Propofol Is Cardioprotective in a Clinically Relevant Model of Normothermic Blood Cardioplegic Arrest and Cardiopulmonary Bypass KELVIN H. H. LIM*, ANDREW P. HALESTRAP,*, GIANNI D. ANGELINI*, ,1 AND M.-SAADEH SULEIMAN* *Bristol Heart Institute and Department of Biochemistry, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom Key words: cardioplegia; ischemia; reperfusion; propofol; cardiac surgery; mitochondria
The general anesthetic propofol has been shown to be cardioprotective. However, its benefits when used in cardioplegia during cardiac surgery have not been demonstrated. In this study, we investigated the effects of propofol on metabolic stress, cardiac function, and injury in a clinically relevant model of normothermic cardioplegic arrest and cardiopulmonary bypass. Twenty anesthetized pigs, randomized to propofol treatment (n = 8) and control (n =12) groups, were surgically prepared for cardiopulmonary bypass (CPB) and cardioplegic arrest. Doses of warm blood cardioplegia were delivered at 15min intervals during a 60-min aortic cross-clamped period. Propofol was continuously infused for the duration of CPB and was therefore present in blood cardioplegia. Myocardial biopsies were collected before, at the end of cardioplegic arrest, and 20 mins after the release of the aortic cross-clamp. Hemodynamic parameters were monitored and blood samples collected for cardiac troponin I measurements. Propofol infusion during CPB and before ischemia did not alter cardiac function or myocardial metabolism. Propofol treatment attenuated the changes in myocardial tissue levels of adenine nucleotides, lactate, and amino acids during ischemia and reduced cardiac troponin I release on reperfusion. Propofol treatment reduced measurable hemodynamic dysfunction after cardioplegic arrest when compared to untreated controls. In conclusion, propofol protects the heart from ischemia-reperfusion injury in a clinically relevant experimental model. Propofol may therefore be a useful adjunct to cardioplegic solutions as well as being an appropriate anesthetic for cardiac surgery. Exp Biol Med 230:413–420, 2005
ropofol is a general anesthetic widely used during cardiac surgery and in postoperative sedation (1, 2). It has also been shown to protect hearts against cardiac insults in a variety of experimental models (3–6). These effects were attributed to its ability to act as a free radical scavenger (7), enhancing tissue antioxidant capacity (6), or through inhibition of plasma membrane calcium channels (8, 9). Oxidative stress and elevated cytosolic calcium concentrations are known to be associated with reperfusion injury and are probably responsible, either directly or indirectly, for damaging the myocyte (10–13). Furthermore, both conditions trigger the opening of the mitochondrial permeability transition (MPT) pore that occurs on reperfusion (13). The MPT causes damage to the heart because it uncouples mitochondria, causing them to hydrolyze rather than synthesize ATP. Drugs that inhibit opening of the MPT pore are cardioprotective, and the extent of functional recovery of a heart is inversely correlated with pore opening (14–18). In this respect, we have shown that the cardioprotective action of propofol at clinically relevant doses is associated with an inhibition of MPT pore opening in the Langendorff perfused rat heart (19). Although there is extensive evidence that propofol provides cardioprotection against ischemia and reperfusion, its benefits when used as an adjunct to cardioplegia during cardiac surgery have not been demonstrated (2). Using cardiac injury or dysfunction as an indicator, the relative merits of propofol have been compared with other methods of anaesthesia using in vivo experimental models of regional ischemia (20, 21) and in humans during open-heart surgery (22, 23). However, such studies were contradictory where the benefits of different anaesthetics remain controversial (24, 25), and none addressed the question of whether
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The British Heart Foundation, the Medical Research Council, the Sir Jules Thorn Charitable Trust, and the Royal College of Surgeons of Edinburgh supported this research. 1 To whom correspondence should be addressed at Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail:
[email protected]
Received November 23, 2004 Accepted March 17, 2005 1535-3702/05/2306-0413$15.00 Copyright Ó 2005 by the Society for Experimental Biology and Medicine
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propofol is cardioprotective when present in cardioplegia and during cardiopulmonary bypass (CPB). Therefore, the aim of the present study was to demonstrate the drug’s efficacy when present during cardioplegic arrest in a pig model of blood cardioplegic arrest and CPB. Preliminary work has already been published as an abstract (26).
