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* From the Imaging Division, Lawson Health Research Institute; the Department of Medical Biophysics, and
the Division of Cardiology,
Faculty of Medicine and Dentistry, University of Western Ontario; and the Department of Nuclear Medicine and Magnetic Resonance,
St. Joseph’s Health Care, London, Canada.
Address correspondence to: Kerry Thompson, Imaging Division, Lawson Health Research Institute, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada. Phone: 519-646-6000 ext. 64787; Fax: 519-646-6135; E-mail: kthompso{at}lri.sjhc.london.on.ca
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Abstract |
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Methods: Using magnetic resonance (MR) techniques, we monitored both regional metabolism (31P MR spectroscopy) and systolic function of the heart (1H MR imaging) throughout a two-hour occlusion of the left anterior descending coronary artery and ten days of reperfusion. Twenty-two beagles were randomized into isoflurane and propofol general anesthesia groups (n = 10, n = 12 respectively). Contrast-enhanced MR imaging was used to measure infarct size (% of left ventricle that was necrotic) and coronary blood flow was determined using radioactively labelled microspheres.
Results: Cardiac metabolism, as monitored by intracellular pH and high-energy phosphate ratios, was not significantly different between the two groups throughout the protocol. Relative to propofol, isoflurane reduced the depression of left ventricular ejection fraction (EF) during the ischemic period [isoflurane 68.5% ± 4.2%, propofol 58.3% ± 2.0% of baseline (B); P = 0.04], propofol increased the recovery of EF at day three (isoflurane 63.9% ± 4.3%, propofol 74.0% ± 2.5% of B; P = 0.05). By day ten, EF in both groups was similar. Infarct sizes were also similar at day ten (isoflurane 15.7% ± 3.0%, propofol 13.2% ± 2.2%). Normalizing these by the region at risk (volume of tissue with low blood flow during the occlusion) to assess infarct ratios was also not significant (isoflurane 0.58% ± 0.08%, propofol 0.54% ± 0.07%).
Conclusions: There were no significant differences between the two anesthetic groups at day ten, suggesting that any apparent dissimilarities in early cardiovascular effects were short-term only. These results indicate that isoflurane and propofol produce equivalent long-term cardiovascular effects following ischemia/reperfusion.
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Introduction |
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The primary mechanism of the cardioprotection associated with isoflurane is thought to be through the activation of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels.2,6,7 This, along with other potential mechanisms, has been studied in a variety of ischemia/reperfusion models; with evidence for the following clinically important endpoints: reduction in infarct volume;1–3,7–10 improved functional recovery;4,5 and preservation of ATP.4,6 The purported mechanisms of cardioprotection by propofol include oxygen free radical scavenging,15,16 reductions in Ca2+ overloading,15 and increases in coronary flow.15 Enhanced functional recovery,13,15–17 as well as reductions in myocardial necrosis,15 and retention of ATP16 have all been reported with propofol.
We have previously reported the protective benefits of propranolol, nitroglycerin, and superoxide dismutase on limiting infarct size with our laboratory’s canine two-hour occlusion/ten-day reperfusion model.20,21 The current study was undertaken to directly compare the cardiovascular effects of two commonly used general anesthetics: propofol and isoflurane. Rather than create a true control group, the two anesthetics were directly compared against one another, as there is no acceptable anesthetic that has not been shown to have some effects on the cardiovascular system.
We used both 31Phosphorus (31P) MR spectroscopy (MRS) and 1H MR Imaging (MRI) to determine if any differences exist in the cardiovascular effects of propofol and isoflurane, as general anesthetics, during and following ischemia/reperfusion. 31P spectroscopy monitored changes in regional myocardial metabolism by assessing the high-energy phosphate ratios as well as intracellular pH, and 1H MRI determined the functional effects on systolic left ventricular performance and myocardial salvage (infarct extent) following ten days of reperfusion.
