Xenon protects left ventricular diastolic function during acute ischemia, less than ischemic preconditioning.

Anesthetics modify regional left ventricular (LV) dysfunction following ischemia/reperfusion but their effects on global function in this setting are less clear. Aim of this study was to test the hypothesis that xenon would limit global LV dysfunction as caused by acute anterior wall ischemia, comparable to ischemic preconditioning. In an open-chest model under thiopental anesthesia, 30 pigs underwent 60-minute left anterior descending coronary artery occlusion, followed by 120 minutes of reperfusion. A xenon group (constant inhalation from previous to ischemia through end of reperfusion) was compared to control and ischemic preconditioning. Load-independent measures of diastolic function (end-diastolic pressure-volume relation, time constant of relaxation) and systolic function (end-systolic pressure-volume relation, preload-recruitable stroke work) were determined. Heart rate, arterial pressure, cardiac output, and arterial elastance were recorded. Data were compared in 26 pigs. Ischemia impaired global diastolic but not systolic function in control, which recovered during reperfusion. Xenon limited and preconditioning abolished diastolic dysfunction during ischemia. Arterial pressure decreased during reperfusion while arterial elastance increased. Tachycardia and antero-septal wall edema during reperfusion were observed in all groups. In spite of ischemia of 40% of LV mass, global systolic function was preserved. Deterioration in global diastolic function was limited by xenon and prevented by preconditioning.

Myocardial blood flow during general anesthesia with xenon in humans: a positron emission tomography study.

BACKGROUND: Xenon has only minimal hemodynamic side effects and induces pharmacologic preconditioning. Thus, the use of xenon could be an interesting option in patients at risk for perioperative myocardial ischemia. However, little is known about the effects of xenon anesthesia on myocardial blood flow (MBF) and coronary vascular resistance in humans. METHODS: Myocardial blood flow was noninvasively quantified by H2¹5O positron emission tomography in six healthy volunteers (age: 38 ± 8 yr). MBF was measured at baseline and during general anesthesia induced with propofol and maintained with xenon, 59 ± 0%. Absolute quantification of MBF was started after the calculated plasma concentration of propofol had decreased to less than 1.5 µg · ml⁻¹. RESULTS: Compared with baseline (MBFbaseline, 1.03 ± 0.09 ml · min⁻¹ · g⁻¹; mean ± SD), MBF was decreased insignificantly by xenon (MBFxenon, 0.80 ± 0.22 ml · min⁻¹ · g⁻¹; -21%, P = 0.11). Xenon decreased the rate-pressure product (RPP; heart rate × systolic arterial pressure), an indicator of cardiac work and myocardial oxygen consumption (-15%, P < 0.04). When correcting for the RPP, the decrease in MBF observed during xenon anesthesia was reduced to -9% (MBFcorr-xenon, 1.42 ± 0.28 ml · g⁻¹ · mmHg⁻¹ vs. MBFcorr-baseline, 1.60 ± 0.28 ml · g⁻¹ · mmHg⁻¹, P = 0.32). Xenon did not affect the dependency of MBF on the RPP. Coronary vascular resistance did not significantly change (+15 ± 23%, P = 0.18) during xenon anesthesia. CONCLUSIONS: In healthy subjects, xenon has only minimal effects on coronary flow dynamics. These effects are probably of indirect nature, reflecting the decrease in myocardial oxygen consumption induced by the effects of xenon anesthesia on cardiac work.

Continuous right ventricular volumetry by fast-response thermodilution during right ventricular ischemia: head-to-head comparison with conductance catheter measurements.

