脓毒症及其免疫调理治疗

脓毒症（sepsis）是严重创伤、烧伤、休克、大手术和感染后的常见并发症。美国每年约有75万脓毒症患者,我国每年约有300万例患者发生脓毒症。随着微生物耐药、老年人口的增长以及人们对脓毒症的认识水平的提高,脓毒症发病率还有增加的趋势。现代医学的进步挽救了很多危重病患者的生命。     

Immunomodulating effects of halothane in mice

Twenty mice were acutely exposed to 1.5% halothane anaesthesia for 4 h. The mice were sequentially killed during the first 3 days after halothane exposure. Another 14 mice were chronically exposed to 0.25% halothane for 1 h daily, four times weekly for 3 months. The mice were sequentially killed every week. Acute exposure to halothane anaesthesia resulted in an increase in lymphocyte count per spleen, a decrease in serum IgG concentrations (Day 2), a reduction in spontaneous 3H-thymidine lymphocytic uptake (Day 1), and an increase in concanavalin-A-stimulated uptake. All immunometric assays returned to control levels on Day 3 after halothane exposure. Chronic non-anaesthetic concentrations of halothane exposure produced a decrease in serum IgG concentrations and an increase in spontaneous and stimulated lymphocyte 3H-thymidine uptake. It is concluded that acute exposure of mice to anaesthetic halothane results in a transient depression of the immune response, while chronic non-anaesthetic concentrations produce a differential effect on the two moieties of the immune system, a depressed humoral response and overactive cellular response.     

Effects of alcohol and other drugs on traumatized patients

During a six-month period, blood was drawn from 615 traumatized patients for alcohol determination and general toxicology screen. The patients were divided into four groups: alcohol only, other drugs only, alcohol and other drugs, and no alcohol or other drugs. Each group was analyzed for severity of injury, length of hospitalization, complications, and mortality. In 362 patients (58.9%) we found alcohol in the blood; 74% had alcohol levels greater than 100 mg/dL. Twenty patients (3.3%) had other drugs, while 34 patients (5.5%) had both alcohol and other drugs. There were no differences between the groups except that the patients with drugs only had a significantly higher incidence of shock, severity of injury, and mortality.     

Human recombinant interleukin-1 alpha protection against the lethality of endotoxin and experimental sepsis in mice

Human recombinant interleukin-1 alpha (IL-1) has a diverse range of physiological activities which may be beneficial or deleterious to the host. Pretreatment with doses of IL-1 has been shown to protect mice against a subsequent lethal bacterial injection; however, the protective effects of a single intravenous (iv) dose of IL-1 have not been well characterized. The current experiments were performed to determine the best dose, timing, and duration of action of a single iv dose of IL-1 against a subsequent lethal challenge with intraperitoneal endotoxin (LPS) or experimental sepsis induced by cecal ligation and puncture (CLP). Female C57B1/6 mice treated with iv IL-1 24 hr prior to 30 mg/kg LPS ip had improved survival compared to saline-treated controls (P less than 0.01). IL-1 was also protective when given 6 to 72 hr, but not 2 or 96 hr, prior to LPS. IL-1 protection against LPS lethality was similar to protection seen with an iv dose of tumor necrosis factor (TNF). After CLP, survival was improved with IL-1 versus saline pretreatment (P = 0.02). Unlike previous work with TNF, no toxicity or lethality was observed at any dose of IL-1 administered. A single iv dose of IL-1 protects against the lethality of LPS and CLP in mice. IL-1 may be a useful treatment strategy in patients at risk for the development of life-threatening sepsis.     

Antiviral cellular resistance in acute sepsis]

The antiviral cellular resistance was studied in 22 patients with acute sepsis of different etiology. The acute sepsis was found to develop as a rule against the background of substantially decreased antiviral cellular resistance. So, treatment of this category of patients should include not only antibacterial and antimycotic, but also antiviral methods of therapy.     

Host resistance in sepsis and trauma.