Materials and Methods The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996). In-Vivo Pig Model of Cardiopulmonary Bypass and Blood Cardioplegic Arrest. Anesthesia and Surgery. Twenty adult farm-bred Large-White-Landrace crossbred pigs (characteristics are shown in Table 1) were used in this study. Each pig was given an intramuscular injection of ketamine (10 mg/kg) before induction of anesthesia by mask inhalation of halothane-enriched oxygen. An endotracheal tube was inserted, and the anesthesia was continued using halothane delivered together with oxygen and nitrous oxide (50:50% mix). Blood oxygen saturation (SpO2) was monitored using a pulse-oximeter probe applied to the tail. The level of anesthesia was gradually deepened until cessation of spontaneous breathing. Mechanical assisted ventilation was then commenced using a Blease Brompton BM2P Ventilator (Chesham, Bucks, UK), with an initial minute volume setting of 150 ml/kg/min at 15–18 breaths/min and a minimum tidal volume of 500 ml. These were subsequently adjusted to maintain capillary SpO2 . 97%. Anesthesia was maintained throughout the experiment using an intravenous triple regime of sodium thiopentone (10 mg/kg as a slow intravenous bolus followed by 10 mg/kg infused over 30 mins), Diazepam (1 mg/kg intravenous bolus), and Fentanyl (15 lg/kg bolus followed by a continuous infusion at 50 lg/ kg/hr). Nasopharyngeal temperature and ECG were continuously monitored. Measurements of cardiovascular hemodynamic function were made using a Swan-Ganz catheter. Cardiopulmonary Bypass and Cardioplegic Arrest. The CPB circuit was primed with a mixture of Hartman’s solution (1 l), Gelofusin (500 ml), mannitol 20% (500 mg/kg), and heparin (5000 IU). Nonpulsatile CPB was started using a Sto¨ckert Multiflow Roller Pump (Sorin Group GmbH, Munich, Germany) to achieve a target flow rate of 70–90 ml/kg/min of blood through the hollow fiber– membrane oxygenator apparatus (Dideco D708 CompactFlo, Sorin Biomedica, Via Crescentio, Italy). During CPB, the body temperature was kept normothermic (378–388C), and mean arterial blood pressure was maintained between 60 and 80 mm Hg. A protocol of intermittent-antegrade-warm-blood-cardioplegia used in coronary artery bypass surgery (18, 27) was adopted in this study (Table 2). An initial dose (600 ml)
of warm hyperkalemic cardioplegia (pig’s blood supplemented with K+ and Mg2+) was delivered into the coronary arteries via the aortic root. More cardioplegia was delivered at 15, 30, and 45 mins (Table 2). No myocardial inotropic support agents were used throughout the protocol. During the cross-clamp period, distension of the cardioplegiaarrested heart was prevented by removing excess fluid using a catheter (DLP, Grand Rapids, MI) introduced into the left ventricle through a small incision in the left atrial appendage. Myocardial septal temperature was monitored throughout. After removal of the aortic cross-clamp, CPB support was continued for 30 mins to simulate clinical surgery when the proximal anastomoses of the aorto-coronary grafts are performed before weaning from CPB. The total cross-clamp time was 60 mins, and total CPB was 2 hrs. A summary of the protocol is provided in Figure 1. Propofol Infusion. An initial dose of 1 mg/kg propofol was given at the onset of CPB and was followed by a continuous infusion of 6 mg/kg/hr for the duration of CPB (2 hrs), which is comparable to that used in human cardiac surgery to achieve a steady-state blood concentration and therapeutic level of sedation. As blood cardioplegia is drawn from the systemic arterial circuit of the CPB, propofol would be delivered into myocardium and remain during cardioplegic arrest. Propofol was administered