Possible erythrocyte contributions to and exacerbation of the post-thrombolytic no-reflow phenomenon.

BACKGROUND: Reperfusion injury often occurs with therapeutic intervention addressing the arterial occlusions causing acute myocardial infarction and stroke. The no-reflow phenomenon has been ascribed to leukocyte plugging and blood vessel constriction in the microcirculation. OBJECTIVE: To assess possible red cell contributions to post-thrombolytic no-reflow phenomenon. METHODS: Blood clots were formed by recalcifying 1 ml of citrated fresh human venous blood and then lysed by adding 1,000 units of streptokinase (SK) at several intervals within 1 hour. Red cell deformability was tested by both a microscopic photometric and a filtration technique, viscosity by a cone and plate viscometer, and erythrocyte aggregation by an optical aggregometer. RESULTS: Two sampling methods were devised for the microscopic photometric test, both of which indicated increases of erythrocyte stiffness after being lysed from the clot by SK. In accompanying experiments, the viscosity, aggregation and filterability of the post-lytic erythrocytes were assessed. Results indicated increased viscosity in Ringer's, decreased aggregation index and filterability through a 5 µm pore size Nuclepore membrane. CONCLUSION: Findings demonstrated that post-lytic changes in red cell deformability do occur which could contribute to the no-reflow phenomenon.

Clinical significance of ankle systolic blood pressure following exercise in assessing calf muscle tissue ischemia in peripheral artery disease.

Our primary objective assessed whether a decline in ankle systolic blood pressure (SBP) to less than 50 mm Hg after treadmill exercise is associated with lower extremity ischemia, as measured by calf muscle hemoglobin oxygen saturation (StO(2)). Eighty-four patients with peripheral artery disease (PAD) completed a treadmill test. Ankle SBP <50 mm Hg following exercise was observed in only 49% (group 1), whereas 51% had ankle SBP ≥50 mm Hg (group 2). No group differences were observed for the decline in calf muscle StO(2) to a minimum value (group 1: 18 ± 21%, group 2: 20 ± 20%; P = .60) and for the time to reach minimum StO(2) (group 1: 224 ± 251 seconds, group 2: 284 ± 283 seconds; P = .30). Requirement of ankle SBP to decrease below 50 mm Hg after exercise has little clinical significance for assessing ischemia in calf muscle of patients with PAD limited by intermittent claudication.

Caffeine and blood pressure response: sex, age, and hormonal status.

PURPOSE: The pressor effect of caffeine has been established in young men and premenopausal women. The effect of caffeine on blood pressure (BP) remains unknown in postmenopausal women and in relation to hormone replacement therapy (HRT) use. MATERIALS AND METHODS: In a randomized, 2-week cross-over design, we studied 165 healthy men and women in 6 groups: men and premenopausal women (35-49 yrs) vs. men and postmenopausal women (50-64 yrs), with postmenopausal women divided into those taking no hormone replacements (HR), estrogen alone, or estrogen and progesterone. Testing during one week of the study involved 6 days of caffeine maintenance at home (80 mg, 3x/day) followed by testing of responses to a challenge dose of caffeine (250 mg) in the laboratory. The other week involved ingesting placebos on maintenance and lab days. Resting BP responses to caffeine were measured at baseline and at 45 to 60 min following caffeine vs placebo ingestion, using automated monitors. RESULTS: Ingestion of caffeine resulted in a significant increase in systolic BP in all 6 groups (4 +/- .6, p < 0.01). Diastolic BP significantly increased in response to caffeine in all (3 +/- .4, p < 0.04) but the group of older men (2 +/- 1.0, p = 0.1). The observed pressor responses to caffeine did not vary by age. CONCLUSIONS: Caffeine resulted in an increase in BP in healthy, normotensive, young and older men and women. This finding warrants the consideration of caffeine in the lifestyle interventions recommended for BP control across the age span.

The effect of hypercholestrolemia on calf muscle hemoglobin oxygen saturation in patients with intermittent claudication.

The purpose was to compare calf muscle hemoglobin oxygen saturation and exercise performance in hypercholesterolemic and normocholesterolemic patients with peripheral arterial disease. Hypercholesterolemic and normocholesterolemic patients had similar ankle/ brachial index (0.72 +/- 0.24 vs 0.79 +/- 0.28, [mean +/- SD]; P = .334). Hypercholesterolemic patients had shorter initial claudication distance (214 +/- 168 m vs 331 +/- 185 m, P = .026), absolute claudication distance (391 +/- 219 m vs 549 +/- 211 m, P = .035), and lower calf muscle hemoglobin oxygen saturation at the occurrence of initial claudication distance (27 +/- 21% vs 39 +/- 20%; P = .013), and absolute claudication distance (26 +/- 21% vs 36 +/- 21%; P = .021). Hypercholesterolemia is associated with shorter walking distances and calf muscle hemoglobin oxygen saturation during exercise in patients limited by intermittent claudication.

