Inspiratory duty cycle responses to flow limitation predict nocturnal hypoventilation

H. Schneider, V. Krishnan, L. E. Pichard, S. P. Patil, P. L. Smith, A. R. Schwartz
European Respiratory Journal 2009 33: 1068-1076; DOI: 10.1183/09031936.00063008

Abstract

Upper airway obstruction (UAO) can elicit neuromuscular responses that mitigate and/or compensate for the obstruction. It was hypothesised that flow-limited breathing elicits specific timing responses that can preserve ventilation due to increases in inspiratory duty cycle rather than respiratory rate.

By altering nasal pressure during non-rapid eye movement (non-REM) sleep, similar degrees of UAO were induced in healthy males and females (n = 10 each). Inspiratory duty cycle, respiratory rate and minute ventilation were determined for each degree of UAO during non-REM sleep and compared with the baseline nonflow-limited condition.

A dose-dependent increase in the inspiratory duty cycle and respiratory rate was observed in response to increasing severity of UAO. Increases in the inspiratory duty cycle, but not respiratory rate, helped to acutely maintain ventilation. Heterogeneity in these responses was associated with variable degrees of ventilatory compensation, allowing for the segregation of individuals at risk for hypoventilation during periods of inspiratory airflow limitation.

Upper airway obstruction constitutes a unique load on the respiratory system. The inspiratory duty cycle, but not the respiratory rate, determine the individual's ability to compensate for inspiratory airflow limitation during sleep, and may represent a quantitative phenotype for obstructive sleep apnoea susceptibility.

Obstructive sleep apnoea comprises a spectrum of patients with varying degrees of upper airway obstruction (UAO) as manifested by snoring with intermittent arousals (upper airway resistance syndrome and respiratory effort-related arousals), obstructive hypopnoeas and apnoeas 1–3. While male sex and obesity constitute strong risk factors for the varied manifestation of obstructive sleep apnoea 4–6, heritable factors can also play a significant role in the risk of this disorder 7–13, contributing to the heterogeneity in the expression of this disorder. Nevertheless, physiological mechanisms that explain the heterogeneity of sleep-disordered breathing severity are not known.

UAO during sleep plays a pivotal role in the pathogenesis of obstructive sleep apnoea 14 and is caused by structural defects and disturbances in neuromuscular control 14, 15. UAO can elicit neuromuscular responses that mitigate and/or compensate for the obstruction. Under conditions of UAO (inspiratory airflow limitation), immediate responses in respiratory timing indices can help restore ventilation 16–19 and blunt disturbances in gas exchange 20. Nevertheless the impact of respiratory pattern responses on ventilation during periods of UAO remains unclear.

The purpose of the current study is to examine ventilatory responses to UAO during sleep in normal males and females. It was hypothesised that flow-limited breathing elicits specific timing responses that can preserve ventilation with increases in inspiratory duty cycle (tI/ttot) rather than respiratory frequency (fR). To test this hypothesis, responses to defined levels of UAO were examined that were experimentally imposed in non-rapid eye movement (non-REM) sleep. Responses in tI/ttot, fR and minute ventilation (V′E) were evaluated in body mass index (BMI) and age matched normal males and females, and have been partially reported in abstract form 21, 22.

MATERIALS AND METHODS

Conceptual approach

Although the mechanisms involved in stabilising ventilation in the presence of UAO have not been well defined, UAO is known to increase respiratory drive 19, which normally should increase mean inspiratory flow (VT/tI). However, as the upper airway collapses; such increases in drive can not produce further increase in VT/tI because inspiratory flow is limited to a maximal level, despite increased effort 23, 24. Therefore, during periods of inspiratory flow limitation, increases in inspiratory effort (drive) cannot maintain ventilation during sleep. Instead, ventilation can only be preserved by prolonging the tI/ttot 17, 18, which will maintain and stabilise ventilation during periods of inspiratory flow limitation (fig. 1⇓ and table 1⇓). In contrast, for a given tI/ttot, increases in fR (fig. 1 and table 1⇓) would decrease tidal volume (VT). As VT falls, the dead space fraction will increase, and alveolar ventilation (V′A) will decrease accordingly. Thus, tI/ttot and fR responses to a given level of UAO may determine the degree of hypoventilation during sleep. Specifically, as the tI/ttot increases, an individual can maintain V′A which protects them against sleep-disordered breathing, whereas increases in fR may compromise V′A and increase the susceptibility to sleep-disordered breathing. V′A was calculated by assuming a dead space volume (VD) of 150 mL and the following equation, in which V′D is dead space ventilation.

