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C Natanson

Publications and source records attributed to C Natanson.

At least 37 records · Page 2Linked to original sources
PubMed1995

New strategies for combatting sepsis: the magic bullets missed the mark ... but the search continues.

Despite the high expectations of scientists and industry, multiple clinical trials of anti-endotoxin- and anti-cytokine-based therapies for sepsis have failed to demonstrate benefit. Indeed, in some cases, the agents used were actually harmful to patients. In retrospect, perhaps the therapeutic premises on which these therapies were based were flawed. In the future, a better understanding of sepsis should lead to the development of accurate laboratory and clinical predictors that will identify when, and which, patients can benefit from a given therapy. Much has been learned from the efforts of industry and academia and, hopefully, the search for new therapies for this lethal syndrome will continue.

Animals↗
PubMed1995

Hemodynamic effects of dopamine, norepinephrine, and fluids in a dog model of sepsis.

To study how sepsis affects hemodynamic responses to catecholamines and fluids, either Escherichia coli-infected (septic, n = 8) or sterile (controls, n = 6) fibrin clots were implanted intraperitoneally into 2-yr-old beagles. Hemodynamics were measured at each of four doses of dopamine (0, 5, 10, and 20 micrograms.kg-1.min-1) and norepinephrine (0, 10, 20, and 40 micrograms.min-1), before and after infusion of fluid (Ringer 40 ml.kg-1). Septic animals had lower mean arterial pressure (MAP, P = 0.04), stroke volume index (SVI, P = 0.0001), and left ventricular (LV) ejection fraction (LVEF) (P = 0.0001) than controls. During this time, increasing doses of dopamine and norepinephrine produced corresponding increases (P < 0.001) in LVEF, SVI, and MAP. However, during sepsis, the ability of dopamine to increase MAP diminished, while its ability to increase LVEF and SVI was maintained. Conversely, the ability of norepinephrine to increase LVEF and SVI diminished, but its ability to increase MAP was maintained. During sepsis, fluids alone increased (P < 0.05) MAP, LVEF, SVI, and cardiac index (CI). Fluids with catecholamines also significantly increased (P < 0.05) MAP with only minimal increases in LVEF, SVI, and CI. These data demonstrate that during sepsis without catecholamines, fluids improve cardiac performance and systemic pressures, but with catecholamines, fluids have minimal effects on cardiac performance and augment MAP. Furthermore, during sepsis dopamine is more effective than norepinephrine in increasing LV performance, but norepinephrine is more effective than dopamine in increasing systemic pressures.

Animals↗
PubMed1995

Differential hemodynamic effects of L-NMMA in endotoxemic and normal dogs.

We studied the differential hemodynamic effects of N omega-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, in normal and endotoxemic dogs and examined its activity across the venous, pulmonary, and systemic circulations. Survival was used to determine therapeutic efficacy. In both normal and endotoxemic animals, L-NMMA similarly increased systemic (P = 0.01) and pulmonary (P = 0.047) vascular resistance, marginally increased mean arterial pressure (P = 0.07), and decreased oxygen delivery (P = 0.01) compared with normal saline. In contrast, the effect of L-NMMA on mean pulmonary arterial pressure, central venous pressure, and pulmonary capillary wedge pressure was different in endotoxemic than in normal animals (P < 0.05), but this differential effect occurred > 6 h after endotoxin challenge. L-NMMA (1-10 mg.kg-1.h-1) did not significantly increase survival rates or times in endotoxemic animals, but the highest dose decreased survival times (P < 0.05). Thus the effect of L-NMMA was similar on the systemic arterial circulation in endotoxemic dogs compared with normal dogs but was increased in the venous and pulmonary vascular beds after endotoxin, suggesting that the induction of NO production was greater in low-resistance vessels. We were unable to show that nonselective inhibition of NO production was beneficial in endotoxemic dogs.

Animals↗
PubMed1995

Therapeutic trial of reconstituted human high-density lipoprotein in a canine model of gram-negative septic shock.