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Surgery
Twenty-two female beagles ranging in weight from 9 to 15 kg were used for this study. The dogs were randomly separated into a control group (isoflurane anesthesia n = 10) and a treatment group (propofol anesthesia only, n = 12). General anesthesia was induced intravenously with 4 mg•kg–1 propofol [Abbott Laboratories, Saint-Laurent, QC, Canada; 2,6-diisopropylphenol in a lipid emulsion (10 mg•mL–1, 1% w/v)] in both groups. Anesthesia was maintained in the isoflurane group with 1.5–2.5% isoflurane (Abbott Laboratories, Montreal, QC, Canada) whereas in the propofol group anesthesia was maintained with a constant infusion of propofol at a rate of 0.6–1.0 mg•kg–1•min–1.22 The dogs were intubated with an endotracheal tube and ventilated using an A.D.S. 1000 (Engler Engineering Corp., Hialeah, FL, USA) pressure limited respirator, using oxygen-enriched room air to maintain arterial pH (
7.40), pO2 (> 100 mmHg), and pCO2 (< 40 mmHg). A pulse oximeter (Nonin, Plymouth, MN, USA) was used for constant monitoring of heart rate and pO2. A capnograph (Datex: Capnomac Ultima, Helsinki, Finland) monitored pCO2, pO2, and isoflurane levels at all times.
Subsequently, a left thoracotomy was performed between the fourth and fifth intercostal space, the pericardium was incised, and the heart was exposed. The left anterior descending coronary artery (LAD) was dissected free just distal to the first major diagonal branch. A ligature was positioned around the isolated region of the LAD, and the ligature ends were then threaded through a chest tube, acting as a snare. The left atrial appendage was cannulated for microsphere injections. A femoral artery was catheterized to allow an arterial blood reference sample to be taken for microsphere blood flow measurements. A cephalic vein was also catheterized for administration of drugs and/or fluids. Body temperature, during anesthesia, was maintained between 36.0°C and 38.0°C using hot water bottles placed around the animal’s torso.
Experimental protocol
All 22 dogs underwent a two-hour occlusion (after an average of 4.75 hr of anesthetic) followed by ten days of reperfusion. The anesthetic protocol used on the day of surgery for each dog was exactly the same during all subsequent experiments. The protocol incorporated approximately 12 hr of anesthesia on the day of surgery, 3.5 hr on day three, and 4.75 hr on day ten. Images were obtained with a 55-cm bore Siemens Vision 1.5T MR scanner (Siemens, Erlangen, Germany). Cine MR images and 31P chemical shift imaging (CSI) spectra were acquired on the day of surgery (before, during, and immediately following the release of the occlusion), as well as three days and ten days postoperation. Radioactively labelled microspheres were injected at baseline (B), occlusion, reperfusion, and day ten to assess regional myocardial blood flow. On day ten the dogs were sacrificed and the hearts excised for imaging and dissection.
MR set-up and protocol
A) 31P SPECTROSCOPY
Two-dimensional 31P CSI was performed seven times throughout the ten-day protocol with a Siemens 1H-31P radiofrequency surface coil, as previously described.20,21,23 The data were acquired from a 30-mm thick slice, positioned in the transverse plane, and centered just proximal to the most apical region of the heart. Multivoxel 31P 2D-CSI [TR 500 msec, 
90°, field of view (FOV) 320 mm, Bandwidth ± 2 kHz, acquisition time 34 min] were obtained from this transverse slice once at B, twice during the occlusion period (O1 and O2), twice immediately upon reperfusion (R1 and R2) and once at each follow-up (D3 and D10 respectively).
Using Siemens’ software the raw data were filtered and zero filled (2,048 points) during the initial localized reconstruction. These spectra were then fitted using FITMAN, a software package designed in our laboratory, which incorporates prior knowledge of the spectrum as determined from the literature and our previous results.20,21,23,24 Each slice consisted of 2 x 2 cm2 voxels through the 3-cm thick transverse slab, in a 16 x 16 grid that could be positioned retrospectively. This ensured that the volumes of interest (VOI) contained predominantly or exclusively, infarcted tissue, as opposed to non-infarcted tissue.
