Insomnia symptoms combined with nocturnal hypoxia associate with cardiovascular comorbidity in the European sleep apnea cohort (ESADA).

PURPOSE: The aim of the current study was to further investigate the concept of previously reported high occurrence of comorbidities in obstructive sleep patients (OSA) with insomnia-like symptoms. We hypothesized that this finding at least partly is mediated by nocturnal hypoxia. Moreover, we speculated that the spectrum of the clinical OSA phenotypes differs between European geographical regions. METHODS: Cohort of the European Sleep Apnea Database (n = 17,325; 29.9% females) was divided into five subcohorts according to geographical region (North, East, South, West, Central) and further into four clinical presentation phenotypes based on daytime symptoms (EDS) and characteristics suggestive of insomnia. RESULTS: The insomnia phenotype (alone or together with EDS) dominated in all European regions. Isolated insomnia, however, was less common in the West. Insomnia phenotype was associated with the highest proportion of cardiovascular comorbidity (51.7% in the insomnia vs. 43.9% in the EDS type). Measures of nocturnal hypoxemia were independently associated with cardiovascular comorbidity in phenotypes with insomnia-like symptoms. The burden of comorbidities was high across all geographical regions and clinical phenotypes. Regional differences were clinically relevant for age (48 vs. 54 years), BMI (29 vs. 34 kg/m2), and ODI (15 vs. 32/h). CONCLUSION: High prevalence of particularly cardiovascular comorbidity among patients with insomnia-like symptoms was linked to nocturnal hypoxemia. Considerable differences in clinical presentation were found among OSA patients across Europe. Our data underline that physicians should ask their patients with suspected OSA also for insomnia symptoms. It remains to be explored if a reduction of nocturnal hypoxemia predicts the improvement of insomnia symptoms.

The European Sleep Apnoea Database (ESADA): report from 22 European sleep laboratories.

The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 programme. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5,103 patients (1,426 females, mean±sd age 51.8±12.6 yrs, 79.4% with apnoea/hypopnoea index (AHI) ≥5 events·h(-1)) were included from March 15, 2007 to August 1, 2009. Morbid obesity (body mass index ≥35 kg·m(-2)) was present in 21.1% of males and 28.6% of females. Cardiovascular, metabolic and pulmonary comorbidities were frequent (49.1%, 32.9% and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 versus 29.1±26.3 events·h(-1), p<0.0001). The ESADA is a rapidly growing multicentre patient cohort that enables unique outcome research opportunities and genotyping. The first cross-sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSA.

Management of obstructive sleep apnea in Europe.

OBJECTIVES: In Europe, the services provided for the investigation and management of obstructive sleep apnoea (OSA) varies from country to country. The aim of this questionnaire-based study was to investigate the current status of diagnostic pathways and therapeutic approaches applied in the treatment of OSA in Europe, qualification requirements of physicians involved in diagnosis and treatment of OSA, and reimbursement of these services. METHODS: Two questionnaires were sent to 39 physicians in 22 countries in Europe. In order to standardize the responses, the questionnaire was accompanied by an example. RESULTS: Sleep centers from 21 countries (38 physicians) participated. A broad consistency among countries with respect to the following was found: pathways included referral to sleep physicians/sleep laboratories, necessity for objective diagnosis (primarily by polysomnography), use of polygraphic methods, analysis of polysomnography (PSG), indications for positive airway pressure (PAP) therapy, application of standard continuous PAP (CPAP) therapy (100% with an CPAP/APAP ratio of 2.24:1), and the need (90.5%) and management of follow-up. Differences were apparent in reimbursement of the diagnostic procedures and follow-up, in the procedures for PAP titration from home APAP titration with portable sleep apnea monitoring (38.1%) up to hospital monitoring with PSG and APAP (85.7%), and in the qualification requirements of sleep physicians. CONCLUSIONS: Management of OSA in different European countries is similar except for reimbursement rules, qualification of sleep specialists and procedures for titration of the CPAP treatment. A European network (such as the one accomplished by the European Cooperation in Science and Technology [COST] B26 Action) could be helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective.

