Jerome A. Dempsey

The Occurrence of Sleep-Disordered Breathing among Middle-Aged Adults

BACKGROUND Limited data have suggested that sleep-disordered breathing, a condition of repeated episodes of apnea and hypopnea during sleep, is prevalent among adults. Data from the Wisconsin Sleep Cohort Study, a longitudinal study of the natural history of cardiopulmonary disorders of sleep, were used to estimate the prevalence of undiagnosed sleep-disordered breathing among adults and address its importance to the public health. METHODS A random sample of 602 employed men and women 30 to 60 years old were studied by overnight polysomnography to determine the frequency of episodes of apnea and hypopnea per hour of sleep (the apnea-hypopnea score). We measured the age- and sex-specific prevalence of sleep-disordered breathing in this group using three cutoff points for the apnea-hypopnea score (> or = 5, > or = 10, and > or = 15); we used logistic regression to investigate risk factors. RESULTS The estimated prevalence of sleep-disordered breathing, defined as an apnea-hypopnea score of 5 or higher, was 9 percent for women and 24 percent for men. We estimated that 2 percent of women and 4 percent of men in the middle-aged work force meet the minimal diagnostic criteria for the sleep apnea syndrome (an apnea-hypopnea score of 5 or higher and daytime hypersomnolence). Male sex and obesity were strongly associated with the presence of sleep-disordered breathing. Habitual snorers, both men and women, tended to have a higher prevalence of apnea-hypopnea scores of 15 or higher. CONCLUSIONS The prevalence of undiagnosed sleep-disordered breathing is high among men and is much higher than previously suspected among women. Undiagnosed sleep-disordered breathing is associated with daytime hypersomnolence.