In a controlled, randomized trial, the authors investigated the effects of reconstituted human high-density lipoprotein (R-HDL) on survival, endotoxemia, cytokine production and pathophysiologic and metabolic events in an animal model of gram-negative septic shock. At 0.5, 8 and 16 hr after implantation of a clot infected with Escherichia coli, canines received intravenous R-HDL (n = 13), control lipid (n = 7) or human serum albumin (HSA, n = 7) divided into three doses (0.3, 0.1 and 0.1 g/kg, respectively) at an hourly rate of 0.1 g/kg. All animals were treated with antibiotics and fluids. Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA (all P < .05). The survival times of lipid- and HSA-treated animals were similar (P = .3) and were significantly greater than those of R-HDL-treated animals (P = .02). During the first 6 hr after clot implantation, R-HDL-treated animals had significantly greater abnormalities in liver function test findings compared with lipid- and HSA-treated animals (all P < .05). For the first 24 hr, R-HDL-treated animals had significant increases in HDL levels; however, there were no significant relationships between these levels and the constituents of HDL (apolipoprotein AI and phosphatidylcholine) or liver function abnormalities and survival times (all r < .2, P > .3). In normal animals, administration of R-HDL (in similar doses) caused transient elevation of liver enzymes; in animals given sterile clot i.p., R-HDL caused seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Continuous arteriovenous hemofiltration does not improve survival in a canine model of septic shock.

BACKGROUND: We examined whether or not continuous arteriovenous hemofiltration (CAVH), in the absence of renal failure, would improve either hemodynamic abnormalities or survival in a canine model of septic shock. STUDY DESIGN: Escherichia coli 0111, as an intraperitoneal clot, was surgically implanted into 21 one- to two-year-old purpose-bred beagles. The dogs were randomized to no CAVH (control group, n = 7), sham CAVH (extracorporeal circulation without hemofiltration, n = 7), or true CAVH (hemofiltration with removal of 600 mL/hour of ultrafiltrate, n = 7). Hemofiltration began one hour after clot implantation and continued for six hours. All dogs received antibiotics and had serial hemodynamic and laboratory evaluations. RESULTS: During the first seven hours of the study, all dogs displayed a progressive, significant decrease in mean arterial pressure, cardiac index, left ventricular ejection fraction, and serum pH (all p < 0.05). Two of seven dogs in the control group, one of seven dogs in the sham CAVH group, and one of seven dogs in the true CAVH group survived seven days after clot implantation. True CAVH, which included fluid replacement with lactated Ringer's solution, significantly increased serum lactate and decreased serum bicarbonate levels after six hours (both p < 0.05). However, pH did not differ between the three treatment groups (p > 0.20). Continuous arteriovenous hemofiltration therapy had no significant effect on cardiovascular abnormalities or survival. CONCLUSIONS: The results of this study suggest that CAVH would be unlikely to provide benefit to patients with gram-negative septic shock, in the absence of renal failure.

Animals↗
PubMed1994

Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis.

PURPOSE: To review selected new therapies for septic shock designed to inhibit bacterial toxins or endogenous mediators of inflammation. DATA SOURCES: Scientific journals, scientific meeting proceedings, and Food and Drug Administration advisory committee proceedings. STUDY SELECTION AND EXTRACTION: Preclinical and clinical data from trials using core-directed antiendotoxin antibodies and anticytokine therapies for sepsis and studies in animal models of sepsis from our laboratory. RESULTS OF DATA SYNTHESIS: Ten clinical trials using core-directed antiendotoxin antibodies produced inconsistent results and did not conclusively establish the safety or benefit of this approach. Both anti-interleukin-1 and anti-tumor necrosis factor (TNF) therapies have been beneficial in some animal models of sepsis but did not clearly improve survival in initial human trials, and one anti-TNF therapy actually produced harm. Neutrophils, another target for therapeutic intervention, protect the host from infection but may also contribute to the development of tissue injury during sepsis. In a canine model of septic shock, granulocyte colony-stimulating factor increased the number of circulating neutrophils and improved survival, but an anti-integrin (CD11/18) antibody that inhibits neutrophil function worsened outcome. Nitric oxide, a vasodilator produced by the host, causes hypotension during septic shock but may also protect the endothelium and maintain organ blood flow. In dogs challenged with endotoxin, the inhibition of nitric oxide production decreased cardiac index and did not improve survival. CONCLUSIONS: No new therapy for sepsis has shown clinical efficacy. Perhaps more accurate clinical and laboratory predictors are needed to identify patients who may benefit from a given treatment strategy. On the other hand, the therapeutic premises may be flawed. Targeting a single microbial toxin such as endotoxin may not represent a viable strategy for treating a complex inflammatory response to diverse gram-negative bacteria. Similarly, the strategy of inhibiting the host inflammatory response may not be beneficial because immune cells and cytokines play both pathogenic and protective roles. Finally, our scientific knowledge of the complex timing of mediator release and balance during sepsis may be insufficient to develop successful therapeutic interventions for this syndrome.

