Influence of obstructive sleep apnoea on circadian blood pressure profile

SUMMARY  A high prevalence of systemic hypertension in obstructive sleep apnoea (OSA) has been described but data on circadian blood pressure (BP) profile are limited and give inconsistent results. The present study examines 24-h BP in 106 patients referred because of loud snoring or excessive daytime sleepiness in combination with snoring. Patients were classified as OSA ( n = 62) or habitual snorers (HS) ( n = 44). Respiratory disturbance index (RDI) in OSA was 47 ± 24 vs. 2 ± 2 in HS. Mean age and body mass index in OSA was significantly higher.
BP was measured non-invasively at 15-min intervals during a 24-h period. Daytime and night-time BP was higher in OSA compared to HS. BP night/day ratio in OSA was 0.92 ± 0.07 vs. 0.86 ± 0.06 in HS ( P < 0.05). To investigate the influence of variables other than breathing abnormalities during sleep on our results we compared BP profiles of 25 OSA and 25 HS matched for sex, age and body weight. Again differences in daytime and night-time BP and BP night/day ratio were significant. Using a value of at least 10% fall in nocturnal BP to describe a regular BP profile (dipper) 68% of OSA were classified as non-dippers vs. 24% of HS.
Influence of short-term (2–4 days) nCPAP therapy on circadian BP profile was investigated in 34 patients with OSA. Systolic and diastolic nocturnal (but not daytime) BP was significantly reduced. The percentage of non-dippers was 79% before and 50% after treatment. In conclusion results of this study indicate a causal link between OSA and abnormal circadian BP profile.     

Clinical significance of ventricular late potentials in patients with obstructive sleep apnoea

SUMMARY  Patients with obstructive sleep apnoea (OSA) have an increased cardiovascular mortality and probably also an increased incidence of sudden cardiac death. Thus the question arises whether ventricular late potentials can constitute markers for an increased electric vulnerability in these patients. Signal-averaged electrocardiograms were recorded in 64 patients (6 female, 58 male; mean age 53.2 y) with OSA (mean apnoea-hypopnoea index (AHI) 41.7 h^-1 ± 24.3 h^-1). Furthermore, a continuous ambulatory electrocardiogram and gated radionuclide ventriculography were performed. Ventricular late potentials were recorded in 5 men out of 64 patients. Two of them had coronary artery disease (1 patient post-myocardial infarction), 2 hypertension, and 1 nocturnal hypertension. No correlation could be traced between left ventricular ejection fraction, severity and extent of ventricular premature beats, or severity of OSA and occurrence of ventricular late potentials. It was noticeable, however, that the patients with ventricular late potentials had severe OSA (mean AHI 50.2/h vs. 40.9/h). Although OSA may lead to structural myocardial changes that could be the basis for re-entrant circuits, ventricular late potentials were found in only 7.8% of these patients. The results of this study demonstrate that at present ventricular late potentials and signal-averaged electrocardiograms do not prove useful as screening methods for risk stratification of patients with OSA.     

Effects of acupuncture on obstructive sleep apnea severity,blood pressure control and quality of life in patients with hypertension: A randomized controlled trial

Obstructive sleep apnea (OSA) is a common condition among patients with hypertension and treatment with continuous positive airway pressure (CPAP) can decrease blood pressure (BP). However, CPAP is not well tolerated by a significant proportion of patients. The authors investigated the effects of acupuncture on OSA severity and BP control in patients with hypertension. Hypertensive patients with mild to moderate OSA (apnea–hypopnea index, 5–30 events/hr) were randomly assigned to receive acupuncture or sham‐acupuncture treatment. Patients were assessed at baseline and after 10 acupuncture sessions using polysomnography, 24‐hr ambulatory BP monitoring and a quality of life questionnaire. Forty‐four patients (34% men; mean age, 57.0 ± 5.4 years; body mass index, 29.6 ± 3.2 kg/m²; apnea–hypopnea index, 16.3 ± 6.7 events/hr) completed the study. There were no differences in pre–post‐intervention apnea–hypopnea index, daytime or nocturnal BP, or quality of life between the acupuncture and sham‐acupuncture groups (p > .05). Acupuncture therapy in hypertensive patients with OSA did not reduce OSA severity, daytime or nocturnal BP, or quality of life.     

Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea

Polycythaemia, peripheral oedema formation and hypertension have classically been described in association with obstructive sleep apnoea (OSA). However, there is very limited information about blood volume in OSA and how it changes during long-term treatment with nasal continuous positive airway pressure (nCPAP). Plasma (PV) and red-cell volumes (RCV), 24-h ambulatory blood pressure (BP), 24-h natriuresis and morning plasma aldosterone, renin activity and atrial natriuretic peptide in 11 men with a mean age of 47 y (range 37–55), apnoea index (AI) of 55 (22–106), body mass index of 36 (30–43) and seated BP of ≥140/90 mmHg without any medication were measured. BP-measurements were repeated after 3 weeks and all measurements after 3 mo of nCPAP treatment. Aldosterone and 24-h mean heart rates decreased during treatment. Twenty-four-h BP decreased after 3 weeks but that decrease did not persist after 3 mo of treatment. There was a relationship between changes in night-time mean BP and PV and aldosterone. The haematocrit declined in every patient. No significant changes were found in the mean PV or RCV. They were in all instances lower than has earlier been described for normal, non-obese subjects. These data also suggest that OSA causes divergent individual disturbances in blood volume homeostasis which can be corrected by nCPAP.     

Respiration in NREM and REM sleep after upper airway surgery for obstructive sleep apnoea

SUMMARY  To verify whether upper airway surgery in obstructive sleep apnoea syndrome affects differently respiration in NREM and REM sleep, 22 patients were studied by polysomnography before and three months after surgical treatment. On the average, treatment improved respiration during both sleep states, but no significant interaction was found between sleep state and effect of surgical treatment. According to the response to treatment, three groups of patients were identified: the first group ( N = 6), with an improvement in apnoea-hypopnoea index (AHI), percentage of sleep time spent in apnoea and hypopnoea (time in AH) and mean oxyhaemoglobin saturation (SaO₂) in both NREM and REM sleep; the second group ( N = 5), with an improvement in AHI only in NREM sleep, associated with improvement in mean SaO₂ in both sleep states; the third group ( N = 11), without any improvement in AHI and time in AH, either associated ( N = 5) or not ( N = 6) with an improvement in mean SaO₂ in both sleep states. An increase in the percentage of hypopnoeas out of the total AHI after treatment could partly account for the apparent discrepancy between AHI and mean SaO₂ behaviour in the subjects of the second group, but not in the patients of the third group who improved their mean SaO₂. Mixed apnoeas occurred before surgery in six subjects; they remained numerous after surgery only in two subjects who did not show any SaO₂ improvement. In conclusion, the degree of improvement in respiration after upper airway surgery was similar in every patient in NREM and REM sleep.     

Sleep-related sweating in obstructive sleep apnoea: association with sleep stages and blood pressure

