Rationalisatie van slaapmiddelen: een sisyfusarbeid?

Ondanks meerdere sensibilisatiecampagnes gedurende de afgelopen jaren blijft langdurig gebruik van slaapmiddelen een prevalent probleem. Gezien de snelle tolerantie voor het effect in combinatie met de bijwerkingen is langdurig gebruik veelal schadelijk voor de patiënt. Indien er geen andere mogelijkheid is dan het gebruik van slaapmiddelen, moet men de duur beperken tot twee weken en moet er systematisch getracht worden om bij langdurig gebruik deze middelen af te bouwen en finaal te stoppen. De afbouw van slaapmiddelen is een uitdaging gezien de psychologische en de fysieke afhankelijkheid aan deze middelen. De winst na afbouw treedt echter snel op. Bij het gebruik van deze geneesmiddelen bij ouderen is het risico op ongewenste effecten groter, met name een verminderd cognitief vermogen en verminderde motorische functies, met als gevolg een grotere kans op ongewenste sedatie, vallen en fracturen.status: publishe

Pharmacokinetics of 2 oral paracetamol formulations in hospitalized octogenarians

Aims: It is currently unclear how paracetamol should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of 2 oral paracetamol formulations and its metabolites in hospitalized octogenarians. Methods: Geriatric inpatients aged 80 years and older received a 1000-mg paracetamol tablet or granulate at 08.00, 14.00 and 20.00. After at least 4 consecutive gifts, plasma samples were collected around the 08.00 dose (trough, +0.5, +1, +2, +4, +5 and +6 h). Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (C avg) of 10 mg/L. Results: The mean (±standard deviation) age was 86.78 (±4.20) years. The majority (n = 26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a C avg above 10 mg/L. The median [interquartile range] time to reach the peak concentration was 50.5 [31.50–92.50] and 42.50 [33.75–106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for time to reach the peak concentration and 30% for C avg of paracetamol. A correlation of C avg of paracetamol was observed with female sex and total serum bilirubin. Conclusion: Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate

Polypharmacy and excessive polypharmacy in community-dwelling middle aged and aged adults between 2011 and 2015

Aims We aimed to assess the prevalence, components and evolution of polypharmacy and to evaluate risk factors associated with polypharmacy.Methods A retrospective dynamic cohort study was performed, using a primary healthcare database comprising Flemish community-dwelling adults aged >= 40 years between 2011 and 2015. Polypharmacy and excessive polypharmacy were defined as the use of 5-9 or minimum 10 different medications during 1 year, respectively. Temporal changes were analysed using an autoregressive error model. Risk factors for polypharmacy were evaluated using logistic regression.Results In total, 68 426 patients were included in the analysis. The prevalence of polypharmacy was 29.5% and 16.1% for excessive polypharmacy in 2015. The age-standardised prevalence rate of patients using minimum five medications increased with 1.3% per year (95% confidence interval (CI): 0.1968-2.4279). The mean number of unplanned hospital admissions was 0.07 (standard deviation (SD) 0.33) for polypharmacy patients and 0.19 (SD 0.53) for excessive polypharmacy patients. Four risk factors were found to be significantly correlated with polypharmacy: age (odds ratio (OR) 1.015; 95% CI: 1.013-1.017), female gender (OR 1.161; 95% CI: 1.108-1.216), number of chronic diseases (OR 1.126; 95% CI: 1.114-1.139) and number of general practitioner contacts (OR 1.283; 95% CI: 1.274-1.292).Conclusion The prevalence of polypharmacy increased between 2011 and 2015. Polypharmacy and excessive polypharmacy patients appeared to differ based on our observations of characteristics, drug therapy and outcomes. Age, female gender, number of chronic diseases and number of general practitioner contacts were associated with polypharmacy

Highly Variable Paracetamol Pharmacokinetics After Multiple Oral Dosing in Frail Older People:A Population Pharmacokinetic Analysis

Introduction: Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. Methods: A population PK analysis, using NONMEM 7.2, was performed on 245 paracetamol samples in 40 geriatric inpatients (median age 87 [range 80–95] years, bodyweight 66.4 [49.3–110] kg, 92.5% frail [Edmonton Frail Scale]). All subjects received paracetamol 1000 mg as tablet (72.5%) or granulate (27.5%) three times daily. Simulations of dosing regimens (1000 mg every 6 hours [q6h] or q8h) were performed to determine target attainment, using mean steady-state concentration (Css-mean) of 10 mg/L as target. Results: A one-compartment model with first order absorption and lag time best described the data. The inter-individual variability was high, with absorption rate constant containing the highest variability. The inter-individual variability could not be explained by covariates. Simulations of 1000 mg q6h and q8h resulted in a Css-mean of 10.8 [25–75th percentiles 8.2–12.7] and 8.13 [6.3–9.6] mg/L, respectively, for the average geriatric inpatient. The majority of the population remained off-target (22.2% [q6h] and 52.2% [q8h] 12 mg/L). Conclusion: A population of average geriatric inpatients achieved target Css-mean with paracetamol 1000 mg q6h, while q8h resulted in underexposure for the majority of them. Due to high unexplained variability, a relevant proportion remained either above or below the target concentration of 10 mg/L. Research focusing on PK, efficacy and safety is needed to recommend dosing regimens

