Sleep apnea in end-stage renal disease patients: Impact on cardiovascular and neurological outcomes.

INTRODUCTION: Sleep apnea (SA) is an important comorbidity in end-stage renal disease (ESRD) patients. The association between SA and cardiac and neurological disease is known. This study investigates the relationship between SA and cardiovascular and cerebrovascular outcomes in the ESRD population. METHODS: In a retrospective cohort study, the United States Renal Data System was queried to identify ESRD patients aged 18-100 years in whom hemodialysis had been initiated between 2005 and 2013. Diagnoses of SA and clinical comorbidities were determined from International Classification of Disease-9 codes. Demographic variables were obtained from Centers for Medicare and Medicaid Services Form-2728. Logistic regression was used to examine the association of SA with myocardial infarction (MI) or with stroke, controlling for demographic and clinical variables. RESULTS: Of 858,131 subjects meeting the inclusion criteria, 587 had central SA, and 22,724 had obstructive SA. The SA cohort was younger, more likely to be male and Caucasian compared to the non-SA cohort. Patients with SA also had more tobacco and alcohol use, hypertension, heart failure, and diabetes. Central SA (aRR = 1.69, 95% CI = 1.28-2.23) and obstructive SA (aRR = 1.15, 95% CI = 1.09-1.21) were associated with an increased risk of stroke but not MI. CONCLUSION: In the ESRD population, a diagnosis of central SA or obstructive SA increased the risk of stroke, but not MI. Early identification and treatment of SA in the ESRD population may help reduce the risk of stroke in these patients.

Nasal resistance in obstructive sleep apnea.

BACKGROUND: Acute increases in nasal resistance are known to induce upper airway occlusion in predisposed subjects. With the limited efficacy of nasal surgery alone in the treatment of obstructive sleep apnea (OSA), the relevance of chronically increased nasal resistance in the pathophysiologic features of OSA remains undetermined. METHODS: Seventy-one patients with OSA (apnea+hypopnea index > 15 [AHI]) and 70 antisocial snorers (ASS [AHI < 15]) referred for routine assessment of sleep-disordered breathing had concomitant measurement of combined (CNR) and highest unilateral (HUNR) nasal resistance by anterior rhinomanometry. RESULTS: Nine individuals (five of 71 in the OSA group and 4 of 70 in the ASS group, 0.5 < p < 0.75) had an abnormally elevated CNR. The HUNR was increased in 21 individuals (11 of 70 in the ASS group and 10 of 71 in the OSA group, 0.25 < p < 0.5). There was no significant difference between CNR in OSA (1.5[0.5]) (mean [SE]) and ASS (1.6 [0.2]) groups. No correlation was found between CNR and the AHI in OSA or in ASS. The Mean HUNR in the OSA group was 5.5 (0.9) (mean [SE]) and in ASS was 5.3(0.6), which were not significantly different (p = 0.89). The HUNR also did not correlate with the AHI in either OSA or ASS. CONCLUSION: Chronic changes in nasal resistance are not a significant risk factor for the development or severity of OSA.

Dynamics of carbon dioxide elimination following ventilator resetting.

BACKGROUND: Carbon dioxide elimination (VCO2) at steady state corresponds to the metabolic rate. A change in tidal ventilation will lead to a transient response in VCO2 if other determinants of VCO2 are constant. This principle may be applied in the critical care unit to reset ventilators. OBJECTIVE: To define and characterize the transient response of VCO2 to a well-defined change in ventilation. METHODS: Forty-four patients in stable condition receiving volume-controlled mechanical ventilation had trend recordings of ventilator pressures, flow, volumes, VCO2, and end-tidal CO2 (ETCO2) for 20 min. At time t0, the minute ventilation was either increased (n = 22) or decreased (n = 22) by 10% after which these parameters were monitored over 30 min. Blood gas values were measured 5 and 20 min after the change in ventilation and the dead space fractions were computed using the single breath-CO2 test. DATA ANALYSIS: The first ten breaths (till t1) after a change in ventilation were excluded. The time constant (tau) of the relative change in VCO2 (delta VCO2) was calculated by fitting exponential regressions to delta VCO2 for periods up to 20 min after t1. RESULTS: The delta VCO2 at t1 was proportional to the relative change in tidal volume (delta VT). The proportionality decreased gradually during 20 min. The proportionality of the relative change in ETCO2 (delta ETCO2) or PaCO2 (delta PaCO2) with delta VT was minimal at t1 and increased during the 20 min. tau increased progressively when calculated over longer periods (p < 0.001). tau was similar in the groups with increased and decreased ventilation up to 5 min, after which it was longer in the group with decreased ventilation (p < 0.05). The delta PaCO2 after 20 min correlated best with delta VCO2 at t1 (r = -0.8) and with delta ETCO2 at the end of 20 min (r = 0.8). CONCLUSIONS: Noninvasively monitored VCO2 provides an instantaneous indication of the change in alveolar ventilation in well-sedated, mechanically ventilated patients in stable condition without significant cardiopulmonary disease.

