The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients.

BACKGROUND: Morbidly obese patients are at increased risk to develop venous thromboembolism (VTE), especially after bariatric surgery. Adequate postoperative thrombosis prophylaxis is of utmost importance. It is assumed that morbidly obese patients need higher doses of low molecular weight heparin (LMWH) compared to normal-weight patients; however, current guidelines based on relative efficacy in obese populations are lacking. OBJECTIVES: First, we will evaluate the relationship between body weight descriptors and anti-Xa activity prospectively. Second, we will determine the dose-linearity of LMWH in morbidly obese patients. SETTING: This study was performed in a general hospital specialized in bariatric surgery. METHODS: Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight (TBW) of ≥ 140 kg. Patients (n = 50, 64% female) received a daily postoperative dose of 5700 IU of nadroparin for 4 weeks. Anti-Xa activity was determined 4 h after the last nadroparin administration. To determine the dose linearity, anti-Xa was determined following a preoperative dose of 2850 IU nadroparin in another 50 patients (52%). RESULTS: TBW of the complete group was 148.5 ± 12.6 kg. Mean anti-Xa activity following 5700 IU nadroparin was 0.19 ± 0.07 IU/mL. Of all patients, 32% had anti-Xa levels below the prophylactic range. Anti-Xa activity inversely correlated with TBW (correlation coefficient - 0.410) and lean body weight (LBW; correlation coefficient - 0.447); 67% of patients with a LBW ≥ 80 kg had insufficient anti-Xa activity concentrations. No VTE events occurred. CONCLUSIONS: In morbidly obese patients, a postoperative dose of 5700 IU of nadroparin resulted in subprophylactic exposure in a significant proportion of patients. Especially in patients with LBW ≥ 80 kg, a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels.

[Sepsis: new insights, new definition]. / Sepsis: nieuwe inzichten, nieuwe definitie.

- Incidence of sepsis is increasing, partly due to an ageing population, increased use of immunosuppressants, and antibiotic resistance. Sepsis survival has improved substantially, in part because of continuously improving intensive care and implementation of evidence-based guidelines.- Sepsis is defined as 'life-threatening organ dysfunction due to a dysregulated host response to infection'. The Sequential Organ Failure Assessment (SOFA) score can be used to estimate organ dysfunction severity.- In this article, we discuss the new sepsis definitions - including reactions to these definitions, an overview of current insights in sepsis pathogenesis, and the new treatment guidelines.- Prevention of sepsis, faster pathogen detection, new lung and kidney function-preserving treatment strategies, further individualisation of patient care and attention to long-term consequences of sepsis will determine the research agenda for the coming years.

[It is all about the form - adrenaline in anaphylaxis: intravenous or intramuscular administration?] / Het gaat om de formulering, niet om de inhoud.

BACKGROUND: Medication errors are a frequent problem in the accident and emergency (A&E) department. CASE DESCRIPTION: A 17-year-old boy was referred to our A&E department with an anaphylactic reaction to peanuts. Because of various shortcomings in the care process in A&E, adrenaline was administered intravenously instead of intramuscularly, resulting in a broad complex tachycardia. We analysed these shortcomings using the 'Prevention and recovery information system for monitoring and analysis' (PRISMA) method. CONCLUSION: Medication errors are usually a result of shortcomings in non-technical skills, such as communication and situational awareness. Training these skills by applying the concept 'Crew resource management' may reduce medication errors and improve patient safety.

[Aggression and restlessness following baclofen overdose: the narrow line between intoxication and withdrawal symptoms]. / Agressie en onrust na overdosis baclofen.

BACKGROUND: Baclofen is increasingly prescribed for alcohol dependency. Subsequently, the risk of self-intoxication with this medicinal product is increasing. CASE DESCRIPTION: A 23-year-old man with a history of alcohol dependence was admitted to our hospital after self-intoxication with 2700 mg baclofen and 330 mg mirtazapine. Respiratory insufficiency as a result of the baclofen intoxication required intubation and admission to the ICU. During the first day, despite the use of sedatives, the patient became intermittently agitated and aggressive. In the following days, he developed severe delirium, probably due to baclofen withdrawal. The reintroduction of baclofen quickly resolved these symptoms. CONCLUSION: In the case of baclofen, in practice it is difficult to differentiate between intoxication and withdrawal. To prevent potentially severe withdrawal symptoms, we recommend reintroduction of baclofen when the first signs of restlessness and agitation arise following intoxication.

Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis.

UNLABELLED: Essentials Few data exist on outcome of upper extremity deep and superficial vein thrombosis (UEDVT and UESVT). We followed 102 and 55 patients with UEDVT or UESVT, respectively, for a median of 3.5 years. Risk of recurrent venous thromboembolism was low in both diseases, and the mortality high. Postthrombotic symptoms were infrequent and cancer patients had a higher risk of recurrent VTE. SUMMARY: Background There is scant information on the optimal management and clinical outcome of deep and superficial vein thrombosis of the upper extremity (UEDVT and UESVT). Objectives To explore treatment strategies and the incidence of recurrent venous thromboembolism (VTE), mortality, postthrombotic symptoms, and bleeding in patients with UEDVT and UESVT and to assess the prognosis of cancer patients with UEDVT. Patients/methods Follow-up of patients with UEDVT or UESVT, who were enrolled previously in a diagnostic management study. Results We followed 102 and 55 patients with UEDVT and UESVT, respectively, both for a median of 3.5 years. Anticoagulant treatment was started in 100 patients with UEDVT (98%) and in 40 (73%) with UESVT. Nine patients with UEDVT (9%) developed recurrent VTE, 26 (26%) died, 6 (8%) of 72 patients had moderate postthrombotic symptoms, and 5 (5%) experienced major bleeding. One patient with UESVT had a recurrent VTE, 18 (33%) died, none had moderate postthrombotic symptoms, and none had major bleeding. Of the cancer patients with UEDVT, 18% had recurrent VTE vs. 7.5% in non-cancer patients (adjusted hazard ratio 2.2, 95%CI 0.6-8.2). The survival rate was 50% in cancer patients with UEDVT vs. 60% in those without (adjusted HR 0.8, 95%CI 0.4-1.4). Conclusions The risk of recurrent VTE was low in patients with UEDVT, and negligible for UESVT. Mortality was high for both diseases. Postthrombotic symptoms were infrequent and mild. Anticoagulant therapy of UEDVT carried a substantial risk of major bleeding. Cancer patients had a significant risk of recurrent VTE.

Hepatic and peripheral insulin sensitivity do not improve 2 weeks after bariatric surgery.

OBJECTIVE: Bariatric surgery has rapid metabolic effects on glucose metabolism before the occurrence of clinically significant weight loss. This suggests an acute effect of the surgery itself, e.g., resulting from bypassing the nutrient flow from the proximal gastrointestinal tract. Rapid effects of Roux-en-Y gastric bypass surgery (RYGB) on glucose metabolism were defined. DESIGN AND METHODS: Glucose metabolism and total triglyceride hydrolysis in the basal state and during a hyperinsulinemic euglycemic clamp using stable isotopes 2 weeks were studied before and after RYGB. RESULTS: Eighteen pre-menopausal women scheduled for RYGB were included. 2 weeks after RYGB median weight loss was 7.8 kg. Basal insulin and glucose levels decreased after surgery. Endogenous glucose production (EGP) was lower after surgery. In addition, insulin levels were lower during the clamp after surgery, suggesting enhanced clearance. Hepatic and peripheral insulin sensitivity did not change. Free fatty acid (FFA) levels increased after surgery both in the basal state and during the first step of the clamp. Total triglyceride hydrolysis did not change in the basal state and tended to be higher during hyperinsulinemia. CONCLUSIONS: Within 2 weeks, RYGB reduces basal EGP as well as insulin and glucose levels without an acute beneficial effect on hepatic or peripheral insulin sensitivity. The latter may be explained by higher rates of lipolysis and exposure to FFA induced by the hypocaloric state.

