The effect of xenon on isoflurane protection against experimental myocardial infarction.

OBJECTIVES: To investigate if the protective effects of xenon and isoflurane against myocardial ischemia-reperfusion damage would be additive. DESIGN: A prospective, randomized laboratory investigation. SETTING: An animal laboratory of a university hospital. PARTICIPANTS: Thirty-six pigs (female German landrace). INTERVENTIONS: In an open-chest preparation with thiopental anesthesia, the left anterior descending artery was occluded to produce ischemia for 60 minutes. One hour previously, ischemic preconditioning, isoflurane (0.55 minimum alveolar concentration [MAC]) alone, or isoflurane together with xenon (0.55 MAC each) were started in the respective groups. A fourth (control) group received no protective intervention. Myocardial ischemia was followed by 2 hours of reperfusion. MEASUREMENTS AND MAIN RESULTS: Hearts were excised and stained (Evans Blue/TTC) to measure infarct size as related to the area at risk. Myocardial infarct size was reduced (means +/- standard deviation) from 64% +/- 9% of the area at risk in the control group to 19% +/- 12% with ischemic preconditioning to 46% +/- 12% with isoflurane and to 39% +/- 13% with isoflurane and xenon. All intervention groups were significantly different from the control (p < 0.05), and both anesthetic groups were significantly different from ischemic preconditioning (p < 0.05). CONCLUSION: Combined isoflurane/xenon anesthesia reduced infarct size but not more than isoflurane alone. Ischemic preconditioning was more effective than the anesthetics.

The effect of xenon anesthesia on the size of experimental myocardial infarction.

BACKGROUND: Volatile anesthetics protect the myocardium from ischemia reperfusion damage. Our hypothesis for this study was that xenon reduces the size of myocardial infarction similar in extent to the reduction associated with ischemic preconditioning. METHODS: Thirty-six pigs weighing 30-35 kg were anesthetized with thiopental and then randomized into four groups: control (myocardial ischemia only), ischemic preconditioning (five 5-min episodes of intermittent myocardial ischemia), xenon preconditioning (three 10-min exposures to xenon 70% followed by myocardial ischemia), and xenon anesthesia (xenon 70%, continued before and after myocardial ischemia). Myocardial ischemia was induced by placing a tourniquet around the left anterior descending coronary artery for 60 min followed by 2 h of reperfusion. Myocardial infarct size and the area at risk for myocardial infarction were measured by Evans Blue and triphenyl tetrazolium chloride staining, respectively. RESULTS: Mean (sd) myocardial infarct size was reduced from 64% +/- 9% of the area at risk in the control group to 19% +/- 12% with ischemic preconditioning (P < 0.001), and to 50% +/- 9% with xenon anesthesia (P < 0.05 versus control, P < 0.001 versus ischemic preconditioning). Myocardial infarct size was not reduced with xenon preconditioning compared with the control group (59% +/- 11%, P = 0.41). CONCLUSION: Myocardial infarct size was reduced by ischemic preconditioning but less so by xenon anesthesia. Brief, intermittent exposure to xenon before myocardial ischemia did not reduce myocardial infarct size.

Phosphodiesterase III inhibition affects platelet-monocyte aggregate formation depending on the axis of stimulation.

OBJECTIVE: The purpose of this study was to investigate the effect of the phosphodiesterase (PDE) type 3 inhibitor milrinone on the adhesion of platelets to monocytes in vitro. DESIGN: Prospective study. SETTING: University experimental laboratory. PARTICIPANTS: Ten healthy volunteers. INTERVENTIONS: Whole blood was incubated with 1, 10, or 100 micromol/L of milrinone. After stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP) or adenosine-5-diphosphate (ADP), platelet-monocyte adhesion and CD11b, PSGL-1, GPIIb/IIIa, and P-selectin expression were measured by flow cytometry. MEASUREMENTS AND RESULTS: The formation of platelet-monocyte conjugates after PDE3 inhibition depended on the type of stimulation. In unstimulated and FMLP-stimulated blood platelet monocytes, aggregation was enhanced by increasing concentrations of milrinone. This augmentation was accompanied by a rise in P-selectin expression in platelets. In ADP-stimulated blood the number of platelet-monocyte aggregates decreased with increasing concentrations of milrinone. Concurrent with the reported antiinflammatory properties of PDE-inhibition, an inhibition of CD11b expression was found in monocytes after stimulation with FMLP. In contrast, in unstimulated samples lower concentrations of milrinone caused an increase in CD11b. CONCLUSIONS: These findings suggest that the effects of PDE3 inhibition on platelets and monocytes are modified by the type of stimulation and only partially suppress the inflammatory response of platelets and monocytes. The increase in platelet-monocyte conjugates in unstimulated and FMLP-stimulated blood suggested that PDE3 inhibition may also trigger proinflammatory reactions.

