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Fibronectin in severe sepsis
259
ABSTRACTS
(bacterial translocation) to invade the mesentcric lymph nodes and other organs if the normal indigenous microflora is disrupted, allowing bacterial overgrowth. To determine whether T-cell-mediated immunity (T..CM I) was important in preventing translocation after thermal injury in animals with an intact normal flora, conventional ( + / + ) , athymic (nu/nu), and heterozygous ( n u / + ) mice receiving a 30% third.degree burn were killed at various intervals after burn and their organs cultured. Bacterial translocation did not occur in control or burned specific pathogen-free mice with intact T-CMI bul did occur in athymic mice with deficient T-CMI. Both the incidence of positive organs and the numbers of translocated bacteria per gram of organ were increased after thermal injury. Bacterial overgrowth was not responsible for these findings, since the levels of cecal enteric bacteria were not different between the burned and nonburned groups. Since translocation occurred to a greater extent in athymie burned mice than control athymie mice, it appears that a thermal injury promotes translocation by impairing other host defense systems in addition to the T-CMI. (Reprinted with permission.)
(t - I, t - 2, and t - 3) with concomitant hemodynamic and metabolic variables were obtained. Group I (n - 2 1 ) consisted of survivors and group !I (n - 21) of nonsurvivors. Group !1 was divided into three subgroups: group lla (n - 4) consisted of nonsurvivors with liver cirrhosis, group lib (n - 9) patients with final CI < 4 1 • min -~ • m -2, and group lie (n - 8) patients with final C1 > 4 i - rain-~ - m -s. At t 1 no significant differences in hemodynamic variables were found between groups I and II, and all patients, whether survivingor not, were able to increase C! to similar levels. At t - 3 group 11 showed a marked decrease in mean arterial pressure and systemic vascular resistance index compared with group 1 (p < 0.001), whereas CI did not differ significantly. The nonsurvivors showed progressive lactic acidemia. Even group lib patients showed persistent vasodilation despite a decrease in CI. Our data suggest that many patients in septic shock die as a result of peripheral vascular rather than cardiac failure, since persistent vasodilation, irrespective of CI, was a major hemodynamic determinant in nonsurrivers, of whom 57% maintained a high C! until shortly before death. (Reprinted with permission.)
Intestinal Bacteria Translocate Into Experimental I n t r a Abscesses. Wells CL, Rotsteita OD, Pruett TL, et
Role of Free Radicals in lschemie Rat Liver Cell Injury: Prevention of Damage by ~t-Tocopharol Administration,
aL Arch Surg 121:102, 1986.
Marubayashi S, Dohi Ko Ochi K, et al. Surgery 99:184, 1986.
abdominal
Experimental Jaffa-abdominal abscesses were initiated by surgical implantation of a fibrin clot contaminated with either Bacteroides fragilis, Bacteroides thetalotaomicron, or B fragilis-Escherichia coll. Seven days after surgery the numbers of bacteroides (per gram) in B fragilis and B thetalotaomicron abscesses were typically log~0 8.4 ± 0.5 (n - 6) and Ioglo6.4 ± 0.6 (n - 4), respectively; Bfragilis-E coil abscesses typically contained Iogl0 8.9 ± 0.5 B fragilis and log107.6 ± 0.6 E coil (n - 5). Of 38 Bfragitis abscesses, 14 B fragilis-E coil abscesses, and nine B thetalotaomicron abscesses, additional intestinal bacteria were recovered .from 21 (55%), 13 (93%), and seven (89%) abscesses, respectively. The additional organisms, in decreasing order of frequency, were enterococci, E coil, staphylococci, c~-streptococci, lactobacilli, and Proteus species in numbers ranging from 2.5 Ioglo to 7.9 logao per gram of abscess. Histologic sections of contaminated abscesses adherent to the intestine, liver, or spleen revealed normal tissue histology and no breakdown of the abscess wall. Thus, intestinal bacteria translocated into intra-abdominal abscesses by a mechanism that did not appear to be surgical sollage. (Reprinted with permission.) Hamodynamic Determinants of Mortality in Human Septic Shock, Groeneveld ABJ, Bronsveld W, Thijs LG. Surgery
99:140, 1986. To assess the relative importance of cardiac versus peripheral vascular failure in patients dying of septic shock, a series of 42 patients with documented septic shock was retrospectively evaluated. Patients were included in the study if serial hemodynamieand metabolic studies had been performed: the first one within 12 hours after onset of septic shock and the last one within 12 hours (median 2 hours; range 0.1 to 12 hours) before death in nonsurvivors. Nonsurvivors were included only if they died in shock. From the patient records the first, highest, and last measured cardiac indexes (CI)
