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Biomedical subjects

E C Rackow

Publications and source records attributed to E C Rackow.

At least 19 recordsLinked to original sources
PubMed1996

Non-ICU care of hemodynamically stable mechanically ventilated patients.

OBJECTIVE: To analyze a 4 1/2-year experience caring for hemodynamically stable mechanically ventilated patients on a nonmonitored respiratory care floor (RCF) for therapeutic outcome, utilization, and costs. DESIGN: A retrospective medical records review. SETTING: ICUs and an RCF of a university-affiliated tertiary care center. PARTICIPANTS: Two hundred twenty-four patients requiring more than 24 h of mechanical ventilation cared for on the RCF. RESULTS: The mean age of patients was 67 +/- 17 years. Of the admissions, 58% were from the medical ICU, 28% were from surgical ICUs, and 9.4% were from general medical floors. Patients spent 50 +/- 66 days mechanically ventilated on the RCF. Overall survival was 50.4% with 93.8% of surviving patients successfully weaned from mechanical ventilation. Survival by diagnostic group demonstrated highest probability of survival in patients with trauma and lowest in patients with multisystem failure. Of the survivors, 39% were discharged home, 34% to a rehabilitation unit, and 24% to a skilled nursing facility. Savings based on differential of costs between the ICU and RCF, primarily from reduced staffing requirements, were estimated at $4.1 million. CONCLUSION: Use of a nonmonitored RCF for the care of hemodynamically stable mechanically ventilated patients yields acceptable therapeutic outcomes while providing the institution with increased flexibility in critical care bed management and significant financial savings.

Aged↗
PubMed1995

Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double-blind, randomized, controlled trial.

OBJECTIVES: Endotoxin is one of the principal mediators of Gram-negative septic shock. Pretreatment with monophosphoryl lipid A, a hydrolyzed derivative of endotoxin from Salmonella minnesota R595, induces endotoxin tolerance and nonspecific resistance to infection in experimental animals. The present clinical trial was undertaken to test the response to monophosphoryl lipid A in humans and the ability of monophosphoryl lipid A to attenuate the response of normal human volunteers to U.S. Reference Ec-5 endotoxin. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Clinical research center. PATIENTS: Forty-four healthy volunteers. INTERVENTIONS: In part 1 of the study, 29 volunteers were randomized in varying ratios to receive vehicle control or monophosphoryl lipid A intravenously in a double-blind dose escalation trial. In part 2 of the study, 12 volunteers were randomized to receive either monophosphoryl lipid A (20 micrograms/kg) or vehicle control and, 24 hrs later, all 12 volunteers were challenged with U.S. Reference Ec-5 endotoxin (20 units/kg intravenous, bolus injection). Systemic response to endotoxin challenge was evaluated and compared between the monophosphoryl lipid A and vehicle control-pretreated subjects. MEASUREMENTS AND MAIN RESULTS: In part 1 of the study, subjective effects and increases in cytokine levels were not observed until a dose of 10 micrograms/kg of monophosphoryl lipid A was administered. Six volunteers receiving a maximum dose of 20 micrograms/kg experienced mild-to-moderate symptoms that did not require therapy. Moderate increases in temperature, heart rate, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 release were observed. IL-1 alpha and IL-1 beta were not detected but a significant increase in IL-1 receptor antagonist was observed. In part 2 of the study, monophosphoryl lipid A pretreatment reduced the number of volunteers who experienced one or more subjective complaints after endotoxin administration (3/6 vs. 6/6; p = .09). The febrile response and tachycardic response to endotoxin were significantly reduced by pretreatment with monophosphoryl lipid A. Monophosphoryl lipid A-pretreated volunteers demonstrated significantly reduced concentrations of TNF-alpha after endotoxin challenge, as compared with subjects treated with vehicle control (84 +/- 76 vs. 244 +/- 128 pg/mL; p < .05). IL-6 concentrations (100 +/- 91 vs. 268 +/- 171 pg/ml; p < .05) and IL-8 concentrations (136 +/- 86 vs. 632 +/- 323 pg/mL; p < .05) elicited by endotoxin challenge were also significantly reduced by monophosphoryl lipid A pretreatment. CONCLUSIONS: Data indicate that monophosphoryl lipid A, in a dose 10,000 times that of endotoxin, used in experimental pyrogenicity trials, is well tolerated in human volunteers. Pretreatment of normal human volunteers with monophosphoryl lipid A attenuated the systemic response to bacterial endotoxin. These data support further clinical testing of monophosphoryl lipid A for the prevention or amelioration of the severe sequelae of sepsis.

