Erythropoietin does not attenuate renal dysfunction or inflammation in a porcine model of endotoxemia

Background: Erythropoietin (EPO) is a multifunctional cytokine with anti‐apoptotic, anti‐inflammatory, and organ protective effects. EPO protects against ischemia–reperfusion injuries, and recent reports suggest that EPO also prevents organ dysfunction in experimental sepsis. The aims of this study were to determine whether EPO prevents endotoxemia‐induced organ dysfunction in a porcine model and to characterize the immunomodulatory and anti‐apoptotic effects of EPO. Methods: Twenty‐eight pigs were randomly assigned to three groups: (1) endotoxemia treated with EPO 5000 IU/kg, (2) endotoxemia treated with placebo, and (3) a sham group anesthetized and submitted to sham operation without treatment. A laparotomy was performed, and a flow probe was placed around the left renal artery, which allowed renal blood flow (RBF) measurements. Endotoxemia was induced by an infusion of lipopolysaccharide. After 2 h, the infusion was reduced to a maintenance dose and the animals were fluid resuscitated. The glomerular filtration rate (GFR), RBF, renal oxygen consumption, and plasma cytokines [interleukin (IL)‐1β, IL‐6, IL‐8, IL‐10, and tumor necrosis factor‐alpha] were analyzed. Renal biopsies were analyzed for cytokine content and apoptosis. Results: Endotoxemia elicited impaired renal function, estimated as GFR, and increased the levels of renal apoptotic cells, with no modifying effect of EPO. Furthermore, EPO had no effect on RBF, renal oxygen consumption, or the systemic hemodynamic response to endotoxemia. EPO did not modify the inflammatory response, measured as changes in cytokine levels in plasma and organs. Conclusion: EPO did not confer renal protection in this fluid‐resuscitated porcine model of endotoxemia, and EPO did not modify the inflammatory response.     

Erythropoietin administration is associated with short-term improvement in glomerular filtration rate after ischemia-reperfusion injury

Background: Erythropoietin (EPO) is a cytokine with organ‐protective properties. We hypothesized that EPO could attenuate acute renal dysfunction and inflammation in a porcine model of ischemia–reperfusion (IR). Furthermore, we aimed to characterize the impact of EPO on systemic and renal hemodynamics, and renal oxygen consumption. Methods: Twenty‐four pigs were randomly assigned to three groups: (1) EPO (5000 IU/kg) administered intravenously before IR (n=9), (2) placebo administered before IR (n=9), or (3) sham group, anesthetized and operated on only (n=6). IR was induced by clamping the left renal artery for 45 min. Hemodynamics and renal blood flow (RBF) were analyzed continuously. Glomerular filtration rate (GFR), renal oxygen consumption, and plasma cytokines (IL‐1β, IL‐6, IL‐8, IL‐10, and TNF‐α) were analyzed hourly. Renal biopsies were analyzed for cytokine content and apoptosis. Results: GFR was higher during reperfusion in the EPO group than in the placebo group (P<0.01). No differences between the IR groups were found in hemodynamics, RBF, oxygen consumption, or renal apoptosis. The levels of TNF‐α in the plasma (P=0.036) and the levels of TNF‐α and IL‐10 in the renal cortex (P=0.04 and P=0.01, respectively) were lower in the EPO group compared with the sham group. Conclusion: EPO attenuated the renal dysfunction as estimated as GFR. This effect was not related to changes in the hemodynamics. The immunomodulatory effects of EPO were manifested as decreased levels of TNF‐α and IL‐10 in renal biopsies and TNF‐α levels in plasma.     

Inoprotection: the perioperative role of levosimendan

Levosimendan is emerging as a novel cardioprotective inotrope. Levosimendan augments myocardial contractility by sensitising contractile myofilaments to calcium without increasing myosin adenosine triphosphatase activity or oxygen consumption. Levosimendan activates cellular adenosine triphosphate-dependent potassium channels, a mechanism which is postulated to protect cells from ischaemia in a manner similar to ischaemic preconditioning. Levosimendan may therefore protect the ischaemic myocardium during ischaemia-reperfusion as well as improve the contractile function of the heart. Adenosine triphosphate-dependent potassium channel activation by levosimendan may also be protective in other tissues, such as coronary vascular endothelium, kidney and brain. Clinical trials in patients with decompensated heart failure and myocardial ischaemia show levosimendan to improve haemodynamic performance and potentially improve survival. This paper reviews the known pharmacology of levosimendan, the clinical experience with the drug to date and the potential use of levosimendan as a cardioprotective agent during surgery.     

