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.

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.

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.

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)

L-arginine does not prevent the renal effects of endothelin in humans.

The infusion of endothelin to obtain plasma levels as present in sodium-retaining conditions such as heart failure and hepatorenal syndrome has been shown to cause sodium retention and renal vasoconstriction. Whether these renal effects of endothelin could be modulated by the stimulation of nitric oxide production by the infusion of L-arginine was examined. Therefore, the renal and endocrine effects of the systemic administration of endothelin (2.5 ng/kg per minute for 90 min), L-arginine (5 mg/kg per minute for 90 min), or the combination of endothelin and L-arginine were studied in healthy subjects under clearance conditions. During endothelin infusion, plasma endothelin levels rose from 3.0 +/- 0.2 to 14.1 +/- 2.4 pmol/L (P < 0.01). Mean arterial pressure increased by 7 mm Hg (P < 0.01). The effects on renal function were disproportionately large: renal vascular resistance increased from 77.5 +/- 3.2 to 124.1 +/- 6.7 mm Hg/min per liter (P < 0.01), and sodium excretion fell from 178 +/- 30 to 83 +/- 11 mumol/min (P < 0.01). Endothelin had no effect on urinary nitrite excretion. L-Arginine caused a fall in blood pressure of 5 mm Hg (P < 0.01) and decreased renal vascular resistance by 12% (P < 0.05). Sodium excretion increased twofold. This was associated with an increase in urinary nitrite excretion from 112 +/- 36 to 465 +/- 190 nmol/min (P < 0.01), suggesting stimulation of renal nitric oxide production. During the combination of endothelin and L-arginine, urinary nitrite excretion increased similarly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of endothelin-1 on renal function in humans: implications for physiology and pathophysiology.

Elevated levels of the vasocontrictor peptide endothelin-1 have been demonstrated in various pathological conditions that are characterized by sodium retention and/or renal vasoconstriction, such as heart failure, hepatorenal syndrome, renal failure and during administration of cyclosporin and radiocontrast. In the present study we studied in seven healthy subjects the renal and endocrine effects of systemic administration of endothelin-1 (0.5, 1.0 and 2.5 ng/kg/min). During endothelin-1 infusion plasma levels rose from 3.2 +/- 0.5 to respectively 5.0 +/- 0.8, 6.2 +/- 0.5 and 8.5 +/- 1.1 pmol/liter, values that can also be observed in physiological and pathological conditions. Infusion of low dosages of endothelin-1, that result in a twofold increase in plasma levels, decreased sodium excretion by 36%, without a significant effect on systemic and renal hemodynamics. Infusion of 2.5 ng/kg/min of endothelin-1 further enhanced sodium retention and, in addition, increased renal vascular resistance by 37%. Blood pressure did not change significantly. Pretreatment with the calcium channel blocker nifedipine caused renal vasodilation, which compensated for the renal vasocontriction by endothelin-1 and prevented sodium retention. Apparently, endothelin-1 participates in volume homeostasis in human, whereas pathophysiological concentrations can contribute to renal vasoconstriction and sodium retention. Calcium channel blockers may protect against these effects of endothelin-1.