Hypoxemia alone does not explain blood pressure elevations after obstructive apneas

In patients with obstructive sleep apnea (OSA), substantial elevations of systemic blood pressure (BP) and depressions of oxyhemoglobin saturation (SaO2) accompany apnea termination. The causes of the BP elevations, which contribute significantly to nocturnal hypertension in OSA, have not been defined precisely. To assess the relative contribution of arterial hypoxemia, we observed mean arterial pressure (MAP) changes following obstructive apneas in 11 OSA patients during non-rapid-eye-movement (NREM) sleep and then under three experimental conditions: 1) apnea with O2 supplementation; 2) hypoxemia (SaO2 80%) without apnea; and 3) arousal from sleep with neither hypoxemia nor apnea. We found that apneas recorded during O2 supplementation (SaO2 nadir 93.6% +/- 2.4; mean +/- SD) in six subjects were associated with equivalent postapneic MAP elevations compared with unsupplemented apneas (SaO2 nadir 79-82%): 18.8 +/- 7.1 vs. 21.3 +/- 9.2 mmHg (mean change MAP +/- SD); in the absence of respiratory and sleep disruption in eight subjects, hypoxemia was not associated with the BP elevations observed following apneas: -5.4 +/- 19 vs. 19.1 +/- 7.8 mmHg (P less than 0.01); and in five subjects, auditory arousal alone was associated with MAP elevation similar to that observed following apneas: 24.0 +/- 8.1 vs. 22.0 +/- 6.9 mmHg. We conclude that in NREM sleep postapneic BP elevations are not primarily attributable to arterial hypoxemia. Other factors associated with apnea termination, including arousal from sleep, reinflation of the lungs, and changes of intrathoracic pressure, may be responsible for these elevations.     

Postevent ventilation as a function of CO(2) load during respiratory events in obstructive sleep apnea.

Maintenance of eucapnia during sleep in obstructive sleep apnea (OSA) requires a balance between CO(2) loading during apnea and CO(2) elimination. This study examines individual respiratory events and relates magnitude of postevent ventilation to CO(2) load during the preceding respiratory event in 14 patients with OSA (arterial PCO(2) 42-56 Torr). Ventilation and expiratory CO(2) and O(2) fractions were measured on a breath-by-breath basis during daytime sleep. Calculations included CO(2) load during each event (metabolic CO(2) production - exhaled CO(2)) and postevent ventilation in the 10 s after an event. In 12 of 14 patients, a direct relationship existed between postevent ventilation and CO(2) load during the preceding event (P < 0.05); the slope of this relationship varied across subjects. Thus the postevent ventilation is tightly linked to CO(2) loading during each respiratory event and may be an important mechanism that defends against development of acute hypercapnia in OSA. An inverse relationship was noted between this postevent ventilatory response slope and the chronic awake arterial PCO(2) (r = 0.90, P < 0.001), suggesting that this mechanism is impaired in patients with chronic hypercapnia. The link between development of acute hypercapnia during respiratory events asleep and maintenance of chronic awake hypercapnia in OSA remains to be further investigated.     

Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema

In five patients with hypoxic chronic bronchitis and emphysema we measured ear O2 saturation (SaO2), chest movement, oronasal airflow, arterial and mixed venous gas tensions, and cardiac output during nine hypoxemic episodes (HE; SaO2 falls greater than 10%) in rapid-eye-movement (REM) sleep and during preceding periods of stable oxygenation in non-REM sleep. All nine HE occurred with recurrent short episodes of reduced chest movement, none with sleep apnea. The arterial PO2 (PaO2) fell by 6.0 +/- 1.9 (SD) Torr during the HE (P less than 0.01), but mean arterial PCO2 (PaCO2) rose by only 1.4 +/- 2.4 Torr (P greater than 0.4). The arteriovenous O2 content difference fell by 0.64 +/- 0.43 ml/100 ml of blood during the HE (P less than 0.05), but there was no significant change in cardiac output. Changes observed in PaO2 and PaCO2 during HE were similar to those in four normal subjects during 90 s of voluntary hypoventilation, when PaO2 fell by 12.3 +/- 5.6 Torr (P less than 0.05), but mean PaCO2 rose by only 2.8 +/- 2.1 Torr (P greater than 0.4). We suggest that the transient hypoxemia which occurs during REM sleep in patients with chronic bronchitis and emphysema could be explained by hypoventilation during REM sleep but that the importance of changes in distribution of ventilation-perfusion ratios cannot be assessed by presently available techniques.     

