Experimental Endotoxin Shock Research Articles

Choline or CDP-choline restores hypotension and improves myocardial and respiratory functions in dogs with experimentally – Induced endotoxic shock

Endotoxin shock is associated with severe impairments in cardiovascular and respiratory functions. We showed previously that choline or cytidine-5′-diphosphocholine (CDP-choline) provides beneficial effects in experimental endotoxin shock in dogs. The objective of the present study was to determine the effects of choline or CDP-choline on endotoxin-induced cardiovascular and respiratory dysfunctions.Dogs were treated intravenously (i.v.) with saline or endotoxin (LPS, 0.1 mg/kg) 5 min before i.v. infusion of saline, choline (20 mg/kg) or CDP-choline (70 mg/kg). Blood pressure, cardiac rate, myocardial and left ventricular functions, respiratory rate, blood gases, serum electrolytes and cardiac injury markers were determined before and at 0.5-48 h after endotoxin. Plasma tumor necrosis factor alpha (TNF-α), high mobility group box-1 (HMGB1), catecholamine and nitric oxide (NO) levels were measured 2 h and 24 h after the treatments.Endotoxin caused immediate and sustained reductions in blood pressure, cardiac output, pO2 and pH; changes in left ventricular functions, structure and volume parameters; and elevations in heart rate, respiratory rate, pCO2 and serum electrolytes (Na, K, Cl, Ca and P). Endotoxin also resulted in elevations in blood levels of cardiac injury markers, TNF-α, HMGB1, catecholamine and NO. In choline- or CDP-choline-treated dogs, all endotoxin effects were much smaller in magnitude and shorter in duration than observed values in controls.These data show that treatment with choline or CDP-choline improves functions of cardiovascular and respiratory systems in experimental endotoxemia and suggest that they may be useful in treatment of endotoxin shock in clinical setting.

Generalized Shwartzman Reaction as an Experimental Endotoxin Shock Model: Role of Intermediate T Cell Receptor-Expressing Innate T Lymphocytes in its Pathogenesis

Endotoxin and its induced exaggerative responses of proinflammatory cytokines such as Tumor Necrosis Factor (TNF) cause human septic shock. The generalized Shwartzman reaction is considered as an experimental endotoxin shock model and its representative features are high lethality and hypersensitive inflammatory response to endotoxin, in particular excessive TNF production. The generalized Shwartzman reaction can be induced by Interleukin (IL)-12 priming and subsequent endotoxin challenge. IL-12 primes the intermediate T cell receptor (TCR)-expressing innate T lymphocytes (natural killer T cells and CD8+CD122+ T cells in mice, CD56+ T cells and CD57+ T cells in human) to produce IFN-γ, which in turn preconditions macrophages to produce a large amount of TNF in response to endotoxin. These intermediate TCR innate T lymphocytes play a pivotal role for the occurrence of this generalized Shwartzman reaction. Some of the intermediate TCR-expressing innate T lymphocytes (CD8+CD122+ T cells in mice and CD57+ T cells in human), which are considered as extrathymically developed T lymphocytes, are increased with age and closely involved in age-dependent augmentation of murine generalized Shwartzman reaction and human Shwartzman-like reaction, which may reflect an exacerbation of septic shock in elderly. However, these intermediate TCR innate T lymphocytes normally augment host immunity against malignant tumors and refractory bacterial infections, which are critical threats in aged hosts. Thus, intermediate TCR-expressing innate T lymphocytes may be a double-edged sword on the host defense, especially elderly hosts.

Immune Mechanisms Underlying Susceptibility to Endotoxin Shock in Aged Hosts: Implication in Age-Augmented Generalized Shwartzman Reaction.

