Treatment with polymyxin B-immobilized fiber reduces platelet activation in septic shock patients: Decrease in plasma levels of soluble P-selectin, platelet factor 4 and β-thromboglobulin

OBJECTIVE: To clarify whether plasma concentrations of soluble P-selectin, platelet factor-4 (PF-4) and beta-thromboglobulin (betaTG) are altered in patients with septic shock and whether polymyxin B-immobilized fiber (PMX-F) treatment affects these changes. SUBJECTS: Thirty patients with septic shock who were treated with PMX-F (group A), 20 such patients who received conventional therapies (group B) and 20 healthy control subjects(group C). METHODS: ELISA using commercial kits. Endotoxin elimination by direct hemoperfusion using PMX-F. RESULTS: Blood endotoxin levels decreased significantly from 49.4+/-8.8 pg/ml to 13.0+/-4.5 pg/ml after PMX-F treatment. The pretreatment plasma concentrations of soluble P-selectin, PF-4 and betaTG in patients in groups A and B were significantly higher than those in group C (p<0.001). Plasma concentrations of these factors decreased significantly in group A after PMX-F treatment (p<0.01); however, the concentrations in group B were not altered after conventional treatment. The survival rate of group A (60%) was higher than that of group B (30%). CONCLUSIONS: Our findings suggest that soluble P-selectin, PF-4 and betaTG may be associated with septic shock and that PMX-F is effective in reducing these markers in patients with septic shock.     

Effects of hemoperfusion on serum cardiac troponin T concentrations using polymyxin B-immobilized fibers in septic patients undergoing hemodialysis

We investigated whether serum cardiac troponin T levels are altered in septic patients undergoing hemodialysis and whether polyinyxin B-immobilized fiber (PMX-F) treatment affects these levels. Fourteen heinodialysis patients with sepsis, 14 hemodialysis patients without sepsis, and 12 age matched healthy controls were included in this study. Cardiac troponin T levels in hemodialysis patients with sepsis (0.56+/-0.28 microg/L) were higher than levels in hemodialysis patients without sepsis (0.16+/-0.06 microg/L, p < 0.01) and healthy control subjects (0.03+/-0.01 microg/L, p < 0.001). The 14 hemodialysis patients with sepsis were randomly assigned to one of two treatment approaches: PMX-F treatment (n = 7) or conventional treatment (n = 7). Plasma endotoxin levels were significantly reduced from 46.6+/-17.8 pg/mI to 8.2+/-2.4 pg/ml, p < 0.01, in patients treated with PMX-F, and serum cardiac troponin T levels were also reduced from 0.62+/-0.30 microg/L to 0.26 = 0.12 microg/L, p < 0.05. Cardiac troponin T levels were unchanged in patients under conventional treatment. These data suggest that cardiac troponin T is indeed elevated in septic patients undergoing hemodialysis and niay reflect subclinical myocardial cell damage. PMX-F is effective in reducing myocardial damage, in part, due to reducing plasma endotoxin levels.     

Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C₁₈ extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 ± 24.9, 178.6 ± 23.0, 167.2 ± 21.8 pg/ml; ANP: 240.2 ± 28.7, 166.7 ± 21.3, 133.0 ± 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 ± 1.8%, ANP 40.2 ± 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 ± 1.0 and 60.3 ± 4. 0 pg/ml in patients with normal LVEDP and 31.7 ± 3.6 and 118.3 ± 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001 or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations. The present results provide support that other factors than volume overload, for example, decreased renal clearance, are also involved in the elevationin BNP and ANP plasma levels in chronic renal failure. The stronger elevation in BNP concentrations in patients with chronic renal failure and in patients with elevated LVEDP and the less pronounced decrease during hemodialysis suggest a different regulation of BNP and ANP plasma concentrations.[/ p]Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide - LVEDP left ventricular end-diastolic pressure Correspondence to: C. Haug     

