BJA Advance Access published online on March 19, 2007
British Journal of Anaesthesia, doi:10.1093/bja/aem049
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Effects of sevoflurane and propofol on ischaemia–reperfusion injury after thoracic-aortic occlusion in pigs
1 Clinic of Anaesthesiology
2 Institute for Surgical Research
3 Institute for Pathology, Ludwig-Maximilians-University, Munich, Germany
* Corresponding author: Clinic of Anaesthesiology, University Hospital, Nussbaumstr. 20, D-80336 Munich, Germany. E-mail: peter.conzen{at}med.uni-muenchen.de
Accepted for publication January 4, 2007.
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Abstract |
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Background: Thoraco-abdominal-aneurysm surgery predicts high mortality. Propofol and sevoflurane are commonly used anaesthetics for this procedure. Halogenated anaesthetics induce organ protection similar to ischaemic preconditioning. We investigated which anaesthetic regimen would lead to a better protection against ischaemia–reperfusion injury induced by temporary thoracic-aortic occlusion.
Methods: Following initial fentanyl–midazolam anaesthesia for surgical preparation, 18 pigs were randomly assigned to two groups: group one received propofol (n=9) and group two sevoflurane (n=9) before, during, and after lower body ischaemia in an investigator blinded fashion. Ten animals without aortic occlusion served as time controls (propofol, n=5; sevoflurane, n=5). For induction of ischaemia, the thoracic aorta was occluded by a balloon-catheter for 90 min. After 120 min of reperfusion, the study anaesthetics were discontinued and fentanyl–midazolam re-established for an additional 180 min. Goal-directed therapy was performed during reperfusion. Fluid and catecholamine requirements were assessed. Serum samples and intestinal tissue specimens were obtained.
Results: Severe declamping shock occurred in both study groups. While norepinephrine requirements in the sevoflurane group were significantly reduced during reperfusion (P < 0.05), allowing cessation of catecholamine support in 4/9 animals, all 9/9 animals were still catecholamine dependent at the end of the experiment in the propofol group. Serum activities of lactate dehydrogenase, aspartate transaminase, and alanine aminotransferase were lower with sevoflurane (P < 0.05). Small intestine tissue specimens did not differ histologically.
Conclusions: Use of sevoflurane compared with propofol attenuated the haemodynamic sequelae of reperfusion injury in our model. Release of serum markers of cellular injury was also attenuated.
Keywords: anaesthetics i.v., propofol; anaesthetics volatile, sevoflurane; arteries, aortic clamp; surgery, vascular
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Introduction |
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Poor outcome after surgery requiring crossclamping of the thoracic aorta is, beside other well-known risks of major surgery, largely related to a systemic inflammatory response initiated by abdominal and lower body ischaemia–reperfusion. Aside from direct haemodynamic consequences, declamping of the aorta and reperfusion is accompanied by significant pro- and anti-inflammatory cytokine release, neutrophil granulocyte and platelet activation, and oxygen free radical production.1 2
The impact of commonly applied anaesthetics such as sevoflurane and propofol on this type of ischaemia–reperfusion injury has not been investigated. Cardio- protection by volatile anaesthetics is well established to date.3–7 As far as the cellular mechanisms of protection are concerned, volatile anaesthetics have been shown to activate KATP channels8 and to reduce platelet and leucocyte interactions with the vascular endothelium during reperfusion.9–11
However, these processes are not restricted to the heart and, therefore, positive effects on other organs are most likely. In accordance, protection of the kidneys12 against reperfusion injury and reduced release of markers of renal dysfunction13 and hepatic injury14 after coronary artery bypass surgery have been reported. In contrast, beneficial effects of volatile anaesthetics on hepatic ischaemia–reperfusion injury are controversial.15 16 Benefits of i.v. anaesthesia with propofol have been reported, presumably due to attenuation of free radical production.17 18
To assess a potential difference between anaesthetics, we compared i.v. anaesthesia with propofol against inhalation anaesthesia with sevoflurane in a standardized model of severe porcine ischaemia–reperfusion injury. Our aim was to quantify injury severity via catecholamine requirements to achieve stable haemodynamic conditions together with histological assessment, and quantification of liberation of the intracellular enzymes lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine aminotransferase (ALT) as markers of tissue injury. As a previous study6 showed beneficial effects of halogenated anaesthetics compared with total-i.v. anaesthesia on myocardial ischaemia–reperfusion injury, we hypothesized that sevoflurane would lead to a reduction in ischaemia–reperfusion injury compared with propofol.
