neuromuscular fatigue occur after the drop in Pdi. We believe that these ventilatory changes are dictated by the mechanical capability of the respiratory muscles or induced by a decrease in central neural output to these muscles or both.     

Lung mechanics and neuromuscular output during CO2 inhalation after airway anesthesia

Airway anesthesia with aerosolized lidocaine has been associated with an increase in minute ventilation (VE) during CO2 inhalation. The increase in VE may be due to increased neuromuscular output or decreased mechanical load on breathing. To evaluate this we measured VE, breathing pattern, mouth occlusion pressure, and lung mechanics in 20 normal subjects during room-air breathing and then inhalation of 6% CO2-94% O2, before and after airway anesthesia. Measurements of lung mechanics included whole-lung resistance, dynamic and static compliance, and functional residual capacity. Airway anesthesia had no detectable effect on any measurements during room-air breathing. During CO2 inhalation, airway anesthesia produced increases in VE and mean inspiratory flow rate (VT/TI) and more negative inspiratory pleural pressure but had no detectable effect on lung mechanics or mouth occlusion pressure. Pleural pressure was more negative during the latter 25% of inspiration. We concluded that airway receptors accessible to airway anesthesia play a role in determining neuromuscular output during CO2 inhalation.     

Effects of acute exposure to high altitude on ventilatory drive and respiratory pattern

To assess changes in ventilatory regulation in terms of central drive and timing, on exposure to high altitude, and the effects of induced hyperoxia at high altitude, six healthy normal lowland subjects (mean age 19.5 +/- 1.64 yr) were studied at low altitude (518 m) and on the first 4 days at high altitude (3,940 m). The progressive increase in resting expired minute ventilation (VE; control mean 9.94 +/- 1.78 to 14.25 +/- 2.67 l/min on day 3, P less than 0.005) on exposure to high altitude was primarily due to a significant increase in respiratory frequency (f; control mean 15.6 +/- 3.5 breaths/min to 23.8 +/- 6.2 breaths/min on day 3, P less than 0.01) with no significant change in tidal volume (VT). The increase in f was due to significant decreases in both inspiratory (TI) and expiratory (TE) time per breath; the ratio of TI to TE increased significantly (control mean 0.40 +/- 0.08 to 0.57 +/- 0.14, P less than 0.025). Mouth occlusion pressure did not change significantly, nor did the ratio of VE to mouth occlusion pressure. The acute induction of hyperoxia for 10 min at high altitude did not significantly alter VE or the ventilatory pattern. These results indicate that acute exposure to high altitude in normal lowlanders causes an increase in VE primarily by an alteration in central breath timing, with no change in respiratory drive. The acute relief of high altitude hypoxia for 10 min has no effect on the increased VE or ventilatory pattern.     

Ventilatory response to high-frequency airway oscillation in humans

To investigate respiratory control during high-frequency oscillation (HFO), ventilation was monitored in conscious humans by respiratory inductive plethysmography during application at the mouth of high-frequency pressure oscillations. Studies were conducted before and after airway and pharyngeal anesthesia. During HFO, breathing became slow and deep with an increase in tidal volume (VT) of 37% (P less than 0.01) and inspiratory duration (TI) of 34% (P less than 0.01). Timing ratio (TI/TT) increased 14% (P less than 0.05) and respiratory frequency (f) decreased 12% (P less than 0.01). Mean inspiratory flow (VT/TI) did not change during HFO. Following airway anesthesia, VT increased only 26% during HFO (P less than 0.01), whereas significant changes in TI, TI/TT, and f were not observed. Pharyngeal anesthesia failed to diminish the effect of HFO on TI, TT, or f, although the increase in VT was reduced. These results indicate that 1) HFO presented in this manner alters inspiratory timing without affecting the level of inspiratory activity, and 2) receptors in the larynx and/or lower airways may in part mediate the response.     

Mechanical impedance as determinant of inspiratory neural drive during exercise in humans

Five healthy males exercised progressively with small 2-min increments in work load. We measured inspiratory drive (occlusion pressure, P0.1), pulmonary resistance (RL), dynamic pulmonary compliance (Cdyn), transdiaphragmatic pressure (Pdi), and diaphragmatic electromyogram (EMGdi). Minute ventilation (VE), mean inspiratory flow rate (VT/TI), and P0.1 all increased exponentially with increased work load, but P0.1 increased at a faster rate than did VT/TI or VE. Thus effective impedance (P0.1/VT/TI) rose throughout exercise. The increasing P0.1 was mostly due to augmented Pdi and coincided with increased EMGdi during this initial portion of inspiration. We found no consistent change in RL or Cdyn throughout exercise. With He breathing (80% He-20% O2), RL was reduced at all work loads; P0.1 fell in comparison with air-breathing values and VE, VT, and VT/TI rose in moderate and heavy work; and P0.1/VT/TI was unchanged with increasing exercise loads. Step reductions in gas density at a constant work load of any intensity showed an immediate reduction in the rate of rise of EMGdi and Pdi followed by increased VT/TI, breathing frequency, and hypocapnia. These changes were maintained during prolonged periods of unloading and were immediately reversible on return to air breathing. These data are consistent with the existence of a reflex effect on the magnitude of inspiratory neural drive during exercise that is sensitive to the load presented by the normal mechanical time constant of the respiratory system. This "load" is a significant determinant of the hyperpneic response and thus of the maintenance of normocapnia during exercise.     

