Clinical Experience with Off-Label Intrathecal Administration of Selected Antibiotics in Adults: An Overview with Pharmacometric Considerations.

Drain-associated intracerebral infections are life-threatening emergencies. Their treatment is challenging due to the limited penetration of antibiotics to the site of infection, resulting in potentially inadequate exposure. The emergence of multidrug-resistant pathogens might force the use of off-label intrathecal (IT) doses of antibiotics. We reviewed the literature on general aspects determining intrathecal dosing regimen, using pharmacometric knowledge. We summarised clinical experience with IT doses of antibiotics that are usually not used intrathecally, as well as the outcome of the cases and concentrations reached in the cerebrospinal fluid (CSF). Factors determining the IT regimen are the size of the ventricle system and the CSF drainage volume. With regard to pharmacometrics, pharmacokinetic/pharmacodynamic indices are likely similar to those in non-cerebral infections. The following number (N) of cases were described: benzylpenicillin (>50), ampicillin (1), ceftazidime (2), cephaloridine (56), ceftriaxone (1), cefotiam (1), meropenem (57), linezolid (1), tigecycline (15), rifampicin (3), levofloxacin (2), chloramphenicol (3) and daptomycin (8). Many side effects were reported for benzylpenicillin in the 1940-50s, but for the other antibiotics, when administered correctly, all side effects were minor and reversible. These data might help when choosing an IT dosing regimen in case there is no alternative option due to antimicrobial resistance.

Clinical response following hypertension induction for clinical delayed cerebral ischemia following subarachnoid hemorrhage: A retrospective, multicenter, cohort study.

BACKGROUND: Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high-quality studies on its efficacy are lacking. We studied immediate and 3-/6-month clinical efficacy of HTI in aSAH patients with clinical DCI. METHODS: A retrospective, multicenter, comparative, observational cohort study in aSAH patients with clinical deterioration due to DCI, admitted to three tertiary referral hospitals in the Netherlands from 2015 to 2019. Two hospitals used a strategy of HTI (HTI group) and one hospital had no such strategy (control group). We calculated adjusted relative risks (aRR) using Poisson regression analyses for the two primary (clinical improvement of DCI symptoms at days 1 and 5 after DCI onset) and secondary outcomes (DCI-related cerebral infarction, in-hospital mortality, and poor clinical outcome [modified Rankin Scale 4-6] assessed at 3 or 6 months), using the intention-to-treat principle. We also performed as-treated and per-protocol analyses. RESULTS: The aRR for clinical improvement on day 1 after DCI in the HTI group was 1.63 (95% CI 1.17-2.27) and at day 5 after DCI 1.04 (95% CI 0.84-1.29). Secondary outcomes were comparable between the groups. The as-treated and per-protocol analyses yielded similar results. CONCLUSIONS: No clinical benefit of HTI is observed 5 days after DCI due to spontaneous reversal of DCI symptoms in patients treated without HTI. The 3-/6-month clinical outcome was similar for both groups. Therefore, these data suggest that one may consider to not apply HTI in aSAH patients with clinical DCI.

Palliative Care in Severe Neurotrauma Patients in the Intensive Care Unit.

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide and many patients with TBI require intensive care unit (ICU) management. When facing a life-threatening illness, such as TBI, a palliative care approach that focuses on noncurative aspects of care should always be considered in the ICU. Research shows that neurosurgical patients in the ICU receive palliative care less frequently than the medical patients in the ICU, which is a missed opportunity for these patients. However, providing appropriate palliative care to neurotrauma patients in an ICU can be difficult, particularly for young adult patients. The patients' prognoses are often unclear, the likelihood of advance directives is small, and the bereaved families must act as decision-makers. This article highlights the different aspects of the palliative care approach as well as barriers and challenges that accompany the TBI patient population, with a particular focus on young adult patients with TBI and the role of their family members. The article concludes with recommendations for physicians for effective and adequate communication to successfully implement the palliative care approach into standard ICU care and to improve quality of care for patients with TBI and their families.

Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial.

PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking. METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment. RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes. CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Safety and efficacy of C1-inhibitor in traumatic brain injury (CIAO@TBI): study protocol for a randomized, placebo-controlled, multi-center trial.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI. OBJECTIVE: To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients. METHODS: CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis. DISCUSSION: We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04489160. Registered on 27 July 2020. EudraCT 2020-000140-58.

Association Between an Increase in Serum Sodium and In-Hospital Mortality in Critically Ill Patients.

OBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival. DESIGN: Retrospective cohort study. SETTING: Ten Dutch ICUs between January 2011 and April 2017. PATIENTS: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25]). CONCLUSIONS: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia.

Sulpiride intoxication: Case report of a rare intoxication.

Intoxications with sulpiride, an antipsychotic, are rare, and only limited literature is available. We describe a successful treatment of a sulpiride intoxication. A 67-year-old female, with a history of intentional suicide attempt, was admitted to the emergency department (ED) because of a suspected out-of-hospital cardiac arrest. At presentation, she was haemodynamically unstable, with a Glasgow Coma Scale of 3 and slight prolongation of QTc time. History taken from her husband raised suspicion of a suicide attempt with medication. Consultation of the on-call pharmacist and performance of a toxicology screening accelerated the diagnosis of a sulpiride intoxication. The patient was intubated because of respiratory insufficiency, admitted to the Intensive Care Unit (ICU) and treated with activated charcoal, laxatives and sodium bicarbonate. The following day, she was extubated with stable haemodynamics and a normalized ECG. Treatment of sulpiride intoxications is mainly symptomatic and consists of supportive care. An important note is the avoidance of antiarrhythmic drugs, except for lidocaine, epinephrine and dopamine, as they might worsen arrhythmia and hypotension.

Peripheral Neuropathy, Episodic Rhabdomyolysis, and Hypoparathyroidism in a Patient with Mitochondrial Trifunctional Protein Deficiency.

A combination of unexplained peripheral neuropathy, hypoparathyroidism, and the inability to cope with metabolic stress could point to a rare inborn error of metabolism, such as mitochondrial trifunctional protein (MTP) deficiency.Here, we describe a 20-year-old woman who was known since childhood with axonal motor sensory polyneuropathy of unknown origin. She presented with progressive dyspnoea, and increased muscle weakness, preceded by 6 days of fever, vomiting, and diarrhoea. Laboratory testing showed rhabdomyolysis, and hypocalcaemia with low parathyroid levels. The patient was intubated because of respiratory insufficiency and a viral and bacterial pneumonia was diagnosed. She was discharged after 16 days of admission. Metabolic screening, performed at the time of rhabdomyolysis, showed increased concentrations of long-chain 3-hydroxyacyl carnitine species, together with elevated urinary excretion of 3-hydroxy dicarboxylic acids. Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase in peripheral lymphocytes and fibroblasts confirmed a MTP deficiency. Sequence analysis of the HADHB gene showed two heterozygous variants: c.209+1G>C (splicing defect) and c.980T>C (p.Leu327Leu). When the acylcarnitine profile was repeated after the episode of rhabdomyolysis had resolved it showed no abnormalities.Our case illustrates a cluster of peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with MTP deficiency caused by mutations in the HADHB gene. It stresses the importance of performing metabolic screening when patients are most symptomatic, as normal results can be found at times when no metabolic stress is present. Screening is relatively easy and timely diagnosis has important implications for treatment.

How TK-TD and population models for aquatic macrophytes could support the risk assessment for plant protection products.