Animals↗
PubMed1994

The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure.

We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotoxic shock, and if it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controlled investigation, six Brittany spaniels that were homozygous for a genetically determined deficiency of C3 (C3 deficient, < 0.003% of normal serum C3 levels) and six heterozygous littermates (controls, approximately 50% of mean normal serum C3 level) were given 2 mg/kg of reconstituted Escherichia coli 026:B6 acetone powder as a source of endotoxin, intravenously. All animals were given similar fluid and prophylactic antibiotic therapy, and had serial hemodynamic variables obtained. After E. coli endotoxin infusion, C3-deficient animals had higher peak levels of endotoxin and less of a rise in temperature than controls (P < 0.05). During the first 4 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean central venous pressure and mean pulmonary artery pressure than controls (P < 0.02). During the first 48 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean arterial pH, left ventricular ejection fraction, and mean pulmonary capillary wedge pressure, and greater increases in mean arterial lactate, arterial-alveolar O2 gradient, and transaminases (aspartate aminotransferase and alanine aminotransferase) than controls, (all P < 0.05). After E. coli endotoxin infusion, C3-deficient animals compared to controls had significantly less of a decrease in mean C5 levels (P < 0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage neutrophils, and protein, and similar (P = NS) decreases in blood leukocytes and platelets. Two of six C3-deficient animals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxin, canines with C3 deficiency have decreased endotoxin clearance and worse E. coli endotoxin-induced shock and organ damage. Thus, the third component of the complement system plays a beneficial role in the host defense against E. coli endotoxic shock.

Analysis of Variance↗
PubMed1994

Cardiopulmonary effects of granulocyte colony-stimulating factor in a canine model of bacterial sepsis.

We investigated the effects of recombinant granulocyte colony-stimulating factor (G-CSF) in a canine model of septic shock. Awake 2-yr-old beagles were studied before and after intraperitoneal placement of an Escherichia coli-infected clot. Nine days before and until 3 days after clot placement, animals received daily high-dose (G-CSF (5 microgram/kg body wt; n = 17), low-dose G-CSF (0.1 microgram/kg body wt; n = 17), or a control protein (5 micrograms/kg body wt; n = 20). Survival rate was greater (P < 0.04, Wilcoxon test) in the high-dose G-CSF group (14/17) than in the low-dose G-CSF (10/17) and control (12/20) groups. High-dose G-CSF improved cardiovascular function, as evidenced by increased left ventricular ejection fraction (day 1 after clot; P < 0.001) and mean arterial pressure (day 2; P < 0.02) compared with low-dose G-CSF and control groups. High-dose G-CSF increased (P < 0.001) mean peripheral neutrophils before (-3 days) and after (2 h to 4 days) clot and produced a more rapid (P < 0.001) rise (day 2) and fall (day 4) in mean alveolar neutrophil numbers compared with the low-dose G-CSF and control groups. High-dose G-CSF decreased mean serum endotoxin (2-8 h; P < 0.002) and tumor necrosis factor (2 h; P < 0.02) levels and lowered blood bacteria counts (2-6 h; P < 0.04) compared with the low-dose G-CSF and control groups. Thus, in this canine model, G-CSF sufficient to increase peripheral neutrophils before and during peritonitis and septic shock enhances host defense, reduces cytokine (tumor necrosis factor) levels, and improves cardiovascular function and survival.

Animals↗
PubMed1993

A controlled trial of HA-1A in a canine model of gram-negative septic shock.

