Thromboxane and prostacyclin release in adult respiratory distress syndrome

Plasma thromboxane B₂ (TXB₂) and 6-ketoprostaglandin F₁ (6-keto-PGF₁) were measured in 84 patients at risk of developing adult respiratory distress syndrome (ARDS) (44 patients following multiple trauma, 29 patients following abdominal surgery and 11 patients with acute pancreatitis). Forty-nine of these 84 patients developed an ARDS. High (>140 pg/ml plasma) TXB₂ values were found in 52/84 patients. The median values of TXB₂ were: 360 pg/ml in multiple injured, 250 pg/ml in abdominal surgery and 410 pg/ml in acute pancreatitis patients. The median TXB₂ value was 575 pg/ml in patients developing ARDS and 140 pg/ml in those without this complication: this difference was statistically significant (p<0.05). The median values of 6-keto-PGF₁ were 55pg/ml in multiple injured, 25 pg/ml in abdominal surgery and 120 pg/ml in acute pancreatitis patients. The median 6-keto-PGF₁ value was 122 pg/ml in ARDS patients and 25 pg/ml in non-ARDS patients (statistically significant: p<0.05). High TXB₂ and 6-keto-PGF₁ values were particularly related to sepsis in abdominal surgery patients (p<0.05) and in multiple injured patients (p<0.01). No relation could be established between abnormal TXB₂ or 6-keto-PGF₁ values and death. High TXB₂ values often persisted for several days and were observed particularly at the time ARDS diagnostic criteria were fulfilled. An imbalance between TXB₂ and 6-keto-PGF₁ was observed: 6-keto-PGF₁ values were always lower than TXB₂ values and did not persist for more than 24 h except in four cases. Our data demonstrate a significant production of prostanoids in ARDS patients particularly in sepsis and indicate a disturbance in balance of the prostacyclin/thromboxane axis.     

Role of thromboxane,prostaglandins and leukotrienes in endotoxic and septic shock

Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB₂ and 6-keto-PGF₁ in a large number of species. A smaller, delayed and more prolonged increase in TxB₂ and 6-keto-PGF₁ are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA₂ exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB₂ and 6-keo-PGF₁ concentrations in patients with septic shock, and elevated LTD₄ in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered.     

Combined effects of NO inhalation and intravenous PGF2α on pulmonary circulation and gas exchange in an ovine ARDS model

Objectives Inhalation of nitric oxide (NO) selectively dilates pulmonary vessels in well-ventilated regions. Prostaglandin F₂ (PGF₂) is a vasoconstrictor and is reported to enhance hypoxic pulmonary vasoconstriction. The objective of this study was to examine whether the combination of intravenous PGF₂ and inhaled NO in ARDS lungs has a beneficial effect on oxygenation.Design We investigated the effect of intravenous PGF₂ infusion (0.05–10.0 g/kg per min) with and without NO inhalation (60 ppm) on the hemodynamics and gas exchange in an ovine ARDS model, examining the pulmonary artery pressure versure the flow plot by varying cardiac output.Measurements and results After lung lavage, NO inhalation reduced the mean pulmonary arterial pressure (MPAP) by decreasing the zero-flow pressure intercept from 10.6±3.8 (mean±SD) to 8.5±3.8 mmHg (p<0.05) with no significant change in slope. NO inhalation improved PaO₂ from 56±12 to 84±38 mmHg (p<0.005) and reduced pulmonary shunt from 65±5 to 53±8% ( ) (p<0.001). The dose-dependent effects of PGF₂ infusion were: (1) increased MPAP attributed to an increased slope in pulmonary artery pressure-flow plot; (2) decreased cardiac index; (3) decreased with unchanged PaO₂. The dose-dependent decrease in after PGF₂ infusion was attributed to the decreased cardiac output.Conclusions It is suggested that inhalation of NO reduced the critical vascular pressure near alveoli without affecting upstream vessels, while infused PGF₂ constricted the larger upstream pulmonary artery vessels without appreciably affecting the critical pressure. Inhalation of NO into well-ventilated lung areas shifted perfusion to well-oxygenated areas, and there was no supplemental shift in blood flow by adding an infusion of PGF₂.This study was supported by USPHS grant HL 42391 to W.M.Z. and a Kitasato Research Foundation grant to H.K.     

