Cysteine proteinases and their inhibitors--a traditional topic of the Portoroz conferences.
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Animals↗
Biomedical subjects
M Jochum
Publications and source records attributed to M Jochum.
Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses.
Cortisol is known to be an immunomodulatory hormone that exerts suppressive and permissive effects on the immune response. Little is known regarding the evolution of the cytokine response in human septic shock in the presence of hypercortisolemia induced by infusion of stress doses of hydrocortisone. Twenty-four consecutive patients with high-out-put circulatory failure (cardiac index, >4 liters/min per m(2)) who met the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee criteria for septic shock were enrolled in a prospective, double-blind study. The severity of illness at the time of enrollment was graded using the Acute Physiology and Chronic Health Evaluation II system, and the evolution of sepsis-induced organ dysfunction syndrome was assessed using Sepsis-Related Organ Failure Assessment scores. After randomization, hyper-cortisolemia was induced in 12 patients by infusion of 100 mg of hydrocortisone, followed by continuous infusion of 0.18 mg/kg per h. Levels of the circulating cytokines tumor necrosis factor alpha (TNF), interleukin 6 (IL-6), IL-8, and IL-10 were serially measured at prospectively defined time points during the first 5 d after randomization. The infusion of hydrocortisone was associated with significant reductions in serum IL-6 and IL-8 levels and with earlier resolution of the sepsis-induced organ dysfunction syndrome. IL-6 levels started to differ between the groups on day 5. The TNF and IL-10 responses were not altered by hydrocortisone infusion. Hydrocortisone infusion in septic shock differentially regulated the cytokine responses. IL-6 and IL-8 levels decreased significantly and IL-6 levels differed between the groups, whereas TNF and IL-10 levels were not affected by hydrocortisone. Stress doses of hydrocortisone may be a valuable immunomodulatory therapy for septic shock.
Adjuvants, Immunologic↗
Influence of alcohol exposure on S-100b serum levels.
Recent assessment of the glia cell-derived neuroprotein S-100b in serum has been considered as a screening method for possibly occult brain injury in patients with minor head trauma (MHT). Since MHT is associated with alcohol intoxication in up to 50% of patients requiring emergency treatment, the blood-brain barrier (BBB) as well as neuronal cell integrity may be also affected by alcohol abuse. So far, however, no valid data are available on the release of S-100b after alcohol exposure. Thus, the aim of our study was to investigate S-100b serum levels in a controlled alcohol exposure paradigm. 22 healthy volunteers were included in the study, blood samples were drawn prior to and about 90 minutes after drinking. The amount of alcohol was adjusted to the body weight. A mean of 66.7 +/- 14.81 g was consumed giving raise to a blood alcohol concentration of 0.827 +/- 0.158@1000. S-100b serum levels assayed by a luminescence immunoassay were compared with those of MHT patients. The still preliminary results suggest no increase of the serum S-100b levels (0.0509 +/- 0.048 ng/ml versus 0.0422 +/- 0.044 ng/ml) after moderate alcohol consumption. In contrast, MHT patients with alcohol intoxication (1.6 +/- 0.77@1000) revealed a significant up to 10fold elevation of S-100b serum levels. Because of the much higher blood alcohol concentration in the MHT patients compared to the control collective, a potential relationship between excessive alcohol consumption and the release of S-100b in minor head trauma can still not be excluded. Further investigations on this topic are in progress.
Adult↗
S-100b as a screening marker of the severity of minor head trauma (MHT)--a pilot study.