Nurse practitioners improve quality of care in chronic kidney disease: two-year results of a randomised study.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular risk. Here we evaluate whether strict implementation of guidelines aimed at multiple targets with the aid of nurse practitioners (NP) improves management in patients with CKD. METHODS: MASTER PLAN is a randomised controlled clinical trial, performed in nine Dutch hospitals. Patients with CKD (estimated glomerular filtration rate (eGFR) 20-70 ml÷min) were randomised to receive NP support (intervention group (IG)) or physician care (control group (CG)). Patients were followed for a median of five years. Presented data are an interim analysis on risk factor control at two-year follow-up. RESULTS: We included 788 patients (532 M, 256 F), (393 CG, 395 IG), mean (±SD ) age 59 (±13) years, eGFR 38 (±15) ml÷min÷1.73m(2), blood pressure (BP) 138 (±21)÷80 (±11) mmHg. At two years 698 patients (352 IG, 346 CG) could be analysed. IG as compared with CG had lower systolic (133 vs 135 mmHg; p= 0.04) and diastolic BP (77 vs 80 mmHg; p=0.007), LDL cholesterol (2.30 vs 2.45 mmol(-l); p= 0.03), and increased use of ACE inhibitors, statins, aspirin and vitamin D. The intervention had no effect on smoking cessation, body weight, physical activity or sodium excretion. CONCLUSION: In both groups, risk factor management improved. However, changes in BP control, lipid management and medication use were more pronounced in IG than in CG. Lifestyle interventions were not effective. Coaching by NPs thus benefits everyday care of CKD patients. Whether these changes translate into improvement in clinical endpoints remains to be established.

Hospital specific factors affect quality of blood pressure treatment in chronic kidney disease.

BACKGROUND: Blood pressure (BP) is the most important modifiable risk factor for cardiovascular (CV) disease and progression of kidney dysfunction in patients with chronic kidney disease. Despite extensive antihypertensive treatment possibilities, adequate control is notoriously hard to achieve. Several determinants have been identified which affect BP control. In the current analysis we evaluated differences in achieved BP and achievement of the BP goal between hospitals and explored possible explanations. METHODS: At baseline, BP was measured in a supine position with an oscillometric device in 788 patients participating in the MASTER PLAN study. We also retrieved the last measured office BP from the patient records. Additional baseline characteristics were derived from the study database. Univariate and multivariate analyses were performed with general linear modelling using hospital as a random factor. RESULTS: In univariate analysis, hospital was a determinant of the level of systolic and diastolic BP at baseline. Adjustment for patient, kidney disease, treatment or hospital characteristics affected the relation. Yet, in a fully adjusted model, differences between centres persisted with a range of 15 mmHg for systolic BP and 11 mmHg for diastolic BP. CONCLUSION: Despite extensive adjustments, a clinically relevant, statistically significant difference between hospitals was found in standardised BP measurements at baseline of a randomised controlled study. We hypothesise that differences in the approach towards BP control exist at the physician level and that these explain the differences between hospitals.

Decontamination of the digestive tract and oropharynx in ICU patients.

BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.)

Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study.

BACKGROUND: The aim of this study was to investigate whether inflammatory markers (interleukin-6 [IL-6] and C-reactive protein [CRP]) in the acute phase of deep vein thrombosis (DVT) are associated with elevated venous outflow resistance (VOR), thrombosis score (TS), reflux and the development of clinical post-thrombotic syndrome (PTS). METHODS: In 110 patients with a first DVT, plasma concentrations of IL-6 and CRP were determined on the day of admission. VOR, TS and reflux were measured 7 days, 1 and 3 months after diagnosis. After 1 year patients were evaluated for PTS using the Clinical, Etiologic, Anatomic and Pathophysiologic (CEAP) classification and Villalta scale. RESULTS: Median levels of IL-6 and CRP were 7 pg mL(-1) and 21 mg L(-1), respectively. After 3 months, VOR was elevated in 33 patients (30%), TS in 33 (30%) and reflux in 57 (52%). Incidence of PTS was 36.7% using CEAP>or=3 and 35.4% using Villalta-scale>or=5. Elevated levels of IL-6 and CRP were related to higher outcomes of VOR after 3 months [relative risks (RR) 2.4 (95% CI 1.5-3.9) and 1.4 (1.1-3.3), respectively] and for IL-6 to TS [1.5 (1.1-2.1)]. For reflux no relation was found. After 90 days, elevated outcomes of VOR, TS and reflux were related to PTS after 1 year. The association of IL-6 and CRP with PTS was weak using the CEAP classification with a RR of 1.2 (0.7-2.2) and 1.8 (0.9-3.3) and absent according to the Villalta scale 0.6 (0.2-1.4) and 1.2 (0.6-2.5), respectively. CONCLUSION: The results of this study suggest that inflammation might play a role in incomplete thrombus clearance, venous outflow obstruction and the development of PTS after 1 year.

