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* From the Departments of Anesthesiology, and
Surgery, University Hospital of Salamanca, Salamanca; and the
Department of Anesthesiology, Rodríguez-Chamorro Hospital, Zamora, Spain.
Address correspondence to: Dr. José María Rodríguez-López, Servicio de Anestesiología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain. Phone: 0034-923291353; E-mail: jmrodlop{at}terra.es
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Abstract |
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Methods: Twenty young male piglets were anesthetized with either propofol 4 mg·kg–1·hr–1 (n = 10) or sevoflurane 1.5% end-tidal concentration (n = 10). Animals were subjected to aorta-aortic bypass with suprarenal aortic clamping for 30 min. At specific intervals (basal -before the start of surgery; reperfusion 15 min after unclamping the aorta; at 24, 48 and 72 hr after surgery, and on the seventh day after surgery) the levels of the following were determined: plasma creatinine, renal myeloperoxidase, tumour necrosis factor-
, interleukin 1-ß, and interferon-
; kidney superoxide anion and its detoxifying enzyme superoxidase dismutase, kidney malondialdehyde and the activity of inducible nitric oxide synthase. Seven days after surgery, the animals were anesthetized using the described techniques, and after blood withdrawal and kidney sampling they were sacrificed.
Results: In comparison with sevoflurane, propofol was associated with a lower concentration of plasma creatinine (P < 0.05) together with lower concentrations of myeloperoxidase, tumour necrosis factor-, interleukin 1-ß, interferon-, superoxide anion and superoxidase dismutase, malondialdehyde and inducible nitric oxide synthase (P < 0.05).
Conclusion: In an experimental model of aortic reconstructive surgery, and compared with sevoflurane, propofol anesthesia is associated with less neutrophil infiltration, lower plasma proinflammatory cytokine levels, lower production of oxygen free radicals, less lipid peroxidation, and reduced inducible nitric oxide synthase activity. These observations suggest a possible renal protective effect of propofol in this surgical setting.
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Introduction |
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In keeping with the above, the aims of the present study were to develop an experimental model comparable to human clinical practice – abdominal aortic surgery with renal IR, which causes important but reversible renal ischemia - with a view to assessing the effect of anesthetic technique on renal injury through a comparison of different mediators of the SIR. Specifically, we sought to compare the potential renal protective effects of propofol vs sevoflurane at clinically relevant anesthetic concentrations.
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Methods |
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Based upon the type of maintenance hypnotic agent used, the animals were divided into two groups: in ten animals, hypnosis was maintained with propofol (Group P); the other ten animals received sevoflurane (Group S). The study was blinded by ensuring the investigators did not know to which group the analyzed samples belonged. Anesthesia proceeded as follows: all animals were premedicated with ketamine 20 mg·kg–1 im, diazepam 0.5 mg·kg–1 im and atropine 0.05 mg·kg–1 im. Following premedication, a dorsal ear vein was cannulated with a 20-G iv catheter, through which iv anesthetic drugs were administered. Both induction and maintenance of anesthesia proceeded under conditions identical to those employed in humans. For induction, animals in Group P received propofol 1.5 mg·kg–1 iv, and animals in Group S received thiopental sodium 3 mg·kg–1 iv. These drugs were titrated gradually until hypnosis had been achieved in each animal, without causing apnea. The animals were placed on a table under restraint, while monitoring their electrocardiograms and heart rates. The trachea of each animal was intubated under direct laryngoscopy with the aid of Magill forceps, using a #5 endotracheal tube. The animals were then connected to a ventilator (Boyle 2000 anesthesia station, Datex-Ohmeda, Essex, UK) with the following parameters: tidal volume, 10 mL·kg–1; respiratory rate, 15 min; inspiration/expiration rate 1:2, and an oxygen/air mixture of 50%. Mivacurium chloride 0.2 mg·kg–1 iv was administered for muscle relaxation, and all pigs received cefazolin 1 g iv. Maintenance of anesthesia was provided by propofol 4 mg·kg–1·hr–1 iv in Group P or by sevoflurane 1.5% inspired in Group S. Animals in both groups received fentanyl 2 µg·kg–1·hr–1 iv and mivacurium chloride 1 mg·kg–1·hr–1 iv.