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Methods |
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Study design
The experiments were conducted on 28 pigs [German landrace, mean body weight 29 (3) kg] with approval of the local governmental authorities (AZ-209.1/211–2531–54/04) and in accordance with the principles of good animal care.19
Surgical preparation and instrumentation
I.M. injections of midazolam (1 mg kg–1; Ratiopharm, Ulm, Germany) and azaperone (12 mg kg–1, Janssen-Cilag, Neuss, Germany) were given for premedication. Anaesthesia was subsequently induced by i.v. injection of fentanyl (15 µg kg–1, Janssen-Cilag, Neuss, Germany), propofol (2 mg kg–1, AstraZeneca, Wedel, Germany), and atracurium bromide (2 mg kg–1, Hexal, Holzkirchen, Germany). Oxygen saturation was monitored. After tracheal intubation, the animals lungs were ventilated at an inspired oxygen fraction of 1.0 (Servo 900C, Siemens, Solna, Sweden). Ventilatory frequency (23–27 min–1) and tidal volume (10–15 ml kg–1) were adjusted to achieve normocapnia (Capnomax Ultima, Datex, Helsinki, Finland). Animals were placed in the supine position on a heating-pad and anaesthesia for surgical preparation was continued by infusion of midazolam (1.5 mg kg–1 h–1) and fentanyl (45 µg kg–1 h–1). No further neuromuscular blocking drugs were used.
A normal saline solution was administered at a rate of 15 ml kg–1 h–1. Catheters were installed via a modified Seldinge
s technique: a multilumen central venous catheter, a pulmonary artery catheter, and a microtip catheter for central venous pressure monitoring. Carotid arteries were cannulated for blood sampling and arterial pressure measurement in the upper body (SPC 350, Millar Instruments, Houston, USA). Correct position of all catheters was verified by fluoroscopy.
A 5 F introducer sheath was placed in the right femoral artery for distal pressure monitoring. For temporary aortic occlusion, a 22 F balloon-tipped catheter (Edwards Lifesciences, Irvine, USA) was inserted through the left femoral artery. The tip of this catheter was advanced above the diaphragm and placed immediately distal to the left subclavian artery under X-ray guidance. A sternotomy was then performed and two transit time flow probes (inner diameters 14 or 16 mm, Medi-Stim AS, Grefsen, Norway) were placed around the ascending aorta and the pulmonary artery, respectively. The portal vein was cannulated through a median laparotomy and a 6 mm ultrasonic flow probe (Medi-Stim AS, Grefsen, Norway) was placed around it.
Interventions
Midazolam was stopped at the end of the preparation period and the animals were randomly allocated to study groups by choosing an envelope.
- propofol pre-, during, and post-ischaemia (n=9; propofol: 10 mg kg–1 h–1; propofol 2%, AstraZeneca, Wedel, Germany);
- sevoflurane pre-, during, and post-ischaemia (n=9; sevoflurane: 2.0 vol.% end-tidal; Abbott, Wiesbaden, Germany).
Fentanyl (45 µg kg–1 h–1) was given throughout the experiments. After the study anaesthetic had been given for 60 min, 2500 IE heparin was administered and the thoracic aorta blocked by inflating the occlusion catheter. Complete occlusion was verified both by angiography and by disappearance of distal arterial pressure and portal flow signals. After 90 min of ischaemia, reperfusion was initiated by deflating the balloon. The study anaesthetic was continued for another 120 min. Propofol or sevoflurane was then stopped and midazolam (1.5 mg kg–1 h–1) was re-established until the end of the experiment.
To assess effects over time, 10 additional pigs were subjected to identical protocols but without aortic occlusion [non-occlusion animals (NOA); propofol–NOA, n=5; sevoflurane–NOA, n=5]. One investigator (T.A.) was blinded regarding the anaesthetic study drug during conduct of the experiments by covering the vaporizer, gas-analyser, infusion pump, and lines, and by numeric codes during the entire duration of the data evaluation process.