Posthypoxic ventilatory decline during NREM sleep: influence of sleep apnea.

We wished to determine the severity of posthypoxic ventilatory decline in patients with sleep apnea relative to normal subjects during sleep. We studied 11 men with sleep apnea/hypopnea syndrome and 11 normal men during non-rapid eye movement sleep. We measured EEG, electrooculogram, arterial O(2) saturation, and end-tidal P(CO2). To maintain upper airway patency in patients with sleep apnea, nasal continuous positive pressure was applied at a level sufficient to eliminate apneas and hypopneas. We compared the prehypoxic control (C) with posthypoxic recovery breaths. Nadir minute ventilation in normal subjects was 6.3 +/- 0.5 l/min (83.8 +/- 5.7% of room air control) vs. 6.7 +/- 0.9 l/min, 69.1 +/- 8.5% of room air control in obstructive sleep apnea (OSA) patients; nadir minute ventilation (% of control) was lower in patients with OSA relative to normal subjects (P < 0.05). Nadir tidal volume was 0.55 +/- 0.05 liter (80.0 +/- 6.6% of room air control) in OSA patients vs. 0.42 +/- 0.03 liter, 86.5 +/- 5.2% of room air control in normal subjects. In addition, prolongation of expiratory time (Te) occurred in the recovery period. There was a significant difference in Te prolongation between normal subjects (2.61 +/- 0.3 s, 120 +/- 11.2% of C) and OSA patients (5.6 +/- 1.5 s, 292 +/- 127.6% of C) (P < 0.006). In conclusion, 1) posthypoxic ventilatory decline occurred after termination of hypocapnic hypoxia in normal subjects and patients with sleep apnea and manifested as decreased tidal volume and prolongation of Te; and 2) posthypoxic ventilatory prolongation of Te was more pronounced in patients with sleep apnea relative to normal subjects.     

Obstructive Sleep Apnea Is Associated with Liver Damage and Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease

Background/Aims

We assessed whether obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with severity of liver fibrosis and carotid atherosclerosis in patients with biopsy-proven NAFLD and low prevalence of morbid obesity. Secondary aim was to explore the association of OSA and hypoxemia with NASH and severity of liver pathological changes.

Methods

Consecutive patients (n = 126) with chronically elevated ALT and NAFLD underwent STOP-BANG questionnaire to estimate OSA risk and ultrasonographic carotid assessment. In patients accepting to perform cardiorespiratory polygraphy (PG, n = 50), OSA was defined as an apnea/hypopnea index ≥5. A carotid atherosclerotic plaque was defined as a focal thickening >1.3 mm.

Results

Prevalence of high OSA risk was similar in patients refusing or accepting PG (76% vs 68%, p = 0.17). Among those accepting PG, overall OSA prevalence was significantly higher in patients with F2-F4 fibrosis compared to those without (72% vs 44%; p = 0.04). Significant fibrosis was independently associated with mean nocturnal oxygen saturation (SaO₂)<95% (OR 3.21, 95%C.I. 1.02–7.34; p = 0.04). Prevalence of OSA tended to be higher in patients with, than in those without, carotid plaques (64% vs 40%; p = 0.08). Carotid plaques were independently associated with %time at SaO2<90% >1 (OR 6.30, 95%C.I. 1.02–12.3; p = 0.01).

Conclusions

In NAFLD patients with chronically elevated ALT at low prevalence of morbid obesity, OSA was highly prevalent and indexes of SaO₂ resulted independently associated with severity of liver fibrosis and carotid atherosclerosis. These data suggest to consider sleep disordered breathing as a potential additional therapeutic target in severe NAFLD patients.     

