[Adjuvant therapy for sepsis and ARDS].
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Critical Care↗
Biomedical subjects
M Thiel
Publications and source records attributed to M Thiel.
First clinical implications of perioperative red cell volume measurement with a nonradioactive marker (sodium fluorescein).
UNLABELLED: We measured red cell volume (RCV) with the nonradioactive marker sodium fluorescein (SoF) in 30 patients undergoing gynecological operations. Sixteen patients underwent preoperative isovolemic hemodilution (PIHD). RCV measurements were performed before and after PIHD and at the end of the operation. All RCVs were related to corresponding hematocrit (hct) levels. We report a simplified method for its clinical application by reducing the number of blood samples required. To validate our method, we compared RCV within the PIHD bags (bag RCV) with the difference of the patients' RCV before and after PIHD. Bag RCV obtained during PIHD (mean 399+/-81 mL) was measured with a precision of 4.2% by using SoF. There was a significant difference (mean 286+/-401 mL; P < 0.05) between intraoperatively estimated and measured blood loss. The blood loss tended to be underestimated and, in some cases, was underestimated or overestimated substantially. Preoperative and postoperative hct values only offered an imprecise estimation of the patients' RCV. We conclude that RCV measurement using SoF is a precise method for monitoring changes in RCV during PIHD and surgical operation. IMPLICATIONS: We measured red cell volume changes of 30 patients with the nonradioactive marker sodium fluorescein before and after hemodilution and postoperatively with a high precision. We frequently found large differences between intraoperatively estimated and measured blood loss. Preoperative hematocrit values offered an imprecise estimation of the patients' red cell volume.
Adult↗
Effects of adenosine on cardiopulmonary functions and oxygen-derived variables during endotoxemia.
OBJECTIVES: To determine the effects of a prophylactic intravenous infusion of adenosine on cardiopulmonary functions and oxygen-derived variables in a porcine model of endotoxemia. DESIGN: Prospective, randomized, placebo-controlled, unblinded study. SETTING: University research laboratory. SUBJECTS: Thirty country bred pigs, aged 6 to 7 wks, weighing 24.9 +/- 0.65 (SEM) kg body weight. INTERVENTIONS: Pigs were anesthetized by i.v. pentobarbital and fentanyl, intratracheally intubated, and mechanically normoventilated with a gas mixture of nitrous oxide/oxygen = 1:1. Intravascular catheters were inserted to allow for determination of arterial, central venous blood pressure, pulmonary artery occlusion pressure, cardiac output, and sampling of blood for gas analyses. Group 1 (n = 10) received a 330-min intravenous infusion of Salmonella abortus equi endotoxin (5 microg/kg body weight x hr). Group 2 (n = 10) received an additional intravenous infusion of adenosine (150 microg/kg body weight x min), started 30 mins before the infusion of endotoxin. Control groups 3 and 4 (n = 5 for both groups) received adenosine or physiologic saline, respectively. MEASUREMENTS AND MAIN RESULTS: Parameters of cardiopulmonary function and oxygen-derived variables were calculated from pulmonary artery catheter measurements and blood gas analyses using standard formula. Plasma concentrations of purine compounds (adenosine, inosine, hypoxanthine) were determined by high-performance liquid chromatography. Since tumor necrosis factor-alpha plays a central role in the development of endotoxic shock, concentrations of this cytokine were determined in serum by enzyme-linked immunosorbent assay. Infusion of adenosine before the beginning of the infusion of endotoxin increased plasma concentrations of the nucleoside from 193 +/- 72 to 553 +/- 65 nmol/L and decreased the systemic vascular resistance by 50%. Although acting as a potent vasodilator under control conditions, adenosine did not aggravate the arterial hypotension elicited by endotoxemia but significantly increased cardiac output by a comparably small decrease in systemic vascular resistance, prevention of pulmonary vasoconstriction, and improvement of left ventricular performance. Despite significant pulmonary vasodilation, gas exchange was not worsened but slightly improved by adenosine. With the increase in cardiac output and arterial oxygenation, systemic oxygen delivery almost doubled. This adenosine-induced oxygen flux was not a surplus but was most likely utilized by tissues, as suggested by the much earlier beginning of the increase in the systemic oxygen consumption and the attenuation of the decrease in the gastric mucosal pHi. No effects of adenosine were observed on the endotoxin-induced increase in serum concentrations of tumor necrosis factor-alpha. CONCLUSIONS: Infusion of adenosine might be useful to improve flow-dependent oxygen delivery and tissue oxygenation during endotoxic shock without the induction of adverse cardiopulmonary side effects. The beneficial hemodynamic effects of adenosine appear not to be mediated by the inhibition of the release of tumor necrosis factor-alpha.
