Women Have a Greater Ventilatory Responses to Upper Airway Obstruction Than Men

Pichard LE., Patil SP, Gladmon E, Smith PL, Schwartz AR, Schneider H Division of Pulmonary Medicine, Johns Hopkins University, Baltimore, MD

Abstract: However, inspiratory time depends on the total length of

the respiratory cycle (TTOT) nd this equation is better expressed as follows: where [VT]Ins is the inspired tidal volume, [VI] the mean inspiratory airflow, TI/TTOT is the inspiratory dutyof the respiratory cycle. Asbreathing, three distinct respinspiratory tidal volume. Theinspiratory airflow, the seconthird is the total length of tDuring upper airway obstructin ventilatory drive cannot gmean inspiratory airflow becbe limited to a maximal leveeffort increases [2,8]. Durinobstruction, therefore, patientstidal volume by prolonging ththe length of the respiratory cy

We examined whether gender specific differences exist in defending inspiratory tidal volumes in the face of upper airway obstruction. In normal weight- and aged-matched men (n=9) and women (n=9), we induced upper airway obstruction with inspiratory flow limitation during NREM sleep by exposing individuals to sub-atmospheric nasal pressure. The mean inspiratory airflow was used to define three distinct levels of upper airway obstruction, based on a mean inspiratory airflow of 175-225 ml/s, 125-175 ml/s and 75-125 ml/s. While duty cycle responses were similar between genders, women had a greater response in TTOT at all flow limited conditions. (p<0.05). However, the greater response in TTOT led to a more pronounced decline in tidal volume in women compared to men (p<0.05), particularly during the mild and moderate upper airway obstruction. Our data demonstrate that the respiratory rate determines the tidal volume during periods of upper airway obstruction and indicate that individuals with a higher respiratory rate are at risk to develop hypoventilation in face of upper airway obstruction. Because women have a more brisk response in the respiratory rate than men, this may explain the difference in the expression of sleep disordered breathing between genders.

[

Specific Aim: To examinedifference exist in defending the face of upper airway obstr

Keywords: ventilation, upper airway, obstruction, flow limitation, obstructive sleep apnea, sleep, gender, normals 2. Subjects: Individuals

breathing were recruited forsignificant co-morbid condhypertension.

I. INTRODUCTION

Women differ substantially in the expression of sleep disordered breathing from men. As such, women are less likely to have obstructive apneas in NREM than men, and the upper airway resistance syndrome is predominantly present in female rather than male subjects [4,9]. These differences in the expression of obstructive breathing episodes have been primarily attributed to gender related differences in the upper airway function [6] and arousability [4] from sleep. Recently, investigators demonstrated a greater ventilatory response to arousal in men compared to women [4], suggesting that differences in the expression of sleep disordered breathing might stem from gender specific differences in the ventilatory control.

3. Experimental Methods: studies were performed with ia nasal mask during NREM s[1,2].

4. Experimental Protocol: InCPAP and the nasal pressure+5 cmH2O, and reduced intcmH2O for five breaths to indas illustrated in Fig. 1. Fig. 1: Induction of Upper A

EOG(µV) 50

II. METHODOLOGY

1. Conceptual Approach: The following conceptual framework forms the basis for our approach to determine the respiratory response to periods of upper airway obstruction. According to the classic relationship: VT = (VI) x (TI), where VT is the inspired tidal volume, VI the mean inspiratory airflow and TI is the inspiratory time.

a

cycle and TTOT is the length can be seen, during normal iratory components defend

first component is the mean d is the duty cycle and the he respiratory cycle (TTOT). ion, however, such increases enerate any increase in the ause inspiratory flow would l that cannot be exceeded as g periods of upper airway can only defend inspiratory e inspiratory duty cycle and cle.