Standard goal-directed therapy
To enable stable haemodynamic conditions during the reperfusion period, a standardized protocol for interventions was developed and a goal-directed therapy performed by the blinded investigator. This consisted of 100 ml sodium bicarbonate (8.4%) and 0.1 mg norepinephrine given to every animal immediately before reperfusion. Mean arterial pressure (MAP) was kept above 50 mm Hg by fluid infusion and vasopressors. Repeated boli (50 ml) of a saline solution (NaCl 0.9%; Braun AG, Melsungen, Germany) and pentastarch 6% (Voluven 130/0.4; Fresenius Kabi, Bad Homburg, Germany) were given in a 2:1 ratio to maintain pulmonary capillary wedge pressure (PCWP) above 5 mm Hg. If MAP decreased below 50 mm Hg, volume loading was repeated until no further increase in MAP was achieved. A continuous infusion of norepinephrine was then started. If cardiac output decreased below 80% of baseline in spite of PCWP above 5 mm Hg and a MAP above 50 mm Hg could not be achieved by norepinephrine, an intravenous epinephrine infusion was initiated. Catecholamines were increased to a maximum dose of 6 mg h–1. Base excess was kept between –5 and +5 mmol litre–1 by sodium bicarbonate. Buffer requirements were calculated using standard formulae.
Measurements
Data were collected at the following time points:
- T1: baseline (before aortic occlusion);
- T2: 15 min ischaemia;
- T3: 75 min ischaemia;
- T4: 5 min reperfusion;
- T5: 60 min reperfusion;
- T6: 120 min reperfusion;
- T7: 180 min reperfusion;
- T8: 240 min reperfusion;
- T9: 300 min reperfusion.
- T2: 15 min ischaemia;
In NOA-groups, measurements were made after equivalent periods of time had evolved.
Haemodynamics and ventilation
Aortic and central venous pressures were recorded online at 250 Hz (DasyLab; Measx, Mönchengladbach, Germany) from catheter tip manometers. Pulmonary and femoral artery pressures were measured via standard pressure transducers. Pulmonary, portal venous, and aortic flows were continuously recorded using precalibrated ultrasonic flow probes (CardioMed medical volume flowmeter, CM 1008, Medi-Stim AS, Oslo, Norway). End-expiratory carbon dioxide and sevoflurane concentrations, ventilatory frequency, and tidial volume were monitored (Capnomax Ultima; Datex, Helsinki, Finland) on a breath-by-breath basis. Infused fluid volume and catecholamine requirements were noted.
Blood samples
Arterial, central venous, mixed venous, and portal venous blood samples were withdrawn simultaneously and analysed in a blood gas analyser (BGA 860, Chiron Diagnostics, Fernwald, Germany) and a cell counter (Coulter Counter T 540, Coulter, Krefeld, Germany). At each data collection time point, approximately 20 ml blood were withdrawn. Total protein, LDH, ALT, and AST activities were measured using standard tests in the hospital central laboratory. To adjust for dilutional changes, enzyme activities were normalized to total protein content of the respective samples.
Wet to dry ratio and histological examination
Transmural small intestine tissue specimens were taken at T1, T3, T6, and T9 from isolated jejunal loops. To evaluate the wet-to-dry weight ratio (w/d-ratio), tissue samples were weighed immediately after biopsy and then after being dried at 60°C for 21 days. For histological examination, tissue was fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with eosin and haematoxylin. The sections were blinded with a numeric code and analysed by a pathologist (I.B.). Injury was graded using a scale published by Chiu and colleagues20 (Grade 0: normal mucosal villi; Grade 1: subepithelial Gruenhage
s space often with capillary congestion; Grade 2: extension of the subepithelial space with moderate lifting of the epithelial layer from the lamina propria; Grade 3: massive epithelial lifting down the sides of villi, few tips denuded; Grade 4: denuded villi with lamina propria and dilated capillaries exposed, increased cellularity of lamina propria may be noted; Grade 5: digestion and disintegration of lamina propria, haemorrhage, and ulceration). Additional slices were stained with chloracetate esterase for staining granulocytes. The average number of granulocytes found in 15 visual fields was determined and compared with the baseline cell count.
Statistics
Kolmogorov–Smirnov test was used to verify normal distribution. Data sets were compared using two-way analysis of variance (ANOVA) for repeated measures. This was followed by Student–Newman–Keuls test, if a difference between groups had been detected. Changes over time in non-normally distributed data sets were tested by Friedman repeated-measures ANOVA on ranks. P < 0.05 was considered statistically significant (SigmaStat, Systat Software, Richmond, USA).
