Study Objectives Conventional metrics of sleep quantity/depth have serious shortcomings. Odds-Ratio-Product (ORP) is a continuous metric of sleep depth ranging from 0 (very deep sleep) to 2.5 (full-wakefulness). We describe an ORP-based... more
Study Objectives Conventional metrics of sleep quantity/depth have serious shortcomings. Odds-Ratio-Product (ORP) is a continuous metric of sleep depth ranging from 0 (very deep sleep) to 2.5 (full-wakefulness). We describe an ORP-based approach that provides information on sleep disorders not apparent from traditional metrics. Methods We analyzed records from the Sleep-Heart-Health-Study and a study of performance deficit following sleep deprivation. ORP of all 30-second epochs in each PSG and percent of epochs in each decile of ORPs range were calculated. Percentage of epochs in deep sleep (ORP < 0.50) and in full-wakefulness (ORP > 2.25) were each assigned a rank, 1–3, representing first and second digits, respectively, of nine distinct types (“1,1”, “1,2” … ”3,3”). Prevalence of each type in clinical groups and their associations with demographics, sleepiness (Epworth-Sleepiness-Scale, ESS) and quality of life (QOL; Short-Form-Health-Survey-36) were determined. Results Thr...
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BACKGROUND Brain maturation is reflected in the sleep electroencephalogram (EEG) by a decline in non-rapid eye movement (NREM) slow wave activity (SWA) throughout adolescence and a related decrease in sleep depth. However, this trajectory... more
BACKGROUND Brain maturation is reflected in the sleep electroencephalogram (EEG) by a decline in non-rapid eye movement (NREM) slow wave activity (SWA) throughout adolescence and a related decrease in sleep depth. However, this trajectory and its sex and pubertal differences lack replication in population-based samples. We tested age-related changes in SWA (0.4-4 Hz) power and odds ratio product (ORP), a standardized measure of sleep depth. METHODS We analyzed the sleep EEG of 572 subjects aged 6-21 y (48% female, 26% racial/ethnic minority) and 332 subjects 5-12 y followed-up at 12-22 y. Multivariable-adjusted analyses tested age-related cross-sectional and longitudinal trajectories of SWA and ORP. RESULTS SWA remained stable from age 6 to 10, decreased between ages 11 and 17, and plateaued from age 18 to 21 (p-cubic<0.001); females showed a longitudinal decline 23% greater than males by 13 y, while males experienced a steeper slope after 14 y and their longitudinal decline was 21% greater by 19 y. More mature adolescents (75% female) experienced a greater longitudinal decline in SWA than less mature adolescents by 14 y. ORP showed an age-related increasing trajectory (p-linear<0.001) with no sex or pubertal differences. CONCLUSIONS We provide population-level evidence for the maturational decline and sex and pubertal differences in SWA in the transition from childhood to adolescence, while introducing ORP as a novel metric in youth. Along with previous studies, the distinct trajectories observed suggest that age-related changes in SWA reflect brain maturation and local/synaptic processes during this developmental period, while those of ORP may reflect global/state control of NREM sleep depth.
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The usefulness of exercise tests is considerably enhanced if the treating physician becomes involved in interpretation of their results. Interpretation is facilitated through the use of a graphic approach that can be implemented with... more
The usefulness of exercise tests is considerably enhanced if the treating physician becomes involved in interpretation of their results. Interpretation is facilitated through the use of a graphic approach that can be implemented with inexpensive desk-top computers. The relevant relations and the clinical and pathophysiologic significance of abnormalities in these graphs are discussed.
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Study Objectives New electroencephalogram (EEG) features became available for use in polysomnography and have shown promise in early studies. They include a continuous index of sleep depth (odds-ratio-product: ORP), agreement between... more
Study Objectives New electroencephalogram (EEG) features became available for use in polysomnography and have shown promise in early studies. They include a continuous index of sleep depth (odds-ratio-product: ORP), agreement between right and left sleep depth (R/L coefficient), dynamics of sleep recovery following arousals (ORP-9), general EEG amplification (EEG Power), alpha intrusion and arousal intensity. This study was undertaken to establish ranges and reproducibility of these features in subjects with different demographics and clinical status. Methods We utilized data from the two phases of the Sleep-Heart-Health-Study (SHHS1 and SHHS2). Polysomnograms of 5,804 subjects from SHHS1 were scored to determine the above features. Feature values were segregated according to clinical status of obstructive sleep apnea (OSA), insomnia, insomnia plus OSA, no clinical sleep disorder, and demographics (age, gender, and race). Results from SHHS visit2 were compared with SHHS1 results. Re...
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RATIONAL Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure (CPAP) in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious... more
RATIONAL Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure (CPAP) in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with heightened apnea/hypopnea-related pulse rate response. METHODS We measured the pulse rate response to apneas/hypopneas (∆HR) in the Multi-Ethnic Study of Atherosclerosis (MESA, N=1395) and the Sleep Heart Health Study (SHHS, N=4575). MESA data were used to determine the functional form of association between ∆HR and subclinical cardiovascular biomarkers, while primary analyses tested the association of ∆HR with non-fatal/fatal CVD and all-cause mortality in longitudinal data from the SHHS. RESULTS In MESA, U-shaped relationships were observed between subclinical CVD biomarkers (coronary artery calcium; NT-proBNP; Framingham risk score) and ∆HR; notably, high ∆HR (upper quartile) was associated with elevated biomarker scores compared to mid ∆HR (25th-75th centiles). In SHHS, individuals with high ∆HR compared to mid ∆HR were at increased risk of non-fatal/fatal CVD and all-cause mortality (non-fatal: 1.60 [1.28-2.00]; fatal: 1.68 [1.22-2.30]; all-cause: 1.29 [1.07-1.55], adjusted hazard ratio [95%CI]). The risk associated with high ∆HR was particularly high in those with substantial hypoxic burden (non-fatal: 1.93 [1.36-2.73]; fatal: 3.50 [2.15-5.71]; all-cause: 1.84 [1.40-2.40]) and was exclusively observed in non-sleepy individuals. CONCLUSIONS Individuals with OSA who demonstrate elevated pulse rate response are at increased risk of cardiovascular morbidity and mortality. This study identifies a prognostic biomarker for OSA that appears useful for risk stratification and patient selection for future clinical trials.
