Nonoperative management of hip fractures in very frail elderly patients may lead to a predictable short survival as part of advance care planning.

Background and purpose - Surgical treatment is still the mainstay of care even in very frail elderly hip fracture patients. However, one may argue whether surgery is in the best interest of all patients. We elucidated mortality rates of nonoperative management (NOM) of a hip fracture after shared decision-making in a cohort of very frail elderly patients.Patients and methods - Orthogeriatric patients (age > 70 years) admitted with a hip fracture between 2011 and 2019 were included. In the presence of fragility features the motivation for surgery or NOM was supported by advance care planning (ACP) and shared decision-making through geriatric assessment. Mortality rates after NOM were assessed and also presented for the remaining surgical group for reference.Results - In 1,279 out of 3,467 patients, geriatric assessment was indicated and subsequently 1,188 (93%) had surgery versus 91 (7%) NOM. The motivation for NOM was based on patient and family preferences in only 20% of patients, medical grounds in 54%, and a combination of both in 26%. The 30-day and 1-year mortality in the frail NOM group was 87% and 99% respectively, whereas this was 7% and 28% in the surgery group. No statistical comparison between groups was performed due to profound bias by indication.Interpretation - This study provides further insight into the predictable and high short-term mortality after NOM in carefully selected very frail elderly hip fracture patients. This information may help to consider NOM as an alternative treatment option to surgery when no significant gain from surgery is anticipated.

Life-sustaining treatment preferences in older patients when referred to the emergency department for acute geriatric assessment: a descriptive study in a Dutch hospital.

BACKGROUND: In many cases, life-sustaining treatment preferences are not timely discussed with older patients. Advance care planning (ACP) offers medical professionals an opportunity to discuss patients' preferences. We assessed how often these preferences were known when older patients were referred to the emergency department (ED) for an acute geriatric assessment. METHODS: We conducted a descriptive study on patients referred to the ED for an acute geriatric assessment in a Dutch hospital. Patients were referred by general practitioners (GPs), or in the case of nursing home residents, by elderly care physicians. The referring physician was asked if preferences regarding life-sustaining treatments were known. The primary outcome was the number of patients for whom preferences were known. Secondary outcomes included which preferences, and which variables predict known preferences. RESULTS: Between 2015 and 2017, 348 patients were included in our study. At least one preference regarding life-sustaining treatments was known at referral in 45.4% (158/348) cases. In these cases, cardiopulmonary resuscitation (CPR) policy was always included. Preferences regarding invasive ventilation policy and ICU admission were known in 17% (59/348) and 10.3% (36/348) of the cases respectively. Known preferences were more frequent in cases referred by the elderly care physician than the GP (P < 0.001). CONCLUSIONS: In less than half the patients, at least one preference regarding life-sustaining treatments was known at the time of referral to the ED for an acute geriatric assessment; in most cases it concerned CPR policy. We recommend optimizing ACP conversations in a non-acute setting to provide more appropriate, desired, and personalized care to older patients referred to the ED.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Temporal Relationship Between Cognitive and Physical Performance in Middle-Aged to Oldest Old People.

BACKGROUND: Cognitive and physical impairment frequently co-occur in older people. The aim of this study was to assess the temporal order of these age-related changes in cognitive and physical performance and to assess whether a relationship was different across specific cognitive and physical domains and age groups. METHODS: Cognitive domains included global, executive, and memory function; physical domains included gait speed and handgrip strength. These domains were assessed in two population-based longitudinal cohorts covering the age ranges of 55-64, 65-74, 75-85, and 85-90 years with a follow-up of 5-12 years. Cross-lagged panel models were applied to assess the temporal relationships between the different cognitive and physical domains adjusting for age, sex, education, comorbidity, depressive symptoms, and physical activity. RESULTS: Over all age groups, poorer executive function was associated with a steeper decline in gait speed (p < .05). From the age of 85 years, this relationship was found across all cognitive and physical domains (p < .02). From the age of 65 years, slower gait speed and/or weaker handgrip strength were associated with steeper declines in global cognitive function (p < .02), with statistically significant results across all cognitive domains in the age group of 75-85 years (p < .04). CONCLUSIONS: The temporal relationship between cognitive and physical performance differs across domains and age, suggesting a specific rather than a general relationship. This emphasizes the importance of repeated measurements on different domains and encourages future research to the development of domain- and age-specific interventions.