Immunomodulation by a combination of nitric oxide and glucocorticoids in a human endotoxin model

Background: Inflammatory reactions arise in reaction to a variety of pathogenic insults. The combination of inhaled nitric oxide (iNO) and glucocorticoids (GC) may attenuate endotoxin‐induced inflammatory responses. It has been shown that the combination of iNO (30 p.p.m.) and steroids blunted the inflammatory response in a porcine endotoxin model, but not in humans. Therefore, we investigated whether a clinically ‘maximal’ dose of iNO in combination with GC could modulate the systemic inflammatory response in a human endotoxin model. Methods: A double‐blind, cross‐over, placebo‐controlled randomized study including 15 healthy Caucasian volunteers (five females, 10 males). Performed at the Intensive Care Unit in a university hospital. iNO 80 p.p.m. or placebo (nitrogen) was started 2 h before administration of endotoxin (2 ng/kg). Thirty minutes later, GC (2 mg/kg, hydrocortisone) was administered intravenously. Blood samples and clinical signs were collected before and up to 24 h after the endotoxin injection. Results: Body temperature and heart rate increased significantly subsequent to endotoxin challenge. The plasma levels of IFN–γ, IL‐1β, IL‐2, 4 5, 6, 8, 10, 12, 13 and TNFα were markedly elevated. However, HMGB‐1 and sRAGE were unaffected. No difference between placebo/GC and iNO/GC treatment was observed in the clinical or cytokine response, neither was there any difference between the first and the second exposure to endotoxin. Conclusions: Pre‐treatment with iNO 80 p.p.m. along with GC (2 mg/kg) administrated after the endotoxin challenge could not modulate the systemic inflammatory response in this model of human experimental inflammation.     

The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock

Background: Impaired renal microcirculation has been suggested as a factor contributing to the development of renal dysfunction in sepsis. This study was conducted to elucidate the role of endothelin‐1 (ET‐1)in mediating reductions in renal microcirculatory blood flow during endotoxemic shock. Methods: A prospective, randomized, and experimental study was performed with 16 anesthetized and mechanically ventilated pigs. After 2 h of lipopolysaccaride‐induced endotoxemia, eight animals received a bolus dose of the dual endothelin receptor antagonist tezosentan (1 mg/kg), followed by a continuous infusion of 1 mg/kg/h throughout the experiment. Eight animals served as the control group. Renal microcirculation, total renal blood flow, plasma creatinine levels, cardiac index, and mean arterial pressure were measured. Plasma samples were collected for the measurement of tumor necrosis factor α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐10 (IL‐10), ET‐1, angiotensin II, and aldosterone. Results: Endotoxin infusion resulted in a state of circulatory shock with impairment of renal microcirculation. An increase in the plasma levels of TNF‐α, IL‐6, IL‐10, ET‐1, angiotensin II, and aldosterone was also observed. Tezosentan attenuated the decrease in renal microcirculation and renal blood flow, and attenuated the increase in plasma creatinine. Treatment with tezosentan did not significantly affect the plasma cytokine, angiotensin II, or aldosterone response to endotoxemia. Conclusion: These results indicate that treatment with the dual endothelin receptor tezosentan in endotoxemic shock attenuates the reduction of renal microcirculation and total renal blood flow independently of plasma changes in the renin–angiotensin–aldosterone system or early plasma cytokine response.     

Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels

We tested the hypothesis that levosimendan, a new positive inotropic drug that activates adenosine triphosphate-regulated potassium (K(ATP)) channels in vitro, decreases myocardial infarct size in vivo. Myocardial infarct size was measured after a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion in dogs receiving either IV vehicle (0.9% saline) or levosimendan (24 microg/kg bolus followed by an infusion of 0.4 microg x kg(-1) x min(-1)) in the presence or absence of glyburide (a K(ATP) channel antagonist) pretreatment (100 microg/kg). Levosimendan increased (P < 0.05) the maximal rate of increase of left ventricular pressure and decreased myocardial infarct size from 24%+/-2% (control experiments) to 11%+/-2% of the left ventricular area at risk for infarction. Glyburide did not alter the hemodynamic effects of levosimendan but blocked levosimendan-induced reductions of infarct size. Subendocardial collateral blood flow was similar among groups. However, levosimendan increased subepicardial and midmyocardial collateral perfusion in the absence, but not in the presence, of glyburide. Levosimendan exerts cardioprotective effects via activation of K(ATP) channels at a dose that simultaneously enhances myocardial contractility. IMPLICATIONS: Levosimendan may be advantageous in patients requiring inotropic support who are also at risk of myocardial ischemia. Activation of adenosine triphosphate-regulated potassium channels during infusion of levosimendan may produce cardioprotective effects while simultaneously enhancing ventricular contractile function.     

Levosimendan in acute pulmonary embolism

Levosimendan has been used successfully in the treatment of ischaemic cardiac failure and myocardial stunning. There is growing evidence from both human and animal experiments that levosimendan has particularly favourable effects on the right ventricle. We describe a case of life-threatening pulmonary embolus supported by the use of levosimendan.     

Continuous Renal Replacement Therapy Reduces the Systemic and Pulmonary Inflammation Induced by Venovenous Extracorporeal Membrane Oxygenation in a Porcine Model

Pulmonary changes in veno‐venous extracorporeal membrane oxygenation (VV‐ECMO) are rarely determined. We compared the contribution of VV‐ECMO and cannulation based on the observation of pulmonary inflammatory reaction and parenchymal construction in a porcine model of low tidal volume (V_T) ventilation. We also evaluated the effect of adding continuous renal replacement therapy (CRRT) to the ECMO circuit, because CRRT is known to reduce systemic cytokine release induced by VV‐ECMO. A total of 18 pigs undergoing low‐V_T ventilation were randomly divided into three groups (group 1, cannulation; group 2, VV‐ECMO; group 3, VV‐ECMO + CRRT) and studied for 24 h. Hemodynamic and ventilation parameters were recorded. We assessed plasma and alveolar cytokines, expression of pulmonary inflammatory genes, histopathological grading, and ultrastructural changes of the lungs. During the process, inspiratory volume increased and PaO₂ decreased in group 1. Systemic tumor necrosis factor‐α (TNF‐α) and interleukin 6 (IL‐6) levels increased at 2 h in group 2 and partly decreased in group 3. At 24 h, the levels of bronchoalveolar lavage fluid, TNF‐α, and IL‐6 in group 2 were remarkably higher than those in groups 1 and 3. Pulmonary mRNA expression of cytokines did not differ between the groups. We observed an increased score of pulmonary pathological findings in pro‐inflammatory cell infiltration and interstitial thickening of the lungs in group 2. The epithelium of the blood–air barrier after VV‐ECMO was swollen. In group 3, the pulmonary parenchyma and blood–air barrier were well preserved. We concluded that in a porcine model of low‐V_T ventilation, both VV‐ECMO and VV‐ECMO in combination with CRRT provided adequate oxygenation and carbon dioxide removal. Compared with VV‐ECMO alone, VV‐ECMO in combination with CRRT better preserved the lung parenchyma by eliminating systemic cytokines.     

Myocardial depression associated with pneumococcal septic shock reversed by levosimendan

Levosimendan is a myocardial calcium sensitiser and potassium-ATP channel opener Levosimendan has been used in critically ill patients in various conditions to support myocardial function as an inotrope, lusitrope and vasodilator. We report the use of levosimendan in a patient with invasive streptococcal septic shock.     

Cardiac and Renal Effects of Levosimendan, Arginine Vasopressin, and Norepinephrine in Lipopolysaccharide-treated Rabbits

Background: Because sepsis-induced myocardial dysfunction related to sepsis is at least partially related to a decrease in cardiac myofilament response to calcium, the use of the new myofilament-calcium sensitizer, levosimendan, has been proposed. In addition, arginine vasopressin is increasingly proposed as a vasopressor in septic patients, although data on its effects on cardiac function are still scarce. The aim of the current study was to assess, invasively and noninvasively, whether levosimendan, arginine vasopressin, and norepinephrine, either alone or combined, may modify sepsis-induced myocardial dysfunction and renal hemodynamics.