OBJECTIVE: To investigate the therapeutic efficacy and microbiological and physiological effects of a human IgM monoclonal antibody (HA-1A) directed against the lipid A component of endotoxin in a canine model of sepsis that simulates the cardiovascular abnormalities of human septic shock. DESIGN: Blinded, placebo-controlled 28-day trial. INTERVENTIONS: Purpose-bred beagles were implanted with an intraperitoneal clot infected with Escherichia coli O111:B4. At clot placement, animals received HA-1A (10 mg.kg-1), control human IgM antibody (10 mg.kg-1), or control human serum albumin intravenously. All animals were given antibiotic and fluid therapy. MEASURES: Survival and microbiological and physiological events. RESULTS: Only two (15%) of 13 animals in the HA-1A group, compared with eight (57%) of 14 control animals (combined control human IgM antibody and control human serum albumin groups) (P = .05), survived 28 days. At 24 hours, the HA-1A group had lower mean arterial pressure (P = .04) and cardiac index (P = .004) and higher lactate levels (P = .05) compared with the combined-controls group. In addition, these parameters in the HA-1A group were significantly more predictive of death. The HA-1A and combined-controls groups had similar significant increases in the level of endotoxemia and bacteremia. Studies of toxic effects showed no harmful effects of control human IgM antibody in infected animals or HA-1A in non-infected animals. CONCLUSION: In a canine model of E coli sepsis, HA-1A did not alter levels of bacteremia or endotoxemia and actually decreased survival. If these data are relevant to human septic shock, HA-1A therapy should be limited until the conditions under which this monoclonal antibody has beneficial or deleterious effects are more completely defined.

Animals↗
PubMed1993

Plasma exchange does not improve survival in a canine model of human septic shock.

Whether plasma exchange would improve survival in antibiotic-treated canines with septic shock was investigated. Escherichia coli O86H8 (1.4 X 10(10)) was surgically implanted as an intraperitoneal clot in 18 two-year-old (10-12 kg) purpose-bred beagles. Beginning 4 hours after surgery, all animals received cefoxitin and gentamicin for 5 days. Three treatment groups were defined: 1) a no apheresis, or control group, (n = 6); 2) a sham apheresis group, whose whole blood plasma was removed, separated, and then transfused (n = 6); and 3) a plasma exchange group from whom blood and plasma were removed and separated, to whom the blood was returned, and in whom infected plasma was replaced with compatible fresh-frozen canine plasma (n = 6). For the sham apheresis and plasma exchange groups, a commercial blood cell processor was used to separate 1.5 blood volumes of plasma at 5 and 24 hours after surgery. Serial radionuclide left ventricular ejection fractions and femoral and pulmonary arterial catheter hemodynamics were measured simultaneously in awake animals. All six animals in the plasma exchange group died. In both the sham and control groups, only one of six animals survived. Survival times were ordered (median in hours) (control [372 h] > sham apheresis [48 h] > plasma exchange [24 h] [p < 0.038]). Decreases in mean cardiac index and mean arterial pressure (from before apheresis to after) at 5 to 7 hours after surgery were ordered (plasma exchange > sham apheresis > control; p < 0.03). Thus, plasma exchange in this controlled trial of septic shock was associated with decreased survival and worsened hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Therapeutic trial of lipid X in a canine model of septic shock.

Three groups of dogs were given lipid X (0, 1, or 10 mg/kg) every 8 h for for seven doses, starting simultaneously with the intraperitoneal placement of Escherichia coli-containing fibrin clots. All animals developed bacteremia, hypotension, and a pattern of decreased left ventricular ejection fraction characteristic of septic shock (P = .01). Survival rates and survival times were not significantly different between treatment groups (P > .2). In a similar experiment, higher doses of lipid X resulted in a significantly decreased survival time compared with concurrent controls (P = .04). Animals receiving lipid X did not differ from controls in serial determinations of temperature, hemodynamic measurements, or laboratory parameters (except serum total protein). Although lipid X has antiendotoxin effects, no benefit could be demonstrated in this antibiotic-treated, gram-negative bacillary-infected model of septic shock. These data do not support a therapeutic role for lipid X in the treatment of gram-negative sepsis.

Animals↗
PubMed1993

Acute hemorrhage in dogs: construction and validation of models to quantify blood loss.

