Complementary DNA (cDNA) sequence of baboon tumor necrosis factor alpha.

Baboons are less LPS-sensitive than humans, even though their immune response mechanisms are similar. Since TNFalpha is a central mediator of the LPS-response we cloned and sequenced the baboon TNFalpha cDNA and compared the resulting sequence with the human TNFalpha sequence. Analysis of the TNFalpha protein coding region indicated 97% homology and of the 3' UTF 89%. The predicted baboon TNFalpha amino acid sequence differed at 10 positions from the human sequence. "TA" rich motifs within the 3' UTR were 100% homologous.

Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production.

Interleukin (IL) 8 was measured in CSF of 14 patients with severe traumatic brain injury. IL-8 levels were significantly higher in CSF (up to 8,000 pg/ml) than serum (up to 2,400 pg/ml) (p < 0.05), suggesting intrathecal production. Maximal IL-8 values in CSF correlated with a severe dysfunction of the blood-brain barrier. Nerve growth factor (NGF) was detected in CSF of 7 of 14 patients (range of maximal NGF: 62-12,130 pg/ml). IL-8 concentrations were significantly higher in these patients than in those without NGF (p < 0.01). CSF containing high IL-8 (3,800-7,900 pg/ml) induced greater NGF production in cultured astrocytes (202-434 pg/ml) than samples with low IL-8 (600-1,000 pg/ml), which showed a smaller NGF increase (0-165 pg/ml). Anti-IL-8 antibodies strongly reduced (52-100%) the release of NGF in the group of high IL-8, whereas in the group with low IL-8, this effect was lower (0-52%). The inability of anti-IL-8 antibodies to inhibit the synthesis of NGF completely may depend on cytokines like tumor necrosis factor alpha and IL-6 found in these CSF samples, which may act in association with IL-8. Thus, IL-8 may represent a pivotal cytokine in the pathology of brain injury.

Influence of the xanthine derivate HWA 138 on endotoxin-related coagulation disturbances: effects in non-sensitized vs D-galactosamine sensitized rats.

We have evaluated the effects of the xanthine derivate HWA 138 in rat endotoxemia in order to 1) prevent coagulation disturbances and other endotoxin-induced physiological abnormalities and 2) to reduce mortality. We performed two studies using two different models (sensitized vs non-sensitized rats) with a similar mortality but different severity of coagulation disturbances: a) LPS (15 mg/kg) alone or with HWA 138 (80 mg/kg) as a treatment modality 30 min pre LPS, b) galactosamine (500 mg/kg) simultaneously with LPS (100 micrograms/kg) with or without HWA 138 (80 mg/kg) pretreatment. Experiments c) and d) employed D-galactosamine and/or LPS similar to experiments a) and b), while HWA 138 was applied simultaneously. We found significant 1) amelioration of life-threatening coagulation disturbances in non-sensitized rats, 2) prevention of liver dysfunction in sensitized rats, 3) reduction of TNF formation in both models, and 4) improvement of survival in all groups receiving HWA 138. Our data indicate protective effects of HWA 138 against clotting disturbances either directly via reduced LPS-induced formation of procoagulant activity or indirectly via reduced TNF formation.

Clinical detection of LPS and animal models of endotoxemia.

The interest in the study of endotoxemia in the clinical area has increased recently as a result of a) improved and simplified endotoxin determination e.g. chromogenic-kinetic microplate methods (also an improved blood sampling tool is available), b) incidence of sepsis has increased due to improvement in early (e.g. posttraumatic) survival, c) interest in and good evidence for gut translocation as a source of endotoxemia, d) agents have developed, which can antagonize endotoxins. There is evidence that patients with positive endotoxin test in the ICU have a higher incidence of organ failure. To study the pathophysiological consequences of endotoxemia and possible ways of intervention animal models are necessary. The choice of the experimental setting depends on the aim of the study e.g. whether prolonged observation is necessary in survival studies or whether hemodynamic variables have to be measured or whether therapeutic agents only crossreact with primates. Since LPS levels are quite low in clinical studies, an important factor for selection of a relevant animal might be LPS sensitivity, or the use of additional sensitization techniques e.g. galactosamine. Another important aspect in this context is whether LPS is given as bolus or infused up to several days. In this review the dose, time, and route of LPS administration is also discussed. For screening purposes rodents are usually used, or sometimes rabbits due to their higher LPS sensitivity. Another very sensitive animal model is the sheep, which can be chronically instrumented and as a specialty allows lung lymph drainage and thus studies of LPS effects on pulmonary permeability. Pigs are used for hemodynamic studies and often in therapeutical studies if species-specificity of the drug tested is not important, in cases where a large animal is necessary. Finally the non-human primates offer a number of advantages due to human-like physiology, due to the cross-reactivity of human assay systems and accordingly also cross-reactivity of human therapeutic agents. While the chimpanzee also shares the LPS sensitivity of humans, baboons are insensitive like rodents. Thus each model serves to provide some useful purpose and the selection must be made to meet the requirements of the specific questions to be asked, with special emphasis of the chosen endotoxin model on relevance for the human sepsis state.

