Bernd M. Sanner

Influence of treatment on leptin levels in patients with obstructive sleep apnoea

Obstructive sleep apnoea syndrome (OSAS) is a common disorder in obesity. Leptin, an adipocyte-derived signalling factor, plays an important role in metabolic control. There is growing evidence that leptin regulation is altered in OSAS. Therefore, the aim of this study was to test the hypothesis that effective treatment will influence leptin levels in OSAS patients. Serum leptin levels were determined in 86 consecutive patients (aged 57.5±11.0 yrs) with polysomnographically verified OSAS. In addition, leptin levels were reassessed and treatment efficacy was evaluated by polysomnography after 6 months of therapy. Patients were treated with continuous or bilevel positive airway pressure, a mandibular advancement device or conservatively, depending on the clinical symptoms. Mean serum leptin levels did not change with treatment in the whole study group (7.3±5.0 versus 7.5±4.8 ng·mL−1), however, leptin levels decreased in effectively treated patients (8.5±5.0 versus 7.4±5.1 ng·mL−1) while they increased in ineffectively treated patients (5.0±4.0 versus 7.7±4.1 ng·mL−1). Furthermore, not only was there a significant and independent correlation between the change in leptin levels with treatment and the change in body mass index, but also with the change in apnoea/hypopnoea index. Effective treatment of sleep-disordered breathing may have significant effects on leptin levels in obstructive sleep apnoea syndrome patients. Changes in leptin levels are related to changes in apnoea/hypopnoea index in obstructive sleep apnoea syndrome patients.

Right ventricular dysfunction in patients with obstructive sleep apnoea syndrome.

There is conclusive evidence that obstructive sleep apnoea syndrome (OSAS) influences right heart haemodynamics and can also induce pulmonary hypertension. It is not known, however, whether right ventricular dysfunction can occur in patients with OSAS in the absence of lung disease. We studied 107 patients (94 males, 13 females, mean age 55 +/- 11 yrs) with polysomnographically verified OSAS in whom clinically significant lung disease was excluded. Right ventricular ejection fraction (RVEF) was determined by radionuclide ventriculography. In addition, pulmonary function tests, arterial blood gas analysis and right heart catheterization were performed. RVEF was impaired in 19 patients (18%). Eighteen (95%) had signs or symptoms consistent with mild right ventricular failure. Patients with or without impaired RVEF did not differ with respect to body mass index, age or lung function. Stepwise multiple logistic regression analysis revealed that RVEF was significantly associated with the apnoea/hypopnoea index (r = -0.68; p = 0.0009) and the extent of nocturnal oxyhaemoglobin saturation (r = 0.42; p = 0.035), but not with age, body mass index, blood gas analysis, gender, lung function, pulmonary artery pressure and left ventricular ejection fraction. We conclude that in patients with otherwise unexplained right ventricular failure, obstructive sleep apnoea syndrome may underlie the right ventricular dysfunction.

Effect of continuous positive airway pressure therapy on 24-hour blood pressure in patients with obstructive sleep apnea syndrome.

BACKGROUND Patients with obstructive sleep apnea syndrome (OSAS) are subject to an increased cardiovascular morbidity including systemic hypertension. Little is known about the effects of treatment with nasal continuous positive airway pressure (CPAP) on systemic hypertension. METHODS Automated ambulatory 24-h blood pressure (BP) monitoring was performed in 88 consecutive patients who were referred for evaluation of snoring or suspected OSAS. In addition, the long-term effects of CPAP therapy on 24-h BP were assessed. RESULTS A total of 62 patients had OSAS and 26 habitual snoring. Patients with OSAS had significantly higher mean arterial BP values than snorers (102.7 +/- 10.7 v 94.0 +/- 10.2 mm Hg; P < .01). Multiple stepwise linear regression analysis disclosed that the degree of systemic hypertension was independently associated with the severity of OSAS as determined by the apnea/hypopnea index (R = 0.43; P < .001), but not with age, body mass index, or smoking habits. Of the 62 patients with OSAS, 52 were treated with CPAP and reevaluated after 9 months. The CPAP resulted in a significant decrease in mean arterial BP (from 103.7 +/- 10.4 to 99.1 +/- 10.8 mm Hg; P < .05). For those patients with systemic hypertension whose BP improved with CPAP therapy, 24-h mean pulse pressure at baseline (r = -0.36; P < .05) as well as average heart rate during the day (r = -0.35; P < .05) turned out as predictors. CONCLUSIONS Obstructive sleep apnea syndrome contributes, at least in part, to the development of systemic hypertension, and CPAP may improve BP values in treated OSAS patients. Predictors of a beneficial CPAP effect on BP are a high heart rate and a high pulse pressure before treatment.