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One of the most devastating complications of respiratory disease is the limitation it imposes on the individual’s capacity to engage in physical activity. As disease progresses in severity, the capacity to exercise progressively... more
One of the most devastating complications of respiratory disease is the limitation it imposes on the individual’s capacity to engage in physical activity. As disease progresses in severity, the capacity to exercise progressively decreases. In very severe disease, the subject becomes dyspneic on minimal exertion, or even at rest. In this chapter, the normal respiratory responses to exercise will first
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Study Objectives Sleep spindles, a defining feature of stage N2 sleep, are maximal at central electrodes and are found in the frequency range of the electroencephalogram (EEG) (sigma 11–16 Hz) that is known to be heritable. However,... more
Study Objectives Sleep spindles, a defining feature of stage N2 sleep, are maximal at central electrodes and are found in the frequency range of the electroencephalogram (EEG) (sigma 11–16 Hz) that is known to be heritable. However, relatively little is known about the heritability of spindles. Two recent studies investigating the heritability of spindles reported moderate heritability, but with conflicting results depending on scalp location and spindle type. The present study aimed to definitively assess the heritability of sleep spindle characteristics. Methods We utilized the polysomnography data of 58 monozygotic and 40 dizygotic same-sex twin pairs to identify heritable characteristics of spindles at C3/C4 in stage N2 sleep including density, duration, peak-to-peak amplitude, and oscillation frequency. We implemented and tested a variety of spindle detection algorithms and used two complementary methods of estimating trait heritability. Results We found robust evidence to supp...
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Study Objectives To compare delta spectral power (delta) and odds ratio product (ORP) as measures of sleep depth during sleep restriction with placebo or a drug that increases delta. Methods This is a secondary analysis of data from a... more
Study Objectives To compare delta spectral power (delta) and odds ratio product (ORP) as measures of sleep depth during sleep restriction with placebo or a drug that increases delta. Methods This is a secondary analysis of data from a study of 41 healthy participants randomized to receive placebo or gaboxadol 15 mg during sleep restriction. Participants underwent in-laboratory sleep studies on two baseline, four sleep restriction (5-h), and two recovery nights. Relation between delta or ORP and sleep depth was operationally defined as the degree of association of each metric to the probability of arousal or awakening occurring during the next 30 s (arousability). Results ORP values in wake, N1, N2, N3, and REM were significantly different. Delta differed between both N2 and N3 and other sleep stages but not between wake and N1 or N1 and REM. Epoch-by-epoch and individual correlations between ORP and delta power were modest or insignificant. The relation between ORP and arousability ...
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Introduction The odds ratio product (ORP) is a new highly-validated electroencephalogram biomarker of sleep depth. ORP has been validated as such by several studies investigating the effect of sleep disorders, responses to sleep... more
Introduction The odds ratio product (ORP) is a new highly-validated electroencephalogram biomarker of sleep depth. ORP has been validated as such by several studies investigating the effect of sleep disorders, responses to sleep deprivation and traffic noise. ORP during REM sleep varies considerably among individuals. Whether ORP reflects sleep depth also in REM sleep is unknown. We hypothesized that subjects with high REM ORP are more prone to REM sleep fragmentation. Methods Using data from the baseline (SHHS1; N=5,537) and follow-up (SHHS2; N=2,595) visits of the Sleep Heart Health Study, we calculated and summarized ORP in 30-second intervals corresponding to manually scored sleep stage epochs. We developed a heuristic to identify REM periods, defined as sequences of REM sleep epochs separated by no more than 10 minutes of other sleep stages or wake epochs. Using general linear models adjusted by age, sex, body mass index, race and ethnicity, we evaluated the relationship betwee...
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To determine the relationship between sleep spindle characteristics (density, power and frequency), executive functioning and cognitive decline in older adults, we studied a convenience subsample of healthy middle‐aged and older... more
To determine the relationship between sleep spindle characteristics (density, power and frequency), executive functioning and cognitive decline in older adults, we studied a convenience subsample of healthy middle‐aged and older participants of the Brain in Motion study. Participants underwent a single night of unattended in‐home polysomnography with neurocognitive testing carried out shortly afterwards. Spectral analysis of the EEG was performed to derive spindle characteristics in both central and frontal derivations during non‐rapid eye movement (NREM) Stage 2 and 3. Multiple linear regressions were used to examine associations between spindle characteristics and cognitive outcomes, with age, body mass index (BMI), periodic limb movements index (PLMI) and apnea hypopnea index (AHI) as covariates. NREM Stage 2 total spindle density was significantly associated with executive functioning (central: β = .363, p = .016; frontal: β = .408, p = .004). NREM Stage 2 fast spindle density was associated with executive functioning (central: β = .351, p = .022; frontal: β = .380, p = .009) and Montreal Cognitive Assessment score (MoCA, central: β = .285, p = .037; frontal: β = .279, p = .032). NREM Stage 2 spindle frequency was also associated with MoCA score (central: β = .337, p = .013). Greater spindle density and fast spindle density were associated with better executive functioning and less cognitive decline in our study population. Our cross‐sectional design cannot infer causality. Longitudinal studies will be required to assess the ability of spindle characteristics to predict future cognitive status.
