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Ann Thorac Surg 2009;87:1205-1213. doi:10.1016/j.athoracsur.2009.01.041
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Multidose Cold Oxygenated Blood Is Superior to a Single Dose of Bretschneider HTK-Cardioplegia in the Pig

Tord Fannelop, MDa,c,*, Geir Olav Dahle, MDa, Pirjo-Riitta Salminen, MDc, Christian Arvei Moenb, Knut Matre, MS, PhDb, Arve Mongstadc, Finn Eliassenc, Leidulf Segadal, MD, PhDa,c, Ketil Grong, MD, PhDa

a Surgical Research Laboratory, Department of Surgical Sciences, University of Bergen, Bergen, Norway
b Institute of Medicine, University of Bergen, Bergen, Norway
c Section of Cardiothoracic Surgery, Department of Heart Disease, Haukeland University Hospital, Bergen, Norway

Accepted for publication January 16, 2009.

* Address correspondence to Dr Fannelop, Department of Surgical Sciences, University of Bergen, Haukeland University Hospital, Bergen, NO-5021, Norway (Email: tfan{at}online.no).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: A single-dose strategy for cardioplegia is desired in minimal invasive approaches to valve surgery and aortic arch repairs. We hypothesized that a single infusion of Bretschneider HTK solution offers myocardial protection comparable to repeated cold oxygenated blood.

Methods: Sixteen pigs on bypass with 60 minutes of aortic cross-clamping were randomized to a single dose of Custodiol (HTK group) or repeated oxygenated blood cardioplegia (CBC group). Left ventricular function and perfusion were evaluated by conductance catheter, echocardiography, and microspheres. Myocardial injury was assessed with serum troponin-T.

Results: Baseline values showed no group differences. One hour after declamping cardiac index was reduced in the HTK group, 3.5 ± 0.2 L · min–1 · m–2 (mean ± standard error of the mean) compared with 4.7 ± 0.4 L · min–1 · m–2 in the CBC group (p < 0.0005), decreasing to 4.0 ± 0.2 and 3.9 ± 0.2 L · min–1 · m–2 after 2 and 3 hours, respectively (p < 0.005 versus 1 hour). In the HTK group cardiac index remained low and unchanged. In the CBC group preload recruitable stroke work was 72.6 ± 1.2 mm Hg 1 hour after declamping, decreasing to 65.2 ± 2.5 and 60.3 ± 3.9 mm Hg after 2 and 3 hours, respectively (p < 0.05 versus 1 hour). In the HTK group corresponding values after 1, 2, and 3 hours were low at 47.2 ± 4.4, 48.4 ± 4.2, and 50.7 ± 4.3 mm Hg, respectively (p < 0.025 versus CBC for all). Subendocardial radial peak systolic strain averaged 80.5% ± 4.8% after declamping in the CBC group versus 53.4% ± 5.5% in the HTK group (p = 0.002). Serum troponin-T release was lower in the CBC group.