Due to its neural tissue specificity S-100b is considered as a screening marker of cerebral injury in head trauma patients. However, the occurrence and relevance of an increased S-100b serum level in minor head trauma (MHT) is still debated. Therefore, the purpose of our study was to evaluate the diagnostic utility of S-100b measurements in a level I trauma center emergency room (ER). Eighty patients presenting with clinical symptoms of MHT (GCS score of 13-15, transitory loss of consciousness, amnesia, nausea) were prospectively recruited. Blood samples were drawn at 0 h, 6 h and 24 h after admission, and a cerebral computed tomography (CT) was performed. The reference group consisted of 10 patients with severe head injury (GCS score < 8), the control group of 20 healthy volunteers. Concentrations of S-100b in serum were determined by an immunoluminometric assay. The results were compared with the plasma levels of polymorphonuclear (PMN) elastase as an established general trauma marker. In the MHT group, the S-100b serum level revealed 1.26 +/- 0.57 ng/ml at study entry (73.46 +/- 47.53 min after trauma). In comparison, the S-100b concentration was significantly elevated in patients with severe head trauma (5.26 +/- 1.65 ng/ml, p = 0.009), but no significant difference became evident in relation to the control group (0.05 +/- 0.01 ng/ml). Starting values of PMN elastase in plasma amounted to 66.40 +/- 14.92 ng/ml in severe trauma, and to 60.52 +/- 10.75 ng/ml in MHT showing significant differences only in relation to the control group (23.36 +/- 1.53 ng/ml). When correlated with the severity of the later clinical course, the first S-100b measurements exhibited steadily increasing values as demonstrated in MHT outpatients (0.29 +/- 0.11 ng/ml), MHT in-hospital patients (0.70 +/- 0.19 ng/ml) and MHT intensive care unit patients (5.03 +/- 3.18 ng/ml). PMN elastase levels revealed no significant differences concerning the three MHT subgroups. Thus, in contrast to the general trauma marker PMN elastase, assessment of the specific neuroprotein S-100b early after traumatic insult appears to be a promising laboratory marker for the prognosis of the severity of brain injury in MHT patients. Nevertheless, further investigations are required to better understand its predictive value.
Biomarkers↗
Antithrombin III and local serum application: adjuvant therapy in peritonitis.
BACKGROUND: Patients with diffuse peritonitis show an overall mortality of about 20%, probably caused by the breakdown of local defence mechanisms combined with a systemic outspread of bacteria and toxins, which often results in sepsis syndrome. DESIGN: In a prospective, randomized, controlled study 50 patients with diffuse secondary peritonitis were included. Patients in the therapy group were treated with an adjuvant medication consisting of a continuous intravenous infusion of antithrombin III and two intraperitoneal instillations of fresh frozen human donor serum. The aim of the study was the reduction of mortality and incidence of multiple organ failure. RESULTS: Mean antithrombin III plasma levels in the therapy group were raised above 140% for 4 days and were significantly higher than in the control group. With the intraperitoneal application of fresh frozen serum and antithrombin III opsonic capacity as well as thrombin, inhibitory activity in the exudate could be significantly elevated over 2 days. The 90-day-mortality rate was 6/26 (23%) in the control group and 6/24 (25%) in the therapy group. Although no improvement of mortality was achieved, a slight but not significant reduction of the severity of the multiple organ failure was seen. CONCLUSIONS: The chosen therapeutic approach was feasible and showed no side-effects. Yet, neither mortality nor multiple organ failure were significantly improved by the applied short-term adjuvant therapy. Thus, for future trials in severely-ill patients a longer treatment period and/or combinations of antithrombin III with other anti-inflammatory agents should be considered.
APACHE↗
Effect of cardiopulmonary bypass and hemofiltration on plasma cytokines and protein leakage in pigs.