Vitamin D supplementation in nursing home patients: randomized controlled trial of standard daily dose versus individualized loading dose regimen.

BACKGROUND: Supplementation of cholecalciferol 800 IU daily appears to be insufficient to raise vitamin D levels to >75 nmol/l in nursing home (NH) patients. OBJECTIVE: Our objective was to compare the efficacy of an individualized cholecalciferol loading dose (LD) regimen and a daily dose (DD) regimen of cholecalciferol 800 IU in reaching 25-OH vitamin D (25OHD) levels >75 nmol/l. METHODS: A total of 30 NH patients with 25OHD levels <50 nmol/l were included. Patients were randomized using the minimization method in the LD or DD group. The cholecalciferol LD, calculated with an algorithm based on serum 25OHD level and body weight, was administered in divided doses of 50,000 IU twice a week, followed by a monthly maintenance dose of either 50,000 or 25,000 IU. The DD regimen consisted of cholecalciferol 800 IU daily for 26 weeks. Serum 25OHD, calcium, creatinine, phosphate, and parathyroid hormone were measured, and 2-minute walking test, handgrip strength, and timed get up and go test were assessed at baseline (T 0), after 5 weeks (T 5), 12 weeks (T 12), and 26 weeks (T 26). The primary endpoint was the percentage of patients with 25OHD levels >75 nmol/l at T 5. Secondary endpoints were the proportion of patients with 25OHD levels >75 nmol/l at T 26, safety of LD regimen, and improvement of performance tests with normalization of vitamin D levels. RESULTS: Median baseline 25OHD levels (interquartile range) were comparable between the 14 DD and 16 LD patients: 20.9 (15.9-29.6) and 21.7 (16.4-32.8) nmol/l, respectively. Levels of 25OHD >75 nmol/l at T 5 were reached in 79 % of the 14 LD patients, but in none of the 13 DD patients (p < 0.001). At T 26, 25OHD levels >75 nmol/l were reached in 83 % of the 12 LD patients and in 30 % of the ten DD patients (p < 0.05). Side effects or hypercalcemia were not observed. No improvement of performance tests was observed. CONCLUSION: In NH patients with severe 25OHD deficiency, an individualized calculated cholecalciferol LD is likely to be superior to a DD of cholecalciferol 800 IU in terms of the ability to rapidly normalize vitamin D levels.

Predicting survival in oldest old people.

OBJECTIVE: Measures of physical performance are regarded as useful objective clinical tools to estimate survival in elderly people. However, oldest old people, aged 85 years or more, are underrepresented in earlier studies and frequently unable to perform functional tests. We studied the association of gait speed and survival in a cohort of oldest old people and the association of Instrumental Activities of Daily Living by questionnaire and survival as an alternative prognostic marker of survival. METHODS: The Leiden 85-plus Study was used, a prospective population-based study with a follow-up period of 12 years. The study comprised 599 participants all aged 85 years at baseline. Survival rate was the measurement. RESULTS: At age 85 years, 73 participants (12.2%) did not perform the walking test. Gait speed faster than 0.8 m/s was present in only 48 participants (9%), and gait speed faster than 1.0 m/s was present in 10 participants (1.9%). Risk for all-cause mortality was higher in participants with slow gait speed after 2 and 12 years of follow-up (hazard ratio [HR], 2.66; 95% confidence interval [CI], 1.49-4.75; P<.001; and HR, 2.04; 95% CI, 1.61-2.59; P=.100, respectively). Significance was lost after adjustment for common confounders. Poor Instrumental Activities of Daily Living ability was associated with an increased risk of mortality after 2 and 12 years of follow-up (HR, 6.11; 95% CI, 3.44-10.87; P<.001; and HR, 2.75; 95% CI, 2.22-3.40; P<.001, respectively). Adjustment for possible confounders attenuated the relation but remained significant. CONCLUSIONS: The cutoff points for gait speed in oldest old people need to be reevaluated. In oldest old people aged 85 years, slow gait speed (≤0.40 m/s in women and ≤0.45 m/s in men) and Instrumental Activities of Daily Living disability are both predictors of survival. Assessment of Instrumental Activities of Daily Living could be a better tool for short- and long-term prognostication of survival in oldest old people.

