Malnutrition in Very Old Hospitalized Patients: A New Etiologic Factor of Anemia?

BACKGROUND: Anemia and malnutrition are highly prevalent, frequently concomitant and associated with negative outcomes and mortality in the elderly. OBJECTIVES: To evaluate the association between these two entities, and test the hypothesis that protein-energy deficit could be etiology of anemia. DESIGN: Prospective case-control study. SETTING: Geriatric and Rehabilitation Hospital, Geneva University Hospitals, Switzerland. PARTICIPANTS: 392 patients (mean age 84.8 years old, 68.6% female). MAIN OUTCOME MEASURES: Hematological (hemoglobin (Hb)), chemical (iron work up, cyanocobalamin, folates, renal function, C-Reactive Protein (CRP)) and nutrition (albumin, prealbumin) parameters, and mini nutritional assessment short form (MNA-SF). RESULTS: The prevalence of anemia (defined as Hb<120 g/l) was 39.3%. Anemic patients were more frequently malnourished or at risk of malnutrition according to the MNA-SF (p=0.047), with lower serum albumin (p <0.001) and prealbumin (p <0.001) levels. Thirty-eight percent of these patients had multiple causes and 14.3% had no cause found for anemia. Among the latter 90.9% of patients with unexplained anemia had albumin levels lower than 35g/l. After exclusion of iron,vitamin B12 and folic acid deficits, anemic patients had lower albumin (p<0.001) and prealbumin (p 0.007) levels. Albumin level explained 84.5% of the variance in anemia. In multivariate analysis albumin levels remain associated with Hb only in anemic patients, explaining 6.4% of Hb variance (adj R2) and 14.7% (adj R2) after excluding inflammatory parameters (CRP>10). CONCLUSIONS: Albumin levels are strongly associated with anemia in the elderly. Screening for undernutrition should be included in anemia assessment in those patients. Further prospective studies are warranted in order to explore the effect of protein and energy supplementation on hemoglobin level.

Hypothermia is a frequent sign of severe hypoglycaemia in patients with diabetes.

AIM: Hypothermia is a recognized complication of severe hypoglycaemia, but its prevalence and characteristics are poorly studied. For this reason, this study aimed to evaluate hypothermia in severely hypoglycaemic patients. METHODS: A retrospective chart review was performed including all patients discharged between 2007 and 2010 from the Emergency Department of the Geneva University Hospital with a diagnosis of severe hypoglycaemia. RESULTS: Hypothermia was identified in 30 (23.4%) out of 128 patients with severe hypoglycaemia. Its incidence was not affected by age, type of diabetes, season or time of day (day/night). Using linear regression, the lowest recorded temperature was associated with the Glasgow coma scale (GCS) score (r2 = 13.8%, P < 0.0001) and inversely associated with the leukocyte count (r2 = 13.1%, P = 0.001). CONCLUSION: Hypothermia is a frequent sign of severe hypoglycaemia in patients with diabetes. The associations between hypothermia and the GCS score and the leukocyte count suggest that it is a marker of hypoglycaemia severity and/or duration. Hypothermia may represent an important compensatory mechanism in severe hypoglycaemia, reflecting a decrease in energy demand during glucose deprivation.

Diabetes, comorbidities and increased long-term mortality in older patients admitted for geriatric inpatient care.

AIMS: To study the specific impact of diabetes on long-term mortality in very old subjects with multiple comorbidities and functional disabilities. METHODS: The prevalence of vascular disorders, global comorbidity load (cumulative illness rating scale [CIRS]) and functional disabilities (activities of daily living [ADL] and Lawton's instrumental ADL [IADL] scores) were determined according to diabetes status in a cohort of 444 patients (mean age 85.3±6.7 years; 74.0% women) admitted to our geriatric service. Also, the specific impact of diabetes on 4-year mortality was analyzed using Cox proportional-hazards models. RESULTS: Diabetic patients had higher BMI scores (27.1±4.9 vs. 23.4±4.7 kg/m(2) in controls; P<0.001), and higher prevalences of hypertension (81.9% vs. 65.1%, respectively; P=0.003) and ischaemic heart disease (33.7% vs. 22.2%, respectively; P=0.033), but not of stroke and renal insufficiency. They also had more comorbidities (CIRS score excluding diabetes: 15.1±4.5 vs. 13.8±4.8, respectively; P=0.016) and functional disabilities. Diabetes was associated with mortality (HR: 1.42, 95% CI: 1.02-1.99; P=0.041) after adjusting for age, gender and BMI, and this persisted after adjusting for individual vascular comorbidities, but disappeared after adjusting for CIRS, ADL or IADL scores. CONCLUSION: Diabetes was associated with 4-year mortality after adjusting for the inverse relationship between mortality and BMI. This association was better accounted for by the global comorbidity load and functional disabilities than by the individual vascular comorbidities. These findings suggest that the active management of all--rather than selected--comorbidities is the key to improving the prognosis for older diabetic patients.