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We measured the "effective" dead space of five commonly used respiratory valves: Hans Rudolph valve, two-way J valve, triple-J valve, and modified Otis-McKerrow valves without and with vane. The dead space was measured using a... more
We measured the "effective" dead space of five commonly used respiratory valves: Hans Rudolph valve, two-way J valve, triple-J valve, and modified Otis-McKerrow valves without and with vane. The dead space was measured using a technique that mimicked the operation of valves during ordinary laboratory procedures. The valves were ventilated with tidal volumes ranging from 0.35-3.00 liters and at different frequencies. With all valves, there was a marked tendency for "effective" dead space to be tidal volume dependent. The measured dead space approached the water-displacement volume of the common chamber of the valve only at tidal volumes in excess of 2.0 liters. The relation between valve dead space and tidal volume was independent of frequency.
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The mechanism of ventilatory stimulation that accompanies increases in cardiac output is unknown. Previous studies addressing this issue have been inconclusive. However, only steady pulmonary blood flow was used. The effect of flow... more
The mechanism of ventilatory stimulation that accompanies increases in cardiac output is unknown. Previous studies addressing this issue have been inconclusive. However, only steady pulmonary blood flow was used. The effect of flow pulsatility merits consideration, because increasing cardiac output raises not only mean pulmonary arterial pressure but also pulse pressure; mechanoreceptors with an important dynamic component to their responses may cause a response to pulsatile, but not steady, flow. Studies were done on anesthetized cats (n = 4) and dogs (n = 4). The right pulmonary artery was cannulated within the pericardium, and systemic blood was pumped from the left atrium to the right pulmonary artery. The right pulmonary circulation was perfused at different levels of flow, which was either steady or pulsatile. Steady-state flow of up to 150 ml.kg-1.min-1 (270 ml.kg-1.min-1 when corrected for the proportion of lung tissue perfused) did not affect breathing pattern. When high pu...
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We studied whether exercise endurance under normobaric hypoxia can be enhanced by increasing hypoxic ventilatory sensitivity with almitrine bismesylate (ALM). On both ALM and placebo (PL) days, resting subjects breathed a hypoxic gas... more
We studied whether exercise endurance under normobaric hypoxia can be enhanced by increasing hypoxic ventilatory sensitivity with almitrine bismesylate (ALM). On both ALM and placebo (PL) days, resting subjects breathed a hypoxic gas mixture (an inspired O2 fraction of 10.4-13.2%), which lowered resting arterial O2 saturation (SaO2) to 80%. After 15 min of rest there was a 3-min warm-up period of exercise at 50 W (light) on a cycle ergometer, followed by a step increase in load to 60% of the previously determined maximum power output with room-air breathing (moderate), which was maintained until exhaustion. With PL, SaO2 decreased rapidly with the onset of exercise and continued to fall slowly during moderate exercise, averaging 71.0 +/- 1.8% (SE) at exhaustion. With ALM, saturation did not differ from PL during air breathing but significantly exceeded SaO2 with PL, by 3.4% during resting hypoxia, by 4.0% at the start of exercise, and by 5.9% at exhaustion. Ventilation was not affec...
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Clinical disorders associated with pulmonary venous hypertension frequently result in tachypnea and hyperpnea. The response to pulmonary vascular congestion (PVC) in anesthetized or decerebrate animals has consisted of modest and... more
Clinical disorders associated with pulmonary venous hypertension frequently result in tachypnea and hyperpnea. The response to pulmonary vascular congestion (PVC) in anesthetized or decerebrate animals has consisted of modest and bidirectional changes in respiratory rate with no hyperpnea. We hypothesized that anesthesia or decerebration in previous animal experiments may have attenuated the hyperpneic response that would otherwise have been evident. A conscious dog model was developed in which the left lower lobe (LLL) pulmonary circulation could be reversibly isolated and pressurized. Occluders were placed outside the LLL pulmonary artery (PA) and vein. Two fine catheters were introduced through the wall of the LLLPA distal to the arterial occluder. A pleural catheter was used to monitor pleural pressure swings. After recovery from surgery PVC was initiated by inflation of the occluders and injection of warm saline or fresh warm blood through one of the catheters. PVC resulted in ...
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When an electrical stimulus is applied to the cervical vagus during inspiration it results in earlier termination of that phase. We investigated the temporal behavior of the effect of such a stimulus in the interval between its... more
When an electrical stimulus is applied to the cervical vagus during inspiration it results in earlier termination of that phase. We investigated the temporal behavior of the effect of such a stimulus in the interval between its application and inspiratory termination to gain insight into the central processing of these signals. In pentobarbital-anesthetized cats we determined the threshold for inspiratory termination by delivering stimulus trains of constant duration to one vagus nerve at different times after inspiratory onset. The threshold frequency was obtained when the other nerve was unstimulated and when it was stimulated using trains of constant frequency (conditioning stimulus) beginning soon after inspiratory onset. The difference in threshold between the two test indicated the effectiveness of the conditioning stimulus in reducing threshold for inspiratory termination. The effectiveness of the conditioning stimulus increased progressively, reached a peak value at approximately 0.8 s, and progressively declined thereafter. This behavior indicates substantial integrative and accommodative processing of inspiratory terminating vagal inputs.
