Improved follow-up by peripheral arterial tonometry in CPAP-treated patients with obstructive sleep apnea and persistent excessive daytime sleepiness.

BACKGROUND: OSA-patients with persistent excessive daytime sleepiness (EDS) despite CPAP treatment are challenging in daily clinical life. To rule out residual sleep-disordered breathing (SDB), CPAP device-derived data are used in outpatient setting. In case of no pathological finding, a more intensive work-up with is necessary. 6-channel portable monitoring (6Ch-PM) is frequently used to exclude residual SDB. Peripheral arterial tonometry (PAT), as embodied in the WatchPAT device, represents an alternative technique for detecting SDB based on changes in autonomic tone. We wanted to investigate whether PAT might be a useful tool to improve diagnostic work-up in this specific patient group by better identifying residual SDB due to insufficient CPAP-adjustment. METHODS: Forty-nine OSA patients (39 male, 10 female) with sufficient CPAP treatment according to device-derived data were consecutively recruited. EDS was assessed by Epworth Sleepiness Scale (ESS). All patients underwent home-based CPAP therapy control by 6Ch-PM and portable monitoring using PAT technology on two consecutive nights. A sequence of both types of monitoring was randomized to prevent possible first night effect bias. RESULTS: Twelve out of 49 patients showed persistent EDS according to ESS (ESS > 10 points). 6Ch-PM showed a residually increased AHI under CPAP-treatment in 2 of those 12 subjects (positive predictive value, PPV = 16.7%). PAT-PM revealed 5 patients of those 12 with residual SDB (PPV = 41.7%). CONCLUSION: PAT could detect significantly more residual SDB under CPAP treatment than 6Ch-PM. Diagnostic work-up of CPAP-treated OSA patients with persistent EDS might be optimized, as insufficient pressure level adjustments could be recognized more precisely in time, possibly preventing more resource-consuming procedures, and potentially increased morbidity. CLINICAL TRIAL REGISTRATION: DRKS00007705.

[Diagnosis of sleep disordered breathing using portable methods]. / Diagnostik schlafbezogener Atmungsstörungen mittels portabler Verfahren.

Portable monitoring of sleep disordered breathing is the first diagnostic method not only in Germany but today in other countries as well. The conditions under which portable monitoring can be done with reliable results are now well defined. The limitations for the use of portable monitoring are specified as well. The devices used for portable monitoring are classified in four categories according to the number and the kind of signals recorded. New technical developments in the field of portable monitoring (polygraphy) use an indirect assessment of sleep disordered breathing based on signals not directly recording respiration. The recording of ECG and deriving respiration, the analysis of the plethysmographically recorded pulse wave, the recording of jaw movements using magnets, and advanced analysis of respiratory sounds are recent approaches. These new methods are presented with few studies until now. More and larger clinical studies are needed in order to show which of these systems is useful in the diagnosis of sleep disordered breathing and which are the specific strengths and weaknesses.

Use of drug-induced sleep endoscopy in Germany-an analysis based on claims data.

Background: Drug-induced sleep endoscopy (DISE) has recently gained relevance as a diagnostic tool for obstructive sleep apnea (OSA). However, it is unclear to what extent and in which patient cohorts DISE is used in Germany. With introduction of specific coding for this method in 2021 (Operationen- und Prozedurenschluessel, OPS code), usage can now be analyzed based on diagnosis-related groups (DRG) claims data. Methods: Aggregated data from all inpatient DISE procedures conducted in German hospitals in 2021 were obtained from the publicly available Institut fuer das Entgeltsystem im Krankenhaus (InEK) database. Patient-relevant information as well as data on hospitals providing the examinations were exported and analyzed. Results: Between January and December 2021, a total of 2765 DISE procedures were conducted and documented using the newly introduced specific code (1-611.01). Most patients were male (75.6%), in the age categories 30-39 (15.2%) and 40-49 years (17.2%), and presented with the lowest patient clinical complexity level (PCCL; class 0 = 81.88%). Pediatric use was rare (1.8%). Leading main diagnoses of patients were G47.31 (OSA) and J34.2 (deviation of nasal septum). The most common procedures conducted together with DISE were nasal surgery, and the examination was mostly provided in large public hospitals with more than 800 beds. Conclusion: Though the OSA prevalence in Germany is high, use of DISE as a diagnostic tool is low and represented only 4.4% of cases with a main diagnosis of OSA in 2021. Since specific coding was only introduced in January 2021, trends cannot yet be identified. Noticeable is the frequent combination of DISE with nasal surgery, which is not obviously related to a diagnosis of OSA. Limitations of the study are mainly related to the underlying data, which are available for the inpatient sector only, and due to potentially limited use of the OPS code, which was introduced recently and might not be known to all hospitals.