Effect of Continuous Positive Airway Pressure Therapy on Infectious Complications in Patients with Obstructive Sleep Apnea Syndrome

Background: Nasal continuous positive airway pressure (CPAP) is a well-established, widely used and effective treatment of obstructive sleep apnea syndrome (OSAS). Unfortunately, side effects are frequent during CPAP treatment. Objectives: Little is known about the effects of CPAP on infectious complications in patients with OSAS. Methods: We retrospectively analyzed the kinds and rate of infections of the upper airway in 246 consecutive patients (mean age, 59.7 years) with polysomnographically verified OSAS using CPAP with or without a heated humidifier and compared them with OSAS patients who received non-CPAP therapy. Results: Of the 246 patients, 40 received conservative therapy and 206 CPAP treatment, 36 of them with a heated humidifier. The mean follow-up period of the study group was 165.4 ± 92.1 weeks and did not differ between the three groups. Infectious diseases were frequent in all three groups, but patients using CPAP without humidifier suffered from upper airway infections significantly more frequently than controls (42.9 vs. 25%; p < 0.05), and more patients on CPAP therapy with humidifier than controls (22.2 vs. 2.5%; p < 0.01) reported an increased rate of upper airway infections since initiation of CPAP therapy or diagnosis of OSAS. Especially patients using a hot water bath humidifier who cleaned their devices inadequately had significantly more upper airway infections since diagnosis (57.1 vs. 20%; p < 0.05) or during the past 6 months (52.4 vs. 13.3%; p < 0.05) than patients who regularly cleaned CPAP machines, humidifiers and ventilatory circuits. Conclusions: Our results suggest that patients using CPAP therapy either with or without heated humidity seem to be at an increased risk of upper airway infections compared to conservatively treated patients.

Prospective randomized comparison of impedance-controlled auto-continuous positive airway pressure (APAPFOT) with constant CPAP

Background: The measurement of impedance permits reliable detection of obstructive apneas, hypopneas and upper airways resistance syndrome. Objective: To establish whether impedance-controlled self-adjusting positive airway pressure therapy (APAPFOT) is equally as good as constant continuous positive airway pressure (CPAP) in the treatment of sleep apnea syndrome (OSAS). Methods: Twenty men and five women with OSAS (age 52.8±9.0 years, body mass index (BMI) 31.4±5.0 kg/m2, AHI 32.2±18.1/h (mean±SD)) underwent baseline polysomnography, manual CPAP titration and two nights of treatment, one with APAPFOT, one with constant CPAP. Results: With both modes, a significant reduction in respiratory disturbances was seen (apnea/hypopnea index (AHI) baseline 32.2±18.1/h, constant CPAP 6.6±8.7, APAPFOT 5.5±3.8/h, P<0.001 baseline vs. each treatment mode). Under APAPFOT, the sleep profile was normalized (S3/4 baseline 16.3±13.9% total sleep time (TST), APAPFOT 21.6±10.9% TST, P<0.05, rapid eye movement (REM) 14.2±6.7% TST vs. 20.3±7.3% TST, P<0.01), while with constant CPAP, a tendency towards improvement was found. The mean treatment pressure with APAPFOT was significantly lower than the constant CPAP (5.7±2.1 vs. 8.3±1.6 mbar, P<0.001). Conclusion: We conclude that APAPFOT is at least as effective as constant CPAP in normalizing sleep and breathing in OSAS.

Effects of glucocorticoids on generation of reactive oxygen species in platelets.

Since prednisolone and dexamethasone are known as potent anti-inflammatory agents, the effects of prednisolone and dexamethasone on production of intracellular reactive oxygen species (ROS) were investigated in human platelets. Platelet ROS were measured using the intracellular fluorescent dye dichlorofluorescein diacetate after activation of protein kinase C by phorbol-12-myristate-13-acetate (PMA) or 1-oleoyl-2-acetyl-sn-glycerol (OAG). NAD(P)H oxidase activity was measured photometrically. PMA and OAG significantly increased ROS in platelets (P<0.001). Prednisolone or dexamethasone concentration-dependently reduced the PMA-induced ROS production. The PMA-induced ROS increase was significantly reduced in the presence of 10 micromol/l prednisolone to 9+/-1% (n=31; P<0.001) or in the presence of 10 micromol/l dexamethasone to 9+/-1% (n=24; P<0.001). The inhibitory effect of prednisolone or dexamethasone could also be observed in the presence of the glucocorticoid receptor inhibitor, mifepristone (RU486). Administration of testosterone or aldosterone did not significantly reduce PMA-induced ROS increase. Prednisolone had no effect on platelet NAD(P)H oxidase activity. The inhibition of oxidative phosphorylation by sodium azide reduced platelets ROS to 8+/-1% (n=35). It is concluded that glucocorticoids, prednisolone and dexamethasone, directly inhibit production of intracellular ROS. This effect may contribute to the anti-inflammatory actions of these agents.