This case study of the Society of Environmental Toxicology and Chemistry (SETAC) workshop MODELINK demonstrates the potential use of mechanistic effects models for macrophytes to extrapolate from effects of a plant protection product observed in laboratory tests to effects resulting from dynamic exposure on macrophyte populations in edge-of-field water bodies. A standard European Union (EU) risk assessment for an example herbicide based on macrophyte laboratory tests indicated risks for several exposure scenarios. Three of these scenarios are further analyzed using effect models for 2 aquatic macrophytes, the free-floating standard test species Lemna sp., and the sediment-rooted submerged additional standard test species Myriophyllum spicatum. Both models include a toxicokinetic (TK) part, describing uptake and elimination of the toxicant, a toxicodynamic (TD) part, describing the internal concentration-response function for growth inhibition, and a description of biomass growth as a function of environmental factors to allow simulating seasonal dynamics. The TK-TD models are calibrated and tested using laboratory tests, whereas the growth models were assumed to be fit for purpose based on comparisons of predictions with typical growth patterns observed in the field. For the risk assessment, biomass dynamics are predicted for the control situation and for several exposure levels. Based on specific protection goals for macrophytes, preliminary example decision criteria are suggested for evaluating the model outputs. The models refined the risk indicated by lower tier testing for 2 exposure scenarios, while confirming the risk associated for the third. Uncertainties related to the experimental and the modeling approaches and their application in the risk assessment are discussed. Based on this case study and the assumption that the models prove suitable for risk assessment once fully evaluated, we recommend that 1) ecological scenarios be developed that are also linked to the exposure scenarios, and 2) quantitative protection goals be set to facilitate the interpretation of model results for risk assessment.

NT-proBNP, blood pressure, and cognitive decline in the oldest old: The Leiden 85-plus Study.

OBJECTIVE: To study the relation between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, used as a marker of heart failure in clinical practice, blood pressure (BP), and cognitive decline in the oldest old. METHODS: In 560 participants of the Leiden 85-plus Study, we measured NT-proBNP levels and BP at age 85 years, at baseline, and global cognitive function (Mini-Mental State Examination [MMSE]) annually during the follow-up of 5 years. RESULTS: Subjects in the highest tertile of NT-proBNP levels scored 1.7 points lower on the MMSE at age 85 years than subjects in the lowest tertile (p = 0.004), and had a 0.24-point-steeper decline in MMSE score per year (p = 0.021). The longitudinal association disappeared after full adjustment for possible confounders (0.14-point-steeper decline, p = 0.187). Subjects in the category "highest tertile of NT-proBNP and the lowest tertile of systolic BP" had a 3.7-point-lower MMSE score at baseline (p < 0.001) and a 0.49-point-steeper decline in MMSE score per year (p < 0.001) compared with subjects in the other categories. CONCLUSIONS: In the oldest old, high NT-proBNP levels are associated with lower MMSE scores. The combination of high NT-proBNP levels and low systolic BP is associated with worst global cognitive function and the steepest cognitive decline. Possibly, a failing pump function of the heart results in lower BP and lower brain perfusion with resultant brain dysfunction.

N-terminal pro-brain natriuretic peptide and cognitive decline in older adults at high cardiovascular risk.

OBJECTIVE: Elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with cognitive impairment, which might be explained by cardiovascular diseases or risk factors. The aim of this study was to investigate the association of NT-proBNP with cognitive function and decline in older adults at high risk of cardiovascular disease. METHODS: We studied 5,205 men and women (mean age = 75 years) who were recruited into the PROspective Study of Pravastatin in the Elderly at Risk. All participants had pre-existing cardiovascular disease or risk factors thereof. Four domains of cognitive function were tested at baseline and repeated during a follow-up period of 3.2 years. RESULTS: Participants with higher NT-proBNP (≥450ng/l) had worse baseline cognitive function, including reaction time (mean difference high vs low group = 3.07 seconds, 95% confidence interval [CI] = 0.83 to 5.32), processing speed (-1.02 digits coded, 95% CI = -1.65 to -0.39), and immediate memory (-0.13 pictures remembered, 95% CI = -0.29 to 0.04). There was no significant difference in delayed memory (-0.14, 95% CI = -0.38 to 0.10) between the NT-proBNP groups. Participants with higher NT-proBNP had a steeper cognitive decline, including reaction time (mean annual change high vs low group = 0.60 seconds, 95% CI = 0.14 to 1.07), processing speed (-0.15 digits coded, 95% CI = -0.25 to -0.05), immediate memory (-0.05 pictures remembered, 95% CI = -0.09 to 0.00), and delayed memory (-0.05 pictures remembered, 95% CI = -0.11 to 0.01). Associations were independent of cardiovascular diseases and risks. INTERPRETATION: Higher NT-proBNP associates with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases and risks. Further studies to unravel the underlying mechanisms are warranted.

Recovery based on plot experiments is a poor predictor of landscape-level population impacts of agricultural pesticides.