Hemoperfusion with polymyxin B immobilized fibers for urinary albumin excretion in septic patients with trauma

We investigated whether microalbuminuria/urinary creatinine ratio (MACR) is increased in septic patients with trauma and whether polymyxin B immobilized fiber (PMX-F) treatment decreases MACR. Twelve trauma patients without sepsis, 18 trauma patients with sepsis, and 10 healthy controls were included in this study. The 18 trauma patients with sepsis were randomly assigned to one of two groups, PMX-F treatment or conventional treatment. Urinary microalbumin and creatinine were measured before and after treatment. Plasma endotoxin levels were determined by endospecy test. Hemoperfusion with PMX-F was carried out twice, for 2 hours, at a flow rate of 100 ml/min. MACR increased in the 30 trauma patients (5.2+/-2.2 mg/mmol) in comparison to that in the healthy controls (1.0+/-0.6 mg/mmol, p < 0.01). In the 18 trauma patients with sepsis, MACR after sepsis (16.6+/-4.8 mg/mmol) was significantly greater than that before sepsis (5.5+/-2.3 mg/mmol, p < 0.01). There was a significant correlation between plasma endotoxin levels and MACR in septic trauma patients (p < 0.001). MACR was reduced from 17.0+/-5.0 mg/mmol to 4.2+/-1.5 mg/mmol (p < 0.01) with PMX-F, and plasma endotoxin levels were also reduced from 34.5+/-18.5 pg/ml to 10.8+/-6.6 pg/ml (p < 0.01). Neither MACR nor plasma endotoxin levels were affected by conventional treatment, however. In summary, trauma patients with sepsis appear to show increased MACR, and PMX-F therapy may be effective for attenuating the increase in MACR.     

Polymyxin B-immobilized fiber hemoperfusion with low priming volume in an elderly septic shock patient with marked endotoxemia

An 84-year-old woman with septic shock caused by pyelonephritis is described herein. She was admitted for severe back pain and high fever. Her white blood cell (WBC) count and C-reactive protein (CRP) and endotoxin levels were elevated at 38,000/microl, 40.0 mg/dl, and 8,400 pg/ml, respectively. Her blood pressure was 80/34 mm Hg. Urinalysis revealed occult blood with innumerable WBCs. Plain abdominal radiography showed calcium stones in both kidneys. Septic shock with endotoxemia was diagnosed, and the patient was treated with antibiotics, gamma-globulin, and dopamine. However, her plasma endotoxin level remained high for 3 days. We performed direct hemoperfusion twice using a polymyxin B-immobilized fiber (PMX-F) column with a low priming volume. After PMX-F treatment, the patient's temperature decreased to 36.8 degrees C; her WBC count and CRP level decreased to 9,200/microl and 3.8 mg/dl, respectively. Her plasma endotoxin level decreased to 840 pg/ml after the first treatment and to 188 pg/ml after the second treatment. The next day, her blood endotoxin level further decreased to 32 pg/ml. Her blood pressure increased to 92/60 mm Hg after the first treatment and to 118/76 mm Hg after the second treatment. The patient was discharged on day 26 after admission. Our experience in this case suggests that PMX-F treatment with a low priming volume may be beneficial in elderly patients with septic shock and marked endotoxemia.     

Brain natriuretic peptide

Plasma levels of various neurohumoral factors are activated and have an important role of the pathophysiology of congestive heart failure (CHF). Atrial natriuretic peptide (ANP) and brain (or B-type) natriuretic peptide (BNP) are secreted from cardiomyocytes in response to atrial or ventricular wall stretch. The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to myocardial injury. Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure. In patients with left ventricular systolic dysfunction, a high plasma BNP level is an independent prognostic predictor of CHF patients, suggesting that the compensatory activity of the cardiac natriuretic peptide system is attenuated as mortality increases in chronic CHF patients with high plasma levels of ANP and BNP. BNP is more useful than ANP for diagnosis and management of CHF. Recently, rapid BNP assay is available in our country, rapid measurement of BNP in the emergency department may improve the evaluation and treatment of patients with acute dyspnea and thereby reduced the time to discharge and the total cost of treatment. In addition, BNP-guided treatment of heart failure may reduce total cardiovascular events, and delayed time to first event combination with intensive clinically guided treatment.     