Following sterile cervical dissection, the internal jugular vein was cannulated with a double-lumen polyethylene catheter through which fluids (normal saline at 10 mL·kg–1·hr–1) were administered, together with anesthetic medications. The carotid artery was cannulated with a 20-G arterial catheter to monitor invasive arterial pressure and to obtain blood samples. Hemodynamic monitoring consisted of continuous electrocardiogram, heart rate and invasive arterial pressure (Monitor Dash 3000, Marquette Medical Systems, Freiburg, Germany). Routine ventilatory parameters were recorded.
The animals were subjected to a median laparotomy under aseptic conditions. The retroperitoneum was dissected to expose the abdominal aorta from the renal arteries to the aortic bifurcation. Prior to aortic clamping, heparin was administered (1 mg·kg–1 iv). The aorta was clamped suprarenally (below the superior mesenteric artery) and distally, immediately proximal to the iliac arteries. Whenever clamping extended beyond 30 min, the suprarenal clamp was moved from the suprarenal to an infrarenal position. Two 1-cm aortotomies were established to perform aorto-aortic bypass, with a latero-terminal anastomosis using a 6-mm diameter collagen-lined Dacron tube graft (previously submerged for 15 min in a solution of rifampicin). Finally, the clamps were removed and sodium bicarbonate was infused (1 mEq·kg–1 iv). Hemostasis was restored and the laparotomy was closed. With the exception of anatomical differences, the surgical technique was designed to mirror the surgical approach used in humans. Anesthesia was reversed by discontinuing the infusion of propofol or sevoflurane, depending on the group. When animals had recovered spontaneous breathing, the endotracheal tube was removed, and they were returned to the designated animal care area. Metamizol 1.2 g iv was administered for postoperative analgesia.
During surgery, the following hemodynamic variables were recorded: heart rate, and systolic, diastolic and mean arterial pressure. Intraoperatively and over the next seven days, blood was sampled, and the kidneys were biopsied at the following times: basal (before the start of surgery); reperfusion (15 min after unclamping the aorta); at 24, 48 and 72 hr after surgery, and on the seventh day after surgery. From 24 until 72 hr postoperatively percutaneous renal biopsies were performed under an im injection of ketamine hydrochloride (20 mg·kg–1) together with diazepam (0.5 mg·kg–1) and atropine (0.05 mg·kg–1). A Bard Monopty Biopsy Instrument (Covington, GA, USA) was employed and the needle was guided by ultrasonography (Sigma AC Start; Kontron Instruments, Montigny le Bretoneux, France). The following variables were recorded: plasma creatinine levels as a measure of kidney function; renal myeloperoxidase (MPO) as a measure of the degree of neutrophil infiltration into tissues; plasma proinflammatory cytokine levels, tumour necrosis factor- (TNF-) interleukin 1-ß (IL-1ß), and interferon-gamma (INF-); renal superoxide anion (SOA) and its detoxifying enzyme superoxide-dismutase (SOD), and renal malondialdehyde (MDA) to assess lipid peroxidation. Finally, the activity of inducible nitric oxide synthase (iNOS) was assessed 72 hr after surgery. On the seventh day, the animals were anesthetized using the techniques described above, and after the withdrawal of blood and kidney samples, were sacrificed by administration of iv potassium chloride.
Determination of plasma creatinine levels
As a marker of renal function, serum creatinine concentrations were determined, using a Hitachi 747–200 automatic analyzer (Boerhinger Mannheim, Indianapolis, IN, USA).
Determination of MPOin kidney tissue
The presence of MPO, an enzyme specific for neutrophils and used as an index for the assessment of neutrophil accumulation, was determined in kidney tissue with the method of Bradley,13 as modified by Mullane.14 We have reported this technique previously. 15,16 After collection, the samples were immediately weighed on ice, homogenized in phosphate buffer, frozen in liquid nitrogen and stored at –80°C until assayed. A double-beam spectrophotometer was used. Kidney samples were obtained by direct or percutaneous biopsy.
Determination of proinflammatory cytokines
Commercial kits were used for the determination of TNF-, IL-1ß and INF- (factor-XX ELISA kit, A. Menarini Diagnostics, Menarini Labs, Badalona, Spain) based on enzyme-linked immunosorbent assay (ELISA). Recordings were carried out on a plate reader (GEST, General Elisa System Technology, Menarini) for the automatic ELISA technique, with the possibility of reading three plates at the same time. Both the supernatants from cell cultures and the serum samples could be tested with the kit. In our case, we used blood samples, which must not be hemolyzed. Immediately after withdrawal, the blood samples were centrifuged and the serum separated, divided into aliquots and placed in Eppendorf tubes. These were then frozen and stored at –80°C in a manner to avoid freezing and thawing processes.