Self-Adjusting Continuous Positive Airway Pressure Therapy Based on the Measurement of Impedance

Background: Measurement of impedance using forced oscillation technique is a sensitive means of detecting airway obstructions, including the obstructive sleep apnea syndrome (OSAS). Objective: The present study was conducted to determine whether treatment with an automated impedance-controlled continuous positive airway pressure (CPAP) device (APAPFOT) is possible in patients with OSAS, and which is the best range of pressure variation in automatical CPAP treatment. We investigated two modes of APAPFOT with different pressure ranges: (1) the widest technically possible pressure range and (2) a range with individually defined minimum pressure. Methods: Ten patients [9 men, age 56.6 ±10.5 years, BMI 32.0 ± 4.5 kg/m2, apnea/hypopnea index (AHI) 18.2 ± 13.3 /h] had a diagnostic polysomnography (baseline). After manual titration of positive airway pressure they were submitted, in randomized order, to two modes of the APAPFOT device, namely pressure range of 4.0– 15.5 mbar (mode 1 free range) and an individually fixed higher minimum pressure with a maximum pressure of 15.5 mbar (mode 2). Results: While the manually titrated pressure was 8.0 ± 1.3 mbar, in mode 1 it was 5.6 ± 2.1 mbar (p < 0.01); in mode 2 7.3 ± 1.6 mbar (p < 0.05). Both of these modes suppressed abnormal respiratory events (baseline AHI 18.2 ± 13.3/h; mode 1: 2.5 ± 1.9; mode 2: 1.8 ± 0.7, p < 0.01 in each case), and increased slow wave sleep (baseline: 10.6 ± 8.0%, mode 1: 20.2 ± 10.4%, p < 0.05; mode 2: 22.3 ± 9.3%, p < 0.01). In mode 1, the pressure was lower than that titrated manually in 73.2% of total sleep time, in mode 2 in 48.6%, while pressures higher than those derived manually were observed in 13.0% in mode 1 and in 19.1% in mode 2. Conclusions: The data indicate that impedance-controlled CPAP (APAPFOT) allows adequate treatment of OSAS patients at significantly lower pressures as compared with manually titrated pressure. Differences between the two modes are only minor.

A Test for the Determination of Sustained Attention in Patients with Obstructive Sleep Apnea Syndrome

Background and Objectives: To investigate the parameter daytime sleepiness in patients with the sleep apnea syndrome (SAS), a test for measurement of sustained attention was developed. The present studies were performed on volunteers undergoing preemployment medical examinations and SAS patients to determine the extent to which test results are in agreement with the symptoms of SAS and traffic accident reports, and also with daytime sleepiness, and whether learning or therapeutic effects can be seen with repeated tests prior to and following treatment with nasal continuous positive airway pressure (nCPAP). Methods: Participants: 125 healthy volunteers, and two groups of 28 SAS patients each. Design: Study A: The volunteers underwent a single attention test and completed a questionnaire concerned with traffic accidents and symptoms of sleep-related breathing disorders. Study B: SAS patients underwent two attention tests before treatment. Study C: SAS patients underwent one attention test before and one after nCPAP therapy. Results: Study A: The error rate in volunteers without symptoms of sleep-related breathing disorders (51 persons) was 4.7 ± 4.3% (number of errors 14.1 ± 12.9), 95% CI: 1.2 (number of errors 3.6). No dependence of the error rate on age, BMI or sex was found. In persons with a history of apneic events (n = 10), the error rate was 10.6 ± 10.0% (number of errors 31.8 ± 30), in those with more than two accidents during the last 5 years (n = 4), it was increased to 15.3 ± 9.7% (number of errors 45.9 ± 29.1). Study B: Among SAS patients, no significant learning effect was seen, and prolongation of the test duration beyond 30 min had no effect on the test results. Study C: The error rate improved significantly with nCPAP [10.6 ± 13.5 vs. 6.4 ± 8.9% (number of errors 31.8 ± 40.5 vs. 19.2 ± 26.7), p < 0.001]. Conclusions: The attention test can be helpful for the measurement of daytime sleepiness, and CPAP therapy can improve test performance.