Transcutaneous carbon dioxide profile during sleep reveals metabolic risk factors in post-menopausal females.

The risks of metabolic syndrome and sleep-disordered breathing increase around the time of the menopause. We have previously shown that features of the nocturnal transcutaneous carbon dioxide (TcCO2) profile are associated with metabolic variables such as cholesterol, glycosylated haemoglobin A1C (GHbA1C) and blood pressure in patients with sleep apnoea. In the present study, we investigated whether these metabolic variables can be predicted using noninvasive TcCO2 measurements during sleep in generally healthy post-menopausal females. 22 post-menopausal females underwent an overnight polygraphic sleep study that involved the continuous monitoring of arterial oxygen saturation (S(a,O2)) and TcCO2. Body composition, GHbA1C, plasma cholesterol and blood pressure were measured prior to the sleep study. Nocturnal TcCO2 features were the most important predictors of lipoprotein cholesterols, triglycerides and blood pressure levels. A longer sleep period and higher TcCO2 levels were linked with lower GHbA1C, and fragmented sleep with lower high-density lipoprotein cholesterol. Neither nocturnal S(a,O2) indices nor the apnoea/hypopnoea index had a predictive power. The results suggest that nocturnal TcCO2 events revealed metabolic risk factors already present in healthy post-menopausal females.

Hypertensive women with the metabolic syndrome are at risk of renal insufficiency more than men in general population.

The prevalence of renal insufficiency in hypertensive participants without comorbidities affecting renal function is unknown. The objective of this study was to assess the prevalence and predictors of renal insufficiency in general hypertensive population. We examined 994 hypertensive participants aged 45-70 years without previously diagnosed diabetes, cardiovascular disease or chronic kidney disease. Renal insufficiency was defined as estimated glomerular filtration rate <60 ml min(-1) per 1.73 m(2) by the Modification of Diet in Renal Disease formula. The metabolic syndrome was defined according to the International Diabetes Federation and the US National Cholesterol Education Program Third Adult Treatment Panel criteria. Glucose homoeostasis was assessed with an oral glucose tolerance test. The prevalence of renal insufficiency was 6.7% (95% confidence interval (CI) 5.3-8.5). In a multivariate model, the presence of renal insufficiency was predicted by female gender (odds ratio (OR) 3.57 (95% CI 1.90-6.72)), older age (OR 1.13 (95% CI 1.07-1.18)), use of diuretics (OR 2.13 (95% CI 1.19-3.82)) and metabolic syndrome (OR 2.79 (95% CI 1.34-5.79)). Newly diagnosed diabetes or prediabetes did not predict renal insufficiency. The prevalence of renal insufficiency was found to be lower than previously reported in hypertensive general population. Metabolic syndrome, but not newly diagnosed diabetes or prediabetes per se, was strongly associated with renal insufficiency especially in women. Renal insufficiency was also associated with the use of diuretics, but the clinical relevance of this finding needs to be clarified.

Sleep-disordered breathing and hormones.

Sleep-disordered breathing (SDB) is not only a problem of the upper airway but is a systemic condition with endocrine and metabolic interactions. The accumulating body of evidence shows that SDB induces changes in the serum levels or secretory patterns of several hormones. Conversely, various endocrine disorders and hormone therapies may induce, exacerbate or alleviate SDB. Much of the understanding of the interactions between hormones and sleep-disordered breathing derive from intervention studies with nasal continuous positive airway pressure therapy. Better understanding of hormones and breathing may open new perspectives in developing strategies to prevent, alleviate or cure sleep-disordered breathing and its systemic consequences.

Effect of medroxyprogesterone on arterial blood gases, leptin and neuropeptide Y in postmenopausal females.