[Sleep apnoea syndrome in the rehabilitation setting]. / Das Schlafapnoe-Syndrom in der Rehabilitation.

Sleep-related breathing disorders are a common finding in patients undergoing cardiological rehabilitation. Sleep apnoea is recognized as a major risk factor for cardiovascular disorders. The diagnosis of sleep-related breathing disorders begins with taking a thorough sleep medicine-related patient history and answering dedicated questionnaires. The second step involves portable monitoring to assess oxygen saturation, heart rate, respiratory flow and effort. Portable monitoring is able to detect the severity of the breathing disorder and forms the basis on which to refer the patient for further sleep laboratory diagnosis or, in the case of positive results, to initiate appropriate treatment. In order to exclude a sleep-related breathing disorder, to distinguish between obstructive and central sleep apnoea, or to diagnose other sleep disorders a cardiorespiratory polysomnography in a sleep laboratory is required. Polysomnography is also needed if comorbidities are present. Appropriate and prompt treatment of sleep-related breathing disorders can shorten cardiological rehabilitation and improve outcomes in this patient group.

[Digital respiratory sleep medicine-part I: diagnosis]. / Digitale respiratorische Schlafmedizin ­ Teil I: Diagnostik: Aktueller Stand, Perspektive, Vision.

Novel methods of eHealth already offer smart solutions for currently insufficiently addressed problems in the field of sleep-disordered breathing. Telemedical concepts, such as video consultation, help bring affected patients to sleep medical expertise at an early stage. Cloud-based diagnostics can help reduce existing inner- and intrasectoral problems and can improve interdisciplinary communication within established diagnostic pathways. New sensors and applications for digital devices (apps) open up opportunities for broad screening for the widespread disease of sleep apnea. However, in order to be able to use these methods clinically at all, they have to be certified as medical products. The Digital Supply Act (DVG) enables inclusion of health apps in the list of digital health applications (DiGA) after evaluation by the Federal Institute for Drugs and Medical Devices (BfArM). These "apps by prescription" are then reimbursable by the statutory health insurance. The vast amounts of collected data can only be analyzed for links and patterns using computer-based analysis methods. These findings are not intended to replace medical doctors, but rather to support them in their decision-making-in terms of real precision medicine including participation of the patient. The informed patient has to have data sovereignty at all times.

Studies on reproductive toxicity of iloprost in rats, rabbits and monkeys.

A reproduction toxicological test program was performed with the carbaprostacyclin derivative iloprost, an analogue to the endogenous prostacyclin PGI2, in order to detect possible effects on fertility and reproductive performance, on preimplantational, embryonal and fetal development, on delivery as well as on lactation and postpartum development. While in humans iloprost is administered as an i.v. infusion for 6 h/day, it was administered i.v. to rats, rabbits and monkeys by continuous infusion with a subcutaneously implanted pump. No influence on mating or reproductive parameters was found after treatment of male or female rats during the premating phase up to day 7 post coitum (p.c.). Embryonal and fetal development were not remarkably impaired in rabbits or monkeys after treatment throughout the period of organogenesis. The only remarkable observations in the embryotoxicity and peri-/postnatal studies in the rat were defects on the digits (reductions of phalangeal structures) in single individuals. These malformations were interpreted as resulting from a compound-related hypotonia with subsequent change in the regional blood flow and the consequence of temporary impairments of placental blood supply leading to hypoxia in the affected structures.

Studies on the design of animal tests for the corrosiveness of industrial chemicals.

Using a defined method for the determination of irritant and corrosive effects, the effects of varying the exposure time and the extent of occlusion were investigated and compared in rabbit skin experiments (by occlusive and semi-occlusive methods, each at exposure times of 1 hr and 4 hr). The results for 23 substances demonstrate that exposure for 1 hr normally leads to a realistic assessment of corrosiveness, in agreement with those given in the EEC 'Dangerous Substances Directive' (67/548/EEC; Off. J. Europ. Commun. 1967, 196, 1). With several substances, the 4-hr exposure leads to corrosive effects that do not occur under practical conditions. Moreover, a 4-hr exposure does not lead to a realistic hazard assessment in every case; some substances exhibit a corrosive effect in this test but are not classified as "corrosive" in the EEC Guideline Annex I, no. 1.1. Results using the semi-occlusive method did not usually differ from those obtained with the occlusive method. In general, the semi-occlusive method can be used, and in the case of volatile substances it is strongly advocated.