Plasma glutathione S-transferase as an early marker of posttraumatic hepatic injury in non-human primates.

We have hypothesized that the measurement of alpha-glutathione S-transferase (alpha-GST) in serum may provide a suitable sensitive marker of shock-induced liver damage. Six male adult baboons were studied. Hemorrhage was induced by blood withdrawal of 60-70% of the total blood volume down to an arterial pressure of 35-40 mmHg. Then the reinfusion was performed with the heparinized shed blood plus the same amount of Ringer's solution over the next 4 h. Before the start of hemorrhage, 2 mL/kg zymosan-activated plasma was infused to simulate trauma-related complement activation. alpha-GST antigen levels were determined using an anti-human alpha-GST immunoassay (Hepkit). Concentrations of alpha-GST at baseline in baboon were found to be 3.1 +/- 1.8 ng/mL; at the end of the shock period a significant increase in alpha-GST serum levels (74.8 +/- 13.8 ng/mL) was found. In contrast, transaminase levels did not significantly change. From the current evidence in posttraumatic non-human primates, which resemble the clinical situation in several aspects, alpha-GST measurements are a suitable marker of early hepatocellular injury.

Myocardial function in septic sheep.

There is an ongoing discussion whether the heart is the primary target organ responsible for the development of cardiovascular failure during septic shock as well as its onset. We tried to study the reaction of the heart to sepsis in the early phase of 8 h, using a sublethal model of sepsis in six awake cross-bred Austrian mountain sheep. Sepsis was induced by infusion of a live Escherichia coli suspension at a dose of 5 x 10(7) colony-forming units per kg body weight over 8 h. Standard hemodynamic, hematologic and serum tumor necrosis factor (TNF) measurements were obtained. For evaluation of left ventricular performance we used the following methods, tested in five pilot experiments: 1) The shift of the end-systolic pressure-diameter relation. This was characterized by the calculated shift of the transverse external end-systolic diameter of the left ventricle at a "midrange" end-systolic pressure of 100 mmHg (end-systolic ventricular diameter deviation, ESVDD100). Calculations were performed using a second order regression function of the end-systolic pressure diameter points obtained by variation of afterload by a cuff occluder on the aorta; 2) The shift of the (dP/dt)max over end-diastolic diameter ratio compared to control values estimated by a graphical approach. Mean pulmonary pressure increased from 21 +/- 1 to 36 +/- 2 mmHg in the first hour after starting the E. coli infusion and remained elevated during the entire 8 h observation period. Serum TNF was found to peak 1 hour after start of E. coli infusion and was hardly detectable after 3 hours of bacteremia. Mean aortic pressure showed minor changes (maximum 105 +/- 3 mmHg, minimum 91 +/- 2 mmHg) and there were no statistically significant alterations of the cardiac index. ESVDD100 showed an "oscillatory" reaction in the first phase and a statistically significant decrease of contractility in the second phase (at 4 h). This was confirmed by the graphical method of the (dP/dt)max over end-diastolic diameter ratio. We may therefore conclude that there is no early depression of myocardial function or if so, it may be masked by adrenergic stimulation. In the later phase of the 8 h experiment there is a significantly decreased contractility of the heart. This may be compensated (e.g., "Starling" mechanism or heart rate increase) in this sublethal model.

Anti-tumor necrosis factor antibody treatment of recurrent bacteremia in a baboon model.