Natural progesterone, a potent respiratory stimulant, stimulates leptin production in premenopausal females. Leptin and its counterpart neuropeptide Y (NPY) have recently been linked with respiration. The effect of medroxyprogesterone acetate (MPA) on arterial blood gases, serum leptin and NPY was evaluated in this study. Fourteen postmenopausal females with respiratory impairment, due mostly to chronic obstructive pulmonary disease, were recruited for a randomised, double-blind, placebo-controlled crossover trial. Arterial blood gases, serum leptin and NPY concentrations were measured at baseline and after 14 days of treatment with placebo and MPA, separated by a 6-week washout period. Thirteen patients completed the trial. The mean+/-SD carbon dioxide tension in arterial blood (Pa,CO2) was 5.4+/-0.6 kPa at baseline, and decreased by 0.8+/-0.3 kPa during treatment with MPA. The oxygen tension in arterial blood (Pa,O2) and pH did not change. At baseline, the mean base excess was 0.6+/-1.9 mmol x L(-1) and the mean bicarbonate (HCO3-) concentration was 25.1+/-1.6 mmol x L(-1). With MPA, base excess decreased by 2.2+/-1.2 mmol x L(-1) and HCO3- by 1.9+/-1.0 mmol x L(-1) from baseline. The mean concentrations of serum leptin (19.8+/-9.9 microg x L(-1) at baseline, 19.7+/-9.8 microg x L(-1) with MPA) or NPY (94.0+/-18.3 pmol x L(-1) at baseline, 85.1+/-41.2 pmol x L(-1) with MPA) did not change. However, the reduction in Pa,CO2 correlated with the reduction of serum leptin concentration. Medroxyprogesterone acetate effectively decreased the carbon dioxide tension in postmenopausal females with chronic respiratory impairment. The results suggest that a decrease in the carbon dioxide tension of > or = 0.9 kPa is necessary for a reduction in serum leptin concentration.

Effect of medroxyprogesterone on pulmonary arterial pressure, exhaled nitric oxide, ECG and arterial blood gases.

OBJECTIVES: To evaluate the effect of medroxyprogesterone acetate (MPA) therapy on pulmonary arterial pressure (PAP), exhaled nitric oxide (NO), electrocardiogram (ECG), and on arterial blood gases (ABG). DESIGN: A double-blind randomized placebo-controlled cross-over trial. SETTING: University hospital in Turku, Finland. SUBJECTS: Fourteen postmenopausal women with respiratory impairment. INTERVENTIONS: A 2-week placebo and a 2-week MPA period (60 mg day -1) followed by 6-week placebo or MPA washout periods. MAIN OUTCOME MEASURES: The systolic PAP was estimated by Doppler echocardiography. PAP, ECG, NO and ABG were monitored at baseline, after 2-week placebo and MPA periods, and after 3- and 6-week placebo and MPA washout periods. RESULTS: The mean PaCO2 at baseline was 5.4 +/- 0.6 kPa (mean +/- SD). The average decrease of PaCO2 on MPA was -0.8 +/- 0.3 kPa (P < 0.001) and 0.3 +/- 1.0 kPa (P = 0.007) at the 3-week washout. The mean systolic PAP at baseline was 44.3 +/- 14.5 mm Hg. MPA did not change PAP until the 6-week washout, when the average increase of + 6.9 +/- 19.8 mm Hg (P = 0.002) was observed. No changes occurred in PaO2, exhaled NO or the ECG axes. The PR interval was shorter only on MPA (15.9 +/- 27.0 ms, P = 0.020) whereas the QRS duration remained shorter up to 3-week washout (3.9 +/0 5.5 ms, P = 0.008 and 4.0 +/- 14.3 ms, P = 0.032). The systolic and diastolic BP and the heart rate did not change. CONCLUSIONS: Despite prolonged decrease in PaCO2, short-term MPA had no effect on exhaled NO and did not decrease systolic PAP in postmenopausal women with respiratory impairment. MPA shortened the PR interval and the QRS duration, the latter effect being sustained at least up to 3 weeks.

Aetiology and treatment of sleep disturbances during perimenopause and postmenopause.