In recent decades, the elderly population has been rapidly increasing in many countries. Such patients are susceptible to Gram-negative septic shock, namely endotoxin shock. Mortality due to endotoxin shock remains high despite recent advances in medical care. The generalized Shwartzman reaction is well recognized as an experimental endotoxin shock. Aged mice are similarly susceptible to the generalized Shwartzman reaction and show an increased mortality accompanied by the enhanced production of tumor necrosis factor (TNF). Consistent with the findings in the murine model, the in vitro Shwartzman reaction-like response is also age-dependently augmented in human peripheral blood mononuclear cells, as assessed by enhanced TNF production. Interestingly, age-dependently increased innate lymphocytes with T cell receptor-that intermediate expression, such as that of CD8+CD122+T cells in mice and CD57+T cells in humans, may collaborate with macrophages and induce the exacerbation of the Shwartzman reaction in elderly individuals. However, endotoxin tolerance in mice, which resembles a mirror phenomenon of the generalized Shwartzman reaction, drastically reduces the TNF production of macrophages while strongly activating their bactericidal activity in infection. Importantly, this effect can be induced in aged mice. The safe induction of endotoxin tolerance may be a potential therapeutic strategy for refractory septic shock in elderly patients.

Cerebral metabolism during experimental endotoxin shock and after preconditioning with monophosphoryl lipid A

PurposePreconditioning with low doses of monophosphoryl lipid A (MPL) has been shown to induce endotoxin tolerance and to reduce the metabolic and hemodynamic consequences of endotoxin shock. However, no data are available about the effects of endotoxin preconditioning on cerebral metabolism during endotoxemia. The study was designed to determine the effects of endotoxin preconditioning with MPL on cerebral metabolism via microdialysis compared to muscle tissue metabolism during experimental endotoxemia. MethodsIn a controlled animal study, continuous endotoxin infusion (1μg/kg b.w. per h) was administrated to 7 female mixed-breed pigs after pretreatment with MPL in incremental doses of endotoxin during days 5–2 before the experiments. In the control group, 7 animals received a saline pretreatment. In addition to hemodynamic monitoring and blood gas analyses, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle and cerebral tissue were measured using in vivo microdialysis. ResultsThere were no significant differences between the two groups with respect to hemodynamic parameters, while mixed venous oxygen saturation (SvO2), arterial blood pH and mean pulmonary arterial pressure (MPAP) were significantly higher in the preconditioned group. Cerebral perfusion pressure (CPP) and brain tissue oxygen pressure (ptiO2) values stayed stable throughout the experiment with no inter-group differences. While interstitial concentrations of lactate and glycerol as well as the lactate/pyruvate (LP) and the lactate/glucose (LG) ratio in muscle tissues were significantly increased in control animals compared to those who had been pretreated with MPL; the results of cerebral microdialysis showed no significant changes in interstitial lactate or glycerol levels in both groups. However, the lactate/glucose (LG) ratio in the control group showed a significantly higher increase than in the preconditioned group. ConclusionsPreconditioning with low doses of MPL ameliorates the negative metabolic effects of endotoxin shock in muscle tissue. With regard to cerebral metabolism, the present study suggests that MLP preconditioning provides moderate advantages, at least in an experimental model of endotoxin shock.

Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice

Although ursodeoxycholic acid (UDCA) has long been used for patients with chronic cholestatic liver diseases, particularly primary biliary cirrhosis, it may modulate the host immune response. This study investigated the effect of UDCA feeding on experimental hepatitis, endotoxin shock, and bacterial infection in mice. C57BL/6 mice were fed a diet supplemented with or without 0.3% (wt/vol) UDCA for 4 wk. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-γ production by liver mononuclear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it increased mortality of mice following Escherichia coli infection due to the worsening of infection. UDCA-fed mice showed suppressed serum IL-18 levels and production of IL-18 from liver Kupffer cells, which together with IL-12 potently induce IFN-γ production. However, unlike normal mice, exogenous IL-18 pretreatment did not increase the serum IFN-γ levels after E. coli, LPS, or Con-A challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC of the UDCA-fed mice but not in their whole liver tissue homogenates. Silencing GR in the liver MNC abrogated the suppressive effect of UDCA on LPS- or Con-A-induced IFN-γ production. Furthermore, RU486, a GR antagonist, restored the serum IFN-γ level in UDCA-fed mice after E. coli, LPS, or Con-A challenge. Taken together, these results suggest that IFN-γ-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18-independent manner.