BACKGROUND: The hypothesis that an inflammatory process during and after cardiopulmonary bypass (CPB) impairs hemodynamics and causes increased capillary protein leakage and that this is possibly ameliorated by hemofiltration (HF) was tested. METHOD: 26 anesthetized pigs were subjected to 120 min CPB (90 min cardioplegia followed by 30 min reperfusion, combined with conventional and modified HF in 13 animals). Hemodynamics, leukocytes, cytokines (IL-1ra, IL-8, IL-10, TNF-alpha), LNPI, plasma protein, and the half-life of i.v. injected Evans Blue (t/2) were assessed before and after CPB. RESULTS: CPB was followed by depression of left ventricular function and activation of inflammatory mediators. Although a slight elimination of some inflammatory mediators occurred, HF did neither improve cardiac function nor reduce the inflammatory process. Plasma protein was lost during CPB and hemofiltration by protein trapping to the surfaces of the CPB system, by filtration across the hemofilter, and by increased microvascular filtration (solvent drag). The latter was probably due to an increased filtration pressure in consequence of the reduction of plasma colloid osmotic pressure by the crystalloid primed CPB. t/2 did not indicate an increased microvascular protein leakage after CPB. CONCLUSION: Hemofiltration is ineffective in improving cardiac function or reducing the inflammatory response of CPB in the pig model.
Animals↗
Bradykinin B2-receptor antagonism attenuates fatal cardiocirculatory breakdown induced by severe experimental pancreatitis.
OBJECTIVES: To investigate the impact of the long-acting bradykinin B2 receptor antagonist HOE 140 (Icatibant) on survival time in a model of severe porcine pancreatitis. DESIGN: Randomized, controlled intervention trial. SUBJECTS: Thirty domestic pigs of either gender anesthetized by intravenous application of piritramide, midazolam, and pancuronium and mechanically ventilated. INTERVENTIONS: Pancreatitis was induced by an injection of sodium taurocholate (5%, 1 mL/kg body weight [BW]) and enterokinase (10 U/kg BW). Control animals (group 1, n = 10) underwent the spontaneous course of the disease. In two treatment groups, Icatibant was administered either in a low (100 nmol/kg BW; group 2, n = 10) or in a high dosage (5000 nmol/kg BW; group 3, n = 10). MEASUREMENTS AND MAIN RESULTS: Mean survival time was significantly prolonged by Icatibant (controls, 6.6 hrs; group 2, 9.8 hrs; p = .022; group 3, 10.9 hrs; p = .007). Six hours postinduction, the decline of total peripheral resistance (52% of baseline) and cardiac index (92% of baseline) in controls was significantly improved by Icatibant, both in the low (16% and 44%; p < .05) and high (6% and 45%; p < .05) dosage. The concentrations of free, nonreceptor-bound kinin in plasma 6 hrs postinduction were significantly lower in controls than in groups 2 and 3 animals (111+/-50 vs. 208+/-40 and 237+/-52 fmol/mL, respectively). Six hours postinduction, the pretreatment with Icatibant was associated with significantly higher plasma concentrations of phospholipase A2 (controls, +1194%; group 2, +2000%; group 3, +2285% of baseline values) and interleukin-1 receptor antagonist (controls, 1900+/-800; group 2, 3100+/-800; group 3, 3600+/-800 pg/mL). In contrast, the increase of urinary trypsinogen activation peptides indicating local pancreatic damage (589+/-114 nmol/L in controls) was substantially attenuated by pretreatment with Icatibant (group 2, 467+/-102, NS; 352+/-91 nmol/L in group 3; p = .022 vs. controls). Systemic inflammatory reactions, however, as quantified by C-reactive protein and the extracellularly discharged neutrophil cytosolic inhibitor leukocyte neutral proteinase inhibitor were not influenced by the bradykinin B2-receptor antagonist. CONCLUSIONS: Pretreatment with the bradykinin B2 receptor antagonist Icatibant resulted in prolonged survival time and in delayed impairment of major macrocirculatory and pulmonary variables. Icatibant resulted in elevated concentrations of free, circulating kinin. This was associated with increased concentrations of phospholipase A2 and interleukin-1 receptor antagonist, suggesting that circulating kinins strengthen the activation of some mediator cascades, the association of which with the kinin metabolism requires further experimental clarification. Other variables indicating a systemic inflammatory response (C-reactive protein, leukocyte neutral proteinase inhibitor) remained unaffected by Icatibant. Bradykinin antagonism distinctly ameliorated the local pancreatic damage, indicated by increased urinary concentrations of trypsinogen activation peptides. It is concluded that the kinin metabolism plays an important role in the pathophysiology of systemic complications after severe experimental pancreatitis.
