A Patient Reported Experience Measure (PREM) for use by older people in community services.

BACKGROUND: intermediate care (IC) services operate between health and social care and are an essential component of integrated care for older people. Patient Reported Experience Measures (PREMs) offer an objective measure of user experience and a practical way to measure person-centred, integrated care in IC settings. OBJECTIVE: to describe the development of PREMs suitable for use in IC services and to examine their feasibility, acceptability and scaling properties. SETTING: 131 bed-based and 143 home-based or re-ablement IC services in England. METHODS: PREMs for each of home- and bed-based IC services were developed through consensus. These were incorporated into the 2013 NAIC and distributed to 50 consecutive users of each bed-based and 250 users of each home-based service. Return rates and patterns of missing data were examined. Scaling properties of the PREMs were examined with Mokken analysis. RESULTS: 1,832 responses were received from users of bed-based and 4,627 from home-based services (return rates 28 and 13%, respectively). Missing data were infrequent. Mokken analysis of completed bed-based PREMs (1,398) revealed 8 items measuring the same construct and forming a medium strength (Loevinger H 0.44) scale with acceptable reliability (ρ = 0.76). Analysis of completed home-based PREMs (3,392 records) revealed a medium-strength scale of 12 items (Loevinger H 0.41) with acceptable reliability (ρ = 0.81). CONCLUSIONS: the two PREMs offer a method to evaluate user experience of both bed- and home-based IC services. Each scale measures a single construct with moderate scaling properties, allowing summation of scores to give an overall measure of experience.

Suppression of sympathetic nervous system during fasting.

Two days of fasting in rats significantly reduces the turnover of norepinephrine in the heart. In contrast to the effects of ganglionic blockade in fed controls, similar blockade in fasted animals is without significant effect on [3H]-norepinephrine retention or endogenous norepinephrine in the heart. These data are consistent with suppression of centrally mediated sympathetic activity in the fasted state. The decrease in norepinephrine turnover during fasting is completely reversed by 1 day of refeeding.

Hypotensive effect of fasting: possible involvement of the sympathetic nervous system and endogenous opiates.

Fasting lowers blood pressure to a greater extent in spontaneously hypertensive rats than in normotensive rats. While fasting reduced cardiac sympathetic activity to an equivalent extent in both groups of animals, only in the hypertensive rats did fasting elicit an opiate-mediated vasodepressor response that was independent of sympathetic withdrawal. Both sympathetic nervous system suppression and endogenous opiate activation, therefore, may contribute to the hypotensive effect of fasting in the spontaneously hypertensive rat.

Reduced sympathetic nervous system responsivity associated with the relaxation response.

Sympathetic nervous system activity was assessed in experimental and control subjects who were exposed to graded orthostatic and isometric stress during monthly hospital visits. After the first session, the experimental subjects practiced a technique that elicited the relaxation response. Their concentrations of plasma norepinephrine during subsequent graded stresses were significantly higher. No such changes were noted in the control group. These results were than replicated in the control group in a crossover experiment. The groups did not differ in their heart rate and blood pressure responses. These observations are consistent with reduced norepinephrine end-organ responsivity after regular elicitation of the relaxation response.

Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse.

Sympathetic activity in rats and mice is diminished by fasting and increased by sucrose feeding. The central neural mechanisms coordinating changes in the functional state of sympathetic nerves with changes in dietary intake are unknown, but a role for neurons in the ventromedial hypothalamus (VMH) is suggested by the existence of sympathetic connections within the VMH and the importance of this region in the regulation of feeding behavior. To investigate the potential role of the VMH in dietary regulation of sympathetic activity [(3)H]norepinephrine turnover was measured in the hearts of fasted and sucrose-fed mice after treatment with gold thioglucose (AuTG). In control mice, norepinephrine (NE) turnover was 1.60+/-0.92 ng NE/heart per h (95% confidence limits) after 1 d of fasting and 4.58+/-0.98 after 3 d of sucrose feeding, although, in AuTG-treated mice, cardiac NE turnover in fasting was 5.45+/-1.56 and with sucrose feeding, 5.44+/-0.76. Experiments with ganglionic blockade indicate that the absence of dietary effect on NE turnover in AuTG-treated mice reflects a corresponding lack of change in central sympathetic outflow. AuTG administration, therefore, disrupts dietary regulation of sympathetic activity by abolishing the suppression of sympathetic activity that occurs with fasting. This effect of AuTG is unrelated to duration of fasting (up to 3 d) and is specific for AuTG because neither treatment with another gold thio compound (gold thiomalate) nor the presence of genetic obesity (ob/ob) prevented fasting suppression of sympathetic activity. Moreover, AuTG treatment did not impair sympathetic activation by cold exposure (4 degrees C) nor adrenal medullary stimulation by 2-deoxy-d-glucose. Thus, AuTG treatment selectively impairs dietary regulation of sympathetic activity, possibly by destruction of neurons in the VMH.