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Results |
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Animals in both intervention groups did not differ in terms of sex (M/F: 4/5) and body weight [propofol, 29 (2) kg; sevoflurane, 28(3) kg]. At baseline (T1), comparable standard values of haemodynamic variables were obtained (Table 1). MAP was slightly lower in the sevoflurane group (*P < 0.05).
Aortic occlusion
Occlusion of the thoracic aorta led to comparable tachycardia in both groups whereas MAP and SVRI increased to a greater degree in the sevoflurane group (*P < 0.05; Table 1). Left ventricular stroke work during clamping period was initially higher with sevoflurane (*P < 0.05). Cardiac index did not differ between groups throughout the occlusion period (Table 1).
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Ischaemia led to a marked reduction in whole body oxygen consumption. This was accompanied by excessive lactate production (Fig. 1). In both groups, the small intestine histology damage score had deteriorated towards the end of ischaemia (Table 2). Intestinal granulocyte sequestration was also noted at that time point (Table 2). Small intestine tissue w/d weight-ratios remained unchanged during the occlusion period as did serum activities of LDH, AST, and ALT (Fig. 2).
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P < 0.05 T1 vs T9Reperfusion and goal-directed therapy
Reperfusion resulted in significant reductions of MAP and SVRI (T3 vs T4, Table 1). Multiple interventions were required in all animals according to the goal-directed therapy protocol. Because of effective therapy, there were no differences among groups in MAP, PCWP, CI, and SVRI within the remaining experimental period (Table 1). Despite comparable systemic haemodynamic parameters (MAP, PCWP, and CI), heart rate decreased towards normal beginning with T6 in the sevoflurane group (*P < 0.05; Table 1). This was associated with a higher stroke volume.
Oxygen consumption was almost equal in both groups in the reperfusion period (Fig. 1). Neither total O2-ER nor mesenteric O2-ER differed significantly between the groups until T9, when whole body oxygen extraction was slightly higher after sevoflurane (*P < 0.05, Table 1).
Fluid and buffer requirements did not differ between groups (Table 3). Norepinephrine infusion rate was turned down significantly over time, but only in the sevoflurane group (T4–T9: sevoflurane, Friedman-test #P < 0.05; Table 3). Thus, 4/9 pigs in the sevoflurane group were no longer dependent on vasopressor therapy at the end of the experiment, whereas 9/9 animals in the propofol group still needed support. Supplemental epinephrine was necessary in four and three animals, respectively (propofol/sevoflurane; Table 3). Two animals after sevoflurane and three animals after propofol required norepinephrine at the maximum cut-off dose at the end of the experiment.
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Haemoglobin concentration decreased over time with no significant difference between groups (Table 4). A decrease in leucocyte count developed in both groups after reperfusion. During the first hour of reperfusion, white blood cell count was significantly lower with propofol (*P < 0.05; Table 4).
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Serum LDH, AST, and ALT activities increased after reperfusion. This was significantly greater after propofol than sevoflurane (*P < 0.05; Fig. 2). Lactate concentrations tended to normalize towards the end of the experiment, but only after sevoflurane (T4–T9: P < 0.05; Fig. 1).
Up to 2 h following reperfusion, the intestinal w/d-ratio remained essentially unchanged with sevoflurane, whereas it had increased significantly in animals tested with propofol (Table 2). At the end of the experiment, w/d-ratio had also increased after sevoflurane. Histology score and granulocyte infiltration did not differ significantly between groups, despite a tendency to lower granulocyte counts at the end of the experiment in the sevoflurane group (Table 2).
Non-occlusion animals
Baseline MAP in sevoflurane-NOA was lower than in propofol-NOA. All animals had stable MAP without necessity for vasopressor support during the experimental period. Base excess and lactate levels remained in the normal range. Serum activity of intracellular enzymes increased only moderately in both groups during the observation period (Table 5).
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Discussion |
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All animals displayed a severe reperfusion injury following 90 min occlusion of the thoracic aorta. However, animals receiving sevoflurane showed less signs of reperfusion injury as assessed by systemic haemodynamic instability than animals receiving propofol for the same intervention. Animals tested with sevoflurane had a less pronounced increase of serum enzyme activities indicative of tissue injury.