Iotasul, a water-soluble contrast agent for direct and indirect lymphography. Results of preclinical investigations.

Iotasul, a non-ionic dimeric water-soluble contrast agent with outstanding physico-chemical properties is well suited for direct as well as indirect lymphography, as demonstrated in experimental animals. The contrast medium is eliminated practically completely within 24 hours by the renal route. The tolerance of this agent is far better than that of oily contrast media.

[Sleep-disordered breathing and atrial fibrillation]. / Schlafbezogene Atmungsstörungen und Vorhofflimmern.

Sleep-disordered breathing is one of the most common sleep disorders. Especially obstructive sleep apnea (OSA) is an independent cardiovascular risk factor. Clinical studies have proven a significant association between OSA and atrial fibrillation, the most common cardiac arrhythmia. Currently, there is no proven evidence for causality. Untreated OSA seems to be a risk factor for failure of rhythm control strategy in atrial fibrillation. The recurrence rate after cardioversion is higher in case of additional untreated OSA. Continuous positive airway pressure (CPAP) therapy in OSA patients could reduce relapse rate. However, there is a lack of randomized controlled clinical trials with defined end points on this topic. A specific sleep medicine interview as well as sleep studies with portable monitoring and cardiorespiratory polysomnography are recommended when sleep-disordered breathing is suspected. Procedures for the management of patients with atrial fibrillation are given.

Effect of CPAP therapy on daytime cardiovascular regulations in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a sleep disorder with a high prevalence that causes pathological changes in cardiovascular regulation during the night and also during daytime. We investigated whether the treatment of OSA at night by means of continuous positive airway pressure (CPAP) improves the daytime consequences. Twenty-eight patients with OSA, 18 with arterial hypertension, 10 with normal blood pressure, were investigated at baseline and with three months of CPAP treatment. Ten age and sex matched healthy control subjects were investigated for comparisons. We recorded a resting period with 20min quiet breathing and an exercise stress test during daytime with ECG and blood pressure (Portapres). The bicycle ergometry showed a significant reduction of the diastolic blood pressure at a work load of 50W and 100W (p<0.05 and p<0.01, respectively) and a decrease of the heart rate recovery time after the stress test (p<0.05). These results indicate a reduction of vascular resistance and sympathetic activity during daytime. The coupling analysis of the resting periods by means of symbolic coupling traces approach indicated an effect of the CPAP therapy on the baroreflex reaction in hypertensive patients where influences of the systolic blood pressure on the heart rate changed from pathological patterns to adaptive mechanisms of the normotensive patients (p<0.05).

Preclinical testing of iopromide. 2nd communication: toxicological evaluation.

Toxicological characteristics of the non-ionic monomeric X-ray contrast agent iopromide (Ultravist, CAS 73334-07-3) were evaluated in rats, rabbits, guinea-pigs and dogs. The scope of investigations included acute toxicity studies, systemic tolerance investigations with repeated applications, reproduction toxicity studies, examinations on the genotoxic and contact-sensitizing potential and local tolerance studies. Iopromide could be shown to be well tolerated in all the tests and species.

Circadian plasma level profile of lisuride in rats and mice after continuous administration via the diet.

Lisuride (Dopergin, CAS 18016-80-3), a dopamine D2 agonist, was administered to male and female rats and mice continuously via the diet for 14 days. The doses were 0.2 mg/kg/d in mice and 1 mg/kg/d in mice and rats. Plasma level profiles (0-22 or 24 h) were determined by measuring lisuride concentrations by radioimmunoassay. At all doses a plateau-like plasma level of lisuride was observed. A clear circadian rhythm of lisuride concentrations (highs during night, low levels during day) was found for male rats (1 mg/kg/d) and for male mice (0.2 mg/kg/d). Female animals did not show this phenomenon as pronounced. At the same dose of 1 mg/kg/d rats showed higher plasma levels than mice. For males the ratio of total AUCs was 1.9 and for female animals 8.6.

Tolerance to iotrolan after subarachnoid injection in animals.

Neural tolerance after intracisternal administration of iotrolan was compared with that after iohexol, iopamidol, and metrizamide in mice, rats, and guinea pigs. Around the level of the ED50 (approximately two to four times the human dose) tolerance to iotrolan appeared to be much better than tolerance to the other agents. A study in rabbits comparing iotrolan with iohexol produced approximately the same result. High doses of iotrolan, iohexol, and iopamidol were almost equally well tolerated by rats, as were iotrolan and iohexol by rabbits. Tolerance to metrizamide by rats and to iopamidol by guinea pigs was vastly inferior. In support of this very good general tolerance histologic examinations of the spinal tract and of the brain did not reveal any substance-related changes in beagles after lumbar administration of a high dose. An investigation in rats using mannitol and sorbitol formulations with differing osmotic pressures indicates that contrast tolerance is influenced primarily by the chemotoxicity and not by increased osmotic pressure. As shown by the results of the preclinical investigations, iotrolan should be ideal for use in myelography and also appears highly suitable for the examination of other body cavities.