Methods: Thirty-six hours after lipopolysaccharide or saline administration, rabbits were studied either after slight sedation for echocardiography or after general anesthesia with sodium pentobarbital for the following measurements: aortic flow velocity and maximum acceleration of blood flow in the ascending aorta and renal macrocirculation and microcirculation.

Results: Levosimendan improved, within 30 min of administration, both maximum acceleration of blood flow by 20 +/- 12% (n = 8; P < 0.05) and left ventricular shortening fraction by a similar extent. Furthermore, low doses of arginine vasopressin markedly deteriorated cardiac function via an afterload-independent mechanism, even when animals were pretreated with levosimendan, whereas norepinephrine showed no detrimental effects on cardiac function. The study also showed that norepinephrine often improved renal medullary blood flow, whereas arginine vasopressin consistently decreased it.     

Acute hyperinsulinemia restrains endotoxin-induced systemic inflammatory response: an experimental study in a porcine model

BACKGROUND: Intensive insulin therapy in critically ill patients reduces morbidity and mortality. The current study elucidates whether acute hyperinsulinemia per se could attenuate the systemic cytokine response and improve neutrophil function during endotoxin (lipopolysaccharide)-induced systemic inflammation in a porcine model. METHODS: Pigs were anesthetized, mechanically ventilated, randomized into four groups, and followed for 570 min: group 1 (anesthesia solely, n = 10), group 2 (hyperinsulinemic euglycemic clamp [HEC], n = 9), group 3 (lipopolysaccharide, n = 10), group 4 (lipopolysaccharide-HEC, n = 9). Groups 3 and 4 were given a 180-min infusion of lipopolysaccharide (total, 10 microg/kg). Groups 2 and 4 were clamped (p-glucose: 5 mM/l, insulin 0.6 mU.kg(-1).min(-1)) throughout the study period. Changes in pulmonary and hemodynamic function, circulating cytokines, free fatty acids, glucagon, and neutrophil chemotaxis were monitored. RESULTS: Tumor necrosis factor alpha and interleukin 6 were significantly reduced in the lipopolysaccharide-HEC group compared with the lipopolysaccharide group (both P = 0.04). In the lipopolysaccharide-HEC group, the glucagon response was diminished compared with the lipopolysaccharide group (P < 0.05). Serum free fatty acid concentrations were decreased in animals exposed to HEC. Animals receiving lipopolysaccharide showed an increase in pulmonary pressure (P < 0.001), but otherwise, there were no major changes in pulmonary or hemodynamic function. Neutrophil function was impaired after lipopolysaccharide administration. CONCLUSION: Hyperinsulinemia concomitant with normoglycemia reduces plasma concentrations of tumor necrosis factor alpha and the catabolic hormone glucagon in lipopolysaccharide-induced systemic inflammation in pigs. The finding strongly supports the role of insulin as an antiinflammatory hormone. Whether the effect to some extent operates via a reduced free fatty acid concentration is unsettled.     

Cardiac and renal effects of levosimendan, arginine vasopressin, and norepinephrine in lipopolysaccharide-treated rabbits

BACKGROUND: Because sepsis-induced myocardial dysfunction related to sepsis is at least partially related to a decrease in cardiac myofilament response to calcium, the use of the new myofilament-calcium sensitizer, levosimendan, has been proposed. In addition, arginine vasopressin is increasingly proposed as a vasopressor in septic patients, although data on its effects on cardiac function are still scarce. The aim of the current study was to assess, invasively and noninvasively, whether levosimendan, arginine vasopressin, and norepinephrine, either alone or combined, may modify sepsis-induced myocardial dysfunction and renal hemodynamics. METHODS: Thirty-six hours after lipopolysaccharide or saline administration, rabbits were studied either after slight sedation for echocardiography or after general anesthesia with sodium pentobarbital for the following measurements: aortic flow velocity and maximum acceleration of blood flow in the ascending aorta and renal macrocirculation and microcirculation. RESULTS: Levosimendan improved, within 30 min of administration, both maximum acceleration of blood flow by 20 +/- 12% (n = 8; P < 0.05) and left ventricular shortening fraction by a similar extent. Furthermore, low doses of arginine vasopressin markedly deteriorated cardiac function via an afterload-independent mechanism, even when animals were pretreated with levosimendan, whereas norepinephrine showed no detrimental effects on cardiac function. The study also showed that norepinephrine often improved renal medullary blood flow, whereas arginine vasopressin consistently decreased it. CONCLUSION: Levosimendan and norepinephrine both exert beneficial effects in endotoxemic animals and should be further explored in human sepsis trials.     