Acute Disease↗
Proteolytic destruction of functional proteins by phagocytes in human peritonitis.
BACKGROUND: Besides phagocyte-derived oxidative autoaggression, proteolytic destruction of functional proteins in the peritoneal cavity may also be involved in the pathomechanism of secondary peritonitis. To evaluate the pattern of proteolysis, 43 patients undergoing initial operation for acute peritonitis (n = 30) or scheduled abdominal lavages (Etappenlavage) for resolution of persistent peritonitis (n = 13) and 16 surgical patients with abdominal exudation without peritonitis were enrolled in our study. MATERIALS AND METHODS: Thirty blood samples and purulent exudates were taken simultaneously in each peritonitis group at the surgical interventions. Sixteen clear exudates were obtained from patients with post-operative non-infectious irritations. The following parameters were measured: (a) elastase (from neutrophils) and cathepsin B (from monocytes/macrophages); (b) alpha1-proteinase inhibitor (alpha1PI) and overall cysteine proteinase inhibitor capacity; and (c) opsonic activity and degradation products of fibrinogen, complement C3 and immunoglobulin IgG. RESULTS: Circulating levels of phagocyte proteinases and of alpha1PI were significantly elevated, whereas antigen concentrations and opsonic activity of C3 and IgG were slightly reduced in peritonitis patients compared to healthy volunteers. No degradation products were detectable in patients' blood. Discharge of phagocyte proteinases was even more pronounced in both types of peritonitis exudates. Although most of the elastase was complexed with alpha1PI, active elastase and its specific fibrinogen split product was found along with significantly reduced inhibitory capacity for elastase and cysteine proteinases. Local opsonic activity was dramatically diminished because of proteolytic degradation of C3 and IgG. Despite some phagocyte proteinase release, no destruction of functional proteins was seen in clear exudates. CONCLUSIONS: Higher values of extracellularly released phagocyte proteinases concomitant with lower opsonin activity in exudates from patients with persistent peritonitis can be taken as a further hint of the involvement of local proteolysis-induced pathomechanisms in the development of lethal multiple organ failure, which occurred more frequently in patients with persistent peritonitis (54%) than in those with acute peritonitis (27%).
Adolescent↗
Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds.
Myocardial dysfunction due to sepsis is common in patients with multiple organ dysfunction syndrome and is believed to be produced by inflammatory mediators. Some of these mediators may be eliminated by continuous hemofiltration, which is a standard procedure in an ICU for renal replacement therapy. This study was designed to directly compare the effects of ultrafiltrates from patients with sepsis (UFs) with ultrafiltrates from healthy volunteers (UFh) in well-characterized cardiomyocyte culture systems. Isovolemic hemofiltration (filtration rate: 2 L/h, polyamide membrane) was performed during 12 hours in 5 patients with severe sepsis (Elebute Score >20) and simultaneously reduced left ventricular contractility (left ventricular stroke work index [LVSWI] <30 g m/m2) and in 5 healthy volunteers. Inflammatory mediator concentrations (interleukin [IL]-1beta, IL-6, IL-8, tumor necrosis factor [TNF] alpha, C3a, and C5a) were measured in plasma and ultrafiltrate samples taken shortly after the beginning of the hemofiltration procedure. Cell culture experiments were done comparing UFs with UFh by using spontaneously beating or electrically driven neonatal rat cardiomyocyte cultures. UFs contained significantly higher amounts of IL-1, IL-8, and C3a when compared to UFh. Simultaneously, UFs induced a decrease in the contraction frequency of electrically-stimulated cardiomyocytes, whereas UFh had no effect. The cardiotoxic effect could be reversed by the addition of a high concentration (2.4 mM) of Ca++. Hemofiltration did not alter parameters of cardiac performance during 12 hours in patients with sepsis. UFs induced significant cardiotoxic effects in rat cardiomyocytes, whereas UFh showed no cardiotoxicity. Contact of blood with the hemofiltration membrane did not induce activation of cardiotoxic mediators. Significantly higher filtration rates may be required to improve left ventricular contractility in patients with sepsis by hemofiltration.
