Circulatory shock最新文献

Plasma levels of glutathione disulfide (GSSG) as an indicator of a vascular oxidant stress, tumor necrosis factor-alpha (TNF-alpha) formation, and liver injury (alanine aminotransferase activity, histology) were monitored in male Fischer rats after 30 min of hepatic ischemia followed by up to 4 hr of reperfusion. The injection of 1 mg/kg Salmonella enteritidis endotoxin at 30 min of reflow potentiated the postischemic oxidant stress and liver injury. TNF-alpha levels increased from 10 +/- 7 pg/ml (baseline) to 3,553 +/- 738 pg/ml after ischemia-reperfusion followed by endotoxin, or to 3,670 +/- 508 pg/ml after endotoxin alone. Depletion of serum complement before ischemia attenuated the endotoxin-mediated increase of reactive oxygen formation by 70% but did not affect TNF-alpha levels. Complement activation with cobra venom factor (CVF) during reperfusion had an effect similar to that of endotoxin on the oxidant stress and liver injury. CVF did not increase TNF-alpha formation during reperfusion. Kupffer cells and neutrophils isolated from the postischemic liver 2.5 hr after endotoxin injection generated 600% and 400% more superoxide, respectively, than cells isolated from control livers. The results demonstrate a substantial priming of hepatic phagocytes for reactive oxygen production but not TNF-alpha formation, even after short periods of hepatic ischemia, and the vulnerability of the postischemic liver to severe endotoxin-induced injury. Activated complement seems to be mainly responsible for the effects. These results may explain the high risk for hepatic failure after extensive liver resection and hypovolemic shock.

Hydrazine sulfate pretreatment has previously been shown in our laboratory to protect normal mice against endotoxin and D-galactosamine-sensitized mice against both exogenous tumor necrosis factor (TNF) and endotoxin. An intact pituitary is required for manifestation of the protective effects. Further, we have demonstrated that hydrazine sulfate pretreatment specifically modulates the TNF response to lipopolysaccharide (LPS) in mouse macrophages in vitro. This in vivo study was performed to test whether a reduced TNF response and/or increased glucocorticoid response may contribute to hydrazine sulfate protection against LPS-induced lethality in vivo. The results presented here establish that hydrazine sulfate pretreatment selectively attenuates circulating TNF levels following LPS challenge. Moreover, adrenalectomy abrogates hydrazine sulfate protection but does not prevent hydrazine sulfate attenuation of circulating TNF levels in response to LPS. Hydrazine sulfate-mediated protection is, however, restored permissively by corticosterone. Thus, the mechanism by which hydrazine sulfate protects against LPS lethality in adrenalectomized mice includes TNF modulation in response to endotoxin, as well as a pivotal requirement for glucocorticoid.

An experimental disseminated intravascular coagulation (DIC) was induced in female CD rats by the intravenous administration of living bacteria (9.5 x 10(7) cfu Klebsiella pneumoniae), sublethal (5 mg/kg) or lethal (50 mg/kg) lipopolysaccharide (LPS), or tissue factor (1.5 micrograms/kg i.v. bolus or 0.4 micrograms/kg x hr i.v. infusion). We used a new fibrin monomer (FM) assay to follow the course of DIC. FM were detected by their ability to stimulate the tissue-type (t-PA) plasminogen activator dependent conversion of plasminogen to plasmin by a chromogenic assay. Miniplasminogen was used instead of plasminogen to avoid interference of the assay by alpha 2-antiplasmin. As a marker of DIC, elevated levels of FM were observed with all DIC-inducing agents (plasma levels were up to 90 micrograms/ml). The kinetics of FM formation were similar to the course of thrombin-antithrombin III (TAT) levels (maximal plasma levels 70 ng/ml); however, in the bacterial infection group, both parameters rose after a lag phase of about 1 hr. A 4 hr infusion of the highly specific thrombin inhibitor recombinant (rec.) hirudin (0.125 mg/kg x hr) resulted in a decrease of FM levels from 89.2 +/- 14.4 micrograms/ml in the LPS group (n = 10) to 27.4 +/- 11.2 micrograms/ml in the rec. hirudin group (n = 10; P < 0.001). The respective values for TAT levels were 73.1 +/- 19.7 micrograms/ml in the LPS group and 52.7 +/- 15.7 ng/ml in the rec. hirudin group (P < 0.001). Other coagulation parameters, such as platelets, fibrinogen, and fibrin(ogen) degradation products, were ameliorated accordingly.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to examine the role of Kupffer cells in polymorphonuclear neutrophils (PMN) activation and infiltration after severe total hepatic ischemia. Male rats pretreated with either normal saline (NS group; n = 58) or gadolinium chloride (7 mg/kg; GC group, n = 57) for 2 days were subjected to 90 min total hepatic ischemia. In addition to 7-day survival rate, aspartate aminotransferase (AST), PMN liver infiltration, plasma myeloperoxidase (MPO), and interleukin-1 (IL-1) levels were serially measured from the end of ischemia to 360 min after reperfusion. Survival rate of the GC group significantly improved to 67% (P < 0.01), whereas that of the NS group remained at 20%. Extremely high AST levels (5,372 +/- 231 IU/liter) were obtained in the NS group, which correlated with the degree of hepatic necrosis. Very high IL-1 (270.3 +/- 91.2 pg/ml) and MPO (1.7 +/- 0.4 U/ml) levels were also seen in the NS group. The GC group significantly inhibited increases in AST, IL-1, and MPO levels as well as PMN infiltration in the liver compared to the NS group (P < 0.05). Our study demonstrated that Kupffer cell activation has an important role in the development of reperfusion injury after total hepatic ischemia through IL-1 release, and PMN activation and infiltration.