The present study was undertaken to determine whether ~r-tocopherol pretreatment could modify cellular free radical metabolism during hepatic ischemia and subsequent reperfusion and prolong the viability of the liver. Although ischemnia of the liver for 90 minutes did not permit survival of the animals, a-tocopherol administration (10 mg/kg of body weight) for 3 days increased the survival rate to 45.5%. The period of isehemia was accompanied by decreases in the hepatic adenosine triphosphale (ATP) level, endogenous c~-tocopherol, and tolal glutathione (reduced a n d oxidized) without any significant increase in endogenous coenzymc Q (CoQ) homologs (CoQ9 and CoQ~0) and lipid peroxide formation. The subsequent restoration of blood flow resulted in a low recovery of ATP and marked dccreases in endogenous e~-tocopherol, total glutathione, and CoQ homologs and, on the contrary, a market increase in lipid peroxide levels. In ot-toeopherol-treated animals, however, resynthesis of ATP was accelerated even after 90 minutes of ischemia, and there were no changes in the levels of total glutathione or CoQ homologs or in the level of the enhanced a-tocopherol during the reperfusion period. The pretreatment also completely suppressed the elevation of lipid peroxide levels. These results are compatible with the assumption that cellular damage caused by hepatic ischemia can be explained by free radical reaction processes during ischemia and especially reperfusion a n d suggest that administration of a free radical scavenger and antioxidant, ~-tocopherol, is effective in ischemic liver cell injury. (Reprinted with permission.) in Severe Sepsis. Stevens LE, Clemmer TP, Laub RM, et aL Surg Gyneeol Obstet 162:222, 1986.
Fibronec¢in
Fibronectin was given in the form of cryoprecipitate of human plasma to patients with severe surgical sepsis in a double blind, prospective and randomized clinical study. Of
260
the 19 patients assigned to the control group receiving no fibroneetin, only eight (42 per cent) survived. Of the 12 patienls given the cryoprecipitate, nine survived (75 per cent) (p < 0.05). in the control group, initial serum fibroneetin levels were depressed to 121 micrograms per milliliter (normal - 313). The mean values in the blank plasma controls did not increase after 24 hours, with a mean of 122. In contrast, the group treated with cryoprecipitatc increased serum fibronectin values after 24 hours to 216 micrograms per milliliter, up from initial values of 161 micrograms per milliliters. Improvements in pulmonary function, serum bilirubin and serum creatinine values were also noted, but the changes fell short of statistical significance. Fihronectin appears to benefit patients in severe surgical sepsis in this study of a relatively small number of patients. (~eprintcd with permission.) Interaction of Prostaglandins, Activated Complement, and Granulocytes in Clinical Sepsis and Hypotension. SIotman
GJ, Burchard KW, Williams J J, et al. Surgery 99:744, 1986. Activated complement, thromboxane Az, prostacyclin, and activated granuloeytes have been implicated in hemodynamie dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-Fla (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group !I, hypovolcmic shock, group Iii, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups 1II and IV versus groups I and !1. C3a was increased in group IV versus groups 11 and I11. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups 1 through 111. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PG1. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemie and septic shock. (Reprinted with permission.)
ABSTRACTS
lung injury produced by the same dose given intravenously. We noted a marked increase in burn tissue TxA2 production after subeschar cndotoxin as reflected in significant increases in burn lymph and pulmonary artery TxB2 levels. Pulmonary artery pressure increased from 22 to 38 mm Hg and PaOz decreased from 89 to 71 tort while lung lymph flow ((~L) increased only modestly with no evidence of increased lung permeability. The TxA2 production and the lung response were prevented by the subeschar injection of ibuprofen, 12.5 mg/kg. Circulating endotoxin was noted in only one of five sheep. After intravenous (endotoxin), a significant increase in lung TxA 2 production was noted and a characteristic two-phase lung injury was seen with an initial phase basically identical to that seen with the subeschar injection followed by an increase in lung protein permeability. Burn tissue cndotoxin can stimulate local TxA2 production leading to distant lung dysfunction without the need for circulating endotoxin. The source of the TxA2 is the burn, while with endotoxemia the source is the lung. (Reprinted with permission.) Effects of Prostaglandin E~ in Adult Respiratory Distress Syndrome. Shoemaker WC, Appel PL. Surgery 99:275,
1986. Prostaglandin E~ (PGE~, Prostin VR) in doses of 30 ng/ kg . min was studied in two series of severely ill surgical patients with adult respiratory distress syndrome (ARDS). First the drug was administered in an initial trial in six patients; then a prospective, randomized, blinded trial was conducted in 10 studies on nine patients. PGE~ markedly decreased pulmonary artery pressure, pulmonary and systemic vascular resistance indexed, and venous pressures, while increasing cardiac output, arterial PO2 (PaO~), oxygen delivery, and oxygen consumption when compared with the baseline preinfusion control values and with the response of the placebo-treated control series. The PGEI responses were greater in patients whose ARDS was primarily attributed to the postoperative state with or without sepsis and least in patients with cirrhosis. The data are consistent with the concept that the drug reduces vasoconstriction primarily in the pulmonary circulation but also in the systemic circulation; improved PaO2 Usually follows the hemodynamic effect. We conclude that PGEI may be a useful adjunctive therapy for ARDS. (Reprinted with permission.) Pulmonary Microvascular Fluid Flux in a Large Animal Model of Sepsis: Evidence for Increased Pulmonary Endothelial Permeability Accompanying Surgically Induced Peritonitis in Sheep. Judges D, Sharkey P, Cheung H, el al.