Epinephrine induces tissue perfusion deficit in porcine endotoxin shock: evaluation by regional CO2 content gradients and lactate-to-pyruvate ratios

Epinephrine is widely used as a vasoconstrictor or inotrope in shock, although it may typically induce or augment lactic acidosis. Ongoing debate addresses the question of whether hyperlactatemia per se is a sign of tissue perfusion deficit or aerobic glycolysis. We wanted to test the hypothesis that epinephrine has selective detrimental effects on visceral perfusion and metabolism. We performed rigorous regional venous blood gas analyses as well as intraperitoneal microdialysis. We used a mathematical model to calculate regional arteriovenous CO(2) content gradients and estimated the magnitude of the Haldane effect in a porcine model of prolonged hypotensive shock induced by endotoxin infusion (mean arterial blood pressure < 60 mmHg). Subsequently, vasopressors (epinephrine or norepinephrine) were administered and adjusted to maintain systemic mean arterial pressure > 70 mmHg for 4 h. Epinephrine caused systemic hyperlactatemia and acidosis. Importantly, both systemic and regional venous lactate-to-pyruvate ratios increased. Epinephrine was associated with decreasing portal blood flow despite apparently maintained total splanchnic blood flow. Epinephrine increased gastric venous-to-arterial Pco(2) gradients and CO(2) content gradients with decreasing magnitude of the Haldane effect, and the regional gastric respiratory quotient remained higher after epinephrine as opposed to norepinephrine infusion. In addition, epinephrine induced intraperitoneal lactate and glycerol release. We did not observe these adverse hemodynamic or metabolic changes related to norepinephrine with the same arterial pressure goal. We conclude that high CO(2) content gradients with decreasing magnitude of the Haldane effect pinpoint the most pronounced perfusion deficiency to the gastric wall when epinephrine, as opposed to norepinephrine, is used in experimental endotoxin shock.

Dopexamine reverses colonic but not gastric mucosal perfusion defects in lethal endotoxin shock

Whilst dopexamine appears to increase overall splanchnic blood flow in postoperative and septic patients, the effects on gastric mucosal perfusion are controversial and based on concomitantly increasing mucosal to arterial PCO(2) gradients (PdCO(2)). We hypothesized that dopexamine alters splanchnic blood flow distribution and metabolism during experimental endotoxin shock and modifies the inflammatory response induced by endotoxin. In an experiment with anaesthetized normovolaemic, normoventilated pigs, 21 animals were randomized into: (i). subacute lethal endotoxin shock for 14 h (n=7 at baseline); (ii). endotoxin shock with dopexamine infusion (aiming to exceed baseline cardiac output, n=7); or (iii). controls (n=7). Regional blood flow and metabolism were monitored. Endotoxin produced a hypodynamic phase followed by a normo/hyperdynamic, hypotensive phase. Despite increasing systemic blood flow in response to dopexamine, proportional splanchnic blood flow decreased during the hypodynamic phase. Dopexamine gradually decreased fractional coeliac trunk flow, while fractional superior mesenteric arterial flow increased. Dopexamine induced early arterial hyperlactataemia and augmented the gastric PdCO(2) gradient while colonic luminal lactate release and colonic PdCO(2) gradient were reversed. Dopexamine did not modify the inflammatory response as evaluated by arterial IL-1beta and IL-6 concentrations. Dopexamine protects colonic, but not gastric mucosal epithelium in experimental endotoxin shock. This may be related to redistribution of blood flow within the splanchnic circulation.

Apparent heterogeneity of regional blood flow and metabolic changes within splanchnic tissues during experimental endotoxin shock.