Current European Union regulatory risk assessment allows application of pesticides provided that recovery of nontarget arthropods in-crop occurs within a year. Despite the long-established theory of source-sink dynamics, risk assessment ignores depletion of surrounding populations and typical field trials are restricted to plot-scale experiments. In the present study, the authors used agent-based modeling of 2 contrasting invertebrates, a spider and a beetle, to assess how the area of pesticide application and environmental half-life affect the assessment of recovery at the plot scale and impact the population at the landscape scale. Small-scale plot experiments were simulated for pesticides with different application rates and environmental half-lives. The same pesticides were then evaluated at the landscape scale (10 km × 10 km) assuming continuous year-on-year usage. The authors' results show that recovery time estimated from plot experiments is a poor indicator of long-term population impact at the landscape level and that the spatial scale of pesticide application strongly determines population-level impact. This raises serious doubts as to the utility of plot-recovery experiments in pesticide regulatory risk assessment for population-level protection. Predictions from the model are supported by empirical evidence from a series of studies carried out in the decade starting in 1988. The issues raised then can now be addressed using simulation. Prediction of impacts at landscape scales should be more widely used in assessing the risks posed by environmental stressors.

High blood pressure, physical and cognitive function, and risk of stroke in the oldest old: the Leiden 85-plus Study.

BACKGROUND AND PURPOSE: Epidemiological studies have shown mixed findings on the association between hypertension and stroke in the oldest old. Heterogeneity of the populations under study may underlie variation in outcomes. We examined whether the level of physical and cognitive function moderates the association between blood pressure and stroke. METHODS: We included 513 subjects aged 85 years old from the population-based Leiden 85-plus Study. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure were measured at baseline. Activities of daily living and Mini-Mental State Examination were assessed to estimate level of physical and cognitive function, respectively. Five-year risk of stroke was estimated with Cox regression analysis. RESULTS: In the entire cohort, there were no associations between various measures of blood pressure and risk of stroke except for the inverse relation between pulse pressure and stroke risk (hazard ratio [HR], 0.80 [95% confidence interval [CI], 0.66-0.98]). Among subjects with impaired physical functioning, higher systolic blood pressure (HR, 0.74 [95% CI, 0.59-0.92]), mean arterial pressure (HR: 0.68 [95% CI, 0.47-0.97]), and pulse pressure (HR, 0.71 [95% CI, 0.55-0.93]) were associated with reduced risk of stroke. Likewise, among subjects with impaired cognitive functioning, higher systolic blood pressure was associated with reduced risk of stroke (HR, 0.80 [95% CI, 0.65-0.98]). In subjects with unimpaired cognitive functioning, higher diastolic blood pressure (HR: 1.98 [95% CI, 1.21-3.22]) and mean arterial pressure (HR, 1.70 [95% CI, 1.08-2.68]) were associated with higher risk of stroke. CONCLUSIONS: Our findings suggest that impaired physical and cognitive function moderates the association between blood pressure and stroke.

Cerebrovascular hemodynamics in Alzheimer's disease and vascular dementia: a meta-analysis of transcranial Doppler studies.

BACKGROUND AND PURPOSE: Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing and in different dementia pathologies. The aim of this meta-analysis was to investigate changes in cerebral blood flow velocity and pulsatility index in two most common forms of dementia; Alzheimer's disease and vascular dementia, using transcranial Doppler studies. METHODS: A literature search was conducted in Pubmed, EMBASE and Web of Science. After initial screening of 304 articles and removing duplicates, a total of 53 articles, published between 1980 and 2010, were reviewed. Finally 12 articles were included in the meta-analysis. For each study, effect sizes (ES) indicating the standardized mean differences of the hemodynamic measures between two groups were calculated. Using random effect models, pooled estimates of ES were measured. RESULTS: Patients with Alzheimer's disease (ES=-1.09, 95% CI -1.77 to -0.44, p=0.004) and vascular dementia (ES=-1.62, 95% CI -2.26 to -0.98, p<0.001) had significantly lower cerebral blood flow velocity compared with healthy aged-matched controls. In addition, pulsatility index was significantly higher in both Alzheimer's disease (ES=0.5, 95% CI 0.28-0.72, p<0.001) and vascular dementia patients (ES=2.34, 95% CI 1.39-3.29, p<0.001). Patients with Alzheimer's disease had lower pulsatility index (ES=-1.22, 95% CI -1.98 to -0.46, p=0.002) compared to subjects with vascular type of dementia. CONCLUSIONS: Patients with Alzheimer's disease and vascular dementia have a pronounced disturbance in their cerebrovascular hemodynamics. The severity of disturbances in cerebral hemodynamics is significantly lower in Alzheimer's disease compared to vascular dementia.