Adenosine↗
Buflomedil hydrochloride reduces systemic activation of polymorphonuclear leukocytes during hyperdynamic endotoxemia.
The purpose of the study was to examine the effects of buflomedil hydrochloride (BFL) on the expression of adhesion molecules (beta2-integrins) and oxygen radical production of circulating and emigrated intra-abdominal polymorphonuclear leukocytes (PMNL) in a standardized porcine model of hyperdynamic endotoxemia. A total of 20 anesthetized pigs were randomly assigned to one of the following groups: endotoxin group (endotoxin 5 microg / kg x h, intravenously (i.v.), n = 7), BFL group (BFL (3 mg/kg initial i.v. bolus followed by a continuous infusion (.1 mg / kg x h) and endotoxin 5 microg / kg x h, i.v., n = 7), and control group (NaCl .9%; n = 6). Experiments were terminated at 330 min. Infusion of endotoxin alone resulted in the activation of circulating and emigrated PMNL as evidenced by neutropenia, functional and numerical up-regulation of beta2-integrins, and enhanced oxygen radical production. BFL was able to attenuate functional and numerical up-regulation of beta2-integrins as well as oxygen radical production of circulating and emigrated PMNL. An unexpected decrease in the plasma concentration of BFL during the experiments was associated with an increase in the oxygen radical production of PMNL at the end of the experiments. In addition, BFL attenuated the fall in the intramucosal pH and the increase in plasma concentration of lactate observed in the late phase of endotoxemia. These findings suggest that BFL is able to decrease systemic activation of PMNL and to improve local tissue oxygenation during endotoxemia.
Animals↗
Signaling mechanisms and the activation of leukocyte integrins.
Myeloid cells and lymphocytes primarily circulate in the vascular system but move into the tissues in response to inflammatory signals. Such a mobile lifestyle necessitates the continual making and breaking of cell and cell matrix contacts; the receptors known as the integrins are well suited as mediators of this transient adhesiveness. In general, leukocyte integrins are not constitutively active but become adhesive in response to signaling through other membrane receptors. Candidate receptors for receiving the activating signals are the seven membrane-spanning receptors that are found on all leukocytes. The identity of the signals, however, that are responsible for triggering integrin adhesion in vivo and for promoting directed leukocyte movement into tissues remains incompletely resolved.
Animals↗
[Small-volume resuscitation for hypovolemic shock. Concept, experimental and clinical results].
The concept of small-volume resuscitation, the rapid infusion of a small volume (4 ml/kg BW) of hyperosmolar 7.2-7.5% saline solution for the initial therapy of severe hypovolemia and shock was advocated more than a decade ago. Numerous publications have established that hyperosmolar saline solution can restore arterial blood pressure, cardiac index and oxygen delivery as well as organ perfusion to pre-shock values. Most prehospital studies failed to yield conclusive results with respect to a reduction in overall mortality. A meta-analysis of preclinical studies from North and South America, however, has indicated an increase in survival rate by 5.1% following small-volume resuscitation when compared to standard of care. Moreover, small-volume resuscitation appears to be of specific impact in patients suffering from head injuries with increased ICP and in severest trauma requiring immediate surgical intervention. Results from clinical trials in Austria, Germany and France have demonstrated positive effects of hyperosmolar saline solutions when used for fluid loading or fluid substitution in cardiac bypass and in aortic aneurysm surgery, respectively. A less positive perioperative fluid balance, a better hemodynamic stability and improved pulmonary function were reported. In septic patients oxygen consumption could significantly be augmented. The most important mechanism of action of small-volume resuscitation is the mobilisation of endogenous fluid primarily from oedematous endothelial cells, by which the rectification of shock-narrowed capillaries and the restoration of nutritional blood, flow is efficiently promoted. Moreover, after ischemia reperfusion a reduction in sticking and rolling leukocytes have been found following hyperosmolar saline infusion. Both may be of paramount importance in the long-term preservation of organ function following hypovolemic shock. An increased myocardial contractility in addition to the fluid loading effects of hyperosmolar saline solutions has been suggested as a mechanism of action. This, however, could not be confirmed by pre-load independent measures of myocardial contractility. Some concerns have been raised regarding the use of hyperosmolar saline solutions in patients with a reduced cardiac reserve. A slower speed of infusion and adequate monitoring is recommended for high risk patients. Recently, hyperosmolar saline solutions in combination with artificial oxygen carriers have been proposed to increase tissue oxygen delivery through enhanced O2 content. This interesting perspective, however, requires further studies to confirm the potential indications for such solutions. Many hyperosmolar saline colloid solutions have been investigated in the past years, from which 7.2-7.5% sodium chloride in combination with either 6-10% dextran 60/70 or 6-10% hydroxyethyl starch 200,000 appear to yield the best benefit-risk ratio. This has led to the registration of the solutions in South America, Austria, The Czech Republic, and is soon awaited for North America.