The aim of this study was to investigate sleep-related sweating as a symptom of obstructive sleep apnoea (OSA). Fifteen otherwise healthy male non-smoking patients with untreated moderate-to-severe OSA underwent polysomnography, including measurements of skin and core body temperature and electrodermal activity (EDA) as an objective indicator of sweating. Evening and morning blood pressure was measured as well as catecholamines in nocturnal urine. All measurements were repeated after 3 months on successful continuous positive airway pressure (CPAP) treatment. The untreated OSA subjects had a mean (±SD) apnoea–hypopnoea index of 45.3 ± 3.9 and a mean EDA index during sleep of 131.9 ± 22.4 events per hour. Patients with higher EDA indices had higher systolic blood pressure in the evening and morning ( P  = 0.001 and 0.006) and lower rapid eye movement (REM) sleep percentage ( P  = 0.003). The EDA index decreased significantly to 78.5 ± 17.7 in the patients on CPAP treatment ( P  = 0.04). The decrease correlated with lower evening systolic and diastolic blood pressure ( P  = 0.05 and 0.006) and an increase in REM% ( P  = 0.02). No relationship was observed between EDA and skin or core body temperature, or to catecholamine levels in urine. OSA patients who experience sleep-related sweating may have increased blood pressure and decreased REM sleep compared with other OSA patients. CPAP treatment appears to lower blood pressure and increase REM sleep to a higher extent in these patients compared with other OSA patients.     

A dog model to investigate the relationship between obstructive sleep apnoea and blood pressure regulation

SUMMARY  Patients exhibiting obstructive sleep apnoea (OSA) do not display a normal circadian pattern of blood pressure. It is not clear whether this disruption of the circadian blood pressure pattern is a result of the intermittent airway obstruction during sleep or is the result of confounding factors, such as obesity and age, which are common in OSA and may independently affect blood pressure. To determine if a cause and effect relationship exists between repetitive airway obstruction during sleep and blood pressure regulation a chronically instrumented canine model of OSA has been developed. This canine model has been shown to reproduce the characteristic apnoea and hypersomnolence of human OSA. Furthermore, in this model a 12-h nocturnal period of repetitive airway obstruction during sleep caused an increase in baseline blood pressure of more than 10 mmHg that was sustained for at least two hours following the restoration of normal airway patency. These results imply that there is a cause and effect relationship between intermittent airway obstruction during sleep and elevated blood pressure.     

Arousal in obstructive sleep apnoea patients is associated with ECG RR and QT interval shortening and PR interval lengthening

Sudden cardiac death appears to be more prevalent during the normal sleeping hours in obstructive sleep apnoea (OSA) patients compared with the general population as well as to cardiovascular disease patients. The reasons for this remain unclear, but there are three likely main contributors to nocturnal death in OSA patients; cardiac arrhythmias, stroke/ruptured cerebral aneurism and myocardial infarction. Particularly marked cardiovascular system activation with arousal may play a role in initiating sudden adverse cardiovascular events in OSA. The purpose of this study was to investigate cardiac RR, QT and PR interval changes in the electrocardiogram (ECG) associated with spontaneous and respiratory-related arousals in OSA patients. A detailed observational study of ECG records obtained during conventional diagnostic sleep study with no further interventions was carried out in 20 patients (12 males, age 42.8 ± 2.1 years, body mass index 35.1 ± 1.9 kg m⁻², and respiratory disturbance index 51.8 ± 6.4 events/hour). RR and QT intervals showed significant shortening during arousals. RR interval shortening was found to be greater during respiratory arousals when compared to spontaneous arousals. PR interval showed a trend toward a greater prolongation during respiratory arousal. QT interval shortening was weakly correlated with arterial oxygen saturation levels preceding arousal. In conclusion, these data suggest that despite greater cardiac acceleration following respiratory versus spontaneous arousals from sleep, QT shortening and PR prolongation responses are similar independent of arousal type. These data support that arousals produce quite marked and differential cardiac conduction system activation in OSA and that the degree and pattern of activation may be partly influenced by the presence and severity of preceding respiratory events.     