We conducted a randomized, controlled experiment of prolonged lethal endotoxin shock in pigs aiming at 1) simultaneously measuring perfusion at different parts of the gut to study the potential heterogeneity of blood flow within the splanchnic region; 2) studying the association among regional blood flows, oxygen supply, and different metabolic markers of perfusion; and 3) analyzing the association between histological gut injury and markers of perfusion and metabolism. The primary response to endotoxin was a decrease in systemic and splanchnic blood flow followed by hyperdynamic systemic circulation. Redistribution of blood flows occurred within the splanchnic circulation: superior mesenteric artery blood flow was maintained, whereas celiac trunk blood flow was compromised. Mucosal to arterial PCO(2) gradients did not reflect changes in total splanchnic perfusion, but they were associated with regional blood flows during the hypodynamic phase of shock. During hyperdynamic systemic circulation, PCO(2) gradients increased heterogeneously in the gastrointestinal tract, whereas luminal lactate increased only in the colon. Histological analysis revealed mucosal epithelial injury only in the colon. We conclude that markers of perfusion and metabolism over one visceral region do not reflect perfusion and metabolism in other splanchnic vascular areas. Intestinal mucosal epithelial injury occurs in the colon during 12 h of endotoxin shock while the epithelial injury is still absent in the jejunum. Hyperdynamic and hypotensive shock induces gut luminal lactate release in the colon but not in the jejunum. The association or causality between the mucosal epithelial injury and luminal lactate release remains to be elucidated. Surrogate regional markers of tissue perfusion over one region do not reflect the state of perfusion over another. Therefore, regional metabolic monitoring (microdialysis) in multiple locations is needed. Although tonometry does not differentiate between macro-level regional perfusion defect and tissue injury, intestinal luminal microdialysis detects mucosal lactate release, which may be associated with epithelial injury. The degree of correlation or causality between the two remains to be evaluated.

Increased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice

Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI−/− mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI−/− mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI−/− macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor κB activities after LPS treatment than do SLPI+/+ macrophages. SLPI also affects B cell function. SLPI−/− B cells show more proliferation and IgM production after LPS treatment than SLPI+/+ B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity.

Pulmonary impedance and right ventricular-vascular coupling in endotoxin shock.

We tested the hypothesis that right heart failure during endotoxin shock may result from altered ventriculovascular coupling responsible for impeding power transfer to the pulmonary circulation. The changes in vascular pulmonary input impedance and right ventricular contractility produced by low-dose endotoxin infusion were studied in 6 intact anesthetized dogs. Endotoxin insult resulted in pulmonary hypertension (from 22 +/- 2 to 33 +/- 3 mmHg) associated with significant decreases in stroke volume (from 26.9 +/- 4 to 20.2 +/- 3 ml) and right ventricular ejection fraction (from 41 +/- 3 to 32 +/- 2%). The first minimum of input impedance spectrum and zero phase were shifted towards higher frequencies. Input resistance and characteristic resistance were dramatically increased. The latter change contributed to a significant increase in the pulsatile component of total right ventricular power output from 13 to 21%, indicating a reduction in the hydraulic right ventricle power output delivered into the main pulmonary artery. Overall changes in input pulmonary impedance were indicative of increased afterload facing the right ventricle leading to depressed performance. In contrast, right ventricular systolic elastance was simultaneously increased from 0.56 to 0.93 mmHg/ml indicating an increase in right heart contractility. These data suggest that pulmonary hypertension in the setting of experimental endotoxin shock is accompanied by deleterious changes in the pulmonary impedance spectrum, which are responsible for a mismatch of increased contractile state of the right ventricle to the varying hydraulic load ultimately leading to ventricular-vascular uncoupling.