Exclusion of first-episode deep-vein thrombosis after-hours using D-dimer.

The objective of this study was to test the safety of withholding anticoagulant treatment and additional call-back diagnostic testing with ultrasound in patients who have a negative D-dimer at presentation. Patients with signs and symptoms of deep-vein thrombosis who presented to the emergency department after regular hours and on weekends underwent D-dimer testing using the STA-Liatest D-di. In patients with negative D-dimer results, heparin therapy was withheld, and no further diagnostic testing for deep-vein thrombosis was done as part of the initial evaluation. Patients with positive D-dimer results underwent compression ultrasonography. The primary outcome measure was a diagnosis of new symptomatic venous thromboembolism confirmed by diagnostic testing during the 3-month follow-up period. Of the 260 eligible patients, 81 (31%) had a negative D-dimer and 179 (69%) had a positive D-dimer. No patient with a negative D-dimer at presentation had confirmed venous thromboembolism at 3-month follow-up. Three patients died: one by intracranial hemorrhage secondary to cerebrovascular accident; and two deaths of indeterminate cause almost 3 months after entry. The automated assay for D-dimer, the STA-Liatest D-di, seems to provide a simple method with high clinical utility for excluding acute first-episode deep-vein thrombosis in symptomatic patients who present to the emergency room after regular hours.

The effect of current cigarette smoking on calf muscle hemoglobin oxygen saturation in patients with intermittent claudication.

The purpose of this study was to compare calf muscle hemoglobin oxygen saturation response during exercise between smokers and non-smokers with peripheral arterial disease. Patients limited by intermittent claudication who were smokers (n = 12) were compared with those who had not smoked (n = 28) for at least 1 year prior to investigation. Ankle/brachial index (ABI) measurements were obtained with Doppler ultrasound, and maximal calf blood flow was measured by venous occlusion plethysmography. Hemoglobin oxygen saturation (StO2) of the calf muscle, initial claudication distance (ICD), and absolute claudication distance (ACD) were obtained during a graded treadmill test. Smokers refrained from smoking on the morning of the test. Smokers had similar ABI values compared with non-smokers (0.70 +/- 0.26 vs 0.73 +/- 0.23 [mean +/- SD]; p = 0.808), whereas the smokers had lower values for maximal calf blood flow (8.71 +/- 5.76 %/min vs 11.48 +/- 4.46 %/min; p = 0.038), ICD (122 +/- 123 m vs 243 +/- 177 m; p = 0.023), and ACD (284 +/- 170 m vs 452 +/- 263 m; p = 0.023). Additionally, smokers had lower calf muscle StO2 values at the end of 1 minute (16 +/- 15% vs 37 +/- 19%; p = 0.002) and 2 minutes of exercise (16 +/- 16% vs 35 +/- 25%; p = 0.008), and at the occurrence of ICD (17 +/- 17% vs 32 +/- 23%; p = 0.033) and ACD (16 +/- 16% vs 32 +/- 24%; p = 0.024). After adjusting for blood flow, calf muscle StO2 values remained lower in the smokers (p < 0.05). Finally, calf muscle StO2 at the end of the first minute of exercise was related to ICD (r = 0.611, p < 0.001) and ACD (r = 0.443, p < 0.01). In conclusion, smokers limited by intermittent claudication have lower calf muscle StO2 during exercise than nonsmokers, and lower StO2 during exercise is associated with shorter ICD and ACD.

The relationship between arterial elasticity and metabolic syndrome features.

