Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs.

BACKGROUND: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (ie., tumor necrosis factor alpha, interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CWH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury. METHODS: Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CWH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter. RESULTS: Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CWH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animals at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterialoxygen tension, 268+/-33 vs. 176+/-67 mm/Hg, respectively, P < 0.01). In addition, treatment with CWH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance. CONCLUSION: These results suggest that nonspecific blood purification with high-volume CWH improves arterial oxygenation and lung function in endotoxin-induced acute lung injury in pigs, independent of improved hemodynamics, fluid removal, or body temperature.

Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice.

BACKGROUND: Sepsis can be complicated by severe myocardial dysfunction and is associated with increased nitric oxide (NO) production by inducible NO synthase (NOS2). To investigate the role of NOS2 in endotoxin-induced myocardial dysfunction in vivo, we studied wild-type and NOS2-deficient mice. METHODS AND RESULTS: Serial echocardiographic parameters of myocardial function were measured before and at 4, 7, 16, and 24 hours after an endotoxin challenge. Seven hours after challenge with either endotoxin or saline, systemic and left ventricular pressures were measured, and the first derivative of left ventricular developed pressure (dP/dt), slope of the end-systolic pressure-dimension relationship (Slope(LVESPD)), and time constant of isovolumic relaxation (tau) were calculated. Endotoxin challenge in wild-type mice decreased left ventricular fractional shortening, velocity of circumferential shortening, dP/dt(max), Slope(LVESPD), and dP/dt(min) and increased time constant tau. Endotoxin-induced myocardial dysfunction was associated with increased ventricular NOS2 gene expression and cGMP concentrations. Seven hours after endotoxin challenge, NOS2-deficient mice had greater fractional shortening, dP/dt(max), and Slope(LVESPD) than did endotoxin-challenged wild-type mice. Measures of diastolic function, dP/dt(min) and time constant tau, were preserved in endotoxin-challenged NOS2-deficient mice. After endotoxin challenge in wild-type mice, early (3-hour) inhibition of NOS2 with L-N:(6)-(1-iminoethyl)lysine hydrochloride prevented, whereas later (7-hour) inhibition could not reverse, endotoxin-induced myocardial dysfunction. CONCLUSIONS: These results suggest that NOS2 is required for the development of systolic and diastolic dysfunction in murine sepsis.

Increasing doses of pentoxifylline as a continuous infusion in canine septic shock.

We investigated effects of pentoxifylline during septic shock. Two-year-old (10-12 kg), purpose-bred beagles were infected i.p. with Escherichia coli 0111:B4 (1.2-1.5 x 10(9) colony-forming units per kilogram b.wt.) in a fibrin clot and then immediately treated with one of five doses of pentoxifylline (0.5-20 mg. kg-1. h-1 i.v.) as a 36-h continuous infusion or placebo. All animals received antibiotics and fluid resuscitation. Pentoxifylline levels increased in a dose-dependent manner during (p =.001) and were undetectable 12 h after stopping the infusion. During infusion of pentoxifylline at all doses, there were increases (p =.003), and once the infusion was stopped, there were decreases (p =.049) in endotoxin levels compared with controls. After clot implantation, at all pentoxifylline doses there was a significant increase in tumor necrosis factor levels, compared with controls (p =.025). The relative risk of death was significantly increased with pentoxifylline therapy in a dose-dependent fashion (20 >/= 10 >/= 5.0 >/= 1.0 >/= 0.5 mg. kg-1, p =.008). One hypothesis consistent with these data is that high pentoxifylline levels slowed endotoxin clearance, resulting in high levels of endotoxemia and increased proinflammatory mediator release and death. Pentoxifylline, used as a long-term continuous infusion as is commonly done clinically, can be harmful during Gram-negative septic shock.

Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs.