through a central venous line (internal jugular vein) using a multichannel venous cannula. Based on measurements in clinical studies (e.g., 28–30), the total blood concentration of propofol (bound and unbound) in our model would be around 3.7 lg/ml (20 lM). This concentration would be expected to transiently drop on going on bypass. The unbound drug concentration would be around 30-fold lower than total blood concentration. These are the concentrations delivered to the heart. Markers of Ischemic Stress, Reperfusion Injury, and Cardiac Function. During the experiment, apical myocardial biopsies of the anterior left ventricular wall were collected using a 14 G Tru-Cut Biopsy Needle (Allegiance, Chicago, IL), rapidly frozen using liquid nitrogen, and stored frozen at 808C until assays were performed. Biopsies were collected before aortic cross-clamp (preischemia), at the end of the cross-clamp period (endischemia), and 20 mins after removal of the cross-clamp (reperfusion). These enabled biochemical assays of nucleotides, lactate, and amino acids to monitor metabolic changes that occurred during ischemic cardioplegic arrest and reperfusion (31, 32). Blood was sampled for cardiac troponin I measurement (32) from central venous line (internal jugular vein). The troponin I measured using the Access Immunoassay Systems (Beckman Coulter) is exclusively cardiac protein (cTnI). The cardiospecificity of cTnI (skeletal muscle does not express cTnI) allows distinction between cardiac and skeletal muscle injuries. Hemodynamic function was assessed by measuring cardiac index (CI), derived left ventricular stroke work index, mean arterial pressure (MAP), and central venous
PROPOFOL, CARDIOPLEGIC ARREST, AND CARDIOPULMONARY BYPASS
Table 1.
Pre- and Intraoperative Data for Pigsa Control (n = 12)
Sex (M:F) Weight (kg) CPB (mins) CPB flow rate (ml/kg/min) Cross-clamp time (mins) a
5:7 59 6 4 128 6 3 80 6 4 61 6 0.5
Propofol (n = 8) 4:4 57 6 3 126 6 2 84 6 4 62 6 0.6
CPB, cardiopulmonary bypass. Results are mean 6 SE.
pressure (CVP). Such measurements were initially taken at the start of the experiment for all pigs, but measurements after bypass could be collected only for pigs that were successfully weaned from bypass. The experiment was terminated by a lethal intracardiac bolus administration of Pentobarbitone (4 g), following Schedule 1 of the Animal (Scientific Procedures) Act 1986. Statistical Analysis. Data are expressed as mean 6 SE unless otherwise stated. Differences between groups or time-dependent changes within the same group were calculated using ANOVA (factorial or repeated measures where appropriate) with Fisher’s PLSD post hoc test. Differences were considered to be statistically significant when P , 0.05.
Results There were no differences in the pre- or intraoperative characteristics between control and propofol groups (Table 1). The systemic temperature before CPB was similar for both groups (378–388C) and maintained at these levels throughout CPB. The myocardial temperature dropped slowly during cross-clamp and reached to 338–348C at the end of the procedure. However, after removal of crossclamp, the temperature recovered to preischemia levels (368–378C), and there were no differences between the two groups. This mimics similar conditions seen during coronary heart surgery employing intermittent antegrade warm blood cardioplegia (27). Propofol Reduces Ischemic Stress During Cardioplegic Arrest. Table 3 shows the contents of myocardial metabolites during ischemia and on reperfusion for both groups. There was evidence of significant ischemic stress during cardioplegic arrest as shown by a fall in ATP/ AMP and ATP/ADP ratios, an increase in the glutamate/ Table 2.