Sleep Apnea and Hypertension: A Population-based Study

Transient, nocturnal elevations of blood pressure have been observed during apneic episodes in the sleep apnea syndrome and may be caused by the acute consequences of sleep-disordered breathing such as arousals, high negative intrathoracic pressures, nocturnal desaturation of oxyhemoglobin, hypercapnia, or increased sympathetic nerve activity [1]. However, the mechanism by which these intermittent nocturnal events contribute to sustained, daytime hypertension is not known. It has been postulated that repetitive hemodynamic oscillations caused by frequent apneic episodes occurring in rapid succession may prevent systemic blood pressures from returning to baseline levels and that this may in turn result in neurohumoral or vascular changes leading to elevated waking pressures and sustained hypertension [2]. Several casecontrol and cross-sectional studies suggest that hypertension is highly prevalent (50% to 90%) in patients with the sleep apnea syndrome [1-5]. Sleep apnea has also been reported to occur frequently (22% to 62%) in patients with essential hypertension [6-9]. However, in these studies blood pressure readings were collected at one time of day in the clinic [6, 9] or from records of reported hypertension [7, 8] in highly selected patient populations such as patients with severe obstructive sleep apnea [1-5]. Some studies found a strong association between sleep apnea and hypertension whereas others failed to do so. Inconsistencies in the results are probably caused by nonuniform definitions of hypertension and apnea, differences in methods and populations studied, lack of appropriate control participants, and failure to control for confounding factors such as age, sex, and obesity. Self-reported habitual, heavy snoring has also been associated with hypertension [10-13]. Because most people with sleep apnea snore, however, polysomnographic data are needed to separate participants with sleep apnea and to assess the association with snoring alone. In the earlier surveys, no objective data on breathing during sleep were available, so it was not possible to determine if any or all of the measured association was caused by the inclusion of apneic persons among snorers. In recent epidemiologic studies that included polysomnographic data, it was found that once sleep apnea was incorporated into the analysis, snoring did not contribute independently to the prediction of hypertension [14]. The most compelling evidence that sleep apnea can cause sustained high blood pressure comes from studies that have shown a reduction in blood pressure after sleep apnea was treated [6, 15-22]. However, interpretation of these intervention studies is difficult because of the confounding effect of weight loss that occurred in several studies [17-19, 22] or lack of data on weight change [6, 12, 16, 20, 23]. Weight loss alone has been shown to reduce blood pressure [23]. Collectively, these studies suggest the hypothesis that sleep-disordered breathing plays a causal role in hypertension. In view of recent estimates of sleep apnea prevalence of 9% for women and 24% for men [24], there is a clear need to investigate how sleep-disordered breathing at the milder end of the severity spectrum, including habitual snoring without sleep apnea, is related to blood pressure. Our purpose was to determine how ambulatory blood pressure measurements obtained during an entire 24-hour period, while awake and asleep, differed among people with and without sleep-disordered breathing in the general population. To avoid previous problems of relying on casual blood pressure measurements, of difficulty in separating effects of snoring from those of sleep apnea, and of selection bias between groups, we studied 147 employed adults enrolled in a long-term study of risk factors, natural history, and health consequences of sleep-disordered breathing using 24-hour ambulatory blood pressure monitoring and overnight polysomnography. Methods One hundred and forty-seven persons were recruited from the Wisconsin Sleep Cohort Study, an ongoing prospective study of sleep-disordered breathing. The details of the design and sampling scheme for the Sleep Cohort Study have been described previously [24]. We used a two-stage sampling scheme designed to yield a cohort of men and women with a wide range of sleep-disordered breathing. For the first stage, all state employees, aged 30 to 60 years, from four large agencies were surveyed on sleep characteristics, health history, and sociodemographics by mailed questionnaire. For the second stage, all survey participants reporting habitual (almost every night) snoring, snorting, or breathing pauses, or extremely loud snoring (designated snorers) and a random sample of the remaining participants (designated nonsnorers) were recruited for laboratory sleep studies, with an overall ratio of one nonsnorer for every two snorers. During a 1-year period, 163 employees consecutively studied by overnight polysomnography in the Sleep Research Laboratory at the University of Wisconsin Clinical Research Center were asked to participate in the blood pressure study: Of these, 147 participants agreed and were successfully studied (90% response rate). The protocol was approved by the Human Subjects Committee at the University of Wisconsin Hospital and Clinics, and all participants gave written, informed consent. Data Collection Overnight polysomnography conducted in our sleep laboratory consisted of electroencephalography, electro-oculography, and electromyography to identify sleep stages [25]; measurements of nasal and oral airflow by end-tidal carbon dioxide detection and thermistry; oximetry for arterial oxyhemoglobin saturation; and inductance plethysmography to detect respiratory effort. Body weight and height were measured on all participants to calculate body mass index (kg/m2). Data on sleep problems, sociodemographics, and health history were collected via a structured questionnaire and personal interview. The complete sleep study protocol has been previously reported [24]. Criteria for Sleep Apnea and Habitual Snoring An abnormal breathing event was defined as either a complete cessation of airflow lasting 10 seconds or more (apnea) or a decrease in airflow accompanied by a 4% or greater decrease in arterial oxygen saturation (hypopnea). The average number of abnormal events per hour of sleep (apneahypopnea index) for each person was used as a measure of sleep apnea. For categorical data analysis, cut points were used to represent mild or worse sleep apnea (apneahypopnea index 5) and little or no sleep apnea (apneahypopnea index < 5). Participants with little or no sleep apnea were further categorized as snorers or nonsnorers based on self-reported habitual snoring (every night or almost every night). Criteria for Sleep-Disordered Breathing We categorized participants as participants with sleep-disordered breathing (those with apneahypopnea index 5 and nonapneic snorers with apneahypopnea index < 5) and participants with no sleep-disordered breathing (nonsnorers with apneahypopnea index < 5). Ambulatory Blood Pressure Measurements These measurements were obtained with the Accutracker II (Suntech Medical Instruments/Eutectics Electronics, Raleigh, North Carolina), a 24-hour blood pressure monitoring device that uses a modified auscultatory method of blood pressure measurement. The system consists of a portable two.25-kg console that is connected to three electrocardiographic leads, a cuff, and a microphone positioned over the left brachial artery. The console initiates inflation of the cuff. During the deflation of the cuff set at a rate of 3 mm Hg per second, the persons R-wave complex triggers the microphone to listen for Korotkoff sounds during a window period after a brief pulse-propagation delay. This system, called R-wave gating, reduces the effect of muscle artifact or amount of artifactual sound encountered in noisy environments outside of the office setting. Special computer software identifies the cuff pressures at the onset and disappearance of Korotkoff sounds for each cuff deflation cycle as systolic and diastolic pressures, respectively. At the beginning of all ambulatory blood pressure monitor placements, three seated and three standing pressures were obtained on each participant and calibrated to within 5 mm Hg of a standard mercury sphygmomanometer using a T-tube assembly. Blood pressures were measured at random intervals of 15 to 20 minutes during waking hours and every 30 minutes during periods of sleep. The deflation rate was set at 3 mm Hg per second. All measurements were done with the display monitor off to prevent anticipation of the readings by the participants. Ambulatory pressures while awake included those taken during activities of daily living such as sitting, standing, walking, and eating. Detailed diaries of activity, posture, bedtime, and time on awakening from sleep were kept by all the participants. Participants were instructed to refrain from vigorous exercises and arm movements during inflations. Specific information relevant to blood pressure such as data on history of hypertension and use of antihypertensive medications were obtained at the time of placement of the 24-hour blood pressure monitor. The ambulatory pressure data record for each person included individual readings of systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate at random intervals. The blood pressure data were edited using predetermined criteria and without knowledge of the sleep data. Criteria for deleting individual blood pressure readings included a pulse pressure that was greater than 120 mm Hg or less than 15 mm Hg (biologically implausible), an inconsistent increase or decrease in systolic or diastolic blood pressure greater than 30 mm Hg from previous or subsequent reading occurring during test codes indicating major arm movement, or weak Korotkoff sounds. The reproducibility of t