Conclusions: Repeated oxygenated blood cardioplegia provides better myocardial protection and preservation of left ventricular function than a single dose of HTK during the early hours after declamping.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The Bretschneider HTK solution is widely used for multiorgan preservation for transplantation, but it is also recognized as a cardioplegic agent that allows single-dose administration, and is documented through clinical use [1–4]. There is a growing interest in minimally invasive approaches to valve surgery and also in aortic arch repairs. Particularly in these situations, a single-dose strategy for cardioplegia seems enticing, and has led to a growing interest for the use of HTK solution [5, 6]. There are experimental studies comparing single-dose HTK cardioplegia with standard cardioplegic regimens such as variations of the St. Thomas's crystalloid cardioplegia [7]. However, to our knowledge there is no direct comparison between single-dose HTK cardioplegia versus repeated blood cardioplegia in clinically relevant animal models. We compared the routine method used in our department, multidose cold oxygenated blood cardioplegia (CBC) with a single dose of Custodiol HTK solution. Evaluation of myocardial function before bypass and 1, 2, and 3 hours after aortic declamping was performed in a model with young pigs on cardiopulmonary bypass (CPB) with 60 minutes of aortic cross-clamping and cardiac arrest. The two different methods of cardioplegia were compared by evaluating global and local left ventricular function, myocardial tissue blood flow, and serum troponin-T release. We hypothesized that 60 minutes of cardioplegic arrest with a single dose of HTK solution could offer myocardial protection that is similar to CBC.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Animals and Anesthesia
The experimental protocol was approved by the Norwegian Animal Research Authority and conducted in accordance with international laws and regulations (Project 2006380). Twenty young pigs of either sex weighing 42 ± 4 kg (mean ± standard deviation), premedicated with ketamine (20 mg/kg), diazepam (10 mg), and atropine (1 mg) intramuscularly, were ventilated with oxygen and 3% isoflurane to allow cannulation of ear veins. Anesthesia was induced and maintained with loading doses and continuous infusions of fentanyl (0.02 mg/kg and 0.02 mg · kg–1 · h–1), midazolam (0.3 mg/kg and 0.3 mg · kg–1 · h–1), pancuronium (0.063 mg/kg and 0.14 mg · kg–1 · h–1), and sodium pentobarbital (15 mg/kg and 4 mg · kg–1 · h–1). After tracheotomy, ventilation was commenced with N2O (57% to 58%) and oxygen (Cato M3200, Drägerwerk, Lübeck, Germany) [8]. Fluid substitution was given as 15 mL · kg–1 · h–1 of Ringer's acetate solution with 20 mmo/L KCl added.

Instrumentation
The abdominal aorta and the inferior caval vein were cannulated through the right femoral artery and vein. Repeated arterial blood gas analyses (AVL Optil; AVL Scientific Corporation, Roswell, GA) and blood for serum troponin-T measurements were obtained (Roche Diagnostics GmbH, Mannheim, Germany). Urine was drained and temperature measured with a catheter–thermistor in the bladder. After midline sternotomy, pericardiotomy, and hemostasis, 125 IU/kg of heparin was administered intravenously. A catheter (model MPC-500; Millar Corp, Houston, TX) inserted through the left mammary artery measured central aortic pressure. A 7.5F catheter (Swan-Ganz CCO/VIP; Edward Lifesciences Inc, Irvine, CA) advanced from the left mammary vein into the pulmonary artery was connected to a continuous cardiac output computer (Vigilance; Edward Lifesciences Inc) and two pressure sensors (SensoNor, Horten, Norway) measuring central venous and pulmonary artery pressures. The left atrium was cannulated for microsphere injections. A snare around the inferior vena cava allowed short periods of inflow reduction. A 7F dual-field conductance–pressure catheter (model SPR 788, Millar Corp) placed through the apex of the left ventricle with its tip above the aortic valve was connected to a Sigma 5 signal conditioner (CD Leycom, Zoetermeer, the Netherlands). Correct position was judged by typical left ventricular pressure (low end-diastolic pressure) and segmental volume tracings in phase (maximum at end-diastole) and verified by echocardiography (Vivid 7 Dimension; GE Vingmed Ultrasound, Horten, Norway). Hemodynamic variables were sampled (Gould ES2000; Gould Instrument Systems, Valley View, OH), digitized, and analyzed. After 20 minutes of stabilization, 500 IU/kg heparin was given intravenously and baseline variables were obtained.