The purpose of this study was to examine the effects of metabolic syndrome (MS) features on arterial elasticity of the large and small arteries in apparently healthy adults, to examine the effect of clustered features of MS, and to determine which features are most predictive of large and small artery elasticity. The subjects for this study consisted of 126 men and women, age 45 years and older. The subjects rested supine while pulse contour analysis was measured from the radial artery by using an HDI/Pulsewave CR-2000 instrument (Hypertension Diagnostic, Inc) to assess arterial elasticity in the large and small arteries. Medical history was obtained along with body mass index, waist circumference, body surface area, and blood pressure. Large artery elasticity was lower (p = 0.002) in subjects with hypertension (12.7 -/+ 4.3 mL/mm Hg x 10) than in those with normotension (15.0 -/+ 4.2 mL/mm Hg x 10; mean -/+ SD), and small artery elasticity was lower (p = 0.001) as well (3.9 -/+2.3 mL/mm Hg x 100 vs 5.3 -/+ 2.5 mL/mm Hg x 100). Large artery elasticity was lower (p = 0.02) in obese subjects (12.2 -/+ 4.9 mL/mm Hg x 10) than in nonobese subjects (14.2 -/+ 4.5 mL/mm Hg x 10), and large artery elasticity was lower (p = 0.04) in subjects with abdominal obesity (12.2 -/+ 4.5 mL/mm Hg x 10) than in those without (14.5 -/+ 4.8 mL/mm Hg x 10). Large artery elasticity decreased as the number of features of MS increased (p < 0.01). Multiple regression showed that body mass index and the presence of hypertension were predictors of large artery elasticity (R = 0.61, R2 = 0.37, p = 0.003, SEE = 3.60 mL/mm Hg x 10), and hypertension was a predictor of small artery elasticity (R = 0.53, R2 = 0.28, p = 0.001, SEE = 2.12 mL/mm Hg x 100). Hypertension and obesity are the features of MS that are most predictive of impairment in large and small artery elasticity in apparently healthy middle-aged and older adults. Furthermore, impairment in large artery elasticity is more evident in subjects with at least three features of MS.

The influence of obesity on calf blood flow and vascular reactivity in older adults.

OBJECTIVE: To determine whether differences in vascular reactivity existed among normal weight, overweight, and obese older men and women, and to examine the association between abdominal fat distribution and vascular reactivity. METHODS: Eighty-seven individuals who were 60 years of age or older (age = 69 +/- 7 yrs; mean +/- SD) were grouped into normal weight (BMI < 25; n = 30), overweight (BMI > or = 25 and < 30; n = 28), or obese (BMI > or = 30; n = 29) categories. Calf blood flow (BF) was assessed by venous occlusion strain-gauge plethysmography at rest and post-occlusive reactive hyperemia. RESULTS: Post-occlusive reactive hyperemia BF was lower (p = 0.038) in the obese group (5.55 +/- 4.67%/min) than in the normal weight group (8.34 +/- 3.89%/min). Additionally, change in BF from rest to post-occlusion in the obese group (1.93 +/- 2.58%/min) was lower (p = 0.001) than in the normal weight group (5.21 +/- 3.59%/min), as well as the percentage change (75 +/- 98% vs. 202 +/- 190%, p = 0.006, respectively). After adjusting for age, prevalence in hypertension and calf skinfold thickness, change in BF values remained lower (p < 0.05) in obese subjects compared to the normal weight subjects. Lastly, the absolute and percentage change in BF were significantly related to BMI (r = -0.44, p < 0.001, and r = -0.37, p < 0.001, respectively) and to waist circumference (r = -0.36, p = 0.001, and r = -0.32, p = 0.002). CONCLUSION: Obesity and abdominal adiposity impair vascular reactivity in older men and women, and these deleterious effects on vascular reactivity are independent of conventional risk factors.

Sex differences in the hemodynamic responses to mental stress: Effect of caffeine consumption.

The effect of caffeine on stress responses was compared in 25 men and 22 women in a 2-week placebo-controlled, double-blind, randomized crossover trial. On each week, participants abstained from all dietary sources of caffeine before undergoing a 6-h laboratory protocol under placebo or caffeine exposure followed by a 30-min mental stressor with blood pressure (BP) and cardiovascular hemodynamic assessments. On the placebo session, men and women showed a significant BP increase to stress, although women had significant cardiac responses whereas men had vascular responses. Caffeine ingestion before stress caused both men and women to have enhanced hemodynamic responses to the stressor associated with an increase in cardiac index and a drop in the peripheral resistance index. Caffeine enhances the cardiovascular fight-or-flight response pattern to stress in men and women.

Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels.

OBJECTIVE: Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake. METHODS: Men (N = 48) and women (N = 48) completed a double-blind, crossover trial conducted over 4 weeks. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totaling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected at 8 times from 7:30 AM to 7:00 PM. RESULTS: After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period. CONCLUSION: Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis.

Caffeine tolerance is incomplete: persistent blood pressure responses in the ambulatory setting.