[How to prevent severe hypoglycemia in older patients with type 2 diabetes]. / Hypoglycémie sévère chez le patient diabétique de type 2 âgé: quelle prévention?

Severe hypoglycemia is a feared complication of treatment in older diabetic patients (> 75 years) and a limiting factor for good glycemic control. Its real incidence is not well studied and probably underestimated. Cognitive impairment, malnutrition and/or cachexia, polypharmacy and a recent hospitalization are risk factors for severe hypoglycemia specific for older patients. Cognitive impairment screening can identify patients unable to manage their treatment. Simplification of treatment and/or transferring its execution to relatives must then be considered. Prevention also involves the detection of malnutrition and comorbidities, Age-adjusted therapeutic targets (HbA1c 7-8%) are important to avoid an exceedingly strict glycemic control. However, giving up on good glycemic control is not an adequate prevention strategy in itself.

[The treatment of hypertension in the elderly : can it be done safely?]. / Enjeux et limites du traitement de l'hypertension artérielle chez la personne très âgée.

The treatment of arterial hypertension is important for the prevention of stroke and heart failure even in very old hypertensive patients, but represents a challenge in terms of safety and quality of life. Confirmation of the diagnosis with 24-hour ambulatory blood pressure (BP) monitoring or BP monitoring at home is important. A systolic BP of 150 mmHg (135-140 mmHg with out-of-office measures) is an acceptable cut-off value for both the diagnosis of hypertension and as a target for treatment. The fear of drug-induced orthostatic hypotension is only rarely a reason not to treat. However, in the context of co-morbidities, the risk of other side effects is considerable. Blood pressure may decrease over time, reducing the requirements for anti-hypertensive therapy. Cautious drug prescription, avoiding exceedingly intensive treatments plans, is important for treatment adequacy and safety.

The prevalence, characteristics and metabolic consequences of renal insufficiency in very old hospitalized diabetic patients.

AIMS: We aimed to characterize the determinants and characteristics of renal disease in very old diabetic patients in geriatric care. METHODS: Consecutive diabetic patients (96 women, 38 men) admitted to a geriatric service were studied. Glomerular filtration rate (GFR), albuminuria, vascular and general comorbidities, glycaemic control, malnutrition (using the Mini-Nutritional Assessment [MNA], serum albumin and cholesterol levels), haemoglobin and inflammation (CRP levels) were assessed. RESULTS: (a) 51.2 and 12.4% patients had moderate or severe renal insufficiency. The prevalence of normo-, micro- and macroalbuminuria was 45.0, 38.9 and 16.0% in the whole population, and was similar in patients with or without moderate renal insufficiency. Renal insufficiency was associated with previous stroke (P=0.024), heart failure (P=0.024), and atrial fibrillation (P=0.008), and possibly myocardial infarction (P=0.059, Mann-Whitney test). (b) Albuminaemia was associated with albuminuria, MNA scores, haemoglobin, total and HDL-cholesterol and CRP. However, in multiple linear regression analysis CRP was the only robust determinant of albuminaemia (P<0.0001). (c) Renal insufficiency was not associated with the MNA, serum albumin, haemoglobin and cholesterol levels. CONCLUSION: Renal insufficiency often occurs without albuminuria, suggesting aetiologies distinct from classical diabetic nephropathy, and is strongly associated with vascular comorbidities. Hypoalbuminaemia is more strongly associated with inflammation than with albuminuria and malnutrition. Malnutrition, hypoalbuminaemia, low cholesterol levels and anaemia are not associated with renal insufficiency, likely due to the very high prevalence of these abnormalities in the whole population. These features must be taken into account when organizing the global care of elderly diabetic patients.