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Inspiratory prolongation is an integral component of the response to added inspiratory resistance. To ascertain whether this response depends on the relation between inspiratory flow (V) and the pressure perturbation, we compared the... more
Inspiratory prolongation is an integral component of the response to added inspiratory resistance. To ascertain whether this response depends on the relation between inspiratory flow (V) and the pressure perturbation, we compared the responses when this relationship was made progressively less distinct by creating phase shifts between V and the resulting negative mouth pressure (Pm). This was done with an apparatus that altered Pm in proportion to V (J. Appl. Physiol. 62:2491–2499, 1987). V was passed through low-pass electronic filters of different frequency responses before serving as the command signal to the apparatus. In six normal subjects the average neural inspiratory duration (TI) response (delta TI) was sharply (P less than 0.01) reduced (0.32 +/- 0.07 to 0.12 +/- 0.07 s) when the filter's frequency response decreased from 7.5 to 3.0 Hz. The TI response was essentially flat between tube resistance (i.e., no lag, delta TI = 0.36 +/- 0.11 s) and the 7.5-Hz filter, and th...
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1. Dres M, Younes M, Rittayamai N, Kendzerska T, Telias I, Grieco DL, et al. Sleep and Pathological Wakefulness at the Time of Liberation from Mechanical Ventilation (SLEEWE): a prospective multicenter physiological study. Am J Respir... more
1. Dres M, Younes M, Rittayamai N, Kendzerska T, Telias I, Grieco DL, et al. Sleep and Pathological Wakefulness at the Time of Liberation from Mechanical Ventilation (SLEEWE): a prospective multicenter physiological study. Am J Respir Crit Care Med 2019;199:1106–1115. 2. Thille AW, Reynaud F, Marie D, Barrau S, Rousseau L, Rault C, et al. Impact of sleep alterations on weaning duration in mechanically ventilated patients: a prospective study. Eur Respir J 2018;51:1702465. 3. Thille AW, Coudroy R, Reynaud F, Marie D, Barrau S, Rousseau L, et al. Impact of sleep alterations on weaning duration of mechanically ventilated patients: how much is bad? Eur Respir J 2018;52:1800979. 4. Esquinas AM, Steier JS, Karim HMR. Impact of sleep alterations on weaning duration of mechanically ventilated patients: how much is bad? Eur Respir J 2018;52:1800925.
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We determined the temporal changes in effectiveness of inspiratory-shortening expiratory-prolonging stimulus trains delivered in the region of the nucleus parabrachialis medialis and compared the responses to those observed during trains... more
We determined the temporal changes in effectiveness of inspiratory-shortening expiratory-prolonging stimulus trains delivered in the region of the nucleus parabrachialis medialis and compared the responses to those observed during trains delivered to the vagus in the same animals (pentobarbital, sodium-anesthetized paralyzed cats). The inspiratory inhibitory effect of the pontine stimulus was assessed from the effect the stimulus has on threshold for terminating inspiration. Stimulus effect increased gradually, reached a peak at 0.2–0.4 s, and declined thereafter. The time of occurrence of peak effect was different from that observed in the course of vagal stimulus trains. With long stimulus trains (19–40 s), the initial effect on inspiratory duration (TI) (i.e., shortening) rapidly subsided and, in six of eight animals, was replaced by TI prolongation. The initial effect on expiratory duration (TE) (i.e., prolongation) also gradually declined with time but TE remained above control...
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The effect of inspiratory flow rate on graded inspiratory inhibition was examined in barbiturate-anesthetized paralyzed cats normally ventilated by a phrenic-driven servorespirator. Periodically, the animals were inflated, for a single... more
The effect of inspiratory flow rate on graded inspiratory inhibition was examined in barbiturate-anesthetized paralyzed cats normally ventilated by a phrenic-driven servorespirator. Periodically, the animals were inflated, for a single breath, by a constant-flow volume ramp begun at one of several delays following phrenic onset. The phrenic activity during these volume-ramp test inflations was compared with phrenic activity in the absence of volume feedback. The relation between volume and phrenic inhibition was determined for two different flow rates. Inhibition of phrenic activity began when volume above functional residual capacity (FRC) exceeded a time-dependent threshold and, beyond this threshold, continued in a graded fashion. The threshold for the first detectable inhibition declined as inspiratory time progressed both in intact animals and in pneumotaxic-lesioned animals when phrenic activity reached an apneustic plateau. Inspiratory inhibition was associated with similar l...
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Vagal influence related to lung volume changes results in reduction in tidal volume during spontaneous breathing due primarily to premature termination of inspiration. The strength of this vagal influence was traditionally assessed by the... more
Vagal influence related to lung volume changes results in reduction in tidal volume during spontaneous breathing due primarily to premature termination of inspiration. The strength of this vagal influence was traditionally assessed by the duration of apnea following lung inflation, a method recently shown to be inadequate and potentially misleading. An alternate method is described utilizing analysis of the volume tracing of spontaneous breaths and the tracheal pressure tracing during the first breath following airway occlusion at FRC. A formula was devised which, on the basis of previous observations, should predict the tidal volume to be obtained in the absence of phasic vagal influence. The formula was tested in four pentobarbital-anesthetized rabbits using a technique of vagal cooling which rapidly eliminated the vagal influence under study. It was found that the tidal volume obtained following vagal block could be accurately predicted provided allowances were made for the vagal...