Cardiopulmonary Bypass
With a priming volume of 1.2 L of Ringer's acetate solution, the brachiocephalic artery (18F catheter; Medtronic Inc, Minneapolis, MN) and the right atrial appendage (three-stage Medtronic 29 F) were cannulated for CPB with a pump flow of 90 mL/kg and water temperature of 34°C. During 60 minutes of aortic cross-clamping the left ventricle was vented with a 17F catheter through the left atrial appendage. Body temperature was allowed to drift, and CPB flow was reduced by 20% (to 72 mL/kg) when bladder temperature reached 35°C or after 20 minutes. After 40 minutes, rewarming (water temperature 38°C) was commenced, and the flow was reset to 90 mL/kg. During CPB body and myocardial temperatures (needle electrode in the apical septal wall) were noted at regular intervals, and arterial blood gases were obtained before cross-clamp, after 30 minutes, and before declamping. Lidocaine hydrochloride (1 mg/kg) was administered to both groups 5 minutes before declamping. Ventricular fibrillation at declamping was electroconverted to sinus rhythm. No inotropic or chronotropic support was allowed. Within 20 minutes all animals were weaned from CPB following a standardized protocol, the blood in the reservoir was returned, and all cannulas were removed.

Experimental Groups
Block randomization (five blocks of four) divided animals into two equal groups. If excluded for reasons of technical or surgical failure, the animal was substituted. According to the randomization protocol 60 minutes of aortic cross-clamping and cardiac arrest were obtained with two different methods (Table 1). In the HTK group a single dose of Custodiol (Dr Franz Köhler, Chemie GMBH, Alsbach-Hähnline, Germany) with a temperature of 5°C was administered in the aortic root with a roller pump; 1 mL/min per gram calculated heart weight for 2 minutes followed by 0.5 mL/min per gram calculated heart weight for 6 more minutes. In this group 1 mmol/kg of NaCl was added to the blood reservoir. In the CBC group, repeated, cold (10°C), oxygenated blood cardioplegia was used; 3 minutes of "high potassium" at cross-clamp and 2 minutes of "low potassium" at 20 and 40 minutes of cross-clamping with a flow rate of 7% of CPB flow or 1.26 mL/min per gram calculated heart weight.


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  		Table 1 Final Concentrations and Key Characteristics for the Two Protocols of Cardioplegia
 
Data Acquisition and Calculations
At baseline arterial blood gases, serum troponin-T, hemodynamics, and the first injection of 15-µm fluorescent microspheres (Dye-Trak "F"; Triton Technology Inc, San Diego, CA) was performed. With short periods of respiratory shutoff in end-expiration, epicardial Doppler tissue velocity images in short-axis and four-chamber long-axis views were recorded with a phased-array probe using a silicone pad as offset [9]. Also during respiratory shutoff, pressure-volume loops in a stable situation and during dynamic preload reduction (brief caval occlusion) were obtained followed by three estimates of parallel conductance with injection of hypertonic saline into the pulmonary artery [10]. At 1, 2, and 3 hours after declamping new registration sequences, as described for baseline, were performed. The pigs were euthanized with saturated KCl and exsanguinated, and the heart was quickly removed.

Tissue samples from the anterior part of the left ventricular free wall were divided into subepicardial, midmyocardial, and subendocardial layers and used for measurement of regional tissue blood flow and tissue water content. Microspheres with four different fluorescent colors were used in a randomized sequence, samples were prepared, colors were quantified (Shimadzu RF-5301PC, Kyoto, Japan), and tissue blood flow was calculated [11].

Tissue velocity images were converted to strain rate images and analyzed by the EchoPacPC BT08 software (GE Vingmed Ultrasound, Horten, Norway). Three separate regions of interest (2 x 6 mm) were placed and positions tracked in the anterior subepicardial, midmyocardial, and subendocardial wall throughout a cardiac cycle, and peak systolic strain was calculated. With strain length set to 2 mm, this method can detect dysfunction in one wall layer, as for subendocardial ischemia [12]. Pressure-volume signals were exported from the commercial Conduct 2000 acquisition and analysis software (CD Leycom) and variables were calculated. Volumes were calibrated for blood conductance, parallel conductance, and values from the cardiac output computer [13, 14], and indexed for body surface area (BSA = k BW2/3/100, k = 9 m2 · kg–2/3 and BW = body weight) [15].