Comparison of the clinical usefulness of two quantitative D-Dimer tests in patients with a low clinical probability of pulmonary embolism.

BACKGROUND: Quantitative D-Dimer tests are established methods in the non-invasive diagnostic management to rule out venous thromboembolism (VTE). The diagnostic performance and the clinical efficiency different D-Dimer assays in the exclusion of pulmonary embolism (PE) have not yet been compared in a clinical outcome study. OBJECTIVE: Evaluation of the efficiency and safety of excluding the diagnosis of PE with two different quantitative D-Dimer assays in consecutive patients with clinically suspected PE. PATIENTS AND METHODS: We studied the VTE-failure rate of 2206 consecutive patients with an unlikely clinical probability in whom VIDAS or Tinaquant D-Dimer tests were performed. RESULTS: The prevalence of PE in 1238 patients whose D-Dimer level was analyzed with Tinaquant assay was 11%. The VIDAS assay group consisted of 968 patients with a PE prevalence of 13%. The VIDAS assay had a sensitivity of 99.2% (95%CI; 96- >99.9%), the Tinaquant assay of 97.3% (95%CI; 93 -99%). The negative predictive value (NPV) in the Tinaquant assay group was 99.4% (95%CI 98-99.8%) in comparison to 99.7% (95%CI 99->99.9%) in the VIDAS assay group. During 3 month of follow-up, there were no fatal cases of PE among patients with normal D-Dimer and unlikely clinical probability in both D-Dimer assay groups. In addition, the test efficiency of Tinaquant assay was significantly higher in comparison to VIDAS assay (52% vs 42%, p<0.001). CONCLUSION: Both Tinaquant and VIDAS D-Dimer tests perform equally well in combination with an unlikely clinical probability in excluding PE. The Tinaquant test was shown to be more efficient.

[An early switch from intravenous to oral antibiotics is equally effective as the standard intravenous therapy in severe community acquired pneumonia]. / Vroege omschakeling van intraveneuze naar orale antibiotica even effectief als standaard intraveneuze therapie bij ernstige, buiten het ziekenhuis opgelopen pneumonie.

OBJECTIVE: To compare an early switch from intravenous to oral antibiotics with the standard intravenous therapy in patients admitted to hospital with severe community acquired pneumonia. DESIGN: Multicentre randomised prospective trial with follow-up at 28 days. METHOD: Patients with severe pneumonia who were admitted to hospital were randomised for 7 days intravenous antibiotic therapy (control group) or for an early switch to oral antibiotic therapy after 3 days of intravenous antibiotic therapy (intervention group). An intention-to-treat analysis was performed. The primary outcome measure was clinical cure. The length of hospital stay was a secondary outcome measure. RESULTS: Out of the 302 patients included in the trial, data was analysed from 265 patients. The mortality rate in the intervention group did not differ significantly from that of the control group (mean difference: 2%; 95% CI: -3-8). After 28 days, 83% of the patients in the intervention group and 85% in the control group were clinically cured (mean difference: 2%; 95% CI: -7-10). The length of hospital stay was 1.9 days shorter in the intervention group (95% CI: 0.6-3.2 days). CONCLUSION: An early switch from intravenous to oral antibiotics in patients admitted to hospital for severe community acquired pneumonia is safe and reduces the length of hospital stay by approximately 2 days.

High D-dimer level is associated with increased 15-d and 3 months mortality through a more central localization of pulmonary emboli and serious comorbidity.