Aortic occlusion
Increases in mean arterial pressure and systemic vascular resistance are frequent cardiovascular responses to aortic crossclamping. Heart rate, cardiac filling pressures, and output may or may not increase.2 Gelman and colleagues21 reported that blood flow to organs distal of an aortic occlusion was dependent on proximal arterial pressure in dogs. The more pronounced increase in central arterial pressure in our sevoflurane-anaesthetized animals thereby might have been of advantage due to better maintained collateral flow and improved tissue oxygen supply. However, in this porcine animal model, distal arterial pressure and portal-flow equally decreased to zero immediately after aortic occlusion in both groups. This is indicative of almost complete absence of collateral flow. In addition, comparable increases in lactate concentrations after deflation of the aortic balloon suggest comparable degrees of ischaemic injury with both anaesthetics.
Differences may also be related to differential effects by the anaesthetics on oxygen consumption during the clamping period. However, oxygen extraction and consumption decreased comparably in our model.
Whilst histological measures used in the study did not prove better organ preservation with sevoflurane, this would not necessarily exclude an advantage. As inferred from the high catecholamine dependency, we applied a severe model of complete ischaemia, and the high extent of mucosal destruction seen at the end of aortic occlusion may have rendered a more subtle differentiation of intestinal tissue trauma impossible.
Reperfusion
Deflation of the aortic balloon and reperfusion of previously ischaemic tissue resulted in the well-described decrease in MAP and in tachycardia described as ‘declamping shock’.
In this animal model, we kept systemic haemodynamic variables stable according to a goal-directed therapy protocol. Excessive fluid administration was necessary in both groups. However, at comparable ventricular filling pressures, sevoflurane-treated animals appeared to be less vasoplegic. This is inferred from both a tendency to lower norepinephrine infusion rates immediately after reperfusion and a significant reduction of norepinephrine requirement over time. Also, animals in the sevoflurane group were not as dependent on a high heart rate to maintain their cardiac output, suggesting better maintained ventricular function. These advantages outlasted the duration of study of anaesthetic application.
It has been shown that high doses of propofol (30 mg kg–1 h–1) impair tissue oxygen extraction and this might also have influenced the results reported here.22 However, a much lower infusion rate was chosen in this investigation (10 mg kg–1 h–1) without any difference in oxygen extraction during application of propofol or sevoflurane. Lactate concentrations in both groups reached a maximum within the first 2 h of reperfusion. After that time, concentrations remained stable in the propofol group, whereas they started to decline in sevoflurane-treated animals. Stable lactate levels in the propofol group are considered either to be due to persisting anaerobic metabolism or reduced hepatic clearance.
Serum LDH, AST, and ALT also increased after reperfusion but to a greater extent with propofol compared with sevoflurane. LDH is found in the cytoplasm of various cell types and can be considered a non-specific indicator of tissue injury.23 AST and ALT are markers of liver injury, and have been correlated with histological liver damage.15 In addition, AST is an intestinal seromucosal enzyme and is released during intestinal ischaemia–reperfusion injury.2425 Liberation of intracellular enzymes and their detection in samples from circulating blood is an accepted method to detect tissue injury.6 15 25
In contrast to propofol administration, the intestinal w/d weight-ratio as a marker of oedema formation remained stable during the administration of sevoflurane. After 5 h of reperfusion and when anaesthesia had been switched to midazolam, the weight-ratio also increased in this (sevoflurane) group. Bruegger and colleagues26 recently reported less fluid extravasation in patients undergoing breast surgery when sevoflurane compared with propofol was given for anaesthesia. It is possible that sevoflurane is superior to propofol in maintaining competence of the vascular endothelium as a barrier to fluid extravasation at least in pathological states.
In terms of differential histological signs of intestinal tissue damage, scores with both anaesthetics had already reached a maximum at the end of the ischaemic period. This may be due to insufficient sensitivity of histology to discriminate severe degrees of injury. However, the relevance of reperfusion to aggravate injury of the intestine has been questioned in general.27–29 This has been explained by low xanthine oxidase concentrations, reducing production of oxygen radicals via this pathway.29 Also, experimental evidence suggests that early tissue regeneration after intestinal ischaemia may outweigh the negative effects of reperfusion.28
Blood leucocyte counts decreased less at the end of ischaemia and the beginning of reperfusion in sevoflurane-anaesthetized animals. In both groups, decreases in cell counts were associated with marked accumulation of granulocytes in intestinal tissue specimens (Table 2; Fig. 3). Despite a tendency towards lower tissue cell counts with sevoflurane at T9, this difference did not reach statistical significance. Reduced expression of adhesion molecules and decreased release of mediators contribute to the beneficial effects seen with the halogenated anaesthetics.9–11 Thus, reduction by volatile anaesthetics of granulocyte and endothelium interactions can be considered a potential explanation for reduced reperfusion injury.