The randomization sequence was concealed when analyzing tissue velocity images and pressure-volume signals.

Statistical Analysis
Variables were analyzed with SPSS version 15 (SPSS Inc, Chicago, IL), and given as mean ± standard error of the mean or median (75% quartile–25% quartile) unless otherwise noted. Baseline variables were tested for normality and equal variance by the Kolmogorov–Smirnov and the Levene median tests. When meeting the normality of distribution tests, variables were compared by two-sample Student's t tests; if not, Wilcoxon-Mann-Whitney tests were used. Variables obtained after declamping were compared by two-way analysis of variance (ANOVA) for repeated measurements with time as the within factor and HTK versus CBC as the grouping factor with a Greenhouse-Geisser adjustment of the degrees of freedom if the Mauchly's test of sphericity was significant. When a significant interaction effect was found, analyses of variance for simple main effects were performed [16]. Means were finally compared with Newman-Keuls multiple range tests. The interaction was declared significant when the probability was less than 0.10, for all other analyses a probability of less than 0.05 was noted as significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Group Characteristics
Four animals were excluded for reasons not related to technical failure. In 2 animals from the HTK group rapid supraventricular tachyarrhythmia, unresponsive to repeated synchronized direct current shocks, made meaningful hemodynamic evaluation impossible after declamping. In the CBC group 2 animals developed therapy-resistant ventricular fibrillation. Results are given for 8 animals in each group.

Arterial blood analyses at baseline did not differ between groups; pH averaged 7.49 ± 0.01, partial pressure of carbon dioxide was 5.3 ± 0.1 kPa, partial pressure of oxygen was 25.2 ± 0.6 kPa, hemoglobin was 10.6 ± 0.2 g/dL, serum Na+ was 141 ± 1 mmol/L, and serum K+ was 3.5 ± 0.1 mmol/L. End-tidal carbon dioxide, oxygen, and N2O were 5.2% ± 0.1%, 38% ± 1% and 57% ± 1%, respectively. Bladder temperature was 37.8° ± 0.3°C, and diuresis was 3.6 ± 0.5 mL · kg–1 · h–1 (n = 16 for all). Analyses of baseline variables describing left ventricular function, tissue blood flow, and general hemodynamics showed no significant differences between groups (Table 2).


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  		Table 2 Global and Local Left Ventricular Function, Regional Tissue Blood Flow Rate, and Hemodynamic Variables Measured at Baseline a
 
Cardiopulmonary Bypass
During bypass there were no group differences regarding changes in systemic blood pressure, arterial blood gases, and diuresis. Body temperature decreased to its minimum and was 35.1° ± 0.1°C after 40 minutes of aortic cross-clamping, reaching 37.5° ± 0.1°C at declamping after rewarming. The temperature in the interventricular septum did not differ between groups after the first cardioplegic infusion and increased in both groups (Fig 1). In the CBC group, myocardial temperature was 2.5°C higher (p < 0.025) at 20 minutes, 3.0°C lower (p < 0.01) after 40 minutes, and 3.4°C (p < 0.005) lower at declamping compared with corresponding values in the HTK group. At declamping serum Na+ was 137 ± 1 mmol/L in the HTK group versus 141 ± 1 mmol/L in the CBC group (p < 0.001). Mean aortic pressure averaged 67 ± 2 mm Hg, hemoglobin was 9.5 ± 0.2 g/dL, partial pressure of oxygen was 17.1 ± 0.8 kPa, and serum K+ was 4.8 ± 0.3 mmol/L (n = 16 for all). At declamping, ventricular fibrillation occurred in 8 of 16 animals (6 in the HTK group and 2 in the CBC group), and the animals were immediately electroconverted.


Figure 1
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  		Fig 1. Myocardial temperature after the first cardioplegic infusion, at corresponding time points before repeated blood cardioplegia (CBC) and at declamping are shown. Values reported are mean ± standard error of the mean. § and * significant difference from previous value(s) within the Custodiol Bretschneider solution (HTK; filled symbols) group and the multidose cold oxygenated blood cardioplegia (CBC; open symbols) group; # significant difference between groups.