Plasma adenosine and hypoxemia in patients with sleep apnea

Severe hypoxemia causes ATP depletion and increased adenosine production in many body tissues. Therefore we hypothesized that patients with sleep apnea and severe hypoxemia during sleep have higher adenosine production and higher plasma adenosine levels than patients without hypoxemia. Twelve patients with sleep apnea and six normal volunteers had plasma adenosine levels measured by high-performance liquid chromatography. Each patient with sleep apnea had a polysomnograph sleep study with oxyhemoglobin saturation continuously recorded. Five of 12 patients with sleep apnea had both sleep apnea and severe hypoxemia during sleep. These patients with severe nocturnal hypoxemia had significantly higher plasma adenosine levels (means +/- SD 9.7 +/- 5.5 X 10(-8) M) than either a group of six normal volunteers (3.5 +/- 0.7 X 10(-8) M) or a group of seven patients with sleep apnea without hypoxemia at night (3.1 +/- 1.5 X 10(-8) M) (P less than 0.01). In addition plasma adenosine levels were significantly correlated with two indexes of nocturnal hypoxemia (desaturation index rs = 0.79, and median oxyhemoglobin saturation during sleep rs = -0.75, P less than 0.01). Plasma adenosine markedly fell to a normal level in the only two patients with sleep apnea who had successful treatment of their multiple apneas and accompanying severe hypoxemia during sleep.     

Repetitive apneas induce periodic hypertension in normal subjects through hypoxia.

Periodic increases in blood pressure (BP) can occur in the sleep apnea syndrome (SAS) during recurrent apneas. To investigate the mechanisms causing this periodic hypertension, we simulated SAS by imposing a matching breathing pattern on seven healthy awake male volunteers. Continuous finger arterial BP, electrocardiogram, arterial O2 saturation (SaO2), end-tidal CO2, and tidal volume were measured. The role of hypoxia was studied by comparing apneas during depletion of O2 in the spirometer with those during 100% O2 breathing. In all subjects, BP periodically reached values greater than 150/95 mmHg in the hypoxic series. During the hyperoxic apnea series, however, BP remained stable. End-apneic mean BP was shown to be inversely correlated to SaO2 in six subjects in the SaO2 range from 60 to 100%. Although the hypoxic BP pattern closely mimicked that in SAS, the heart rate pattern in four of our subjects remained distinct from that in patients. Atropine could not prevent large BP swings in the hypoxic series. We conclude that SaO2 is a major determinant of periodic hypertension in recurrent apneas. Its effect probably results from chemoreflex modulation of peripheral resistance.     

Atelectasis affects the rate of arterial desaturation during obstructive apnea

Chronic hemodynamic disturbances are more profound in patients with obstructive sleep apnea when underlying lung disease with abnormal gas exchange (low arterial PO2) is present. Previous studies suggest that pulmonary gas exchange could influence the rate of fall of arterial oxygen saturation (dSaO2/dt) in obstructive sleep apnea. We postulated that abnormal gas exchange in the form of atelectasis would steepen dSaO2/dt and thereby lower nadir arterial oxyhemoglobin saturation (SaO2) for the same duration of apnea. Apneas were created by clamping an indwelling cuffed endotracheal tube at end expiration in eight spontaneously breathing adult baboons. Apneas of the same duration were then repeated during temporary endobronchial occlusion of one lobe of the lung. SaO2 and mixed venous O2 saturation were continuously monitored, and cardiac output was calculated. Worsening of pulmonary gas exchange during atelectasis was documented by an increase in calculated venous admixture from 10.5 +/- 0.8 to 25.0 +/- 0.7% (P less than 0.001). The dSaO2/dt was independent of apnea duration at 30, 45, and 60 s. During endobronchial occlusion, apnea dSaO2/dt increased 20%, and nadir SaO2 was significantly lower. Possible mechanisms for steepening of dSaO2/dt during atelectasis are discussed.     