BACKGROUND: Caffeine in dietary doses is a well-established pressor agent. Tolerance to this pressor effect occurs in only about half of regular consumers in acute laboratory tests. The clinical significance of this incomplete tolerance depends on whether the pressor effect is maintained throughout the day with repeated intake. Therefore, we examined the ability of a standard dose of caffeine (250 mg x 3) to maintain a blood pressure (BP) elevation during 18 hours of ambulatory BP monitoring (ABPM) after 5 days of regular daily intake of varying background doses. METHODS: Eighty-five men and women completed a four-week double blind, crossover trial. During each week, subjects consumed capsules totaling 0, 300, or 600 mg/day of caffeine in 3 divided doses. On day 6, they consumed capsules with either 0 or 250 mg at 9:00 am and 1:00 pm, in the laboratory, and again at 6:00 pm during ABPM. Tolerance was defined as a reduction in the diastolic BP response to two challenge doses given in the lab in response to increasing daily intake. Data were analyzed using multivariate repeated measures analysis of variance. RESULTS: BP responses to caffeine above those found on placebo-placebo (P-P) week were found for both tolerance groups when caffeine was consumed after a week of receiving a placebo. However, only the low tolerance group showed increases, above those found on P-P week, after 300 mg/day in systolic/diastolic BP during the waking hours (mean +/- standard error of the mean = 2.8 +/- 1.1, P = .01/2.2 +/- 0.9, P = .02) and in systolic BP during sleep (2.3 +/- 1, P = .03). CONCLUSIONS: Persistent elevations in BP occurring on a daily basis in some habitual caffeine consumers may hold clinical significance.

Hemodynamic mechanisms underlying the incomplete tolerance to caffeine's pressor effects.

Blood pressure (BP) and cardiovascular hemodynamics were assessed at baseline and after caffeine administration in a 4-week, placebo-controlled, double-blind, randomized, crossover trial of caffeine tolerance formation. Half of the subjects developed tolerance to the pressor effect of caffeine, whereas the other half continued to show increases in BP after caffeine ingestion (F = 16.7, p <0.0001). In the subjects who did not develop tolerance, peripheral resistance increased incrementally as the daily dose of caffeine increased (F = 2.8, p = 0.05).

Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial.

BACKGROUND: All of the available diagnostic tests for deep venous thrombosis (DVT) have limitations for excluding acute recurrent DVT. Measurement of plasma d-dimer by using an automated quantitative assay may be useful as a rapid exclusion test in patients with suspected recurrent DVT. OBJECTIVE: To test the safety of withholding additional diagnostic testing and heparin treatment in patients who have a negative d-dimer result at presentation (using the automated quantitative assay STA-Liatest D-di), regardless of their symptoms. DESIGN: Prospective cohort study. SETTING: Academic medical center in the United States. PATIENTS: 300 consecutive patients with suspected recurrent DVT. INTERVENTION: Patients underwent d-dimer testing at presentation. In patients with negative D-dimer results, heparin therapy was withheld, and no further diagnostic testing for DVT was done as part of the initial evaluation. Patients with positive D-dimer results underwent compression ultrasonography. MEASUREMENTS: The primary outcome measure was a diagnosis of new symptomatic venous thromboembolism confirmed by diagnostic testing during the 3-month follow-up period. RESULTS: Of the 300 study patients, the d-dimer result was negative at presentation in 134 patients (45%; negative cohort) and positive at presentation in 166 patients. Of the 166 patients, compression ultrasonography documented new DVT in 54 patients. Compression ultrasonography findings were normal in 79 patients and were inconclusive in 33 patients. After 3 months of follow-up, 1 of 134 patients in the negative cohort had confirmed venous thromboembolism (0.75% [95% CI, 0.02% to 4.09%]). Venous thromboembolism on follow-up could not be definitively excluded in 5 patients with recurrent leg symptoms and in 1 patient who died. If these patients are considered to have venous thromboembolism, the incidence during the 3-month follow-up period would be 6.0% (CI, 2.6% to 11.4%) (8 of 134 patients). LIMITATIONS: There is no accepted diagnostic reference standard for recurrent DVT. The precision of the estimate of the incidence of venous thromboembolism on follow-up and the generalizability to settings other than an academic health center should be evaluated. CONCLUSIONS: Measurement of plasma d-dimer by using the automated quantitative assay STA-Liatest D-di seems to provide a simple method for excluding acute recurrent DVT in symptomatic patients.

Cardiovascular effects of caffeine in men and women.

