Klaus E. Hecker

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.

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

Previous studies showed that &agr;- or &bgr;-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 &mgr;M). To distinguish receptor-specific effects, a subset of samples was incubated with propranolol (10 &mgr;M) or phentolamine (10 &mgr;M) 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. &bgr;-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 &agr;-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.

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.

Xenon preserves neutrophil and monocyte function in human whole blood

PurposeMost volatile anesthetics are known to inhibit the oxidative and phagocytic function of neutrophils. In the present study, we investigated the effect of xenon on phagocytosis and respiratory burst activity of neutrophils and monocytes in human whole blood.MethodsHeparinized whole blood from 22 healthy volunteers was incubated for 60 min in the presence of 65% xenon. Sixty-five percent nitrous oxide was used as a positive control to prove the reliability of our in vitro system. Phagocytosis of fluorescein isothiocyanate labelled, opsonized Escherichia coli (E. coli) by neutrophils and monocytes was measured using flow cytometry. After induction with either N-formyl-methionyl-leucyl-phenylalanine (FMLP), phorbol-12-myristate-13-acetate or opsonized E. coli, respiratory burst activity was assessed by measuring the oxidation of dihydrorhodamine 123 to rhodamine 123 with a flow cytometer.ResultsExposure of human whole blood to xenon increased the percentage of neutrophils showing phagocytosis (94 ± 3% vs 92 ± 4%; P < 0.01), and the amount of ingested bacteria (P < 0.01). Respiratory burst activity in neutrophils and monocytes was not affected by xenon. Nitrous oxide significantly reduced the percentage of neutrophils showing respiratory burst after FMLP stimulation. Furthermore, E. coliinduced stimulation resulted in a decreased number of reacting neutrophils (84 ± 15% vs 95 ± 5%; P < 0.05) and monocytes (70 ±22% vs 83 ± 11%; P < 0.05) as well as a reduced production of hydrogen peroxide in both cell lines compared to control.ConclusionIn contrast to nitrous oxide, xenon preserves neutrophil and monocyte antibacterial capacity in vitro.RésuméObjectifLa plupart des anesthésiques sont connus pour inhiber la fonction oxydative et phagocytaire des neutrophiles. Dans la présente étude, noua avons examiné l’effet du xénon sur la phagocytose et l’activité de pointe respiratoire des neutrophiles et des monocytes dans le sang entier humainMéthodeDu sang entier hépariné de 22 donneurs en bonne santé a été incubé pendant 60 min en présence de xénon à 65 %. Du protoxyde d’azote à 65 % a été utilisé comme témoin positif permettant de prouver la fiabilité de notre système in vitro. La phagocytose de l’isothiocyanate de fluorescéine marquée, de l’Escherichia coli (E. coli) opsonisé, par les neutrophiles et les monocytes a été mesurée à l’aide de la cytométrie de flux. Après l’induction avec, soit N-formyl-méthionylleucyl-phénylalanine (FMLP), soit phorbol-12-myristate-13-acétate ou E. coli opsonisé, l’activité de pointe respiratoire a été évaluée en mesurant l’oxydation de la dihydrorhodamine 123 en rhodamine 123 avec un cytomètre de flux.RésultatsL’exposition du sang entier humain au xénon augmente le pourcentage de neutrophiles affichant une phagocytose (94 ± 3 % vs 92 ± 4%; P < 0,01) et la quantité de bactéries ingérées (P < 0,01). L’activité de pointe respiratoire dans les neutrophiles et les monocytes n’a pas été affectée par le xénon. Le protoxyde d’azote a significativement réduit le pourcentage de neutrophile montrant une pointe respiratoire après la stimulation avec la FMLP. De plus, la stimulation induite par l’E. coli a entraîné une baisse du nombre de neutrophiles (84 ± 15 % vs 95 ±5%; P < 0,05) et de monocytes (70 ± 22 % vs 83 ± 11 % réactifs; P < 0,05) ainsi qu’une production réduite de peroxyde d’hydrogène dans les deux souches cellulaires comparées aux cellules témoins.ConclusionContrairement au protoxyde d’azote, le xénon préserve la capacité antibactérienne des neutrophiles et des monocytes in vitro.

Xenon does not prolong neuromuscular block of rocuronium.