Temporal relationship between handgrip strength and cognitive performance in oldest old people.

BACKGROUND: cognitive decline and muscle weakness are prevalent health conditions in elderly people. We hypothesised that cognitive decline precedes muscle weakness. OBJECTIVE: to analyse the temporal relationship between cognitive performance and handgrip strength in oldest old people. DESIGN: prospective population-based 4-year follow-up study. SUBJECTS: a total of 555 subjects, all aged 85 years at baseline, were included into the study. METHODS: handgrip strength measured at age 85 and 89 years. Neuropsychological test battery to assess global cognitive performance, attention, processing speed and memory at baseline and repeated at age 89 years. Associations between handgrip strength and cognitive performance were analysed by repeated linear regression analysis adjusted for common confounders. RESULTS: at age 85 and 89 years, better cognitive performance was associated with higher handgrip strength (all, P<0.03), except for attention. There was no longitudinal association between baseline handgrip strength and cognitive decline (all, P>0.10), except for global cognitive performance (P=0.007). Better cognitive performance at age 85 years was associated with slower decline in handgrip strength (all, P<0.01) after adjustment for common confounders. CONCLUSION: baseline cognitive performance was associated with decline in handgrip strength, whereas baseline handgrip strength was not associated with cognitive decline. Our results suggest that cognitive decline precedes the onset of muscle weakness in oldest old people.

Higher blood pressure is associated with higher handgrip strength in the oldest old.

BACKGROUND: Aging is associated with progressive loss of muscle strength. Muscle tissue is vascularized by an elaborate vascular network. There is evidence that blood pressure (BP) is associated with muscle function in middle age. It is unknown how BP associates with muscle function in oldest old people. We studied the association between BP and handgrip strength in middle and old age. METHOD: BP was measured automatically in middle-aged subjects and with a mercury sphygmomanometer in the oldest old. Handgrip strength was measured with a handgrip strength dynamometer. Cross-sectional measurements of handgrip strength and BP were available for 670 middle-aged subjects (mean 63.2 ± 6.6 years) and 550 oldest old subjects (all 85 years). Prospective data were available for oldest old subjects only with a 4-year follow-up at 89 years. The association between BP and handgrip strength was analyzed by linear regression analysis. RESULTS: In middle-aged subjects, BP and handgrip strength were not statistically significantly associated. In oldest old subjects, higher systolic BP (SBP), mean arterial pressure (MAP), and pulse pressure (PP) were associated with higher handgrip strength after adjusting for comorbidity and medication use (all P < 0.02). Furthermore, in oldest old subjects, changes in SBP, MAP, and PP after 4 years was associated with declining handgrip strength (all, P < 0.05). CONCLUSION: In oldest old, higher BP is associated with better muscle strength. Further study is necessary to investigate whether BP is a potential modifiable risk factor for prevention of age-associated decline in muscle strength.

Circulating levels of IGF1 are associated with muscle strength in middle-aged- and oldest-old women.