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Normal subjects preserve tidal volume (VT) in the face of added inspiratory resistance by increasing maximal amplitude and duration of the rising phase of respiratory driving pressure (DP) and by changing the shape of this phase to one... more
Normal subjects preserve tidal volume (VT) in the face of added inspiratory resistance by increasing maximal amplitude and duration of the rising phase of respiratory driving pressure (DP) and by changing the shape of this phase to one that is more concave to the time axis. To explore the possible role of chest wall afferents in mediating these responses, we determined averaged DP in eight quadriplegic subjects during steady-state unloaded breathing and while breathing through an inspiratory resistance (8.5 cmH2O X 1(-1) X s). As with normal subjects, quadriplegics preserved VT (loaded VT = 106% control) by utilizing all three mechanisms. However, prolongation of the inspiratory duration derived from the DP waveform (+22% vs. +42%) and shape response were significantly less in the quadriplegic subjects. Shape response was completely absent in subjects with C4 lesions. The results provide strong evidence that respiratory muscle spindles are responsible for shape response and that cha...
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Pressure in the compliant middle segment of the pulmonary vascular bed (PM), as determined by arterial occlusion, was compared with pressure at the filtration site (effective filtration pressure, EFP), determined by the isofiltration... more
Pressure in the compliant middle segment of the pulmonary vascular bed (PM), as determined by arterial occlusion, was compared with pressure at the filtration site (effective filtration pressure, EFP), determined by the isofiltration technique, at very high (7–10 times normal) pulmonary flow in six in situ perfused canine left upper lobes. At these flow rates inflow and left atrial pressures averaged 41.9 +/- 1.3 and 2.5 +/- 0.5 (SE) mmHg, respectively. PM was 30.9 +/- 1.6 mmHg, and EFP was 32.3 +/- 1.9 mmHg with no significant difference between the two measurements by paired t test. The results indicate that the arterial occlusion technique yields a pressure that is equivalent to EFP even during very high pulmonary blood flow where the longitudinal distribution of resistance is quite different from that obtained during normal flow.
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The role of central respiratory muscle fatigue in determining endurance time (ET) of steady-state ergometry, ventilation (VE), and breathing pattern during exhaustive submaximal exercise is not known. Six normal subjects exercised on a... more
The role of central respiratory muscle fatigue in determining endurance time (ET) of steady-state ergometry, ventilation (VE), and breathing pattern during exhaustive submaximal exercise is not known. Six normal subjects exercised on a cycle ergometer to exhaustion at 72–82% of maximal power output on three occasions. During the second test, inspiratory muscle load was reduced (approximately 50% of baseline load) for all but the last 3 min of exercise. ET was determined, and VE, tidal volume (VT), respiratory rate (f), and sense of breathing effort (Borg scale) were assessed at different points during the assisted exercise and compared with the values obtained at the same time in identical tests without assist, carried out before and after the assisted test (different days). Borg scale rating was less and there was a nonsignificant trend for VT and VE to be higher and for f to be lower when the assist was in place than at the same time during the unassisted runs. In the last 3 min o...
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We describe an apparatus for altering the mechanical load against which the respiratory muscles operate in humans. A closed system incorporates a rolling seal spirometer. The spirometer piston shaft is coupled to a fast-responding linear... more
We describe an apparatus for altering the mechanical load against which the respiratory muscles operate in humans. A closed system incorporates a rolling seal spirometer. The spirometer piston shaft is coupled to a fast-responding linear actuator that develops force in proportion to desired command signals. The command signal may be flow (resistive loading or unloading), volume (elastic loading or unloading), constant voltage (continuous positive or negative pressure), or any external function. Combinations of loads can be applied. Logic circuits permit application of the load at specific times during the respiratory cycle, and the magnitude of the loads is continuously adjustable. Maximum pressure output is +/- 20 cmH2O. The apparatus permits loading or unloading over a range of ventilation extending from resting levels to those observed during high levels of exercise (over 100 l/min). In response to a square-wave input, pressure rises exponentially with a time constant of 20 ms.
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We recently described a model for the relation between respiratory neural and mechanical outputs (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 51: 963–1001, 1981). In this communication we utilize the model to address the... more
We recently described a model for the relation between respiratory neural and mechanical outputs (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 51: 963–1001, 1981). In this communication we utilize the model to address the following questions. 1) How sensitive is tidal volume (VT) to shape and timing of respiratory neural output (N)? 2) How effective are shape and timing characteristics of N in load compensation? 3) For a given VT, what is the most economical shape and timing of N? Using different values of passive respiratory mechanics, we generated the VT profiles associated with theoretical N waveforms having different shape and timing parameters. We found that 1) with normal mechanics VT is moderately sensitive to inspiratory time (TI) but not to shape of N, whereas with high resistance and short TI, VT is very sensitive to shape and timing; 2) changes in shape, within the physiological range, can serve as potent load-compensatory mechanisms; and 3) for a given VT, the...
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Vagal influence on inspiratory motor output was assessed in 20 normal subjects and in 12 patients with respiratory disorders under enflurane anethesia using the method of airway occlusion. The change in inspiratory duration during... more
Vagal influence on inspiratory motor output was assessed in 20 normal subjects and in 12 patients with respiratory disorders under enflurane anethesia using the method of airway occlusion. The change in inspiratory duration during occlusion (delta TI) was measured from mechanical parameters (respiratory flow and tracheal pressure). In eight of the subjects, however, the effect of occlusion and augmentation of tidal volume was further evaluated from diaphragmatic electromyogram. In normal subjects delta TI (mechanical) averaged 0.15 s (range -0.1 to +0.77 s) and correlated with the duration of inspiration during occlusion. Electromyographic observations indicated that the change in neural TI exceeds the change in mechanical TI by approximately 0.2 s and that augmentation of tidal volume shortens TI with no apparent volume threshold. There was a tendency for vagal influence to be higher with restrictive lung disease and lower with obstructive airway disease. These observations indicat...
