Effects of geldanamycin and thalidomide on the Th1/Th2 cytokine balance in mice subjected to operative trauma.

BACKGROUND: Persistence of postoperative immune dysfunction is a critical problem because it increases the risk of serious infectious complications. The mechanisms of the immune dysfunction that occur initially after non-thermal operative injury remain to be fully elucidated. METHODS: Two mouse models of operative trauma (simple laparotomy to represent minor operative injury and ileocecal resection to represent major operative injury) were used to define the characteristics of initial cytokine synthesis. Geldanamycin and thalidomide were independently added intraperitoneally before and after operative injury to examine the effect on postoperative immune dysfunction. Mice were sacrificed at scheduled times (3, 6, 12, and 24 h after operative injury) and TNF-alpha, IL-2, IL-4, and IL-10 were analyzed. Spleen was used for intracellular cytokines and RT-PCR. Sera were used for ELISA. RESULTS: Major operative injury caused an initial upregulation of IL-10 synthesis with delayed synthesis of TNF-alpha and IL-2. Minor operative injury caused an early induction of IL-2 synthesis preceded by an initial induction of IL-4 synthesis. GA caused a specific early upregulation of TNF-alpha mRNA expression and intracellular TNF-alpha synthesis. The GA and THD groups showed early serum IL-2 production with reduction of IL-10 mRNA expression and intracellular IL-10 synthesis in the early post-operative phase. CONCLUSIONS: Major and minor operative injury showed different Th1/Th2 cytokine patterns in the initial post-operative period. Geldanamycin and thalidomide improved the Th1/Th2 imbalance independently after major operative injury.

Cathepsin D activity and protein degradation products in organs and blood during experimental declamping shock.

Aortic cross-clamping in dogs for 60 min causes an increase in cathepsin D activity in the kidney, liver, lung, heart, skeletal muscle and the blood serum. It causes no changes in the content of protein and its degradation products of the examined organs, apart from the lungs, where the above parameters are higher. The intensity of the observed changes in the kidney and other organs does not depend on the level of aortic cross-clamping (above or below renal arteries).

Studies in surgical trauma: oxidative stress in ischaemia-reperfusion of rat liver.

1. Hypovolaemic shock associated with surgical trauma has been studied in a rat liver ischaemia-reperfusion model by determination of oxidative stress, lipid peroxidation and tissue infiltration of polymorphonuclear leucocytes. 2. Liver ischaemia alone resulted in slight liver oedema and polymorphonuclear leucocyte infiltration, a slight increase in thiobarbituric acid-reacting substances (an index of lipid peroxidation) and decreases in liver reduced glutathione and total radical-trapping antioxidant parameter, indices of oxidative stress. Ischaemia plus 30 min of reperfusion further increased liver oedema, polymorphonuclear leucocyte infiltration and thiobarbituric-acid reacting substances, and further decreased liver reduced glutathione and total radical-trapping antioxidant parameter. 3. After 60 and 90 min of reperfusion, oedema (40% increase), polymorphonuclear leucocyte infiltration (40-fold increase) and thiobarbituric-acid reacting substances (20-fold increase) were maximal, and liver reduced glutathione (75-95% decrease) and total radical-trapping antioxidant parameter (85-90% decrease) were at a minimum. 4. All parameters were exacerbated by 24 h starvation. Liver reduced glutathione closely paralleled total radical-trapping antioxidant parameter, and ischaemia alone depleted both by 30% in fed rats and 50% in fasted rats. 5. Oxidative stress and lipid peroxidation were associated more with the period of reperfusion and polymorphonuclear leucocyte infiltration. Polymorphonuclear leucocyte infiltration into lung also occurred after 90 min of liver reperfusion. 6. Possible mechanisms of hepatic ischaemia-reperfusion-induced oxidative stress are discussed.

Metabolic basis for the management of patients undergoing major surgery.

After reviewing our current knowledge of the metabolic response to major abdominal surgery, we present two new studies in which we have followed the changes in body composition, physiologic function, and psychological function for up to 1 year after major surgery. In the first study, 46 patients had changes in body composition, physiologic function, and psychological function measured perioperatively and again at intervals up to 1 year. There was an average loss of weight of 3000 grams (maximum at 2 weeks), and the tissue composition of this weight loss was composed of 1400 grams fat, 600 grams protein, and 1000 grams water. Normal body composition had returned to normal in most patients by 6 months. In the second study of 84 patients, deficits of skeletal muscle function and fatigue were found to be greatest at postoperative day 7. Most patients were back to preoperative levels of muscle function and fatigue 30 days after surgery, and nearly all had normal values 90 days after surgery. Based on these studies we outline our management program for the metabolic care of patients undergoing major abdominal surgery.

Blood transfusion and oxygen consumption in surgical sepsis.