Compartmentalisation of cytokines and cytokine inhibitors in ventilator-associated pneumonia

Objective To examine whether cytokine concentrations change in the pulmonary compartment during the development of ventilator-associated pneumonia (VAP).Design Non-directed bronchial lavage (NBL) was performed every 48 h in critically ill mechanically ventilated patients. Serial measurements of the cytokines tumor necrosis factor (TNF) , interleukin (IL)-1, IL-1, IL-6, and IL-10 and the cytokine inhibitors soluble TNF receptor type I (sTNFRI), IL-1 receptor antagonist (IL-1Ra) and soluble IL-1 receptor II (sIL-1RII) were performed on the NBL fluid and matching plasma samples by ELISA.Setting An adult medical and surgical university hospital intensive care unit.Patients Nine patients who developed VAP and nineteen patients who did not develop VAP served as controls.Interventions None.Results Plasma concentrations of the measured cytokines and cytokine inhibitors did not change significantly in any patients. In control patients, NBL fluid concentrations of sIL-1RII decreased significantly over time (P=0.01). In patients who developed VAP, NBL fluid concentrations of TNF, sTNFRI, IL-1, and IL-1 increased significantly (P=0.002, P=0.03, P=0.04 and P=0.02, respectively). Furthermore, NBL fluid/plasma concentration ratios for TNF, sTNFRI, IL-1, IL-1Ra and IL-6 increased significantly as VAP developed (P=0.001, P=0.001, P=0.04, P=0.03, and P=0.04, respectively).Conclusion Our results suggest that the production of important cytokines and cytokine inhibitors is compartmentalised within the lung in critically ill mechanically ventilated patients who develop VAP.     

Cardiac troponin I release and cytokine response during experimental human endotoxaemia

Objective To study the relationship between cytokine levels and cardiac troponin I (cTnI).Design Prospective experimental study.Setting Intensive care unit of a university hospital.Participants Six healthy male volunteers.Interventions Endotoxin, 4 ng/kg, was given as a 1-min intravenous infusion.Measurements and results Circulating cardiac troponin I levels and proinflammatory cytokines tumour necrosis factor- (TNF-), interleukin-6 (IL-6) and interleukin-8 (IL-8) were analysed at various time points during a 24-h period. TNF- appeared in the circulation 30 min after injection (T=0.5 h), reaching peak levels (5,665±1,910 pg/ml) 2 h after infusion. At T=24 h TNF- was still elevated in the circulation compared to T=0. None of the six volunteers had a cTnI value higher than 0.1 g/l at T=0, 6 h or 24 h.Conclusion The presence of significant amounts of TNF-, IL-6 and IL-8 in the systemic circulation does not lead to increased levels of cTnI in experimental human endotoxaemia.     