Cholesterol and late-life cognitive decline.

High cholesterol levels are a major risk factor for cardiovascular disease, but their role in dementia and cognitive decline is less clear. This review highlights current knowledge on the role of cholesterol in late-life cognitive function, cognitive decline, and dementia. When measured in midlife, high cholesterol levels associate with an increased risk of late-life dementia and cognitive decline. However, when measured in late-life, high cholesterol levels show no association with cognitive function, or even show an inverse relation. Although statin treatment has been shown to associate with a lower risk of dementia and cognitive decline in observational studies, randomized controlled trials show no beneficial effect of statin treatment on late-life cognitive function. Lowering cholesterol levels may impair brain function, since cholesterol is essential for synapse formation and maturation and plays an important role in the regulation of signal transduction through its function as a component of the cell membrane. However, membrane cholesterol also plays a role in the formation and aggregation of amyloid-ß. Factors that influence cholesterol metabolism, such as dietary intake, are shown to play a role in late-life cognitive function and the risk of dementia. In conclusion, cholesterol associates with late-life cognitive function, but the association is strongly age-dependent. There is no evidence that treatment with statins in late-life has a beneficial effect on cognitive function.

Cognitive decline precedes late-life longitudinal changes in vascular risk factors.

INTRODUCTION: Although obesity, hypercholesterolaemia and hypertension in midlife are risk factors for dementia in late life, dementia is associated with lower body mass index, cholesterol levels and blood pressures. It is unclear whether declines in these vascular risk factors are preceded by declines in cognitive function or vice versa. METHODS: Within the Leiden 85-plus Study, a prospective population-based study of 599 subjects aged 85 years, the authors annually measured body mass index, total cholesterol, high-density lipoprotein (HDL) cholesterol, glucose levels and blood pressure, and assessed global cognitive function using the Mini Mental State Examination (MMSE) during a 5-year follow-up. RESULTS: For the whole population who survived up to the age of 90 years, strong annual declines in MMSE score, body mass index, total cholesterol levels, glucose levels, and blood pressure, and an annual increase in HDL cholesterol levels were observed during the follow-up period (all p< or =0.010). Annual changes in MMSE score from age 85 to 87 years were associated positively with annual changes from age 87 to 90 years in total and HDL cholesterol levels (p=0.002 and p=0.013), systolic and diastolic blood pressure (p=0.008 and p=0.048), but not BMI. Parameter value changes from age 85 to 87 years were not associated with changes in MMSE score from age 87 to 90 years. DISCUSSION: In old age, cognitive decline precedes declines in total cholesterol levels, HDL cholesterol levels and blood pressure, and not vice versa. Possibly, brain lesions in metabolic and blood pressure regulation centres cause dysregulation of lipid metabolism and blood pressure.

Dynamics of traditional metabolic risk factors associate with specific causes of death in old age.

BACKGROUND: In contrast to middle age, higher body mass index (BMI), cholesterol levels, and blood pressures associate no longer with increased mortality in old age. With increasing age, these risk factors are prone to change over time. It is unclear whether dynamics of these traditional metabolic risk factors in late life associate with mortality and whether they occur in concert with each other. METHODS: Within the Leiden 85-plus Study, a prospective population-based study of 599 participants aged 85 years, participants were annually assessed during a 5-year follow-up period and observed for mortality for 10 years. RESULTS: BMI, total cholesterol levels, glucose levels, and blood pressures declined and HDL cholesterol levels increased between ages 85 and 90 years (all p < .005). Participants who died at age 90 years had stronger annual declines in BMI, total cholesterol levels, and diastolic blood pressure and weaker increases in HDL cholesterol levels than participants who survived until the end of follow-up (all p < or = .001). In a principal component analysis, annual changes in total, LDL, and HDL cholesterol levels; blood pressures; and glucose, albumin, hemoglobin, leukocyte, and C-reactive protein levels grouped together in one component (all correlation r with component >.40), which associated with all-cause and cancer mortality. CONCLUSIONS: In old age, larger declines in BMI, total cholesterol levels, and blood pressures and weaker increases in HDL cholesterol levels associate with mortality. We identified distinct clustering in the dynamics of these traditional metabolic risk factors and indicators of health and disease in a profile that is suggestive of underlying wasting disease.