Using the chemical shift between the phosphocreatine (PCr) and the inorganic phosphate (Pi) peaks, the myocardial pH was determined for each VOI.20,21,23 A spectral template was used to fit the blood peaks, allowing for the discrimination of the myocardial Pi peaks. If more than one Pi peak was fit within a spectrum then the peak corresponding to the most acidic environment was chosen as the intracellular pH for that VOI. However, only Pi peak areas corresponding to at least 10% of the PCr area were included.
B) CINE MRI
Interleaved with the CSI acquisitions were cine images, acquired with the dogs positioned prone and the heart centred in a rigid Siemens 1H radiofrequency transmit/receive coil, also previously described.25–27 An electrocardiogram-gated segmented cine FLASH sequence with echo sharing (TR/TE 60/4.8 msec, 20°, thickness 6 mm) was used to obtain five to six short axis slices through the heart. Depending on the heart rate, eight to ten cardiac phases were acquired with a rectangular FOV.
End diastole (ED) and end systole (ES) images were identified for each slice through the heart using the Siemens cardiac analysis software ARGUS (Siemens Canada, Mississauga, ON, Canada). Endocardial contours were drawn for each slice providing absolute measurement of ED and ES blood volumes (EDV and ESV respectively). The global left ventricular ejection fraction (EF) was then determined for the entire heart.
C) CONTRAST-ENHANCED MRI
Prior to sacrifice, the dogs received a bolus (0.2 mmol•kg–1) followed by a one-hour constant infusion (0.004 mmol•kg–1•min–1) of Gd-DTPA (gadolinium diethylene triamine pentaacetic acid, MagnevistTM; Berlex Canada, Lachine, QC, Canada). The animal was sacrificed with an iv bolus of 10 mL KCl (149 mg•mL–1, Abbott Laboratories, Montreal, QC, Canada) and the heart was excised and then imaged using a T1-weighted 3D FLASH sequence (TR/TE 22/10 msec, FOV 80–120 mm, thickness 1 mm). Previous works in our laboratory and others have validated this technique of contrast-enhanced MRI against triphenyltetrazolium chloride histochemical staining to delineate myocardial necrosis.20,21,25,26,28
AnalyzeAVW (Biomedical Imaging Resources, Mayo Foundation, Rochester, MN, USA) was used to volume render the Gd-DTPA enhanced 3D ex vivo images. The left ventricle (LV) volume was determined, as was the volume of enhanced tissue, which indicates myocardial necrosis. Therefore, all regions of hyper-enhancement were defined as infarcted tissue. These volumes were summed, as well as the entire LV volume, providing a percentage of infarcted LV or infarct size.
Blood flow measurements
Radioactively labelled microspheres (15 µm diameter, 100 µCi, Dupont Canada, Markham, ON, Canada) were injected as a bolus into the left atrial appendage cannula one minute into a five-minute blood withdrawal (2 mL•min–1) from the femoral artery. Four sets of microspheres were used (isotopes 85Sr, 46Sc, 95Nb, and 141Ce) throughout the protocol. The first three sets were injected prior to, during, and immediately after the release of the occlusion, and the last set was injected ten days postocclusion, just before sacrifice. Blood flow determination (F, expressed in mL•min–1•g–1) has been previously described in detail.20,21,23,26,27
Infarct ratio
To minimize the biological variability between animals we normalized the infarct size based on the region at risk (RAR). The RAR was defined as the volume of tissue with myocardial blood flows less than 0.3 mL•min–1•g–1 during occlusion, as determined by the microsphere data.
Statistics
All data that were measured repeatedly over the course of the ten-day protocol were analyzed with a two-way repeated measures ANOVA with a repeated factor of time and a non-repeated factor of group. One-way single factor ANOVAs were used to determine significance at specific time-points, as well as for infarct size, region at risk, and damage ratio group means. Data are presented as mean ± SEM as well as 95% confidence intervals when specified for all 22 beagles, unless noted. Differences in n-values reflect technical difficulties experienced throughout the protocol. The program SPSS 10.0 (SPSS Inc., Chicago, IL, USA) was employed for all statistical tests.