The assay is an ELISA kit that uses many different antibodies. First, we used a 96-well plate with an anticytokine monoclonal antibody adherant to each well, to capture the corresponding cytokine present in the samples and standards, which were added in duplicate to each of the wells together with the corresponding blanks. After the plates had been washed to remove the non-adhering material, polyclonal anticytokine-conjugated peroxidase was added. Then, the plates were washed again to remove the non-adhering material and the substrate solution was added, thus initiating the peroxidase catalysis. The colour change was achieved by acidification. Absorbance was measured on a plate reader (General Elisa System Technology, Menarini) at a wavelength of 450 nm, the results obtained being proportional to the amounts of cytokine in the samples, which were calculated by interpolation with the curve of the standards.
Determination of oxygen free radicals in kidney tissue
Once withdrawn, for washing, the samples were placed in the homogenized buffer at a temperature between 0° and 4°C to minimize oxidative processes. Samples were then weighed and homogenized. The homogenates were centrifuged at 100,000 x g for 60 min at 4°C. The soluble fraction obtained was divided into aliquots and placed in Eppendorf tubes and stored at –80°C until sample processing. Determination of the rate of SOA production was accomplished with a modification of the technique described by Forman and Boveris.17 Protein concentrations were measured spectrophotometrically, using the Bradford method.18 The enzyme activity of SOD was measured following the technique reported by Misra et al.19 We have reported all these techniques previously.15,16
Determination of malondialdehyde in kidney tissue
Malondialdehyde and four-hydroxyalkanes are the most important products in the decomposition of unsaturated fatty acids. Quantification of these aldehydes is a suitable index of lipid peroxidation.20
Malondialdehyde was determined in kidney samples using the following reagents: 0.1 M phosphate buffer, pH 7.4, and a stock solution composed of 15% trichloroacetic acid, 0.37% thiobarbituric acid and 0.25 N hydrochloric acid. Water was added to a final volume of 50 mL. The samples were weighed and 10 mL of the buffer was added, after which the tissue was homogenized. Then, 1 mL of the homogenate was mixed with 2 mL of the stock solution, incubating the resulting mixture for 30 min at 100°C. It was then cooled on ice and centrifuged for 15 min at 3000 rpm and left to stand. The supernatant was read at a wavelength of 535 nm.
Expression of iNOS in kidney tissue
Kidney samples were obtained by percutaneous biopsy (72 hr after surgery). The samples were immediately frozen in liquid nitrogen and stored in sealed tubes (–80°C). The frozen material was sliced and 3 mL of lysis buffer (40 mM NaCl, 15 mM EDTA, 10% glycerol, 20 mM Tris base, pH 8) per gram of tissue was added at 4°C. Two protease inhibitors were added to this buffer: 2 mM phenylmethylsulfonylfluoride and 50 µg·mL–1 of trypsin inhibitor. The mixture was homogenized at 4°C and the residues of the lyzate were collected in an Eppendorf tube, passing them through a 21-G needle. The samples were kept on ice for 30–60 min and then centrifuged at 4°C and 15.000 x g for 20 min (Mikro 12–24 centrifuge, Hettich, Germany). The supernatant was stored in aliquots at –20°C for determination of protein content according to the method of Bradford18 and for Western blot assays. Primary and secondary antibodies were used (Santa Cruz Biotechnology, Santa Cruz, CA, USA). After digitization of the radioautographs (Scanner® model VM 6552 Trust, Dordrecht, the Netherlands and the Adobe PhotoshopTM 3.0 program, Uxbridge, UK), optical densities were read with the MacBAS V2.2 program (Fuji Medical Systems Inc., Stamford, CT, USA).
Statistical analyses
Data were analyzed using the Fisher exact test and analysis of variance (Student-Newman-Keuls or Scheffe test for normally distributed data and the Kruskall-Wallis Z test for data not normally distributed). Results are expressed as means ± standard error of the mean. Statistical significance was set at P value of < 0.05.