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Changes in respiratory mechanical loads are readily detected by humans. Although it is widely believed that respiratory muscle afferents serve as the primary source of information for load detection, there is, in fact, no convincing... more
Changes in respiratory mechanical loads are readily detected by humans. Although it is widely believed that respiratory muscle afferents serve as the primary source of information for load detection, there is, in fact, no convincing evidence to support this belief. We developed a shell that encloses the body, excluding the head and neck. A special loading apparatus altered pressure in proportion to respired volume (elastic load) in one of three ways: 1) at the mouth only (T), producing a conventional load in which respiratory muscles are loaded and airway and intrathoracic pressures are made negative in proportion to volume, 2) both at the mouth and in the shell (AW), where the same pattern of airway and intrathoracic pressure occurs but the muscles are not loaded because Prs (i.e., mouth pressure minus pressure in the shell is unchanged, and 3) positive pressure in proportion to volume at the shell only, loading the chest wall but causing no change in airway or thoracic pressures (...
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We examined, in five conscious human subjects, the steady-state effects of expiratory resistive loading (ERL; R = 8 cmH2O.l–1.s) on the time course of inspiratory and postinspiratory muscle activities (IA and PIA, respectively) and... more
We examined, in five conscious human subjects, the steady-state effects of expiratory resistive loading (ERL; R = 8 cmH2O.l–1.s) on the time course of inspiratory and postinspiratory muscle activities (IA and PIA, respectively) and ventilatory pattern during quiet breathing. Driving pressure (DP) was calculated by means of a respiratory neuromechanical model (J. Appl. Physiol. 51: 963–989, 1981) that permitted the derivation, from tidal volume and flow, of the occlusion pressure equivalent (at functional residual capacity) of respiratory neural output throughout the breath. ERL caused a prolongation of both neural inspiratory duration (12.2 +/- 6.9% SD) and expiratory duration (25.0 +/- 10.1%) and an increase in the amplitude of DP (16.5 +/- 10.2%) without any changes in the waveshape of IA and in end-expiratory level. The relative time course of PIA was not altered by ERL. Minute ventilation was depressed (-6.75 +/- 2.88%) during ERL with little change in alveolar PCO2. The results...
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The effects of raising tidal volume and positive end-expiratory pressure (PEEP) on rate of edema formation were studied in in situ canine left upper lobe preparations. Edema was induced by increasing blood flow to the left upper lobe (4–8... more
The effects of raising tidal volume and positive end-expiratory pressure (PEEP) on rate of edema formation were studied in in situ canine left upper lobe preparations. Edema was induced by increasing blood flow to the left upper lobe (4–8 times normal). In the same animal, at equivalent flows and microvascular hydrostatic pressures, rate of edema formation observed with larger tidal volumes was significantly higher than that observed with smaller tidal volumes (0.73 +/- 0.29 vs. 0.58 +/- 0.30, P less than 0.001). Edema was also induced under static conditions (i.e., flow = 0) over a wide range of vascular pressures. Rate of edema formation was plotted against pressure and the best-fit linear regression was obtained. The slopes (g.min-1.mmHg-1.100 g-1) of the regression lines were significantly higher with larger tidal volumes compared with smaller tidal volumes [0.106 +/- 0.010 (SE) vs. 0.081 +/- 0.009, P less than 0.01]. The pressure intercepts were not different (16.1 +/- 1.6 vs. ...
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Tidal volume (VT) is usually preserved when conscious humans are made to breathe against an inspiratory resistance. To identify the neural changes responsible for VT compensation we calculated the respiratory driving pressure waveform... more
Tidal volume (VT) is usually preserved when conscious humans are made to breathe against an inspiratory resistance. To identify the neural changes responsible for VT compensation we calculated the respiratory driving pressure waveform during steady-state unloaded and loaded breathing (delta R = 8.5 cmH2O X 1(-1) X s) in eight conscious normal subjects. Driving pressure (DP) was calculated according to the method of Younes et al. (J. Appl. Physiol. 51: 963–989, 1981), which provides the equivalent of occlusion pressure at functional residual capacity throughout the breath. VT during resistance breathing was 108% of unloaded VT, as opposed to a predicted value of 82% of control in the absence of neural compensation. Compensation was accomplished through three changes in the DP waveform: 1) peak amplitude increased (+/- 23%), 2) the duration of the rising phase increased (+42%); and 3) the rising phase became more concave to the time axis. There were no changes in the relative decay ra...
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Increasing inspiratory flow (V˙) has been shown to shorten neural inspiratory time (Ti n) in normal subjects breathing on a mechanical ventilator, but the effect of V˙ on respiratory motor output before inspiratory termination has not... more
Increasing inspiratory flow (V˙) has been shown to shorten neural inspiratory time (Ti n) in normal subjects breathing on a mechanical ventilator, but the effect of V˙ on respiratory motor output before inspiratory termination has not previously been studied in humans. While breathing spontaneously on a mechanical ventilator, eight normal subjects were intermittently exposed to 200-ms-duration positive pressure pulses of different amplitudes at the onset of inspiration. Based on the increase in V˙ above control breaths (ΔV˙), trials were grouped into small, medium, and large groups (mean ΔV˙: 0.51, 1.11, and 1.65 l/s, respectively). We measured Ti n, transdiaphragmatic pressure (Pdi), and electrical activity (electromyogram) of the diaphragm (EMGdi). Transient increases inV˙ caused shortening of Ti n from 1.34 to 1.10 (not significant), 1.55 to 1.11 ( P < 0.005), and 1.58 to 1.17 s ( P < 0.005) in the small, medium, and large ΔV˙ groups, respectively. EMGdi measured at end Ti ...