Fig. 1—
Fig. 1—

a) Normal nonflow-limited breathing compared with b) inspiratory duty cycle (tI/ttot) response and c) respiratory frequency (fR) response to upper airway obstruction (UAO). For illustrative purposes, a reduction in mean inspiratory airflow from 300 mL·s−1 at baseline to 200 mL·s−1 during UAO was assumed. b) Prolongation of the tI/ttot may help maintain alveolar ventilation (V′A) during periods of UAO. In contrast, c) increases in fR would increase the portion of dead space ventilation to minute ventilation, thereby lowering V′A, if tI/ttot remains unchanged. tI: inspiratory time; ttot: total respiratory cycle duration. ▓: Alveolar volume; ▪: dead space volume. See also table 1⇓.

View this table:
Table 1—

Ventilatory responses to upper airway obstruction(UAO) compared with normal nonflow-limited (NFL) breathing

V′A  =  V′E - V′D  =  (VT/tI × tI/ttot) - (VD × fR) (1)

Study subjects

In total, 26 healthy volunteers (10 males and 16 females) were initially recruited from the community for a baseline sleep study with no history of snoring or concurrent illness and no evidence of sleep-disordered breathing (apnoea/hypopnoea index <5 events·h-1) or flow limitation (<50% non-REM time). From the group, 10 females were matched to males based on BMI (±3 kg·m−2) and age (±5 yrs). The study protocol was approved by the Johns Hopkins Bayview Medical Center Institutional Review Board (Baltimore, MD, USA) and all subjects provided written informed consent.

Study methods

Polysomnography

Standard polysomnography included monitoring of electroencephalograms (C3-A2 and C3-O1), left and right electro-oculograms, submental electromyogram, ECG (modified V2 lead), arterial oxygen saturation, body position via infrared video cameras, tidal airflow with a pneumotachometer (model 3700A; Hans Rudolph Inc., Kansas City, MO, USA) affixed to a tight-fitting nasal mask and nasal pressure (Pn) through a side hole in the nasal mask.

Nasal pressure generator

Pn was controlled by a critical pressure machine, which is a modified continuous positive airway pressure device (ResMed, MAP medicine technology, Martinsried, Germany), specifically designed to apply both negative and positive pressure over a range of -20–20 cmH2O (-1.95–1.95 kPa), as previously described 25, 26.

Study design

Altering nasal pressure

During wakefulness, individuals were acclimatised to breathing through a nasal mask at a pressure of 6 cmH2O (holding pressure; 0.59 kPa). When stable non-REM stage 2 sleep was observed for ≥3 min, Pn was abruptly lowered by 2 cmH2O (0.19 kPa) for five breaths or until an arousal occurred. Pn was then returned to holding pressure for ∼120 s, and was repeatedly lowered by additional steps of ∼2 cmH2O decrements until airflow ceased. Note, the Pn at baseline was lowered from 6 cmH2O to either 5 or 4 cmH2O (0.48 or 0.38 kPa; n = 2 and n = 3, respectively) in selected subjects in order to facilitate sleep onset.