OBJECTIVE: To evaluate the accuracy of right ventricular ejection fraction and right ventricular end-diastolic volume obtained by volumetric pulmonary artery catheter, using the conductance catheter as reference method. DESIGN: Prospective, comparative study. SETTING: Research laboratory of a university hospital. SUBJECTS: Seven young female German landrace pigs. INTERVENTIONS: Ligation of the distal right coronary artery to induce temporary acute ischemia. MEASUREMENTS AND MAIN RESULTS: Right ventricular ejection fraction and right ventricular end-diastolic volume were measured simultaneously with a volumetric pulmonary artery catheter and the conductance catheter technique (reference method), in an animal model of acute right ventricular ischemia. Measurements were performed at baseline, during ischemia, and during reperfusion. The methods were compared with Bland-Altman analyses and their diagnostic accuracy to detect ischemia was quantified by receiver operating characteristic curve analysis. For right ventricular ejection fraction measurements, Bland-Altman analysis indicated a bias of -9.9% indicating underestimation by pulmonary artery catheter with limits of agreement ranging from -26% to 6.1%. The data showed a trend for more underestimation at higher right ventricular ejection fraction values. For right ventricular end-diastolic volume, a bias of 31 mL, indicating overestimation by pulmonary artery catheter was found. Limits of agreement ranged from -25 mL to 88 mL. Ischemia induced a decrease in right ventricular ejection fraction and an increase in right ventricular end-diastolic volume, as expected, which was detected by conductance catheter with a significant higher diagnostic accuracy indicated by a receiver operating characteristic area under the curve of 0.98 (p < .001) and 0.92 (p < .001), respectively. Corresponding sensitivity and specificity were 100% and 86%, respectively, for right ventricular ejection fraction conductance catheter (cutoff value = <40%), and 86% and 100% for right ventricular end-diastolic volume conductance catheter (cutoff value = >94 mL). However, diagnostic accuracy for right ventricular ejection fraction pulmonary artery catheter and end-diastolic volume pulmonary artery catheter to detect ischemia was limited with area under the curve 0.76 (p = .06) and 0.57 (p = .65), respectively. CONCLUSIONS: Accuracy of volumetric pulmonary artery catheter in conditions of right ventricular ischemia is low and inadequate for diagnosis of right ventricular ischemia and failure.

Comparison of 3 methods to induce acute pulmonary hypertension in pigs.

Large animal models for acute pulmonary hypertension (PHT) show distinct differences between species and underlying mechanisms. Two embolic procedures and continuous infusion of a stable thromboxane A(2) analogue (U46619) were explored for their ability to induce PHT and their effects on right ventricular function and pulmonary and systemic circulation in 9 pigs. Injection of small (100 to 200 microm) or large (355 to 425 microm) polystyrene beads and incremental dosage (0.2 to 0.8 microg kg(-1) min(-1)) of U46619 all induced PHT. However, infusion of U46619 resulted in stable PHT, whereas that after bead injection demonstrated a gradual continuous decline in pressure. This instability was most pronounced with small beads, due to right ventricular failure and consecutive circulatory collapse. Furthermore, cardiac output decreased during U46619 infusion but increased after embolization with no relevant differences in systemic pressure. This result was likely due to the more pronounced effect of U46619 on pulmonary resistance and impedance in combination with limited effects on pulmonary gas exchange. Coronary autoregulation and adaption of contractility to afterload increase was not impaired by U46619. All parameters returned to baseline values after infusion was discontinued. Continuous infusion of a thromboxane A2 analogue is an excellent method for induction of stable, acute PHT in large animal hemodynamic studies.

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.

Positron emission tomography study of regional cerebral metabolism during general anesthesia with xenon in humans.

BACKGROUND: The precise mechanism by which the gaseous anesthetic xenon exerts its effects in the human brain remains unknown. Xenon has only negligible effects on inhibitory gamma-aminobutyric acid receptors, one of the putative molecular targets for most general anesthetics. Instead, xenon has been suggested to induce anesthesia by inhibiting excitatory glutamatergic signaling. Therefore, the authors hypothesized that xenon, similar to ketamine and nitrous oxide, increases global and regional cerebral metabolism in humans. METHODS: The regional cerebral metabolic rate of glucose (rcMRGlu) was sequentially assessed in two groups of six volunteers each, using F-fluorodeoxyglucose as tracer. In the xenon group, rcMRGlu was determined at baseline and during general anesthesia induced with propofol and maintained with 1 minimum alveolar concentration xenon. In the control group, rcMRGlu was measured using the identical study protocol but without administration of xenon. rcMRGlu was assessed after the plasma concentration of propofol had decreased to subanesthetic levels (< 1.0 microg/ml). rcMRGlu was quantified in 10 cerebral volumes of interest. In addition, voxel-wise changes in rcMRGlu were analyzed using statistical parametric mapping. RESULTS: Xenon reduced whole-brain metabolic rate of glucose by 26 +/- 7% (from 43 +/- 5 micromol x 100 g x min to 31 +/- 3 micromol x 100 g x min; P < 0.005) and significantly decreased rcMRGlu in all volumes of interest compared with the control group receiving propofol only. Voxel-based analysis revealed metabolic depression within the orbitofrontal, frontomesial, temporomesial, occipital, dorsolateral frontal, and lateral temporal cortices and thalami. No increases in rcMRGlu were detected during xenon anesthesia. CONCLUSIONS: Xenon induces metabolic depression in the human brain, suggesting that the inhibition of the glutamatergic system is likely to be of minor significance for the anesthetic action of xenon in vivo.

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.