The sudden and predictable cessation of ovarian endocrinological function at menopause results in a marked decrease of endogenous estrogen and progestogen secretion. In addition to cessation of menstruation, a wide range of biological functions, including sleep, are affected. Sleep disturbances are more common in women than in men and their incidence increases with age. There are 2 distinct mechanisms by which menopause is known to affect sleep quality. One is menopausal insomnia, which can be considered as part of the symptomatology of the climacterium. Another is sleep-disordered breathing, where impairment of sleep quality is secondary to sleep apnoea or partial upper airway obstruction during sleep. The former is effectively controlled with conventional estrogen replacement therapy, whereas the latter could potentially be improved with progestogens. Many age-related conditions without a direct link with the menopause should also be considered when treating postmenopausal sleep disorders.

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.

Analysis of inspiratory flow shapes in patients with partial upper-airway obstruction during sleep.

STUDY OBJECTIVE: To study the spectrum of inspiratory flow signal shapes in patients with partial upper airway obstruction during sleep. DESIGN: We identified seven different inspiratory flow shapes and determined their frequencies in two groups of patients (10 postmenopausal women and 19 men after surgical treatment for sleep apnea) and in 9 control subjects. SETTING: Sleep research unit, Department of Physiology, University of Turku, Finland. MEASUREMENTS AND RESULTS: Nasal flow was recorded with nasal prongs. The shape analyses were performed with an automated attribute grammar recognizer. The inspiratory flow-shape distributions differed significantly between patients and control subjects. The flow shapes were also different between postmenopausal women and men after uvulopalatopharyngoplasty. CONCLUSIONS: The differences in the inspiratory flow-shape distributions between the control subjects and the two patient groups suggest that the upper airways behave differently in the three study groups. Automated inspiratory flow-shape analysis seems to be a promising tool to distinguish patient groups with different upper airway function to be treated with different treatment alternatives. The physiologic correlates of each flow-shape class remain to be elucidated.

Medroxyprogesterone in postmenopausal females with partial upper airway obstruction during sleep.

The aim of the present study was to evaluate the degree and duration of respiratory stimulation caused by medroxyprogesterone acetate (MPA), and compare the effect of MPA to that of nasal continuous positive airway pressure (nCPAP) in sleep-disordered breathing. Ten postmenopausal females with predominantly partial upper airway obstruction during sleep had an overnight sleep study at baseline, on the fourteenth day of treatment with MPA and after a 3-week washout period. Six subjects on nCPAP were also studied 3 months later. At baseline, the overnight mean+/-SD end-tidal pressure of carbon dioxide (Pet,CO2) was 5.5+/-0.4 kPa the arterial oxygen saturation (Sa,O2) 93.0+/-1.2%, Sa,O2 nadir 80.0+/-6.7%, and frequency of oxygen desaturation > or = 4% (ODI4) per hour 2.2+/-1.3. MPA decreased Pet,CO2 by 0.8 kPa (14.5%, p<0.001). After washout, the mean Pet,CO2 remained at 0.5 kPa (9.1%, p<0.001) lower than at baseline. Sa,O2 did not change. Pet,CO2 was lower on MPA than on nCPAP (4.7+/-0.2 kPa versus 5.0+/-0.3 kPa; p=0.037) but Sa,O2 was similar. Apnoea/hypopnoea index tended to be lower on CPAP than on MPA. Medroxyprogesterone acetate at a daily dose of 60 mg improves ventilation in postmenopausal females with partial upper airway obstruction during sleep without compromising sleep. The ventilatory improvement is sustained for at least 3 weeks posttreatment. Medroxyprogesterone acetate was more efficient in decreasing the partial pressure of carbon dioxide but continuous positive airway pressure was superior in decreasing respiratory efforts.

IGF-I and ventilation after short-term progestin in postmenopausal women with chronic respiratory insufficiency.