 
Global and Local Function After Declamping
Heart rate did not differ between groups and averaged 109 ± 5 beats/min (n = 16) 1 hour after declamping, was unchanged after 2 hours, and increased to 123 ± 6 beats/min after 3 hours (p < 0.01; Table 3). End-systolic pressures gradually decreased from 1 to 3 hours after declamping (p w = 0.014) in both groups, but were significantly lower in the HTK group compared with the CBC group (p g = 0.01). In the CBC group the peak positive of the first derivative of left ventricular pressure was high after 1 hour and decreased gradually. In the HTK group corresponding values were significantly lower both after 1 hour (p < 0.001) and after 2 hours (p < 0.05) and did not change with time. Compared with the HTK group, both stroke volume and stroke work were increased after 1 and 2 hours of reperfusion in the CBC group, but decreased with time.


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  		Table 3 Global Left Ventricular Function and General Hemodynamics 1, 2, and 3 Hours After Removal of Aortic Clamp After 60 Minutes of Cardioplegic Arrest a
 
One hour after declamping cardiac index was higher in the CBC group compared with the HTK group (p < 0.0005), but decreased to values not different from corresponding values in the HTK group after 2 and 3 hours (Fig 2, upper left). Left ventricular ejection fraction did not change significantly with time after declamping; a borderline group significance was found, averaging 0.58 ± 0.02 in the HTK group versus 0.66 ± 0.02 in the CBC group. Preload recruitable stroke work, a load-independent variable describing contractility, did not differ between groups at baseline (Fig 2, lower left). One hour after declamping, preload recruitable stroke work was clearly higher in the CBC group compared with the HTK group (p < 0.0005). In the CBC group contractility decreased with time, but remained higher than in the HTK group both after 2 hours (p < 0.0005) and after 3 hours (p < 0.025). However, no significant group differences were found, either for the end-systolic pressure-volume relationship (Fig 2, lower right) or for the x-axis intercepts (p g = 0.26).


Figure 2
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  		Fig 2. Cardiac index, ejection fraction (EF%), and slopes of preload recruitable stroke work (PRSW) and the end-systolic pressure-volume relations (ESPVR) are shown. Values reported are mean ± standard error of the mean. * significant difference from previous value within the multidose cold oxygenated blood cardioplegia group (open symbols); # significant difference between groups. (filled symbols = Custodiol Bretschneider HTK solution; pg = between groups probability; pi = interaction probability; pw = within groups probability.)

 
The left ventricular relaxation constant, {tau}, did not change with time after declamping (p w = 0.53) and averaged 36.3 ± 1.4 in the HTK group versus 33.4 ± 1.3 in the CBC group (p g = 0.13). The load-independent variables describing diastolic function did not change with time after declamping. The slope of the end-diastolic pressure-volume relationship averaged 0.13 ± 0.02 mm Hg/mL in the HTK group versus 0.12 ± 0.01 mm Hg/mL in the CBC group (p g = 0.88). The diastolic stiffness constant, β, averaged 0.023 ± 0.004 and 0.029 ± 0.011 mL–1 (p g = 0.67) in the HTK group and CBC group.

Tissue blood flow rate decreased significantly from 1 hour to 2 hours after declamping in the CBC group in all wall layers (p < 0.005 for all), and was most pronounced in the subepicardium where the blood flow rate was high compared with the corresponding value in the HTK group (p < 0.05; Fig 3, right panels). As found for baseline (Table 2), radial peak systolic strain values were unevenly distributed among wall layers also after declamping (Fig 3, left panels). Compared with the HTK group, radial peak systolic strain in the subendocardium was significantly higher (p g = 0.002) in the CBC group throughout the observation period.