Timely intervention in recurrent episodes of sepsis poses a major problem in intensive care, because the diagnosis is often made after the onset of sepsis, delaying the initiation of treatment. There are only a few animal models that cover this situation. We have developed a baboon model of recurrent bacteremia (3 x 2 h intravenous infusion of 1 x 10(8) CFU Escherichia coli/kg), which leads to late organ failure. In this model (tested on 16 animals) we began anti-tumor necrosis factor antibody treatment (BAYX 1351; Bayer AG, 7.5 mg/kg or saline placebo) after the first bacteremic episode (+4 h), which significantly (p < .05) protected animals from death, none out of eight (100% survival), in the treatment group in contrast to four animals out of eight died (50% survival) in the placebo group. This effect was also reflected in improved organ function and in attenuated cytokine and plasminogen activator inhibitor release. From these studies we conclude that the delayed application of anti-tumor necrosis factor antibodies in recurrent bacteremia is a powerful tool for preventing septic death.

Pteridine and nitrite/nitrate formation in experimental septic and traumatic shock.

Bacterial lipopolysaccharides (LPS) induce the activity of guanosine triphosphate (GTP)-cyclohydrolase I (GTP-CHI), the first enzyme in the biosynthesis of tetrahydrobiopterin (H4bip) from GTP in endothelial cells and macrophages. In these and other cells, LPS also acts costimulatory with cytokines, i.e., mainly tumor necrosis factor-alpha (TNF-alpha). H4bip is the cofactor for nitric oxide synthase (NOS). We were interested in comparing the pteridine and nitrate levels in two baboon models: a hyperdynamic sepsis model and a hemorrhagic traumatic shock model. Our results show a similar response of pteridines (H4bip, neopterin) and nitrite/nitrate levels to an immune stimulus. LPS, which peaks rapidly, induces a sustained increase in pteridine levels in septic animals. Since hemorrhagic animals show very little response in terms of cytokine production, it was not possible to measure the induction of neopterin and nitrite/nitrate. This information could aid our understanding of the regulatory mechanisms in various forms of experimental shock.

Comparison of the efficacy of pentoxifylline and albifyllin (HWA 138) on endotoxin-induced cytokine production, coagulation disturbances, and mortality.

We have evaluated two different xanthine derivatives, pentoxifylline (POF) and albifyllin (HWA), in rat endotoxemia for their ability to reduce 1) cytokine formation, 2) coagulation disturbances, and 3) mortality. The animals were injected with lipopolysaccharide (LPS) (15 mg/kg i.p.) and received HWA or POF (25, 50, or 100 mg/kg) or saline 30 min before LPS administration. The plasma tumor necrosis factor levels were significantly reduced and in a similar manner by pretreatment with HWA or POF in vivo as well as in vitro. Neither the coagulation disturbance nor the characteristic leukopenia that follow an LPS challenge were significantly influenced by the xanthine derivatives. At a dose of 100 mg/kg, the 6 day mortality was significantly reduced by HWA to 36% but only attenuated by POF to 55% as compared to 80% in the control group. The similar effect of both agents on cytokine formation and coagulation disturbances indicate that, at least to a substantial degree, other mechanisms may account for the significant protection of rats against endotoxin-induced mortality by HWA only. HWA 138 may, therefore, be a new powerful agent against endotoxin-related disorders and mortality.

Effect of anti-tumor necrosis factor alpha on leukocyte adhesion in the liver after hemorrhagic shock: an intravital microscopic study in the rat.

Tumor necrosis factor (TNF) plays a well known role during the development of multiple organ failure, in part due to its role for the expression of adhesion molecules on endothelial cells, thereby contributing to inflammatory reactions. The purpose of this study was to investigate the effects of TNF on leukocyte-endothelial interactions in the liver as a key organ during the systemic inflammatory response syndrome. In Sprague-Dawley rats (n = 6/group) hemorrhagic shock was induced by reduction of the mean arterial blood pressure (MAP) to 40 mmHg for 45 min; resuscitation was initiated by retransfusion of shed blood (60%) and Ringer's lactate. At 1 and 5 h after resuscitation, intravital microscopy of the liver was performed after injection of acridine orange as marker of leukocytes in sham-control animals and in shock animals pretreated with anti-TNF monoclonal antibody (2 mg/kg b.w. TN3; Celltech, Slough, UK) or NaCl .9% 2 h prior to shock induction, respectively. At constant systemic hemodynamic conditions in all groups (e.g., normal MAP), sinusoidal diameters and sinusoidal blood flow were comparably decreased to approximately 75% of control values in all shock groups. Significant differences were observed particularly in respect to permanent adherent leukocytes with 31.8 +/- 4.7% in the shock/NaCl group and 20.7 +/- 2.6% (mean +/- S.E., p < .05) in the shock/TN3 group 5 h after resuscitation following hemorrhagic shock. Consistently higher adhesion rates were observed in the portal regions compared to pericentral regions of the liver lobules.(ABSTRACT TRUNCATED AT 250 WORDS)

Local and systemic reactions after lung contusion: an experimental study in the pig.