We investigated the effects of N(omega)-monomethyl-L-arginine (L-NMMA) and fluid loading on tumor necrosis factor (TNF)-induced cardiovascular dysfunction in awake dogs. L-NMMA (40 mg x kg(-1) given intravenously over a period of 10 min, and followed by dosing at 40 mg x kg(-1) x h(-1) for 6 h) and TNF (20 or 45 microg x kg(-1) given intravenously for 20 min), given alone or in combination, significantly decreased stroke volume, cardiac index, oxygen delivery, and left-ventricular (LV) function plots over a period of 6 h. Of note was that the cardiac-depressant effects of TNF and L-NMMA given together were significantly less than additive. Thus, the combination was beneficial (or significantly less harmful to cardiac performance than expected), possibly because L-NMMA augmented cardiac preload as shown by significant increases in both pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP). Fluid challenges at 6 h (Ringer's solution at 80 ml x kg(-1) given over a period of 30 min) also significantly increased PCWP and CVP, and abolished the beneficial preload effect of L-NMMA on cardiac performance. Thus, after fluid loading, the cardiac-depressant effects of TNF and L-NMMA given together became equal to the sum of those produced by TNF and L-NMMA given separately. Although L-NMMA significantly decreased serum nitrite/nitrate levels, TNF did not increase these end products of nitric oxide (NO) production relative to controls. Therefore, after preload abnormalities were eliminated with fluid loading, L-NMMA had no beneficial effect on TNF-induced cardiac depression, and TNF did not increase end products of NO production. These findings are not consistent with NO being the mechanism of TNF-induced acute cardiac depression.

Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E. coli pneumonia and sepsis.

We investigated the effect of inhaled nitric oxide (NO) at increasing fractional inspired O2 concentrations (FIO2) on hemodynamic and pulmonary function during Escherichia coli pneumonia. Thirty-eight conscious, spontaneously breathing, tracheotomized 2-yr-old beagles had intrabronchial inoculation with either 0.75 or 1.5 x 10(10) colony-forming units/kg of E. coli 0111:B4 (infected) or 0.9% saline (noninfected) in one or four pulmonary lobes. We found that neither the severity nor distribution (lobar vs. diffuse) of bacterial pneumonia altered the effects of NO. However, in infected animals, with increasing FIO2 (0.08, 0.21, 0.50, and 0.85), NO (80 parts/million) progressively increased arterial PO2 [-0.3 +/- 0.6, 3 +/- 1, 13 +/- 4, 10 +/- 9 (mean +/- SE) Torr, respectively] and decreased the mean arterial-alveolar O2 gradient (0.5 +/- 0.3, 4 +/- 2, -8 +/- 7, -10 +/- 9 Torr, respectively). In contrast, in noninfected animals, the effect of NO was significantly different and opposite; NO progressively decreased mean PO2 with increasing FIO2 (2 +/- 1, -5 +/- 3, -2 +/- 3, and -12 +/- 5 Torr, respectively; P < 0.05 compared with infected animals) and increased mean arterial-alveolar O2 gradient (0.3 +/- 0.04, 2 +/- 2, 1 +/- 3, 11 +/- 5 Torr; P < 0.05 compared with infected animals). In normal and infected animals alike, only at FIO2 < or = 0.21 did NO significantly lower mean pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance index (all P < 0.01). However, inhaled NO had no significant effect on increases in mean pulmonary artery pressure associated with bacterial pneumonia. Thus, during bacterial pneumonia, inhaled NO had only modest effects on oxygenation dependent on high FIO2 and did not affect sepsis-induced pulmonary hypertension. These data do not support a role for inhaled NO in bacterial pneumonia. Further studies are necessary to determine whether, in combination with ventilatory support, NO may have more pronounced effects.

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls (P = 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P < or = 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin.

Role of endotoxemia in cardiovascular dysfunction and lethality: virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock.

We investigated whether the severity of septic shock is determined by virulence factors associated with or the levels of endotoxemia produced by two Escherichia coli strains. Canines were challenged intraperitoneally with an E. coli strain (O6:H1:K2) that has virulence factors associated with human disease or with an equal dose of a nonvirulent strain (O86:H8) that lacks these factors. Both strains were administered in viable, heat-killed, and purified endotoxin forms. Median survival times with the virulent strain compared with the nonvirulent strain were shorter with viable bacteria (5 x 10(10) CFU/kg) (144 h versus > 672 h; Wilcoxon, P = 0.03), longer with heat-killed bacteria (5 x 10(9) CFU/kg) ( > 676 h versus 26 h; P = 0.03), and similar with purified endotoxin (15 mg/kg) (28 h versus 48 h; P = 0.71). However, whether the challenge contained viable bacteria, heat-killed bacteria, or purified endotoxin, the virulent strain produced less endotoxemia (P = 0.001). Hence, the changing outcomes with differing forms of the two strains cannot be attributed solely to endotoxin levels. The viable virulent strain caused less endotoxemia but more harm, and this does not appear to be explained by a more potent endotoxin or other heat-stable component. This study suggests that circulating endotoxin levels per se are less important in the outcome of septic shock than virulence factors associated with E. coli strains. Furthermore, the data call into question the significance of the endotoxin concentration in the blood in predicting the severity of shock and the lethality of gram-negative infections.