Adult↗
Influence of high- and low-dose aprotinin on activation of hemostasis in open heart operations.
BACKGROUND: The protease inhibitor aprotinin reduces hemostatic activation and blood loss after cardiac operations. The aim of the present study was to investigate the influence of two different aprotinin doses on hemostatic activation and to identify the most effective dose to reduce the postoperative bleeding tendency. METHODS: In a prospective, randomized, double-blind clinical trial, 230 patients scheduled for routine open heart operations received either high-dose (group H) or low-dose (group L) aprotinin. Primary outcome measures were the level of F(1+2) prothrombin fragments as a marker of thrombin generation, the level of D-dimers as an indicator of fibrinolysis, and the amount of postoperative blood loss. Allogeneic blood transfusion was recorded as a secondary outcome measure. RESULTS: Aprotinin plasma concentrations 5 minutes after the onset of cardiopulmonary bypass were 166 +/- 45 kallikrein inactivator units per milliliter in group H and 118 +/- 30 kallikrein inactivator units per milliliter in group L (p < 0.05). Fibrinolytic activation was reduced significantly in group H compared with group L: the level of D-dimers at the end of CPB was 1,027 +/- 781 ng/mL and 1,977 +/- 1,001 ng/mL, respectively, in the two groups (p < 0.05). However, thrombin generation (F(1+2) fragments) did not differ between the two groups (7.4 +/- 3.5 nmol/L in group H and 8.6 +/- 4.3 nmol/L in group L). Twenty-four-hour postoperative blood loss was 663 +/- 461 mL in group H compared with 877 +/- 513 mL in group L (p < 0.05), and the corresponding allogeneic blood requirement was 1.3 +/- 1.9 U in group H and 1.9 +/- 2.3 U in group L (p < 0.05). CONCLUSIONS: A high-dose aprotinin regimen was significantly more effective than a low-dose regimen in attenuating fibrinolysis and reducing the bleeding tendency and allogeneic blood requirements, but not in reducing F(1+2) prothrombin fragments. High-dose aprotinin therapy appears to be superior to low-dose therapy.
Aprotinin↗
Cytokines and adhesion molecules in elective and accidental trauma-related ischemia/reperfusion.
BACKGROUND: The major pathophysiologic role of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6, as well as of the (soluble) adhesion molecules ICAM-1 and E-selectin, has been identified using different experimental models of ischemia/reperfusion injury. Moreover, in intensive care management, evaluation of these agents as diagnostic or prognostic tools is of great interest in ischemia/reperfusion injury caused by surgical or accidental trauma. For this reason, inflammatory mediators including those mentioned above were investigated in three different groups of surgical patients. METHODS: The first group (A, n = 13) comprised patients undergoing elective limb surgery without a tourniquet. The second group (B, n = 36) included patients subjected to limb surgery with a tourniquet. The third group (C, n = 30) was composed of accidental trauma patients who were retrospectively divided into those with and without multiple organ dysfunction (+MOD and -MOD, respectively) as defined by the Denver Score. Serial blood samples were taken during a 5-day (elective surgery) or 14-day (accidental trauma) observation period for monitoring of cytokines and soluble adhesion molecules. The clinical course and the degree of MOD were recorded daily. RESULTS: Only when a tourniquet was applied for a mean time of 105 minutes did elective limb surgery result in significantly increased serum levels of IL-6, IL,-1ra, and IL-10 but not TNF-RII. Yet, the increase in cytokine levels was not sufficient to cause an enhanced shedding of adhesion molecules, and both soluble ICAM-1 and soluble E-selectin remained unchanged in groups A and B throughout the 5-day observation period. In patients with multiple injuries (group C), all parameters increased early after trauma up to 10- to 20-fold in comparison with the