The present study was designed to investigate the consequences of isolated unilateral lung contusion on local alveolar and systemic inflammatory responses in an animal model in the pig. Isolated unilateral lung contusion was induced by bolt shot in eight mechanically ventilated animals under general anesthesia (sham: n=4). Plasma and bronchoalveolar lavage fluid were collected during a period of 8 h following lung contusion. Leukocytes, leukocyte neutral protease inhibitor (LNPI), terminal complement complex (TCC), thrombin-antithrombin-complex (TAT) as well as pulmonary microvascular permeability and surfactant function were determined. Within 30 min, lung contusion was found to cause a significant local and systemic increase in TCC and TAT concentrations and a systemic increase in LNPI concentrations. The latter was accompanied by a sequestration of leukocytes in the contused lung. Complement activation and leukocyte sequestration in the contused lung progressively increased during the investigation period. Although surfactant function decreased in the entire lung 30 min after contusion, TCC, TAT, and leukocyte sequestration was unchanged in the contralateral lung. The first indication of an involvement of the contralateral lung was obtained by an increase in leukocyte sequestration 8 h after lung contusion. Unilateral lung contusion initiates an early systemic activation of humoral and cellular defense systems. Involvement of the contralateral lung appears to be a secondary event caused by a systemic inflammatory reaction.

Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain.

Recent findings support the view that the bioenergetic part of septic organ failure is not caused by insufficient supply of oxygen but by disturbances of the mitochondrial function. Therefore, the aim of the present study was to investigate key enzymes of energy metabolism in septic hearts to answer the question whether or not impairment of mitochondrial or glycolytic enzymes occur under these conditions. For this purpose the well established model of septic baboons was used. Baboons under general anesthesia were made septic by infusion of Escherichia coli. Single challenge with infusion of high amounts of bacteria was compared with a multiple challenge protocol (less bacteria infused). Some animals obtained no E. coli (sham). The hearts of the baboons were removed after 72 h (survival: yes) or after death (survival: no) of the animals, frozen in liquid nitrogen, and stored at -80 degrees C until spectrophotometrical measurement of nine mitochondrial and glycolytic enzymes. A reduction of the activity of NADH:cytochrome-c-reductase (Complex I + III) to 67% and succinate:cytochrome-c-reductase (Complex II + III) to 45% was found in the hearts of surviving animals after infusion of high amounts of bacteria. After multiple challenge with lesser amounts of bacteria, no significant changes in enzyme activity were detectable. After lethal septic shock, activities of Complex I + III (12%) and Complex II + III (13%) as well as of phosphofructokinase (16%) were found to be strongly diminished. Decylubiquinol:cytochrome-c-reductase (Complex III, 59%), cytochrome-c-oxidase (51%), succinate dehydrogenase (60%), glucosephosphate isomerase (61%), lactate dehydrogenase (61%), and citrate synthase (120%) were less or unaffected. Similar but less pronounced effects were found after infusion of lesser amounts of bacteria. By means of inhibitor titrations of succinate: cytochrome-c-reductase, it was shown that the loss of activity is not caused by Complex III but by disturbances in Complex II. It is concluded that E. coli-induced sepsis causes decreased activities of Complex I and Complex II in baboon heart mitochondria in a dose-dependent manner.

Repeated administration of a F(ab')2 fragment of an anti-tumor necrosis factor alpha monoclonal antibody in patients with severe sepsis: effects on the cardiovascular system and cytokine levels.

In an uncontrolled clinical trial the effects of repeated administration of the F(ab')2 fragment of a murine monoclonal anti-tumor necrosis factor alpha (TNF alpha)-antibody (MAK 195F) on cytokine levels and the cardiovascular system were studied in 20 patients with severe sepsis. Patients were treated with a total of 11 single dosages of the anti-TNF alpha-antibody intravenously over 5 days using either 1 mg/kg (n = 10) or 3 mg/kg (n = 10). The anti-TNF alpha-antibody was well tolerated in all patients without signs of toxicity and without development of anti-murine antibodies. As assessed by cytokine levels (TNF alpha, Interleukin-6) and hemodynamics there was no evidence that the higher dosage of the anti-TNF alpha-antibody (3 mg/kg per dose) was more effective than the lower dosage (1 mg/kg per dose). Comparison of our data with recent data from phase I or II trials using a complete murine monoclonal anti-TNF alpha-antibody suggest that the F(ab')2 fragments of the murine monoclonal anti-TNF alpha-antibody may be of similar efficacy. Definitive conclusions, however, with respect to improvement of mortality and improvement of the cardiovascular system, await the results of larger ongoing placebo-controlled trials.