Non-invasive measurement of haemodynamics during sleep apnoea

SUMMARY  Sleep apnoeas are accompanied by large variations in heart rate (HR) and blood pressure (BP). This nocturnal variability in BP may be involved in the increased cardiovascular morbidity of these patients. Due to the complex interaction between asphyxia, intrathoracic pressure, cardiac function and autonomic activation, the exact haemodynamic mechanisms are unclear.
To evaluate the components of the BP surges at resumption of breathing (RB) a non-invasive beat-to-beat measurement was taken of cardiac output (CO) by the pulse contour analysis of the Finapres signal. Six male normotensive patients, free of medication (37–60 y, BMI 26.5–43.0 kg m^-2) were studied during polysomnography (apnoea index: 22–69 h^-1). Systolic blood pressure rose from 126.5 ± 1.3 mmHg at beginning apnoea (P1) to 140.4 ±1.3 at RB ( P <0.01, ANOVA). During sleep Stages 2 and 3, stroke volume decreased during RB to 96% of P1 value (NS). Due to an opposite change in HR, CO tended to rise at RB to 106% of P1. Computed total peripheral resistance rose during RB to 105% of P1 value ( P <0.01).
Therefore, it is concluded that the surge in BP at RB after apnoea is due to concomitant increases in CO and in TPR. Both rises are presumably a consequence of sympathetic nervous activation by the arterial chemoreceptors.     

Chemical control stability in the elderly

The prevalence of central apnoea and periodic breathing is increased in the elderly. This implies that the chemical control of breathing might become less stable with ageing. To investigate this, we measured loop gain in healthy elderly individuals using proportional assist ventilation. Loop gain is an engineering term that describes the stability of a system controlled by feedback loops, such as the respiratory control system. A loop gain close to zero indicates a stable system, whereas a loop gain close to or greater than one indicates an unstable system. Eleven healthy elderly subjects were studied with a mean ± s.d. age and body mass index (BMI) of 71 ± 5 years and 25 ± 3 kg m⁻², respectively. We also studied a small group of elderly individuals with obstructive sleep apnoea (OSA) for comparison ( n = 3, age 68 ± 1 years, BMI 32 ± 11 kg m⁻²). Comparisons were made with previously studied young individuals (age 27 ± 4 years, BMI 23 ± 1 kg m⁻²). We found significantly lower loop gains in the healthy elderly group (loop gain ≤ 0.25) compared with the young group (loop gain ≤ 0.47, P = 0.001). Also, we found quite low loop gains in the elderly OSA group (loop gain ≤ 0.26). We conclude that the chemical control of breathing does not become unstable with ageing and is thus an unlikely cause of central (and possibly obstructive) apnoeas in this population.     

Central apnoeas have significant effects on blood pressure and heart rate in children

Brief central apnoeas (CAs) during sleep are common in children and are not usually considered clinically significant unless associated with oxygen desaturation. CAs can occur spontaneously or following a movement or sigh. The aim of this study was to investigate acute cardiovascular changes associated with CAs in children. Beat‐by‐beat mean arterial pressure (MAP) and heart rate (HR) were analysed across CAs, and spontaneous and movement‐induced events were compared using two‐way analysis of variance with post hoc analyses. Fifty‐three children (28 male/25 female) aged 7–12 years referred for investigation of sleep‐disordered breathing (SDB) and 21 age‐matched healthy controls (8 male/13 female) were studied. Children underwent routine clinical polysomnography with continuous blood pressure (BP) recordings. Movement‐induced, but not spontaneous, CAs were more frequent in children with mild or moderate/severe obstructive sleep apnoea (OSA) compared with healthy controls (P < 0.05 for both). Movement‐induced CAs were associated with significantly larger MAP and HR changes across the event compared with spontaneous CAs. The percentage changes in MAP and HR between late‐event and post‐event were significantly greater for movement‐induced compared with spontaneous CAs (MAP 20.6 ± 2.3 versus 12.2 ± 1.8%, P < 0.01; HR 28.2 ± 2.6 versus 14.7 ± 2.5%, P < 0.001). This study demonstrates that movement‐induced CAs are more common in children with OSA, and are associated with significantly greater changes in HR and BP compared with spontaneous CAs. These data suggest that movement‐induced CAs should be considered when assessing the cardiovascular impact of SDB.     