The high prevalence of malnutrition in elderly diabetic patients: implications for anti-diabetic drug treatments.

BACKGROUND: Type 2 diabetes usually occurs in the context of obesity and associated insulin resistance. Current treatment recommendations are based on lifestyle modifications and incremental drug therapy. However, this approach could lead to inappropriate priorities upon ageing, when diabetes may be compounded by malnutrition and reduced insulin resistance. METHODS: We prospectively evaluated glycaemic and nutritional parameters in 146 consecutive diabetic patients (age 82.5 +/- 7.3 years, mean +/- sd) admitted to our geriatric service. We also implemented nutritional support therapy and a drug therapy adjustment protocol. Oral hypoglycaemic agent withdrawal was attempted in cases of good glycaemic control (HbA(1c) < 7.5% (<47 mmol/mol) or fasting blood glucose < 7.5 mmol/l). RESULTS: Mean BMI and HbA(1c) were 29.6 +/- 7.1 kg/m(2) and 6.9 +/- 1.2% (52 +/- 9 mmol/mol), respectively. Of the patients, 51.4% were taking 1-3 oral hypoglycaemic agents, 30.8% were on insulin and 9.6% on were on insulin and oral hypoglycaemic therapy. Low Mini Nutritional Assessment scores and serum marker levels indicated a high prevalence of malnutrition and/or chronic disease, even in obese patients. Mini Nutritional Assessment scores were positively associated with HbA(1c) values. Among patients treated by oral hypoglycaemic agents, complete drug withdrawal was achieved in 65.8%, much more often than new treatments were added (P = 0.002). Glycaemic control did not worsen after approximately 30 days, despite in-hospital nutritional therapy. Successful oral hypoglycaemic therapy withdrawal was associated with lower Mini Nutritional Assessment scores. CONCLUSIONS: Malnutrition is highly prevalent in elderly diabetic inpatients and, paradoxically, contributes to 'good' glycaemic control. Malnutrition should be screened for in these patients and, when present, should prompt a revision in diet and drug therapy. In particular, the possibility of reducing unnecessary drug therapy should be considered.

Key priorities in managing glucose control in older people with diabetes.

Older people with diabetes represent a major and increasing proportion of our elderly population and their care requires better organisation. Targets for risk factor control and pathways of care must be adjusted to the subject's general health status. It is thus advisable to screen for frailty. We have carried out a detailed literature review of the studies published on diabetes in older people since 1990. Studies were considered if they included groups or subgroups of diabetic patients > 65 years old. This review discusses the elaboration of general targets for care, the approach to risk factor control, the screening and the specific prevention or management of complications, the integration of geriatric concepts in diabetes care and the specificity of education with respect to frailty status.

A call to incorporate the prevention and treatment of geriatric disorders in the management of diabetes in the elderly.

The prevalence of type 2 diabetes increases with age. However, the management of diabetes in the elderly has received surprisingly little attention. Diabetes in the elderly is associated with a high risk of geriatric syndromes including malnutrition and sarcopenia, functional impairments, falls and fractures, incontinence, depression and dementia. Tight glycaemic control for the prevention of vascular complications is often of limited value in the elderly. However, glycaemic control and non-pharmacological therapy may prevent diabetes symptoms and delay geriatric syndromes. The prevention, screening and treatment of both conventional diabetic complications and geriatric syndromes should be integrated in a management plan to optimize the patients' overall health status and quality of life.

Cardiometabolic determinants of mortality in a geriatric population: is there a "reverse metabolic syndrome"?