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).
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). Metabolite ratios determined from the fitted PCr and (-ATP) peak amplitude areas were not significantly different between groups. All dogs did however, experience a reduction in their PCr/-ATP during the occlusion, followed by a PCr overshoot upon reperfusion.
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). B EF measurements were 70.3% ± 4.2% and 71.6% ± 1.4% for the isoflurane (n = 10) and propofol (n = 11) groups respectively (NS). Normalizing all other time-points by these B values resulted in significant differences in EF during the occlusion, where propofol treated animals had slightly lower values; at day three the pattern was reversed and the propofol group had slightly higher values (Figure). By day ten there were no longer any significant differences between the two groups, although these values were lower than the B values.
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].
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).
Infarct ratio
The infarct ratios for both groups were not significantly different (Table III).
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Discussion |
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Propofol has been reported to produce both metabolic and functional effects in the setting of ischemia/reperfusion. Kokita et al. reported that propofol preserved the high-energy phosphates ATP and PCr in their Langendorff rat heart model of hydrogen peroxide-induced myocardial damage.16 Although some have shown propofol to improve contractility following reperfusion,13–17 others have shown no effects.18,19 Reduction of myocardial necrosis by propofol has been reported in a small number of laboratories, mostly using a perfused heart model.15,18 Also, these propofol studies involved induction and/or general anesthesia with different anesthetics, followed by a bolus or infusion of propofol at some specific limited time-point.13,15–19 This leads to further confounding variables within the studies as the two different anesthetics are now integrated, making it extremely difficult to interpret the effects of propofol alone.
Yet another complication of propofol studies is that animals require significantly increased doses of propofol as compared to humans. The recommended dose for maintaining general anesthesia in humans is 0.1–0.2 mg•kg–1•min–1, whereas in dogs it is 0.4–0.5 mg•kg–1•min–1.34 Despite this, complete elimination of propofol following a constant infusion is similar in humans and dogs (four to six hours vs five hours, respectively).34 Bryson et al. have reported that the volume of distribution of propofol at steady-state (Vdss) in humans during a 0.15 mg•kg–1•min–1 infusion is 5.3 L•kg–1, while Nolan and Reid reported a Vdss of 6.51 L•kg–1 in dogs during a 0.4 mg•kg–1•min–1 infusion.22,35 Considering that the canine infusion rate has increased by 167%, it is surprising that the Vdss has only increased by 23%. Therefore, although the infusion rates of propofol are distinctively higher in dogs, it appears that the increase in concentration of the propofol is not linearly related. However, these discrepancies in dose and affect must be taken into consideration.
Isoflurane has been reported to produce beneficial cardioprotective effects in a variety of ischemia/reperfusion settings as compared to many different anesthetic agents. It has been reported to preserve ATP4,6 as well as to improve myocardial contractility following a reperfused ischemic insult through a variety of mechanisms.1,2,5 As was the case with propofol, most laboratories have not maintained anesthesia with isoflurane, but have briefly exposed their animals to isoflurane at some point during the protocol. Using this technique, exposure to isoflurane has reduced infarct size relative to the following anesthetized control groups: ketamine and xylazine,3 sodium pentobarbital,1,2 and propofol.7,9,10
There are only a few studies directly comparing general anesthesia with isoflurane and propofol during a period of ischemia/reperfusion.8,36 One such study assessed the red blood cell (RBC) antioxidant capacity of isoflurane and clinical low- and high-dose propofol. They found high-dose propofol (200 µg•kg–1•min–1) resulted in enhanced RBC antioxidant capacity, suggesting that high-dose propofol anesthesia could increase the threshold for oxidative injury during ischemia/reperfusion.36 Cope et al. have directly compared infarct size in animals where general anesthesia was maintained with either propofol or isoflurane in a model of ischemia/reperfusion. They determined that isoflurane protected the reperfused ischemic rabbit heart from infarction to a greater extent than propofol.8 They used an in vivo rabbit model, with a 30-min occlusion followed by three hours of reperfusion. Normalized myocardial necrosis was significantly lower in the isoflurane group. This would be in agreement with the results from the Cason laboratory where they have used propofol as their general anesthesia in control rabbits. The treatment groups were exposed to 15 min of isoflurane prior to a 30-min occlusion, during which time the propofol infusion was briefly interrupted to ensure a nearly constant level of anesthesia. All of the isoflurane groups resulted in reduced infarcts and infarct ratios as compared to the propofol controls.7,9,10 They have suggested a variety of mechanisms to be involved in these effects that are seen only with isoflurane. By adding colchicine, a drug that depolymerizes microtubules, they blocked the reductions in necrosis found with the isoflurane pre-treatment group, but not the propofol control group.10 Another study by this group found that by adding glyburide, a KATP channel blocker, or 8-(p-sulfophenyl)-theophylline, a non-specific adenosine receptor antagonist, the benefits of isoflurane on infarct size were eliminated.9 Again though, treatment of the propofol controls with either of these blockers did not affect the final volumes of necrotic tissue in these groups.