Changes in skeletal muscle pO2 after administration of anti-TNF alpha-antibody in patients with severe sepsis: comparison to interleukin-6 serum levels, APACHE II, and Elebute scores.

In 20 patients with severe sepsis, skeletal muscle pO2 was continuously measured in order to assess whether a decrease of skeletal muscle pO2 was accompanied by an improvement of sepsis after repeated administration of F(ab')2 fragments of a murine anti-TNF alpha-antibody. Abnormally high skeletal muscle pO2 decreased from 43.5 +/- 10.9 mmHg (day 0) to 36.4 +/- 10.1 mmHg within 24 h after the first administration of anti-TNF alpha-antibody (day 1, p = .006, n = 20) and remained at 34.6 +/- 7.7 mmHg thereafter (mean day 2-7, p = .004). The decrease of skeletal muscle pO2 within 24 h exceeded 5 mmHg (-7 to -19 mmHg) in 11 patients in contrast to nine patients (-4 to +4 mmHg). Only in the patients showing a decrease of skeletal muscle pO2 did sepsis improve as determined by Elebute score, APACHE II score, and interleukin-6 serum levels. The change of skeletal muscle pO2 within 24 h was associated with a change of interleukin-6 serum levels within 24 h (r = .5, n = 20), with a change of Elebute score (r = .7, n = 20) and of APACHE II score (r = .62). These data suggest that a decrease of skeletal muscle pO2 might be an early indicator of improvement of sepsis after administration of anti-TNF alpha-antibodies.

Tumor necrosis factor antibody treatment of septic baboons reduces the production of sustained T-cell suppressive factors.

Post-traumatic septic complications result from impaired cell-mediated immune function, which is caused in part by circulating T-cell suppressive factors (TSFs). We examined whether tumor necrosis factor alpha (TNF-alpha) antibody treatment in a baboon sepsis model influences the production of TSFs, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Sepsis was induced in anesthetized baboons by Escherichia coli infusion, and caused an increase in plasma levels of TNF, TSF activity, IL-10, and active TGF-beta, as well as a decrease in latent TGF-beta. TNF antibody pretreatment reduced TNF levels by 98%. Transient TSF activity (0-4 h) was only marginally influenced, while sustained TSF activity (8-24 h) was markedly reduced. TSF activity at 24 h correlated with peak TNF levels. IL-10 levels, coinciding with early TSF activity, remained unchanged by anti-TNF treatment. Levels of active TGF-beta and the drop in latent TGF-beta were decreased. We conclude that anti-TNF treatment reduces sustained TSF activity and may partially restore impaired cell-mediated immune function.

In vitro properties of mixtures of fibrin seal and antibiotics.

The incorporation of gentamycin, neomycin and Polymyxin E into fibrin seal results in prolonged clotting time after mixture with 4 NIH-units of thrombin per ml in vitro. The aminoglycoside antibiotics gentamycin and neomycin also diminished fibrin-alpha-chain crosslinkage and, as a consequence, clot rigidity, as demonstrated with clots containing gentamycin. Clotting time and the rate of alpha-chain crosslinking can be adjusted to normal values by the use of higher thrombin concentrations and incorporation of additional factor XIII into the sealing system. Drug release from the clots was similar for all three antibiotics tested and mainly dependent on the concentration gradient between the clot and its environment. Under the conditions of the present study, about 85% of the antibiotic content of fibrin seal clots were released within 72 h.

Biocompatibility of xenogeneic bone, commercially available coral, a bioceramic and tissue sealant for human osteoblasts.

The drawbacks of freshly harvested autologous bone have resulted in the search for an alternative, capable of supporting osteogenic cell growth. This capability was examined in potential bone graft materials by culturing human osteoblasts on each material. Test materials included rat bone, Surgibone, Ostilit, Biocoral and Tisseel. After 3 days osteoblasts had adhered to all materials, except Ostilit. With increasing time the cells multiplied on the materials, to varying extents. Cell affinity was greatest for rat bone and Tisseel. Fewer cells attached to Biocoral and Surgibone. Thus all the materials, with the exception of Ostilit, were biocompatible for human osteoblasts.