Surgery 99:120, 1986. Endotoxin-lnduced Prostanoid Production by the Burn Wound Can Cause Distant Lung Dysfunction. Demling RH.
Wenger H, Lalonde CC, et al. Surgery 99:421, 1986. We injected Eschcrichia cell endotoxin, 2 tag/kg, beneath the eschar of sheep with 25% total body surface full-thickness burns to determine whether burn tissue in the presence of endotoxin releases prestanoids, particularly thromboxane A2, (TxA2), and if incre.ased local TxA2 production can lead to distant lung dysfunction. We compared this response to the
To characterize some of the remote effects of systemic sepsis on the lung, we evaluated changes in pulmonary microvascular fluid flux before and during sepsis secondary to a peritoneal focus of inflammation in sheep. We induced peritonitis by cecal ligation, perforation, and devascularization. During a subsequent 72-hour study period, both the mean blood pressure and the pulmonary capillary wedge pressure were unchanged, while the cardi;,c index increased slightly. The PaO2 fell by 48 hours (98 ± 8 to 84 ± 10 mm
ABSTRACTS
(bacterial translocation) to invade the mesentcric lymph nodes and other organs if the normal indigenous microflora is disrupted, allowing bacterial overgrowth. To determine whether T-cell-mediated immunity (T..CM I) was important in preventing translocation after thermal injury in animals with an intact normal flora, conventional ( + / + ) , athymic (nu/nu), and heterozygous ( n u / + ) mice receiving a 30% third.degree burn were killed at various intervals after burn and their organs cultured. Bacterial translocation did not occur in control or burned specific pathogen-free mice with intact T-CMI bul did occur in athymic mice with deficient T-CMI. Both the incidence of positive organs and the numbers of translocated bacteria per gram of organ were increased after thermal injury. Bacterial overgrowth was not responsible for these findings, since the levels of cecal enteric bacteria were not different between the burned and nonburned groups. Since translocation occurred to a greater extent in athymie burned mice than control athymie mice, it appears that a thermal injury promotes translocation by impairing other host defense systems in addition to the T-CMI. (Reprinted with permission.)
(t - I, t - 2, and t - 3) with concomitant hemodynamic and metabolic variables were obtained. Group I (n - 2 1 ) consisted of survivors and group !I (n - 21) of nonsurvivors. Group !1 was divided into three subgroups: group lla (n - 4) consisted of nonsurvivors with liver cirrhosis, group lib (n - 9) patients with final CI < 4 1 • min -~ • m -2, and group lie (n - 8) patients with final C1 > 4 i - rain-~ - m -s. At t 1 no significant differences in hemodynamic variables were found between groups I and II, and all patients, whether survivingor not, were able to increase C! to similar levels. At t - 3 group 11 showed a marked decrease in mean arterial pressure and systemic vascular resistance index compared with group 1 (p < 0.001), whereas CI did not differ significantly. The nonsurvivors showed progressive lactic acidemia. Even group lib patients showed persistent vasodilation despite a decrease in CI. Our data suggest that many patients in septic shock die as a result of peripheral vascular rather than cardiac failure, since persistent vasodilation, irrespective of CI, was a major hemodynamic determinant in nonsurrivers, of whom 57% maintained a high C! until shortly before death. (Reprinted with permission.)