Regional cardiac expression and concentration of natriuretic peptides in patients with severe chronic heart failure.

The purpose of this study was to examine the regional cardiac mRNA expression and concentration of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in relation to the circulating peptide concentrations in patients with chronic heart failure (CHF). The myocardial mRNA levels and peptide concentrations of BNP and ANP were analysed in seven different regions of the heart from patients undergoing cardiac transplantation. Autopsy samples from individuals without known cardiovascular disease were used as controls. The plasma levels of natriuretic peptides and their N-terminal propeptides, Nt-proBNP and Nt-proANP, were measured in the CHF patients and healthy volunteers. In the autopsy specimens, the atrial regions appeared to contain the highest peptide levels for BNP as well as ANP, the atrioventricular ratio being 12-262 and 72-637-fold, respectively. In the CHF patients there was a relative shift towards the ventricle for BNP, reducing the atrioventricular ratio to 6-16-fold. The circulating concentrations of BNP/Nt-proBNP in the CHF patients correlated closely to the BNP mRNA expression in most myocardial regions including the left ventricle (r = 0.72, P < 0.001). For circulating concentrations of ANP/Nt-proANP, such correlation were limited to the left atrium free wall (r = .66, P < 0.002). Thus, of the two natriuretic peptides, BNP/Nt-proBNP may be a better reflector of left ventricular overload.     

Regional cardiac expression and concentration of natriuretic peptides in patients with severe chronic heart failure

The purpose of this study was to examine the regional cardiac mRNA expression and concentration of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in relation to the circulating peptide concentrations in patients with chronic heart failure (CHF). The myocardial mRNA levels and peptide concentrations of BNP and ANP were analysed in seven different regions of the heart from patients undergoing cardiac transplantation. Autopsy samples from individuals without known cardiovascular disease were used as controls. The plasma levels of natriuretic peptides and their N‐terminal propeptides, Nt‐proBNP and Nt‐proANP, were measured in the CHF patients and healthy volunteers. In the autopsy specimens, the atrial regions appeared to contain the highest peptide levels for BNP as well as ANP, the atrioventricular ratio being 12–262 and 72–637‐fold, respectively. In the CHF patients there was a relative shift towards the ventricle for BNP, reducing the atrioventricular ratio to 6–16‐fold. The circulating concentrations of BNP/Nt‐proBNP in the CHF patients correlated closely to the BNP mRNA expression in most myocardial regions including the left ventricle (r=0.72, P < 0.001). For circulating concentrations of ANP/Nt‐proANP, such correlation were limited to the left atrium free wall (r=0.66, P < 0.002). Thus, of the two natriuretic peptides, BNP/Nt‐proBNP may be a better reflector of left ventricular overload.     

Cardiac natriuretic peptide hormones during artificial cardiac pacemaker stimulation and left heart catheterization

Summary Brain natriuretic peptide (BNP) is synthesized and released predominantly in the ventricular myocardium whereas atrial natriuretic peptide (ANP) is produced mainly in the atria. This study evaluated whether artificial pacemaker stimulation or left heart catheterization results in specific changes in BNP and ANP plasma levels. Both BNP and ANP responded sensitively to changes in pacemaker stimulation (single-chamber pacemakers; pacing rates of 72 and 92/min) and during the left heart catheterization procedure. However, whereas higher pacing resulted in a more pronounced increase in plasma BNP levels, a stronger ANP release followed catheterization. This incongruous rise in ANP and BNP plasma concentrations points to at least partly independent mechanisms govering the release of BNP and ANP.Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide     