Accuracy of spleen stiffness measurement for the diagnosis of clinically significant portal hypertension in patients with compensated advanced chronic liver disease: a systematic review and individual patient data meta-analysis

Background: The diagnosis of clinically significant portal hypertension is crucial for prognosis and treatment guidance in patients with compensated advanced chronic liver disease (ACLD). Spleen stiffness measurement (SSM) might improve the non-invasive diagnosis of clinically significant portal hypertension, but previous studies have reported heterogeneous SSM cutoffs. We aimed to evaluate the accuracy of SSM and SSM-based algorithms in this setting. Methods: In this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library from database inception to Dec 31, 2022, for articles, abstracts, and letters, with no restrictions on language. Cross-sectional studies reporting hepatic venous pressure gradient and SSM by different techniques (transient elastography; two-dimensional shear-wave elastography [2D-SWE]; point shear-wave elastography [p-SWE]) in adults (≥18 years) with compensated ACLD were eligible for inclusion. The main outcome was the diagnostic performance of two SSM-based algorithms, with the Baveno VII model as a reference, evaluating sensitivity and specificity, as well as summary negative predictive values (NPVs) and positive predictive values (PPVs). In the Baveno VII model, clinically significant portal hypertension was ruled out if patients had a liver stiffness measurement (LSM) of 15 kPa or less and a platelet count of 150 × 109 platelets per L or higher and ruled in if they had an LSM of greater than 25 kPa. The two SSM-based models combined these same cutoffs with additional criteria. In the Baveno VII-SSM single cutoff model, clinically significant portal hypertension was ruled out if at least two of the following were present: LSM of 15 kPa or less, platelet count of 150 × 109 platelets per L or higher, and SSM of 40 kPa or less; and ruled in if at least two were present: LSM of greater than 25 kPa, platelet count of less than 150 × 109 platelets per L, and SSM of greater than 40 kPa. The Baveno VII-SSM dual cutoff model used the same criteria, but with a cutoff of SSM of less than 21 kPa to rule out, and greater than 50 kPa to rule in, clinically significant portal hypertension. This study is registered with PROSPERO, CRD42019127164. Findings: Of the 44 records assessed for eligibility, 17 studies (with 1245 patients) were included in the meta-analysis. In the transient elastography cohort (n=600), the Baveno VII algorithm was validated for both ruling out (NPV 100%, 95% CI 64–100; sensitivity 100%, 95% CI 70–100) and ruling in (PPV 95%, 85–98; specificity 94%, 95% CI 87–97) clinically significant portal hypertension, but the proportion of patients with indeterminate results (grey zone) was 48% (95% CI 44–52); 57% (95% CI 52–62) of patients with clinically significant portal hypertension were included in the rule-in zone. The Baveno VII-SSM dual cutoff model had adequate NPV (98%, 95% CI 58–100; sensitivity 100%, 95% CI 91–100) and PPV (93%, 95% CI 84–97; specificity 89%, 95% CI 84–93), with 32% (95% CI 28–36) of patients in the grey zone; 76% (95% CI 72–80) of the patients with clinically significant portal hypertension were in the rule-in zone. The Baveno VII-SSM single cutoff model had a sensitivity of 93% (95% CI 85–97) and a NPV of 85% (95% CI 60–96) for ruling out, and a specificity of 86% (95% CI 80–91) and a PPV of 92% (95% CI 83–95) for ruling in, clinically significant portal hypertension. 88% (95% CI 84–91) of patients with clinically significant portal hypertension were included in the rule-in zone and 9% (95% CI 7–12) of patients were in the grey zone. In the 2D-SWE cohort (n=225), all three algorithms could safely rule in clinically significant portal hypertension with adequate PPV (≥90%), but NPV was inadequate for ruling out clinically significant portal hypertension. Insufficient data were available to evaluate the performance of SSM assessed by p-SWE. Heterogeneity was low (I2<25%) for most estimates. Interpretation: Algorithms combining Baveno VII criteria with SSM showed good performance and reduced the diagnostic grey zone for clinically significant portal hypertension compared with Baveno VII criteria alone. Future studies should evaluate whether SSM-based diagnosis allows for the identification of patients who would benefit from non-selective β-blocker treatment. Funding: None