We examined the ability of commonly used clinical parameters to quantify acute hemorrhage in dogs. Eight animals were bled 40 ml/kg body wt over 100 min. Ten hemodynamic and 20 blood laboratory parameters were obtained every 10 min to construct, with use of linear regression analysis, models that quantify blood loss. During model construction, the best indicator of quantity of hemorrhage was arterial base deficit [ABD; coefficient of variation (CV) 35%]. This model was more accurate (P < 0.05) than 27 others (CV range 43 to 63%) and similar to systolic (CV 40%) and mean (CV 40%) arterial pressures. In validation studies in 10 additional animals, our best models based on ABD and systolic and mean arterial pressures each unexpectedly showed a significant (P < 0.05) decrease in accuracy (CV 86, 57, and 60%, respectively) attributable to large baseline (before hemorrhage) variability among animals. To eliminate this variability, models based on changes from baseline measurements were investigated. The best predictor of change in blood volume was change in ABD (CV 27%). This model was significantly (P < 0.05) more accurate than any of 27 others (CV range 36 to 65%) and similar to change in venous base deficit and venous pH (each CV 31%). When validated, acid-base models such as ABD, venous pH, and arterial bicarbonate were the best predictors of volume change (CV range 28 to 40%). With the use of multivariate analysis, pairwise combinations of single parameter models (n = 465) improved prediction errors only minimally. In summary, most commonly used hemodynamic and blood indexes could not be validated as accurate measurements in quantifying hemorrhage. In contrast, changes in acid-base parameters were validated as moderately accurate predictors of blood volume changes and therefore may have utility in the assessment of patients with ongoing hemorrhage.

Acid-Base Equilibrium↗
PubMed1992

N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.

Amino Acid Oxidoreductases↗
PubMed1992

Systemic hemodynamic abnormalities and vasopressor therapy in sepsis and septic shock.

Septic shock, a distributive form of shock, is a common and lethal disease characterized by tachycardia, hypotension, normal or elevated cardiac index, and decreased systemic vascular resistance (SVR). For 2 to 4 days after onset of shock, the left ventricular ejection fraction (LVEF) is depressed; with adequate volume replacement, the left ventricle dilates and cardiac output (CO) is maintained or increased. In survivors, these abnormalities reverse to normal within 7 to 10 days. The myocardial depression found in patients with septic shock is not associated with global myocardial ischemia. In our animal model of sepsis, myocardial depression is not associated with impaired myocardial high-energy stores, or abnormal myocardial oxygen utilization. However, septic animals have histopathologic evidence of coronary nonocclusive microvascular damage and myocyte injury. The majority of human deaths caused by septic shock are related to the peripheral vascular dysfunction and multiorgan system failure that occurs over time. The pathophysiology of this disease is complex. Clinical and experimental evidence support the notion that myocardial depression, peripheral vascular abnormalities, and multiorgan dysfunction result from the combined effect of exogenous and endogenous mediators (eg, endotoxin, cytokines, and nitric oxide) released during septic shock. Although conventional therapy with fluids, vasopressors, and antibiotics is effective, the disease still has a high mortality rate. Studies investigating the effects of bacterial toxins and potentially harmful host mediators offer the greatest hope in finding new ways to eradicate this highly lethal disease.

Animals↗
PubMed1992

Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction.

Three groups of conscious canines were given different intravenous doses of human recombinant tumor necrosis factor (TNF) over 1 h, and the resulting cardiovascular abnormalities were examined for 10 days. As TNF dose increased [0 (controls), 30, 60, and 120 micrograms/kg body wt], the number of deaths increased (P less than 0.025; 0 of 6, 1 of 8, 4 of 8, number of deaths in each group, respectively). In all three groups receiving TNF, the mean left ventricular ejection fraction (LVEF) at 2 h after infusion decreased (P less than 0.003) compared with controls. The group receiving the highest dose of TNF (120 micrograms/kg body wt) had the greatest decrease (P less than 0.05) in LVEF from 0 to 2 h. At 8 h, all three groups receiving TNF had similar LVEF. In these three groups, other multiple measures of LV function at 8 h showed significant and similar decreases in cardiac contractility compared with controls. From 24 to 240 h, however, the time required for cardiac performance (LVEF) to return to normal was dose dependent (30 less than 60 less than 120 micrograms/kg body wt; P less than 0.05). Canines receiving the lowest dose of TNF had near normal cardiac function (LVEF) at 24 h, whereas canines receiving the highest dose had persistent cardiac abnormalities at 240 h. Thus, at 8 h, the severity of cardiac dysfunction is independent of TNF dose, but the rate of onset and the duration of cardiac abnormality are markedly dependent of dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