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Holger Kraiczi

Publications and source records attributed to Holger Kraiczi.

7 recordsLinked to original sources
PubMed2005

Effect of uncertainty about population parameters on pharmacodynamics-based prediction of clinical trial power.

Clinical trial simulation (CTS) may be applied to predict power of intended drug trials on the basis of pharmacokinetic/pharmacodynamic (PKPD) drug models. The validity of such predictions will, among other factors, depend on the degree of uncertainty about population parameters entering the simulation. In the current article, we illustrate how population parameter uncertainty may be incorporated in the overall simulation model, using a worked example to demonstrate our approach. Moreover, we suggest an ANOVA-based method for sensitivity analysis, aimed at distinguishing important population parameters, required to be input in the model with a low degree of uncertainty for precise power predictions, from unimportant parameters, which may be entered with a high degree of uncertainty without affecting the reliability of predictions. Our results from simulations with different settings of hyperparameters and doses suggest that indices derived from this type of sensitivity analysis may be used for grading the influence on prediction quality of uncertainty about different population parameters and, thus, facilitate the allocation of resources expended for the preparation of a successful CTS project.

Computer Simulation↗
PubMed2003

Reduction of sleep-disordered breathing after physostigmine.

The cholinesterase inhibitor physostigmine (PHYS) was investigated in a double-blind, placebo-controlled, randomized, crossover trial of 10 male patients with moderate to severe obstructive sleep apnea. PHYS (0.12 microg/minute/kg, 7-hour infusion) reduced mean apnea/hypopnea index (AHI) by 13.6 (95% confidence interval [CI], 2.2-25.1) corresponding to 21.4% (95% CI, -5.5 to 47.9) and increased minimum SaO2 by 8.7% (95% CI, -0.3 to 17.7) corresponding to 23.2% (95% CI, 4.8-41.3). During the last third of the night, coinciding with predicted plasma concentration steady state, non-REM sleep AHI decreased by 19.2 (95% CI, 0.1-38.3) or 14.9% (95% CI, -43.6 to 77.7) and REM AHI by 33.8 (95% CI, 13.7-54.0) or 67.5% (95% CI, 49.7-85.3). Mean total sleep time was reduced by 74 minutes (95% CI, 33.9-114.9), but patients with the least pronounced sleep shortening had the largest reduction of AHI (r = 0.73, p < 0.02). The nocturnal decline in heart rate was reduced by PHYS. Moreover, resting (early-night placebo heart rate) was positively correlated with proportional reduction of REM apnea index (r = 0.69, p < 0.02). Body mass index was negatively correlated with reduction of REM AHI (r = 0.77, p < 0.02). This, predominantly REM-related, reduction of obstructive sleep apnea after PHYS may provide a new treatment option if the effects are maintained in long-term studies.

Adult↗
PubMed2003

Finger plethysmography--a method for monitoring finger blood flow during sleep disordered breathing.

We investigated a non-invasive measurement for changes in finger blood flow during wakefulness and sleep. Changes in finger blood flow, reflected by pulse wave amplitude (PWA) derived from finger plethysmography, were compared with changes in forearm vascular flow assessed by venous occlusion plethysmography after intra-arterial infusion of norepinephrine (NE), phentolamine, and isoproterenol (n=15, 15, 14 subjects, respectively). Moreover, PWA was assessed during obstructive breathing during sleep (n=8 patients). Vasoconstriction in the finger (PWA) was stronger than that obtained in the forearm vascular bed in the higher NE dose range both without (ANOVA, P=0.002) and with concomitant phentolamine-induced alpha-receptor blockade (P=0.02). Isoproterenol increased forearm blood flow but did not induce flow changes detectable by the finger plethysmographic technique (P<0.001). PWA was significantly reduced during arousal from obstructive sleep apnea (-37.5+/-16.1%, P=0.002, n=6 patients), suggesting vasoconstriction in the digital vascular bed. PWA derived from finger plethysmography allows continuous, non-invasive measurement of changes in finger blood flow during wakefulness and sleep. However, as may be expected from the anatomical and functional differences between the finger and forearm vascular beds and demonstrated by the lack of response to beta(2)-receptor stimulation, PWA does not mimic forearm vascular flow characteristics. Thus, finger plethysmography may be a useful complement to current vascular research techniques, in particular to monitor sympathetic influences on skin blood flow in the finger.