Intestinal Bacteria Translocate Into Experimental I n t r a Abscesses. Wells CL, Rotsteita OD, Pruett TL, et
Role of Free Radicals in lschemie Rat Liver Cell Injury: Prevention of Damage by ~t-Tocopharol Administration,
aL Arch Surg 121:102, 1986.
Marubayashi S, Dohi Ko Ochi K, et al. Surgery 99:184, 1986.
abdominal
Experimental Jaffa-abdominal abscesses were initiated by surgical implantation of a fibrin clot contaminated with either Bacteroides fragilis, Bacteroides thetalotaomicron, or B fragilis-Escherichia coll. Seven days after surgery the numbers of bacteroides (per gram) in B fragilis and B thetalotaomicron abscesses were typically log~0 8.4 ± 0.5 (n - 6) and Ioglo6.4 ± 0.6 (n - 4), respectively; Bfragilis-E coil abscesses typically contained Iogl0 8.9 ± 0.5 B fragilis and log107.6 ± 0.6 E coil (n - 5). Of 38 Bfragitis abscesses, 14 B fragilis-E coil abscesses, and nine B thetalotaomicron abscesses, additional intestinal bacteria were recovered .from 21 (55%), 13 (93%), and seven (89%) abscesses, respectively. The additional organisms, in decreasing order of frequency, were enterococci, E coil, staphylococci, c~-streptococci, lactobacilli, and Proteus species in numbers ranging from 2.5 Ioglo to 7.9 logao per gram of abscess. Histologic sections of contaminated abscesses adherent to the intestine, liver, or spleen revealed normal tissue histology and no breakdown of the abscess wall. Thus, intestinal bacteria translocated into intra-abdominal abscesses by a mechanism that did not appear to be surgical sollage. (Reprinted with permission.) Hamodynamic Determinants of Mortality in Human Septic Shock, Groeneveld ABJ, Bronsveld W, Thijs LG. Surgery
99:140, 1986. To assess the relative importance of cardiac versus peripheral vascular failure in patients dying of septic shock, a series of 42 patients with documented septic shock was retrospectively evaluated. Patients were included in the study if serial hemodynamieand metabolic studies had been performed: the first one within 12 hours after onset of septic shock and the last one within 12 hours (median 2 hours; range 0.1 to 12 hours) before death in nonsurvivors. Nonsurvivors were included only if they died in shock. From the patient records the first, highest, and last measured cardiac indexes (CI)
The present study was undertaken to determine whether ~r-tocopherol pretreatment could modify cellular free radical metabolism during hepatic ischemia and subsequent reperfusion and prolong the viability of the liver. Although ischemnia of the liver for 90 minutes did not permit survival of the animals, a-tocopherol administration (10 mg/kg of body weight) for 3 days increased the survival rate to 45.5%. The period of isehemia was accompanied by decreases in the hepatic adenosine triphosphale (ATP) level, endogenous c~-tocopherol, and tolal glutathione (reduced a n d oxidized) without any significant increase in endogenous coenzymc Q (CoQ) homologs (CoQ9 and CoQ~0) and lipid peroxide formation. The subsequent restoration of blood flow resulted in a low recovery of ATP and marked dccreases in endogenous e~-tocopherol, total glutathione, and CoQ homologs and, on the contrary, a market increase in lipid peroxide levels. In ot-toeopherol-treated animals, however, resynthesis of ATP was accelerated even after 90 minutes of ischemia, and there were no changes in the levels of total glutathione or CoQ homologs or in the level of the enhanced a-tocopherol during the reperfusion period. The pretreatment also completely suppressed the elevation of lipid peroxide levels. These results are compatible with the assumption that cellular damage caused by hepatic ischemia can be explained by free radical reaction processes during ischemia and especially reperfusion a n d suggest that administration of a free radical scavenger and antioxidant, ~-tocopherol, is effective in ischemic liver cell injury. (Reprinted with permission.) in Severe Sepsis. Stevens LE, Clemmer TP, Laub RM, et aL Surg Gyneeol Obstet 162:222, 1986.