Sympathoadrenal activity in fasting pregnant rats. Dissociation of adrenal medullary and sympathetic nervous system responses.

The pattern of urinary catecholamine excretion in fasting differs in pregnant and nonpregnant rats, which suggests that the sympathoadrenal response to fasting is altered by pregnancy. In fasting nonpregnant animals, urinary norepinephrine (NE) excretion decreases and epinephrine (E) excretion remains unchanged, whereas the excretion of both catecholamines rises significantly with refeeding. In contrast, fasting third-trimester pregnant rats exhibit a 420% increase in urinary E and a 345% increase in urinary NE, elevations which fall with refeeding. Specific evaluation of sympathoadrenal activity in fasting pregnant rats reveals stimulation of the adrenal medulla and suppression of sympathetic nerves. In fasting third-trimester rats the adrenal content of E is 37% lower in innervated adrenals as compared with contralateral denervated glands, which indicates the presence of neurally-mediated adrenal medullary activation. Adrenalectomy completely abolishes the fasting-induced rise in urinary E and NE in pregnant rats. Studies with 2-deoxy-D-glucose suggest that stimulation of the adrenal medulla results from hypoglycemia, which is present after 3 d of fasting in pregnant rats (plasma glucose 36.7 mg/dl). Sympathetic nervous system activity, as measured by [(3)H]NE turnover in the heart, decreases in fasting pregnant rats despite hypoglycemia, a response similar to that seen in fasting nonpregnant animals where plasma glucose is maintained above 50 mg/dl. The calculated NE turnover rate is 44% lower in 2-d fasted pregnant rats than in fed pregnant animals (17.6 +/- 1.3 vs. 31.3 +/- 1.8 ng NE/heart per h, respectively). Thus adrenal medullary and sympathetic nervous system responses in fasting pregnant rats appear to be dissociated, which suggests that diet-induced changes in sympathetic activity and stimulation of the adrenal medulla by hypoglycemia may be independently regulated.

Effect of protein on sympathetic nervous system activity in the rat. Evidence for nutrient-specific responses.

Increased energy intake activates the sympathetic nervous system (SNS) in animals and man. While dietary carbohydrate and fat stimulate, the impact of dietary protein on the SNS is not well defined. The present studies examine the effect of protein ingestion on sympathetic function based upon the measurement of [3H]norepinephrine (NE) turnover in heart and interscapular brown adipose tissue (IBAT) as the index of SNS activity. In these experiments, animals were pair-fed mixtures of laboratory chow and refined preparations of casein, sucrose, and lard to permit comparisons among nutrients with total energy intake held constant or with additional energy provided in the form of a single nutrient. After 5 d of eating a 2:1 mixture of chow and either casein or sucrose cardiac, [3H]NE turnover was less (P less than 0.005) in casein-fed rats (6.4%/h and 28.9 ng NE/h) than in animals given sucrose (11.2%/h and 46.5 ng NE/h). Similar results were obtained in IBAT and in experiments using 1:1 mixtures of chow and casein/sucrose. Casein-fed animals also displayed slower rates of NE turnover than lard-fed rats in both heart (7.8%/h vs. 13.2, P less than 0.001) and IBAT (7.0%/h vs. 12.8, P less than 0.01). Addition of casein (50% increase in energy intake) to a fixed chow ration raised NE turnover slightly, but not significantly, in heart (an average increase of 15% in six experiments). Thus, in distinction to SNS activation seen with dietary carbohydrate or fat, the SNS response to dietary protein is minimal in both heart and IBAT, indicating that the effect of increased energy intake on the SNS is dependent upon diet composition.

Sympathoadrenal responses to acute and chronic hypoxia in the rat.