Reduced stroke volume related to pleural pressure in obstructive sleep apnea

Left ventricular stroke volume (LVSV) falls during obstructed inspiration in animals and normal human subjects through mechanisms that may be closely related to pleural pressure. In this study we postulated that a similar reduction in LVSV should occur in patients with obstructive sleep apnea (OSA). Daytime polysomnograms were performed in 10 patients with OSA. A noninvasive electrical impedance method was used to determine LVSV. Pleural pressure was measured by esophageal balloon. In comparison with awake values, during OSA we found reductions in LVSV, cardiac output, and heart rate of 18, 27, and 11%, respectively (P less than 0.01). We observed that systolic pleural pressure did not have a significant effect on LVSV (P greater than 0.05). However, at pleural pressures lower than 10 cmH2O below resting expiratory level, there was a linear relationship between falls in LVSV and falls in middiastolic pleural pressure (P less than 0.0001). We concluded that reduced LVSV shown in patients with OSA was significantly related to diastolic pleural pressure level. Our findings suggested reduced preload as the most likely mechanism for decreased cardiac output in OSA.     

Circulating free nitrotyrosine in obstructive sleep apnea

Obstructive sleep apnea (OSA) has been increasingly linked to cardiovascular disease, endothelial dysfunction, and oxidative stress, generated by repetitive nocturnal hypoxemia and reperfusion. Circulating free nitrotyrosine has been reported as a novel biomarker of nitric oxide (NO)-induced oxidative/nitrosative stress. Nitrosative stress has been implicated as a possible mechanism for development of cardiovascular diseases. We tested the hypothesis that repetitive severe hypoxemia resulting from OSA would increase NO-mediated oxidative stress. We studied 10 men with newly diagnosed moderate to severe OSA who were free of other diseases, had never been treated for OSA, and were taking no medications. Nitrotyrosine measurements, performed by liquid chromatography-tandem mass spectrometry, were made before and after untreated apneic sleep. We compared free nitrotyrosine levels in these patients with those obtained at similar times in 10 healthy male control subjects without OSA, with similar age and body mass index. Evening baseline nitrotyrosine levels were similar before sleep in the control and OSA groups [0.16 +/- 0.01 and 0.15 +/- 0.01 ng/ml, respectively, P = not significant (NS)]. Neither normal nor disturbed apneic sleep led to significant changes of plasma nitrotyrosine (morning levels: control group 0.14 +/- 0.01 ng/ml; OSA group 0.15 +/- 0.01 ng/ml, P = NS). OSA was not accompanied by increased circulating free nitrotyrosine either at baseline or after sleep. This observation suggests that repetitive hypoxemia during OSA does not result in increased NO-mediated oxidative/nitrosative stress in otherwise healthy subjects with OSA.     

Hypoxemia during apnea in normal subjects: mechanisms and impact of lung volume

Seven normal awake males were studied to define the mechanisms and impact of lung volume on the hypoxemia occurring during apnea. During repeated 30-s voluntary breath holding, these subjects were studied at different lung volumes, during various respiratory maneuvers, and in the sitting and supine body positions. Analysis of expired gases and arterial O2 saturation during these repeated breath holdings yielded the following conclusions. Apnea of 30-s duration at low lung volumes is accompanied by severe arterial O2 desaturation in normal awake subjects. Initial lung volume is the most important determinant of hypoxemia during apnea. The hypoxemia of apnea at most lung volumes can be explained by simple alveolar hypoventilation in a uniform lung. The lung does not behave as a single-compartment model at lung volumes at which dependent airways are susceptible to closure.     

Effects of arousal and sleep state on systemic and pulmonary hemodynamics in obstructive apnea.