Serum MIP-1α and IL-8 in septic patients

We studied blood MIP-1 and IL-8 in 38 septic patients and 5 healthy volunteers. Both chemokines were undetectable in the healthy volunteers. In sepsis, serum MIP-1 was detected in 45% of the patients and IL-8 in 84%. The levels of MIP-1, but not of IL-8, correlated with CRP, IL-6 and TNF levels. Complication, including various organ failures and mortality, showed no correlation with serum MIP-1 levels. In contrast, we found increased levels of serum IL-8 in septic patients with disseminated intravascular coagulation, central nervous system (CNS) dysfunction or renal failure, and the mortality rate was higher in the IL-8-detectable group than in the IL-8 undetectable group (50% vs 0%,p<0.05). In conclusion, the production of both MIP-1 and IL-8 was increased and initially detectable levels of circulating IL-8 predicted high mortality in sepsis.Objective To determine the significance of the C-C chemokine MIP-1 and the C-X-C chemokine IL-8 in sepsis.Design Prospective study.Setting Clinical investigation, emergency department and general intensive care unit of university hospital.Patients and participants 38 septic patients and 5 healthy volunteers were studied. Sepsis was diagnosed following the criteria formulated by ACCP/SCCM.Interventions 10–20 ml of blood was drawn from each patient at the time of initial diagnosis of sepsis.Measurements and results MIP-1 and IL-8 were determined by sand-wich ELISA. Both chemokines were undetectable in the healthy volunteers. In sepsis, serum MIP-1 was detected in 45% of the patients and IL-8 was detected in 84%. The levels of MIP-1, but not of IL-8, correlated with CRP, IL-6 and TNF levels. Complications, including various organ failures and mortality, showed no correlation with serum MIP-1 levels. In contrast, we found increased levels of serum IL-8 in patients with disseminated intravascular coagulation (DIC) (p<0.05), central nervous system (CNS) dysfunction (p<0.05), renal failure (p<0.01) and the mortality rates were higher in the IL-8 detectable group than in the IL-8 undetectable group (50% vs 0%,p<0.05).Conclusions The production of MIP-1 and IL-8 was increased in sepsis. Furthermore, an initially detectable level of circulating IL-8, but not MIP-1, predicted a high mortality in sepsis diagnosed according to the ACCP/SCCM criteria.This study was supported in part by a Grant-in-Aid from the Japanese Ministry of Education, Science and Culture, the Waxman Institute Research Fund and the Keio Fukuzawa Fund     

Prostacyclin counteracts the increase in capillary permeability induced by tumour necrosis factor-α

Objective To analyse how prostacyclin interferes with the short-term local circulatory effects of tumour necrosis factor- (TNF) in a skeletal muscle.Design An autoperfused sympathectomised cat gastrocnemius muscle enclosed in a plethysmograph.Interventions Arterial blood flow, total and segmental vascular resistances (large-bore arterial vessels, arterioles and veins), hydrostatic capillary pressure, tissue volume and capillary filtration coefficient were followed during local intraarterial infusion of TNF at various rates (2.5, 5.0 and 7.5 g/kg per min) and during intra-arterial infusion of prostacyclin simultaneously with the highest dose of TNF. The capillary filtration coefficient reflects the capillary surface for fluid exchange.Results Arterial infusion of TNF had no influence on vascular resistance up to 5.0 g/kg per min but induced vasodilation at 7.5 g/kg per min. No effects on the recorded hydrostatic capillary pressure were observed. The capillary filtration coefficient and the capillary filtration increased with the infusion rate of TNF the former by 55%. Simultaneous arterial infusion of prostacyclin (350 ng/kg per min) caused further vasodilation and an increase in hydrostatic capillary pressure and completely restored the capillary filtration coefficient to control. The TNF-induced filtration was partly restored.Conclusions The local circulatory effect of TNF is small apart from a graded increase in the capillary filtration coefficient, most likely reflecting an increase in capillary permeability. The prostacyclininduced decrease in capillary filtration coefficient most likely reflects a restoration of capillary permeability. The TNF-induced transcapillary filtration is not fully reduced by prostacyclin due to a simultaneous increase in hydrostatic capillary pressure.     

Intracavitary therapy of neoplastic effusions with cytokines: comparison among interferon α, β and interleukin-2

