Nitric oxide supports atrial function in sepsis: relevance to side effects of inhibitors in shock

The mechanisms underlying myocardial dysfunction in sepsis remain poorly understood. The theoretical benefits of nitric oxide synthase (NOS) inhibition in reversing the haemodynamic changes that characterise septic shock have not been supported by clinical trials, some of which have demonstrated detrimental myocardial effects. We have therefore assessed the effects of endotoxaemia on NOS enzyme expression as well as a number of functional responses of myocardial tissue from rats. Atrial tissue expressed high levels of mRNA for inducible (i) NOS and released increased levels of nitrite after animals were treated with endotoxin. In parallel, the inotropic response stimulated by isoprenaline was reduced in atria from endotoxin-treated animals, an effect that was reversed when endogenous release of NO was maximised. Our results suggest that myocardial contractility is maintained by NO production and that inhibitors may compromise cardiac output; this may explain the deleterious effects of NOS inhibition on cardiac function in clinical trials.     

Vasoconstrictor responsiveness of tail arteries from endotoxaemic rats

This study investigated the anti-allodynic and anti-oedematogenic effects of the hexanic extract, lignan-rich fraction and purified lignans from a plant used in the traditional medicine, Phyllanthus amarus, in the inflammatory and neuropathic models of nociception. The hexanic extract inhibited the allodynia and the oedema induced by the intraplantar injection of complete Freund's adjuvant (CFA). The inhibition observed was 76 +/- 7% (ipsilateral paw), 64 +/- 7% (contralateral paw), and 41 +/- 2% (oedema). Otherwise, the lignan-rich fraction or the pure lignans did not affect CFA-induced allodynia. Administered chronically, the lignan fraction reduced CFA-induced paw oedema (39 +/- 9%). When evaluated in the model of neuropathic pain caused by partial ligation of sciatic nerve, the hexanic extract inhibited the mechanical allodynia (77 +/- 7%), with a similar efficacy to the gabapentin (71 +/- 10%). The anti-allodynic effects of hexanic extract of P. amarus seem not to be associated with the impairment of motor co-ordination or with the development of tolerance. Finally, the treatment with hexanic extract inhibited the increase of myeloperoxidase activity, either following intraplantar injection of CFA or after sciatic nerve injury. It is concluded that, apart from its anti-inflammatory actions, which are probably linked to the presence of lignans, another as yet unidentified active principle(s) present in the hexanic extract of P. amarus produces pronounced anti-allodynia in two models of inflammatory and neuropathic pain. Considering that few drugs are currently available for the treatment of chronic pain, especially of the neuropathic type, the present results may have clinical relevance and open new possibilities for the development of new anti-allodynic drugs.     

生长抑素对重症胰腺炎患者的疗效及TNF-α表达的影响

目的:探讨生长抑素对重症急性胰腺炎(sever acute panc reatitis,SAP)的疗效及肿瘤坏死因子-α(TNF-α)表达的影响。方法:50例SAP患者分为对照组和治疗组,每组各25例,对照组采用常规治疗,治疗组在常规治疗基础上每天加用生长抑素6mg加入0.9%氯化钠注射液1000mL持续24h静脉滴注,用药7～14d。结果:两组临床症状消失,血淀粉酶和尿淀粉酶恢复时间比较,差异有统计学意义(均P<0.05);入院第7天治疗组TNF-α水平显著下降,与对照组差异有统计学意义(P<0.05)。结论:生长抑素能提高胰腺炎的治愈率,其通过抑制炎性因子的释放,减少炎症细胞损伤和细胞因子链的启动,减少内毒素血症和全身并发症的产生。     

Subcutaneous gas tensions closely track ileal mucosal gas tensions in a model of endotoxaemia without anaerobism