Breath-holding time in normal subjects, snorers, and sleep apnea patients.

BACKGROUND: The onset of irregular inspiratory muscle activity has been observed toward the breakpoint of the breath-holding maneuver. We wondered if this was similar to the increased respiratory effort with paradoxical breathing seen during the resolution of an apnea in obstructive sleep apnea syndrome (OSAS). STUDY OBJECTIVE: To compare the breakpoint of breath holding in normal subjects, OSAS patients, and snorers. METHODS: Thirty normal subjects, 30 patients with OSAS, and 16 snorers performed serial breath-holding maneuvers at functional residual capacity (FRC) under standardized pretest conditions using the rebreathing method of Read. RESULTS: Intergroup comparisons were carried out by analysis of variance with post hoc Tukey's Highest Significant Difference tests. Basal end-tidal carbon dioxide (EtCO2) was significantly higher in OSAS than in normal subjects and snorers. Basal breath-holding time (BHT) was shorter in OSAS as compared with that in normal subjects and snorers (p < 0.05). The maximal EtCO2 level attained was higher in OSAS as compared with normal subjects (p < 0.05) and snorers (p = 0.052). The maximal BHT in OSAS was shorter than in normal subjects (p < 0.05) but not in snorers. The slope of BHT/EtCO2 differed significantly in OSAS compared with normal subjects and snorers (p < 0.05). No significant correlation was found between slope BHT/EtCO2 and age or body mass index using multiple regression analysis. The FRC of OSAS patients and snorers were similar (p = 0.792). CONCLUSION: We conclude that BHT and slope of BHT/EtCO2 are different in OSAS subjects as opposed to those in normal subjects and snorers.

Dynamic properties of body plethysmographs and effects on physiological parameters.

A model incorporating compliance, resistance, inertia, and the thermal time constant of plethysmographs is used to describe the effect of its dynamic properties on measured respiratory parameters. Using numerical simulation we studied the effect of distortion of flow signals from 13 infants in whom flow and esophageal pressure had been recorded. The distortion in amplitude, shape, and timing of the recorded flow patterns was dependent on the dynamic properties of the plethysmograph. For constant-volume "pressure" plethysmographs, errors of derived parameters such as compliance and resistance are very important if the thermal time constant is short. These errors are not corrected by calibrating the plethysmograph at the breathing frequency. Time correction of the flow signals in volume-displacement plethysmographs gives accurate results when the plethysmograph resistance and compliance are low. Overall, a volume-displacement plethysmograph with moderately high resistance of the flowmeter, corrected for internal pressure and inertia, gives the best possible results.

Effect of furosemide on hyperpnea-induced airway obstruction, injury, and microvascular leakage.