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In summary, therefore, several findings from this study show a sevoflurane-related impact in protection of previously ischaemic tissue. These are reduced catecholamine support, less pronounced leucopenia, decrease of lactate concentration, and reduced release of enzymes, which are considered to be markers of cellular injury.
Study design and animal model
In this investigation, we focused on the systemic haemodynamic consequences of thoracic-aortic occlusion and on some markers of tissue integrity. To our knowledge, this is the first investigation including the intestine as a potential target of anaesthetic protection against reperfusion injury. Pigs were chosen as experimental animals because their low intestinal xanthine oxidase concentration is similar to that in man.27 29
Animals were randomized after all surgical preparation and instrumentation had been completed. To reduce potential investigator bias as far as possible, therapy was guided by one of the authors blinded for the anaesthetic used.
Nielsen and colleagues used aortic occlusion in rabbits to investigate the effects of halothane on hepatic ischaemia–reperfusion injury. After 40 min aortic occlusion and 2 h of reperfusion, hepato-cellular enzyme activities and lactate concentrations were increased. These results were attenuated by xanthine oxidase inactivation.15 In their study i.v. anaesthesia with fentanyl and droperidol affected hepatic enzymes and lactate less than halothane. This may appear to contrast with our results where inhalational anaesthesia was found to be superior to an i.v. agent. However, use of droperidol instead of propofol or better maintained hepatic perfusion with sevoflurane vs halothane may explain these differences.30 Recently, Lorsomradee and colleagues14 demonstrated less hepatic injury in patients receiving sevoflurane compared with propofol after coronary surgery.
Several potential limitations exist in this study
First, to mimic the clinical situation of major aortic surgery, we used a highly invasive model requiring sternotomy, median laparotomy, and preparation of several large blood vessels which could have modified our results. As inferred from the NOA-groups, both anaesthetic regimens and surgery were well tolerated. There was no development of haemodynamic instability or lactic acidosis over time, no animal required catecholamine support.
Second, this investigation covers only the first 5 h of reperfusion. Late injury, for example, as a result of apoptosis may occur. Further investigations are necessary to evaluate long-term effects.
Third, both anaesthetic agents were used as part of a multidrug regime. Sevoflurane and propofol were initiated 60 min before onset of ischaemia and continued for 120 min of reperfusion. This protocol was chosen to mimic the clinical situation in which the primary anaesthetic is not changed during the procedure but stopped when the patient is transferred to the ICU. Among the substances used, fentanyl has been shown to afford protection of isolated cells due to activation of mitochondrial KATP channels, whereas midazolam had no effect.31 Even if there were additional influences of other drugs applied for balanced anaesthesia, this would not decrease the significance of the differences observed. All substances were applied in comparable dosages in all animals.
Fourth, lower body ischaemia affects multiple organs and tissues. Although metabolically active organs such as liver or kidneys may be more susceptible to ischaemic insult, others such as skeletal muscle may remain virtually unaffected. Such discrepancies can also be considered to reflect the clinical situation of aortic surgery. As stated earlier, this study was not designed to investigate the consequences of ischaemia and reperfusion on individual organs, but rather on the whole organism as assessed by effects on its systemic circulation.
Fifth, in animals and in clinical practice protective effects of inhaled anaesthetics may be dose-dependent. We used a concentration of sevoflurane, representing approximately 1 MAC in humans. Recent clinical and laboratory investigation reported beneficial effects of this concentration.6 9 Further studies will therefore be needed to evaluate the question of dose-dependency and look for a potential threshold for protection.
Sixth, we can only speculate about the underlying mechanisms of protection observed in sevoflurane anaesthetized animals. In addition to cardiac protection by continuous intraoperative application, both pre- and postconditioning have been described.32 To investigate such processes at the cellular level in a more detailed fashion was beyond the scope of this study. Hence, we could only speculate about potential intra- or extracellular pathways. Nevertheless, it appears sensible to assume that at least some of the mechanisms responsible for cardiac protection—protein kinase C, KATP channels,4 8 leucocyte endothelium interactions9–11—may be active in organs and tissues supplied by the descending aorta, as well.