elective limb surgery patients in groups A and B. When the accidental trauma patients were divided according to the Denver Score for +MOD (n = 8, mean Injury Severity Score = 33.8) and -MOD (n = 22, mean Injury Severity Score = 31.2), a clear difference became evident in serum IL-6 and IL-1ra levels within the first 4 days and in serum IL-10 levels for the first 2 days after trauma, with cytokine levels being significantly higher in the +MOD patients 3 to 4 days before the onset of MOD. Although highly elevated, TNF-RII levels did not differentiate between +MOD and -MOD at any time. The increase in serum cytokine levels was associated with a remarkable expression and shedding of ICAM-1 and E-selectin made obvious by significantly increased soluble serum ICAM-1 levels in +MOD patients compared with the -MOD group between days 3 and 5 after trauma and increased soluble serum E-selectin levels between days 2 and 4 after trauma. CONCLUSION: The release of cytokines and soluble adhesion molecules into the circulation correlates well with the degree of trauma (elective surgery vs. accidental multiple trauma), depending on the extent of the associated ischemia/reperfusion injury. Both groups of mediators are also clearly related to the development of MOD in patients with multiple injuries with generalized ischemia/reperfusion injury caused by hemorrhagic shock. They may be predictive of patients at risk for MOD when measured early in the posttraumatic period.
Adult↗
High-dose antithrombin III treatment of severely injured patients: results of a prospective study.
BACKGROUND: Antithrombin III (AT III) treatment has been shown to reduce disseminated intravascular coagulation and to inhibit thrombin, which plays a central role in the activation of platelets and other inflammatory systems in conditions with severe inflammation. The objective of this study was to evaluate the influence of early and high-dose administration of AT III to patients with severe multiple injuries on the inflammatory response and outcome. METHODS: In a placebo-controlled, double-blind study, 40 consecutive patients with Injury Severity Scores of 29 or greater who met the inclusion criteria were randomized to receive either AT III or placebo within 360 minutes after trauma. Twenty patients were administered AT III for a period of 4 days, aiming to achieve AT III concentrations of 140% of normal. RESULTS: The AT III and placebo groups were comparable with respect to Injury Severity Score, age, incidence of blood pressure less than 80 mm Hg on admission, initial base deficit, and start of the test drug. The patients in the AT III group received a total of about 20,000 IU during the first 4 days. AT III levels of 130 to 140% could be achieved by this regimen, whereas in the control group the AT III concentration averaged about 70%. In the AT III group prothrombin tended to be elevated and prothrombin fragment F1+2 as well as thrombin-AT III complex tended to be lower on the first day. No differences between groups, however, could be observed with respect to partial thromboplastin time, prothrombin time, platelets, plasminogen activator inhibitor I, soluble tumor necrosis factor receptor II, neutrophil elastase, interleukin (IL)-1 receptor antagonist, IL-6, and IL-8. Mortality (15 vs. 5%), incidence of respiratory failure (55 vs. 55%), duration of mechanical ventilation (13 vs. 12 days), and length of stay in the surgical intensive care unit (19 vs. 21 days) were also similar in both treatment groups. The duration of organ failure, however, was shorter in the patients receiving AT III. CONCLUSION: The early and high-dose administration of AT III to patients with severe blunt trauma appears not to attenuate the posttraumatic inflammatory response or to significantly improve outcome.
Adult↗
Effect of delayed treatment with recombinant human granulocyte colony-stimulating factor on survival and plasma cytokine levels in a non-neutropenic porcine model of Pseudomonas aeruginosa sepsis.