The sympathoadrenal responses to acute and chronic hypoxic exposure at 10.5 and 7.5% oxygen were determined in the rat. Cardiac norepinephrine (NE) turnover was used to assess sympathetic nervous system (SNS) activity, and urinary excretion of epinephrine (E) was measured as an index of adrenal medullary activity. The responses of the adrenal medulla and SNS were distinct and dependent upon the degree and duration of hypoxic exposure. Chronic hypoxia at 10.5% oxygen increased cardiac NE turnover by 130% after 3, 7, and 14 d of hypoxic exposure. Urinary excretion of NE was similarly increased over this time interval, while urinary E excretion was marginally elevated. In contrast, acute exposure to moderate hypoxia at 10.5% oxygen was not associated with an increase in SNS activity; in fact, decreased SNS activity was suggested by diminished cardiac NE turnover and urinary NE excretion over the first 12 h of hypoxic exposure, and by a rebound increase in NE turnover after reexposure to normal oxygen tension. Adrenal medullary activity, on the other hand, increased substantially during acute exposure to moderate hypoxia (2-fold increase in urinary E excretion) and severe hypoxia (greater than 10-fold). In distinction to the lack of effect of acute hypoxic exposure (10.5% oxygen), the SNS was markedly stimulated during the first day of hypoxia exposure at 7.5% oxygen, an increase that was sustained throughout at least 7 d at 7.5% oxygen. These results demonstrate that chronic exposure to moderate and severe hypoxia increases the activity of the SNS and adrenal medulla, the effect being greater in severe hypoxic exposure. The response to acute hypoxic exposure is more complicated; during the first 12 h of exposure at 10.5% oxygen, the SNS is not stimulated and appears to be restrained, while adrenal medullary activity is enhanced. Acute exposure to a more severe degree of hypoxia (7.5% oxygen), however, is associated with stimulation of both the SNS and adrenal medulla.

Effect of dietary fat on sympathetic nervous system activity in the rat.

Previous studies from our laboratory have demonstrated that dietary intake affects the sympathetic nervous system (SNS); carbohydrate intake, in particular, has been shown to stimulate sympathetic activity. The present studies were undertaken to characterize the effect of dietary fat on SNS activity in the rat. Sympathetic activity was assessed by measurement of norepinephrine (NE) turnover in heart, interscapular brown adipose tissue (IBAT), and pancreas and by excretion of NE in the urine. When fed a fat-enriched diet (50% chow, 50% lard), fractional NE turnover in heart (k) increased from 6.3 +/- 0.6% h in ad lib. fed controls to 14.7 +/- 1.3% h in the high-fat group (P less than 0.001); calculated NE turnover rate increased from 24.5 +/- 2.4 ng/heart per h to 36.8 +/- 3.5 (P less than 0.05). Urinary NE excretion more than doubled after 6 d of the same high fat diet (P less than 0.001). Ganglionic blockade produced a greater effect on NE turnover in fat-fed, as compared with chow-fed animals, consistent with increased sympathetic activity in the fat-fed group. When fat absorption was blocked with a bile acid binding resin (cholestyramine), the same high-fat diet did not increase cardiac NE turnover, indicating that fat absorption is required for the stimulatory effect on sympathetic activity. In another series of experiments, in which chow (and hence protein) intake was held constant, the effect of fat and isocaloric sucrose supplements on NE turnover was assessed in heart, IBAT, and pancreas. The caloric value of the supplements was 50, 100, and 335% of the chow in the different experiments. An effect of fat on NE turnover in heart and IBAT was demonstrable at the lowest level of fat supplement. Fat increased pancreatic NE turnover when added in amounts sufficient to double the caloric intake. The stimulatory effect of sucrose and fat on NE turnover in heart and IBAT was similar. These experiments demonstrate that fat increases SNS activity in the rat and that the magnitude of the effect is similar to that of sucrose. The results imply that fat may contribute to dietary thermogenesis in this species.

Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat.

Brown adipose tissue (BAT) is an important site of adaptive changes in thermogenesis in the rat. The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue. The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat. Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT. Acute exposure to 4 degrees C increased NE turnover in IBAT 4- to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus. In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure. Alterations in feeding were also associated with changes in NE turnover in IBAT. Fasting for 2 d decreased NE turnover in IBAT (-35% from 29.2+/-4.2 ng NE/h to 18.9+/-5.9) and in heart (-52%). In animals fed a "cafeteria" diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 24.8+/-4.5 ng NE/h to 51.7+/-6.8) and heart (+66%). Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteria-fed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow. Thus NE turnover techniques can be satisfactorily applied to the assessment of sympathetic nervous system activity in IBAT. The experiments reported here demonstrate changes in sympathetic activity in IBAT that parallel known adaptive changes in heat production in the rat. These studies, therefore, support the concept that the increased thermogenesis of chronic cold exposure and of cafeteria feeding occur by similar mechanisms and imply an important role for the sympathetic nervous system, mediated in part through BAT, in the regulation of energy balance in the rat.