In our study of a two-hour occlusion followed by ten days of reperfusion, we found that the high-energy phosphate levels provided cellular metabolic information, but the normalized PCr/-ATP ratios were not significantly different between groups at any time point during the protocol; neither was the intracellular pH. Our functional data indicated that isoflurane reduced the relative negative inotropic effects that occurred during ischemia as compared to propofol anesthesia. However, during the early stages of reperfusion there was a significantly faster recovery of cardiac function in the propofol group as compared to isoflurane. Our final time-point, ten days postocclusion, showed no differences between the two groups suggesting that there are no long-term functional differences between these two anesthetics.
The absolute infarct sizes, and normalized infarct ratios of the two anesthetic groups, as determined at day ten, were not different; contrary to the reports suggesting isoflurane’s relative protective effects vs other anesthetic agents for reducing myocardial necrosis.1–3,7–10 Unfortunately, there have been no previously reported long-term studies on the potential cardiovascular effects of anesthetics when these agents are administered during an acute reperfused ischemic insult. It is documented that reperfusion injury may not become manifest until 72 hr following normalization of blood flow37 and yet all of the infarct size data reported were those obtained within the first four hours of reperfusion.1–3,7–10,18 This significant difference in the model, to a longer period of observation, may contribute to the differences between these results and other studies.
In summary, we have shown the following: 1) propofol, relative to isoflurane, hastens the recovery of global left ventricular function following a reperfused ischemic insult; 2) isoflurane, relative to propofol, better preserved EF during a two-hour period of ischemia; and 3) neither anesthetic is significantly better at limiting the degree of myocardial necrosis. These data suggest that there are no differences in long-term effects of either anesthetic following a period of ischemia and reperfusion. Considering these canine results, one can postulate that either propofol or isoflurane general anesthesia would be appropriate for maintaining a similar cardiovascular outcome following cardiac and major non-cardiac surgery, in patients with significant underlying coronary artery disease. However, further clinical studies would need to address any potential differences associated with these anesthetics in humans as opposed to dogs.
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Acknowledgments |
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Footnotes |
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Revision received August 14, 2002. Accepted for publication April 11, 2002.
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References |
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2 Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC. Isoflurane mimics ischemic preconditioning via activation of KATP channels. Reduction of myocardial infarct size with an acute memory phase. Anesthesiology 1997; 87: 361–70.[Medline]
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8 Cope DK, Impastato WK, Cohen MV, Downey JM. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology 1997; 86: 699–709.[Medline]
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12 Mattheussen M, Rusy BF, Van Aken H, Flameng W. Recovery of function and adenosine triphosphate metabolism following myocardial ischemia induced in the presence of volatile anesthetics. Anesth Analg 1993; 76: 69–75.
13 Javadov SA, Lim KHH, Kerr PM, Suleiman MS, Angelini GD, Halestrap AP. Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res 2000; 45: 360–9.
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