Figure 3
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  		Fig 3. Peak systolic radial strain and tissue blood flow rate in left ventricular anterior wall 1, 2, and 3 hours after declamping are shown. Values reported are mean + standard error of the mean. * significant difference from value to the left within the multidose cold oxygenated blood cardioplegia (CBC; white bars) group; # significant difference between groups. (Epi, Mid, and Endo = subepicardial, midmyocardial, and subendocardial wall layers, respectively; HTK [black bars] = Custodiol Bretschneider solution.)

 
At baseline serum troponin-T was slightly above the reference level (<0.03 01 µg/L) in all animals and averaged 0.07 ± 0.01 µg/L (Fig 4). Three hours after declamping, values were increased compared with baseline and more in the HTK group than in the CBC group (p < 0.05). Tissue water content in the myocardium averaged 79.8% ± 0.1%, 79.8% ± 0.1%, and 80.3% ± 0.1% in the subepicardial, midmyocardial, and subendocardial wall layers, respectively, with no group difference.


Figure 4
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  		Fig 4. Serum troponin-T concentrations at baseline and 3 hours after declamping are shown. Values reported are mean + standard error of the mean. § and * significant difference from baseline within the Custodiol Bretschneider solution (HTK; black bars) group and multidose cold oxygenated blood cardioplegia (CBC; white bars) group; # significant difference between groups at corresponding level.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Multidose oxygenated cold blood cardioplegia is superior to a single dose of Bretschneider HTK solution with respect to preserving the left ventricular systolic function after 60 minutes of aortic cross-clamping in a juvenile pig model. This difference was prominent 1 hour after declamping, when both cardiac index and preload recruitable stroke work were substantially higher in the CBC group. Both preload recruitable stroke work and radial systolic strain in the subendocardial wall layer, describing left ventricular contractility and local systolic function, respectively, were increased in the CBC group compared with the HTK group for up to 3 hours after declamping. The lower levels of serum troponin-T at 3 hours indicate reduced myocardial ischemia–reperfusion damage in the CBC group. These two methods for myocardial protection studied imply several differences that merit discussion.

With both methods myocardial contraction and electrocardiographic activity ceased within 30 seconds and were absent until declamping and reperfusion. Normothermic cardiac arrest reduces myocardial oxygen consumption by approximately 90%; additional hypothermia (22°C) reduces consumption further from 1 to 0.3 mL O2/min per 100 g of myocardium [17]. Myocardial temperature was less than 15°C in both groups and steadily increased after the single administration of HTK cardioplegia. Temperature decreased temporarily during and shortly after each repeated administration of blood cardioplegia and was lower in the CBC group after both 40 and 60 minutes of cardiac arrest. However, these temperature differences were moderate, and it is unlikely that the differences in functional variables could be explained by these temperature differences alone (Fig 1). Because no electrical activity was observed in either of the two groups, improved energy conservation as a result of the repeated potassium infusions and maintained depolarization in the CBC group does not explain the improved postischemic function.

Ischemia–reperfusion and hyperkalemia reduces endothelial nitric oxide synthase activity, leading to endothelial dysfunction. Both cardioplegic methods studied expose the coronary endothelium and the myocardium to high levels of potassium, more so with repeated blood cardioplegia than with HTK cardioplegia. In porcine and human coronary artery preparations, the endothelium-derived hyperpolarizing factor mediates vascular smooth muscle relaxation and vasodilation that is hampered after exposure to hyperkalemia [18]. In the present study the total potassium load was 50 versus 154 mmol per gram of myocardium in the HTK group and CBC group, respectively. The initial infusion (high dose) of blood cardioplegia exposed the coronary endothelium to a potassium level of more than 20 mmol/L (Table 1). However, no signs of hampered myocardial blood flow could be observed in the CBC group after declamping (Fig 3).

