Age, Sleep Apnea
Conditions
Keywords
apneic threshold, central apnea, intermittent hypoxia, aging, ventilation, chemoresponsiveness, carbon-dioxide reserve
Brief summary
The purpose for this research protocol was to examine the role of breathing control mechanisms that determine the development of sleep-disordered breathing in the elderly. This proposal focused on key factors that contribute to the control of ventilation in elderly adults during sleep. The investigators studied the age-specific changes in ventilatory control in older and young adults during NREM sleep.
Detailed description
Sleep apnea-hypopnea syndrome (SAS) is a relatively common disorder in the US population with significant adverse health consequences. Despite the high prevalence of SAS in elderly individuals, the underlying mechanisms have remained elusive. Specifically, the investigators do not know whether the high prevalence of sleep apnea in older adults is due to increased central breathing instability. This proposal focused on investigating age-specific differences in the susceptibility to central breathing instability in adults. This project had the following specific objectives: * To determine age-specific changes in the hypocapnic apneic threshold during NREM sleep in elderly vs young individuals. * To determine age-specific changes in long-term facilitation during sleep in elderly versus young individuals. Procedure: The investigators determined the susceptibility to central breathing instability by mechanically ventilating the subjects during NREM sleep using non-invasive pressure support ventilation. The investigators compared the hypocapnic apneic threshold in old (age\>60 years) and young (age 18-50 years) individuals who were healthy. The investigators also measured the parameters over a continuum of age from 18 to 89 years. \- The investigators investigated whether there was a difference in the susceptibility to long term facilitation of ventilation between young and old healthy individuals in response to episodic hypoxia, while maintaining isocapnia. Sleep apnea is very common in older Veterans and is associated with significant cardiovascular complications. Greater insight into the pathogenesis will have a positive impact on the health of Veterans suffering from this condition. This study furthers the understanding of the pathogenesis of breathing instability leading to sleep-disordered breathing during sleep. The investigators anticipate findings will provide a basis for new approaches to prevention and management of SAS in Veterans.
Interventions
OTHER1) hyperventilation via noninvasive positive pressure ventilation 2) multiple trials of episodic hypoxia
1\) noninvasive hyperventilation to determine apneic threshold; 2) episodic hypoxia to determine ventilatory long term facilitation
Sponsors
VA Office of Research and Development
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy older and young adults
Exclusion criteria
* Pregnancy, * history of active coronary artery disease-including stable and unstable angina, * recent myocardial infarction, * history of congestive heart failure, * stroke, * excessive daytime sleepiness with Epworth Sleepiness Scale of \>15 * patient with OSA- (Obstructive sleep apnea) on therapy * depression, * schizophrenia, * untreated hypothyroidism, * diabetes on insulin, * seizure disorder, * intrinsic renal and liver disorders, * failure to give informed consent, * patients with evidence of pulmonary diseases based on history and abnormal pulmonary function testing, including obstructive (ratio of predicted forced expiratory volume to forced vital capacity, \<80% predicted) or restrictive lung disorders (total lung capacity \<80% predicted) with resting oxygen saturation of \<96% and kyphoscoliosis (chest wall deformities) * patients on certain medications including, opiates derivatives, stimulants, antidepressants, tranquilizers, anti-psychotic agents, theophylline and other central nervous system altering medications * history of alcohol or recreational drug use will also serve as grounds for exclusion, * patients with body mass index (BMI) \>34kg/m2 * subjects with sleep apnea are already using continuous positive airway pressure for more than 7 days as therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apneic Threshold (AT) and Carbon-dioxide (CO2) Reserve | 4-6 wks for each participant | The AT was defined as the end-tidal (PETCO2) that demarcated the central apnea closest to the eupneic PETCO2. The CO2 reserve was defined as the difference in PETCO2 between eupnea and AT. |
| Long-term Facilitation (LTF) of Ventilation, Minute Ventilation Was Measured in Older Adults Only | 4-6 wks for each participant | Episodic hypoxia (EH) leads to sustained elevation of the ventilatory motor output, referred to as LTF, an excitatory mechanism characterized by a sustained elevation in ventilatory motor output following EH. Minute ventilation during recovery period after multiple trials of EH. This is reported in older adults on this grant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypoxic Ventilatory Response | 4-6 wks for each participant | Hypoxic ventilatory response was calculated as the change in minuted ventilation for a change in oxygen saturation during each hypoxia trial. |
| Brief Hyperoxia Response | 4-6 wks for each participant | Brief hyperoxia response was the nadir minute ventilation achieved immediately upon exposure to brief hyperoxia expressed as a percent of eupneic minuted ventilation. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited by posting fliers at the sites approved by the Detroit VA clinical investigations committee and Wayne State IRB (institution review board). They completed a phone interview. If they qualified based on the inclusion/exclusion criteria they completed an informed consent. Dates 2008 to 2014.