Objective Few comparative data exist on the responses of the subcutaneous and splanchnic circulations to evolving endotoxic shock. We therefore compared continuous subcutaneous pO₂ (pO_2sc) and pCO₂ (pCO_2sc) with simultaneous continuous gut luminal pCO₂ (pCO_2gi) in an animal model of endotoxaemia and examined whether changes in gas tensions track tissue energy charge (EC).Design Prospective observational study.Subjects Fourteen anaesthetized rats, 7 controls and 7 experimental.Interventions Controls were injected with saline, the experimental group with 20 mg/kg Klebsiella endotoxin. pCO_2sc, pO_2sc, and pCO_2gi were measured continuously. Plasma lactate concentrations were measured at defined periods during the study. After 2 h ileal segments were snap frozen and assayed for tissue EC.Measurements and results Endotoxaemia resulted in a significant decrease in mean arterial blood pressure (132±9 to 71±20 mmHg) and pO_2sc (71±23 to 33±22 torr) and a significant increase in pCO_2gi (58±10 to 90±20 torr) and pCO_2sc (56±6 to 81±25 torr). During endotoxaemia pCO_2gi was directly correlated with pCO_2sc (R ²=0.5) and inversely correlated with pO_2sc (R ²=0.63). Plasma lactate concentrations were significantly elevated from baseline in the endotoxin limb. The mean EC was not significantly different in the two groups.Conclusions Both subcutaneous tissue gas tensions and intestinal luminal carbon dioxide tensions are rapidly responsive during evolving hypodynamic endotoxic shock. Alterations in tissue gas tensions were not associated with dysoxia.Electronic Supplementary Material Electronic supplementary material to this paper can be obtained by using the Springer Link server located at .This work was made possible by a generous grant from the Australia and New Zealand Intensive Care Society and from institutional funds from the Royal Brisbane Hospital. The Paratrend 7 sensors used in the study were supplied by Diametrics Medical Inc, UK. The work was performed in the Intensive Care Laboratory, Division of Anesthesiology and Critical Care, University of Queensland.     

前列环素及血栓素在实验性肝肾综合征发病中的作用

采用硫代乙酰胺复制大鼠急性肝功能衰竭模型，结果大鼠在出现内毒素血症（ＥＴＭ）的同时，肾功能有明显异常，尿中ＰＧＩ２、ＴＸＡ２及其比值均有异常改变，提示ＥＴＭ的产生与肾脏ＴＸＡ２增多密切相关；ＥＴＭ及ＴＸＡ２均与肾小球滤过率（ＧＦＲ）下降有关。而丹参的防治作用似乎并非仅通过改变ＰＧＩ２、ＴＸＡ２产量及其比值这一单一途径。     

Tigecycline has no effect on cytokine release in an ex vivo endotoxin model of human whole blood

In previous studies, tetracyclines have been shown to decrease the release of cytokines in experimental settings of endotoxaemia. Tigecycline is the first member of the closely related glycylglycines and, due to its broad antimicrobial spectrum, it is considered useful in the treatment of sepsis. We therefore tested its ability to influence the concentrations of the proinflammatory cytokines interleukin (IL)-1β, tumour necrosis factor-alpha (TNFα) and IL-6 in an established ex vivo model of human endotoxaemia. Whole blood from ten healthy volunteers was incubated with either saline (negative control), tigecycline (1 μg/mL [therapeutic concentration] or 100 μg/mL [supratherapeutic concentration]), lipopolysaccharide (LPS; 50 pg/mL, control) or a combination of tigecycline plus LPS (test group). Concentrations of IL-1β, TNFα and IL-6 in the supernatant were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. As expected, incubation with LPS significantly increased the cytokine concentrations in whole blood compared with baseline (P < 0.05). The combination of tigecycline plus LPS did not exert any significant effect on the concentrations of IL-1β, IL-6 and TNFα after 2 h and 4 h of incubation compared with LPS alone. These results indicate that proinflammatory cytokines remained unaffected by tigecycline in an established ex vivo model of systemic inflammatory response.     

Vasopressin release during endotoxaemic shock in mice lacking inducible nitric oxide synthase

We tested the hypothesis that nitric oxide (NO) arising from the action of inducible nitric oxide synthase (iNOS) is responsible for the deficiency in vasopressin (AVP) release and consequent hypotension during endotoxaemic shock. Wild-type (WT) and iNOS knockout mice (iNOS^–/–) were given either saline or Escherichia coli lipopolysaccharide (LPS, 1.0 mg/kg i.v., final volume 0.03 ml). Mean arterial blood pressure (MAP) was measured and plasma AVP levels determined before and after LPS or saline injection. In WT mice, MAP was significantly lower 2 h after LPS administration and remained low for the remainder of the 6-h observation period. AVP plasma levels were increased at the 2nd and 4th h of the experiment, returning thereafter to basal levels. Conversely, LPS injection in iNOS iNOS^–/– mice elicited a sustained increase in plasma AVP concentration and attenuated the fall in blood pressure. These data indicate that NO arising from the iNOS plays an important inhibitory role in AVP release during endotoxaemia and may be responsible for the hypotension occurring during this vasodilatory shock.     