AIMS: Diabetes or insulin resistance, overweight, arterial hypertension, and dyslipidaemia are recognized risk factors for cardiovascular (CV) disease. However, their predictive value and hierarchy in elderly subjects remain uncertain. METHODS: We investigated the impact of cardiometabolic risk factors on mortality in a prospective cohort study of 331 elderly high-risk subjects (mean age+/-SD: 85+/-7 years). RESULTS: Two-year total mortality was predicted by age, diabetes, low BMI, low diastolic blood pressure (DBP), low total and HDL cholesterol, and previous CV events. The effect of diabetes was explained by previous CV events. In non-diabetic subjects, mortality was predicted by high insulin sensitivity, determined by HOMA-IR and QUICKI indices. In multivariate analyses, the strongest mortality predictors were low BMI, low HDL cholesterol and previous myocardial infarction. Albumin, a marker of malnutrition, was associated with blood pressure, total and HDL cholesterol, and HOMA-IR. The inflammation marker CRP was associated with low total and HDL cholesterol, and high HOMA-IR. CONCLUSION: In very old patients, low BMI, low DBP, low total and HDL cholesterol, and high insulin sensitivity predict total mortality, indicating a "reverse metabolic syndrome" that is probably attributable to malnutrition and/or chronic disorders. These inverse associations limit the relevance of conventional risk factors. Previous CV events and HDL cholesterol remain strong predictors of mortality. Future studies should determine if and when the prevention and treatment of malnutrition in the elderly should be incorporated into conventional CV prevention.

Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine.

BACKGROUND: Vascular endothelial growth factor (VEGF) and histamine induce von Willebrand factor (VWF) release from vascular endothelial cells. Protein kinase C (PKC) is involved in the control of exocytosis in many secretory cell types. OBJECTIVES: We investigated the role of PKC and the interactions between PKC and Ca2+ signaling in both VEGF-induced and histamine-induced VWF secretion from human umbilical vein endothelial cells (HUVECs). RESULTS: Several PKC inhibitors (staurosporine, Ro31-8220, myristoylated PKC peptide inhibitor and Go6983) block VEGF-induced but not histamine-induced VWF secretion. PKC-alpha and novel PKCs (PKC-delta, PKC-epsilon, and PKC-eta), but not PKC-beta, are expressed in HUVECs. Both VEGF and histamine activate PKC-delta. However, gene inactivation experiments using small interfering RNA indicate that PKC-delta (but not PKC-alpha) is involved in the regulation of VEGF-induced but not histamine-induced secretion. Both VEGF and histamine induce a rise in cytosolic free Ca2+ ([Ca2+]c), but the response to VEGF is weaker and even absent in a significant subset of cells. Furthermore, VEGF-induced secretion is largely preserved when the rise in [Ca2+]c is prevented by BAPTA-AM. CONCLUSIONS: Our study identifies striking agonist specificities in signal-secretion coupling. Histamine-induced secretion is dependent on [Ca2+]c but not PKC, whereas VEGF-induced secretion is largely dependent on PKC-delta and significantly less on [Ca2+]c. Our data firmly establish the key role of PKC-delta in VEGF-induced VWF release, but suggest that a third, VEGF-specific, signaling intermediate is required as a PKC-delta coactivator.

Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors.

OBJECTIVE: von Willebrand factor (VWF) is acutely released from endothelial cells in response to numerous calcium-raising agents (e.g. thrombin, histamine) and cAMP-raising agents (e.g. epinephrine, adenosine, vasopressin). In contrast, very few inhibitors of endothelial VWF secretion have been described. The neurotransmitter dopamine is a modulator of exocytosis in several endocrine cells, and is possibly involved in the regulation of several endothelial cell functions. We therefore investigated the effect of dopamine on endothelial VWF secretion. RESULTS: Dopamine, D2/D3- and D4-specific agonists inhibited histamine- but not thrombin-induced VWF secretion. Expression of dopamine D2, D3 and D4 receptors was demonstrated by reverse transcription polymerase chain reaction (RT-PCR) in both human aortic (HAEC) and umbilical vein (HUVEC) endothelial cells. D2-D4 agonists did not inhibit histamine-induced rise in [Ca(2+)](i): they inhibited histamine-induced secretion even in the absence of extracellular calcium. Thus, the dopamine effects are not mediated by [Ca(2+)](i)-dependent signalling. D2/D3- and D4-specific agonists inhibited neither the rise in cAMP nor VWF secretion in response to epinephrine and adenosine, arguing against an effect on cAMP-mediated signalling. D1 and D5 receptors were not detected in HAEC or HUVEC by RT-PCR, and the D1/D5-specific agonist SKF 38 393 failed to modulate VWF secretion, arguing against a role for these receptors in endothelial exocytosis. CONCLUSIONS: Dopamine inhibits histamine-induced endothelial exocytosis by activating D2-D4 receptor, via a mechanism distinct from [Ca(2+)](i)-or cAMP-mediated signaling. In contrast, D1 and D5 receptors are not functionally expressed in cultured endothelial cells. Dopamine agonists may be useful as inhibitors of endothelial activation in inflammation and cardiovascular disease.