OBJECTIVE: In aging populations, poor handgrip strength has been associated with physical disability and mortality. IGF1 is an important mediator of muscle growth and regeneration affecting muscle function. We studied the relationship between circulating levels of IGF1, its binding protein 3 (IGFBP3), and handgrip strength and physical performance in middle-aged- and oldest-old subjects. DESIGN: Cross-sectional analysis in two different cohorts composed of middle-aged- (n = 672, mean 63.9 ± 6.7 years) and oldest-old subjects (n = 272, all 89 years). METHODS: Handgrip strength, functional performance and ability, and serum levels of IGF1 and IGFBP3 were measured in all subjects and analyzed by linear regression for men and women separately. RESULTS: IGF1 and IGFBP3 levels declined with chronological age and were positively associated with handgrip strength in middle-aged- and oldest-old women (both, P < 0.05), but not in men of either age group. Furthermore, higher serum levels of IGF1 were associated with slower walking speed in oldest-old men (P = 0.012), and serum levels of IGFBP3 were positively associated with activities of daily living in the oldest-old women (P = 0.002). CONCLUSION: The significant relationship between IGF1 levels and muscle strength found in women but not in men suggests a gender-specific influence of IGF1 on muscle strength. Further studies are necessary to test the relationship with physical performance.

Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old.

BACKGROUND: muscle wasting is associated with a detrimental outcome in older people. Muscle strength measurements could be useful as part of a clinical evaluation of oldest old patients to determine who are most at risk of accelerated decline in the near future. OBJECTIVE: this study aimed to assess if handgrip strength predicts changes in functional, psychological and social health among oldest old. DESIGN: the Leiden 85-plus Study is a prospective population-based follow-up study. SUBJECTS: five-hundred fifty-five, all aged 85 years at baseline, participated in the study. METHODS: handgrip strength was measured with a handgrip strength dynamometer. Functional, psychological and social health were assessed annually. Baseline data on chronic diseases were obtained from the treating physician, pharmacist, electrocardiogram and blood sample analysis. RESULTS: at age 85, lower handgrip strength was correlated with poorer scores in functional, psychological and social health domains (all, P < 0.001). Lower baseline handgrip strength predicted an accelerated decline in activities of daily living (ADL) and cognition (both, P 0.30). CONCLUSION: poor handgrip strength predicts accelerated dependency in ADL and cognitive decline in oldest old. Measuring handgrip strength could be a useful instrument in geriatric practice to identify those oldest old patients at risk for this accelerated decline.

Handgrip strength and mortality in the oldest old population: the Leiden 85-plus study.

BACKGROUND: Poor muscular strength has been shown to be associated with increased morbidity and mortality in diverse samples of middle-aged and elderly people. However, the oldest old population (i.e., over 85 years) is underrepresented in such studies. Our objective was to assess the association between muscular strength and mortality in the oldest old population. METHODS: We included 555 participants (65% women) from the Leiden 85-plus study, a prospective population-based study of all 85-year-old inhabitants of Leiden, Netherlands. We measured the handgrip strength of participants at baseline and again at age 89 years. We collected baseline data on comorbidities, functional status, levels of physical activity, and adjusted for potential confounders. During the follow-up period, we collected data on mortality. RESULTS: During a follow-up period of 9.5 years (range 8.5-10.5 years), 444 (80%) participants died. Risk for all-cause mortality was elevated among participants in the lowest tertile of handgrip strength at age 85 years (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.00-1.82, p = 0.047) and the lowest two tertiles of handgrip strength at age 89 years (HR 2.04, CI 1.24-3.35, p = 0.005 and HR 1.73, CI 1.11-2.70, p = 0.016). We also observed significantly increased mortality among participants in the tertile with the highest relative loss of handgrip strength over four years (HR 1.72, CI 1.07-2.77, p = 0.026). INTERPRETATION: Handgrip strength, a surrogate measurement of overall muscular strength, is a predictor of all-cause mortality in the oldest old population and may serve as a convenient tool for prognostication of mortality risk among elderly people.

High innate production capacity of tumor necrosis factor-alpha and decline of handgrip strength in old age.

Increased signaling of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) elicits apoptosis of skeletal muscle cells in various animal models. Within a population-based prospective follow up study of elderly people aged 85 years we show that a high innate production capacity of TNF-alpha precedes a steeper decline in muscle strength over time.