Dextrans↗
Effects of adenosine on the functions of circulating polymorphonuclear leukocytes during hyperdynamic endotoxemia.
Endotoxin-activated polymorphonuclear leukocytes (PMNL) adhere to the vascular endothelium and cause damage by the release of toxic superoxide anions (O2-). Because adenosine is a potent inhibitor of PMNL in vitro, the present study investigates the effects of this nucleoside on the functions of circulating PMNL in a standardized porcine model of hyperdynamic endotoxemia. Ten anesthesized pigs received an intravenous (i.v.) 330-min infusion of endotoxin (5 microg/kg of body weight per h). Another 10 pigs were also infused with endotoxin plus adenosine (150 microg/kg/min [i.v.]); this treatment was begun 30 min prior to the beginning of endotoxin treatment. Control groups (five animals per group) received either adenosine or physiological saline. Infusion of endotoxin caused severe neutropenia, shedding of L-selectin, upregulation of beta2-integrins, increased binding of C3-coated zymosan particles, and subsequent phagocytosis by PMNL. While phagocytosis-induced production of oxygen radicals appeared to decrease, extracellular release of superoxide anions was strongly enhanced. Infusion of adenosine during endotoxemia had no effect on neutropenia, expression of adhesion molecules, C3-induced adhesion, phagocytosis, or intracellular production of oxygen radicals, whereas extracellular release of O2- was strongly inhibited. Thus, i.v. infusion of adenosine during endotoxemia could be useful in protecting from O2(-)-mediated tissue injury without compromising the bactericidal mechanisms of PMNL.
2-Chloroadenosine↗
Expression of beta 2-integrins and L-selectin on polymorphonuclear leukocytes in septic patients.
Adhesion molecules on polymorphonuclear leukocytes (PMNL) play an important role in nonspecific defense mechanisms directed at invading microorganisms. When local infection, however, cannot be controlled, a systemic inflammatory response syndrome (SIRS) ensues which may progress to septic shock and multiple organ failure, these being major determinants of the patient's outcome. In the present study, the expression of beta 2-integrins and L-selectin on blood PMNL was measured on subsequent days in patients with sepsis (n = 17) and in healthy volunteers (n = 15). beta 2-Integrins and L-selectin molecules were detected by flow cytometry, using the monoclonal antibodies IB4 (anti-CD18) and Dreg200 (anti-CD62L), respectively. Adhesion molecules were determined at baseline immediately after blood collection and also 45 min after incubation of cells in vitro at body temperature to allow for spontaneous regulation. In addition, PMNL were activated by receptor-dependent and receptor-independent stimuli to characterize stimulus-specific adhesion molecule expression. In parallel with the measurement of adhesion molecules, severity of sepsis was assessed by the Elebute score. The results demonstrate significant differences in the basal, spontaneous and stimulus-induced expression of adhesion molecules between healthy volunteers, survivors (n = 11) and nonsurvivors (n = 6). Moreover, when survivors and nonsurvivors with severe sepsis (Elebute score > 12) were compared, basal expressions of both beta 2-integrins and L-selectin were significantly lower in patients who did not survive. Thus, measurement of adhesion molecules on circulating PMNL may be useful to identify septic patients at high risk for lethal outcome.
Adult↗
Small-volume hyperosmolar resuscitation.
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Animals↗
Effect of adenosine on the expression of beta(2) integrins and L-selectin of human polymorphonuclear leukocytes in vitro.