Preliminary studies have suggested that the intracavitary administration of cytokines may represent a new effective palliative therapy of malignant effusions. To define further the therapeutic role of cytokines in the treatment of neoplastic fluid accumulation, 70 cancer patients with pleural, pericardial or peritoneal cytologically proven neoplastic effusions were randomized to receive intracavitary cycles with interleukin-2 (IL-2; 6x10⁶ IU), interferon (IFN; 2x10⁷ U) or IFN (6x10⁶ U) every week for 2 or 3 weeks. A clinical control of fluid accumulation was obtained in 39/70 (56%) patients. In patients with mesothelioma, the response rate was significantly higher with IL-2 than with IFN or-, while there was no difference in patients with tumors other than mesothelioma. Moreover, the duration of the period during which drainage was not required was significantly longer in patients treated with Il-2 than in the other groups. Toxicity was low in all patients. According to preliminary data, this study demonstrates that intracavitary administration of cytokines, including IL-2, IFN and-, is a new well-tolerated palliative therapy for malignant effusions, with an efficacy substantially comparable to that described with the most commonly used treatments with tetracyclines or cytostatic agents.     

Opsonophagocytic dysfunction in patients with liver cirrhosis and low responses to tumor necrosis factor-α and lipopolysaccharide in patients’ blood

To evaluate their defense level against bacterial infection of patients with liver cirrhosis, we compared the luminol-dependent chemiluminescence (CL) response of peripheral blood from 40 patients with that from 40 healthy volunteers. Small quantities of heparinized whole blood (100µl; final dilution, 1:10) were used for phagocytes, and CL was measured on addition of nonopsonized zymosan or Escherichia coli without special opsonization. Whole blood CL in cirrhotic patients was significantly lower than that in the healthy controls. The incidence of lower CL response in patients increased as disease stage advanced. Polymorphonuclear leukocytes (PMN) from cirrhotic patients exibited a slightly lower CL response than those from controls, but this was not statistically significant. In contrast, the CL response of monocytes in patients was significantly lower than that of controls. The opsonizing capacity of the patients sera and ascitic fluid was also decreased. In fact, the levels of opsonins such as complement in the patients sera and both immunoglobulins and complement in the ascitic fluids were found to be lower in cirrhotic patients. On the basis of these findings, defect of opsonophagocytic function seems to participate in the increased susceptibility to infection in cirrhotic patients. Furthermore, whole blood CL induced by nonopsonized zymosan at the onset of relatively severe bacterial infections such as sepsis, pneumonia, or spontaneous bacterial infection was less augmented in the blood of cirrhotic patients than that in noncirrhotic patients. To clarify the reason why whole blood exhibits a lower CL response in the acute phase of bacterial infections, we investigated the priming effects of lipopolysaccharide (LPS) or tumor necrosis factor- (TNF-), well-known CL activators, on the CL response of whole blood obtained from cirrhotic patients in comparison with that from healthy persons. The priming effects were significantly decreased in patients blood when compared with that of healthy persons. These low responses of patients blood to LPS or TNF- support our finding that phagocytes are not fully activated when gram-negative bacterial infections occur.     

Aspirin effect on early and late changes in acute lung injury in sheep

Objective There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B₂ (TxB₂) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep.Design 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i. v.) 30 min before OA, the others saline as placebo.Measurements and results Pulmonary and tissue gas exchange, pulmonary and systemic hemodynamics, respiratory system mechanics, TxB₂ and 6-keto-PGF1, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB₂ generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at 1 in ASA-group compared to its fall to 0.7 in controls.Conclusion Our findings suggest that ASA: 1) is only effective to treat the very transient TxB₂-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB₂; 2) has a transient protective effect on the TxB₂-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO₂.     

Influence of surgical intervention in the immune response of severely injured patients