Polymyxin B-immobilized fiber hemoperfusion in a high school football player with septic shock caused by osteitis pubis

A 17-year-old male high school football player treated by polymyxin B-immobilized fiber (PMX-F) hemoperfusion for mild-moderate septic shock caused by osteitis pubis is described in this study. He was admitted for inguinal pain, gait disturbance, and high fever (40.6°C). His white blood cell (WBC) count and C-reactive protein (CRP), endotoxin, and procalcitonin (PCT) levels were significantly elevated. His blood pressure was 76/46 mm Hg. Magnetic resonance imaging showed bone and muscle injury at the pubic symphysis. Septic shock with high blood endotoxin and PCT concentrations was diagnosed, and the patient was treated with antibiotics, γ-globulin, and dopamine on the admission day. However, the septic shock did not improve. On day 3, we performed direct hemoperfusion twice using a PMX-F column. After the second PMX-F treatment, the patient's temperature decreased to 37.0°C, and his WBC count, CRP levels, blood endotoxin, and PCT levels decreased. The inguinal pain diminished, and the patient's blood pressure increased to 112/76 mm Hg. He was discharged on day 10 after admission. This case reflects association of PMX-F with decreased endotoxin, PCT, and CRP, suggesting the association of PMX-F with clinical improvement in mild-moderate sepsis in a young athlete.     

The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure

The nocturnal secretion profile of the newly identified natriuretic peptide (NP), brain natriuretic peptide (BNP), was studied in 14 patients with obstructive sleep apnoea syndrome (OSAS) (apnoea hypopnoea index: 60.5±3.4, mean±SE) during two separate nights before and during nasal continuous positive airway pressure (NCPAP) therapy. Plasma levels of NPs (atrial natriuretic peptides; ANP and BNP) were measured at 2-h intervals during sleep. Simultaneously, blood pressure was measured by a non-invasive method (Finapres^®, Ohmeda, Englewood, CO, USA) and urine was collected for determing volume and catecholamine levels. Urinary and serum sodium concentration were determined before and after the study. Eight non-snoring subjects were also studied for the investigation of normal nocturnal profiles of BNP levels. To understand the discrete secretion profiles of the two NPs during sleep, blood was sampled from an additional seven patients every 5 min over a 30-min period around 00.00 and 04.00 hours before NCPAP. In patients with OSAS, plasma BNP levels increased from the beginning of sleep (22:00 h) to the morning (06:00 h) before NCPAP therapy (P< 0.01, anova ). Baseline BNP levels were not significantly correlated with patient's clinical and poly- somnographic parameters. However, in the latter half of the sleep period (02:00–06:00 h), increases in BNP levels during the night before NCPAP therapy were significantly correlated with blood pressure elevations (systolic: r=0.784 P< 0.01, diastolic: r=0.587 P< 0.01) and with apnoea duration (r=0.582 P< 0.01). In normal subjects BP and BNP levels were not changed significantly during sleep. Plasma BNP levels were well correlated with concomitant ANP levels (P< 0.001). NCPAP therapy reduced ANP and BNP levels during sleep and in the morning (P< 0.01). Plasma levels of BNP at 5 min intervals before NCPAP therapy revealed few variations. On the other hand, ANP levels fluctuated over the 30-min period. Changes in BNP levels during sleep in the patients with OSAS may be related to blood pressure variations, but may be too small to play a significant physiological role in regulating diuresis in OSAS. Further work is required to determine the precise role of dual natriuretic system in cardiovascular load and natriuresis in OSAS.     