Host resistance to infection was measured by the in vivo response to 5 delayed hypersensitivity antigens and to sensitivity and challenge by dinitrochlorobenzene (DNCB) in 55 seriously ill or injured patients and in 50 preoperative patients. A close correlation between infections, septicemia, death related to infection and anergy was found in the postoperative and post injury patients and was predictive of these complications in the patients studied preoperatively. Decreased body cell mass was noted in both the anergic and non-anergic patients which was consistent with protein-calorie malnutrition but the two groups were not significantly different. A serum factor which inhibited cellular immunity in vitro was found in 4 patients. This factor disappeared in the two patients who recovered. The study suggests the therapeutic value of the in vivo measurement of delayed hypersensitivity in seriously ill and especially preoperative patients in whom specific or non-specific stimulation of cell mediated immunity might alter the risk of infection.     

Anaesthesia affects outcome of sepsis in mice

Purpose

To determine whether the survival curves and rates differ between a mutant strain of mice (C3H/HeJ: endotoxin-resistant) and an endotoxin-susceptible strain (C3H/HeN) when severe sepsis (caecal ligation and puncture: CLP) is performed with different anaesthetics (ketamine or varied exposure to halothane).

Methods

The CLP was performed under a randomly chosen anaesthetic method out of inhalation of halothane in oxygen (15 min, 2 hr, or 6 hr) (100, 120, and 103 mice respectively) or a single injection of ketamineim (127 mice) in paired fashion in eight-week-old male mice of each strain. The daily survival rates were compared between the two strains until the 10th day after CLP for each anaesthetic and among the four anaesthetic methods for each strain using multiple comparisons.

Results

The C3H/HeJ had delayed death relative to the C3H/HeN with every anaesthetic method except a two hours halothane (P < 0.01 at day 1 and day 2–5 in halothane 15 min and 6 hr,P < 0.05 at day 4–6 in ketamine), however, the final survival rates for each method of anaesthesia were the same in the two strains. Regardless of the genetic susceptibility to endotoxin, short exposure to halothane resulted in the most rapid death compared with the other anaesthetic methods (P < 0.05), and two hours halothane showed the best survival.

Conclusion

Endotoxin susceptibility affected the septic course for each anaesthetic method, and the anaesthetic methods influenced the survival from sepsis in both strains.     

Rifampin protection against experimental graft sepsis

The risk of infection in vascular prosthetic conduits appears to be greatest in the perioperative period and the organism most frequently found is Staphylococcus aureus. Previous work suggests that antibiotics must be chemically bonded to the material to resist rapid washout caused by the flow of blood through the graft. The exception to this is rifampin, which remains fixed in Dacron prostheses after passive addition of the agent to aliquots of blood used to clot the interstices of porous Dacron grafts. This characteristic of rifampin is presumed to be caused by its poor water solubility. This potential infection resistance was challenged in a standard model of a canine infrarenal aortic graft by intravenous infusion of S. aureus organisms (10(7)) in the perioperative period. The grafts of five animals were preclotted with 9 ml of autogenous blood plus 1 ml of rifampin (60 mg/ml). A second group had similar procedures with 1 ml of cefazolin (238 mg/ml) substituted for the rifampin, and a control group had 1 ml of saline solution added to the 9 ml aliquot of blood. The animals were killed at 3 weeks and examined for clinically apparent infection. Rings of the graft material were also removed aseptically and cultured. All five grafts preclotted with cefazolin had clinical and culture evidence of infection (S. aureus), as did the grafts of three of the five control dogs. None of the grafts preclotted with rifampin was infected (p less than 0.05). Addition of rifampin to the blood used to clot the graft interstices appears to be a simple way of imparting graft resistance to perioperative sepsis.     

Prophylaxis against sepsis in patients undergoing major surgery

Postoperative infection in general surgical patients is discussed according to operation types. A selection of the huge literature on each group is reviewed, and details from the author's own work and ideas are presented. By discussing these points attempts are made to determine the best regimens for a given set of clinical circumstances. There is a small literature indicating that postoperative chest infection can be prevented by some antibacterial drug regimens, and this question has been addressed; it seems that in the past it has been largely ignored. Some nonantibacterial methods of reducing postoperative infection are also briefly discussed.