Epinephrine enhances platelet-neutrophil adhesion in whole blood in vitro.

Previous studies showed that alpha- or beta-adrenoceptor stimulation by catecholamines influenced neutrophil function, cytokine liberation, and platelet aggregability. We investigated whether adrenergic stimulation with epinephrine also alters platelet-neutrophil adhesion. This might be of specific interest in the critically ill, because the increased association of platelets and neutrophils has been shown to be of key importance in inflammation and thrombosis. For this purpose, whole blood was incubated with increasing concentrations of epinephrine (10 nM, 100 nM, and 1 microM). To distinguish receptor-specific effects, a subset of samples was incubated with propranolol (10 microM) or phentolamine (10 microM) before exposure to epinephrine. After incubation, another subset of samples was also stimulated with 100 nM of N-formyl-methionyl-leucyl-phenylalanine. All samples were stained, and platelet-neutrophil adhesion and CD45, L-selectin, CD11b, P-selectin glycoprotein ligand-1, glycoprotein IIb/IIIa, and P-selectin expression were measured by two-color flow cytometry. Epinephrine significantly enhanced platelet-neutrophil adhesion and P-selectin and glycoprotein IIb/IIIa expression on platelets. CD11b and L-selectin expression on unstimulated neutrophils remained unchanged, whereas N-formyl-methionyl-leucyl-phenylalanine-induced upregulation of CD11b and downregulation of L-selectin were suppressed by epinephrine. beta-Adrenergic blockade before incubation with epinephrine increased platelet-neutrophil aggregates and adhesion molecule expression (CD11b, P-selectin, and glycoprotein IIb/IIIa) even further. These results demonstrate that epinephrine enhances platelet-neutrophil adhesion. The alpha-adrenergic receptor-mediated increase in P-selectin and glycoprotein IIb/IIIa expression on platelets may contribute substantially to this effect. Our study shows that inotropic support enhances the platelet-neutrophil interaction, which might be crucial for critically ill patients.

Minimum anesthetic concentration of sevoflurane with different xenon concentrations in swine.

UNLABELLED: In a previous study, we described a partial antagonism of xenon (Xe) in combination with isoflurane. One hypothetical explanation suggested that Xe and isoflurane probably induced anesthesia via different pathways at the neuronal level. This warranted investigating the combination of Xe with other inhaled anesthetics to examine the relationship between Xe and volatile anesthetics in general. We therefore investigated the influence of Xe on the minimum alveolar concentration (MAC) of sevoflurane. The study was performed in 10 swine (weight 30.8 kg +/- 2.6, mean +/- SD) ventilated with xenon 0%, 15%, 30%, 40%, 50%, and 65% in oxygen. At each Xe concentration, various concentrations of sevoflurane were administered in a stepwise design. For each a supramaximal pain stimulus (claw clamp) was applied. The appearance of a withdrawal reaction was recorded. The sevoflurane MAC was defined as the end-tidal concentration required to produce a 50% response rate. At each Xe concentration, the animals' responses to the pain stimulus were categorized and a logistic regression model was fitted to the results to determine sevoflurane MAC. Sevoflurane MAC was decreased by inhalation of Xe in a linear manner from 2.53 with 0% Xe to 1.54 with 65% Xe. In contrast to Xe and isoflurane, the anesthetic effects of Xe and sevoflurane appear to be simply linear. IMPLICATIONS: We investigated the influence of the anesthetic gas, xenon, on the minimum alveolar concentration (MAC) for the volatile anesthetic sevoflurane. The study was performed in 10 swine ventilated with fixed xenon and various concentrations of isoflurane. The sevoflurane MAC is decreased by inhalation of xenon in a linear relationship.