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Conclusion |
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Sevoflurane showed potential to be superior to propofol in this porcine animal model of severe acute ischaemia induced by occlusion of the thoracic aorta. Reduced reperfusion injury was shown by better maintained haemodynamic stability and by lower release of serum markers of tissue injury, exceeding the application of the study drugs. The underlying mechanisms and the clinical implications of these beneficial effects remain subject to further investigation.
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Acknowledgements |
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The work was supported by a grant from the Friedrich-Baur-Foundation (Reg.-Nr. 0053/2003) and a Research Grant (Förderung von Forschung und Lehre, Reg.-Nr. 388/2004) supplied by Ludwig-Maximilians-University, Munich, Germany (to T.A.). The authors gratefully acknowledge the support of the following persons: Mrs Sylvia Münzing for outstanding technical assistance, Dr Jürgen Peters for statistical review of the data, Mrs Brigitte Blount and team for animal care, Mrs Alke Schropp for preparation of histological cross-sections (all: Institute for Surgical Research, Ludwig-Maximilians-University, Munich, Germany), and Dr Peter Göhring (Institute for Clinical Chemistry, Ludwig-Maximilians-University, Munich, Germany) for serum analyses. The work should be attributed to Clinic of Anaesthesiology, Ludwig-Maximilians-University, Munich, Germany.
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References |
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1 Welborn MB, Oldenburg HS, Hess PJ, et al. (2000) The relationship between visceral ischaemia, proinflammatory cytokines, and organ injury in patients undergoing thoracoabdominal aortic aneurysm repair. Crit Care Med 28:3191–7.[CrossRef][Web of Science][Medline]
2 Gelman S. (1995) The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82:1026–60.[CrossRef][Web of Science][Medline]
3 Cason BA, Gamperl AK, Slocum RE, Hickey RF. (1997) Anesthetic-induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology 87:1182–90.[CrossRef][Web of Science][Medline]
4 Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC. (2003) Anaesthetics and cardiac preconditioning. Part I: signalling and cytoprotective mechanisms. Br J Anaesth 91:551–65.
5 Zaugg M, Lucchinetti E, Garcia C, Pasch T, Spahn DR, Schaub MC. (2003) Anaesthetics and cardiac preconditioning. Part II: clinical implications. Br J Anaesth 91:566–76.
6 Conzen PF, Fischer S, Detter C, Peter K. (2003) Sevoflurane provides greater protection of the myocardium than propofol in patients undergoing off-pump coronary artery bypass surgery. Anesthesiology 99:826–33.[CrossRef][Web of Science][Medline]
7 Garcia C, Julier K, Bestmann L, et al. (2005) Preconditioning with sevoflurane decreases PECAM-1 expression and improves one-year cardiovascular outcome in coronary artery bypass graft surgery. Br J Anaesth 94:159–65.
8 Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, Warltier DC. (1996) Mechanism of myocardial protection by isoflurane: role of adenosine triphosphate-regulated potassium (KATP) channels. Anesthesiology 85:794–807.[CrossRef][Web of Science][Medline]
9 Kowalski C, Zahler S, Becker B, et al. (1997) Halothane, isoflurane, and sevoflurane reduce postischemic adhesion of neutrophils in the coronary system. Anesthesiology 86:188–95.[Web of Science][Medline]
10 Heindl B, Reichle FM, Zahler S, Conzen PF, Becker BF. (1999) Sevoflurane and isoflurane protect the reperfused guinea pig heart by reducing postischemic adhesion of polymorphonuclear neutrophils. Anesthesiology 91:521–30.[CrossRef][Web of Science][Medline]
11 Mobert J, Zahler S, Becker BF, Conzen PF. (1999) Inhibition of neutrophil activation by volatile anesthetics decrease adhesion to cultured human endothelial cells. Anesthesiology 90:1372–81.[CrossRef][Web of Science][Medline]
12 Lee HT, Ota-Setlik A, Fu Y, Nasr SH, Emala CW. (2004) Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo. Anesthesiology 101:1313–24.[Web of Science][Medline]
13 Julier K, da Silva R, Garcia C, et al. (2003) Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology 98:1315–27.[CrossRef][Web of Science][Medline]
14 Lorsomradee S, Cromheecke S, Lorsomradee S, De Hert SG. (2006) Effekts of sevoflurane on biochemical markers of hepatic and renal dysfunction after coronary artery surgery. J Cardiothor Vasc Anesth 20:684–90.[CrossRef][Web of Science][Medline]
15 Nielsen VG, Tan S, Kirk KA, et al. (1997) Halothane and xanthine oxidase increase hepatocellular enzyme release and circulating lactate after ischemia-reperfusion in rabbits. Anesthesiology 87:908–17.[CrossRef][Web of Science][Medline]
16 Imai M, Kon S, Inaba H. (1996) Effects of halothane, isoflurane and sevoflurane on ischemia reperfusion injury in the perfused liver of fasted rats. Acta Anaesthesiol Scand 40:1242–48.[Web of Science][Medline]
17 Murphy PG, Myers DS, Davies MJ, Webster NR, Jones JG. (1992) The antioxidant potential of propofol (2,6-diisoopropylphenol). Br J Anaesth 68:613–18.