Determination of ventilatory responses to UAO

Breaths during non-REM sleep were selected from the holding pressure and each pressure drop as described below. During stable breathing at the holding pressure, the last three breaths prior to the first pressure drop were selected for determining ventilatory parameters for nonflow-limited (NFL) breathing during sleep. Each step decrease in Pn was first assessed for the presence of inspiratory flow limitation. Breaths two to four of each pressure drop with a stable flow limited breathing pattern were then tabulated, and the degree of UAO was categorised as mild, moderate or severe flow limitation based on VT/tI of 200±25 mL·s−1, 150±25 mL·s−1 and 100±25 mL·s−1, respectively. For each category, tI/ttot, fR, VT and V′E were calculated. In addition, VD was calculated using VD norms in males and females, as given (in mL) by the square of the height (in cm) divided by 189 27. V′A was assessed using V′E minus V′D.

Statistical analysis

Two-way ANOVA for repeated measures and Taguchi's method of post hoc analysis of significance were used for comparing ventilatory responses for each degree of UAO within and between sex groups. Linear regression was utilised to examine the relationship between respiratory timing indices in the moderate UAO condition against BMI and sex. A p-value <0.05 was considered statistically significant.

RESULTS

Anthropometric data, sleep study results, lung function tests and smoking history are shown in table 2⇓ for the entire group matched by BMI and age and a subset matched by V′E (±0.5 L·min−1) at baseline.

View this table:
Table 2—

Anthropometric data for the entire group

A total of 141 Pn drops with induced UAO were available for analysis, of which 464 flow-limited breaths (six to seven breaths per UAO category) were analysed and compared with 60 normal NFL breaths (three breaths per subject). While Pn was similar between the sexes for the baseline NFL condition (females 5.2±1.6 versus males 5.8±1.8 cmH2O (0.50±0.15 versus 0.56±0.17 kPa)), Pn was slighty lower (p<0.05) during all flow-limited categories in females (mild -1.5±3.6 versus 0.2±4.3 cmH2O (-0.14±0.35 versus 0.02±0.42 kPa); moderate -2.1±4.0 versus 1.0±2.6 cmH2O (-2.0±0.39 versus 0.10±0.25 kPa); and severe -2.8±4.9 versus -0.1±2.6 cmH2O (-0.27±0.48 versus -0.01±0.25 kPa) for females versus males, respectively).

Baseline ventilatory parameters during NFL breathing

The baseline respiratory parameters of the subjects are presented in table 2. Respiratory timing indices (inspiratory time (tI), total time of respiratory cycle (ttot) and tI/ttot) were similar in both sexes in the NFL state. In contrast, VT/tI and V′E during non-REM sleep were ∼40% lower in females compared with males, indicating a lower ventilatory demand in BMI and age-matched females compared with males during stable non-REM sleep. It should be noted that the anatomic VD was also lower in females compared with males in both groups.⇑

Interindividual variability of ventilatory responses of UAO

Figure 2⇓ and table 3⇓ illustrate V′E and timing responses to experimentally induced UAO in one individual. While V′E declined with increasing degrees of UAO, both tI/ttot and fR increased progressively. Pooled data of all individuals in figure 3⇓ demonstrate that increasing levels of UAO led to a dose-dependent response of tI/ttot and fR. Figure 4⇓ shows that individual responses of tI/ttot and fR to moderate UAO varied markedly from 97% to 140% and 95% to 135%, respectively.

Fig. 2—
Fig. 2—

Recording example from a male illustrating flow signals and ventilatory parameters at baseline and specific levels of upper airway obstruction (UAO). It should be noted that mean inspiratory airflow (VT/tI) deflection represents inhaled flow downward. With decreasing levels of VT/tI, inspiratory duty cycle and respiratory frequency increased while minute ventilation decreased progressively. See also table 3⇓.

Fig. 3—
Fig. 3—

The mean±sem of a) inspiratory duty cycle (tI/ttot) and b) respiratory frequency (fR) in response to increasing severity (mean inspiratory airflow levels were 200, 150 and 100 mL·s−1 for mild, moderate and severe upper airway obstruction (UAO), respectively) of UAO in normal individuals. *: p<0.05 compared with nonflow-limited (NFL) breathing.