High D-dimer levels are predictors of death in patients with pulmonary embolism (PE), as are more proximally located, larger emboli. The direct link between these three has not yet been described. A cohort of 674 consecutive patients with confirmed PE was studied. Patients were followed up for 3 months. D-dimer levels were measured only in patients with an unlikely clinical probability (n = 262). The odds ratio (OR) for death of all variables was calculated. Multivariate analysis was performed to identify independent risk factors for mortality. The best predictive D-dimer cut-off point for mortality was a concentration >3000 ng/ml FEU (OR 7.29). High D-dimer levels were correlated with active malignancy and age over 65 years, both being indicators of 3-month mortality. High D-dimer levels were also correlated with centrally located pulmonary emboli and 15-d mortality. The combination of high D-dimer levels and central emboli increased early mortality risk by 2.2. High D-dimer levels in patients with an unlikely clinical probability were associated with fatal outcome after PE. Centrally located pulmonary emboli were associated with higher D-dimer levels and worse 15-d mortality. Active malignancy, being an inpatient at time of diagnosis and age over 65 years were associated with higher D-dimer levels and worse 3-month survival.

Endothelin-1-induced vasopressor responses in essential hypertension.

The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5+/-0.4 to 11.6+/-1.0 pmol/L (P<.05). Blood pressure rose by approximately 10 mm Hg (P<.05). Cardiac index decreased by 21+/-22%, whereas calculated systemic vascular resistance increased by 27+/-6% (P<.05). Renal blood flow decreased from 1051+/-94 to 707+/-60 mL/min at the end of the ET-1 infusion (P<.05), and calculated renal vascular resistance increased from 118+/-19 to 189+/-19 mm Hg x min/L (P<.05). Sodium excretion decreased from 227+/-39 to 111+/-15 micromol/min (P<.05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119+/-132 to 701+/-75 mL/min, P<.05) and increased renal vascular resistance (from 111+/-16 to 187+/-28 mm Hg x min/L, P<.05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1-induced fall in renal blood flow (from 1088+/-93 to 907+/-68 mL/min) and increase in renal vascular resistance (from 105+/-9 to 133+/-10 mm Hg x min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (P<.05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1.

Role of endothelin receptor subtypes in the systemic and renal responses to endothelin-1 in humans.

The authors recently reported that infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes profound renal vasoconstriction and sodium retention. The relative roles of the ETA- and ETB-receptor subtypes in these effects in humans is unknown. Such information is essential in view of the recent introduction of endothelin-receptor blockers in clinical medicine. The study presented here was designed to define the role of the ETA- and ETB-receptor subtypes in the renal actions of endothelin-1 in humans. Systemic infusion of endothelin-1, a nonselective receptor agonist, was compared with infusion of equimolar dosages of the ETB-selective agonist endothelin-3 in healthy volunteers. Endothelin-1 infusion was associated with an approximate 2.5-fold increase in plasma levels of endothelin-1. This was accompanied by an increase in blood pressure by approximately 6 mm Hg (P < 0.05). During endothelin-1 infusion, RPF decreased from 642 +/- 42 to 480 +/- 36 mL/min (P < 0.05) and GFR from 121 +/- 4 to 109 +/- 7 mL/min (P < 0.05). Sodium excretion rate decreased during endothelin-1 infusion, from a baseline value of 182 +/- 33 to 84 +/- 28 mumol/min at the end of the endothelin-1 infusion. Endothelin-3 infusion also resulted in a approximate 2.5-fold increase of plasma levels of endothelin-3. However, in contrast to the endothelin-1 infusion, endothelin-3 had no effect on blood pressure, renal hemodynamics, and electrolyte excretion. These results suggest that the systemic and renal vasoconstrictor effects of endothelin-1 in humans are predominantly mediated by the ETA receptors.

Health effects of the Chernobyl disaster: illness or illness behavior? A comparative general health survey in two former Soviet regions.