Objective Primary events such as severe injury and elective surgery cause a deterioration of the immune response measurable by reduction of expression of HLA-DR on monocytes or ex vivo LPS-induced TNF production. The further influence of secondary surgery after severe injury on the immune response remains unresolved.Design Prospective observation study.Setting Surgical intensive care unit of an university hospital.Patients Sixteen severely injured patients with an ISS >25 points.Measurements and results On day 1 after trauma and immediately before secondary surgery, mean fluorescence intensity (MFI) of HLA-DR expression on monocytes and TNF ex vivo synthesis was significantly reduced compared to healthy donors. Overall, surgical intervention during the second week after trauma caused no further reduction of HLA-DR expression on monocytes and of the ex vivo TNF-synthesis. However, major surgery such as intramedullary nailing or pelvic osteosynthesis caused reduction of the HLA-DR expression and TNF-synthesis, whereas, minor surgical interventions such as osteosynthesis on peripheral joints exhibited no significant effects on the immune response. Surgical intervention performed to clear septic foci normalised immune response by elevating HLA-DR expression on monocytes and ex vivo TNF synthesis. Severe injury caused elevated serum IL-10 levels, whereas secondary surgery did not induce a further increase in serum IL-10 levels.Conclusion This study shows that initial trauma as well as major secondary surgery causes a suppression of immune functions, whereas minor secondary surgery does not cause significant immune disturbance.     

Low tidal volume ventilation induces proinflammatory and profibrogenic response in lungs of rats

Objective We examined whether mechanical ventilation with low tidal volume induces polymorphonuclear infiltration and proinflammatory and profibrogenic responses in rat lungs compared dependent and nondependent lung region to expression of interleukin-1 (IL-1) and -1 procollagen III (PC III) mRNA.Design An experimental, randomized and controlled protocol with previously normal rats.Interventions Three groups of ten animals were studied. Two groups were ventilated (FIO₂=0.3) in supine position for 1 h without positive end expiratory pressure, one group with a low tidal volume (6 ml/kg), and the other with a high tidal volume (24 ml/kg). In the third group animals were kept in spontaneous ventilation for 1 h.Measurements and results After ventilation the right lung was used to quantify polymorphonuclear infiltration. The left lung was divided into dependent and nondependent regions, and expression of IL-1 and PC III mRNA was quantified by northern blot analysis. The group ventilated with low tidal volume had greater polymorphonuclear infiltration IL-1 and PC III mRNA expression than the nonventilated group. Similar results were observed with high tidal volumes. There was no difference between low and high tidal volume ventilation. Expression levels of IL-1 and PC III mRNA were higher in the nondependent region of ventilated groups and equal in the nonventilated group.Conclusions Even a low tidal volume mode of mechanical ventilation induces proinflammatory and profibrogenic response, with a nondependent predominance for IL-1 and PC III mRNA expression in supine, ventilated, previously normal rats.     

Plaidoyer pour la tisane médicinale

Résumé: La tisane nest pas uniquement un apport deau. Il sagit dune préparation médicinale utile en médecine et en phytothérapie. Elle doit obéir à certains critères pour être de qualité : qualité de la plante, temps dinfusion, conditions dutilisation, correction du goût. La teneur en principe actif est variable, mais elle est effective, quoiquelle dépende de plusieurs facteurs qui en déterminent lefficacité. Des exemples de tisanes pour la pédiatrie sont donnés.     

Effects of volumetric vs. pressure-guided fluid therapy on postoperative inflammatory response: a prospective, randomized clinical trial

Objective To compare intrathoracic blood volume (ITBV) guided fluid management and central venous pressure (CVP) guided therapy in ameliorating the progression of early systemic inflammatory response in patients undergoing major surgery.Design Prospective, randomized clinical trial.Patients Forty patients undergoing major abdominal surgery were randomized into CVP and ITBV groups.Interventions In the CVP group the target CVP was 8–12 mmHg while in the ITBV group the goal was to keep the ITBV between 850 and 950 ml/m² during the operation.Measurements and results Hemodynamic parameters were determined by single arterial thermodilution. Measurements were repeated every 30 min intraoperatively. Serum procalcitonin (PCT) and C-reactive protein (CRP) was monitored preoperatively, on ICU admission, and then daily for 3 days. Serum TNF- levels were measured intraoperatively hourly and then daily for 3 days. There was no significant difference between the two groups regarding hemodynamic parameters at any assessment point. In the overall population changes in the stroke volume index showed a significant correlation with changes in CVP and ITBV. TNF- levels remained in the normal range intraoperatively and during the three postoperative days in both groups. Preoperatively normal PCT and CRP levels increased significantly postoperatively, without significant differences between the groups.Conclusions ITBV guided fluid therapy did not alter the magnitude of inflammatory response as monitored by serum PCT, CRP, and TNF- in the early postoperative period.     