2型糖尿病血管病变时血浆ANP、BNP及CNP的变化及临床意义

目的：探讨血浆心钠素(ANP)、脑利钠肽(BNP)、C型利钠肽(CNP)在2型糖尿病血管病变时的变化及其临床意义。方法:应用酶联免疫吸附法(ELISA)测定正常对照组(9例)、2型糖尿病无血管病变组(34例)及2型糖尿病血管病变组(23例)血浆proANP、BNP fragment及NT-proCNP浓度，分析各组间血浆利钠肽水平的变化及相关因素。结果:2型糖尿病血管病变组血浆ANP、BNP明显高于另外2组（P<0.01），而血浆CNP明显降低（P<0.01），2型糖尿病血管病变组各亚组(微血管病变组、大血管病变组及微血管合并大血管病变组)间血浆利钠肽水平无明显差异（P>0.05）。2型糖尿病血管病变组血浆ANP与BNP间存在显著正相关（r=0.309, P<0.05），ANP与CNP（r=-0.374, P<0.05）以及BNP与CNP（r=-0.653, P<0.01）间存在显著负相关。结论:血浆ANP、BNP及CNP的联合检测可以作为简便、价廉、可靠的糖尿病血管病变的筛选指标。     

急性心肌梗死患者血浆BNP、ANP、ET和CRP水平变化

为观察急性心肌梗死(AMI)患者血浆中脑钠肽(BNP)、内皮素(ET)、C-反应蛋白(CRP)和心钠素(ANP)水平变化, 探讨AMI发病机制,为诊断、治疗及预后判断提供依据, 应用酶联免疫及免疫放射分析法对46例AMI患者治疗前后和30名对照者血浆中的BNP、ET、CRP、ANP水平进行检测.结果显示, AMI患者血浆中BNP、ET、CRP、ANP治疗后均明显下降, 与治疗前比较有显著性差异(P＜0.01); AMI患者BNP、ET、CRP、ANP水平明显高于对照组(P＜0.01); BNP与CRP治疗前水平变化比较呈正相关r=0.847, 治疗后呈明显的下降趋势, 其相关系数为r=0.654; AMI患者治疗前后ANP与ET比较呈正相关, 但经溶栓和相应的支持治疗后ANP基本恢复到正常水平(P＞0.05),而BNP、ET、CRP水平虽然下降明显, 但与对照组比较仍有明显差异(P＜0.05).结论: AMI患者血浆中BNP、ANP、ET、CRP水平的变化说明其参与了急性心肌梗死发生、发展, 特别是冠状动脉粥样斑块的形成和(或)破裂及血栓形成, 其炎症因子是主要因素.因此, 四项指标的观察分析对AMI诊断、治疗、预后判断具有重要意义.     

AMI患者血浆BNP,ET,CRP,ANP水平变化与临床观察分析

目的 :观察急性心肌梗死 (AMI)患者血浆中脑钠肽、内皮素、C -反应蛋白、心钠素水平变化 ,探讨AMI发病机制 ,为其诊断、治疗及预后判断提供依据。方法 :应用免疫放射分析及酶联免疫分析的方法对 4 6例AMI患者治疗前后和 30例正常对照者血浆中的BNP、ET、CRP、ANP水平进行检测。结果 :AMI患者血浆中BNP、ET、CRP、ANP治疗前后比较有显著性差异 (p <0 0 0 1 ) ,正常对照组与AMI治疗前比较有显著性差异 (p <0 0 0 1 ) ,BNP与CRP在AMI治疗前水平变化比较呈正相关 (r=0 874 ) ,治疗后呈明显的下降趋势其相关系数为(r=0 6 5 4 ) ,AMI治疗前后ANP与ET比较呈正相关 ,但AMI经溶栓和相应的支持治疗后ANP水平基本恢复到正常水平 (p >0 0 5 ) ,而BNP、ET、CRP水平虽然下降明显 ,但与正常组比较仍有明显差异 (p <0 0 5 )。结论 :AMI血浆中BNP、ANP、ET、CRP水平的变化说明其参与了急性心肌梗死发生、发展 ,特别是冠状动脉粥样斑块的形成和 (或 )破裂及血栓形成 ,其炎症因子是主要因素。因此 ,四项指标的观察分析对AMI诊断、治疗、预后判断具有重要意义。     