Results are described of a general health survey (n = 3044) that was conducted 6.5 years after the Chernobyl accident in 1986 in a seriously contaminated region in Belarus and a socioeconomically comparable, but unaffected, region in the Russian Federation. The purpose of the study was to investigate whether there are differences in the general health status of the inhabitants of the two regions that may be attributed to the Chernobyl disaster. A broad-based population sample from each of these regions was studied using a variety of self-report questionnaires. A subsample (n = 449) was further examined with a standardized physical and psychiatric examination. The results show significantly higher scores on the self-report questionnaires and higher medical service utilization in the exposed region. No significant differences were observed in global clinical indices of health. Although there were trends for some disorders to be more prevalent in the exposed region, none of these could be directly attributed to exposure to ionizing radiation. The results of this study suggest that the Chernobyl disaster had a significant long-term impact on psychological well-being, health-related quality of life, and illness behavior in the exposed population.

Interactions of nifedipine with the renovascular effects of endothelin in humans.

Infusion of endothelin-1 in humans to obtain pathophysiological plasma levels causes mild hypertension, strong sodium retention and renal vasoconstriction. Animal studies have shown that part of these effects depend upon activation of voltage-dependent calcium channels. However, it is unknown whether hemodynamic effects of endothelin-1 in humans, once established, can be reversed by calcium channel blockers. We therefore studied in healthy subjects whether coinfusion of nifedipine, after 60 min of endothelin-1 infusion, could reverse these effects. During endothelin-1 infusion alone, plasma endothelin increased from 2.9 +/- 0.2 to 8.0 +/- 0.6 pmol/l (P < .05). Blood pressure rose by approximately 6 mm Hg at the end of the endothelin-1 infusion (P < .05). Endothelin-1 caused a marked increase in renal vascular resistance by approximately 34% (P < .05) and in filtration fraction by approximately 25% (P < .05). Sodium excretion decreased from a base-line value of 144 +/- 25 to 81 +/- 15 mumol/min at the end of the endothelin infusion (P < .05). During coinfusion of nifedipine, plasma endothelin levels increased to similar values as found during endothelin-1 infusion alone. Blood pressure increase was prevented, whereas the increase in renal vascular resistance and antinatriuresis were reversed completely. However, nifedipine could not reverse the endothelin-induced increase of filtration fraction, indicating that the effects of endothelin-1 and nifedipine in the renal microcirculation do not overlap completely. Because calcium channel blockers have a preferentially preglomerular effect, this suggests that endothelin-1 maintained vasoconstriction of the efferent arteriole in the kidney during nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of enalapril versus nifedipine to antagonize blood pressure and the renal response to endothelin in humans.

Endothelin-1 infusion into humans to obtain pathophysiological plasma levels causes mild hypertension, strong renal vasoconstriction, and sodium retention. We studied whether oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD) could attenuate these effects of endothelin-1 (2.5 ng/kg per minute for 90 minutes) in six healthy volunteers. Endothelin infusion alone increased plasma endothelin from 3.0 +/- 0.3 to 8.8 +/- 1.0 pmol/L (P < .05). Blood pressure rose by approximately 6 mm Hg (P < .05). Renal function changes were relatively large: Renal blood flow decreased from 941 +/- 76 to 729 +/- 118 mL/min (P < .05) and glomerular filtration rate from 105 +/- 9 to 92 +/- 10 mL/min (P < .05); renal vascular resistance increased from 101 +/- 7 to 152 +/- 20 mm Hg.min/L (P < .05); and sodium excretion decreased from 158 +/- 54 to 86 +/- 27 mumol/min (P < .05). Enalapril treatment reduced blood pressure from 94 +/- 2 to 87 +/- 3 mm Hg (P < .05) and prevented the hypertensive response to endothelin. By contrast, despite renal predilatation, endothelin reduced renal blood flow strongly (from 1063 +/- 127 to 763 +/- 100 mL/min, P < .05), although maximal renal vascular resistance was numerically lower (124 +/- 11 mm Hg.min/L) than during endothelin alone (P < .05). Glomerular filtration rate fell from 118 +/- 11 to 108 +/- 11 mL/min (P < .05). Enalapril did not alter the antinatriuretic effect of endothelin.(ABSTRACT TRUNCATED AT 250 WORDS)