In theory, little oxygen is delivered from cold oxygenated blood cardioplegia to the tissues owing to the leftward shift of the hemoglobin-oxygen dissociation curve. However, as observed during retrograde infusions during aortic valve surgery, some oxygen extraction does take place. It has been demonstrated that oxygen is important for the cardioprotective effect of cold oxygenated blood cardioplegia [19]. Repeated oxygenated blood cardioplegia might enhance the creation of oxygen free radicals and contribute to lethal reperfusion damage. In the pig, activation of the apoptotic signal pathway by repeated HTK cardioplegia is not mediated by free radicals [20]. In a clinical setting, CPB and cold blood cardioplegia induce both apoptotic cell death and cell survival signaling in the myocardium [21]. Repeated infusions of blood cardioplegia also lead to buffering and removal of ischemic metabolites. All together, these factors may render the hearts that are arrested and preserved with repeated cold oxygenated blood cardioplegia less vulnerable to the normothermic reperfusion at declamping. There is an improved relationship between subendocardial function and blood flow in the CBC group compared with the HTK group (Fig 3), which is also present at 2 and 3 hours after declamping when left ventricular volumes do not differ between groups (Table 3). Alternatively, less developed stunning in the CBC group could contribute to the functional differences. Compared with cold crystalloid cardioplegia, repeated cold blood cardioplegia normalizes myocardial metabolism more rapidly after declamping [22].

Limitations
The aim was to compare two different cardioplegic methods in a clinically relevant experimental setting. Both arrhythmias and varying degree of pulmonary hypertension, problems well known in pig models involving CPB and myocardial ischaemia–reperfusion, were observed. Four animals were excluded. In a clinical setting both pharmacologic and respiratory interventions would be used as needed. This, however, would conceal or amplify any beneficial or disadvantageous effects and differences between the two cardioplegic methods.