Fig. 4—
Fig. 4—

The percentage change in a) inspiratory duty cycle and b) respiratory frequency from baseline (100% to moderate upper airway obstruction (UAO)) are shown for each male (□) and female (○) and, on the right of each graph, are presented as mean±sem for each sex.

View this table:
Table 3—

Recording example from a male illustrating flow signals and ventilatory parameters at baseline and specific levels of upper airway obstruction(UAO)

As outlined previously, it was hypothesised that an increase in tI/ttot, rather than fR, will improve V′E. Therefore, quartiles of tI/ttot and fR responses to moderate UAO of individuals were determined (fig. 4⇑). Quartiles for tI/ttot and fR for all individuals did not differ by age, sex or BMI at baseline. In each quartile, V′E compared with the mean V′E of the entire group was calculated. In figure 5⇓, V′E for individuals in each quartile for tI/ttot and fR responses is illustrated. Compared with the mean V′E of 4,279 mL·min−1 for the entire group, individuals with a low tI/ttot response (0.44) had ∼400 mL lower V′E compared with those with a high tI/ttot response (0.51) who had a 500 mL higher ventilation (p<0.01) compared with the entire group. In contrast, fR responses did not contribute to an increase in V′E.

Fig. 5—
Fig. 5—

The effect of increasing levels of a) inspiratory duty cycle and b) respiratory frequency responses on minute ventilation (V′E) compared with the mean V′E, which was 4,279 mL·min−1 of the entire group during moderate upper airway obstruction. *: p<0.05.

Sex differences in ventilatory responses to UAO

Several post hoc analyses were conducted to determine the influence of sex on ventilatory responses to UAO. In the first analysis, all males and females were included and timing indices and V′E were determined in response to decreasing absolute levels of mean VT/tI. While tI/ttot responses were similar between males and females, fR had a greater increase in females compared with males (fig. 6⇓). Nevertheless, V′E during UAO was similar between sexes, despite marked differences in V′E at baseline.

Fig. 6—
Fig. 6—

The mean±sem a and d) inspiratory duty cycle (tI/ttot), b and e) respiratory frequency (fR) and c and f) minute ventilation (V′E) for males (▪) and females (○) matched by body mass index and age (a–c; n = 20) and matched by baseline V′E (d–f; n = 12). Differences were determined by two-way ANOVA. NFL: nonflow limited; UAO: upper airway obstruction. *: p<0.05.

As previously noted (table 2⇑), the VT/tI at baseline was 80 mL lower in females. Thus, categories of flow limitation based on absolute levels of inspiratory airflow represented a smaller per cent reduction in VT/tI in females compared with males. Therefore, two additional post hoc analyses were conducted to account for absolute differences in VT/tI at baseline between males and females. First, VT/tI and V′E was matched in a subgroup of females (n = 6) and males (n = 6; table 2⇑), which produced similar percentage reductions in inspiratory airflow from baseline to mild (89% to 84%), moderate (67% to 63%) and severe (45% to 42%) levels of UAO. This approach produced similar responses between females and males in tI/ttot, fR and V′E.

Secondly, the severity of UAO was defined by a per cent reduction in VT/tI from baseline for all subjects. Comparing females and males, the present authors demonstrated that responses in tI/ttot and fR were similar to the above approaches, indicating that sex differences in ventilatory responses persist regardless of the method used for defining the exposure to UAO (flow limitation; see online supplementary material).

Alveolar ventilation

As outlined previously, a high fR under conditions of a fixed inspiratory airflow and unchanged tI/ttot should increase V′D and thereby lower V′A. Since females had a higher fR at all severities of UAO and tI/ttot was similar between sexes, one would expect lower V′A in females. However, males and females had comparable levels of V′A at all severities of UAO (fig. 7⇓), indicating that a lower VD offset the higher fR in females (table 2⇑).