] [ ] TOTTOT

IiInsT T

TTVV •

•=

whether gender specific inspiratory tidal volumes in

uction.

without sleep disordered this study if they had no ition except obesity and

Standard overnight sleep ndividuals breathing through leep as previously described

dividuals were subjected to was initially maintained at ermittently by steps of 1-2 uce upper airway obstruction

irway Obstruction

50

(ml/s)

EMGSM

VV

EEG(µV)

PN

SaO

10

0(cm H2O)

50

(µV)

1000

100

80(%)

PES(cm H2O)

12

-8

5. Analytic Methods: Data were obtained for the five breaths at each Pn level during non-REM sleep. Limitation in inspiratory airflow was considered to be present when inspiratory airflow reached a maximal level (VImax) and plateaued as respiratory effort continued to increase. Breaths associated with micro-arousals from sleep were excluded from analyses. arousals from sleep were excluded from analyses.

The mean inspiratory airflow from breaths 3-5 at each run was used to define three levels of upper airway obstruction as follows: runs were categorized as mild, moderate and severe upper airway obstruction if the mean inspiratory flows fell into a range between 175-225 ml/s, 125-175 ml/s and 75-125 ml/s, respectively.

The mean inspiratory airflow from breaths 3-5 at each run was used to define three levels of upper airway obstruction as follows: runs were categorized as mild, moderate and severe upper airway obstruction if the mean inspiratory flows fell into a range between 175-225 ml/s, 125-175 ml/s and 75-125 ml/s, respectively.

A computer-based algorithm was used to determine mean TI/TTOT, TTOT, and VT in each category and during a period of non-obstructed breathing (baseline) taken from 5 breaths prior to each run.

A computer-based algorithm was used to determine mean TI/TTOT, TTOT, and VT in each category and during a period of non-obstructed breathing (baseline) taken from 5 breaths prior to each run. III. RESULTS III. RESULTS

1. Anthropometric characteristics1. Anthropometric characteristics: Eighteen men and women without sleep-disordered breathing were recruited for the study. There were no significant differences between men and women with respect to demographic characteristics and level of upper airway obstruction as planned by study design (see Table 1).

Ta

2. Ventilatory Responses to Upper Airway Obstruction: Figure 2 illustrates the effect of flow limitation on ventilatory control in a male (upper panel) and female (lower panel) normal individual. Both individuals had similar breathing pattern at baseline (left panel), while the female, compared to the male,

subject had a greater reduction in TTOT and tidal volume during mild, moderate and severe upper airway obstruction (three right panels). In contrast, duty cycle responses were similar between the two subjects.

Figure 3 shows the pooled data of ventilatory responses to mild, moderate and severe flow limitation for the male and female subjects. While duty cycle responses (left panels) were similar between genders, women had a greater response in TTOT (middle panel) at all flow limited conditions. (p<0.01). However, the greater response in TTOT led to a more pronounced decline in tidal volume in women compared to men (p<0.01), particularly during the mild and moderate flow limited condition. IV. DISCUSSION

The main finding of this study is that the ventilatory response to upper airway obstruction in women is greater than men in an age- and weight-matched control group. Women had a higher breathing rate and a more pronounced increase in the respiratory rate during periods of upper airway obstruction than men. As a result, upper airway obstruction produced a greater reduction in tidal inspiratory volume in women than in men. Our findings suggest that women are at a greater risk than men to develop hypoventilation in face of mild to moderate upper airway obstruction.

Upper airway obstruction is a unique load to the respiratory system. Unlike increased intrinsic resistances and externally applied loads, upper airway obstruction limits the inspiratory airflow to levels that are independent of the diaphragmatic respiratory drive [8]. Therefore, compensatory mechanisms to defend ventilation to upper airway obstruction are also limited to either one, the ability of the upper airway to increase inspiratory airflow or to the timing indices to increase tidal volume [7]. In this study, we tightly controlled the level of inspiratory airflow during periods of upper airway obstruction. Thus, we were able to assess the effect of upper airway obstruction on timing indices and tidal volume independent of the inspiratory airflow.

In a previous study, we demonstrated that the duty cycle infers susceptibility to hypoventilation during periods of upper airway obstruction [7]. Our current study demonstrates that the respiratory rate is an additional risk

ble 1. Characteristics of Patients

Variable Male Subjects (n=9)

Female Subject(n=9)

Age (yr) 42.3 ± 9.6 32.1 ± 11.6Body - Mass Index (kg/m 2 ) 28.5 ± 4.6 31.5 ± 3.6

Mean Inspiratory Airflow Baseline 269.6 ± 16.6 228.1 ± 14.2UAO Mild 198.4 ± 3.0 199.2 ± 3.3UAO Moderate 153.8 ± 3.2 148.2 ± 3.6U A O Severe 98.2 ± 3.2 102.4 ± 3.7

Figure 2: Ventilatory Responses to Upper Airway Obstruction in a Normal Male and Female Individual.