Adrenergic alpha-Antagonists↗
PubMed2002

[Sleep apnea a risk factor of cardiovascular disease].

Obstructive sleep apnea (OSA) affects almost one fifth of the male and 10% of the female middle-aged population. Only one fifth of subjects with more or less severe disorder of breathing report simultaneous daytime sleepiness. There is growing research evidence for an independent association between OSA and cardiovascular disease (CVD). The suggestion that this link is not only correlative but also causative is strongly supported by a series of recent clinical and epidemiological studies. The association between OSA and traditionally recognized cardiovascular risk factors suggests that OSA may provide an additive and synergistic risk in cases with co-existing obesity, insulin resistance, diabetes and/or dyslipidaemia. These recent insights advocate better awareness of OSA and potentially also a wider use of screening-tools for early identification and treatment of sleep related breathing disorders. Moreover, current research within the fields of obesity and cardiovascular prevention needs to identify OSA as a study confounder. Continuous intense research into pathophysiological mechanisms and therapeutic possibilities of CVD related to OSA appears to be an important and potentially rewarding area of disease prevention.

Arrhythmias, Cardiac↗
PubMed2002

Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up.

The incidence of a cardiovascular disease (CVD) was explored in a consecutive sleep clinic cohort of 182 middle-aged men (mean age, 46.8 +/- 9.3; range, 30-69 years in 1991) with or without obstructive sleep apnea (OSA). All subjects were free of hypertension or other CVD, pulmonary disease, diabetes mellitus, psychiatric disorder, alcohol dependency, as well as malignancy at baseline. Data were collected via the Swedish Hospital Discharge Register covering a 7-year period before December 31, 1998, as well as questionnaires. Effectiveness of OSA treatment initiated during the period as well as age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP) at baseline, and smoking habits were controlled. The incidence of at least one CVD was observed in 22 of 60 (36.7%) cases with OSA (overnight oxygen desaturations of 30 or more) compared with in 8 of 122 (6.6%) subjects without OSA (p < 0.001). In a multiple logistic regression model, significant predictors of CVD incidence were OSA at baseline (odds ratio [OR] 4.9; 95% confidence interval [CI], 1.8-13.6) and age (OR 23.4; 95% CI, 2.7-197.5) after adjustment for BMI, SBP, and DBP at baseline. In the OSA group, CVD incidence was observed in 21 of 37 (56.8%) incompletely treated cases compared with in 1 of 15 (6.7%) efficiently treated subjects (p < 0.001). In a multiple regression analysis, efficient treatment was associated with a significant risk reduction for CVD incidence (OR 0.1; 95% CI, 0.0-0.7) after adjustment for age and SBP at baseline in the OSA subjects. We conclude that the risk of developing CVD is increased in middle-aged OSA subjects independently of age, BMI, SBP, DBP, and smoking. Furthermore, efficient treatment of OSA reduces the excess CVD risk and may be considered also in relatively mild OSA without regard to daytime sleepiness.

Aged↗
PubMed2002

Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment.

Sleep apnea syndrome is associated with recurrent episodic hypoxia during sleep, which has been implicated in the development of cardiovascular morbidity. Hypoxia is the major stimulus of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine. In the present article we describe the results of three experiments in which plasma concentrations of VEGF were measured in patients with sleep apnea. In Experiment 1, apnea-hypopnea index was found to be a significant independent predictor of morning VEGF concentrations in 85 male subjects investigated in the sleep laboratory, of whom 47 had an apnea-hypopnea index greater than 20. In Experiment 2, VEGF concentrations measured hourly during the sleep period were found to be significantly higher in a group of five sleep apnea patients compared with six age-similar snorers and six normal young adults (129.1 +/- 43.4 versus 74.6 +/- 11.5 and 32.5 +/- 12.8 pg/ml, respectively [p < 0.007]). In Experiment 3, VEGF concentrations were compared in patients with sleep apnea before and 1 year after nasal continuous positive airway pressure treatment. A significant decrease in VEGF concentrations was found only in patients in whom nocturnal hypoxia improved after treatment (57.1 +/- 62.5 versus 39.6 +/- 46.9 pg/ml, p < 0.01). There was no comparable improvement in patients who did not accept treatment (53.9 +/- 23.6 versus 54.0 +/- 21.5 pg/ml, ns). These results raise the possibility that VEGF may contribute to the long-term adaptation of sleep apnea syndrome to recurrent nocturnal hypoxia.

Adult↗