Progestins stimulate respiration. We have previously shown prolonged ventilatory improvement in chronic respiratory failure with short-term medroxyprogesterone acetate (MPA). The mechanism of the sustained respiratory effect is unknown. Insulin-like growth factor-I (IGF-I) and insulin have anabolic effects which could also improve ventilation in the long-term. To better understand the interactions between hormones and control of breathing, we evaluated the degree and duration of changes in IGF-I, insulin and cortisol after short-term MPA therapy in chronic respiratory insufficiency. Fourteen postmenopausal women with permanent or episodic hypercapnic or hypoxaemic respiratory failure were recruited for a placebo-controlled single-blind trial. After 14 days of placebo treatment and 7 days of washout, a daily dose of 60 mg MPA was administered for 14 days. Serum IGF-I, insulin and cortisol were measured five times at 3-week intervals: at baseline, after 14 days on placebo, after 14 days on MPA, and during the washout, on days 21 and 42. Serum IGF-I levels were 15.2 (SD 4.6), 20.8 (SD 6.8) and 17.2 (SD 6.4) at baseline, on MPA and after a 3-week washout. Serum insulin levels did not change [12.5 mU l(-1) (SD 4.1), 12.2 mU l(-1) (SD 4.8) and 14.5 mU l(-1) (SD 3.6), respectively]. Serum cortisol did not change. On MPA, IGF-I increased on average by 5.6 nmol l(-1) [95% confidence interval (95% CI) 1.4 to 9.9] or 42.0% (95% CI 6.3 to 77.8) from baseline. The IGF-I response coincided with the previously reported ventilatory improvement. MPA 60 mg daily for 2 weeks increases serum IGF-I in postmenopausal women with chronic respiratory insufficiency. During follow-up after MPA, there was a trend towards increased IGF-I and insulin levels. The role of these two hormones to induce prolonged ventilatory stimulation could not be excluded and further studies in larger populations are warranted.

Prolonged endocrine responses to medroxyprogesterone in postmenopausal women with respiratory insufficiency.

OBJECTIVE: To evaluate the endocrinologic changes associated with, and possibly responsible for, prolonged ventilatory improvement after short-term medroxyprogesterone acetate (MPA) in chronic respiratory failure. METHODS: Fourteen postmenopausal women with permanent or previous episodic hypercapnic or hypoxemic respiratory failure were enrolled in a placebo-controlled, 12-week, single-mask trial including 14-day treatment periods with placebo and MPA (60 mg daily) and a 6-week follow-up. We evaluated the duration of MPA-induced alterations on serum concentrations of progesterone, estradiol, testosterone, FSH, LH, sex hormone-binding globulin (SHBG), and prolactin. Hormones were measured four times: at baseline, after 14 days with MPA, and during the washout on days 21 and 42. RESULTS: With MPA, FSH decreased 42.7% (P <.001, 95% confidence interval [CI] -54.2, -31.6), LH 62.1% (P <.01; 95% CI -81. 0, -32.6), and SHBG 58.1% (P <.001; 95% CI -63.0, -43.9). Luteinizing hormone remained decreased (-28.7%; P <.01; 95% CI -42.0, -14.2) at the 3-week washout, whereas FSH and SHBG were back to pretreatment levels. Prolactin had a borderline initial increase of 23.5% (P =.097; 95% CI -3.5, 50.5) with MPA and a significant increase at the 3-week (31.9%; P <.05; 95% CI 1.0, 62.9) and 6-week (26.4%; P <.05; 95% CI 4.4, 48.3) washouts. CONCLUSION: Medroxyprogesterone acetate 60 mg daily for 2 weeks has both immediate (FSH, LH, and SHBG), prolonged (LH), and rebound endocrinologic (prolactin) effects up to 6 weeks after treatment. The MPA-induced widespread endocrine aftereffects could explain the earlier reported prolonged ventilatory improvement.

Respiratory insufficiency in postmenopausal women: sustained improvement of gas exchange with short-term medroxyprogesterone acetate.