OBJECTIVE: To evaluate the use of serum lactic acid values to predict flow-dependent increases in oxygen consumption (VO2) in response to increasing oxygen delivery (DO2) after blood transfusion in surgical sepsis. DESIGN: Prospective study. SETTING: Tertiary care, trauma center. PATIENTS: Twenty-one patients, postsurgical or posttrauma, judged septic by defined criteria. INTERVENTIONS: Serum lactic acid concentrations, DO2, and VO2 were measured before and after transfusion therapy. MEASUREMENTS AND MAIN RESULTS: Overall, the DO2 increased from 532 +/- 146 to 634 +/- 225 (SD) mL/min.m2 (p less than .001), and the VO2 increased from 145 +/- 39 to 160 +/- 56 mL/min.m2 (p = .02). These changes occurred with an Hgb increase from 9.3 +/- 1.1 to 10.7 +/- 1.5 g/dL (p less than .001). The patients were grouped by their pretransfusion serum lactic acid values. In those patients with normal (less than 1.6 mmol/dL) serum lactic acid (n = 10), DO2 increased from 560 +/- 113 to 676 +/- 178 mL/min.m2 (p less than .02), and VO2 increased from 150 +/- 25 to 183 +/- 46 mL/min.m2 (p less than .02). However, in the increased serum lactic acid group (n = 17), VO2 was not significantly changed after transfusion (143 +/- 46 to 146 +/- 58 mL/min.m2) despite increased DO2 (515 +/- 163 to 609 +/- 251 mL/min.m2, p less than .01). CONCLUSIONS: Blood transfusion can be used to augment DO2 and VO2 in septic surgical patients. Increased serum lactic acid values do not predict patients who will respond. The absence of lactic acidosis should not be used in this patient population to justify withholding blood transfusions to improve flow-dependent VO2. Patients who have increased lactate concentrations may have a peripheral oxygen utilization defect that prevents improvement in VO2 with increasing DO2.

[The effect of reduced glutathione on the changes of lipid-peroxide concentration in shock states--clinical and experimental studies].

Lipoperoxide changes and the effect of reduced glutathione (GSH) on that were investigated in cardiopulmonary bypass and endotoxin shock states. In human cardiopulmonary bypass, 26 patients with congenital heart disease were studied and the following results were obtained. Serum lipoperoxide concentration in control group increased in 30 and 60 min after bypass. On the other hand, in the reduced glutathione pretreatment group (100 mg/kg), this change was not observed. In both groups, beta-glucuronidase activity had a tendency to increase after bypass, and it had a close correlation between serum lipoperoxide concentration and beta-glucuronidase activity. In endotoxin shock rats, the results were as follows. 3 hours after injection of endotoxin (10 mg/kg), hepatic lipoperoxide concentration increased and superoxide dismutase (SOD) activity decreased, and hepatic Chemiluminescence counts had a tendency to increase. There was no significant change in serum lipoperoxide concentration after 3 hr, but a significant elevation was observed only after 6 hr. In the reduced glutathione pretreatment group (1,000 mg/kg), serum and hepatic lipoperoxide concentration, hepatic SOD activity, and hepatic Chemiluminescence counts were unchanged. These results suggest that lipoperoxide may increase in shock states and GSH administration may be useful to inhibit lipoperoxide formation.

Oxygen consumption and recovery from surgical shock in rats: a comparison of the efficacy of different plasma substitutes.

Shock was induced in 537 rats by exteriorization of the intestines and occlusion of the superior mesenteric circulation for 1 hour. After 1 hour of this intestinal ischemia shock, oxygen consumption (VO2) decreased to half of the preexperimental values. When no infusion was given, the survival rate at 24 hours was 22%; this was correlated with the degree of restoration of VO2 at 1 hour after shock. VO2 and survival rate improved with infusion of albumin, dextran 40, and dextran 40, and dextran 70. With increasing doses of colloids, both VO2 and survival rate increased; the optimal effect was at the dose of 2 g/kg body weight. When no other therapy was given, colloids at concentrations of 3.5 or 6% solutions had a better effect on survival than the 10% solution. Colloids were more effective than Ringer's acetate when the latter was given in the same volume and up to three times the volume of the colloids.

[Metabolic regulation in surgical patients]. / Stoffwechselregulation bei chirurgischen Patienten.

The concentration of circulating hormones and substrates was determined in 7 patients before, during and after major elective surgery. On the basis of these and other of our studies, as well as data in the literature, a tentative scheme of postoperative and post-traumatic metabolism has been drawn up. It is based on the classical division into a "shock phase", a catabolic healing phase and an anabolic healing phase. The adjustment of intravenous feeding to these metabolic phases is discussed.

Tissue blood exchange and tissue oxygen tension in relation to total body oxygen consumption in experimental surgical shock.

This experimental shock model was well defined by the marked decrease in total body oxygen consumption, muscle PO2 and diffusion capacity during shock. Infusion of large amounts of electrolyte solution did not lead to a restoration of muscle oxygen tension after 1-4 hours. Dextran 40 infusion however restored both local PO2 and blood flow in the muscle as well as total body oxygen consumption.

Homograft of the small intestine. Metabolic and functional changes causing irreversible shock.

Homotransplantation of the small intestine is subject to high mortality in the first 48 hours after operation. We analyzed various causes of death, underlining the importance of postoperative shock, then developed an experiment in dogs with the object of improving the survival. We applied various therapeutic measures in order to reduce the factors which participate in the evolution of chronic, hypovolemic and toxic shock. We attempted to: (1) reduce the consecutive alterations to ischemia of the homotransplant during the non-perfusion period; (2) reduce the deleterious effect of retained fecal matter; (3) reduce the metabolic acidosis secondary to clamping of the great vessels; (4) acknowledge, analyze and correct alterations in fluid and electrolyte balances; (5) correct the blood volume; and (6) prevent infection. With these measures we have increased the survival rate.