Adenosine has been shown to inhibit the adhesion of polymorphonuclear leukocytes (PMNL) to the vascular endothelium. Because the underlying molecular mechanisms have not been fully understood, the present study characterizes the effect of adenosine on the expression of adhesion molecules of human PMNL. When PMNL were activated by N-formyl-methionyl-leucyl-phenylalanine the number of cell surface beta2 integrins increased fivefold, whereas L-selectin molecules were completely shed. Activation-dependent numerical up-regulation Of beta2 integrins and shedding of L-selectin were inhibited by exogenously applied adenosine receptor agonists in a concentration-dependent fashion. The rank order of potencies of adenosine receptor agonists, measured by the agonists' half-maximal inhibitory concentrations, revealed that adenosine inhibited the numerical up-regulation of beta2 integrins and shedding of L-selectin most likely via an A2(a) receptor site. When extracellular concentrations of endogenously formed adenosine were enhanced by the nucleoside uptake inhibitor dipyridamole, up-regulation of beta2 integrins, and shedding of L-selectin was again inhibited. Both effects were reversed by the enzyme adenosine deaminase, which degrades active adenosine to inactive inosine, suggesting that endogenously formed adenosine may play an important role in the regulation of beta2 integrins and L-selectin of human PMNL.
2-Chloroadenosine↗
[The role of polymorphonuclear neutrophilic leukocytes in the pathogenesis of acute respiratory distress syndrome (ARDS)].
Polymorphonuclear leukocytes (PM-NL) constitute the first line of defence in the protection of the host from invading microorganisms. PMNL also contribute to the removal of cellular debris from necrotic tissues during reparative processes. For these purposes PMNL are armed with highly efficient bactericidal mechanisms which, under certain pathophysiological conditions, can be turned against the host himself. A vast body of evidence indicates that PMNL are able to cause lung injury which may be followed by the development of acute respiratory distress syndrome (ARDS). Accordingly, in patients with ARDS blood concentrations of inflammatory activators of PMNL are elevated, cytotoxic mechanisms of PMNL are enhanced and sequestration of these cells has been demonstrated to be inversely proportional to gas exchange. The manifestation of ARDS in leukopenic patients, however, indicates the development of this clinical syndrome independently of the presence of PMNL. The ability to differentiate between PMNL-dependent and PMNL-independent pathways in the pathogenesis of this syndrome is not only of theoretical interest but also of therapeutic significance. Since the patient's systemic inflammatory response may vary according to the stage and type of the underlying disease, an exact qualitative and quantitative analysis of PMNL functions may provide the rationale for new anti-inflammatory drug regimens aimed at modifying the host's response without increasing the risk of infection.
Acute Disease↗
[Anesthesiologic pecularities in patients with latex allergy].
Immediate-type hypersensitivity due to natural rubber (latex) products is an increasing problem for the anaesthetist, because a major part of products used for anaesthesia contains natural rubber. If the patient has a positive history of allergic symptoms after contact to natural rubber like urticaria, bronchospasm or anaphylaxis, preoperative skin tests, in vitro tests, and if necessary even the latex-glove-wearing test should be performed. If preoperative diagnosis of natural latex allergy is established, latex free anaesthesia is strictly recommended; otherwise life-threatening complications may ensue. Accordingly, we report on a patient who developed intraoperative anaphylactic shock following exposure to natural latex. In addition to the treatment with drugs, latex-containing products should be immediately replaced by latex-free ones, in particular all persons should put on latex-free gloves. For prevention of anaphylactic episodes in sensitized patients the reader is provided with an exemplary list of latex-free products for anaesthesia. Because the incidence of immediate-type reactions to latex is still increasing, intraoperative occurrence of an anaphylactic reaction to an unknown agent is likely to be due to allergy to natural rubber.
Anaphylaxis↗
Expression of adhesion molecules on circulating PMN during hyperdynamic endotoxemia.