Although it has been hypothesized that exogenously administered bicarbonate can exacerbate intramyocardial acidosis and compromise contractile function, this phenomenon has not been demonstrated in an intact model in which intramyocardial pH (pH(int)), regional venous pCO2, and regional contractile function have been simultaneously monitored. In 20 anesthetized dogs, we studied the effects of intracoronary infusions of sodium bicarbonate NaHCO3 30 mEg over 15 min, on regional pH(int), (glass electrode) and regional stroke work (SW, sonomicrometry) before and after creating systemic hypercarbic acidosis by hypoventilation. During NaHCO3 administration, regional coronary venous pCO2 increased rapidly during the first minute (eucapnea; 34 +/- 7 to 55 +/- 18 mm Hg; hypercapnea: 70 +/- 15 to 98 +/- 23 mm Hg, P < 0.05 for both increases). Regional venous pH rose from 7.36 +/- .04 to 7.55 +/- .06 (P < 0.05) after the first minute of NaHCO3 infusion during eucapnea and from 7.09 +/- .09 to 7.22 +/- .09 (P < 0.05) during hypercapnea. During the first minute of NaHCO3 infusion, pH(int) declined minimally. However, during the remaining 14 min of each infusion, pH(int) increased significantly (eucapnea: 7.19 +/- 0.10 to 7.43 +/- 0.12; hypercapnea: 6.86 +/- 0.14 to 7.02 +/- 0.15, P < 0.05 for both changes). Regional SW decreased significantly during the first minute of infusion, both during eucapnea (23,400 +/- 7,400 to 18,000 +/- 6,300 ergs/cm2, P < 0.05) and hypercapnea (27,000 +/- 9,100 to 25,000 +/- 10,000 ergs/cm2, P < 0.05). The first minute of contractile dysfunction was followed by recovery and ultimately supranormal contractile function during the remainder of each bicarbonate infusion. To test the hypothesis that transient intracellular acidosis during bicarbonate infusions was underestimated by measurements of pH(int), measurements of intracellular pH using the pH-sensitive dye, BCECF, were performed in isolated guinea pig papillary muscles incubated in vitro. These measurements confirmed the presence of transient intracellular acidosis during bicarbonate infusion. In conclusion, (1) the intracoronary administration of sodium bicarbonate causes a transient depression in myocardial contractile function that is related to transient intracellular acidosis; and (2) despite exacerbating hypercarbia, sodium bicarbonate ultimately neutralizes intracellular acid and augments myocardial contractile function.

To evaluate the clinical relevance of the experimental findings of a more severe cardiac depression in Pseudomonas (P.) than in non-P. sepsis, we retrospectively compared the hemodynamic data in 26 patients with P. sepsis (20 cases, single pathogen; six cases, more positive cultures with P. than with non-P. species), and 102 with non-P. sepsis. As in other studies, the left ventricular stroke work index (LVSWI) was used to assess cardiac performance. The two groups (all numbers are means) had a similar disease and sepsis severity profile (P. vs. non-P: septic shock, 81% vs. 87%; APACHE II scores, 29.1 vs. 29.2; Elebute sepsis scores, 18.1 vs. 18.1; mortality, 58% vs. 62%). Preload (pulmonary capillary wedge pressure 15.0 vs. 16.3 mm Hg) and systemic vascular resistance (588 vs 572 dyn.cm-5.sec) were comparable. Cardiac performance displayed no significant difference (LVSWI, 42.8 vs. 38.3 g.m/m2), a result reproduced in the subgroups with culture-proven bacteremia, with or without preexisting cardiovascular disease or septic shock. Thus, our data suggest that there is no difference in the degree of cardiovascular dysfunction in patients with Pseudomonas compared to non-Pseudomonas sepsis of otherwise equivalent disease severity.