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Resumen La sepsis es una causa importante y común de morbilidad y mortalidad postoperatorias. Las complicaciones se presentan hasta en 50% de los casos en algunas series, y al tomar información radiológica solamente la incidencia alcanza hasta el 70%. La incidencia no ha cambiado en los últimos 30 años. En el Departamento de Cirugía de la Universidad de Auckland, Australia, la incidencia luego de cirugía abdominal superior ha estado alrededor de 40%, en forma consistente. Existen numerosos factores de riesgo, que incluyen obesidad, enfermedad pulmonar crónica, anestesia prolongada y edad avanzada. La malnutrición ha sido reconocida como factor de riesgo, y un estudio realizado en este departamento señaló que la depleción proteica predispone a complicaciones pulmonares postoperatorias.El presente artículo se refiere a la infección postoperatoria en pacientes de cirugía general. Los tópicos han sido agrupados de acuerdo al tipo de operación; se ha hecho una relación de la inmensa literatura disponible para cada grupo, y se presentan detalles de los trabajos propios del autor, en un intento por decidir sobre los mejores regímenes profilácticos para cada cuadro clínico en particular. Existe escasa literatura que indique que la infección torácica postoperatoria pueda ser prevenida mediante regímenes antibacterianos, y este aspecto es destacado en el artículo. También se discuten algunos métodos no-antibacterianos en la reducción de la infección postoperatoria.

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Résumé Cet article traite des infections post-opératoires en chirurgie générale. Pour chaque type d'intervention une sélection de l'abondante littérature est passée en revue et des précisions sur la propre étude des auteurs ainsi que leurs idées sur la question sont présentées. En confrontant ces différentes données une conduite à tenir optimale est proposée pour chaque circonstance clinique donnée. Il y a peu d'article dans la littérature concernant la prévention possible des infections respiratoires post-opératoires par l'administration d'antibiotiques et ce point a été souligné puisqu'il semble que cela ait été largement ignoré par le passé. Quelques moyens visant à réduire le nombre d'infections post-opératoires et qui ne font pas appel à des antibiotiques sont également brièvement envisagés.

     

Immunomodulating therapy in perforated peritonitis

The immunological responsiveness was studied in 160 patients with generalized peritonitis. In the postoperative period, 51 patients underwent immunomodulating therapy. The highest effect was produced by transfusion of 300-400 ml leukoconcentrate.     

一种改良小鼠脓毒症模型的建立

目的 建立一种模拟外科临床实际,早期致死率低,用于脓毒症综合治疗研究的小鼠模型.方法 小鼠随机分为3组,即对照组、盲肠结扎穿孔(CLP)组和改良组.对照组行假手术;CLP组行盲肠结扎穿孔术;改良组通过CLP后8 h行盲肠切除和腹腔生理盐水冲洗建立脓毒症模型.观察各组动物出现死亡时间及24、48、72 h累计死亡率;术后4、12、24 h分别处死动物,检测外周血白细胞计数(VC-BC),血清内毒素、肿瘤坏死因子(TNF)水平及肺、肝病理.结果 改良组动物出现死亡时间较CLP组明显延迟,术后48、72 h累计死亡率虽明显低于CLP组(P＜0.05),但仍分别高达53.3%、80%;术后各时间点WBC较CLP组与假手术组明显升高(P＜0.05);血清内毒素和TNF-α水平明显高于假手术组,但低于CLP组;光镜下见肺泡间隔增宽,间质充血、水肿、大量炎性细胞浸润,肝细胞水肿伴散在点状坏死,肝窦扩张伴间质大量炎性细胞浸润.结论 该脓毒症改良模型具有良好的外科临床相关性,早期致死率低,可重复性好.     