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ABSTRACT
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The progression of chronic obstructive pulmonary disease (COPD) is generally associated with decreased exercise capacity. Differences in forced expired volume in 1 s (FEV1) among patients account for only a fraction of the variability in... more
The progression of chronic obstructive pulmonary disease (COPD) is generally associated with decreased exercise capacity. Differences in forced expired volume in 1 s (FEV1) among patients account for only a fraction of the variability in maximal oxygen consumption (VO2max). We hypothesized that variability in ventilatory response to exercise and in inspiratory mechanics and body mass index contributes importantly to variability in VO2max in this disease. We analyzed the files of 53 patients with established diagnosis of COPD who underwent a recent symptom-limited exercise test. We used inspiratory capacity and maximum inspiratory flow as measures of variability in inspiratory mechanics. The minute ventilation (VE) at the subject's VO2max was divided by the predicted in a normal subject at the same VO2 to obtain a ratio (VE,max/VE,pred). The ventilatory response during exercise provided the best correlation with peak VO2 (r = 0.62). FEV1 and inspiratory capacity also correlated w...
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Because the detection of added loads is a function of the step change in load relative to background level of load (Weber's law), we reasoned that detection may be delayed if the load is increased in very small steps over a protracted... more
Because the detection of added loads is a function of the step change in load relative to background level of load (Weber's law), we reasoned that detection may be delayed if the load is increased in very small steps over a protracted period. This would permit the study of subliminal load responses over a greater range than would otherwise be possible. In 13 healthy males, an external elastic load (delta E) was added in very small steps (load increased every few seconds) such that delta E increased from zero to 6.0 cmH2O/l in 18 min. Each subject underwent a control study in which an identical protocol was followed but no load was added. Five subjects sensed the load after a variable period of load application. Their results were discarded. In the remaining eight subjects, there was no perception of increased load throughout the 18 min. By comparison with the control studies in the same subjects, there was a progressive reduction in tidal volume and breath duration with loading....
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The effect of halothane, fentanyl, Innovar, thiopental, and ketamine on inspiratory output, vagal influence, and chest wall reflex was assessed in seven cats lightly anesthetized with pentobarbital, using the method of airway occlusion... more
The effect of halothane, fentanyl, Innovar, thiopental, and ketamine on inspiratory output, vagal influence, and chest wall reflex was assessed in seven cats lightly anesthetized with pentobarbital, using the method of airway occlusion with and without rapid vagal cooling. All anesthetics depressed inspiratory output, as expressed by deltaP/deltat, of the first occluded inspiration. However, only halothane depressed peak inspiratory output (Pmax). Phasic vagal influence was markedly depressed by 2% halothane but was preserved under other anesthetics. The ability to induce tonic vagal influence (expiratory muscle recruitment) was lost under halothane. Inspiratory inhibitory chest wall reflex was evident in two cats during airway occlusion. Addition of any test anesthetic abolished the reflex. It is concluded that halothane should be avoided in studies dealing with assessment of vagal influence.
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We recently observed rapid shallow breathing during recovery from maximal exercise in some normal subjects. We wondered whether this phenomenon is randomly related to level of exercise or is limited to recovery from very high levels of... more
We recently observed rapid shallow breathing during recovery from maximal exercise in some normal subjects. We wondered whether this phenomenon is randomly related to level of exercise or is limited to recovery from very high levels of exercise. We monitored ventilation, tidal volume, and respiratory frequency in seven normal subjects during and after exercise. Each subject exercised on several occasions on separate days. At least two of the tests were maximal (i.e., subject terminated). In the other tests exercise was terminated by the experimenter at different fractions of the highest level attained by the subject. There was no systematic difference between breathing pattern during exercise and recovery in tests where final O2 consumption (VO2) was 45–92% of the subjects– highest VO2. By contrast 13 of 19 studies in which final VO2 was 92–100% of highest VO2 were followed by relative rapid shallow breathing. We conclude that rapid shallow breathing during recovery from exercise is...
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The purpose of this study was to examine the role of the normal inspiratory resistive load in the regulation of respiratory motor output in resting conscious humans. We used a recently described device (J. Appl. Physiol. 62: 2491–2499,... more
The purpose of this study was to examine the role of the normal inspiratory resistive load in the regulation of respiratory motor output in resting conscious humans. We used a recently described device (J. Appl. Physiol. 62: 2491–2499, 1987) to make mouth pressure during inspiration positive and proportional to inspiratory flow, thus causing inspiratory resistive unloading (IRUL); the magnitude of IRUL (delta R = -3.0 cmH2O.1(-1).s) was set so as to unload most (approximately 86% of the normal inspiratory resistance. Six conscious normal humans were studied. Driving pressure (DP) was calculated according to the method of Younes et al. (J. Appl. Physiol. 51: 963–1001, 1981), which provides the equivalent of occlusion pressure at functional residual capacity throughout the breath. IRUL resulted in small but significant changes in minute ventilation (0.6 1/min) and in end-tidal CO2 concentration (-0.11%) with no significant change in tidal volume or respiratory frequency. There was a s...