During obstructive sleep apnea (OSA), systemic (Psa) and pulmonary (Ppa) arterial pressures acutely increase after apnea termination, whereas left and right ventricular stroke volumes (SV) reach a nadir. In a canine model (n = 6), we examined the effects of arousal, parasympathetic blockade (atropine 1 mg/kg iv), and sleep state on cardiovascular responses to OSA. In the absence of arousal, SV remained constant after apnea termination, compared with a 4.4 +/- 1.7% decrease after apnea with arousal (P < 0.025). The rise in transmural Ppa was independent of arousal (4.5 +/- 1.0 vs. 4.1 +/- 1.2 mmHg with and without arousal, respectively), whereas Psa increased more after apnea termination in apneas with arousal compared with apneas without arousal. Parasympathetic blockade abolished the arousal-induced increase in Psa, indicating that arousal is associated with a vagal withdrawal of the parasympathetic tone to the heart. Rapid-eye-movement (REM) sleep blunted the increase in Psa (pre- to end-apnea: 5.6 +/- 2.3 mmHg vs. 10.3 +/- 1.6 mmHg, REM vs. non-REM, respectively, P < 0.025), but not transmural Ppa, during an obstructive apnea. We conclude that arousal and sleep state both have differential effects on the systemic and pulmonary circulation in OSA, indicating that, in patients with underlying cardiovascular disease, the hemodynamic consequences of OSA may be different for the right or the left side of the circulation.     

Sleep related O2 desaturation in COPD patients with normoxaemia and mild hypoxyaemia

It is unknown whether daytime features predict oxygenation during sleep in COPD patients with normoxaemia or mild hypoxaemia. In this study our purpose was to evaluate by a pulse oxymeter, nocturnal desaturation in 33 COPD with PaO2 > 60 mmHg and to examine some daytime parameters as possible predictors of nocturnal hypoxaemia. A significant nocturnal desaturation has been defined by spending > or = 30% of total sleep-time with a TSTSaO2 < 90% > 30. According to this criterion we classified our patients in Desaturators (D) and Non Desaturators (ND). Our results showed that 39% of our patients were D and 61% ND. Among anthropometric and respiratory functional data we found that daytime SaO2B (r = 0.74 p < 0.001) daytime PaO2 (r = 0.47 p < 0.01) and daytime PaCO2 (r = 0.45 p < 0.05) were significantly correlated with the nocturnal oxygen desaturation and can predict the presence of sleep related hypoxaemia. In conclusion, our study confirms that a relatively high percentage of COPD patients with normoxaemia or borderline hypoxaemia exhibits significant nocturnal hypoxaemia. Further studies will suggest whether sleep related hypoxaemia deserves nocturnal oxygen therapy.     

Induction of airway collapse with subatmospheric pressure in awake patients with sleep apnea

To determine whether the pharyngeal airway is abnormal in awake patients with obstructive sleep apnea (OSA), we measured the ability of the pharyngeal airway to resist collapse from subatmospheric pressure applied to the nose in awake subjects, 12 with OSA and 12 controls. Subatmospheric pressure was applied to subjects placed in the supine position through a tightly fitting face mask. We measured airflow at the mask as well as mask, pharyngeal, and esophageal pressures. Ten patients developed airway obstruction when subatmospheric pressures between 17 and 40 cmH2O were applied. Obstruction did not occur in two patients with the least OSA. Obstruction did not occur in 10 controls; one obese control subject developed partial airway obstruction when -52 cmH2O was applied as did another with -41 cmH2O. We conclude that patients with significant OSA have an abnormal airway while they are awake and that application of subatmospheric pressure may be a useful screening test to detect OSA.     

Stroke volume and cardiac output decrease at termination of obstructive apneas.