With the exception of xenon, the interaction between muscle relaxants and inhaled anesthetics is known. We therefore compared the pharmacodynamics of rocuronium during xenon anesthesia versus a total IV anesthesia with propofol. Anesthesia was induced with propofol and remifentanil in both the xenon and propofol groups (each n = 20). The xenon group received xenon via face mask until an end-expiratory concentration of 60% was maintained for 1 min. Meanwhile, the acceleromyograph (TOF-Watch SX®) was calibrated and a frequent train-of-four stimulation of the musculus adductor pollicis was started. After stabilization of the signal for 5 min, a single bolus of 0.6 mg/kg rocuronium was injected. Anesthesia was maintained with xenon and remifentanil (xenon group) or with propofol and remifentanil (propofol group). There were no significant differences between the groups concerning the onset time (xenon group 125 ± 33 and propofol group 144 ± 43 s), duration (xenon group 33.2 ± 10.8 and propofol group 32.6 ± 8.4 min), recovery index (xenon group 9.4 ± 6.6 and propofol group 8.4 ± 5.3 min), and clinical recovery (xenon group 18.0 ± 10.2 and propofol group 17.1 ± 8.5 min). We conclude that the neuromuscular blocking effects of rocuronium are not different when given during propofol versus xenon anesthesia.

The effects of sevoflurane and desflurane in vitro on platelet-leukocyte adhesion in whole blood.

Summary The interaction between platelets and leukocytes plays an important role in inflammatory and thrombotic processes. We investigated whether the volatile anaesthetics sevoflurane and desflurane alter the formation of platelet–leukocyte aggregates and the expression of P‐selectin on platelets. Whole blood was incubated with 1 and 2 minimum alveolar concentration (MAC) sevoflurane or desflurane. Unstimulated and adenosine diphosphate, or thrombin receptor agonist peptide‐6‐stimulated samples were stained with flourochrome‐conjugated antibodies. The formation of platelet–leukocyte conjugates and the expression of P‐selectin on platelets were measured using flow cytometry. Sevoflurane was found to enhance the binding of platelets to lymphocytes, neutrophils and monocytes, it also increased the expression of P‐selectin on platelets especially in the stimulated samples. Desflurane decreased the percentage of lymphocyte–platelet, neutrophil–platelet and monocyte–platelet conjugates principally in unstimulated samples. The results show that these two volatile anaesthetics have differing effects on the formation of platelet–leukocyte conjugates in vitro. Sevoflurane also enhanced the expression of P‐selectin on platelets.

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.

Sevoflurane Inhibits Unstimulated and Agonist-induced Platelet Antigen Expression and Platelet Function in Whole Blood In Vitro

Background Previous studies have reported conflicting results about the effect of sevoflurane on platelet aggregation. To clarify this point, we investigated the effects of sevoflurane on platelet antigen expression and function in vitro. Methods Human whole blood was incubated for 1 h with 0.5 and 1 minimum alveolar concentration sevoflurane, 21% O2, and 5% CO2. A control sample was kept at the same conditions without sevoflurane. After stimulation with adenosine diphosphate or thrombin receptor agonist peptide 6, samples were stained with fluorochrome conjugated antibodies, and the expression of platelet glycoproteins GPIIb/IIIa, GPIb, and P-selectin, as well as activated GPIIb/IIIa, were measured with two-color flow cytometry. In addition, platelet function was assessed by means of thromboelastography and using the platelet function analyzer 100. Results Already in subanesthetic concentrations, sevoflurane inhibits unstimulated and agonist-induced GPIIb/IIIa surface expression and activated GPIIb/IIIa expression on platelets in whole blood. The agonist-induced redistribution of GPIb into the open canalicular system was also impaired by sevoflurane, whereas no effect on P-selectin expression in activated platelets could be found. Sevoflurane significantly reduced the maximum thromboelastographic amplitude. Furthermore, platelet function analyzer 100 closure times were significantly prolonged. Conclusion The results show that sevoflurane significantly impairs platelet antigen expression in vitro. It is especially the inhibition of GPIIb/IIIa expression and activation that impairs bleeding time as reflected in thromboelastographic measurements and platelet function analyzer 100 closure times. The exact inhibitory mechanism remains unclear.