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To assess the effect of the normal respiratory resistive load on ventilation (VE) and respiratory motor output during exercise, we studied the effect of flow-proportional pressure assist (PA) (2.2 cmH2O.l-1.s) on various ventilatory... more
To assess the effect of the normal respiratory resistive load on ventilation (VE) and respiratory motor output during exercise, we studied the effect of flow-proportional pressure assist (PA) (2.2 cmH2O.l-1.s) on various ventilatory parameters during progressive exercise to maximum in six healthy young men. We also measured dynamic lung compliance (Cdyn) and lung resistance (RL) and calculated the time course of respiratory muscle pressure (Pmus) during the breath in the assisted and unassisted states at a sustained exercise level corresponding to 70–80% of the subject's maximum O2 consumption. Unlike helium breathing, resistive PA had no effect on VE or any of its subdivisions partly as the result of an offsetting increase in RL (0.78 cmH2O.1–1.s) and partly to a reduction in Pmus. These results indicate that the normal resistive load does not constrain ventilation during heavy exercise. Furthermore, the increase in exercise ventilation observed with helium breathing, which is ...
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The isolated effect of cooling the pulmonary circulation on ventilation was quantified in nine anesthetized dogs. The right pulmonary artery (RPA) was cannulated within the pericardium, and systemic blood was pumped from the left atrium... more
The isolated effect of cooling the pulmonary circulation on ventilation was quantified in nine anesthetized dogs. The right pulmonary artery (RPA) was cannulated within the pericardium, and systemic blood was pumped from the left atrium to the RPA between, but not during, periods of cooling. Cooled blood boluses were injected into the RPA under conditions in which either bolus temperature (5-35 degrees C) or volume (0-1.5 ml/kg body wt) varied. Inspiratory time (TI), expiratory time (TE), breath duration (TT), and peak integrated activity (PEAK) were determined from diaphragm EMG. Results for five postinjection breaths were converted to a percent of the values from five preinjection breaths. There was a linear relationship between bolus temperature and TI [r = 0.61, slope (x) = 0.59%/degrees C, P less than 0.001), TE (r = 0.73, x = 1.43%/degrees C, P less than 0.001] as well as TT (r = 0.74, x = 1.10%/degrees C, P less than 0.001), whereas PEAK was unaffected (n = 9). When injection...
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During progressive exercise ventilation (VI) initially increases through increases in both tidal volume (VT) and respiratory frequency (f) but at high levels of exercise further increases in VI are almost completely due to increases in f... more
During progressive exercise ventilation (VI) initially increases through increases in both tidal volume (VT) and respiratory frequency (f) but at high levels of exercise further increases in VI are almost completely due to increases in f and a VT plateau is seen. We wished to determine whether the presence of the VT plateau is due to a tachypneic influence related to very high levels of exercise or whether it represents a stereotypic response of the respiratory system at high levels of VI. We therefore compared breathing pattern in six subjects during maximal incremental exercise (ME) with that in the same subjects when similar levels of VI were obtained by a combination of submaximal exercise and hypercapnia (E/CO2). A VT plateau was seen in all ME and E/CO2 tests. There was no significant difference in the level of the VT plateau between the ME (2.93 +/- 0.17 liters) and E/CO2 (2.97 +/- 0.12 liters) tests. We conclude that the presence and level of the VT plateau during ME is not ...
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To determine whether upper airway mechanoreceptors partly subserve the ventilatory response to external mechanical loading in conscious humans, we studied 11 laryngectomized subjects. The oropharynx (OP) or tracheostomy was selectively... more
To determine whether upper airway mechanoreceptors partly subserve the ventilatory response to external mechanical loading in conscious humans, we studied 11 laryngectomized subjects. The oropharynx (OP) or tracheostomy was selectively loaded (in random order) by attaching the mouth or tracheal tube to a special pressure-generating apparatus, and steady-state ventilatory responses were recorded. Phasic negative pressure changes generated at the OP to simulate inspiratory resistive loading, expiratory resistive unloading, and elastic loading resulted in trivial prolongation of inspiratory duration by 12, 9, and 4%, respectively; other ventilatory variables were not significantly altered. Phasic positive pressure changes at the OP that simulated inspiratory resistive unloading and expiratory resistive loading had little effect on breathing pattern. When the above loads were applied via the tracheostomy, using pressures of similar magnitude, ventilatory responses were qualitatively sim...
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Conscious humans easily detect loads applied to the respiratory system. Resistive loads as small as 0.5 cmH2O.l-1.s can be detected. Previous work suggested that afferent information from the chest wall served as the primary source of... more
Conscious humans easily detect loads applied to the respiratory system. Resistive loads as small as 0.5 cmH2O.l-1.s can be detected. Previous work suggested that afferent information from the chest wall served as the primary source of information for load detection, but the evidence for this was not convincing, and we recently reported that the chest wall was a relatively poor detector for applied elastic loads. Using the same setup of a loading device and body cast, we sought resistive load detection thresholds under three conditions: 1) loading of the total respiratory system, 2) loading such that the chest wall was protected from the load but airway and intrathoracic pressures experienced negative pressure in proportion to inspiratory flow, and 3) loading of the chest wall alone with no alteration of airway or intrathoracic pressure. The threshold for detection for the three types of load application in seven normal subjects was 1.17 +/- 0.33, 1.68 +/- 0.45, and 6.3 +/- 1.38 (SE)...