Does psychological characteristic influence physicians’ communication styles? Impact of physicians’ locus of control on interviews with a cancer patient and a relative

Context Physicians psychological characteristics may influence their communication styles and may thus interfere with patient-centred communication.Objective Our aim was to test the hypothesis that, in interviews with a cancer patient and a relative, physicians with an external locus of control (LOC; who believe that life outcomes are controlled by external forces such as luck, fate or others) have a communication style different from that of physicians with an internal LOC (who believe that life outcomes are controlled by their own characteristics or actions).Design, setting, participants and intervention Eighty-one voluntary physicians practising in the field of oncology were recorded while performing an actual and a simulated interview with a cancer patient and a relative.Main outcome measures Physicians communication skills were assessed using the Cancer Research Campaign Workshop Evaluation Manual. Physicians LOC was assessed using the Rotter I–E scale. The communication skills of the upper and lower quartiles of physicians in respect of their scores on this scale were compared using Students t test.Results In actual interviews, physicians with an external LOC talked more to the relative (P=0.017) and used more utterances with an assessment function (P=0.010) than physicians with an internal LOC. In simulated interviews, physicians with an external LOC used less utterances that give premature information (P=0.031) and used more utterances with a supportive function, such as empathy and reassurance (P=0.029), than physicians with an internal LOC.Conclusion These results provide evidence that physicians LOC can influence their communication styles. Physicians awareness of this influence constitutes a step towards a tailoring of their communication skills to every patients and relatives concerns and needs and thus towards a patient-centred communication.This research program was supported by the Fonds National de la Recherche Scientifique—Section Télévie of Belgium, the Fonds dEncouragement à la Recherche de lUniversité Libre de Bruxelles (Brussels, Belgium) and the CAM Training and Research Group (Brussels, Belgium).     

The Driver's Angry Thoughts Questionnaire: A Measure of Angry Cognitions When Driving

Five forms of driving-related angry cognitions were identified—Judgmental/Disbelieving Thinking ( = .94), Pejorative Labeling/Verbally Aggressive Thinking ( = .92), Revenge/Retaliatory Thinking ( = .93), Physically Aggressive Thinking ( = .93), and Coping Self-instruction ( = .83). Pejorative labeling/verbally aggressive, physically aggressive, and revengeful/retaliatory thinking correlated positively with each other and with driving anger, aggressive driving anger expression, aggression, and risky driving behavior. Coping self-instruction tended to correlate negatively with these variables. Judgmental/disbelieving thinking correlated positively with other forms of angry thinking, but was only somewhat correlated with other variables. Driving-related angry thoughts, except coping self-instruction, correlated positively with general hostile automatic thoughts. Differences in strengths of correlations with specific variables, and contributions to regression analyses supported the discriminant and incremental validity of driving-related angry thoughts. Implications for cognitive processes in anger and interventions were discussed.     

Immune monitoring of patients with septic shock by measurement of intraleukocyte cytokines