Furosemide attenuates hyperpnea-induced airway obstruction (HIAO) in asthmatic subjects via unknown mechanism(s). We studied the effect of furosemide on dry air-induced bronchoconstriction, mucosal injury, and bronchovascular hyperpermeability in a canine model of exercise-induced asthma. Peripheral airway resistance (Rp) was recorded before and after a 2-min dry-air challenge (DAC) at 2,000 ml/min. After pretreatment with aerosolized saline containing 0.75% dimethyl sulfoxide, DAC increased Rp 72 +/- 11% (SE, n = 7) above baseline; aerosolized furosemide (10(-3) M) reduced this response by approximately 50 +/- 6% (P < 0.01). To assess bronchovascular permeability, colloidal carbon was injected (1 ml/kg i.v.) 1 min before DAC, and after 1 h, the vehicle- and furosemide-treated airways were prepared for morphometric analysis. Light microscopy confirmed previous studies showing that DAC damaged the airway epithelium and enhanced bronchovascular permeability. Furosemide did not inhibit dry air-induced mucosal injury or bronchovascular hyperpermeability and in fact tended to increase airway damage and vascular leakage. This positive trend toward enhanced bronchovascular permeability in DAC canine peripheral airways is consistent with the hypothesis that furosemide inhibits HIAO in part by enhancing microvascular leakage and thus counterbalancing the evaporative water loss that occurs during hyperpnea.

Hyperventilation-induced airway injury and vascular leakage in dogs: effects of alpha1-adrenergic agonists.

alpha1-Adrenergic agonists inhibit hyperventilation-induced bronchoconstriction (HIB) in dogs. We tested the hypothesis that alpha-agonists inhibit HIB by reducing bronchovascular leakage and edema that theoretically could cause airway obstruction. Peripheral airways were isolated by using a bronchoscope; pretreated with either methoxamine (Mx), norepinephrine (NE), or saline aerosol; and then exposed to a 2,000 ml/min dry-air challenge (DAC) for 2 min. Colloidal carbon was injected before DAC and used to quantify bronchovascular permeability. Mx-, NE-, and vehicle-treated airways were prepared for morphometric analysis within 1 h after DAC. Light microscopy revealed that the 2-min DAC produced minimal bronchovascular leakage and little epithelial damage. However, pretreatment with either Mx or NE significantly enhanced dry air-induced bronchovascular hyperpermeability and mucosal injury. The increased damage associated with these alpha1-agonists implicates a protective role for the bronchial circulation. The fact that alpha1-agonists inhibit HIB suggests that neither dry air-induced leakage nor injury directly contributes to the development of airway obstruction. In addition, our data suggest that alpha-agonists attenuate HIB in part by augmenting hyperventilation-induced bronchovascular leakage and by replacing airway water lost during a DAC.

Effect of bromhexeine on sputum amoxycillin levels in lower respiratory infections.

Bromhexeine has been widely used as an adjunct in the management of lower respiratory infections and is useful in altering the physical characteristics of sputum. Its effect on the sputum penetration of an antibiotic has been sparsely studied. The present study highlights the improvement in sputum amoxycillin (amoxy) levels when a combination tablet, amoxy 500 mg plus bromhexeine 8 mg, is administered as compared to plain amoxy 500 mg. Sputum amoxy levels were significantly higher in the combination group (0.674 +/- 0.588 micrograms ml-1) as compared to 0.272 +/- 0.19 micrograms ml-1 in the amoxy group (P = 0.028). The clinical responses assessed by the physician as well as the patient were significantly better in the amoxy plus bromhexeine group as compared to the amoxy group. The radiological and bacteriological responses were similar in both groups. There was no increase in the side-effects due to bromhexeine and, overall, its use can be recommended in the treatment of acute lower respiratory infections.

Pulmonary function tests in cirrhotic and non-cirrhotic portal hypertension.

OBJECTIVE: To determine pulmonary functions in portal hypertension of different etiologies and with various grades of ascites. SETTING: Gastrointestinal clinic in a large community based and secondary referral hospital. PATIENTS AND METHODS: Forty five patients with portal hypertension, including 19 cirrhotics with tense ascites, 8 with moderate ascites, 6 with no ascites and 12 patients with non-cirrhotic portal hypertension. All patients underwent basal pulmonary function testing by spirometry and helium dilution technique, and arterial blood gas estimation and measurement of ascitic fluid pressure. Patients with tense ascites underwent paracentesis of up to 2 liters following which ascitic fluid pressure and pulmonary functions were estimated again. MAIN RESULTS: In cirrhotic patients without ascites, FVC (forced vital capacity), RV (residual volume), TLC (total lung capacity) and FRC (functional residual capacity) were lower than predicted values. In patients with ascites, FVC, FEV1 (forced expired volume in one second) and FEF25-75 (forced expired volume in one second) and FEF25-75 (forced expiratory flow rate between 25% and 75% of forced vital capacity) were significantly lower as compared to predicted values. FVC, FEV1, FEF25-75, pO2, pCO2 and SaO2% decreased significantly with increasing ascites. Paracentesis in patients with tense ascites led to clinical improvement and significantly improved lung volumes. CONCLUSIONS: Pulmonary functions are impaired in patients with cirrhosis, and ascites causes further deterioration. Patients with non-cirrhotic portal hypertension have normal pulmonary functions.