Tachyphylaxis of the B1 kinin receptor in porcine endotoxin shock

Previous experiments in anesthetized pigs have demonstrated that blockade of the bradykinin B2 receptor in experimental endotoxin shock attenuates LPS-induced organ failure, lung dysfunction and mortality. Additional B1 receptor blockade in this situation seems to counteract the beneficial effects of B2 blockade. This suggests that the upregulation of B1 receptors during porcine LPS shock may be a useful mechanism of host defense. Furthermore, infusion of a B1 agonist during septic shock may be of therapeutic benefit. In order to prepare an experiment with B1 stimulation in LPS shock, we conducted a study in anesthetized pigs, in which the B1 receptor has been upregulated by infusion of bacterial lipopolysaccharide (LPS), by evaluating the effect of constant intravenous infusions of the B1 agonist des-Arg10-kallidin on the hypotensive response to bolus doses of this agonist. Following infusions of lipopolysaccharide from S. abortus equi, anesthetised pigs received repeated intra-arterial bolus injections of des-Arg10-kallidin before and during continuous infusions of this agonist in doses of 3, 10, 30 and 100 ng/kg/min. We found that all doses greater than 3 ng/kg/min produced attenuation of the hypotensive response produced by bolus administration of the B1 agonist des-Arg10-kallidin. We conclude that tachyphylaxis is an important feature to be considered in experiments with continuous administration of a B1 agonist in LPS shock.

Insoluble glycogen, a metabolizable internal adsorbent, decreases the lethality of endotoxin shock in rats

Insoluble glycogen is an enzymatically modified form of naturally occurring soluble glycogen with a great adsorbing capacity. It can be metabolized by phagocytes to glucose. In this study we used insoluble glycogen intravenously in the experimental endotoxin shock of rats. Wistar male rats were sensitized to endotoxin by Pb acetate. The survival of rats were compared in groups of animals endotoxin shock treated and non-treated with insoluble glycogen. Furthermore, we have determined in vitro the binding capacity of insoluble glycogen for endotoxin, tumour necrosis factor alpha, interleukin-1 and secretable phospholipase A2. Use of 10 mg/kg dose of insoluble glycogen could completely prevent the lethality of shock induced by LD50 quantity of endotoxin in rats. All animals treated survived. Insoluble glycogen is a form of ‘metabolizable internal adsorbents’. It can potentially be used for treatment of septic shock.

Injection time of interleukin-6 determines fatal outcome in experimental endotoxin shock.

Circulating interleukin-6 (IL-6) levels are directly correlated to fatal outcome in both patients and animal models with endotoxin shock. However, whether IL-6 is deleterious or protective in regard to survival is obscure. We investigated the action of IL-6 in the pathogenic progress of endotoxin shock. C3H/HeN mice received 10 micrograms of natural human IL-6 (Hu-IL-6) s.c. at various times before or after challenge with Escherichia coli lipopolysaccharide (LPS) at a lethal dose. Pretreatment with Hu-IL-6 0, 1, and 4 h before LPS administration improved the survival rate of the mice. However, no protection was observed when Hu-IL-6 was administered 24 h before or 1 h after the LPS injection. The protective mechanism of Hu-IL-6 pretreatment was not explained on the changes in the circulating levels of tumor necrosis factor and endogenous murine IL-6 (Mu-IL-6). The induction of fibrinogen and immunosuppressive acidic protein, a type of acute-phase proteins, may have contributed to the protection. The results show that the order and the time interval in which the administered Hu-IL-6 and the Mu-IL-6 induced by LPS act are the key to the determination of fatal outcome.

Cloning, expression and characterization of plasma platelet-activating factor-acetylhydrolase from guinea pig.

In a previous study, we purified PAF-acetylhydrolase, which converts PAF to an inactive metabolite, lysoPAF, from peritoneal fluid of guinea pigs subjected to experimental endotoxin shock and found that this purified enzyme had similar biochemical properties to the plasma enzyme [Karasawa, K., Yato, M., Setaka, M., and Nojima, S. (1994) J. Biochem. 116, 374-379]. In this study, we isolated a homogeneous enzyme preparation from guinea pig plasma using a similar procedure. The molecular mass of this purified enzyme, as determined by SDS-PAGE was 58-63 kDa, larger than that (43 kDa) of the human enzyme. To elucidate the molecular structure of this enzyme and clarify its relationships with PAF-acetylhydrolases of other species, we isolated and sequenced a cDNA encoding this enzyme. Its cDNA contains an open reading frame encoding 436 amino acids and its predicted molecular mass (49 kDa) is lower than that of the native enzyme, suggesting that guinea pig plasma PAF-acetylhydrolase, unlike the human enzyme, is modified post-translationally, perhaps by glycosylation.