Intrathoracic pressure changes and cardiovascular effects induced by nCPAP and nBiPAP in sleep apnoea patients

SUMMARY  The effect of nasal continuous positive airway pressure (nCPAP) and nasal bi-level positive airway pressure (nBiPAP) on intrathoracic pressure and haemodynamics during wakefulness was studied in a group of nine patients with severe sleep apnoea. No patient took cardiovascular medication.
Patients were studied with a Swan Ganz catheter, an arterial line and an oesophageal balloon. nCPAP and nBiPAP were applied in the following pressure sequence: 5, 10 and 15 cm H₂O of CPAP and 10/5 and 15/10 cm H₂O of nBiPAP. Measurements were made at the end of a 5-min period at each pressure level. Intrathoracic pressure was noted to increase to a level of approximately 50% of the pressure delivered at the mask. At a CPAP of 10 cm H₂O and above, as well as at BiPAP of 10/5 or higher, there was a decrease in cardiac output (CO) and cardiac index (CI). CI fell below the normal value in two of the patients. Transmural pulmonary artery pressure (PPA_tm) decreased at a CPAP of 15 cm H₂O and at both BiPAP levels. Transmural right atrial pressure (PRA_tm) decreased at both BiPAP levels. There were no differences in CO, CI, PPA_tm and PRA_tm between nCPAP and nBiPAP at equal inspiratory pressures. SaO₂ increased during BiPAP 15/10 cm H₂O, whereas heart rate and arterial blood pressure did not change significantly. The data presented here are consistent with the literature on positive end-expiratory pressure (PEEP) applied via intratracheal tube and are likely to be due to a reduced venous return. It is concluded that nasally applied positive pressure may have acute negative effects on cardiac function in patients with sleep apnoea.     

Evaluation of a new simple treatment for positional sleep apnoea patients

Obstructive sleep apnoea syndrome is a common clinical problem. Positional sleep apnoea syndrome, defined as having a supine apnoea-hypopnoea index of twice or more compared to the apnoea-hypopnoea index in the other positions, occurs in 56% of obstructive sleep apnoea patients. A limited number of studies focus on decreasing the severity of sleep apnoea by influencing sleep position. In these studies an object was strapped to the back (tennis balls, squash balls, special vests), preventing patients from sleeping in the supine position. Frequently, this was not successful due to arousals while turning from one lateral position to the other, thereby disturbing sleep architecture and sleep quality. We developed a new neck-worn device which influences sleep position by offering a vibration when in supine position, without significantly reducing total sleep time. Thirty patients with positional sleep apnoea were included in this study. No side effects were reported. The mean apnoea-hypopnoea index dropped from 27.7 ± 2.4 to 12.8 ± 2.2. Seven patients developed an overall apnoea-hypopnoea index below 5 when using the device in ON modus. We expect that positional therapy with such a device can be applied as a single treatment in many patients with mild to moderate position-dependent obstructive sleep apnoea, while in patients with a more severe obstructive sleep apnoea such a device could be used in combination with other treatment modalities.     

Does caffeine confound relationships among adrenergic tone,blood pressure and sleep apnoea?

The purpose of this study was to determine whether caffeine consumption confounds the relationship among adrenergic tone, as measured by urinary norepinephrine (NE), blood pressure (BP) and obstructive sleep apnoea (OSA). Data were analysed using correlation and regression analysis, analysis of covariance and t-tests. Subjects included normotensives and hypertensives with and without OSA: 38 men, 23 women, aged 30-60 y; 100-150% of ideal body weight; without other major illness. Patients were studied using polysomnography, caffeine consumption was assessed, 24-h urinary NE levels were examined and ambulatory BP was recorded. Patients with OSA (N=27) reported significantly greater caffeine consumption than those without OSA (N=34) (295 vs. 103 mg, P=0.010), but caffeine was not significantly correlated with their ambulatory BP. In contrast, NE excretion correlated with caffeine consumption (r=0.24, P=0.041), apnoea severity (r=0.65, P < 0.001) and BP (r=0.34, P < 0.005). Significant OSA-NE and BP-NE relationships remained even after controlling for caffeine consumption. Patients with OSA consumed nearly three times the amount of caffeine as patients without OSA. While caffeine partially explains the increased adrenergic tone in patients with OSA and the relationship between BP and NE, it does not appear to contribute significantly to the relationship between OSA and elevated BP.     