Exercise-induced arterial hypoxaemia in healthy human subjects at sea level.

We determined the incidence of exercise‐induced arterial hypoxaemia and its determinants in sixteen highly trained, healthy runners who were capable of achieving and sustaining very high metabolic rates (maximal O2 uptake = 72 +/‐ 2 ml kg‐1 min‐1 or 4.81 +/‐ 0.13 l min‐1). Arterial blood gases and acid‐base status were determined at each load of a progressive short‐term exercise test and repeatedly during constant‐load treadmill running while breathing air and during inhalation of mildly hypoxic, hyperoxic, and helium‐enriched gases. Three types of responses to heavy and maximum exercise were evident and highly reproducible within subjects. Four runners maintained arterial PO2 (Pa, O2) within 10 mmHg of resting values, another four showed 10‐15 mmHg reductions in Pa, O2, and the remaining eight showed reductions of 21‐35 mmHg, i.e. in all cases to a Pa, O2 of less than 75 mmHg and to less than 60 mmHg in two cases. During constant‐load exercise, Pa, O2 was often maintained during the initial 30 s when hyperventilation was greatest; then hypoxaemia occurred and in most cases was either maintained or worsened over the ensuing 3‐4 min. The most severe hypoxaemia during heavy exercise was associated with no or little alveolar hyperventilation (Pa, CO2 greater than 35 mmHg and PA, O2 less than 110 mmHg) and an alveolar to arterial PO2 difference [(A‐a)DO2] in excess of 40 mmHg. During 3‐4 min of heavy exercise alveolar PO2 (PA, O2) decreased by 20 mmHg in mild hypoxia (0.17 FI, O2; inspired % O2) and increased by 20 mmHg during mild hyperoxia (0.24 FI, O2) and 10 mmHg during the hyperventilation which accompanied normoxic helium breathing. In all cases Pa, O2 changed in proportion to PA, O2 with no consistent change in the alveolar to arterial PO2 difference [(A‐a)DO2]. In view of the correction of hypoxaemia with mild hyperoxia and the very high ratios of alveolar ventilation to pulmonary blood flow (VA/QC = 4‐6) achieved during heavy exercise, we think it unlikely that non‐uniformity of the VA/QC distribution or veno‐arterial shunt could explain the hypoxaemia observed in most of our subjects. By exclusion, we suggest that hypoxaemia may be attributed to a diffusion limitation secondary to very short red cell transit times in at least a portion of the pulmonary circulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Exercise-induced diaphragmatic fatigue in healthy humans