We studied the effect of dynorphin A-(1-13), dynorphin A-(1-17), des-tyr dynorphin A-(2-17) (inactive at opioid receptor) or normal saline (NS) microinjected into the paraventricular nucleus (PVN) (n = 9/treatment) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and left ventricular stroke work (LVSW) during fixed-volume hemorrhage in conscious rats. Microinjection of dynorphin A-(1-13) (6 nmol) into PVN at 15 min following the termination of fixed volume hemorrhage (8 ml/300 g) significantly decreased MAP from 50 min to 2 hr postinjection (P < 0.05 compared to animals receiving NS), while dynorphin A-(1-17) (6 nmol) significantly decreased MAP from 30 min up to 2 hr postinjection (P < 0.05). Microinjection of des-tyr dynorphin A-(2-17) (6 nmol) into the PVN did not significantly affect MAP following hemorrhage. Recovery of MAP in the dynorphin A-(1-13) and dynorphin A-(1-17) groups following hemorrhage was found to be significantly attenuated compared to the NS group (P < 0.05 and P < 0.01, respectively). Dynorphin A-(1-13) increased heart rate at 20 min and decreased stroke volume at 60 min after microinjection directly into the PVN following hemorrhage when compared with the NS group (P < 0.05). Both dynorphin A-(1-13) and dynorphin A-(1-17) significantly decreased LVSW after PVN injection following hemorrhage compared to NS group (both P < 0.05). No significant effects were observed on CO following microinjection of active or inactive opioid peptides into the PVN following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertonic saline (HTS) resuscitation improves outcome after trauma. We studied the effect of HTS on immune function. In vitro T-cell proliferation of human and rabbit peripheral blood mononuclear cells (PBMC) was doubled at 25 mM increased extracellular Na+ concentrations. Further increased hypertonicity (more than 40 mM with human cells, and 80 mM with rabbit cells) caused progressive suppression of proliferation. Human and rabbit monocyte functions (tumor necrosis factor production) were augmented by 300% at 30 mM hypertonicity, indicating that HTS-enhanced accessory cell function of monocytes may cause increased T-cell proliferation. Substitution of HTS with KCl also enhanced T-cell proliferation, suggesting an involvement of osmotic effects. HTS (up to 30 mM) increased Ca2+i of nonstimulated human PBMC. HTS injection in rabbits increased cell-mediated immune function (delayed-type hypersensitivity reaction). Our findings suggest that increased plasma osmolality may up-regulate cellular immune function. HTS resuscitation of trauma patients may thus reverse posttraumatic immunosuppression and reduce the risk of sepsis.

Effects of treatment in vivo and in vitro with lipopolysaccharide (LPS) on the responsiveness of rat thoracic aorta were examined. The endothelium-denuded aortic strips isolated 6 hr after intraperitoneal (i.p.) administration of LPS (20 mg/kg), which could produce hemodynamic changes, relaxed in response to L-arginine. The same amplitude of relaxation was produced by L-arginine in the aortic strips incubated with a lower dose of LPS (1 microgram/ml) in vitro for 6 hr. Both relaxing responses were inhibited by NG-nitro-L-arginine (L-NOARG). The contractile responses to phenylephrine and KCl were reduced by LPS treatment in vivo or in vitro, but the extent of inhibition was greater in vivo than in vitro. Further, the attenuation of contractile responses was completely reversed by L-NOARG in the strips treated in vitro, whereas the reversal by L-NOARG was incomplete in the strips treated with LPS in vivo. Endothelium-dependent relaxation induced by acetylcholine was attenuated by LPS in vivo but not in vitro. These results suggest that the hyporesponsiveness of rat thoracic aorta after treatment in vitro with LPS, which can produce hemodynamic changes, may be related to an enhanced NO production in the smooth muscle cells, while not only the NO pathway but also additional factors may be involved in the vascular hyporesponsiveness of the sepsis rats.

The relationship of translocation of bacteria from the gut of burned guinea pigs and the in vitro production of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, and prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-stimulated mesenteric lymph node and splenic macrophages was investigated at two early times after thermal injury. Two hr postburn, there was a large number of translocated bacteria in the mesenteric lymph nodes and a large proportion was killed; at 24 hr postburn, there were fewer translocated bacteria, but a large proportion was viable. In some cases, there were very large differences compared to controls in the amounts of TNF, IL-6, and PGE2, but not of IL-1, produced by the macrophages at different times postburn and at different in vitro incubation times. The results suggest that the macrophages were primed by the burn or the translocated bacteria to produce in vitro different and sometimes large amounts of cytokines or PGE2 after further stimulation with LPS. Although there was no direct correlation between production of cytokines or PGE2 and time postburn, the early increased production of PGE2 by splenic macrophages could have depressed the animal's ability to kill translocated bacteria by 24 hr postburn, and could be one of the mechanisms of the cause of systemic infection after burn injury.