BACKGROUND: Neutrophils are of great importance for the host's defense against invading organisms. Granulocyte colony-stimulating factor (G-CSF) has been used to augment both the neutrophil number and function, and its prophylactic administration has proved beneficial in animal models of sepsis. However, pretreatment with G-CSF is not practical under clinical conditions. We therefore investigated the effect of recombinant human (rh)G-CSF, administered only after infection, on the survival rate as well as the hemodynamic and cytokine response of the animals. METHODS: Chronically catheterized conscious pigs were challenged with Pseudomonas aeruginosa (8 x 10(7) colony-forming units kg(-1) x h(-1) for 120 h (control group, n = 10). Animals in the G-CSF group (n = 7) also received rhG-CSF (5 microg kg(-1) x day(-1)), the first dose being given 3 h after beginning bacterial infusion. RESULTS: The mortality rate was 50% (5/10) and 29% (2/7) in the control and G-CSF groups, respectively (p = NS, control vs. G-CSF group). Fever, severe pulmonary hypertension, and a hyperdynamic response were recorded in all of the animals. In spite of a prompt and significant recovery from the initial leukopenia (p < .05 vs. control group), the animals of the G-CSF group showed no significant differences in the parameters investigated from those of the controls. Compared with the survivors, the interleukin-1 receptor antagonist was markedly elevated in all nonsurvivors after 6 h of sepsis (p < .05). CONCLUSIONS: These data suggest that treatment with rhG-CSF after the onset of bacterial sepsis might not significantly improve the chances of survival for non-neutropenic patients.
Animals↗
Pentoxifylline decreases the incidence of multiple organ failure in patients after major cardio-thoracic surgery.
We assessed the safety and efficacy of intravenous pentoxifylline [3,7-dimethyl-1-(5-oxohexyl)-xanthine] in patients at risk for developing multiple organ failure after major cardio-thoracic surgery in a single-center, randomized, placebo-controlled study. Of 816 consecutive patients who underwent major cardio-thoracic surgery, 40 who had Acute Physiology and Chronic Health Evaluation II score values > or = 19 at the first postoperative day after the surgery were included. Patients were randomized to receive either placebo (control; n = 25) or intravenous pentoxifylline treatment (pentoxifylline; n = 15) at a dosage of 1.5 mg/kg/h as an adjunct to standard supportive therapy. Main outcome measurements were duration of required ventilator support, intensive care unit stay, and incidence of renal failure. Thirty-seven patients were eligible for evaluation. No significant adverse events related to pentoxifylline treatment were observed. The duration of mechanical ventilation was significantly greater for control patients (8.3 +/- 3.1 days) compared with pentoxifylline-treated patients (3.1 +/- .9 days; p < .05). Patients treated with pentoxifylline experienced fewer days on hemofiltration (1.2 +/- .8 vs. 6.8 +/- 3.3; p < .05) and a shorter intensive care unit stay (5.2 +/- 1.1 vs. 11.4 +/- 3.1 days). There were no intergroup differences in mortality. Mortality was 33% in the pentoxifylline group and 36% among control group patients. In conclusion, supplemental pentoxifylline treatment may decrease the incidence of multiple organ failure in patients at risk of systemic inflammatory response syndrome after cardiac surgery. Additional studies are required to determine the validity of the observed effects.
APACHE↗
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.
Animals↗
Effect of antithrombin III supplementation on inflammatory response in patients with severe sepsis.