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alanine ratio, and an accumulation of lactate (Fig. 2). An increase in the alanine/glutamate ratio has been used as indicator of the degree of ischemic stress in animal and human hearts (e.g., 18, 27). It is evident that the propofol group had significantly less ischemic stress compared to the control group (Fig. 2). Metabolic stress was also seen during reperfusion where the tissue lactate and alanine/glutamate remained relatively high in the control group compared to the propofol group (Fig. 2). Furthermore, the large accumulation of inosine during ischemia was significantly reduced in pigs hearts treated with propofol. Propofol Reduces Reperfusion Injury. Reperfusion following ischemic cardioplegic arrest was associated with significant myocardial injury as seen by a timedependent release of cardiac troponin I (Fig. 3). The extent of the release was significantly less in the propofol group. The presence of propofol tended to improve the ability of animals to be weaned successfully off bypass. In the control group, 7 out of 12 (58%) were successfully weaned off bypass following removal of the cross-clamp, whereas in the propofol group this was achieved in 6 out of 8 pigs (75%). However, these differences were not statistically significant. It must be noted that in these experiments, animals were weaned off bypass without inotropic support, hence the relatively high percentage of pigs that could not be weaned off. This approach was crucial to compare the efficacy of propofol. Propofol Improves Recovery of Hemodynamic Parameters. Hemodynamic parameters were completed for animals that were successfully weaned from CPB. The changes in clinically relevant cardiovascular functional parameters are shown in Table 4. Prior to CPB (preischemia), there were no significant differences between the two groups. After 60 mins of reperfusion (30 mins after CPB), there was a significant impairment in all parameters except CVP (control) and CI (propofol). No improvement in any parameter was observed after 120 mins of reperfusion where all parameters (including CVP) were impaired, although in the propofol group, neither CI nor CVP was significantly different from preischemia levels. These differences were not due to propofol exerting direct effects on the systemic vascular resistance (SVR), as there were no differences in SVR levels before or after reperfusion. On reperfusion, SVR levels were 1536 6 172 vs. 1527 6 200 dynesec/cm5 after 1 hr and 1335 6 219 vs. 1285 6 164 dynesec/cm5 after 2 hrs of reperfusion for the control and the propofol group,
Cardioplegia Delivery Protocol
Dose
Timing of delivery during cross-clamp (mins)
Delivery rate (ml/min)
Duration (mins)
Approx. [K+] in cardioplegia (mM)
Approx. [Mg2+] in cardioplegia (mM)
1 2 3 4
0 15 30 45
300 200 200 200
2 2 2 3
18–20 20 15 10
5 5 4 2.5
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Figure 1. Diagram showing different stages of cardiopulmonary bypass and cardioplegic arrest. When present, propofol was continuously infused throughout cardiopulmonary bypass and propofol was present in blood cardioplegia. * indicates ventricular biopsy collection.
respectively. Additionally propofol infusion was stopped after 30 mins of reperfusion. It must be emphasized that measurements of cardiovascular function were performed only on those hearts that were successfully weaned off CPB. Since weaning tended to be more successful for the propofol-treated pigs (6 out of 8) than for control pigs (7 out of 12), the protective effects of propofol are underestimated by the measurements of cardiovascular function.
propofol used in the present experiments are lower than in many other studies and are more typical of concentrations employed in clinical anaesthesia (1, 24, 25, 33, 34). This is important because higher concentrations of propofol have been reported to influence metabolism and sarcolemmal ion channels (35–37), which may account for reports that propofol has no cardioprotective effects on reperfusion injury in dog, pig, or rabbit hearts (21, 38–40). Infusion of propofol in pigs on CPB and before cardioplegic arrest did not significantly alter cardiovascular function. Furthermore, the drug had no effects on the metabolic state of the myocardium (no changes in ATP and its catabolites or lactate and amino acids). However, during ischemic cardioplegic arrest, the presence of propofol resulted in a significant reduction in markers of ischemic
Discussion This is the first study to demonstrate that propofol is cardioprotective in an experimental model of normothermic blood cardioplegic arrest and CPB that closely resembles the setting in cardiac surgery. The concentrations of
Table 3.