Minimum alveolar anesthetic concentration of isoflurane with different xenon concentrations in Swine.

UNLABELLED: For patients requiring a fraction of inspired oxygen more than 0.3, the use of xenon (Xe) as the sole anesthetic is limited because of its large minimum alveolar anesthetic concentration (MAC) of 71%. This warrants investigating the combination of Xe with other inhaled anesthetics. We therefore investigated the influence of Xe on the MAC of isoflurane. The study was performed in 10 swine (weight, 28-35 kg) ventilated with Xe 0%, 15%, 30%, 40%, 50%, and 65% in oxygen. For each Xe concentration, various concentrations of isoflurane were administered in a step-wise design. For each combination, a supramaximal pain stimulus (claw-clamp) was applied, and the appearance of a withdrawal reaction was recorded. The isoflurane MAC was defined as the end-tidal concentration required to produce a 50% response rate. At each Xe concentration, the responses to the pain stimulus were categorized, and a logistic regression model was fitted to the results to determine isoflurane MAC. Isoflurane MAC was decreased by inhalation of Xe in a nonlinear manner from 1.92% (95% confidence interval, 1.70%-2.15%) with 0% Xe to 1.17% (95% confidence interval, 0.75%-1.59%) with 65% Xe. Although this indicates partial antagonism of the two anesthetics, a combination of Xe with isoflurane may prove valuable for patients requiring a fraction of inspired oxygen more than 0.3. IMPLICATIONS: We investigated the influence of the anesthetic gas xenon on the minimum alveolar anesthetic concentration (MAC) for isoflurane (another anesthetic gas). The study was performed in 10 swine ventilated with fixed xenon and various concentrations of isoflurane. The isoflurane MAC is decreased by inhalation of xenon in a nonlinear relationship.

Effect of halothane and isoflurane on binding of ADP- and TRAP-6- activated platelets to leukocytes in Whole blood.

BACKGROUND: Adhesion of activated platelets to neutrophils and monocytes has an important role in the regulation of inflammatory processes. This study investigates whether halothane and isoflurane affect binding of activated platelets to leukocytes in human whole blood. METHODS: Citrated whole blood was incubated for 60 min with either 1 or 2 minimum alveolar concentration (MAC) halothane or isoflurane. After stimulation with adenosine-5-diphosphate (ADP) or the thrombin receptor agonist protein TRAP-6, platelet-leukocyte adhesion and surface expression of CD62P on platelets were evaluated by flow cytometry. RESULTS: Halothane led to an inhibition of agonist-induced adhesion of activated platelets to neutrophils and monocytes. One MAC halothane reduced the formation of TRAP-6-induced platelet-monocyte conjugates. After exposure to 2 MAC halothane, agonist-induced platelet-monocyte and platelet-neutrophil adhesion were inhibited. Surface expression of CD62P on ADP- and TRAP-6-stimulated platelets were significantly reduced after 1 and 2 MAC halothane. After 2 MAC isoflurane, the authors observed an increase of the percentage of lymphocytes with bound platelets after activation with ADP. The percentage of neutrophils with bound platelets after activation with ADP or TRAP-6 was also increased in this group. Two MAC isoflurane led to an increase of the percentage of platelets expressing CD62P in the unstimulated and TRAP-6 stimulated samples, and of the amount of CD62P epitopes on the surface of platelets in the ADP-stimulated samples. CONCLUSION: This study indicates that halothane inhibits, whereas isoflurane enhances, adhesion of agonist-activated platelets to leukocytes. Interaction of both anesthetics with the expression of CD62P on platelets contribute to theses effects.