1. Twelve healthy subjects (33 +/‐ 3 years) with a variety of fitness levels (maximal oxygen uptake (VO2, max) = 61 +/‐ 4 ml kg‐1 min‐1, range 40‐80), exercised at 95 and 85% VO2, max to exhaustion (mean time = 14 +/‐ 3 and 31 +/‐ 8 min, expired ventilation (VE) over final minute of exercise = 149 +/‐ 9 and 126 +/‐ 10 l min‐1). 2. Bilateral transcutaneous supramaximal phrenic nerve stimulation (BPNS) was performed before and immediately after exercise at four lung volumes, and 400 ms tetanic stimulations were performed at 10 and 20 Hz. The coefficients of variation of repeated measurements for the twitch transdiaphragm pressures (Pdi) were +/‐ 7‐10% and for compound muscle action potentials (M wave) +/‐ 10‐15%. 3. Following exercise at 95% of VO2, max, group mean Pdi twitch values were reduced at all lung volumes (range ‐8 +/‐ 3 to ‐32 +/‐ 5%) and tetanically stimulated Pdi values were reduced at both 10 and 20 Hz (‐21 +/‐ 3 and ‐13 +/‐ 2%, respectively) (P = 0.001‐0.047). Following exercise at 85% VO2, max, stimulated Pdi values were reduced at all lung volumes and stimulating frequencies, but only significantly so with the twitch at functional residual capacity (‐15 +/‐ 5%). Stimulated Pdi values recovered partially by 30 min post‐exercise and almost completely by an average time of 70 min. 4. The fall in stimulated Pdi values post‐exercise was significantly correlated with the percentage increase in diaphragmatic work (integral of Pdi min‐1) from rest to end‐exercise and the relative intensity of the exercise. 5. The integral of Pdi min‐1 and the integral of Po min‐1 (Po, esophageal pressure) rose together from rest through the fifth to tenth minute of exercise, after which integral of Pdi min‐1 plateaued even though integral of Po min‐1, VE and inspiratory flow rate all continued to rise substantially until exercise terminated. Thus, the relative contribution of the diaphragm to total respiratory motor output was progressively reduced with exercise duration. 6. We conclude that significant diaphragmatic fatigue is caused by the ventilatory requirements imposed by heavy endurance exercise in healthy persons with a variety of fitness levels. The magnitude of the fatigue and the likelihood of its occurrence increases as the relative intensity of the exercise exceeds 85% of VO2, max.

Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans.

Changing arterial oxygen content (C  aO 2 ) has a highly sensitive influence on the rate of peripheral locomotor muscle fatigue development. We examined the effects of C  aO 2 on exercise performance and its interaction with peripheral quadriceps fatigue. Eight trained males performed four 5 km cycling time trials (power output voluntarily adjustable) at four levels of C  aO 2 (17.6–24.4 ml O2 dl−1), induced by variations in inspired O2 fraction (0.15–1.0). Peripheral quadriceps fatigue was assessed via changes in force output pre‐ versus post‐exercise in response to supra‐maximal magnetic femoral nerve stimulation (ΔQtw; 1–100 Hz). Central neural drive during the time trials was estimated via quadriceps electromyogram. Increased C  aO 2 from hypoxia to hyperoxia resulted in parallel increases in central neural output (43%) and power output (30%) during cycling and improved time trial performance (12%); however, the magnitude of ΔQtw (−33 to −35%) induced by the exercise was not different among the four time trials (P > 0.2). These effects of C  aO 2 on time trial performance and ΔQtw were reproducible (coefficient of variation = 1–6%) over repeated trials at each F  IO 2 on separate days. In the same subjects, changing C  aO 2 also affected performance time to exhaustion at a fixed work rate, but similarly there was no effect of ΔC  aO 2 on peripheral fatigue. Based on these results, we hypothesize that the effect of C  aO 2 on locomotor muscle power output and exercise performance time is determined to a significant extent by the regulation of central motor output to the working muscle in order that peripheral muscle fatigue does not exceed a critical threshold.