The Myocardial Concentration (nmol/mg protein) of Metabolites During Cardioplegic Arrest and Reperfusiona Pre-ischemia Control
ATP ADP AMP Inosine Glutamate Alanine a
34.1 9.4 1.6 1.9 38.0 6.6
6 6 6 6 6 6
2.1 0.7 0.1 0.3 2.6 0.6
End-ischemia
Propofol 31.3 8.4 1.3 2.8 40.4 5.7
6 6 6 6 6 6
2.4 1.0 0.2 1.3 2.7 0.3
Control 17.6 9.4 3.0 14.2 16.8 31.5
6 6 6 6 6 6
2.0 0.9 0.3 2.4 1.7 1.9
Reperfusion
Propofol 23.4 8.3 2.1 7.1 21.0 26.3
6 6 6 6 6 6
3.0 1.1 0.4 2.2* 1.2 1.7
Control 23.0 6.6 1.5 2.7 27.3 19.3
6 6 6 6 6 6
2.3 à 0.8 à 0.4à 0.5à 3.1 à 1.7 à
Propofol 24.7 6.7 1.1 2.6 31.0 15.7
6 6 6 6 6 6
3.5 1.0 0.2à 1.0à 3.2 à 1.7 à
Biopsies were collected at the beginning (preischemia), end of cardioplegic arrest (end-ischemia), and 20 mins after reperfusion. Results are mean 6 SE (n ¼ 12 for control and 8 for propofol). P , 0.05 vs. corresponding preischemia. à P , 0.05 vs. corresponding end-ischemia. * P , 0.05 vs. corresponding control.
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Figure 2. Changes in markers of myocardial ischemic stress in pig hearts subjected to warm intermittent blood cardioplegia and subsequent reperfusion. Data are plotted as means 6 SE. P , 0.05 vs. corresponding preischemia; à P , 0.05 vs. corresponding end-ischemia; * P , 0.05 vs. corresponding control.
stress as measured by different markers of ischemia (Fig. 2). The fact that propofol did not alter the metabolic state before ischemia suggests that the drug, which is present in blood cardioplegia, is providing support during the cardioplegic arrest itself. The maintenance of higher ATP/AMP and ATP/ADP ratios with a reduction in the accumulation of lactate during this ischemic phase would be consistent with propofol preventing the reversal of the mitochondrial proton–translocating ATPase during ischemia. Such AT-
Figure 3. Myocardial injury (cardiac troponin I release) in pigs following cardioplegic arrest and reperfusion. Pre-ischemic samples were collected before institution of cardiopulmonary bypass. P , 0.05 vs. corresponding preischemia; * P , 0.05 vs. corresponding control; à P , 0.05 vs. all other time points within the same group.
Pase activity would hydrolyse glycolytically derived ATP, and the resulting drop in ATP/ADP ratio (and increased AMP concentrations) would stimulate glycolysis. Activation of the mitochondrial proton–translocating ATPase would occur if the MPT pore opens during ischemia, although most studies (14, 17, 19, 41, 42), but not all (43, 44), have indicated that pore opening occurs only on reperfusion. The improved metabolic state of the propofol group during ischemia was associated with significantly less reperfusion injury (Fig. 3). Although most metabolites gradually returned to preischemic levels 20 mins after reperfusion, the return was slower in the control group. Once again, this may reflect less MPT pore opening and faster subsequent closure in the propofol group when compared to controls. This would also account for the greater myocardial injury seen in the control group that was associated with fewer pigs being able to wean from CPB. It is probable that the ability of the cardiac pump to take over the circulation is dependent on the extent of injury during reperfusion. These effects are not likely to be due to direct action of the drug on the cardiovascular system, as it has already been removed from the circulation and there were no differences in SVR levels during the reperfusion period. The observation that propofol is cardioprotective when present in warm blood cardioplegia along with our earlier finding that propofol is protective when added to cold crystalloid cardioplegia (19) indicate that the mechanism(s)
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Table 4.