Prevention of experimental endotoxin shock by a monocyte activator.

In patients with polytrauma or major surgery, severe bacterial infections leading to septic shock and multiorgan failure are still a major cause of death. Prevention of septic shock in patients at risk would be an alternative to treatment of patients with overt septic shock. We therefore conducted a trial with the monocyte activator muramyl tripeptide phosphatidylethanolamine (MTP-PE) in an experimental pig model. Liposome encapsulated MTP-PE (50 micrograms/kg of body weight) or liposomes alone were given intravenously at 72 or 24 h before endotoxemia was induced by lipopolysaccharide (LPS), simultaneously with the induction of endotoxin shock, or 1 h thereafter. Pretreatment with MTP-PE at 72 and 24 h before endotoxemia was induced resulted in a reduction of endotoxin shock-induced mortality from 81.8% (9 of 11 animals) in the control group to 8.3% (1 of 12 animals) of the MTP-PE-pretreated animals (P < 0.001). The administration of MTP-PE 24 h before the induction of endotoxin shock was more effective (P < 0.01) than administration of MTP-PE 72 h before endotoxemia was induced (P = 0.05). The pretreated animals did not develop fever or cardiovascular complications, and pulmonary function was significantly improved. Furthermore, the alpha-form of the soluble CD14 LPS receptor in pig serum showed a marked decrease in LPS-treated animals, and this decrease was reduced by MTP-PE pretreatment at 24 h before endotoxemia was induced. When MTP-PE was given simultaneously with the induction of septic shock or 1 h thereafter, it did not influence either mortality or morbidity. In conclusion, pretreatment of pigs with MTP-PE improves several parameters of endotoxin shock and it reduces mortality. Patients with high risk of developing septic complications might benefit from a pretreatment with this monocyte-activating substance.

Beneficial effects of a novel platelet-activating factor receptor antagonist, ST 899, on endotoxin-induced shock in mice.

The effect of ST 899, a novel platelet-activating factor (PAF) receptor antagonist, on serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice. In this model, animals receiving 40 mg/kg lipopolysaccharide (LPS) (Escherichia coli 055:B5) intraperitoneally were pretreated with ST 899 administered according to two different schedules. ST 899 pretreatment dose dependently reduced the mortality induced by LPS injection. The PAF receptor antagonist was also able to reduce significantly the LPS-induced increase in serum TNF. Although serum IL-6 levels were not affected, we found that ST 899, when administered intraperitoneally 60 min and intravenously 10 min prior to LPS challenge, had a tendency (at higher doses) to decrease circulating IFN-gamma levels. It is suggested that ST 899 may be beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of PAF, TNF, and IFN-gamma such as septic shock.

Anti-shock effect of pituitary adenylate cyclase activating polypeptide (PACAP) on experimental endotoxin shock in dogs

Effects of pituitary adenylate cyclase activating polypeptide with 38 amino acid residues (PACAP-38) on both cardiovascular functions and plasma hormone levels during endotoxin shock were studied in anesthesized dogs. When PACAP-38 (a bolus 420 pmol/kg injection or a bolus 420 pmol/kg injection followed by a continuous 30 pmol/kg/min infusion for 60 min) was administered intravenously 5 min after application of endotoxin, both mean arterial pressure and cardiac output were restored at 10 min. The continuous administration of PACAP-38 was more effective in improving the symptoms of shock. Plasma adrenalin and cortisol levels were significantly increased by both regimens. These results clearly indicate that the anti-shock properties of PACAP-38 may be attributed to its abilities to increase plasma cortisol and adrenalin levels and to stimulate cardiac function.