Bridging of peripheral nerve defects with exogenous laminin-fibrin matrix in silicone tubes in a rat model.

Fibrin matrix (FM) is a biological substance involved in the comprehensive wound healing process, and has been used in local applications as a carrier of nerve growth factor (NGF) to achieve an effective local neurotrophic concentration by slow release of the factor. In the present experiment, an exogenous fibrin matrix enriched with laminin (LM) and tubulized by a silicone conduit was used to improve the bridging effect of a peripheral nerve defect in a rat model. A 10 mm nerve defect was bridged with a 14 mm silicone conduit which was prefilled either with 25 µl fibrin matrix enriched without or with laminin (0.1 µg/ml), serving as groups FM and LM-FM, or with the same amount of saline solution for control (CTR group) (n = 10). After 12 weeks, the nerve conduction velocity and the distal latency were calculated from the electromyographic recordings. In addition, morphological semi-quantitative evaluations in longitudinal and transversal sections were carried out by immuno-histochemical staining with a monoclonal antibody against neurofilament. An improvement in nerve conduction velocity and distal latency, and a better orientation of the regenerated nerve fibers in the gap area were achieved in the LM-FM group than in the CTR and FM groups. These results indicate that the bridging of peripheral nerve defect in a rat model may be improved by the use of exogenous fibrin matrix enriched with laminin (as a filling material) in a silicone conduit.

Posttraumatic complications and inflammatory mediators.

In a series of 71 patients with trauma, we measured weekly the blood levels of a number of complement proteins and activation products. We also measured the following: leukocytes, platelets, granulocyte enzyme elastase, alpha 1-antitrypsin, total protein, albumin, haptoglobin, and fibronectin. The intensity of complement activation and the blood levels of elastase correlated with the following factors: injury severity (especially the severity of limb injury), development of adult respiratory distress syndrome, development and severity of multiple organ failure, and probability of a fatal outcome. The plasma elastase level seemed to be the best predictor of adult respiratory distress syndrome and the best correlate of injury severity and multiple organ failure severity. Our findings support the hypothesis that posttraumatic activation of the complement system leads to activation of granulocytes, followed by microvascular injury and finally by organ failure.

Systemic inflammatory response syndrome after cardiac operations.

BACKGROUND: A systemic inflammatory response after open heart operation may be responsible for hyperdynamic circulatory instability and organ dysfunction. To what extent mediator release is involved needs to be clarified. METHODS: Ten patients with postoperative hyperdynamic circulatory dysregulation (group I) requiring application of alpha-constrictors and 10 patients with routine cardiac procedures and stable postoperative hemodynamic indices (group II) were analyzed for mediator release and metabolic and hemodynamic changes until the third postoperative day. RESULTS: Group I patients showed a significantly increased cardiac index and decreased systemic vascular resistance after bypass (cardiac index, group I: 5.2 +/- 1.2 L.min-1.m-2, group II: 2.5 +/- 1.6 L.min-1.m-2; systemic vascular resistance, group I: 495 +/- 204 dyne.s. cm-5, group II: 1,356 +/- 466 dyne.s.cm-5) and at 3 hours (cardiac index, group I: 4.4 +/- 0.8 L.min-1.m-2, group II: 2.9 +/- 0.6 L.min-1.m-2; systemic vascular resistance, group I: 567 +/- 211 dyne.s.cm-5, group II: 1,053 +/- 273 dyne.s.cm-5). Significantly higher serum levels of interleukin-6 were assessed in group I (postbypass, group I: 6,812 +/- 9,293 pg/mL, group II: 295 +/- 303 pg/mL; 3 hours, group I: 3,474 +/- 5,594 pg/mL, group II: 286 +/- 296 pg/mL). Concentrations of elastase, tumor necrosis factor, soluble tumor necrosis factor receptor, and interleukin-8 were elevated in group I (not significant). Early postoperative levels of soluble E-selectin and soluble intercellular adhesion molecule were also higher in group I (not significant). Continuously increased levels of endotoxin could be detected in only 3 of 10 patients in group I. Severe lactic acidosis (> or = 5 mmol/L) occurred in group I only. CONCLUSIONS: Postoperative hyperdynamic instability after open heart operations appears to be associated with a certain pattern of mediator release. In particular, interleukin-6 appears to be involved in circulatory dysregulation and metabolic derangement.