Antithrombin III (AT III) is an important inhibitor of thrombin activity, as well as of many other proteases of the coagulation system. AT III administration showed beneficial effects on septic multiple organ dysfunction in clinical and experimental studies. It was the aim of this study to determine whether continuous long-term AT III supplementation alters the systemic inflammatory response in patients with severe sepsis. In a prospective study, 29 surgical patients with severe sepsis were randomly assigned to receive either conventional intensive care treatment (n = 15, control group) or additional AT III supplementation to achieve a plasma AT III activity >120% during a 14 day study period (n = 14, AT III group). Plasma concentrations of interleukin (IL)-6 and IL-8 and of the circulating soluble adhesion molecules sICAM-1 and sE-selectin, as well as of PMN elastase, were determined daily. Additionally, total leukocyte count and C-reactive protein (CRP) were measured daily, and body temperature was registered. Compared to control patients, a down-regulation of plasma IL-6 was observed in the AT III group (p < or = .01). AT III supplementation prevented the continuous increase in sICAM-1 plasma concentration observed in control patients and led to a significant fall in soluble sE-selectin and CRP concentration (p < or = .01). This fall corresponded to a down-regulation of body temperature over time (p < or = .01). There was no AT III effect on IL-8, PMN-elastase concentration, or total leukocyte count. Our results show that long-term AT III supplementation attenuates the systemic inflammatory response in patients with severe sepsis. The down-regulation of IL-6 may also explain the fall in endothelium-derived adhesion molecules and may represent the molecular basis by which AT III exerts its beneficial effects on organ function.
Adult↗
Chloroquine inhibits proinflammatory cytokine release into human whole blood.
Excessive synthesis and release of proinflammatory cytokines during endotoxemia causes severe pathophysiological derangements and organ failure. Because the lysosomotropic agent chloroquine has been effective in the treatment of diseases associated with increased secretion of proinflammatory cytokines such as malaria or rheumatoid arthritis, this study evaluates the potential effect of chloroquine on endotoxin-induced cytokinemia using human whole blood from healthy volunteers. Chloroquine revealed a dose-dependent inhibitory effect on endotoxin-induced secretion of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 that was associated with reduced cytokine mRNA expression. Moreover, ammonia and methylamine, which react as weak bases like chloroquine, reduced synthesis and secretion of proinflammatory cytokines. These data indicate a potent anti-inflammatory effect of chloroquine on endotoxin-induced synthesis of proinflammatory cytokines that may be due to its weak base effect. Thus chloroquine may be of therapeutic benefit not only, during chronic inflammation but also in diseases that are related to bacteria-induced inflammation.
Ammonia↗
p-ANCA target antigens in ulcerative colitis.
INTRODUCTION: Data about the nature and pathophysiological relevance of the target antigens reacting with perinuclear antineutrophil cytoplasmatic autoantibodies (p-ANCA) in ulcerative colitis are inconsistent and partly conflicting. In the majority of the previous studies only one singular potential target antigen was investigated. The present study aimed on the simultaneous assessment of five different p-ANCA subtypes in patients with ulcerative colitis and attempted to detect reactivity against one of the previously described antigens and to correlate specificity for different target antigens with clinical features of the disease. METHODS: Sera from 61 patients with ulcerative colitis and from 56 healthy controls were tested using indirect immunofluorescence and enzyme-linked immunosorbent assays specific for elastase, lactoferrin, cathepsin G, myeloperoxidase and bactericidal permeability increasing protein (BPI). p-ANCA subtypes were correlated with clinical features of ulcerative colitis like disease extent or presence of extraintestinal manifestations. Moreover, a possible correlation to current immunosuppressive therapy was evaluated. RESULTS: In 46% (28/61) of patients with ulcerative colitis and in 4% (2/56) of the controls p-ANCA were detected. p-ANCA subtypes were distributed as follows: 26% (16/61) anti-BPI. 16% (10/61) anticathepsin G, 15% (9/61) antielastase, 7% (4/61) antilactoferrin, 5% (3/61) antimyeloperoxidase. Presence of anticathepsin G antibodies was negatively correlated with immunosuppressive therapy. No further correlations between p-ANCA subtypes and clinical characteristics were observed. DISCUSSION: p-ANCA subtypes in inflammatory bowel disease react with a variety of different target antigens and are not correlated with clinical features of the disease.
Adult↗