Effect of protein ingestion on urinary dopamine excretion. Evidence for the functional importance of renal decarboxylation of circulating 3,4-dihydroxyphenylalanine in man.

Since dietary protein increases urinary dopamine (DA) excretion in animals, this study was undertaken to assess the role of DA production in the acute changes in renal function following protein ingestion in man. Excretion of DA, sodium, potassium, water, solute, and creatinine were measured in six normal men in 30-min intervals over 5 h after oral ingestion of protein and/or carbidopa, an inhibitor of DA formation from 3,4-dihydroxyphenylalanine (DOPA). Overall, protein increased urinary DA 50% (P = 0.031) while carbidopa reduced it 70% (P less than 0.0001), although suppression of DA excretion by carbidopa was not uniform over the 5 h of observation. Carbidopa doubled the level of DOPA in venous plasma and greatly magnified the DOPA response to protein. Inhibition of decarboxylase activity reduced excretion of sodium, potassium, solute and water after protein ingestion. These results indicate that extraneuronal DOPA decarboxylation in kidney contributes to acute protein-induced changes in renal function in man and suggest a general role for the decarboxylation of circulating DOPA in the expression of dopaminergic effects on the kidney in vivo.

Reduced rearing temperature augments responses in sympathetic outflow to brown adipose tissue.

Sympathetic outflow to brown adipose tissue (BAT) contributes to both thermoregulation and energy expenditure in rats through regulation of BAT thermogenesis. Acute cold exposure in mature animals augments BAT thermogenesis; however, the enhanced BAT thermogenic response returns to normal shortly after cessation of the cold exposure. In this study, we sought to determine whether cold exposure in early neonatal life could induce enhanced responses in the sympathetic outflow to BAT and whether this altered sympathetic regulation would be sustained after the cold stimulus was removed. BAT sympathetic nerve activity (SNA) was recorded in urethane-chloralose-anesthetized, artificially ventilated rats that were raised from birth in either 18 or 30 degrees C environments and then, at 8 weeks of age, were maintained in 23 degrees C for at least 4 weeks. An acute hypothermic stimulus, disinhibition of a brainstem thermogenic network in the raphe pallidus, or electrical stimulation in this raphe site produced increases in BAT SNA that were twice as great in rats reared at 18 degrees C as in those reared at 30 degrees C. The norepinephrine content of the interscapular BAT (IBAT) and the number of sympathetic ganglion cells projecting to interscapular BAT were 70% greater in the 18 degrees C-reared rats. We conclude that neonatal exposure to a cold environment induces a permanent developmental alteration in the capacity for sympathetic stimulation of BAT thermogenesis that may be mediated, in part, by a greater number of sympathetic ganglion cells innervating BAT in cold-reared animals.

Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure.

BACKGROUND: Endothelin-1, a powerful mediator of vasoconstriction, is increased in patients with congestive heart failure and appears to be a prognostic marker that strongly is correlated with the severity of disease. However, little is known about the potential immediate beneficial effects of acute blockade of the endothelin system in patients with symptomatic left ventricular dysfunction. We assessed the hemodynamic effects and safety of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with moderate to severe heart failure. METHODS AND RESULTS: This randomized placebo-controlled study evaluated the hemodynamic effects of 6-hour infusions of tezosentan at 5, 20, 50, and 100 mg/h compared with placebo in 61 patients with New York Heart Association class III to IV heart failure. Plasma endothelin-1 and tezosentan concentrations were also determined. Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo. Tezosentan also dose-dependently reduced pulmonary capillary wedge pressure and pulmonary and systemic vascular resistances, with no change in heart rate. No episodes of ventricular tachycardia or hypotension requiring drug termination were observed during tezosentan infusion. Tezosentan administration resulted in dose-related increased plasma endothelin-1 concentrations. CONCLUSIONS: The present study demonstrated that tezosentan can be safely administered to patients with moderate to severe heart failure and that by virtue of its ability to antagonize the effects of endothelin-1, it induced vasodilatory responses leading to a significant improvement in cardiac index. Further studies are under way to determine the clinical effects of tezosentan in the setting of acute heart failure.

High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound.