Participants by arm
| Arm | Count |
|---|---|
| Health Young Adults Health Young adults, age 18-50 yrs
hyperventilation and episodic hypoxia: noninvasive hyperventilation to determine apneic threshold; episodic hypoxia to determine long term facilitation | 15 |
| Healthy Older Adults Healthy Older adults, age \>55-60yrs
hyperventilation and episodic hypoxia: noninvasive hyperventilation to determine apneic threshold; episodic hypoxia to determine long term facilitation | 19 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | sleep apnea, inadequate signals/sleep | 9 | 8 |
| Overall Study | Withdrawal by Subject | 25 | 18 |
Baseline characteristics
| Characteristic | Health Young Adults | Healthy Older Adults | Total |
|---|---|---|---|
| Age, Continuous | 35.9 years STANDARD_DEVIATION 9.9 | 66.9 years STANDARD_DEVIATION 5.4 | 48.3 years STANDARD_DEVIATION 17.6 |
| Body mass index | 26.4 kg/m2 STANDARD_DEVIATION 2.4 | 27.3 kg/m2 STANDARD_DEVIATION 3.2 | 26.8 kg/m2 STANDARD_DEVIATION 3.6 |
| Region of Enrollment United States | 15 participants | 19 participants | 34 participants |
| Sex: Female, Male Female | 8 Participants | 12 Participants | 20 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
| Sex/Gender, Customized Apneic Threshold & CO2 Reserve Analysis Population Female | 8 Participants | 6 Participants | 14 Participants |
| Sex/Gender, Customized Apneic Threshold & CO2 Reserve Analysis Population Male | 7 Participants | 4 Participants | 11 Participants |
| Sex/Gender, Customized Brief Hyperoxia Response Analysis Population Female | 3 Participants | 6 Participants | 9 Participants |
| Sex/Gender, Customized Brief Hyperoxia Response Analysis Population Male | 6 Participants | 4 Participants | 10 Participants |
| Sex/Gender, Customized Hypoxic Ventilatory Response Analysis Population Female | 6 Participants | 7 Participants | 13 Participants |
| Sex/Gender, Customized Hypoxic Ventilatory Response Analysis Population Male | 4 Participants | 6 Participants | 10 Participants |
| Sex/Gender, Customized LTF and Minute Ventilation Analysis Population Female | NA Participants | 8 Participants | NA Participants |
| Sex/Gender, Customized LTF and Minute Ventilation Analysis Population Male | NA Participants | 6 Participants | NA Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 50 | 0 / 42 |
| serious Total, serious adverse events | 0 / 50 | 0 / 42 |
Outcome results
Primary
Apneic Threshold (AT) and Carbon-dioxide (CO2) Reserve
The AT was defined as the end-tidal (PETCO2) that demarcated the central apnea closest to the eupneic PETCO2. The CO2 reserve was defined as the difference in PETCO2 between eupnea and AT.
Time frame: 4-6 wks for each participant
Population: Older adults : n=10, 6 females/4 males Young n=15, 8 females/ 7 males; participants with data available were included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Young Adults | Apneic Threshold (AT) and Carbon-dioxide (CO2) Reserve | Apneic Threshold | 39.8 mm Hg | Standard Error 0.9 |
| Healthy Young Adults | Apneic Threshold (AT) and Carbon-dioxide (CO2) Reserve | Carbox-dioxide reserve | -4.1 mm Hg | Standard Error 0.4 |
| Healthy Old Adults | Apneic Threshold (AT) and Carbon-dioxide (CO2) Reserve | Apneic Threshold | 36.7 mm Hg | Standard Error 1.3 |
| Healthy Old Adults | Apneic Threshold (AT) and Carbon-dioxide (CO2) Reserve | Carbox-dioxide reserve | -2.6 mm Hg | Standard Error 0.4 |
Comparison: T- test was conducted to compare the 2 groups.p-value: <0.05t-test, 2 sided
Primary
Long-term Facilitation (LTF) of Ventilation, Minute Ventilation Was Measured in Older Adults Only
Episodic hypoxia (EH) leads to sustained elevation of the ventilatory motor output, referred to as LTF, an excitatory mechanism characterized by a sustained elevation in ventilatory motor output following EH. Minute ventilation during recovery period after multiple trials of EH. This is reported in older adults on this grant.
Time frame: 4-6 wks for each participant
Population: Older adults 8 women/6 men;participants with data available were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Young Adults | Long-term Facilitation (LTF) of Ventilation, Minute Ventilation Was Measured in Older Adults Only | 94.4 percentage of control minute ventilation | Standard Error 3.5 |
p-value: <0.05ANOVA
Secondary
Brief Hyperoxia Response
Brief hyperoxia response was the nadir minute ventilation achieved immediately upon exposure to brief hyperoxia expressed as a percent of eupneic minuted ventilation.
Time frame: 4-6 wks for each participant
Population: young adults: 3 women/6 men; older adults: 6 women/4 men; participants with data available were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Young Adults | Brief Hyperoxia Response | 89.7 percentage of eupneic minute ventilaion | Standard Error 8.4 |
| Healthy Old Adults | Brief Hyperoxia Response | 79.6 percentage of eupneic minute ventilaion | Standard Error 9.6 |
p-value: <0.05t-test, 2 sided
Secondary
Hypoxic Ventilatory Response
Hypoxic ventilatory response was calculated as the change in minuted ventilation for a change in oxygen saturation during each hypoxia trial.
Time frame: 4-6 wks for each participant
Population: older adults: 7 women/6 men; young adults: 6 women/4 men;participants with data available were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Young Adults | Hypoxic Ventilatory Response | 0.21 Liter/minute/%saturation | Standard Error 0.05 |
| Healthy Old Adults | Hypoxic Ventilatory Response | 0.53 Liter/minute/%saturation | Standard Error 0.36 |
p-value: <0.05t-test, 2 sided