18 Aldemir O, Celebi H, Cevik C, Duzgun E. (2001) The effects of propofol or halothane on free radical production after tourniquet induced ischaemia-reperfusion injury during knee arthroplasty. Acta Anaesthesiol Scand 45:1221–5.[CrossRef][Web of Science][Medline]
19 Institutes of Laboratory Animal Resources, Commission of Life Sciences, National Research Council. (1996) Guide for the Use and Care of Laboratory Animals(National Academy Press, Washington, DC) pp. 8–125.
20 Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. (1970) Intestinal mucosal lesion in low-flow states. Arch Surg 101:478–83.
21 Gelman S, Reves JG, Fowler K, Samuelson PN, Lell WA, Smith LR. (1983) Regional blood flow during cross-clamping of the thoracic aorta and infusion of sodium nitroprusside. J Thorac Cardiovasc Surg 85:287–91.[Abstract]
22 Van der Linden P, Schmartz D, Gilbart E, Engelman E, Vincent JL. (2000) Effects of propofol, etomidate, and pentobarbital on critical oxygen delivery. Crit Care Med 28:2492–99.[CrossRef][Web of Science][Medline]
23 Abrahâo MS, Montero EFS, Junqueira VBC, Giavarotti L, Juliano Y, Fagundes DJ. (2004) Biochemical and morphological evaluation of ischemia-reperfusion injury in rat small bowel modulated by ischemic preconditioning. Transplant Proc 36:860–2.[CrossRef][Web of Science][Medline]
24 Sachs SM, Morton JH, Schwartz SI. (1982) Acute mesenteric ischemia. Surgery 92:646–53.[Web of Science][Medline]
25 Caglayan F, Caglayan O, Gunel E, Elcuman Y, Cakmak M. (2002) Intestinal ischemia-reperfusion and plasma enzyme levels. Pediatr Surg Int 18:255–7.[CrossRef][Web of Science][Medline]
26 Bruegger D, Bauer A, Finsterer U, Bernasconi P, Kreimeier U, Christ F. (2002) Microvascular changes during anesthesia: sevoflurane compared with propofol. Acta Anaesthesiol Scand 46:481–7.[CrossRef][Web of Science][Medline]
27 Blikslager AT, Roberts MC, Rhoads JM, Argenzio RA. (1997) Is reperfusion injury an important cause of mucosal damage after porcine intestinal ischemia? Surgery 121:526–34.[CrossRef][Web of Science][Medline]
28 Juel IS, Solligård E, Lyng O, et al. (2004) Intestinal injury after thoracic aortic cross-clamping in the pig. J Surg Res 117:283–95.[CrossRef][Web of Science][Medline]
29 Morales J, Kibsey P, Thomas PD, Poznansky MJ, Hamilton SM. (1992) The effects of ischemia and ischemia-reperfusion on bacterial translocation, lipid peroxidation, and gut histology: studies on hemorrhagic shock in pigs. J Trauma 33:221–6.[Web of Science][Medline]
30 Frink EJ, Morgan SE, Coetzee A, Conzen PF, Brown BR. (1992) The effects of sevoflurane, halothane, enflurane and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76:85–90.[CrossRef][Web of Science][Medline]
31 Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Garcia C, Schaub MC. (2002) Differential effects of anesthetics on mitochondrial KATP channel activity and cardiomyocyte protection. Anesthesiology 97:15–23.[CrossRef][Web of Science][Medline]
32 De Hert SG, Van der Linden PJ, Cromheecke S, et al. (2004) Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 101:299–310.[CrossRef][Web of Science][Medline]
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