Adolescent↗
PubMed1995

Microvascular function and rheologic changes in hyperdynamic sepsis.

OBJECTIVE: To investigate the rheologic changes and circulatory abnormalities at the microvascular level during severe sepsis. DESIGN: Prospective, controlled trial. SETTING: Medical and surgical intensive care units of a university-affiliated hospital. PATIENTS: Nine normal controls and eight adult patients with severe sepsis who met the study entrance criteria. INTERVENTIONS: Forearm blood flow was measured at rest and during reactive hyperemia by air plethysmography. Simultaneous hemodynamic measurements and blood samples for rheologic measurements were taken. MEASUREMENTS AND MAIN RESULTS: Red blood cell deformability index was determined using a simple filtration procedure. Leukocyte aggregation in whole human blood was detected by using a leukergy test. Expression of the neutrophil adhesion molecule CD11b/CD18 was measured using a monoclonal antibody and flow cytometry. All data were taken within 24 hrs of the patient meeting criteria for entrance into the study. Cardiac output, oxygen delivery, and oxygen consumption measurements were consistent with the hyperdynamic phase of severe sepsis. Forearm blood flow was significantly (p < .05) greater in septic patients (21 +/- 3 mL/min) than in controls (12 +/- 2 to 36 +/- 5 mL/min (p < .05), while in the septic patients, forearm blood flow during reactive hyperemia increased from 21 +/- 3 to 32 +/- 4 mL/min. The ratio of forearm blood flow during reactive hyperemia to forearm blood flow at rest was 3.2 +/- 0.1 in the controls and 1.6 +/- 0.1 in the septic patients (p < .01). The red blood cell deformability index in whole blood was significantly (p < .01) decreased in the septic patients compared with the control subjects (0.41 +/- 0.07 vs. 0.98 +/- 0.08 mL/min). This difference remained true when the hematocrit was adjusted to 45% (0.82 +/- 0.06 vs. 1.04 +/- 0.06 mL/min; p < .05). Increased expression of the neutrophil adhesion molecule CD11b/CD18 was observed in septic patients (349 +/- 46 logarithmic fluorescence units) as compared with control subjects (233 +/- 26 logarithmic fluorescence units; p < .05). Leukergy was also significantly (p < .05) increased in septic patients (17.7 +/- 3.8%) as compared with control subjects (8.9 +/- 1.6%). A significant correlation was observed between leukergy and the expression of the neutrophil adhesion molecule CD11b/CD18 in controls and septic patients (r2 = .62; p < .01). Leukergy was also inversely correlated with whole blood red blood cell deformability index (r2 = .28; p < .05). CONCLUSIONS: Reactive hyperemia in the forearm is significantly diminished in patients with sepsis, suggesting impaired microvascular blood flow. Rheologic changes, including impaired red blood cell deformability, increased leukocyte aggregation, and endothelial adherence, may contribute to this abnormality by compromising effective capillary cross-sectional area.

Adult↗
PubMed1994

Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.

OBJECTIVE: To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION: A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS: There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

Adult↗
PubMed1994

Increased venous-arterial carbon dioxide tension difference during severe sepsis in rats.

OBJECTIVE: To test the hypothesis that decreases in blood flow during septic shock lead to increases in the venous-arterial PCO2 difference in a rat model of sepsis. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Research laboratory. SUBJECTS: Fifteen Sprague-Dawley rats. INTERVENTIONS: Severe sepsis was induced by cecal ligation and perforation. Ten animals were randomized to no treatment or fluid infusion to maintain the cardiac output at baseline values. An additional five rats served as sham-operated controls. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements, arterial and central venous blood gases were obtained at baseline, and then at 3 hrs and 6 hrs after abdominal surgery. In the five septic rats that did not receive volume infusion, cardiac output decreased from 331 +/- 32 to 172 +/- 9 mL/min/kg (p < .001). This decrease in cardiac output was associated with an increase of 13 +/- 2 torr (1.7 +/- 0.2 kPa) in the venous-arterial PCO2 difference (p < .001). Furthermore, the venous-arterial PCO2 gradient correlated linearly with the cardiac output in the same animals (r2 = .52, p < .001). In the septic animals that received volume infusion and in sham animals, cardiac output and the venous-arterial PCO2 remained unchanged from baseline at 6 hrs. CONCLUSION: We conclude that the increase in the venous-arterial PCO2 gradient in severe sepsis appears to be related to reductions in cardiac output.

Acidosis↗
PubMed1994

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.