Elevated serum neopterin level: its relation to endotoxaemia and sepsis in patients with major burns

The present study was conducted to determine the relationship between levels of neopterin and endotoxin in the circulation, and whether the neopterin level was related to the development of severe sepsis after extensive burns. This prospective study included 35 patients with burn size greater than 30% (30–98%), and 22 healthy volunteers who served as a comparison group. Neopterin levels increased in most patients on day 3 post-burn, but they were not significantly correlated with the extent of the burn surface ( P  > 0.05). A high serum neopterin level was found in patients with sepsis ( n  = 15), and a marked elevation persisted throughout the observation period. The difference between septic and non-septic patients ( n  = 20) became significant on 14 and 28 days post-burn. Although the presence of early endotoxaemia did not influence the alterations in serum neopterin, patients with endotoxaemia had much higher neopterin values than those who showed no endotoxaemia from the second week onward ( P  < 0.05–0.01). In addition, circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxaemia on day 14 ( r  = 0.368, P  < 0.05) and day 21 ( r  = 0.439, P  < 0.01) after major burns. These results suggest that thermal injury can lead to an elevation of serum neopterin independent of the burn surface area. The initial increase in the neopterin level may be a part of the acute-phase response to tissue injury itself, whereas the endotoxin release in the circulation may be responsible for the continuous induction of neopterin during the late stage. In addition, the presence of a constant high neopterin level is associated with a critical event in the development of severe burn sepsis.     

粪菌移植改善肥胖和糖尿病病人的研究进展

肥胖和2型糖尿病的患病率逐年增高,已成为严重威胁人类健康的全球性疾病,除了生活方式、遗传和环境等传统因素,越来越多的研究表明,肠道菌群在这些代谢性疾病中扮演了关键的角色。近年来,肠道菌群分析成为医学界众多疾病的研究热点,在肥胖、糖尿病病人肠道菌群的分析中发现,肠道菌群组成的改变在系统性慢性炎症的发生、发展中可能起着重要作用。为了更好地防治代谢性疾病,有必要深入了解肠道菌群在机体糖、脂代谢过程中的作用,并从内毒素血症、短链脂肪酸、胆汁酸稳态等角度进行研究。粪菌移植可重建肠道微生态系统,有望成为纠正代谢性疾病肠道菌群紊乱的有效治疗手段。以下介绍肠道菌群在肥胖、2型糖尿病中的变化特点及其诱发代谢性疾病的可能机制,探讨调节肠道菌群作为治疗目标的临床尝试。     

Endotoxaemia in patients with severe sepsis or septic shock

Objective: To examine the incidence and the bacteriological and clinical significance of endotoxaemia in ICU patients with severe sepsis or septic shock. Design: Prospective review. Setting: A 15-bed general ICU in a university hospital. Patients: One hundred sixteen patients hospitalised in our ICU fulfilling Bone's criteria for severe sepsis or septic shock and with an available early endotoxin assay (chromogenic limulus assay). Interventions: None. Measurements and results: The clinical characteristics of the population were: age 63.6 ± 11.4 years; SAPS II: 45.4 ± 15.6; mechanical ventilation: 72.4 %; septic shock: 51.7 % (n = 60); bacteraemia: 28.4 % (n = 33); gram-negative bacteria (GNB) infection 47.4 % (n = 55); ICU mortality: 39.6 % (n = 46). Detectable endotoxin occurred in 61 patients (51.2 %; mean level: 310 ± 810 pg/ml). There was no relationship between detectable endotoxin and severity of infection at the moment of the assay. Endotoxaemia was associated with a higher incidence of bacteraemia (39.3 % vs 16.3 %; p = 0.01). There was a trend (p = 0.09) towards an association between positive endotoxin and gram-negative bacteraemia or GNB infection but this was non-significant. This relationship became significant only in the case of bacteraemia associated with GNB infection irrespective of the site of infection. Conclusion: Early detection of endotoxaemia appeared to be associated with GNB infection only in cases of bacteraemic GNB infection. Early endotoxaemia correlated neither to occurrence of organ dysfunction nor mortality in patients with severe sepsis or septic shock. This study suggests that the use of endotoxaemia as a diagnostic or a prognostic marker in daily practice remains difficult. Received: 28 September 1999 Final revision received: 31 January 2000 Accepted: 1 February 2000