Caffeine increases blood pressure (BP). In men, acute BP elevations after caffeine intake are due to an increase in vascular resistance, with no change in cardiac output. The hemodynamic effects of caffeine have not been studied in women. Accordingly, BP and hemodynamic responses to caffeine were measured in a double-blind trial comparing age-matched men and women at rest and during mental stress. Caffeine (3.3 mg/kg, equivalent to 2 to 3 cups of brewed coffee) or placebo was given to separate groups of women (n = 21 and 21) and men (n = 16 and 19) (mean ages 29 and 27 years, respectively). BP, cardiac output, and vascular resistance were observed at rest, during a stressful public-speaking simulation, reading aloud, and recovery. Caffeine caused nearly identical systolic and diastolic BP elevations in women (4.5 and 3.3 mm Hg, respectively) and men (4.1 and 3.8 mm Hg, respectively). Men given caffeine versus placebo showed the expected elevation in vascular resistance throughout the remainder of the protocol (p <0.001), with no difference in cardiac output. In contrast, women responded to caffeine with increases in stroke volume (p <0.001) and cardiac output (p <0.001), with no difference in vascular resistance from women taking placebo. Men and women have similar BP responses to caffeine, but the BP responses may arise from different hemodynamic mechanisms. Women who consume a dietary dose of caffeine showed an increase in cardiac output, whereas men showed increased vascular resistance.

Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings.

BACKGROUND: The diagnosis of pulmonary embolism is difficult because the clinical diagnosis is nonspecific and all of the objective tests have limitations. The assay for plasma d-dimer may be useful as an exclusion test if results are negative. We conducted a prospective cohort study that evaluated the clinical utility (usefulness) of an automated quantitative d-dimer test in the diagnosis of patients with suspected pulmonary embolism. METHODS: Consecutive eligible patients who had clinically suspected PE with nondiagnostic lung scans or negative helical CT scan of the chest results underwent d-dimer testing. RESULTS: The d-dimer results were negative in 11 of 103 inpatients (10.6%, 95% confidence interval [CI], 5.5 to 18.3%) and 7 of 22 outpatients (31.8%, 95% CI, 13.9 to 54.9%; p = 0.02). CONCLUSIONS: Measurement of plasma d-dimer is of limited clinical utility for inpatients with clinically suspected pulmonary embolism and nondiagnostic lung scans or negative helical CT results at a US academic health center.

Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption.

Caffeine acutely raises blood pressure (BP). The clinical significance of this effect depends on whether BP responses persist in persons who consume caffeine on a daily basis. Accordingly, the ability of caffeine to raise BP after 5 days of regular daily intake was tested in a randomized controlled trial. Individual differences in tolerance formation were then examined. Men (n=49) and women (n=48) completed a double-blind, crossover trial conducted over 4 weeks. During each week, subjects abstained for 5 days from dietary caffeine and instead used capsules totaling 0 mg, 300 mg, and 600 mg of caffeine per day in 3 divided doses. On day 6, in the laboratory, they used capsules with either 0 mg or 250 mg of caffeine at 9:00 am and 1:00 pm. Systolic/diastolic BP increases as a result of 250 mg of caffeine remained significant (P<0.006/0.001) at all levels of previous daily consumption. Individual difference comparisons found that although half the subjects had complete loss of systolic and diastolic BP responses to the challenge doses, the other half showed no loss in BP response, even after using 600 mg of caffeine per day for the previous 5 days (F >7.90, P <0.001). The sexes did not differ in degree of tolerance formation. Daily caffeine consumption failed to eliminate the BP response to repeated challenge doses of caffeine in half of the healthy adults who were tested. Caffeine may therefore cause persistent BP effects in persons who are regular consumers, even when daily intake is at moderately high levels.

Sensitivity and specificity of ultrasonography in the diagnosis of upper extremity deep vein thrombosis: a systematic review.

OBJECTIVES: To determine the sensitivity and specificity of ultrasonography in the diagnosis of upper extremity deep vein thrombosis and to determine the safety of withholding anticoagulant therapy in patients with negative ultrasonographic results. DATA SOURCES: The MEDLINE database was searched for literature published from January 1, 1980, to December 31, 2000, that evaluated ultrasonography for the diagnosis of upper extremity deep vein thrombosis. Bibliographies of the retrieved articles were cross-checked to identify additional studies. STUDY SELECTION: All prospective English-language studies were selected. Retrospective studies, review articles, and case reports were excluded. DATA EXTRACTION: Two of us (B.O.M. and S.W.R.) used predefined criteria to independently assess each study. Data on sensitivity and specificity and the associated 95% confidence intervals were recorded when available. DATA SYNTHESIS: Only one study met all of the predefined criteria for adequately evaluating sensitivity and specificity. The sensitivity of duplex ultrasonography ranged from 56% to 100%, and the specificity ranged from 94% to 100%. No study evaluated the safety of withholding anticoagulant therapy without additional testing in patients with negative ultrasonographic results. CONCLUSION: The safety of withholding anticoagulant treatment in a patient with suspected upper extremity deep vein thrombosis and negative ultrasonographic results is uncertain.