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Kidney function
Plasma creatinine concentrations after IR were significantly increased over time in both groups in comparison with the basal levels observed before the start of surgery (P < 0.01). After 24 hr, the magnitude of the change was significantly smaller in the animals anesthetized with propofol (P < 0.05). On the seventh day, creatinine values tended to decrease in both groups (Figure 1
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, IL-1ß and INF- was observed after IR as compared with the pigs anesthetized with sevoflurane (P < 0.05, Table II). The maximum amount of TNF- was observed in the plasma of the animals anesthetized with sevoflurane at 72 hr in comparison with those receiving propofol during the same period (417.4 ± 68.5 pg·mL–1 vs 258.8 ± 52.6 pg·mL–1). The same was the case with the IL-1ß plasma concentrations (396.2 ± 39.9 pg·mL–1 vs 257.3 ± 34.4 pg·mL–1) and the concentrations of INF- (345.6 ± 39.8 pg·mL–1 vs 199.4 ± 44.6 pg·mL–1).
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Discussion |
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Usually under experimental conditions, renal function is completely recovered after seven days, even in situations of severe renal failure if there is no persistent hypotension or sepsis. Thus, we limited the duration of the study to seven days. Previous experimental work carried out by our group, with a clamping time of more than 30 min, induced situations of paraplegia, intra-abdominal infection, and/or postoperative mortality. It is notable that in this study, all animals survived with a functioning aortic bypass, regardless of group allocation, and were healthy after seven days
Several studies have demonstrated the antioxidant properties of propofol in both in vivo and in vitro models,5–7 suggesting the potential benefit of the drug as an antioxidant in situations of IR that lead to SIR. Other investigators have also reported that, in vivo, propofol increases the antioxidant capacity of erythrocytes, 2,20 decreases lipid peroxidation and preserves myocardial contractile function,21 while appearing to decrease OFR production.22 Several in vitro studies demonstrate that propofol inhibits lipid peroxidation in human liver microsomes23 and in different tissues of Wistar rats in which, additionally, increases in reduced glutathione levels have been reported.24,25 Corcoran et al.,26 showed that the administration of propofol before aortic cross-clamp release in patients undergoing elective coronary artery bypass graft surgery decreases myocardial lipid peroxidation, attenuates the inflammatory response to myocardial reperfusion, and limits the inflammatory cascade.
The antioxidant properties of propofol, observed both in vivo and in vitro, are evident at drug doses comparable to those used in clinical anesthesia to achieve plasma levels that will allow appropriate induction and maintenance of anesthesia.5,20,22–24,27 Several studies suggest that it is the active principle of propofol and not its solvent (Intralipid®) which exerts the antioxidant action.26 Certain immunomodulatory effects of propofol, such as suppression of respiratory bursts of neutrophils by propofol, may be caused by intralipid, while other actions, such as the ability to scavenge free radicals, appear to be a property of propofol itself.6,8,23 Propofol’s beneficial properties have been shown to be independent of intralipid.26
Attempts to link the propofol molecule and the observed antioxidant effect in SIR have been developed on the basis of different studies. Murphy et al.6 reported that on the basis of its chemical structure, propofol must behave in a similar fashion to vitamin E, by binding to cell membranes or their phospholipids, reacting with the peroxylipid radicals that are formed when lipid peroxidation begins, and giving rise to a stable phenoxy- radical that would not propagate lipid peroxidation in the cell membrane. Kahraman et al.8 suggest that propofol is in itself a scavenger of peroxynitrites, preventing or decreasing their noxious action. As in the case of others studies, 2,9,24,25 these authors propose that propofol would inhibit, or at least decrease lipid peroxidation. Studies on antioxidant defensive cell enzyme systems by De La Cruz et al.,24,25 suggest that, at clinically relevant doses, apart from inhibiting lipid peroxidation, propofol may also act on enzyme systems (in particular on the glutathione system) which would lead to a decrease in the activity of glutathione peroxidase and an increase in the activities of glutathione reductase and glutathione transferase. This effect would yield an increase in cellular deposits of reduced glutathione, and hence in defensive cellular deposits of antioxidants, thereby protecting tissues from oxidative stress. Other studies have failed to demonstrate a protective effect of propofol on myocardial function during ischemia and reperfusion.28,29 Javadov et al.,30 suggest that the mechanism by which propofol may confer protection against myocardial reperfusion injury appears to be independent of adenosine triphosphate-sensitive potassium channels, and may be attributable to an action at the mitochondrial transition pore.