Fig. 7—
Fig. 7—

a) Alveolar ventilation (V′A; mean±sem) for males (▪) and females (○). b) Relative percentage changes in V′A compared with baseline (100%). Differences were determined by a paired t-test. NFL: nonflow limited. *: p<0.05.

Females also had markedly lower V′E at baseline, indicating a lower ventilatory demand during non-REM sleep. In contrast, females had similar V′A at all severities of UAO compared with males (fig. 7a⇑). Relative to baseline (fig. 7b⇑), females preserved V′A better than males during mild and moderate flow limited conditions.

BMI effect on ventilatory responses

To explore the influence of BMI on ventilatory responses to UAO in males and females, timing responses during conditions of moderate UAO (VT/tI 150±25 mL·s−1) were analysed using linear regression analysis with BMI and sex as independent variables. Marked differences in respiratory timing responses in both males and females were observed across the spectrum of BMI. In males, neither the fR nor tI/ttot responses varied significantly with BMI. In contrast, females increased the absolute difference and percentage change in fR with increasing BMI. Specifically, an increase in BMI of 10 kg·m−2 was associated with an increase of 5 breaths·min−1 and a 30% change from baseline (p<0.01 for both).

DISCUSSION

The acute effects of UAO on respiratory patterns during sleep were examined. During periods of inspiratory airflow limitation, there was a dose-dependent increase in tI/ttot and fR in response to increasing levels of UAO. Heterogeneity in these responses led to variable degrees of ventilatory compensation to UAO. In particular, increases in the tI/ttot, not fR, helped to maintain ventilation and stabilise breathing acutely. Moreover, responses in the tI/ttot were independent of sex and BMI; however, the female sex and obesity were associated with a greater response in fR. Thus, UAO constitutes a unique load on the respiratory system, and the respiratory timing responses determine the ability to stabilise ventilation and compensate for UAO during sleep.

Timing responses to UAO

In the current study, brief periods of UAO elicited compensatory increases in the tI/ttot and fR. This prolongation of tI/ttot and fR was dose-dependent and instantaneous, suggesting that upper airway and pulmonary mechanoreceptors, rather than chemoreceptors, mediated these immediate responses to UAO 28–33. The increase in tI/ttot should help to stabilise V′E at any given level of UAO, as described by the following equation 17, 18, 20, which was imposed experimentally.

V′E =  tI/ttot × VT/tI           (2)

Under conditions of UAO, the VT/tI approximates the peak inspiratory airflow rate during inspiratory airflow limitation. In the current study, compensatory increases in tI/ttot were associated with greater degrees of ventilatory compensation, as reflected by greater increases in V′E (fig. 5⇑). In contrast, increases in fR would be expected to decrease ttot and tI proportionally (fig. 1⇑ and table 1⇑), thereby leaving tI/ttot and V′E unchanged. Thus, UAO is a unique load for which V′E is independent of fR at any given level of tI/ttot and VT/tI.

It is intriguing that tI/ttot and fR responses to UAO varied markedly among subjects. This variability in timing responses may be related to differences in metabolic rate, which is known to vary widely between individuals 34, 35. At the moderate flow-limited condition, the increases in tI/ttot varied markedly among individuals, ranging from 7% (0.39–0.42) to 48% (0.39–0.57; fig. 4⇑). Similarly, fR response varied substantially at moderate levels of UAO. It has been previously demonstrated that the tI/ttot response to hypercapnia is an intermediate physiological phenotype linked to mouse chromosome 5 17. Thus, tI/ttot and fR responses to UAO may represent constitutive traits that determine the individual's ability to compensate for a given degree of UAO during sleep.

Sex differences in ventilatory responses to UAO

Timing responses

While the tI/ttot response to UAO was similar between the sexes, fR increased more in females than males. As outlined previously (fig. 1⇑ and table 1⇑), under conditions of unchanged tI/ttot, V′D will increase as fR rises, and the magnitude of this increase will be determined by the subject's VD. An increase in fR would have little impact on V′D if the VD is negligible, but will increase the V′D markedly if the VD comprises a large proportion of the VT. VD was considerably lower in females than males (132±11 versus 179±24 mL), thereby minimising the impact of elevations in fR on V′D in females. Thus, a lower VD makes females relatively tolerant to a rise in fR during periods of UAO.