Objective To assess the immune competence of patients presenting with septic shock by measuring on-line the production of intracellular cytokines by circulating leukocytes.Design and setting Prospective study in a 18-bed medical intensive care unit of a university hospital.Patients and participants 21 patients with septic shock, and 11 volunteers.Interventions Single-step isolation of leukocytes from whole blood obtained within the first 24 h after admission. Leukocytes were fixed immediately or after treatment with lipopolysaccharide (LPS) and/or heterologous plasma.Measurements and results Leukocytes were permeabilized, and the intracellular cytokine expression of TNF- and IL-10 was quantified by immunostaining and flow cytometry. LPS treatment significantly increased monocyte intracellular cytokine TNF- and IL-10 as well as lymphocyte intracellular cytokine IL-10 in normal leukocytes. Septic monocytes and granulocytes had nonstimulated intracellular cytokine TNF- concentrations lower than those measured in volunteers and were severely hyporesponsive to LPS. These phenotypic changes were correlated with disease severity and could be reproduced by treatment of normal leukocytes with plasma from patients with septic shock.Conclusions Intracellular cytokine staining is a simple and rapid method to assess in situ and on-line the inflammatory balance and responsiveness of leukocyte subpopulations and could therefore represent a useful monitoring tool to assess the immune competence of critically ill patients. This study identifies the cellular source of cytokines in whole blood and confirms prior reports showing that septic phagocytes are characterized by a predominant anti-inflammatory phenotype, with hyporesponsiveness to LPS, depending on a plasma deactivation factor.     

Disturbances of selected plasma proteins in hyperdynamic septic shock

This study was performed on patients (n=18) suffering from strictly defined hyperdynamic septic shock. Plasma factors (C-reactive protein, acid ₁-glycoprotien, fibrinogen, fibrinopeptide A, fibrinogen-fibrin split products, factor XIII, antithrobin III, complement factors C3 and C4, inter--trypsin-inhibitor and ₂-macroglobulin) measured during hyperdynamic septic shock were highly abnormal. The activation and consumption of clotting, fibrinolytic and complement factors due to system-specific proteinases (such as thrombokinase or plasminogen activators) seemed to be intensified by the nonspecific proteolytic activity of granulocytic proteinases probably released by the action of endotoxins. Possible therapeutic measures to maintain the endogeneous defence mechanism against enhanced proteolysis during septic shock are discussed.     

Intermittent high permeability hemofiltration in septic patients with acute renal failure

Objective High permeability hemofiltration (HP-HF) is a new renal replacement modality designed to facilitate the elimination of cytokines in sepsis. Clinical safety data on this new procedure is still lacking. This study investigates the effects of HP-HF on the protein and coagulation status as well as on cardiovascular hemodynamics in patients with septic shock. In addition, the clearance capacity for interleukin-6 (IL-6) and tumor necrosis factor- (TNF-) is analyzed.Design Prospective, single-center pilot trial.Setting University hospital.Patients Sixteen patients with multiple organ failure (MOF) induced by septic shock were studied.Intervention Patients were treated by intermittent high permeability hemofiltration (iHP-HF; nominal cut-off point: 60 kilodaltons). Intermittent HP-HF was performed over 5 days for 12 h per day and alternated with conventional hemofiltration.Measurements and results Intermittent HP-HF proved to be a safe hemofiltration modality in regard to cardiovascular hemodynamics and its impact on the coagulation status. However, transmembrane protein loss occurred and cumulative 12-h protein loss was 7.60 g (IQR: 6.2–12.0). The filtration capacity for IL-6 was exceptionally high. The IL-6 sieving coefficient approximated 1 throughout the study period. The total plasma IL-6 burden, estimated by area under curve analysis, declined over time (p<0.001 vs baseline). The TNF- elimination capacity was poor.Conclusions High permeability hemofiltration is a new approach in the adjuvant therapy of sepsis that facilitates the elimination of cytokines. HP-HF alternating with conventional hemofiltration is well tolerated. Further studies are needed to analyze whether HP-HF is able to mitigate the course of sepsis.     

Positive end-expiratory pressure: Implications for tidal volume changes in anesthesia machine ventilation

In clinical practice, the addition of positive end-expiratory pressure (PEEP) into a standard anesthesia circle circuit decreases the delivered tidal volume (DTV) to a patient. We studied the magnitude of the DTV/PEEP relationship in two commonly used anesthesia systems. In addition, the magnitude of the DTV/PEEP relationship varies with both pulmonary compliance and volume of gas contained in the patient's breathing system between the ventilator and PEEP valve site, and this was also evaluated. Routine monitoring of expired tidal volume should be used whenever PEEP is added to an anesthesia circuit.