BACKGROUND: Most of our knowledge about atherosclerosis at young ages is derived from necropsy studies, which have inherent limitations. Detailed, in vivo data on atherosclerosis in young individuals are limited. Intravascular ultrasonography provides a unique opportunity for in vivo characterization of early atherosclerosis in a clinically relevant context. METHODS AND RESULTS: Intravascular ultrasound was performed in 262 heart transplant recipients 30.9+/-13.2 days after transplantation to investigate coronary arteries in young asymptomatic subjects. The donor population consisted of 146 men and 116 women (mean age of 33.4+/-13.2 years). Extensive imaging of all possible (including distal) coronary segments was performed. Sites with the greatest and least intimal thickness in each CASS segment were measured in multiple coronary arteries. Sites with intimal thickness >/=0.5 mm were defined as atherosclerotic. A total of 2014 sites within 1477 segments in 574 coronary arteries (2.2 arteries per person) were analyzed. An atherosclerotic lesion was present in 136 patients, or 51.9%. The prevalence of atherosclerosis varied from 17% in individuals <20 years old to 85% in subjects >/=50 years old. In subjects with atherosclerosis, intimal thickness and area stenosis averaged 1.08+/-0.48 mm and 32.7+/-15.9%, respectively. For all age groups, the average intimal thickness was greater in men than women, although the prevalence of atherosclerosis was similar (52% in men and 51.7% in women). CONCLUSIONS: This study demonstrates that coronary atherosclerosis begins at a young age and that lesions are present in 1 of 6 teenagers. These findings suggest the need for intensive efforts at coronary disease prevention in young adults.

Ventilatory and heart rate responses to exercise : better predictors of heart failure mortality than peak oxygen consumption.

BACKGROUND: An abnormally low chronotropic response and an abnormally high ventilatory response (V(E)/V(CO2)) to exercise are common in patients with severe heart failure, but their relative prognostic impacts have not been well explored. METHODS AND RESULTS: Consecutive patients with heart failure referred for metabolic stress testing who were not taking beta-blockers or intravenous inotropes (n=470) were followed for 1.5 years. The chronotropic index was calculated while peak V(O2) and V(E)/V(CO2) were directly measured. Chronotropic index and peak V(O2) were considered abnormal if in the lowest 25th percentiles of the patient cohort, whereas V(E)/V(CO2) was considered abnormal if in the highest 25th percentile. For comparative purposes, a group of 17 healthy controls underwent metabolic testing as well. Compared with controls, heart failure patients had markedly abnormal ventilatory and chronotropic responses to exercise. In the heart failure cohort, there were 71 deaths. In univariate analyses, predictors of death included high V(E)/V(CO2) low chronotropic index, low V(O2), low resting systolic blood pressure, and older age. Nonparametric Kaplan-Meier plots demonstrated that by dividing the population according to peak V(E)/V(CO2) and peak V(O2), it is possible to identify low, intermediate, and very high risk groups. In multivariate analyses, the only independent predictors of death were high V(E)/V(CO2) (adjusted relative risk [RR] 3.20, 95% CI 1.95 to 5.26, P<0.0001) and low chronotropic index (adjusted RR 1.94, 95% CI 1.18 to 3.19, P=0.0009). CONCLUSIONS: The ventilatory and chronotropic responses to exercise are powerful and independent predictors of heart failure mortality.

Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays.

BACKGROUND: Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure. METHODS AND RESULTS: We used high-density oligonucleotide arrays to explore changes in expression of approximately 7000 genes in 2 nonfailing and 2 failing human hearts with diagnoses of end-stage ischemic and dilated cardiomyopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsarcomeric myosin regulatory light chain-2 [MLC(2)], and ss-actin); (2) genes responsible for degradation and disassembly of myocardial proteins (alpha(1)-antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in metabolism (ATP synthase alpha-subunit, succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose reductase, and TIM17 preprotein translocase); (4) genes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (alphaB-crystallin and mu-crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we then compared expression of proteins encoded by the differentially expressed genes, alphaB-crystallin, SLIM1, gelsolin, alpha(1)-antichymotrypsin, and ubiquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein expression was also increased in cardiomyopathic hearts from tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET) mice. CONCLUSIONS: Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.

High plasma norepinephrine concentrations at birth in infants of diabetic mothers.

Analysis of plasma norepinephrine (NE) concentrations in umbilical artery and vein from infants of diabetic and nondiabetic mothers revealed high plasma NE values in those of diabetic mothers. While birth weight and arterial plasma NE did not correlate in infants of nondiabetic mothers (r = 0.07, NS), birth weight and plasma NE were related inversely in infants of diabetic mothers (r = -0.73, P less than 0.05).

Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin.

The concentration of insulin in plasma is determined by both its rate of secretion and its rate of clearance from the plasma compartment. The effect of marked insulin resistance on insulin clearance in vivo has not been determined in man. We have employed the euglycemic insulin clamp technique to measure insulin sensitivity and insulin clearance in 16 control subjects and in 4 subjects with marked target-cell resistance to insulin. Two insulin-resistant patients had reduced receptor concentration on peripheral mononuclear cells, and two patients had normal receptor number and affinity. During 80-mU/m2/min insulin clamp studies, the clearance rate in each insulin-resistant patient was lower than that in any controls; the mean insulin clearance rate was 511 +/- 74 ml/m2/mon in control subjects and 205 ml/m2/min (P less than 0.001) in insulin-resistant patients. These findings demonstrate an association between marked target-cell resistance to insulin and impaired in vivo insulin clearance, and suggest an important role for receptor-mediated pathways in insulin clearance in vivo.

Economic outcomes of withdrawal of digoxin therapy in adult patients with stable congestive heart failure.

OBJECTIVES: This study sought to analyze the health and economic outcomes of withdrawal of digoxin therapy among U.S. adult patients with stable congestive heart failure. BACKGROUND: New information regarding the outcomes of digoxin withdrawal has been provided by the Prospective Randomized Study of Ventricular Failure and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) trials. We interpreted and extrapolated the results of these trials to describe implications on a national level. METHODS: We used a decision-analytic model to estimate the outcomes of two alternative strategies to 1) continue and 2) withdraw digoxin in patients with congestive heart failure with normal sinus rhythm, New York Heart Association functional class II or III and left ventricular ejection fraction < or = 35%. Epidemiologic assumptions were derived from published reports and expert opinion. Assumptions regarding the effectiveness of digoxin therapy were derived from the RADIANCE and PROVED digoxin withdrawal trials. Hospital and Medicare data were used for economic assumptions. Calculated outcomes included treatment failures, cases of digoxin toxicity and health care costs. RESULTS: The continuation of digoxin therapy in these patients with congestive heart failure nationally would avoid an estimated 185,000 clinic visits, 27,000 emergency visits and 137,000 hospital admissions for congestive heart failure. After accounting for an estimated 12,500 cases of digoxin toxicity, the net annual savings would be $406 million, with a 90% range of uncertainty of $106 to $822 million. One-way sensitivity analysis indicated that digoxin therapy is cost-saving when the assumed annual incidence of digoxin toxicity is < or = 33%. CONCLUSIONS: The continuation of digoxin therapy in patients with stable congestive heart failure should be strongly considered, because this strategy is likely to lead to both lower costs and greater health benefits on the basis of available information.

Efficacy and safety of a short-term (6-h) intravenous infusion of dopexamine in patients with severe congestive heart failure: a randomized, double-blind, parallel, placebo-controlled multicenter study.

Dopexamine hydrochloride is a new synthetic catechol that offers a unique profile of adrenergic and dopaminergic activity. In this multicenter, parallel design, placebo-controlled study, 45 patients with functional class III or IV chronic congestive heart failure were randomized to receive a placebo infusion or one of three different doses of dopexamine. After a 2-h dose titration sequence, patients received a 6-h constant dose infusion. During this 6-h period, dopexamine was infused at rates of 1, 2 and 4 micrograms/kg body weight per min in the low, intermediate and high dose groups, respectively. In patients receiving high dose infusion, dopexamine produced a 78% increase in cardiac index associated with a 43% decrease in systemic vascular resistance and 24% increase in heart rate (p less than 0.05 vs. placebo for all three variables). There was a trend (p = NS) toward a moderate increase in cardiac index at low and intermediate doses. In patients randomized to receive dopexamine, right atrial, systemic arterial, pulmonary artery and pulmonary capillary wedge pressures showed minimal change from baseline and did not differ statistically from the placebo response. Very few patients developed adverse reactions related to dopexamine, although five patients randomized to receive high dose and three patients randomized to receive intermediate dose dopexamine required dose reduction because hemodynamic variables exceeded arbitrary safety limits or the patients developed symptoms related to the study medication. dopexamine in higher doses effectively increases cardiac index in association with a reduction in systemic vascular resistance. Additional clinical studies are indicated to evaluate the merits of dopexamine in comparison with other inotropic and vasodilator medications.