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.

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.

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)

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.

Myocardial energy metabolism and morphology in a canine model of sepsis.

The mechanism responsible for sepsis-induced myocardial depression is not known. To determine if sepsis-induced myocardial depression is caused by inadequate free energy available for work, we studied myocardial energy metabolism in a canine model of sepsis. Escherichia coli-infected (n = 18) or sterile (n = 16) fibrin clots were implanted intraperitoneally into beagles. Myocardial function and structure was assessed using radionuclide ventriculograms, echocardiograms, and light and electron microscopy. The adequacy of energy metabolism was evaluated by comparing catecholamine-induced work increases [myocardial O2 consumption (MVO2) and rate pressure product (RPP)] with a simultaneously obtained estimate of intracellular free energy [phosphocreatine-to-adenosine triphosphate ratio (PCr:ATP)] determined by 31P-magnetic resonance spectroscopy. When compared with control animals, septic animals had a decrease in left ventricular ejection fraction (EF, P < 0.0001) on day 1 and fractional shortening (FS, P < 0.0003) on day 2 after clot implantation. On day 2, neither septic nor control animals had statistically significant decreases in PCr:ATP, despite catecholamine-induced increases in MVO2 and RPP (mean maximal increases in septic animals 135 +/- 31 and 51 +/- 10%, respectively). Light and electron microscopic findings showed that hearts of septic animals, compared with control animals, had a greater degree of morphological abnormalities. Thus, in a canine model of sepsis with alterations in myocyte ultrastructure and documented myocardial depression (decreased EF and FS), intracellular free energy levels (PCr:ATP) were maintained despite catecholamine-induced increases in myocardial work (increased MVO2 and RPP), suggesting high-energy synthetic capabilities are not limiting cardiac function.

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.

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.

High-dose ifosfamide is associated with severe, reversible cardiac dysfunction.

OBJECTIVE: To determine the incidence and characterize the occurrence of cardiac toxicity with high-dose ifosfamide. DESIGN: Retrospective chart review. SETTING: Biomedical research referral center. PATIENTS: Fifty-two consecutive patients with advanced lymphoma or carcinoma enrolled in phase I trials of high-dose ifosfamide as part of combination chemotherapy with autologous bone marrow transplantation. INTERVENTIONS: Patients were given escalating doses (10 to 18 g/m2) of ifosfamide in combination with carboplatin and etoposide or with lomustine and vinblastine. MEASUREMENTS: The chart review focused on clinical, radiographic, or electrocardiographic evidence of cardiovascular dysfunction. Data from invasive hemodynamic monitoring, radionuclide cineangiography, and echocardiography were also reviewed. RESULTS: Nine of the patients treated with ifosfamide developed congestive heart failure (17%; 95% Cl, 8% to 30%). Eight of these patients, experiencing dyspnea, tachycardia, weight gain, and signs of pulmonary edema, required admission to an intensive care unit. Left ventricular contractility was found to be depressed when evaluated by radionuclide cineangiography, echocardiography, or both. Most patients responded to diuretic, vasodilator, and inotropic therapies. Two patients developed malignant ventricular arrhythmias. One patient died of intractable cardiogenic shock. Five patients died of multiorgan failure, despite showing improvement in left ventricular ejection fraction. Three patients survived and regained baseline left ventricular ejection fraction. CONCLUSIONS: High-dose ifosfamide is associated with severe but usually reversible myocardial depression and malignant arrhythmias.

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.

Reconstrucao total de arco mandibular e assoalho da boca com retalho osteomiocutaneo bilateral do trapezio e escapula. / Total reconstruction of mandibular arch and mouth floor with bilateral osteomyocutaneous flap of the trapezius and scapula

Os autores apresentam um caso inedito de reconstrucao imediata total do arco mandibular e assoalho de boca com retalho osteomiocutaneo bilateral do trapezio e escapula, seguindo resseccao de cancer avancado da boca, num unico tempo cirurgico. Sao apresentadas uma descricao detalhada das consideracoes anatomicas e tecnica cirurgica. Os varios tipos de retalhos osseos para reconstrucao mandibular sao discutidos. Experiencia com este retalho sugere que ele pode ser o mais versatil e confiavel em largas reparacoes de mandibula e assoalho de boca