Intraluminal Papaverine with pH 3 Doubles Blood Flow in the Internal Mammary Artery

Abstract

Objectives. Levosimendan is an inodilator indicated for acute heart failure (AHF). Its vasodilatory and anti-ischemic effects are mediated by the opening of ATP-dependent potassium channels (K_ATP channels). Diabetes mellitus is common in AHF patients and sulfonylureas are often prescribed. Sulfonylureas act by blocking the K_ATP channels. An interaction between levosimendan and sulfonylureas has been shown in preclinical models and could be hypothesized in clinical practice. Design. We produced a pooled analysis of six randomized levosimendan trials (in total of 3004 patients of which 1700 were treated with levosimendan and 226 both with levosimendan and sulfonylureas) with the aim to study the influence of concurrent sulfonylurea treatment to the levosimendan effects. Invasive and non-invasive hemodynamics, biomarkers (BNP), adverse events related to myocardial ischemia, and survival were evaluated. Results. In our relatively small data set, we could not detect any clinically relevant interactions between the sulfonylureas and levosimendan. Similar decreases in systolic and diastolic blood pressure, pulmonary capillary wedge pressure and BNP, and similar survival and adverse event profiles were seen in sulfonylurea users and non-users exposed to levosimendan. Conclusions. Concomitant use of sulfonylureas with levosimendan does not attenuate the hemodynamic or other effects of levosimendan.     

Rolle von Levosimendan in der intensivmedizinischen Behandlung des myokardialen Pumpversagens

Levosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.     

新型正性肌力药左西孟旦的作用机制及临床应用

左西孟旦是一种新型正性肌力药--钙增敏剂,可通过钙敏作用增强心肌收缩力,激活K+通道使血管扩张,且并不增加心肌氧耗和心率,因而具有改善心功能和心肌保护等作用.可应用于治疗急性失代偿心力衰竭、心肌缺血后心脏收缩力异常、心肌顿抑以及用于心脏手术期间循环的调控等方面.     

Levosimendan cardioprotection reduces the metabolic response during temporary regional coronary occlusion in an open chest pig model

BACKGROUND: Inotropic and myocardial anti-ischemic effects have been demonstrated with levosimendan. The comparison of levosimendan started before an ischemia-reperfusion event as compared with levosimendan started during ischemia has not been studied. METHODS: In anesthetized pigs, a major branch of the circumflex artery was completely occluded for 30 min and then reperfused. The metabolism in the ischemic myocardium and in non-ischemic control myocardium was studied with microdialysis concomitantly with monitoring of global hemodynamics and coronary artery flow in the chosen artery. In the protection group (PRO, n= 6), a levosimendan infusion was started 30 min before coronary artery occlusion, and in the treatment group (TRE, n= 6), a levosimendan infusion was started 10 min after the coronary artery occlusion with a loading dose of 13.3 microg/kg followed by an infusion of 0.67 microg/kg/min. A two-way repeated measures ANOVA completed with Bonferroni's multiple comparison procedure was applied to the data. A P < 0.05 was considered significant. RESULTS: During the ischemic period, the cardiac output and contractility (dp/dt(max)) were higher in the PRO as compared with the TRE and the systemic vascular resistance was lower. The myocardial microdialysate glucose concentration in the ischemic area during ischemia was higher in the PRO as compared with the TRE, and the lactate/pyruvate ratio and the lactate concentration were lower. The differences in the metabolites persisted into the first 10 min of reperfusion. No differences were found for the non-ischemic areas. CONCLUSION: Levosimendan used throughout myocardial ischemia-reperfusion might have a cardioprotective affect on the response to myocardial ischemia as compared with levosimendan started during the ischemia.     

Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal-arterial pCO2 gradient in abdominal aortic aneurysm surgery

Background: Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. Methods: Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double‐blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG‐PDR) was used to estimate the total splanchnic blood flow. Results: The immediate post‐operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8–4.7) l/min/m² vs. 2.6(2.3–3.6) l/min/m²; P<0.05] and the gastric mucosal–arterial pCO₂ gradient was lower in levosimendan‐treated patients [0.9(0.6–1.2) kPa vs. 1.7(1.2–2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG‐PDR, was comparable [29(21–29)% vs. 20(19–25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post‐operative day. Conclusion: Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation.     

Does brain death induce a pro‐inflammatory response at the organ level in a porcine model?

Background: Organs from brain-dead donors have a poorer prognosis after transplantation than organs from living donors. A possible explanation for this is that brain death might initiate a systemic inflammatory response, elicited by a metabolic stress response or brain ischemia. The aim of this study was to investigate the effect of brain death on the cytokine content in the heart, liver, and kidney. In addition, the metabolic and hemodynamic response caused by brain death was carefully registered.
Methods: Fourteen pigs (35–40 kg) were randomized into two groups (1) eight brain-dead pigs and (2) six pigs only sham operated. Brain death was induced by inflation of an epidurally placed balloon. Blood samples for insulin, glucose, catecholamine, free fatty acids (FAA), and glucagon were obtained during the experimental period of 360 min. At the conclusion of the experiment, biopsies were taken from the heart, liver, and kidney and were analyzed for cytokine mRNA and proteins [tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-10).
Results: We found a dramatic response to brain death on plasma levels of epinephrine ( P =0.004), norepinephrine ( P =0.02), FAA ( P =0.0001), and glucagon ( P =0.0003) compared with the sham group. There was no difference in cytokine content in any organ between the groups.
Conclusion: In this porcine model, brain death induced a severe metabolic response in peripheral blood. At the organ level, however, there was no difference in the cytokine response between the groups.     

严重创伤患者血浆细胞因子变化及其与器官功能损害的关系

作者通过观察１７例严重创伤患者血浆肿瘤坏死因子（ＴＮＦ）、白介素－６（ＩＬ－６）和白介素－８（ＩＬ－８）水平的变化及其与内脏功能损害和内毒素血症的关系,旨在阐明细胞因子在创伤后器官功能损害中的作用及其产生机制。结果显示,严重创伤后患者血浆细胞因子水平可相继明显升高,其中ＴＮＦ升高较早,其变化分别与伤情记分（ＩＳＳ）、心肝酶谱、肾功能指标以及血浆内毒素水平呈显著正相关。提示ＴＮＦ、ＩＬ－６和ＩＬ－８参与了严重创伤后器官功能损害的发生发展过程,创伤后细胞因子释放与创伤早期内毒素大量侵入体内有一定关系。     

Levosimendan compared with dobutamine in low output patients

There are 2 studies which have investigated the hemodynamic efficacy of levosimendan compared to dobutamine in congestive heart failure patients. The first is a dose finding comparative 24-h infusion trial which included 95 NYHA II-III patients to different doses of levosimendan and 20 patients to dobutamine administered as a continuous, open-label infusion of 6 microg/kg/min. Efficacy and safety of levosimendan in severe low-output heart failure a randomized, double-blind comparison to dobutamine study compared the short- and long-term efficacy and safety of a single 24-hour infusion of levosimendan (n=103) with dobutamine (n=100) in hospitalised patients in acute heart failure. This double-blind, parallel-group, randomised trial showed that, irrespective of the aetiology of the heart failure, levosimendan produced significantly greater improvement in major determinants of cardiac function in heart failure patients compared to dobutamine. Levosimendan produced significantly greater haemodynamic improvements than dobutamine by significantly reduced mortality at 31 days compared with dobutamine; this reduction was maintained at 180 days. Levosimendan significantly increased the number of days alive and out of hospital, compared with dobutamine. It was better tolerated than dobutamine and fewer patients receiving levosimendan experienced arrhythmias and myocardial ischaemia, compared with dobutamine. Levosimendan produced haemodynamic responses that were unaffected by concomitant use of beta blockers.