利尿钠肽在诊断心力衰竭中的应用价值

探讨利尿钠肽的水平对心力衰竭（心衰）早期诊断的应用价值。采用放免法、ELISA法检测了129例心衰患者血浆中的心房利尿钠肽（ANP）、脑利尿钠肽（BNP）、N末端脑钠肽前体蛋白（NT-proBNP）水平,并与30例健康对照者进行了比较分析。结果显示,心衰患者血浆中的ANP、BNP、NT-proBNP显著高于健康对照组,且均随着NYHA分级的升高而逐渐增加,其含量在NYHA Ⅳ级时到达最高,心衰患者的血浆ANP、NT-proBNP水平与LVEF呈明显负相关。检测血浆中的ANP、BNP、NT-proBNP含量简便、快捷,可用于心衰诊断及NYHA分级判断。     

Effects of estrogen replacement therapy on natriuretic peptides and blood pressure

OBJECTIVE: Estrogen replacement therapy (ERT) has been reported to affect blood pressure. Since natriuretic peptides have natriuretic and vasodilatory activity and also inhibit the renin-angiotensin-aldosterone system and lower blood pressure, it was hypothesized that the changes in blood pressure effected by ERT might be mediated via changes in natriuretic peptides. METHODS: Fifty-eight postmenopausal hysterectomized women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate 2 mg/day or transdermal estradiol gel containing 1 mg estradiol/day for 6 months. Blood pressure was measured by using an automatic, oscillometric device. Plasma atrial natriuretic peptide (ANP), N-terminal fragment of proANP (NT-proANP), B-type natriuretic peptide (BNP), aldosterone, and renin were determined by radioimmunoassay. RESULTS: The mean decrease in diastolic blood pressure was -6 mmHg both in the peroral group (n = 26) (P = 0.002) and in the gel group (n = 27) (P = 0.001), and the corresponding decreases in systolic blood pressure were -4 mmHg (P = 0.070) and -7 mmHg (P = 0.028) in the sitting position. Plasma NT-proANP rose from 212 to 264 pmol/l (P = 0.001) on peroral ERT and from 240 to 292 pmol/l (P = 0.008) on transdermal ERT. No significant changes were observed in the plasma ANP, BNP, aldosterone, and renin levels. CONCLUSIONS: Both peroral and transdermal ERT result in elevated plasma levels of NT-proANP, indicating an activation of the natriuretic peptide system. This could explain, at least in part, the lowering of blood pressure during ERT.     

COPD患者血清ANP、BNP和CNP测定及其临床意义

目的：探讨慢性阻塞性肺疾病（COPD）患者血清心钠素（ANP）、脑钠肽（BNP）、C型钠尿肽（CNP）水平的变化及其临床意义。方法：采用放射免疫分析79例COPD患者和36例健康对照组血清ANP、BNP和CNP水平,并进行统计分析。结果：COPD组血清ANP、BNP和CNP水平显著地高于健康对照组（t=3.6841,P〈0.01;t=11.70,P〈0.01;t=2.177,P〈0.05）,但Ⅰ、Ⅱ、Ⅲ和Ⅳ级组间血清ANP、BNP和CNP水平方差检验无显著性意义（F=2.123、F=1.515、F=0.165,P均〉0.05）。相互间相关性分析揭示：ANP、BNP和CNP三者间均呈显著正相关（r=0.369,P〈0.01;r=0.354,P〈0.01;r=0.426,P〈0.01）。住院期间死亡的患者血清ANP、BNP和CNP水平显著地高于好转出院的患者（t=5.149,P〈0.01;t=4.875,P〈0.01;t=2.830,P〈0.01）。结论：COPD患者血清ANP、BNP和CNP显著升高,且与病人的稳定情况、肺动脉压力及预后相关。     