Casitas b-lineage lymphoma-deficient mice are protected against high-fat diet-induced obesity and insulin resistance

Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl(-/-) mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated energy expenditure. In the study reported here, we examined the effect of a high-fat diet on energy homeostasis and glucose metabolism in these animals. When c-Cbl(-/-) mice were fed a high-fat diet for 4 weeks, they maintained hyperphagia, higher whole-body oxygen consumption (27%), and greater activity (threefold) compared with wild-type animals fed the same diet. In addition, the activity of several enzymes involved in mitochondrial fat oxidation and the phosphorylation of acetyl CoA carboxylase was significantly increased in muscle of high-fat-fed c-Cbl-deficient mice, indicating a greater capacity for fat oxidation in these animals. As a result of these differences, fat-fed c-Cbl(-/-) mice were 30% leaner than wild-type animals and were protected against high-fat diet-induced insulin resistance. These studies are consistent with a role for c-Cbl in regulating nutrient partitioning in skeletal muscle and emphasize the potential of c-Cbl as a therapeutic target in the treatment of obesity and type 2 diabetes.     

白介素2对创伤小鼠细胞免疫功能及感染后死亡率的影响

利用小鼠截肢伤模型，观察白介素２（ＩＬ－２）在体内对创伤小鼠细胞免疫功能及感染后死亡率的影响。结果显示，创伤后小鼠迟发型皮肤超敏反应（ＤＴＨ），Ｔ淋巴细胞转化，ＩＬ－２的产生，ＩＬ－２受体（ＩＬ－２Ｒ）的表达，ＩＬ－２ｍＲＮＡ及ＩＬ－２ＲｍＲＮＡ水平均明显受抑。ＩＬ－２体内应用可明显逆转创伤小鼠ＤＴＨ反应，Ｔ淋巴细胞转化，ＩＬ－２Ｒ及ＩＬ－２ＲｍＲＮＡ的受抑状态，此外ＩＬ－２时创伤小鼠经盲肠结扎穿     

盲肠不同部位结扎穿孔致脓毒症模型的研究

目的 通过盲肠不同部位结扎穿孔致脓毒症模型的研究,探索一种理想的、符合临床病理过程的脓毒症模型。方法 40只C57bL/6雄性小鼠按随机化原则分为两组,即盲肠结扎穿孔组（CLP）和假手术组（sham）,前者根据盲肠结扎部位和程度又分为轻度脓毒症组（Min）、中度脓毒症组（Mod）、重度脓毒症组（Sev）,每组10只,分别结扎盲肠25%、50%、75%（从盲肠远端起至回盲瓣）,sham组仅行开腹、关腹程序。造模后24 h取血样,测定血清TNFα浓度;按照肠粘膜损伤分级评估肠粘膜损伤程度;另外40只C57bL/6雄性小鼠造模后做死亡生存分析。结果 TNF水平、肠粘膜损伤程度和脓毒症严重程度呈正相关;假手术组死亡率为0,轻度脓毒症为10%,中度为40%,重度为100%。结论 中度脓毒症模型是符合临床的一种理想动物模型。     

Penicillin and natural immunity protect against postsplenectomy sepsis

Prophylactic penicillin, splenic autotransplantation, and immunization using pneumococcal vaccine have all been shown to reduce the incidence and mortality of postsplenectomy sepsis. However, little is known regarding the effect of penicillin in established infection or the effect of prior infection in either asplenic controls or animals with autotransplanted splenic tissue. An animal model with bacterial introduction via the lungs was used to investigate the effect of penicillin, splenic autotransplantation, and previous exposure to the infecting organism on the mortality of postsplenectomy sepsis. One hundred fifty-nine rats underwent either sham celiotomy, intraperitoneal splenic autotransplantation, or splenectomy. Twelve weeks postoperatively all animals were challenged using Streptococcus pneumoniae delivered transtracheally. Half of each group received procaine penicillin by intramuscular injection for 5 days beginning 24 hr post bacterial inoculation and mortality was observed. Eight weeks later surviving rats that had received penicillin were reinoculated with the same organism and mortality was again observed. Splenic autotransplantation reduced the early mortality in postsplenectomy sepsis. Prior bacterial exposure reduced the mortality in postsplenectomy sepsis, even in splenectomized animals. Treatment with penicillin produced a marked reduction in mortality even when administration was postponed for 24 hr after bacterial inoculation.