Association of polycystic ovary syndrome and a non-dipping blood pressure pattern in young women

OBJECTIVE

The association between polycystic ovarian syndrome and increased cardiovascular disease risk is still a controversial issue. In light of data documenting some common pathways or common end-points, the present study was undertaken to determine whether there is a relationship between sleep blood pressure pattern disturbances and polycystic ovarian syndrome in young women.

METHOD

The daytime and nighttime ambulatory blood pressures (BPs) were determined for each subject, according to the actual waking and sleeping times recorded in their individual diaries, in this cross-sectional study.

RESULTS

The study group comprised 168 women (mean age: 25.7±5.5) diagnosed with polycystic ovarian syndrome, while the control group included 52 age- and BMI-matched healthy subjects (mean age: 26.1±5.4). When nocturnal BP declines very little or not at all, with the BP falling less than 10% during sleep compared with waking values, this pattern is classified as a non-dipping BP pattern. However, the non-dipping pattern of BP changes was significantly more common in polycystic ovarian syndrome patients compared to the control group (p<0.01). The prevalence of a non-dipping BP pattern was 43.4% (73 patients) in polycystic ovarian syndrome patients and 3.9% (2 patients) in the control group.

CONCLUSION

Our cross-sectional study revealed that a non-dipping BP pattern is highly prevalent in polycystic ovarian syndrome patients, even if they are young and non-obese.     

Automatic CPAP based on impedance-comparison of constant CPAP with an individual pressure range

Summary Introduction   Self-adjusting positive airways pressure treatment based on the impedance of the airways (APAP_FOT) has proven effective in obstructive sleep apnoea syndrome. To avoid patient discomfort during periods of high treatment pressure we lowered the upper pressure limit with APAP_FOT and investigated whether this provided equally as effective treatment as constant CPAP. Methods   37 patients (33 males, 57.9 ± 9.9 years, BMI 32.5 ± 3.8 kg/m²) underwent after diagnostic polysomnography and manual nCPAP titration two treatment nights in randomized order, one with constant nCPAP (mode 1), one with APAP_FOT (mode 2). Under APAP_FOT treatment pressure varied between 4 hPa (set lower limit for all patients) and 13.3 ± 1.4 hPa (individually variable upper pressure limit). Results   AHI was reduced from 32.8 ± 18.1/h to 4.6 ± 4.9/h (mode 1, p < 0.01) and to 5.0 ± 4.1/h (mode 2, p < 0.01). Rapid eye movement sleep (REM) and respiratory arousals improved significantly with both modes. With APAP_FOT, the mean pressure was 5.7 ± 1.7 hPa as compared to 8.3 ± 1.4 hPa with constant nCPAP (p < 0.01). Conclusions   APAP_FOT with a reduced upper pressure is as effective as constant nCPAP for OSAS. With APAP_FOT the mean pressure is substantially reduced.     

Climacteric vasomotor symptoms do not predict nocturnal breathing abnormalities in postmenopausal women.