Atrial natriuretic peptide during exercise in patients with coronary heart disease before and after single dose atenolol and acebutolol

Plasma atrial natriuretic peptide (ANP) was measured during dynamic exercise in 10 patients with coronary heart disease before and after single dose atenolol 50 mg and acebutolol 200 mg, respectively. Systolic blood pressure, heart rate and the rate-pressure product increased during exercise before and after beta-blockade, but levels were lower after beta-blockade. Plasma ANP levels at rest were unchanged after atenolol, but rose after acebutolol (p less than 0.01). During exercise plasma ANP increased significantly both before and after beta-blockade, but plasma ANP levels were higher after acebutolol at all workloads (p less than 0.05), whereas plasma ANP levels after atenolol were higher at 125 W exclusively (p less than 0.05). The augmented ANP levels during exercise after beta-blockade probably reflect catecholamine-stimulated ANP release, whereas the elevated plasma ANP levels after acebutolol at rest might be a beta-adrenoceptor-mediated ANP release due to the intrinsic sympathomimetic effect of acebutolol.     

Multi-scale analysis of the toraymyxin adsorption cartridge. Part I: molecular interaction of polymyxin B with endotoxins

Endotoxins or lipopolysaccharides are the main constituents of the outer leaflet of Gram-negative bacteria membrane and play a central role in the pathogenesis of the septic shock. Polymyxin B has both antibacterial and antiendotoxin capability; indeed it is able to destroy the bacterial outer membrane and bind endotoxin neutralizing its toxic effects. Cartridges containing polymyxin B-immobilized fibers (Toraymyxin PMX-F, Toray Industries, Japan) are used in extracorporeal hemoperfusion to remove circulating endotoxin. The aim of this study is the characterization of the polymyxin B-endotoxin system at the molecular level, thus providing quantitative evaluation of the binding forces exerted in the molecular complex. Polymyxin B was interfaced with five molecular models of lipopolysaccharides differing in their structure and molecular mechanics simulations were performed at different intermolecular distances aimed at calculating the interaction energies of the complex. Binding forces were calculated by fitting interaction energies data. Results show that in the short range the polymyxin B-endotoxin complex is mediated by hydrophobic forces and in the long range the complex is driven by ionic forces only. From a mechanical standpoint, polymyxin B-endotoxin complex is characterized by maximum binding forces ranging between 1.39 nN to 3.79 nN. The knowledge of the binding force behavior at different intermolecular distances allows further investigations at higher scale level (Part II).     

Effects of polymyxin B immobilized fiber on urinary N-acetyl-beta-glucosaminidase in patients with severe sepsis

Severe sepsis is known to cause multiple organ failure, including renal dysfunction. During sepsis, endotoxin targets the renal proximal tubular cells, the function of which can be evaluated on the basis of urinary N-acetyl-beta-glucosaminidase (NAG). We investigated whether urinary NAG activity is altered in patients with severe sepsis and whether treatment with polymyxin B immobilized fibers (PMX-F) affects this activity. Subjects of this study were 120 patients with severe sepsis and 60 healthy volunteers matched for age and gender. Patients were randomly assigned to one of two treatments: PMX-F treatment (n = 70) or conventional treatment (n = 50). The plasma endotoxin level was significantly reduced, from 34.6 +/- 10.2 to 6.8 +/- 2.4 pg/ml (p < 0.01) in patients treated with PMX-F, and the urinary NAG/creatinine ratio was reduced from 46.5 +/- 26.8 U/gm to 18.6 +/- 13.6 U/gm (p < 0.01). The plasma endotoxin level and urinary NAG/creatinine ratio were unchanged in patients who received conventional treatment. The increased urinary NAG/creatinine ratio in patients with severe sepsis may reflect proximal tubular dysfunction. PMX-F is effective in reducing proximal tubular dysfunction, in part owing to reduced plasma endotoxin levels.