Polysomnography in acute African trypanosomiasis.

Sirs: Sleeping sickness is one of the sleep disorders listed in the International Classification of Sleep Disorders (3.C.1). To date there have been only few reports of sleep studies in chronic sleeping sickness [1, 2, 3] and, to our knowledge, no reports of sleep studies in acute sleeping sickness. We describe a case of acute African trypanosomiasis with disturbed sleep following travel to the tropics and the results of the sleep studies in this patient. A 47-year-old woman was admitted to hospital because of high remittent fever, insomnia during night, hypersomnia by day, and jaundice. Symptoms had started 5 days prior to admission, 7 days after returning from a 20-day trip to Zambia, Zimbabwe, and Tanzania. The patient had a fever of 39.2°C, an ulcerated and indurated lesion of 3 cm in diameter at the right first carpometacarpal joint, discrete nontender axillary lymphadenopathy on the right side, and jaundice. Abdominal ultrasound, chest radiography, and echocardiography on the day of admission were completely normal. Three blood cultures and microscopy of blood smears isolated no organisms. During the next 2 days her condition deteriorated, fever rose to 40.9°C, she became more sleepy during the day and was restless at night, and developed multiorgan failure with hepatitis, myocarditis, nephritis, pancreatitis, polyserositis, and disseminated intravascular coagulation. Again, microscopy of peripheral blood smears was performed, and this time trypanosomes were found. The indirect fluorescent antibody test for African trypanosomiasis was initially negative but turned positive (1:20) during the following 3 days. Due to the history, clinical findings, and microscopy results acute infection with Trypanosoma brucei rhodesiense with septic and multiorgan involvement was diagnosed. Treatment with suramin was initiated immediately, and she recovered completely over the following days. Lumbar puncture was performed on day 9 of suramin treatment, when there were no more trypanosomes in the peripheral blood smear, and the platelet count was normal; this yielded no direct evidence of central nervous system involvement. Total protein level of the spinal fluid was slightly elevated (0.65 g/l), but there was an increase neither in cells nor in the IgM level. Free immunoglobulin light chains were not present. Polysomnography was performed according to widely accepted methods on days 7, 9, and 15 and 6 months after the onset of trypanosomiasis [4]. Sleep was staged manually using the methods of Rechtschaffen and Kales [5], and arousals and leg movements were classified according to ASDA recommendations [6, 7]. Sleep examination revealed a poor sleep efficiency and decreased slow wave sleep, while the amount of arousals and awakenings was increased (Table 1). Furthermore, the patient had periodic limb movements (PLM) during sleep with a PLM index of 27.2/h and a PLM arousal and wake index of 11.7/h. Repeat polysomnographic measurements during follow-up showed an increase in sleep efficiency and amount of slow wave sleep and a decrease in arousals and awakenings, but PLM remained. MRI of the brain conducted on day 10 of disease onset showed a small angioma at the right frontal pole and was otherwise unremarkable. Mobile long-term EEG recording (24 h duration) was performed on day 22. The eight-channel monitoring revealed an alpha rhythm (10/s) with recurrent short naps (nonrapid eye movement sleep 2) during the day. Night recording confirmed polysomnographic data showing a poor sleep efficiency with frequent awakenings and arousals. At sleep onset generalized high theta activity and steep potentials were observed. There were no signs of encephalitis. Laboratory examination on day 25 after onset of the disease showed normal values for vitamin B1, vitamin B6, and vitamin E. The nerve conduction study using surface electrodes to record compound muscle action potentials revealed prolonged conduction velocity of the right peroneal nerve (38 m/s), left tibial nerve (34 m/s), and left LETTER TO THE EDITORS

Fulminant disease simulating bacterial sepsis with disseminated intravascular coagulation after a trip to East Africa.

the diagnosis [4]. The central catheterisation through the left external jugular vein and, later, the procedure of changing the catheter on a guide wire could have caused a small perforation in the termination of the main thoracic duct, which is close to the junction between left external jugular vein and left subclavian vein. On the other hand, a sudden increase in intraductal pressure from coughing in the postoperative period together with the possible damaging effect of chemotherapy on the endothelium of the duct could have initiated a leak. Chylothorax is a rare complication following cannulation of the left subclavian and internal jugular veins. To the best of our knowledge, the case presented here is the first one to be reported in the literature after cannulation of the left subclavian vein through the left external jugular vein. Considering the number of patients receiving TPN from central vein catheters, there may be more cases in the future where the differential diagnosis will have to be made between chylothorax and leakage of TPN.