Patients with obstructive sleep apnea (OSA) experience repetitive nocturnal oscillations of systemic arterial pressure that occur in association with changes in respiration and changes in sleep state. To investigate cardiac function during the cycle of obstruction (apnea) and resumption of ventilation (recovery), we continuously measured left ventricular stroke volume (LVSV) and mean arterial blood pressure (MAP) during non-rapid-eye-movement sleep in six males with severe OSA (apnea/hypopnea index > or = 30 events/h associated with oxygen saturation < 82%). LVSV was assessed continuously using an ambulatory ventricular function monitor (VEST; Capintec). The apnea-recovery cycle was divided into three phases: 1) early apnea (EA), 2) late apnea (LA), and 3) recovery (Rec). In all subjects recovery was associated with an abrupt decrease in LVSV [54.0 +/- 14.5 (SD) ml] compared with either EA (91.4 +/- 14.7 ml; P < 0.001) or LA (77.1 +/- 15.2 ml; P < 0.005). Although heart rate increased with recovery, the increase was not sufficient to compensate for the decrease in LVSV so that cardiac output (CO) fell (EA: 6,247 +/- 739 ml/min; LA: 5,741 +/- 1,094 ml/min; Rec: 4,601 +/- 1,249 ml/min; EA vs. Rec, P < 0.01; LA vs. Rec, P < 0.025). Recovery was also associated with a significant increase in MAP. We speculate that such abrupt decreases in LVSV and CO at apnea termination, occurring coincident with the nadir of oxygen saturation, may further compromise tissue oxygen delivery.     

Repetitive apneas reduce nonlinear dynamical complexity of the human cardiovascular control system.

We tested the hypothesis that intermittent apneas performed by awake subjects simulate obstructive sleep apnea (OSA) and change dynamic complexity of the cardiovascular control system by repetitive short time stimulation of arterial chemoreceptors. Correlation dimension (CD) and reccurent plot quantification calculated as ratio % determinism versus % recurrence (RDR) were used.as indices of chaotic dynamics. Thirty three normotensive subjects of mean age 21,58 +/- 4,1 performed 10 voluntary apneas 1 min. each separated by 1 min free breathing period. Systolic (SYS), diastolic (DIAS) arterial blood pressure was continuously recorded by finger volume clamp. Stroke volume (SV) was estimated by pulse pressure analysis. Cardiac output (CO) and total peripheral resistance (TPR) were calculated by Portapress system. Cardiac inter-beat interval (IBI) was measured from R-R intervals of ECG. Standard deviation (SD), an index of linear variability, was calculated in 1 min epoch. Dynamics of cardiovascular variables was computed in each subject during 20 min. rest (C), 20 min. of 10 apneas, 1 min each, separated by 1 min free breathing (A), and in 20 min. recovery free breathing (R). In A period CD of all circulatory variables was significantly reduced and RDR augmented. In 23 out of 33 subjects decreased nonlinear dynamics of TPR was carried over from A to R. In contrast, SD increased significantly in A. In conclusion, intermittent brief chemoreflex stimulations by repetitive apneas increase blood pressure and TPR and decrease chaotic behaviour and complexity of the cardiovascular autonomic control system, presumably by inhibition of some regulatory loops such as baroreflex, less vital for survival at oxygen deprivation. Reduced complexity could be implicated in the mechanism of arterial hypertension linked with OSA.     

Chronic Intermittent Hypoxia Is Independently Associated with Reduced Postoperative Opioid Consumption in Bariatric Patients Suffering from Sleep-Disordered Breathing

BackgroundEvidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO₂) < 90% and minimum nocturnal SaO₂ on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery.MethodsWith Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO₂ < 90%, (b) the minimum nocturnal SaO₂, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders.ResultsTwo hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO₂ < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO₂ < 90% was not associated with pain. The minimum nocturnal SaO₂ was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep.ConclusionsPreoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.     

Diagnosis of obstructive sleep apnea syndrome]

Symptoms and signs in 12 patients with severe obstructive sleep apnea (OSA) syndrome have been presented. The most common symptoms were snoring , increased motor activity during sleep and excessive daytime somnolence. The factors predisposing to OSA syndrome were obesity and anatomic abnormalities of the upper airway structure. In some cases the signs of OSA syndrome included hypertension, right heart failure, chronic alveolar hypoventilation and polycythemia. Polysomnography showed sleep fragmentation and the prevalence of light sleep stages. Obstructive sleep apneas repeated 73 +/- 23 times per hour of sleep. The mean apnea duration was 19 +/- 8 s. The mean arterial oxygen saturation during apnea was 72 +/- 14%.