In a porcine model of hyperdynamic endotoxemia, we studied the numerical expression of L-selectin and beta 2-integrins on circulating polymorphonuclear leukocytes (PMN). Functional changes of beta 2-integrins were determined by the adhesion of PMN to C3-coated zymosan particles. Anesthesized pigs received a continuous infusion of Salmonella abortus-equi endotoxin (5 micrograms.kg body wt-1.h-1) for 270 min (endotoxin group; n = 7). A control group received 0.9% NaCl (n = 6). L-selectin had decreased 30 min after the induction of endotoxemia [59.1 +/- 11.9 vs. 91.6 +/- 15.5 relative fluorescence units (RFU) at baseline; P < 0.05], reaching minimal values after 150 min (23.9 +/- 3.9 RFU in endotoxin group vs. 95.2 +/- 30.4 RFU in control group; P < 0.05). PMN adhesion to C3-coated zymosan increased at 30 min (41.3 +/- 9.9% in endotoxin group vs. 2.4 +/- 1.1% in control group; P < 0.05) and remained significantly elevated thereafter. In contrast to the rapid shedding of L-selectin and functional upregulation of beta 2-integrins, the numerical expression of beta 2-integrins remained unchanged until 60 min (44.8 +/- 2.8 vs. 32.2 +/- 1.7 RFU at baseline; P < 0.05); compared with the control group, significantly elevated values were observed 150 min after the start of endotoxin (48.9 +/- 2.4 RFU in endotoxin group vs. 36.5 +/- 2.7 RFU in control group; P < 0.05). We conclude that numerical and functional expressions of beta 2-integrins are dissociated during endotoxemia. Although upregulation of beta 2-integrins might render PMN more adhesive to the vascular endothelium, the presence of activated PMN in the circulation suggests that low expression of L-selectin might impede adhesion.
Animals↗
[Natural latex, a bioproduct with sensitizing action].
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Gloves, Surgical↗
Leukocyte integrins.
Lymphocytes, monocytes and granulocytes, which are collectively known as 'leukocytes', circulate primarily within the vascular system and lymphoid tissue but are found in essentially all tissues of the body. This mobile lifestyle necessitates the constant making and breaking of adhesive contacts with targets in their immediate environment. The adhesion receptors termed integrins, which are expressed in abundance by leukocytes, are well suited to carry out the transient interactions in which these cells engage. Major advances in the leukocyte integrin field this year have been the realization of the extensive roles for alpha 4 integrins in leukocyte function, the solution of the crystal structure of an I domain and its identification as a major ligand-binding site, and the initial understanding of how divalent cations may function in an active integrin.
Cell Adhesion↗
Acting via A2 receptors, adenosine inhibits the production of tumor necrosis factor-alpha of endotoxin-stimulated human polymorphonuclear leukocytes.
Human polymorphonuclear leukocytes (PMNLs) have recently been shown to release cytokines in response to a variety of inflammatory stimuli. Because adenosine (AR) modulates numerous functions of human PMNLs, the effect of the metabolic stable AR derivative 2-chloro-adenosine was tested on the production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide-stimulated PMNLs. In addition, the highly selective A1-receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and the A2 receptor agonist 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA) were compared for their effects on the lipopolysaccharide-stimulated TNF-alpha production. All AR agonists inhibited the lipopolysaccharide-stimulated production of TNF-alpha in a concentration-dependent fashion. The rank order of the half-maximal inhibitory concentration (IC50) of the different agonists was as follows: IC50 (2-chloro-adenosine) approximately 10(-6) mol/L > IC50 (CCPA) approximately 5 x 10(-7) mol/L >> IC50 (CPCA) = 5 x 10(-10) mol/L. Because the A2 receptor agonist was 1000 times more effective than the A1 agonist, adenosine analogs inhibited the lipopolysaccharide-stimulated production of TNF-alpha of human PMNLs most likely via an A2 receptor site. Of note, CPCA inhibited the TNF-alpha production even when PMNLs had been stimulated by lipopolysaccharide for 2 hours previously. The potential pathophysiologic implications for patients with sepsis are discussed.
Adenosine↗
[Insulin-dependent diabetes mellitus for 58 years].
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Aged↗
[Drug therapy of sepsis. An indication for pentoxifylline?].
The interaction of immunocompetent cells with the vascular endothelium is of prime importance for the development of septic multiple organ failure. There is evidence from in-vitro studies that the methylxanthine derivative pentoxifylline can attenuate the extent of inflammatory reactions by amplification of cell-derived endogenous regulators. For instance, pentoxifylline potentiates the anti-inflammatory actions of adenosine, prostacyclin, and prostaglandins of the E series by its synergistic action on intracellular cyclic AMP. By this mechanism, pentoxifylline inhibits the oxygen-radical production of polymorphonuclear leukocytes, the aggregation of platelets, disseminated intravascular coagulation, and the production of cytokines. Consequently, pentoxifylline improves perfusion in the microcirculation as well as tissue oxygenation. Further studies will clarify whether the promising results obtained with pentoxifylline in experimental septic shock will be confirmed under clinical conditions.
Humans↗