Figure 3: Ventilatory Reponses to UAO

150150

150150

Baseline Flow limitationMild Moderate Severe

5 sec.

TI/TTOT= .4TTOT = 6.0

TI/TTOT= .5TTOT = 5.4

VT =482.6

TI/TTOT= .5TTOT = 5.7

TI/TTOT= .5TTOT = 5.2

TI/TTOT= .3TTOT = 6.1

VT =453.9

TI/TTOT= .5TTOT = 3.8

TI/TTOT= .5TTOT = 3.7

VT =251.1

TI/TTOT= .5TTOT = 3.1

VT =173.9

VT =445.8 VT =374.0 VT =263.8

VT =345.5

PN (H2O)

PN (H2O)

V(ml/sec)

.

SaO2

SaO2

V(ml/sec)

.

100

80

100

80

1000

1000

6

-6

6

-6Male

Age=43 BMI=23.8

Male

Age=34 BMI=30.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 1 2 3 40.30

0.35

0.40

0.45

0.50

0.55

0.60

0 1 2 3 4

Female

0

100

200

300

400

500

600

0 1 2 3 4(VI ml/s) BL 200 150 100 (VI ml/s) BL 200 150 100 (VI ml/s) BL 200 150 100

Women

Men

Men

Women

TI/TTOT TTOT (sec) VT (ml)

factor constituting to hypoventilation in face of upper airway obstruction. As laid out in our conceptual framework, an increased respiratory rate (decreased TTOT) can only be counterbalanced by increases in the duty cycle or mean inspiratory airflow. Our study demonstrates that the duty cycle responses are similar between the genders. Thus, we predicted that individuals with a higher respiratory rate are at risk to develop hypoventilation in face of inspiratory flow limitation.

Women had a higher respiratory rate at baseline and greater ventilatory responses to upper airway obstruction than men. A gender dependency has been demonstrated for the ventilatory control during wakefulness and sleep as well as in response to extrinsic mechanical and chemical loads [4]. The gender effect has been attributed to hormonal, metabolic and structural differences of the respiratory system [5]. These factors have been demonstrated to influence mechanoreceptive reflexes to upper airway obstruction of the upper airway muscles [1]. To our knowledge, our study first demonstrated a gender difference in the ventilatory response to upper airway obstruction. Irrespective of the precise mechanism involved, the increased ventilatory responses to upper airway obstruction may play a role in the differences in susceptibility the expression of OSA between genders.

Our findings demonstrate that women compared to men are more likely to hypoventilate at any given level of upper airway obstruction. At first sight, this finding may seem to be counterintuitive to the clinical observations that women are more likely to have hypopneas and upper airway resistance syndrome than men. However, our finding is consistent with this observation. For example: during the moderate upper airway obstruction with a mean inspiratory airflow of 150 ml/s, women had a tidal volume of approximately 200 ml, while men still conserved their tidal volume above 300 ml (see Figure 3). Assuming a physiologic dead space of 150 ml, women breathing at low tidal volumes would reduce alveolar ventilation much faster than individuals breathing at higher tidal volumes. As a consequence, arterial CO2 would also reach the arousal threshold faster and individuals would be more likely to have respiratory-related arousals even though the mean inspiratory airflow was not markedly reduced. Thus, the differences in the expression of sleep disordered breathing may depend on the baseline respiratory rate and how much tidal volume declines at a given level of upper airway obstruction.

In summary, our data show that the respiratory rate determines the tidal volume during periods of upper airway obstruction and indicate that individuals with a higher respiratory rate are at risk to develop hypoventilation in face of upper airway obstruction. Because women have a more brisk response in the respiratory rate than men, this may explain the difference in the expression of sleep disordered breathing in women.

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