Effect of the platelet‐activating factor antagonist, TCV‐309, and the cyclo‐oxygenase inhibitor, ibuprofen, on the haemodynamic changes in canine experimental endotoxic shock

1. The present study was conducted in order to examine the effects of the platelet-activating factor (PAF) antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the acute haemodynamic responses to endotoxin in anaesthetized dogs. 2. Endotoxin (2 mg kg-1, i.v.) induced a severe hypotension by decreasing both total peripheral resistance (TPR) and cardiac output. Endotoxin also decreased central venous pressure and increased effective vascular compliance (EVC), indicating a blood pooling in the capacitance vessels. 3. The endotoxin-induced hypotension but not the fall in cardiac output, was markedly attenuated by ibuprofen. Ibuprofen abolished the decrease in TPR and even caused a systemic vasoconstriction. Ibuprofen abolished the increase in EVC. 4. The hypotension caused by endotoxin was attenuated by TCV-309 to a lesser extent than ibuprofen. However, the reduction in cardiac output produced by endotoxin was markedly attenuated by the PAF antagonist. TCV-309 also abolished the increase in EVC. In contrast to ibuprofen, TCV-309 did not affect the decrease in TPR caused by endotoxin. 5. Combined treatment with ibuprofen and TCV-309 markedly attenuated the endotoxin-induced hypotension, but not the fall in cardiac output. Nevertheless, when compared with animals treated with ibuprofen alone, treatment with ibuprofen and TCV-309 partly attenuated the endotoxin-induced reduction in cardiac output and systemic vasoconstriction. 6. These data indicate that dilatation of both resistance vessels and capacitance vessels contributes to the endotoxin-induced hypotension. It is suggested that (i) both prostanoids and PAF are involved in dilatation of capacitance vessels, (ii) prostanoids, but not PAF cause dilatation of resistance vessels and(iii) PAF may partly contribute to prostanoid-independent reduction in cardiac output in acute canine experimental endotoxin shock.

LPS‐induced serum TNF production and lethality in mice: effect of L‐carnitine and some acyl‐derivatives

The effect of L-carnitine and some of its acyl derivatives on serum TNF production and lethality in a murine experimental endotoxin shock model was investigated. In some instances, serum IL-6 production was also evaluated. In this experimental model, C57BL/6 mice received 30 mg/kg LPS (E. cell 055:B5) injected intraperitoneally, while L-carnitine and its derivatives were administered according to different schedules. Serum levels of TNF and IL-6 were evaluated 1 h following LPS injection. The treated animals were also monitored daily for differences in body temperature, feeding, and survival for 10 days after LPS injection. Although some derivatives were able to significantly affect TNF production, the marked decrease in serum TNF levels of LPS-treated mice was not paralleled by a substantial increase in survival.

Adrenergic support during anesthesia in experimental endotoxin shock: norepinephrine versus dobutamine

The effects of norepinephrine and dobutamine were compared during endotoxin shock in dogs anesthetized either with enflurane (E: 1.5%, N = 12) or with i.v. ketamine (K: 5 mg.kg-1 + 0.2 mg.kg-1.min-1, N = 12). An i.v. bolus of 1.5 mg.kg-1 E. coli endotoxin was followed by saline infusion to restore left-sided filling pressures at baseline. With E, heart rate, mean arterial pressure and stroke index decreased (P less than 0.01). The decrease in oxygen delivery (DO2) and in oxygen consumption (VO2) was associated with an increase in blood lactate. In contrast, K anesthesia was associated with remarkable hemodynamic stability. DO2 was well maintained, VO2 decreased (P less than 0.01) and blood lactate did not change. Under E anesthesia, mean arterial pressure increased more with norepinephrine and heart rate increased more with dobutamine. Under K anesthesia, cardiac index, stroke index and left ventricular stroke work index increased similarly with both agents. In both groups DO2 and VO2 increased markedly. The amount of fluid infused was higher with dobutamine than with norepinephrine. Thus, enflurane but not ketamine had depressant cardiovascular effects at the doses used in this model. With both anesthetics, norepinephrine and dobutamine could effectively improve cardiac function. Dobutamine could therefore represent a valuable alternative to norepinephrine for cardiovascular support during anesthesia in septic shock.