Changes in Cardiac Function in Successfully Weaned Pigsa
HR (beats/min) Pre-ischemia Control Propofol Reperfusion (60 mins) Control Propofol Reperfusion (120 mins) Control Propofol
MAP (mm Hg)
CVP (mm Hg)
MPAP (mm Hg)
PCWP (mm Hg)
CI
80 6 4 75 6 5
87 6 5 90 6 4
8.1 6 0.6 8.1 6 0.7
20 6 2 21 6 2
7.7 6 0.5 7.3 6 0.4
3.1 6 0.2 2.9 6 0.2
40 6 3 39 6 3
124 6 7 106 6 12
67 6 6 76 6 3
9.4 6 0.5 11.7 6 0.7*
26 6 2 29 6 2
12.3 6 0.7 12.3 6 1.2
2.4 6 0.1 2.7 6 0.2
20 6 2 27 6 3*
127 6 10 107 6 11
60 6 4 66 6 4
12 6 0.9 9.8 6 0.7
27 6 1 28 6 2
13 6 0.5 10.5 6 0.7*
2.4 6 0.3 2.8 6 0.1
20 6 3 27 6 2
SVI
a Pre-ischemia measurements were taken before cardiopulmonary bypass. The first reperfusion measurements (60 mins) were taken 30 mins after weaning from bypass. HR, heart rate; MAP, mean arterial pressure; CVP, central venous pressure; MPAP, mean pulmonary artery pressure; PCWP, pulmonary central wedge pressure; CI, cardiac index; SVI, stroke volume index. Results are mean 6 SE (n ¼ 7 for control and n ¼ 6 for propofol). * P , 0.05 vs. corresponding control. P , 0.05 vs. preischemia values.
underlying the cardioprotective action of the drug is independent from cardioprotection conferred by cardioplegia and hypothermia alone (34). The main component of cardioplegia is high K+ that depolarizes the plasma membrane, inducing an immediate arrest of the heart, thus reducing and delaying the disruption to metabolic and ionic homeostasis triggered by ischemia. The benefits of added high Mg2+ are many but most notably its reported action as an inhibitor of Ca2+ channels and Na+/Ca2+ exchangers (45). Hypothermia can be protective by reducing basal metabolism but can have disadvantages (34). The ability of propofol to enhance the protective effects of cardioplegia and hypothermia support the widely held view that propofol is protective because of its ability to act as a free radical scavenger in its own right (7) and possibly also enhance the tissue’s own antioxidant capacity (6). This will enhance the ability of the heart to withstand the oxidative stress associated with ischemia and reperfusion and so can account for the ability of propofol to inhibit opening of the MPT pore on reperfusion (19). The extent of MPT pore opening during reperfusion has been directly linked to the fate of the myocytes following ischemia/ reperfusion (18). Another possible mechanism of action of propofol could include effects on membrane channels, including calcium and the ATP-sensitive potassium (KATP) channels (8, 9). However, these effects are not likely to occur at clinical doses of propofol (46, 47). The same can be said for possible effects by propofol on the coronary vasculature, as the drug is ineffective at concentrations lower than 5 lg/ml (48). Furthermore, propofol perfusion before ischemia did not alter functional parameters (Table 4). Intralipid emulsion (the vehicle used to deliver propofol) was not investigated in this study. We have previously shown that the intralipid emulsion alone was not cardioprotective when added to crystalloid cardioplegia (19). This was in contrast to propofol (in intralipid), which
significantly improved recovery. Others investigating the cardioprotective action of propofol against global ischemia, without using cardioplegia, have also shown that intralipid emulsion is not cardioprotective (e.g., 49–51). Additionally, propofol has been shown to inhibit cellular oxidative damage and increase the antioxidant defense of glutathione measured in platelets from surgical patients. This effect was not seen when intralipid emulsion alone was used (49). Finally, the aim of this work was essentially to show that propofol in intralipid emulsion (as used in cardiac surgery) is cardioprotective. In conclusion, the present study provides direct evidence that propofol is cardioprotective in a clinically relevant model of normothermic cardioplegic arrest and CPB as well as being an anesthetic agent used in cardiac surgery. We are grateful to our colleagues for their help and advice during surgery. GD Angelini is a BHF professor of cardiac surgery.
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