OBJECTIVE: To study the association of climacteric vasomotor symptoms and nocturnal breathing abnormalities in a sample of healthy postmenopausal women. METHODS: Out of 71 postmenopausal women who took part in a large sleep study, 65 women were included into the present study. Sleep was monitored with polysomnography and nocturnal breathing with a static-charge sensitive bed and a pulse oximeter. Climacteric vasomotor symptoms were scored daily for 14 days and levels of oestradiol and FSH were measured in the serum. RESULTS: Altogether 21 (32.3%) women had some degree of breathing abnormalities during the study night. The occurrence of clinically significant sleep apnoea was low (1.5%) and of moderate type (OP-2). In contrast, increased respiratory resistance pattern, typical for partial upper airway obstruction, was frequent (16.9%). Seventy-eight per cent of the women had arterial oxyhaemoglobin desaturation events, but only in 4.6% of the women these events occurred more than 5 times/h of time in bed. Older women had more simple periodic breathing (P-1) and lower mean arterial oxyhaemoglobin saturation (SaO(2)). Body mass index (BMI) correlated with the apnoea frequency (OP-2) and inversely with the mean SaO(2). The severity of climacteric vasomotor symptoms or serum oestradiol concentration did not correlate with nocturnal breathing abnormalities. CONCLUSIONS: Nocturnal breathing abnormalities, especially partial upper airway obstruction, are common in postmenopausal women, but climacteric vasomotor symptoms do not predict their occurrence or severity. Increasing age and high BMI are important determinants of nocturnal breathing abnormalities.     

Hot flashes are associated with increased ambulatory systolic blood pressure

OBJECTIVE: To determine the association between ambulatory blood pressure (BP) and hot flash experience. DESIGN: The participants in the study were 154 women (mean age=46 years, range=18-65 years), who were evaluated as part of a cross-sectional study on ethnicity, socioeconomic status, and diurnal BP patterns. Participants could be either normotensive or mildly hypertensive. Participants wore an ambulatory BP monitor for 24 hours and recorded their awake and sleep times. Hot flashes were assessed using an everyday complaint questionnaire that embeds symptoms associated with menopause into a list of everyday complaints. RESULTS: Thirty-three percent of participants reported having had hot flashes during the 2 weeks before they completed the questionnaire. Compared with women who did not report hot flashes, mean awake and sleep systolic BP values were significantly higher (P<0.004 and P=0.007, respectively) in women who reported having had hot flashes. Hot flashes continued to independently predict average awake and sleep systolic BP (both P=0.03) after controlling for age, race/ethnicity, body mass index, and menopausal status. Hot flashes were not associated with diastolic BP or nocturnal dipping of BP. CONCLUSIONS: Hot flashes are associated with increased awake and sleep systolic BP independent of menopausal status. Further investigation is warranted to elucidate the mechanisms by which hot flashes are associated with BP.     

Development of respiratory control instability in heart failure: a novel approach to dissect the pathophysiological mechanisms

Observational data suggest that periodic breathing is more common in subjects with low   F _ETCO2  , high apnoeic thresholds or high chemoreflex sensitivity. It is, however, difficult to determine the individual effect of each variable because they are intrinsically related. To distinguish the effect of isolated changes in chemoreflex sensitivity, mean   F _ETCO2  and apnoeic threshold, we employed a modelling approach to break their obligatory in vivo interrelationship. We found that a change in mean CO₂ fraction from 0.035 to 0.045 increased loop gain by 70 ± 0.083% ( P < 0.0001), irrespective of chemoreflex gain or apnoea threshold. A 100% increase in the chemoreflex gain (from 800 l min⁻¹ (fraction CO₂)⁻¹) resulted in an increase in loop gain of 275 ± 6% ( P < 0.0001) across a wide range of values of steady state CO₂ and apnoea thresholds. Increasing the apnoea threshold   F _ETCO2  from 0.02 to 0.03 had no effect on system stability. Therefore, of the three variables the only two destabilizing factors were high gain and high mean CO₂; the apnoea threshold did not independently influence system stability. Although our results support the idea that high chemoreflex gain destabilizes ventilatory control, there are two additional potentially controversial findings. First, it is high (rather than low) mean CO₂ that favours instability. Second, high apnoea threshold itself does not create instability. Clinically the apnoea threshold appears important only because of its associations with the true determinants of stability: chemoreflex gain and mean CO₂.