Effect of 3 week oxygen therapy on functional and haemodynamic parameters in chronic obstructive pulmonary disease.

Sixteen patients with advanced chronic obstructive pulmonary disease (COPD) and stable chronic respiratory failure (pO2 less than 60 mm Hg, pCO2 greater than 45 mm Hg) were given 2-3 L/min oxygen 18 hours/day for 3 weeks. These were serially assessed for changes in pO2, pCO2, ECG, chest radiographs and haemodynamics. Initially all patients were in grade IV heart failure. There was no change in lung function after oxygen treatment but right descending pulmonary artery diameter and cardiothoracic ratio decreased significantly (P less than 0.01), as also the height of the P wave in ECG (P less than 0.05). There were significant changes in mean pO2 (51.8 to 61.9 mmHg; P less than 0.01), pCO2 (55.3 to 47.6 mmHg; P less than 0.001), mean pulmonary artery pressure (41.8 to 34.5 mmHg; P less than 0.01) and pulmonary vascular resistance (PVR) (346.4 to 163.3 dynes; P less than 0.05). The initial (P less than 0.05) and 3 week (P less than 0.01) pO2 levels correlated with the right descending pulmonary artery diameter. The height of the P wave also correlated with pO2 (P less than 0.01). The changes in pO2 levels correlated with those of the PVR and pulmonary blood flow (P less than 0.05). Three week oxygen therapy resulted in objective improvement in advanced COPD cases.

Anti-inflammatory action of steroid inhalers.

With mucosal inflammation contributing to the pathogenesis of asthma, it is increasingly accepted that long term steroid inhalers may induce remission in chronic long standing asthmatics. The present study involved 44 stable asthmatics who were randomly given either beclomethasone dipropionate inhaler (50 ug) 2 puffs qds or salbutamol inhaler (100 mcg) 2 puffs tds in addition to their oral bronchodilators. Pulmonary function testing, bronchoalveolar lavage and complete blood count were done at basal and weekly intervals and at the end of the study. The absolute eosinophil count showed a significant drop in the beclomethasone group as compared to the salbutamol group. Serial lung functions showed a significant improvement in the pre-bronchodilator PEFR and the pre-bronchodilator FVC in the beclomethasone group as compared to the salbutamol group. There was no significant change in the lavage eosinophil count pre and post-bronchodilator in both groups. Steroid inhalers are thus useful in long term management of bronchial asthma especially with respect to reducing bronchodilator requirement.

Assessment of exercise tolerance in chronic bronchitis and interstitial lung disease.

Cardiopulmonary exercise testing has a definitive place in objective evaluation of the subjective sensation of breathlessness. In the present study 21 patients with COPD, 10 with ILD and 17 normals were subjected to stage 1 exercise testing and correlations were sought between Vo2 and work, FVC, FeV1, Ve, respiratory rate and tidal volume and between VCO2 and work. In COPD and ILD the Vo2 correlated with work, Fev1, Fvc and Ve whereas in normals it correlated with the VE but not with the FeV1 and FVC. In COPD VO2 correlated with TV though this was not the case in ILD. Thus stage 1 exercise testing can be a useful additional method to assess the disability in COPD and ILD although differentiation between these two respiratory diseases on basis of exercise testing alone may not be possible.

Gene therapy for cystic fibrosis: a potential cure.