Characterization of a new potent heparin. 1 communication: Determinations of anticoagulant activity of a high potency heparin preparation in vivo using dog as an experimental animal and in vitro using dog and human plasma.

The anticoagulant effect of a highly potent heparin preparation was compared with a commercially available heparin in vivo after i.v. application in beagle dogs. The anticoagulant activity was determined using thrombin time, activated partial thromboplastin time and whole blood clotting time 5, 10 and 30 min after application. The relative potency of the heparin preparation (Schering) was found to be 1.62 to 2.52 times higher than heparin used for comparison (150 USP units/mg). The anticoagulant properties of both preparations were also studied in vitro using heparin concentrations from 0.44 to 7.0 microgram/ml dog and human plasma. The relative potency in vitro experiments using dog or human plasma were 1.62 and 1.63, respectively, on the basis of activated partial thromboplastin time. It was further demonstrated that the anticoagulant effect as determined by activated partial thromboplastin time in vitro on human plasma was 2 to 2.4 times more pronounced in both heparin preparations when compared to the effect exerted on dog plasma.

Characterization of a new potent heparin. 4th communication: The effect of a new potent heparin preparation on lipid components and leucocytes in rats after subcutaneous application.

The effect of a new potent heparin preparation on blood lipid components and leucocytes after a single subcutaneous application in rats was investigated and compared with a commercially available heparin. The analysis of plasma cholesterol, glycerol, triglycerides and free fatty acids as well as leucocyte counts and differential counts were performed 1, 2, 4 and 8 h after heparin application. The main effects observed were a marked increase in free fatty acids with a maximum already after 1 h and a state of leucocytosis with a maximum and 4 h after application, besides other minor changes in blood lipid components. However, these effects were less pronounced after a dose of the new heparin of 16.6 mg/kg, which is equipotent with 5000 USP units of the commercially available heparin used in this study on anticoagulant activity on the basis of factor Xa inactivation assay. The biological relevance of the increase in the plasma free fatty acids and the mechanism of heparin induced leucocytosis are discussed.

Characterization of a new potent heparin. 6th communication: The comparison of the anticoagulant effect of the sodium and calcium salts of a new potent heparin after s.c. injection in beagle dogs.

The anticoagulant effect of the sodium and the calcium salts of a new potent heparin was compared in beagle dogs following a single s.c. injection. The determinations of whole-blood clotting time, activated partial thromboplastin time and plasma heparin levels using the amidolytic assay 1, 2, 4, 6, 8, 10 and 12 h post injection revealed that the calcium salt was just slightly more active than the sodium salt of heparin. The influence of the molecular composition in particular the inorganic ion content associated with heparin on the anticoagulation activity achieved after subcutaneous injection, is discussed.

Comparative pharmacokinetics of abecarnil in rat following single and multiple intragastric treatment and continuous administration via the diet.

The anxiolytic beta-carboline abecarnil was administered to female rats at doses of 10, 50, and 250 mg/kg/day for 4 weeks either intragastrically once a day or continuously via the feed. On days 1, 3, 7, 14, and 28, plasma level profiles (0-24 hr) and, additionally, on day 28, concentration profiles (0-24 hr) in liver, kidney, and brain were determined in identical groups of animals. Fecal excretion of unchanged abecarnil also was determined as a measure for enteric absorption. After both routes of administration, absorption was practically complete. Drug uptake via the feed resulted in a plateau-like plasma level without explicit maxima or minima. Indications were observed for a positive food intake plasma level correlation with lower plasma levels during the day and higher concentrations at night, for a slight increase of drug plasma levels during the 4-week period, and a dose-proportional increase of mean plasma concentrations. Intragastric treatment was characterized by clearly distinguishable absorption and disposition phases with prominent peaks after the 10 and 50 mg/kg doses, a plateau-like plasma level probably due to prolonged absorption after the 250 mg/kg dose, slight accumulation of drug in the plasma during continuous once-daily treatment, and a dose-proportional increase of the AUC. The drug load of the animals measured as concentrations in plasma and tissues was different after both routes of administration. Peak plasma levels were greater after intragastric treatment by a factor of 5, and the AUC was double compared to the feed experiment.(ABSTRACT TRUNCATED AT 250 WORDS)