Insulinemia and leptinemia in geriatric patients: markers of the metabolic syndrome or of undernutrition?

The metabolic syndrome (MS) describes a cluster of metabolic disturbances including type 2 diabetes and/or insulin resistance, hypertension, dyslipidemia and obesity, which predict a high risk of cardiovascular disorders. The associated hyperinsulinemia and hyperleptinemia may contribute to the cardiovascular risk. However, the operational value of the MS in elderly patients is questionable. We therefore investigated the prevalence and significance of the MS in geriatric care. In a survey of 98 consecutive admissions of diabetic patients, <40% had a MS; this is a low value compared to younger diabetic adults, due to a low prevalence of obesity and dyslipidemia. We found a high prevalence of low BMI (<20 kg/m2), hypoalbuminemia and low total cholesterol levels, suggesting that the MS may be modified by undernutrition. The interplay between the MS and undernutrition was further studied in 30 non-diabetic patients. Both leptinemia and insulin resistance indexes (HOMA-IR and QUICKI) were strongly associated with BMI and body fat (measured by Bioelectrical impedance Analysis). BMI, leptinemia and insulin resistance indexes were associated with the Mini Nutritional Assessment (MNA) score. Thus, undernutrition is associated with low leptin and insulin levels and may obscure the association of these parameters with cardiovascular risk. In conclusion, the MS has a low prevalence in our population of elderly diabetic patients, and is of questionable prognostic value. It can be oveshadowed by undernutrition, which is associated with low body weight, leptinemia and insulin resistance indexes. Prevention of undernutrition and/or adjustment to its consequences should receive higher priority in the care of elderly diabetic patients.

[When can the treatment of isolated systolic hypertension be avoided?]. / Hypertension artérielle systolique isolée chez la personne âgée: faut-il toujours traiter?

The treatment of isolated systolic hypertension (ISH) in the elderly reduces the cardiovascular (CV) risk, in particular in patients with diabetes or previous CV events. However, in the very old (> 80-85 years) the treatment of ISH may increase global mortality, although it still decreases the risk of stroke. The benefits of treatment on the risk of dementia remain uncertain. To verify the indication for therapy, the diagnosis of ISH should be confirmed by ambulatory blood pressure monitoring. Since the absolute benefit of treatment is related to its duration, a limited life expectancy may restrict the real impact of treatment. The advantages and limitations of anti-hypertensive therapy in the elderly should be discussed individually, respecting the patient's autonomy.

von Willebrand factor, endothelial dysfunction, and cardiovascular disease.

von Willebrand factor (VWF), a glycoprotein involved in arterial thrombus formation, is released into the circulation by secretion from endothelial cells. Plasma VWF levels are determined by genetic factors including ABO blood groups and VWF mutations, and by non-genetic factors including aging, impaired nitric oxide production, inflammation, free radical production and diabetes. Plasma VWF levels have been proposed as a risk factor for cardiovascular events. Although they are only weakly associated with the risk of coronary heart disease (CHD) in the general population, they are a more promising CHD risk factor in high-risk populations with previous cardiovascular events, diabetes or old age. However, is it still unclear whether VWF levels directly determine the rate and severity of arterial thrombus formation or whether they merely reflect alteration in other endothelial functions. The future status of VWF levels as a cardiovascular risk factor depends on additional studies on the genetic determinants of both VWF levels and cardiovascular outcomes. Further studies on VWF levels as a predictor of the risk of stroke (rather than CHD) in elderly or other high-risk population are also promising. Such studies could lead to the clinical use of plasma VWF levels to refine the estimation of the cardiovascular risk and of the expected benefit of antithrombotic agents.