STUDY OBJECTIVES: The degree and duration of respiratory stimulation of medroxyprogesterone acetate (MPA) in postmenopausal women. DESIGN: A placebo-controlled single-blind trial. SETTING: University hospital in Turku, Finland. PATIENTS: Fourteen postmenopausal women with permanent or previous episodic hypercapnic or hypoxemic respiratory failure. INTERVENTIONS: A 12-week trial including 14-day treatment periods with placebo and MPA (60 mg daily) and a 6-week follow-up. RESULTS: Thirteen of 14 patients completed the trial. The mean (+/- SD) PaCO2 at baseline was 42.8+/-4.5 mm Hg and the mean PaO2 was 71.2+/-9.0 mm Hg. The average reduction of PaCO2 was 6.3 mm Hg (14.7%, p < 0.001) on MPA and 3.0 mm Hg (6.1%, p = 0.001) after a 3-week washout. At 6 weeks after MPA, the PaCO2 had returned to baseline. The mean changes in PaO2 (+6.0+/-18.0 mm Hg on MPA and +3.8+/-22.5 mm Hg after a 3-week washout) were not significant. The PaO2/PaCO2 ratio increased, and bicarbonate and base excess decreased (p < 0.001) on MPA but not during washout. The systolic BP did not change on MPA but decreased on average 14.8+/-15.0 mm Hg (p = 0.016) after a 3-week washout. The diastolic BP remained unchanged. CONCLUSIONS: Our results suggest that postmenopausal women with chronic respiratory insufficiency consistently improve on MPA at a dose of 60 mg daily for 14 days. Lower PaCO2 is sustained for at least 3 weeks after cessation of MPA. The sustained effects in gas exchange and favorable after-effects in BP warrant further studies into the therapeutic efficacy and possible benefits of MPA pulse therapy.

Classification of nasal inspiratory flow shapes by attributed finite automata.

In a significant proportion of individuals, the physiologic decrease of muscle tone during sleep results in increased collapsibility of the upper respiratory airway. At peak inspiratory flow, the pharyngeal soft tissues may collapse and cause airflow limitation or even complete occlusion of the upper airway (sleep apnea). While there are plenty of methods to detect sleep apnea, only a few can be used to monitor flow limitation in sleeping individuals. Nasal prongs connected to pressure sensor provide information of the nasal airflow over time. This paper documents a method to automatically classify each nasal inspiratory pressure profile into one without flow limitation or six flow-limited ones. The recognition of the sample signals consists of three phases: preprocessing, primitive extraction, and word parsing phases. In the last one, a sequence of signal primitives is treated as a word and we test its membership in the attribute grammars constructed to the signal categories. The method gave in practical tests surprisingly high performance. Classifying 94;pc of the inspiratory profiles in agreement with the visual judgment of an expert physician, the performance of the method was considered good enough to warrant further testing in well-defined patient populations to determine the pressure profile distributions of different subject classes.

Complement components and their activation products in pleural fluid.

STUDY OBJECTIVES: The aim of this study was to determine the role of complement components in pleural effusion measured with novel markers of complement activation, to assess which pathway of activation is predominant in different diseases, and to find out whether the analysis of complement components and their activation products could help in diagnostic procedure differentiating the etiologies of pleural effusion. PATIENTS: The study population consisted of 71 patients who had pleural effusion secondary to tuberculosis (n=23), rheumatic disease (n=10), or malignancy (n=38). MEASUREMENTS: Complement components and their activation products, including the soluble terminal complex SC5b-9, were measured in plasma and pleural fluid. RESULTS: In all patients with rheumatic pleurisy, pleural fluid SC5b-9 was higher than 2 AU/mL and in all patients with malignant pleural fluid it was lower than 2 AU/mL. The mean level of SC5b-9 in rheumatic pleural effusion was also significantly higher than in tuberculosis. In addition, the concentrations of pleural fluid C3 and C4 were significantly lower and the ratio C4d/C4 was significantly higher in rheumatic compared with tuberculous or malignant pleurisy. In plasma, both SC5b-9 and C1s-C1r-C1INH-complexes were significantly higher in rheumatic subjects than in other patients. In stepwise multinominal logistic regression analyses, the most significant predictors for rheumatic pleural fluid were high pleural fluid SC5b-9 and low C4. CONCLUSIONS: These observations indicate that the complement cascade is activated through both the classic and the alternative pathways in rheumatic pleurisy. Determinations of SC5b-9 and C4d/C4 in pleural fluid were the best variables differentiating rheumatic, tuberculous, and malignant effusions.