Ventilation

UAO produced similar reductions in V′E and V′A in males and females. Nevertheless, the relative per cent change in V′A from baseline was less in females than males (fig. 7⇑). V′A tracks metabolic rate during sleep 35, which is ∼30% lower in females than males due to body composition and stature 34–39. At comparable levels of UAO, females are less likely to hypoventilate than males. Thus, both a lower ventilatory demand and lower VD in females are likely to make females less susceptible to ventilatory instability during periods of UAO.

Limitations

There are several limitations to be considered. First, the analyses of timing responses were limited to acute periods of UAO. Responses to sustained periods of UAO might differ from acute conditions due to differences in the chemical control of ventilation and upper airway neural and mechanical control 15, 40, 41. Secondly, VD was estimated rather than directly measured. The present authors’ attempts to directly measure VD with the Fowler technique 42, 43 demonstrated a high inter- and intra-rater variability. Therefore, estimates of VD were used based on anthropometric data, which appears to be more reliable in subjects without underlying lung diseases. Finally, the current authors did not consider controlling the impact of oral contraceptives or menstrual phase on timing responses. Hormonal differences may explain some of the variability in timing responses in females. Nevertheless, males had a similar variability in timing responses, making the present authors suspect that hormones did not account for variations in timing responses in females, but may explain the greater fR response in females compared with males.

Implications

The present authors have shown that timing responses to UAO allowed for the segregation of individuals based on their propensity to preserve ventilation or to hypoventilate in the face of UAO. Crisp intermediate phenotypes such as these are required to probe for the genetic basis of obstructive sleep apnoea susceptibility. Moreover, the respiratory pattern may predict the susceptibility and expression of sleep-disordered breathing independent of the upper airway properties. First, diseases of the lungs and chest wall produce resistive and elastic loads to the respiratory system, which impact tI/ttot and fR 44, 45. Because VT/tI responses during UAO are limited (fixed), compensation to defend ventilation are primarily dependent on responses of the tI/ttot and the baseline fR. Further work is required to examine the role of elastic and restrictive loads on the degree of hypoventilation during periods of UAO compared with normal breathing. Secondly, individuals who have an increased metabolic rate (pregnancy) or VD (lung diseases) may be susceptible to hypoventilation if compensatory increases in tI/ttot are limited and fail to increase V′A. Thus, variations in tI/ttot and fR may explain disturbances in gas exchange across a spectrum of sleep-disordered breathing aetiologies.

In summary, the present findings indicate that upper airway obstruction elicits specific respiratory responses that may serve as quantitative intermediate traits for obstructive sleep apnoea and suggest that these factors may play a role in sex differences in the expression of sleep-disordered breathing.

Support statement

Funded by grants: HL 72126, HL 50381, HL 37379, HL077137 and P50 HL084945-01 from the National Institutes of Health (NIH; Washington, DC, USA). This publication was also made possible by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR; Bethesda, MD, USA), a component of the NIH (Bethesda) and NIH Roadmap for Medical Research (Bethesda). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at www.ncrr.nih.gov Information on re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp

Statement of interest

None declared.

Acknowledgments

The current authors would like to thank S.L. Kamsheh, L.A. Frame and S.B. Squier (Johns Hopkins University, Baltimore, MD, USA) for their contributions to the present study, which included technical support and help in the preparation of tables and figures.

Footnotes

  • Received April 24, 2008.
  • Accepted December 3, 2008.

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Inspiratory duty cycle responses to flow limitation predict nocturnal hypoventilation
H. Schneider, V. Krishnan, L. E. Pichard, S. P. Patil, P. L. Smith, A. R. Schwartz
European Respiratory Journal May 2009, 33 (5) 1068-1076; DOI: 10.1183/09031936.00063008
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