Major lower limb amputations in the elderly observed over ten years: the role of diabetes and peripheral arterial disease.

BACKGROUND: Major amputation is a dreaded event with high mortality and morbidity. However, few studies have investigated the epidemiology of amputation in the elderly over time, in the face of evolving management and prevention efforts. METHODS: We undertook a retrospective study to determine the incidence rate, etiology and prognosis of major lower limb amputations (transtibial or higher) in elderly patients (> 65 years). Cases were identified over a 10-year period in the Geneva (Switzerland) area, where all amputations are performed in a single center and reliable demographic data are available. RESULTS: The rate of amputation varied from 1.8 to 11.4/10000 patients/year, increasing with age and male gender. Diabetes was present in 48% patients, and conferred a 10 times higher risk of amputation. Severe peripheral arterial disease (PAD) was present in > 94% patients. The prognosis remains poor, 47% patients had died after two years and only 53% patients could be equipped with a prosthetic limb. Over 10 years we found a progressive increase in age at amputation; this encouraging increase was mostly accounted for by diabetic patients (> 6 months per year). CONCLUSIONS: The rate of amputation observed among elderly patients was low. Neither the rate nor the prognosis improved over the decade studied. However, the age at amputation increased by > 6 months/year, particularly in diabetic amputees, suggesting that current management successfully delays amputation. Amputations were almost exclusively performed for severe PAD. Further reduction in the rate of amputation will require progress in the prevention and management of PAD.

Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP).

The synthetic analog of vasopressin desmopressin (DDAVP) is widely used for the treatment of patients with von Willebrand disease (VWD), hemophilia A, several platelet disorders, and uremic bleeding. DDAVP induces an increase in plasma levels of von Willebrand factor (VWF), coagulation factor VIII (FVIII), and tissue plasminogen activator (t-PA). It also has a vasodilatory action. In spite of its extensive clinical use, its cellular mechanism of action remains incompletely understood. Its effect on VWF and t-PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium, via activation of endothelial vasopressin V2R receptor and cAMP-mediated signaling. This leads to exocytosis from Weibel Palade bodies where both VWF and t-PA are stored, as well as to nitric oxide (NO) production via activation of endothelial NO synthase. The mechanism of action of DDAVP on FVIII plasma levels remains to be elucidated. The hemostatic effect of DDAVP likely involves additional cellular effects that remain to be discovered.

Desmopressin (DDAVP) induces NO production in human endothelial cells via V2 receptor- and cAMP-mediated signaling.

The hemostatic agent desmopressin (DDAVP) also has strong vasodilatory effects. DDAVP is a selective agonist for the vasopressin V2 receptor (V2R), which is coupled to cAMP-dependent signaling. DDAVP-induced vasodilation may be due to endothelial NO synthase (eNOS) activation. This hypothesis implies cAMP-mediated eNOS activation. It also implies wide extrarenal, endothelial V2R expression. We show that in human umbilical vein endothelial cells (HUVECs) the cAMP-raising agents forskolin and epinephrine increase NO production, as measured by a l-NMMA-inhibitable rise in cellular cGMP content. They also increase eNOS enzymatic activity, in a partly calcium-independent manner. cAMP-mediated eNOS activation is associated with phosphorylation of residue Ser1177, in a phosphatidyl inositol 3-kinase (PI3K)-independent manner. HUVECs do not express V2R. However, after heterologous V2R expression, DDAVP induces cAMP-dependent eNOS activation via Ser1177 phosphorylation. We have previously found V2R expression in cultured lung endothelial cells. By real time quantitative RT-PCR, we now find a wide V2R distribution notably in heart, lung and skeletal muscle. These results indicate that DDAVP and other cAMP-raising agents can activate eNOS via PI3K-independent Ser1177 phosphorylation in human endothelial cells. This mechanism most likely accounts for DDAVP-induced vasodilation.