Monophosphoryl lipid A protects against gram-positive sepsis and tumor necrosis factor.

Monophosphoryl lipid A (MPL) is a less toxic derivative of lipid A that enhances survival from endotoxemia. This study examined whether MPL induced resistance to Gram-positive sepsis and cytokines. Mice were administered MPL or saline (phosphate-buffered saline) and challenged 24 h later with live Staphylococcus aureus (SA), staphylococcus enterotoxin B (SEB), toxic shock syndrome toxin (TSST-1), and tumor necrosis factor (TNF). Survival was determined at 72 h. A separate set of animals was phlebotomized for determination of cytokines. MPL increased survival from S. aureus bacteremia from 20 to 87% (p < .05). Interleukin-6 (IL-6) and interleukin-1 (IL-1) and TNF were also significantly decreased. SEB and TSST survival were enhanced from 10 to 90% (p < .05). In SEB-treated animals, TNF and IL-6 levels were significantly decreased. Survival from TNF infusion was increased from 20 to 100% with MPL, however, no significant differences in cytokines were observed. These data suggest that MPL induces resistance to Gram-positive sepsis and cytokine-mediated activity.

Sublingual capnometry and indexes of tissue perfusion in patients with circulatory failure.

OBJECTIVE: To examine the relationship between sublingual PCO(2) (PslCO(2)) and other indexes of tissue perfusion. DESIGN: Prospective observational study. SETTING: Medical and coronary ICUs in a tertiary-care teaching hospital. SUBJECTS: Twenty-five patients with circulatory failure, 19 patients with sepsis, and 6 patients with cardiac failure. MEASUREMENTS AND MAIN RESULTS: PslCO(2), gastric intramucosal PCO(2) (PiCO(2)), arterial lactate concentration, systemic oxygen delivery, and systemic oxygen consumption were measured at baseline and at 1, 3, 6, 12, and 24 h after the beginning of the study. PslCO(2) and the PslCO(2)-PaCO(2) gradient were increased but not significantly different in nonsurvivors compared to survivors at baseline. At 24 h, the mean (+/- SE) PslCO(2) was 45 +/- 4 mm Hg in survivors and 61 +/- 4 mm Hg in nonsurvivors (p = 0.06), while the PslCO(2)-PaCO(2) gradient was 14 +/- 3 mm Hg in survivors and 29 +/- 4 mm Hg in nonsurvivors (p < 0.05). No other significant differences in survivors and nonsurvivors were observed in any other index of perfusion. For all patients, the correlations between PslCO(2) and PiCO(2) (r = 0.459; p < 0.05) and cardiac index (r = 0.285; p < 0.05) were observed. The PslCO(2)-PaCO(2) gradient also was correlated with the PiCO(2)-PaCO(2) gradient (r = 0.323; p < 0.05). When patients were placed into subsets of sepsis and cardiac failure, the strength of the correlations increased in the patients with cardiac failure (PslCO(2) vs lactate, r = 0.611 and p < 0.05; PslCO(2) vs PiCO(2), r = 0.613 and p < 0.05; PslCO(2) vs PiCO(2)-PaCO(2) gradient, r = 0.648 and p < 0.05). CONCLUSION: PslCO(2) correlated best with PiCO(2) and arterial lactate concentration in patients with cardiac failure. PslCO(2) and the PslCO(2)-PaCO(2) gradient may be useful as indexes of the severity of perfusion failure.

Comparison of the induction of endotoxin tolerance in endotoxemia and peritonitis by monophosphoryl lipid A and lipopolysaccharide.

We compared the induction of endotoxin tolerance with Salmonella minnesota monophosphoryl lipid A (MPL), a nontoxic derivative of lipid A, and S. minnesota endotoxin (LPS) in lethal endotoxemia and peritonitis. Lethal endotoxemia was induced by injecting 750 micrograms/mouse LPS intravenously. Cecal ligation and perforation was used to induce peritonitis. Tumor necrosis factor (TNF) was measured by immunoassay at 2 hr after lethal endotoxin infusion and 24 hr after peritonitis. A dose of 0.1 micrograms/mouse of MPL or LPS significantly reduced endotoxin mortality from 100% to 50% and 27%, respectively (P < 0.05). The LD50 for a 0.1 micrograms dose of MPL was 750 micrograms of LPS and the LD50 for a 0.1 micrograms dose of LPS was 1150 micrograms of endotoxin (P < 0.05). TNF levels decreased linearly when increasing doses of MPL and LPS were used to induce tolerance. At higher pretreatment doses of LPS, survival benefits were attenuated despite the reduction in TNF levels. A 25 micrograms dose of LPS reduced mortality from peritonitis from 93% to 45% (P < 0.05). Although MPL reduced short-term mortality, overall mortality was not significantly reduced despite using large doses of MPL. TNF levels peaked at 24 hr and were significantly lower than those following lethal endotoxemia. The induction of endotoxin tolerance by LPS and MPL is dose dependent, and LPS is modestly more effective in inducing endotoxin tolerance than MPL. Both LPS and MPL are significantly less effective in protecting against lethality from peritonitis.