Animals↗
PubMed1994

Relationships between plasma cytokine concentrations and leukocyte functional antigen expression in patients with sepsis.

OBJECTIVE: To determine the relationships between cytokine concentrations and alterations in leukocyte functional antigen expression in sepsis. DESIGN: Prospective, cross-sectional study. SETTING: Respiratory, coronary, and medical intensive care units in a university hospital. PATIENTS: Forty subjects consisting of: a) patients with severe sepsis, b) patients with sepsis, c) critically ill nonseptic patients, and d) normal controls. INTERVENTIONS: None. MEASUREMENTS: Plasma concentrations of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, interleukin-1 receptor antagonist (IL-1Ra), and tumor necrosis factor (TNF)-alpha were determined by enzyme-linked immunosorbent assay (ELISA). Peripheral blood monocyte HLA-DR and CD14 expression and neutrophil CD11b expression were determined by flow cytometry. Measurements were taken within 24 hrs of admission to the intensive care unit and/or clinical presentation. MAIN RESULTS: Significantly increased plasma IL-6, IL-8, IL-10, and TNF-alpha concentrations were observed in the severe sepsis group compared to normal controls. Increases in IL-1Ra were not significant. Monocyte HLA-DR expression, significantly decreased in patients with severe sepsis, was correlated both with IL-6 (p < .005) and IL-8 concentrations (p < .001). Both of these cytokines had close correlations to Acute Physiology and Chronic Health Evaluation (APACHE) II scores which were also correlated with monocyte HLA-DR. Neutrophil CD11b, which was increased in all infected patients, was significantly correlated with the ratio between IL-1 and IL-1Ra concentrations (p < .001). The percent of CD14+ monocytes was lowest in patients with severe sepsis and showed a significant covariate effect from IL-8 concentrations (p < .001). CONCLUSION: These findings suggest that the expression of specific functional molecules on peripheral blood leukocytes is variably related to the net production of certain monokines in sepsis.

APACHE↗
PubMed1994

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)

Animals↗
PubMed1993

Alterations in C3, C4, factor B, and related metabolites in septic shock.

Forty subjects consisting of (i) patients with septic shock, (ii) patients with sepsis without shock, (iii) critically ill non-septic patients, and (iv) normal controls were studied for plasma C3, C4, factor B, iC3b, C4d, Bb, and SC5b-9 levels in an attempt to profile the pattern of complement activation in sepsis. Significant decreases in plasma C3 and C4 concentrations were observed in septic shock patients compared to normal as well as to critically ill subjects. When adjusted for illness severity, levels of C3 but not C4 showed significant differences between septic shock and critically ill patients. Concentrations of the complement metabolite Bb as well as the Bb to factor B ratio were significantly increased in septic shock patients. SC5b-9 levels were significantly higher in septic shock patients compared to normal as well as to critically ill subjects. No increases in C4d or iC3b were observed, but the iC3b to C3 ratio was higher in septic shock patients compared to that in normal subjects. In septic shock patients, there were significant correlations between SC5b-9 and Bb (P = 0.0213) concentrations and between C3 and Factor B concentrations (P = 0.0041). SC5b-9 levels also were correlated with lactate levels in septic shock patients (P = 0.0091). These findings demonstrate a metabolite pattern consistent with primarily alternative and terminal pathway activation in septic shock patients. Decreases in C4, a classical pathway component, may not be specific for septic shock and do not appear to be necessarily due to significant complement consumption/activation.

Adult↗
PubMed1993

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.

Animals↗
PubMed1993

Intramyocardial hypercarbic acidosis during cardiac arrest and resuscitation.

OBJECTIVE: To define changes in intramyocardial pH and PCO2 during cardiac arrest and resuscitation. DESIGN: Prospective and observational trial. SETTING: Mammalian research laboratory utilizing a porcine model of cardiac arrest. SUBJECTS: Sixteen domestic pigs. INTERVENTIONS: Ventricular fibrillation was induced by an alternating current delivered to the epicardium. Precordial compression was begun after 3 mins of untreated cardiac arrest and was initially adjusted to produce a coronary perfusion pressure of 10 mm Hg. Electrical defibrillation was attempted after an additional 8 mins of precordial compression. MEASUREMENTS AND MAIN RESULTS: A rapid-response, ion-selective field effect transistor sensor was adapted for measurement of intramyocardial PCO2. Intramyocardial PCO2 progressively increased from 54 to 346 torr (7.2 to 46.1 kPa) during the 11-min interval of cardiac arrest. Intramyocardial hydrogen ion concentrations were simultaneously measured with a glass electrode. The intramyocardial hydrogen ion value increased from 65 nmol/L (pH 7.20) to 441 nmol/L (pH 6.38) over the same interval. The increases in myocardial PCO2 were inversely correlated with coronary perfusion pressure and with the likelihood of successful resuscitation. Within 30 mins after successful cardiac resuscitation, myocardial PCO2 had almost completely returned to prearrest levels. CONCLUSIONS: Striking increases in myocardial PCO2 and hydrogen ion values accompany the global myocardial ischemia of cardiac arrest. The increases in myocardial PCO2, rather than decreases in pH, reflected more precisely the hemodynamic efficacy of the resuscitation effort, correlated inversely with coronary perfusion pressure, and predicted the likelihood of successful resuscitation.