Conclusions
In an experimental pig model both one single infusion of HTK cardioplegic solution and repeated oxygenated cold blood cardioplegia result in rapid cardiac arrest. One hour after declamping following 60 minutes of cardiac arrest, contractility and cardiac index are better preserved and subendocardial radial strain is better maintained in hearts arrested with blood cardioplegia. The difference is less pronounced, but still present for up to 3 hours after declamping. Reduced release of troponin-T indicates better ischemic protection.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
Custodiol was generously supplied by NorMedica, Copenhagen, Denmark. Financial support was obtained from the Bergen University Heart Fund, from Locus for Cardiac Research, University of Bergen, and the Western Norway Regional Health Authority. We acknowledge the technical assistance of Lill-Harriet Andreassen, Cato Johnsen, Gry-Hilde Nilsen, Anne Aarsand, and Inger Vikøyr and the staff at the Vivarium, University of Bergen.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Arslan A, Sezgin A, Gultekin B, et al. Low-dose histidine-tryptophan-ketoglutarate solution for myocardial protection Transplant Proc 2005;37:3219-3222.[Medline]
  2. Careaga G, Salazar D, Tellez S, Sanchez O, Borrayo G, Arguero R. Clinical impact of histidine-ketoglutarate-tryptophan (HTK) cardioplegic solution on the perioperative period in open heart surgery patients Arch Med Res 2001;32:296-299.[Medline]
  3. Sunderdiek U, Feindt P, Gams E. Aortocoronary bypass grafting: a comparison of HTK cardioplegia versus intermittent aortic cross-clamping Eur J Cardiothorac Surg 2000;18:393-399.[Abstract/Free Full Text]
  4. Holper K, Meisner H, Hahnel C, Massoudy P. Technical refinements in myocardial protection: infants—adults Thorac Cardiovasc Surg 1998;46(Suppl 2):292-297.[Medline]
  5. Savini C, Camurri N, Castelli A, et al. Myocardial protection using HTK solution in minimally invasive mitral valve surgery Heart Surg Forum 2005;8:E25-E27.[Medline]
  6. Salvador L, Mirone S, Bianchini R, et al. A 20-year experience with mitral valve repair with artificial chordae in 608 patients J Thorac Cardiovasc Surg 2008;135:1280-1287.[Abstract/Free Full Text]
  7. Kober IM, Obermayr RP, Brull T, Ehsani N, Schneider B, Spieckermann PG. Comparison of the solutions of Bretschneider, St. Thomas' Hospital and the National Institutes of Health for cardioplegic protection during moderate hypothermic arrest Eur Surg Res 1998;30:243-251.[Medline]
  8. Fannelop T, Dahle GO, Matre K, Segadal L, Grong K. An anaesthetic protocol in the young domestic pig allowing neuromuscular blockade for studies of cardiac function following cardioplegic arrest and cardiopulmonary bypass Acta Anaesthesiol Scand 2004;48:1144-1154.[Medline]
  9. Matre K, Fannelop T, Dahle GO, Heimdal A, Grong K. Radial strain gradient across the normal myocardial wall in open-chest pigs measured with Doppler strain rate imaging J Am Soc Echocardiogr 2005;18:1066-1073.[Medline]
  10. Steendijk P, Staal E, Jukema JW, Baan J. Hypertonic saline method accurately determines parallel conductance for dual-field conductance catheter Am J Physiol Heart Circ Physiol 2001;281:H755-H763.[Abstract/Free Full Text]
  11. Glenny RW, Bernard S, Brinkley M. Validation of fluorescent-labeled microspheres for measurement of regional organ perfusion J Appl Physiol 1993;74:2585-2597.[Abstract/Free Full Text]
  12. Matre K, Moen CA, Fannelop T, Dahle GO, Grong K. Multilayer radial systolic strain can identify subendocardial ischemia: an experimental tissue Doppler imaging study of the porcine left ventricular wall Eur J Echocardiogr 2007;8:420-430.[Abstract/Free Full Text]
  13. Baan J, van der Velde ET, de Bruin HG, et al. Continuous measurement of left ventricular volume in animals and humans by conductance catheter Circulation 1984;70:812-823.[Abstract/Free Full Text]
  14. Baan J, van der Velde ET, Steendijk P, Koops J. Calibration and application of the conductance catheter for ventricular volume measurement Automedica 1989;11:357-365.
  15. Hawk CT, Leary SL, Morris SL. Formulary for laboratory animals3rd ed.. Ames: Blackwell Publishing; 2005.
  16. Winer BJ. Statistical principals in experimental design2nd ed.. New York: McGraw-Hill; 1971.
  17. Buckberg GD, Brazier JR, Nelson RL, Goldstein SM, McConnell DH, Cooper N. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. J Thorac Cardiovasc Surg 1977;73:87-94.[Abstract]
  18. Yang Q, Zhang RZ, Yim AP, He GW. Release of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in porcine coronary arteries exposed to hyperkalemia: effect of nicorandil Ann Thorac Surg 2005;79:2065-2071.[Abstract/Free Full Text]
  19. Vinten-Johansen J, Julian JS, Yokoyama H, et al. Efficacy of myocardial protection with hypothermic blood cardioplegia depends on oxygen Ann Thorac Surg 1991;52:939-948.[Abstract/Free Full Text]
  20. Fischer UM, Klass O, Stock U, et al. Cardioplegic arrest induces apoptosis signal-pathway in myocardial endothelial cells and cardiac myocytes Eur J Cardiothorac Surg 2003;23:984-990.[Abstract/Free Full Text]
  21. Ramlawi B, Feng J, Mieno S, et al. Indices of apoptosis activation after blood cardioplegia and cardiopulmonary bypass Circulation 2006;114(1 Suppl):I-257-I-263.[Abstract/Free Full Text]
  22. Runge M, Hughes P, Peter Gotze J, Petersen RH, Steinbruchel DA. Evaluation of myocardial metabolism with microdialysis after protection with cold blood- or cold crystalloid cardioplegia. A porcine model. Scand Cardiovasc J 2006;40:186-193.[Medline]

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