Opioid‐mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans

We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development of peripheral fatigue during high‐intensity endurance exercise. In a double‐blind, placebo‐controlled design, eight cyclists randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5KPlac, L3–L4) or intrathecal fentanyl (5KFent, L3–L4) to impair cortical projection of opioid‐mediated muscle afferents. Peripheral quadriceps fatigue was assessed via changes in force output pre‐ versus postexercise in response to supramaximal magnetic femoral nerve stimulation (ΔQtw). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5KFentversus 5KPlac by 12 ± 3% (P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 ± 2% higher during the first and 11 ± 2% lower during the second 2.5 km of 5KFentversus 5KPlac (both P < 0.05). Capillary blood lactate was higher (16.3 ± 0.5 versus 12.6 ± 1.0%) and arterial haemoglobin O2 saturation was lower (89 ± 1 versus 94 ± 1%) during 5KFentversus 5KPlac. Exercise‐induced ΔQtw was greater following 5KFentversus 5KPlac (−46 ± 2 versus−33 ± 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive development of peripheral muscle fatigue.

Locomotor muscle fatigue modifies central motor drive in healthy humans and imposes a limitation to exercise performance

We asked whether the central effects of fatiguing locomotor muscle fatigue exert an inhibitory influence on central motor drive to regulate the total degree of peripheral fatigue development. Eight cyclists performed constant‐workload prefatigue trials (a) to exhaustion (83% of peak power output (Wpeak), 10 ± 1 min; PFT83%), and (b) for an identical duration but at 67%Wpeak (PFT67%). Exercise‐induced peripheral quadriceps fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQtw,pot) from pre‐ to post‐exercise in response to supra‐maximal femoral nerve stimulation (ΔQtw,pot). On different days, each subject randomly performed three 5 km time trials (TTs). First, subjects repeated PFT83% and the TT was started 4 min later with a known level of pre‐existing locomotor muscle fatigue (ΔQtw,pot−36%) (PFT83%‐TT). Second, subjects repeated PFT67% and the TT was started 4 min later with a known level of pre‐existing locomotor muscle fatigue (ΔQtw,pot−20%) (PFT67%‐TT). Finally, a control TT was performed without any pre‐existing level of fatigue. Central neural drive during the three TTs was estimated via quadriceps EMG. Increases in pre‐existing locomotor muscle fatigue from control TT to PFT83%‐TT resulted in significant dose‐dependent changes in central motor drive (−23%), power output (−14%), and performance time (+6%) during the TTs. However, the magnitude of locomotor muscle fatigue following various TTs was not different (ΔQtw,pot of −35 to −37%, P= 0.35). We suggest that feedback from fatiguing muscle plays an important role in the determination of central motor drive and force output, so that the development of peripheral muscle fatigue is confined to a certain level.

Mechanisms of hypoxia‐induced periodic breathing during sleep in humans.

Ventilation was studied during wakefulness and sleep in six healthy humans in normoxia (mean barometric pressure (PB) = 740 torr), and in hypobaric hypoxia (PB = 455 torr). Hypoxia caused hyperventilation and hypocapnic alkalosis (delta Pa,CO2 = ‐7 torr) during wakefulness and in all sleep states. Periodic breathing was the predominant pattern of breathing in all stages of non‐rapid eye movement (non‐r.e.m.) sleep in hypoxia, but was rarely observed during wakefulness or r.e.m. sleep. Periodic breathing was composed of repetitive oscillations of reproducible cycle length characterized by clusters of breaths with augmented inspiratory effort (VT/TI) and highly variable distribution of breath‐to‐breath minute ventilation (VE) and tidal volume (VT), which alternated regularly with prolongations of the expiratory pause of the last breath of each cluster (apnea duration = 5‐18 sec). Hypoxia‐induced periodic breathing was eliminated by: (a) acute restoration of normoxia coincident with a 3‐6 torr increase in Pa,CO2; and (b) augmented FI,CO2 (at constant arterial oxygen saturation) which rapidly and reversibly eliminated apneas and stabilized breathing pattern with a less than 2 torr increase in Pa,CO2. If hypocapnia was prevented (by augmented FI,CO2) during acute induction of hypoxia in non‐r.e.m. sleep, periodic breathing was also prevented. We propose that the genesis of hypoxia‐induced periodic breathing requires the combination of hypoxia and hypocapnia. Periodicity results from oscillations in CO2 about a CO2‐apnea threshold whose functional expression is critically linked to sleep state.

Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans

We examined the effects of hypoxia severity on peripheral versus central determinants of exercise performance. Eight cyclists performed constant‐load exercise to exhaustion at various fractions of inspired O2 fraction (FIO2 0.21/0.15/0.10). At task failure (pedal frequency < 70% target) arterial hypoxaemia was surreptitiously reversed via acute O2 supplementation (FIO2= 0.30) and subjects were encouraged to continue exercising. Peripheral fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQtw,pot) as measured pre‐ versus post‐exercise in response to supramaximal femoral nerve stimulation. At task failure in normoxia (haemoglobin saturation (SpO2) ∼94%, 656 ± 82 s) and moderate hypoxia (SpO2∼82%, 278 ± 16 s), hyperoxygenation had no significant effect on prolonging endurance time. However, following task failure in severe hypoxia (SpO2∼67%; 125 ± 6 s), hyperoxygenation elicited a significant prolongation of time to exhaustion (171 ± 61%). The magnitude of ΔQtw,pot at exhaustion was not different among the three trials (−35% to −36%, P= 0.8). Furthermore, quadriceps integrated EMG, blood lactate, heart rate, and effort perceptions all rose significantly throughout exercise, and to a similar extent at exhaustion following hyperoxygenation at all levels of arterial oxygenation. Since hyperoxygenation prolonged exercise time only in severe hypoxia, we repeated this trial and assessed peripheral fatigue following task failure prior to hyperoxygenation (125 ± 6 s). Although Qtw,pot was reduced from pre‐exercise baseline (−23%; P < 0.01), peripheral fatigue was substantially less (P < 0.01) than that observed at task failure in normoxia and moderate hypoxia. We conclude that across the range of normoxia to severe hypoxia, the major determinants of central motor output and exercise performance switches from a predominantly peripheral origin of fatigue to a hypoxia‐sensitive central component of fatigue, probably involving brain hypoxic effects on effort perception.

Fatiguing inspiratory muscle work causes reflex reduction in resting leg blood flow in humans

1 We recently showed that fatigue of the inspiratory muscles via voluntary efforts caused a time‐dependent increase in limb muscle sympathetic nerve activity (MSNA) ( St Croix et al. 2000 ). We now asked whether limb muscle vasoconstriction and reduction in limb blood flow also accompany inspiratory muscle fatigue. 2 In six healthy human subjects at rest, we measured leg blood flow (Q̇L) in the femoral artery with Doppler ultrasound techniques and calculated limb vascular resistance (LVR) while subjects performed two types of fatiguing inspiratory work to the point of task failure (3‐10 min). Subjects inspired primarily with their diaphragm through a resistor, generating (i) 60 % maximal inspiratory mouth pressure (PM) and a prolonged duty cycle (TI/TTOT= 0.7); and (ii) 60 % maximal PM and a TI/TTOT of 0.4. The first type of exercise caused prolonged ischaemia of the diaphragm during each inspiration. The second type fatigued the diaphragm with briefer periods of ischaemia using a shorter duty cycle and a higher frequency of contraction. End‐tidal PCO2 was maintained by increasing the inspired CO2 fraction (FI,CO2) as needed. Both trials caused a 25–40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation. 3 Q̇ L and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, Q̇L subsequently decreased (‐30 %) and LVR increased (50‐60 %) relative to control in a time‐dependent manner. This effect was present by 2 min in all subjects. During recovery, the observed changes dissipated quickly (< 30 s). Mean arterial pressure (MAP; +4‐13 mmHg) and heart rate (+16‐20 beats min−1) increased during fatiguing diaphragm contractions. 4 When central inspiratory motor output was increased for 2 min without diaphragm fatigue by increasing either inspiratory force output (95 % of maximal inspiratory pressure (MIP)) or inspiratory flow rate (5 × eupnoea), Q̇L, MAP and LVR were unchanged; although continuing the high force output trials for 3 min did cause a relatively small but significant increase in LVR and a reduction in nQ̇L. 5 When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and Q̇L increased significantly; these changes were attributed to the negative feedback effects on MSNA from augmented tidal volume. 6 Voluntary increases in inspiratory effort, in the absence of diaphragm fatigue, had no effect on Q̇L and LVR, whereas the two types of diaphragm‐fatiguing trials elicited decreases in Q̇L and increases in LVR. We attribute these changes to a metaboreflex originating in the diaphragm. Diaphragm and forearm muscle fatigue showed very similar time‐dependent effects on LVR and Q̇L.