Contribution of central and reflex nervous activity to the rapid increase in pulmonary ventilation at the start of muscular exercise in man

To investigate the relative contributions of the central and peripheral neural drive to hyperventilation at the onset of muscular exercise, five volunteers were tested during the first ten breaths while performing both voluntary (VM) and passive (PM) ankle rotations with a frequency of 1 Hz and through an angle of 10 degrees. Resulting breathing patterns for the two movements were compared. Hypocapnic hyperventilation, found in both PM and VM, indicated its neural origin. Respiratory changes were higher in VM than in PM. In both experimental conditions, increases in ventilation (VE) depended more on respiratory frequency (f) than on tidal volume (VT). Moreover, increases in VT adapted, breath-by-breath, to values lower than the initial ones, while increases in f rose progressively. Expiratory time was reduced more than inspiratory time (TI); increases in inspiratory flow (VT/TI) depended to the same extent on changes in both TI and VT. Increases in expiratory tidal volume were initially higher than in inspiratory tidal volume, thereby producing a reduction in functional residual capacity. Because PM respiratory changes could be considered to be of nervous reflex origin only, the identical breathing patterns in PM and VM indicated that the hyperventilation found also in VM was mainly of reflex origin. The increase in VE was considered to be dependent on a greater stimulus from muscle proprioreceptors.     

Driving and timing components of the breathing pattern during hypoxia in anaesthetized cats

The effects of acute hypoxic hypoxia elicited by N2 inhalation on the driving and timing components of the breathing pattern were studied in 18 adult anaesthetized cats. Two phases could be distinguished in the ventilatory response to acute hypoxia. During the first phase, mean inspiratory flow (VT/TI) increased exponentially up to 240% of the initial value. During the second phase, VT/TI gradually decreased, reaching the control values in the last preapnoeic breaths during the first exposure and remained higher than normal with earlier respiratory arrest in three repeated N2 inhalations. No significant changes could be observed in the timing component of breathing pattern (TI/TT) in the course of the first hypoxic exposure, and the changes in TI/TT did not exceed 7% in repeated attacks. This suggests that the shortening of both inspiratory and expiratory durations increased the breathing frequency up to 130% of its resting value. Moreover, tachypnoea was preserved until respiratory arrest. Accordingly, it is concluded that the decrease in ventilation with the appearance of apnoea during the second phase of N2 inhalation in anaesthetized cats is not due to a failure of respiratory timing, but to a depression of the driving mechanisms which are responsible for this phenomenon.     

Selected contribution: variation in acute hypoxic ventilatory response is linked to mouse chromosome 9.

Genetic determinants confer variation among inbred mouse strains with respect to the magnitude and pattern of breathing during acute hypoxic challenge. Specifically, inheritance patterns derived from C3H/HeJ (C3) and C57BL/6J (B6) parental strains suggest that differences in hypoxic ventilatory response (HVR) are controlled by as few as two genes. The present study demonstrates that at least one genetic determinant is located on mouse chromosome 9. This genotype-phenotype association was established by phenotyping 52 B6C3F2 (F2) offspring for HVR characteristics. A genome-wide screen was performed using microsatellite DNA markers (n = 176) polymorphic between C3 and B6 mice. By computing log-likelihood values (LOD scores), linkage analysis compared marker genotypes with minute ventilation (&Vdot;E), tidal volume (VT), and mean inspiratory flow (VT/TI, where TI is inspiratory time) during acute hypoxic challenge (inspired O2 fraction = 0.10, inspired CO2 fraction = 0.03 in N2). A putative quantitative trait locus (QTL) positioned in the vicinity of D9Mit207 was significantly associated with hypoxic VE (LOD = 4.5), VT (LOD = 4.0), and VT/TI (LOD = 5.1). For each of the three HVR characteristics, the putative QTL explained more than 30% of the phenotypic variation among F(2) offspring. In conclusion, this genetic model of differential HVR characteristics demonstrates that a locus approximately 33 centimorgans from the centromere on mouse chromosome 9 confers a substantial proportion of the variance in VE, VT, and VT/TI during acute hypoxic challenge.