Cystic fibrosis is a lethal autosomal recessive disorder. In 1989, the cystic fibrosis gene was isolated on chromosome 7. Positional cloning, linkage analysis, saturation cloning, and chromosome jumping enabled the isolation and cloning of the gene that encodes the cystic fibrosis transmembrane conductance regulator. Current work focuses on the safe, efficient delivery of a functional cystic fibrosis transmembrane conductance gene to patients who are afflicted with cystic fibrosis and the expression of the gene in somatic cells to correct the genetic defect and restore chloride channel function. It is hoped that successful gene therapy will be a feasible and cost-efficient approach that will lead to a cure.

Effect of ipratropium bromide in bronchial asthma.

The effect of inhalation of ipratropium bromide was evaluated in 20 patients with bronchial asthma. It was observed that there was no significant improvement in the forced vital capacity and the forced expired volume in one second, while there was significant improvement in the peak expiratory flow rate (PEFR) measured at 9 pm, after inhalation of 2 puffs of ipratropium bromide aerosol (0.02mg/puff) three to four times a day for 2 weeks. Since PEFR is a measure of large airway function and cholinergic mechanisms are primarily involved for airflow obstruction at large airways, improvement in PEFR by ipratropium bromide highlights its role as a useful bronchodilator in patients in whom vagal reflexes are responsible for the provocation of bronchoconstriction.

Effect of detergent combined with large tidal volume ventilation on alveolocapillary permeability.

The combined effect of large tidal volume ventilation (LTVV) and detergent-induced surfactant dysfunction on the clearance kinetics of technetium-99m-labelled diethylene triamine pentaacetate was investigated. Four groups of rabbits (n = 6 in each) were studied: (1) controls, (2) detergent, (3) LTVV, and (4) detergent + LTVV. Clearance was measured for 3 h and the kinetics was analysed by fitting mono- and biexponential equations to the clearance curve and was expressed as a half-life (T 1/2). Pulmonary clearance of 99mTc-DTPA was monoexponential in control animals (T 1/2 = 194 min) and in animals ventilated with LTVV (T 1/2 = 43 min, P < 0.01 compared with controls). In contrast, clearance was biexponential after detergent administration with or without LTVV. T 1/2 values of the fast and slow compartments were 5.4 and 80 min, respectively, with the fast fraction comprising 81% of the radioactivity after detergent alone. When detergent was combined with LTVV, clearance was bicompartmental as with detergent alone, with the same size of the fast fraction. However, clearance from each of the slow (P < 0.01) and fast compartments (P < 0.05) increased significantly. Clearance from the slow compartment was thus similar to T 1/2 during LTVV alone. Large tidal volume ventilation induced a faster than normal clearance of a single compartment, whereas detergent induced kinetics that was distinctly bicompartmental. The mechanisms increasing permeability of the alveolocapillary barrier after detergent and during LTVV seem different and may be additive.

Additive nature of distension and surfactant perturbation on alveolocapillary permeability.

The aim of this study was to determine whether the effects of alveolar distention and surfactant dysfunction on alveolocapillary barrier function are different and additive. Pulmonary clearance of aerosolized technetium-99m-labelled human serum albumin (99mTc-HSA) was used to characterize barrier function after perturbing the surfactant system with the detergent dioctyl sodium sulphosuccinate either singly or in combination with large tidal volume ventilation (LTVV). Clearance was measured for 3 h (Experimental ventilation) in four groups (n = 6 each) of rabbits: 1) Controls; 2) Detergent; 3) LTVV; and 4) Detergent + LTVV. Restoration of clearance (Recovery) was studied for 3 h under conventional ventilation. The half-life of clearance (t 1/2) decreased during LTVV (305 min) compared to 1,055 min in Controls. Detergent induced a biexponential clearance with slow (t 1/2S) and fast (t 1/2F) half-lives of 670 and 15.4 min, respectively. The fast fraction (fF) was 0.20. Clearance in the Detergent + LTVV group was also biexponential. The t 1/2F and fF were similar to the Detergent group. The t 1/2S was similar to the LTVV group. The fF in this group increased to 0.36 during Recovery (p < 0.01 versus Detergent group and p < 0.05 versus Experimental ventilation). The diverse kinetics of clearance during large tidal volume ventilation and surfactant dysfunction suggest the presence of different mechanisms affecting the barrier. The mechanisms have additive characteristics, which superimpose to produce lung injury.