Diphosphoryl lipid A from Rhodopseudomonas sphaeroides induces tolerance to endotoxic shock in the rat.

OBJECTIVES: To examine the hemodynamic effects of diphosphoryl lipid A from Rhodopseudomonas sphaeroides and to examine the ability of this substance to induce tolerance to endotoxic shock. DESIGN: Randomized, prospective, controlled study comparing the hemodynamic actions of R. sphaeroides diphosphoryl lipid A to those effects of lipopolysaccharide form Salmonella minnesota, followed by a prospective, randomized, controlled study comparing pretreatment with R. sphaeroides diphosphoryl lipid A and phosphate-buffered saline in the induction of tolerance to endotoxic shock. SETTING: Laboratory of the Section of Critical Care Medicine at a University Hospital. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Eight rats were randomized to receive intravenous R. sphaeroides diphosphoryl lipid A, 0.5 mg/100 g body weight or S. minnesota lipopolysaccharide, 0.5 mg/100 g body weight. Ten rats were then randomized to receive R. sphaeroides diphosphoryl lipid A, 0.5 mg/100 g body weight, or phosphate-buffered saline intravenously 48 hrs before receiving S. minnesota lipopolysaccharide, 5 mg/100 g body weight, by intravenous infusion. MEASUREMENTS AND MAIN RESULTS: Cardiac index was significantly decreased from baseline in rats treated with lipopolysaccharide; there was no significant change in the R. sphaeroides diphosphoryl lipid A group. Peak circulating tumor necrosis factor (TNF) concentrations in the lipopolysaccharide-treated rats were higher than in R. sphaeroides diphosphoryl lipid A-treated rats (3.1 +/- 1.0 vs. 1.5 +/- 0.4 ng/mL). R. sphaeroides diphosphoryl lipid A significantly attenuated lipopolysaccharide-induced changes in mean arterial pressure and cardiac index. At baseline, there was no significant difference in serum TNF concentrations between rats pretreated with R. sphaeroides diphosphoryl lipid A and those rats pretreated with phosphate-buffered saline. TNF levels peaked at 1 hr post-lipopolysaccharide infusion at 4.3 +/- 0.6 ng/mL in the phosphate-buffered saline group and at 2.0 +/- 0.5 ng/mL in the R. sphaeroides diphosphoryl lipid A group (p < .02). Four of five rats pretreated with R. sphaeroides diphosphoryl lipid A survived endotoxic shock, whereas none of the phosphate-buffered saline-pretreated rats survived (p = .05). CONCLUSIONS: These observations are consistent with previous reports of the limited toxic effects of R. sphaeroides diphosphoryl lipid A and suggest that this molecule retains the ability to induce tolerance to endotoxic shock.

Induction of endotoxin tolerance with monophosphoryl lipid A in peritonitis: importance of localized therapy.

Endotoxin is a principle mediator of septic shock during peritonitis. Induction of endotoxin tolerance with monophosphoryl lipid A (MPL), a nontoxic derivative of lipid A, improves survival from peritonitis. The induction of tolerance with intravenous versus intraperitoneal administration of MPL before peritonitis was compared. Mice were pretreated with varying doses of MPL (intravenously) and MPL (intraperitoneally) 48 hours before peritonitis was induced by cecal ligation and perforation. Survival was determined at 72 hours, and serum and peritoneal levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) were assayed at 24 hours. Survival was 0% in control animals, 20% in MPL (100 micrograms intravenously) animals, and 70% in MPL (100 micrograms intraperitoneally) animals (p < 0.05 versus control, MPL [intravenously]). Cytokine release was compared in control animals and animals receiving MPL 100 micrograms (intraperitoneally) or MPL 100 micrograms (intravenously). In MPL (intraperitoneally)-treated animals, serum and peritoneal TNF-alpha levels, 160 +/- 7 pg/ml and 204 +/- 25 pg/ml, were significantly lower than those in control animals, 429 +/- 34 pg/ml and 642 +/- 108 pg/ml, and MPL (intravenously)-treated animals, 302 +/- 68 pg/ml and 495 +/- 97 pg/ml, (p < 0.05). Similarly, IL-1 alpha levels were significantly lower in MPL (intraperitoneally)-treated animals than in control animals. Because the development of tolerance appears to be a cytokine-mediated process, a subsequent experiment compared peritoneal and serum TNF-alpha and IL-1 alpha levels at 2 hours after MPL (intraperitoneally) or MPL (intravenously). Peritoneal TNF-alpha and IL-1 alpha release was greatest after MPL (intraperitoneally); serum levels were greatest after MPL (intravenously).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of perfusion pressure on tissue perfusion in septic shock.