Our observation that propofol decreases lipid peroxidation, is consistent with other investigations.5,20,21 We observed that MDA values were significantly lower in the animals receiving propofol from 24 up to 72 hr. The reduced neutrophil infiltration observed in the group of animals anesthetized with propofol, reflected in the lower activity of kidney MPO after reperfusion, is an important element in identifying the possible mechanism of propofol’s moderation of the SIR. Neutrophils play a crucial role in the propagation of the damage caused by ischemia, and above all by reperfusion, since these white blood cells are able to release cytokines, oxygen free radicals and other proinflammatory substances. Kato et al.,4 reported that in their in vitro experimental models, propofol decreased neutrophil activity, although they failed to offer any mechanism of action through which this might occur. Sevoflurane also appears to exhibit cardioprotective effects against reperfusion injury, and this effect has been attributed to its free radical scavenging properties and the reduction of postischemic adhesion of neutrophils.31,32 Recently, a small study comparing sevoflurane with propofol showed that sevoflurane was superior to propofol in terms of reperfusion injury and contractile function in humans,33 although the two groups were not homogenous with respect to preoperative ejection fraction and the number of surgical techniques. In our study, in animals anesthetized with propofol, we observed lower plasma inflammatory cytokine levels, these being able to stimulate and increase neutrophil infiltration. Neutrophils are responsible for the synthesis of these cytokines, and in turn are targets of the actions of the latter. Additionally, TNF- is a potent inducer of SOA release by other neutrophils, which would increase damage to other cells, amongst them, endothelial cells, favouring a greater migration of neutrophils.34 The lower TNF- levels in the animals anesthetized with propofol would decrease this process of autocrine neutrophil activation.
Tumour necrosis factor-, IL-1ß and INF- are able to induce iNOS expression in different types of cells;35–37 this response to the mediators of inflammation is associated with an excessive production of nitric oxide (NO) and may serve an additional role as part of the innate immune response-programmed cell death. The role of NO in IR is controversial, but its cytotoxic effect is believed to be due to the formation of free radicals derived from NO, such as the peroxynitrites generated when NO is combined with SOA. Furthermore, NO is a potent vasodilator, and it is known that the reestablishment of blood flow to ischemic tissues may exacerbate the tissue lesion, leading to a lesion due to reperfusion. Inhibition of iNOS activity would lead to a decrease in the tissue lesion due to reperfusion.38 The decrease in cytokine levels in animals anesthetized with propofol is associated with reduced activation of iNOS in reperfusion, with a reduced release of NO, less vasodilatation, less migration and neutrophil infiltration, and reduced peroxynitrite formation, accompanied by less extensive tissue injury. In our case, the reduced formation of peroxynitrites could be explained on the basis of either a reduced activation of iNOS, or reduced production of SOA observed in the animals anesthetized with propofol.
Indeed, we observed less iNOS activity in animals anesthetized with propofol at 72 hr after surgery; this could be explained by the lower levels of proinflammatory cytokines and a reduced production of SOA. Inducible NO synthase activity is controlled mainly by gene expression and mainly at transcriptional levels through the activation of several transcription factors, such as nuclear transcription factor kappa B (NF
B).39 In some in vitro studies carried out in experimental models with macrophages cultured in a medium with lipopolysaccharide (an inducer of iNOS) propofol was added at clinical therapeutic concentrations; the authors reported an inhibition of iNOS activity and of the mRNA for iNOS. All this suggests a possible direct action of propofol at transcription factor level that would govern iNOS activity,40 or alternatively, an indirect action through the decreases in SOA, TNF- and IL-1ß, each being an inducer of NFB expression. 41,42 In our study, after the IR in animals anesthetized with propofol, we observed a decrease in SOA, TNF- and Il-1ß levels, which could lead to a reduced expression of NFB.
In conclusion, the results of this in vivo experimental model of reversible renal IR show that, in comparison with sevoflurane, clinically relevant doses of propofol decrease lipid peroxidation and increase the antioxidant capacity of the kidney. Propofol also plays a role in modulation of the mechanisms involved in SIR, with reduced accumulation of neutrophils in kidney tissue, and moderation of the release of proinflammatory cytokines. Our results also show that propofol has the ability to reduce the synthesis of NO through the inhibition of renal iNOS during reperfusion. The cumulative effects result in a moderation of altered renal function associated with aortic cross clamping and Dacron grafting. In clinical practice, whether this protective action of propofol exerts a beneficial outcome effect in patients presenting for major vascular surgery warrants further investigation.
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Accepted for publication January 30, 2006. Revision accepted March 13, 2006.
This article is accompanied by an editorial. Please see Can J Anesth 2006; 53: 643–5..
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References |
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D. M. Ansley Is anesthesia good for you? Timing is everything!/L'anesthesie est-elle bonne pour vous ? Tout est dans le bon moment ! Can J Anesth, July 1, 2006; 53(7): 643 - 645. [Full Text] [PDF]
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