Acidosis, Respiratory↗
PubMed1993

Altered leukocyte immunophenotypes in septic shock. Studies of HLA-DR, CD11b, CD14, and IL-2R expression.

To evaluate the role of cellular activation markers and functional surface molecules in sepsis, specific immunophenotypes on peripheral blood leukocytes were studied in 40 subjects consisting of the following: (1) patients with septic shock; (2) patients with sepsis; (3) critically ill nonseptic patients; and (4) normal control subjects. These assays included phagocyte adhesion molecule CD11b expression, monocyte receptors HLA-DR and CD14, and lymphocyte activation markers IL-2R and HLA-DR. Patients with septic shock and sepsis had significantly increased neutrophil CD11b expression compared with normal subjects. Neutrophil HLA-DR expression did not significantly differ between groups. Monocytes from septic shock patients had significantly less HLA-DR expression than normal subjects and there was a trend toward a lower proportion of gated monocytes that expressed CD14 in septic shock patients. Septic shock patients had no significant increases in IL-2R or HLA-DR expression on CD3 lymphocytes compared with control subjects, but they had significantly lower numbers of total, CD3, CD4, and CD8 lymphocytes and a higher prevalence of anergy. Septic shock patients manifested an increase in neutrophil CD11b expression that may play a role in organ injury. In contrast, a more specific decrease in monocyte expression of functional antigens is also observed in patients with septic shock that may have implications for immunologic defense mechanisms.

Adult↗
PubMed1993

Intravascular volume and fluid therapy for severe sepsis.

Hypovolemia is one of the principal defects contributing to cardiovascular instability and circulatory failure during septic shock. Fluid infusion is the mainstay of initial resuscitation. Large amounts of fluids may be required and should be titrated to optimal hemodynamic effects while attempting to minimize the development of pulmonary and systemic edema. Hemoglobin and hematocrit should be carefully monitored, with transfusions being used as necessary to maintain adequate levels of systemic oxygen delivery. Crystalloids and colloids are equally effective, although the volume of fluids required with crystalloids is two to four times that of colloids. In older patients, where high filling pressures may be required for optimal hemodynamic effect, colloids may be associated with a lower frequency of pulmonary edema.

Animals↗
PubMed1993

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.

Animals↗
PubMed1993

Pathophysiology and treatment of circulatory shock.

Circulatory shock is a syndrome characterized by imbalance between oxygen supply and demand. Myriad different mediators are responsible for the systemic manifestations of shock. The therapeutic approach requires initial interventions directed at increasing oxygen delivery followed by definitive therapy for the causative process. Areas of ongoing research involve mediated-directed therapy, reperfusion injury, and immunologic interventions directed at reducing infectious complications in the survivors of circulatory shock.

Animals↗
PubMed1993

Mechanisms and management of septic shock.

Septic shock continues to be associated with high mortality. The systemic effects of severe infections are related to the release and activation of a myriad of mediator systems, central to which are bacterial toxins and cytokines. Therapy includes three facets--resuscitation, treatment of the underlying infection, and interventions directed at ameliorating mediator activity.

Anti-Bacterial Agents↗
PubMed1993

Assessing perfusion failure during circulatory shock.

In patients with circulatory shock, monitoring of tissue perfusion requires assessment of systemic oxygen metabolism. The presence of lactic acidosis helps identify critical hypoperfusion as marked by anaerobic metabolism. Mixed venous oxygen tension and saturation help determine the use of compensatory mechanisms to maintain oxidative metabolism. Measurements of systemic oxygen consumption and oxygen delivery help define underlying pathophysiology and the direction for therapeutic intervention. Tonometrically measured gastric intramucosal pH appears to be a useful method for monitoring splanchnic hypoperfusion and may have implications for assessing global perfusion failure.

Blood Gas Analysis↗