OBJECTIVE: To measure the effects of increasing mean arterial pressure (MAP) on systemic oxygen metabolism and regional tissue perfusion in septic shock. DESIGN: Prospective study. SETTING: Medical and surgical intensive care units of a tertiary care teaching hospital. PATIENTS: Ten patients with the diagnosis of septic shock who required pressor agents to maintain a MAP > or = 60 mm Hg after fluid resuscitation to a pulmonary artery occlusion pressure (PAOP) > or = 12 mm Hg. INTERVENTIONS: Norepinephrine was titrated to MAPs of 65, 75, and 85 mm Hg in 10 patients with septic shock. MEASUREMENTS AND MAIN RESULTS: At each level of MAP, hemodynamic parameters (heart rate, PAOP, cardiac index, left ventricular stroke work index, and systemic vascular resistance index), metabolic parameters (oxygen delivery, oxygen consumption, arterial lactate), and regional perfusion parameters (gastric mucosal Pco2, skin capillary blood flow and red blood cell velocity, urine output) were measured. Increasing the MAP from 65 to 85 mm Hg with norepinephrine resulted in increases in cardiac index from 4.7+/-0.5 L/min/m2 to 5.5+/-0.6 L/min/m2 (p < 0.03). Arterial lactate was 3.1+/-0.9 mEq/L at a MAP of 65 mm Hg and 3.0+/-0.9 mEq/L at 85 mm Hg (NS). The gradient between arterial P(CO2) and gastric intramucosal Pco2 was 13+/-3 mm Hg (1.7+/-0.4 kPa) at a MAP of 65 mm Hg and 16+/-3 at 85 mm Hg (2.1+/-0.4 kPa) (NS). Urine output at 65 mm Hg was 49+/-18 mL/hr and was 43+/-13 mL/hr at 85 mm Hg (NS). As the MAP was raised, there were no significant changes in skin capillary blood flow or red blood cell velocity. CONCLUSIONS: Increasing the MAP from 65 mm Hg to 85 mm Hg with norepinephrine does not significantly affect systemic oxygen metabolism, skin microcirculatory blood flow, urine output, or splanchnic perfusion.

Monophosphoryl lipid A attenuates the effects of endotoxic shock in pigs.

Monophosphoryl lipid A (MPL) is a nontoxic lipid A derivative that maintains many of the beneficial immunomodulatory activities of the parent lipopolysaccharide molecule, including the induction of tolerance to endotoxin. The hemodynamic effects of Salmonella minnesota MPL (300 mg/kg) and S. minnesota lipopolysaccharide (300 micrograms/kg) were compared in 20 minipigs. Decreases in cardiac output and arterial pressure and increases in pulmonary artery pressure and lactic acidosis were significantly greater in animals treated with lipopolysaccharide. These changes were associated with peak tumor necrosis factor (TNF) levels of 1373 +/- 79 U/ml in animals treated with LPS and 157 +/- 31 U/ml in animals treated with MPL. Ten minipigs were subsequently randomized to receive S. minnesota MPL (30 micrograms/kg) or diluent intravenously 48 hours before receiving S. minnesota lipopolysaccharide (300 micrograms/kg IV). MPL significantly attenuated lipopolysaccharide-induced decreases in mean arterial pressure, cardiac index, stroke volume index, and mixed venous oxygen saturation. At baseline, no significant difference could be seen in TNF levels between diluent and MPL pigs. TNF levels peaked 2 hours after LPS infusion at 1190 +/- 156 U/ml in diluent pigs and at 539 +/- 126 U/ml in MPL pigs (p less than 0.05). Each of the pigs pretreated with MPL survived endotoxic shock, whereas only one of the five diluent pigs survived. These observations are consistent with the induction of endotoxin tolerance by pretreatment with MPL.