Fibronec¢in
Fibronectin was given in the form of cryoprecipitate of human plasma to patients with severe surgical sepsis in a double blind, prospective and randomized clinical study. Of
260
the 19 patients assigned to the control group receiving no fibroneetin, only eight (42 per cent) survived. Of the 12 patienls given the cryoprecipitate, nine survived (75 per cent) (p < 0.05). in the control group, initial serum fibroneetin levels were depressed to 121 micrograms per milliliter (normal - 313). The mean values in the blank plasma controls did not increase after 24 hours, with a mean of 122. In contrast, the group treated with cryoprecipitatc increased serum fibronectin values after 24 hours to 216 micrograms per milliliter, up from initial values of 161 micrograms per milliliters. Improvements in pulmonary function, serum bilirubin and serum creatinine values were also noted, but the changes fell short of statistical significance. Fihronectin appears to benefit patients in severe surgical sepsis in this study of a relatively small number of patients. (~eprintcd with permission.) Interaction of Prostaglandins, Activated Complement, and Granulocytes in Clinical Sepsis and Hypotension. SIotman
GJ, Burchard KW, Williams J J, et al. Surgery 99:744, 1986. Activated complement, thromboxane Az, prostacyclin, and activated granuloeytes have been implicated in hemodynamie dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-Fla (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group !I, hypovolcmic shock, group Iii, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups 1II and IV versus groups I and !1. C3a was increased in group IV versus groups 11 and I11. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups 1 through 111. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PG1. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemie and septic shock. (Reprinted with permission.)
ABSTRACTS
lung injury produced by the same dose given intravenously. We noted a marked increase in burn tissue TxA2 production after subeschar cndotoxin as reflected in significant increases in burn lymph and pulmonary artery TxB2 levels. Pulmonary artery pressure increased from 22 to 38 mm Hg and PaOz decreased from 89 to 71 tort while lung lymph flow ((~L) increased only modestly with no evidence of increased lung permeability. The TxA2 production and the lung response were prevented by the subeschar injection of ibuprofen, 12.5 mg/kg. Circulating endotoxin was noted in only one of five sheep. After intravenous (endotoxin), a significant increase in lung TxA 2 production was noted and a characteristic two-phase lung injury was seen with an initial phase basically identical to that seen with the subeschar injection followed by an increase in lung protein permeability. Burn tissue cndotoxin can stimulate local TxA2 production leading to distant lung dysfunction without the need for circulating endotoxin. The source of the TxA2 is the burn, while with endotoxemia the source is the lung. (Reprinted with permission.) Effects of Prostaglandin E~ in Adult Respiratory Distress Syndrome. Shoemaker WC, Appel PL. Surgery 99:275,
1986. Prostaglandin E~ (PGE~, Prostin VR) in doses of 30 ng/ kg . min was studied in two series of severely ill surgical patients with adult respiratory distress syndrome (ARDS). First the drug was administered in an initial trial in six patients; then a prospective, randomized, blinded trial was conducted in 10 studies on nine patients. PGE~ markedly decreased pulmonary artery pressure, pulmonary and systemic vascular resistance indexed, and venous pressures, while increasing cardiac output, arterial PO2 (PaO~), oxygen delivery, and oxygen consumption when compared with the baseline preinfusion control values and with the response of the placebo-treated control series. The PGEI responses were greater in patients whose ARDS was primarily attributed to the postoperative state with or without sepsis and least in patients with cirrhosis. The data are consistent with the concept that the drug reduces vasoconstriction primarily in the pulmonary circulation but also in the systemic circulation; improved PaO2 Usually follows the hemodynamic effect. We conclude that PGEI may be a useful adjunctive therapy for ARDS. (Reprinted with permission.) Pulmonary Microvascular Fluid Flux in a Large Animal Model of Sepsis: Evidence for Increased Pulmonary Endothelial Permeability Accompanying Surgically Induced Peritonitis in Sheep. Judges D, Sharkey P, Cheung H, el al.
Surgery 99:120, 1986. Endotoxin-lnduced Prostanoid Production by the Burn Wound Can Cause Distant Lung Dysfunction. Demling RH.
Wenger H, Lalonde CC, et al. Surgery 99:421, 1986. We injected Eschcrichia cell endotoxin, 2 tag/kg, beneath the eschar of sheep with 25% total body surface full-thickness burns to determine whether burn tissue in the presence of endotoxin releases prestanoids, particularly thromboxane A2, (TxA2), and if incre.ased local TxA2 production can lead to distant lung dysfunction. We compared this response to the
To characterize some of the remote effects of systemic sepsis on the lung, we evaluated changes in pulmonary microvascular fluid flux before and during sepsis secondary to a peritoneal focus of inflammation in sheep. We induced peritonitis by cecal ligation, perforation, and devascularization. During a subsequent 72-hour study period, both the mean blood pressure and the pulmonary capillary wedge pressure were unchanged, while the cardi;,c index increased slightly. The PaO2 fell by 48 hours (98 ± 8 to 84 ± 10 mm