Pravastatin and cognitive function in the elderly. Results of the PROSPER study.

Observational studies have given conflicting results about the effect of statins in preventing dementia and cognitive decline. Moreover, observational studies are subject to prescription bias, making it hard to draw definite conclusions from them. Randomized controlled trials are therefore the preferred study design to investigate the association between statins and cognition. Here we present detailed cognitive outcomes from the randomized placebo-controlled PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cognitive function was assessed repeatedly in all 5,804 PROSPER participants at six different time points during the study using four neuropsychological performance tests. After a mean follow-up period of 42 months, no difference in cognitive decline at any of the cognitive domains was found in subjects treated with pravastatin compared to placebo (all p > 0.05). Pravastatin treatment in old age did not affect cognitive decline during a 3 year follow-up period. Employing statin therapy in the elderly in an attempt to prevent cognitive decline therefore seems to be futile.

Use of benzodiazepines, depressive symptoms and cognitive function in old age.

OBJECTIVE: Benzodiazepine use is more frequently observed in depressive and cognitively impaired subjects. The temporal relation behind this association is unknown. Here, we studied whether benzodiazepine use is associated with depressive symptoms and cognitive function and what the temporal relation underlying the associations is. METHODS: Within the Leiden 85-plus Study, a prospective population based study of 599 subjects aged 85 years at baseline, we assessed benzodiazepine use, depressive symptoms, and cognitive function annually during a 5-year follow-up period. RESULTS: Benzodiazepine users were more likely to be female, be institutionalized, and have a low education. Benzodiazepine users scored 0.76 points higher on the 15-item Geriatric Depression Scale than non-users (95% CI: 0.27-1.25, p = 0.002). They were 1.6-fold more likely to develop new depressive symptoms in 1 year when compared to non-users (95% CI: 1.05-2.55, p = 0.028). Benzodiazepine use did not associate with cognitive function, but discontinued benzodiazepine users had a 4.0 points lower Mini Mental State Examination (MMSE) score in the year before discontinuation than continued benzodiazepine users (95% CI: 1.31-6.73, p = 0.004). CONCLUSIONS: In old age the use of benzodiazepines is associated with depressive symptoms and the use of benzodiazepines may precede the development of depressive symptoms. Treating physicians seem to be aware of the detrimental effects of benzodiazepines on cognitive function. However, they should be cautious in prescribing a new benzodiazepine in old age and monitor elderly benzodiazepine users for development of depressive symptoms.

The influence of age on the association between cholesterol and cognitive function.

With the increasing emphasis on vascular disease as a risk factor for dementia and cognitive impairment, lowering cholesterol has received much attention to maintain cognitive function. Observational studies have shown that high total serum cholesterol levels in middle age, but not in old age, associate with cognitive impairment in later life. This can be explained in part since the association between high levels of total serum cholesterol levels and cardiovascular disease becomes weaker with increasing age and is absent in old age. Most studies on HDL-cholesterol levels show a protective association with cardiovascular disease up to old age, whereas data on the protective association with late-life cognitive impairment is absent. In contrast to general belief, randomized controlled trials and most longitudinal observational studies do not show a positive effect of statin treatment on the risk of dementia when prescribed in later life. In conclusion, high total serum cholesterol in middle age is associated with cognitive impairment and statin therapy is likely to have a benefit on cognitive function via a decrease of cardiovascular pathologies. However, a beneficial effect of cholesterol lowering on cognitive function in old age is uncertain.