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Eur J Cardiothorac Surg 2007;32:501-506. doi:10.1016/j.ejcts.2007.05.021
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Department of Cardiovascular Surgery, Thorax Institute, Hospital Clinic of Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain
Received 28 February 2007; received in revised form 25 May 2007; accepted 30 May 2007.
* Corresponding author. Address: Department of Cardiovascular Surgery, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932275515; fax: +34 932275749. (Email: danielpereda{at}telefonica.net).
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Key Words: Cardioplegia • Organ preservation • Arrhythmia • Myocardial protection • Aortic valve replacement
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Celsior, an extracellular-type, low-potassium, low-viscosity solution, includes many solutes representing the most advanced concepts in organ preservation and specifically for heart transplantation (see Table 1 ). It contains glutamate, a precursor of Krebs cycle intermediates shown to improve myocardial performance after ischemia by enhancing energy production and preventing contracture lesions [16]. To limit oxidative stress, it contains reduced glutathione, a coronary endothelial protector and oxygen free radicals scavenger [17]. Finally, the solution also contains mannitol and lactobionate to prevent cell swelling and a high magnesium content to limit calcium overload. The main buffer is histidine, also present in other transplantation solutions because of its good pH control at temperatures under 10 °C [18].
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Randomization codes were concealed in numbered sealed opaque envelopes. Patients were assigned to a group by opening the next envelope shortly before the operation by the perfusionists. Patients, surgeons, and all the medical team in charge during the postoperative period were blinded for group allocation until patient discharge.
Predictive mortality score was calculated perioperatively using the European System for Cardiac Operative Risk Evaluation (EuroSCORE) in all patients.
Exclusion criteria included prior cardiac surgery, programmed concomitant cardiac surgery, renal failure requiring hemodialysis, child B/C hepatic failure, patients with COPD requiring oral steroids or supplemental oxygen therapy, known allergy to any of the products included in both perfusates used, and failure to sign informed consent. Patients with known prior history of ischemic heart disease or coronary interventions were also excluded. Coronary angiography was obtained in all patients before the operation and those showing significant lesions in the left main coronary artery (defined as >50% stenosis) or in other vessels (defined as >70% stenosis) were also excluded.
2.1 Operative procedure
Standard operative technique was employed for all patients. All operations were electively performed through total median sternotomy, under extracorporeal circulation and normothermia. Cardiac protection during ischemia was performed by intermittent administration of cold blood cardioplegia (7–8 °C) through the coronary ostia, except if the first shot that was administered through the aortic root if minimal or if no aortic valve insufficiency was present. Blood cardioplegia was 4:1 (blood-cardioplegic solution), except before aortic re-opening, when normothermic blood was administered, with potassium if electrical activity was present. Cardioplegia dosages were 12 ml/kg for induction and 10 ml/kg every 20 min thereafter for maintenance. Infusion pressure was 200 mmHg measured at the infusion pump. In order to ensure cardiac arrest with blood-diluted cardioplegia, potassium concentration was increased adding KCl with a syringe in the cardioplegia infusion circuit. During induction potassium was added according to weight as follows: 
40 kg:12 mEq; 41–60 kg:14 mEq; 61–80 kg:16 mEq; 
81 kg:18 mEq. In maintenance and reperfusion dosages, potassium was added only if electromechanical activity was present by addition of successive 2 mEq KCl bolus until arrest was achieved. After every administration, serum potassium concentration was measured.
Ventricular temperature was measured during ischemia by insertion of a temperature sensor (Genesee BioMedical Inc., Denver, CO) in the cardiac apex in a reduced number of patients in both groups to verify the degree of myocardial hypothermia. The aortic valve was replaced by a prosthesis in all cases.
2.2 Clinical data
Intraoperative and postoperative clinical data were prospectively collected. Heart rhythm and rate were monitored continuously and an automatic arrhythmia detector was used during the ICU stay. Twelve-lead EKG was obtained preoperatively, at ICU arrival and daily until ICU discharge. Serial venous blood samples for troponin I measurements were obtained preoperatively and 12 and 24 h postoperatively. Troponin I levels were measured using the Dade Behring immunoassay on the RxL-HM analyzer (Dade Behring, Maurepas, France). Upper reference limit in a control population was 0.1 ng/ml.
Diagnostic criteria for perioperative myocardial infarction were new Q waves wider than 0.04 ms and/or a reduction in R waves greater than 25% in at least two leads. Biochemical diagnostic criteria were peak troponin I concentration higher than 13 ng/ml any time after operation. We used this cut-off point because it has been previously validated to assess short- and mid-term outcome postoperatively [19].
In order to have quantitative measures of the inotropic and vasoconstrictor support, dobutamine and/or dopamine requirement data were obtained recording the total amount administered to each patient during the whole ICU stay, expressing it as mg/kg. We did the same for norepinephrine administration. We also considered for comparisons the number of patients requiring inotropic drugs in each group, the duration of this support and the need for intra-aortic balloon pump (IABP).
2.3 Statistical analysis
The study was designed as a non-inferiority pilot study to assess the safety and effectiveness of Celsior used as blood cardioplegia in elective cardiac surgery. The primary end-point of the study was to evaluate myocardial necrosis by the release of troponin I after surgery. Categorical variables were analyzed using the 
2-test and the Fisher's exact test when appropriate. Comparisons between continuous variables were made using Student's t-test or the Mann–Whitney U-test depending on normal distribution of the variable verified with the Kolmogorov–Smirnov test. The p-values less than or equal to 0.05 were considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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In the St. Thomas group, one patient required prosthesis replacement before discontinuing CPB because of malposition with occlusion of the left coronary ostium. Two patients in this group required a prolongation of CPB after aortic unclamping for hemodynamic instability while trying to wean from CPB. All these patients had good postoperative courses.
One patient in the Celsior group underwent a non-programmed concomitant septal myectomy because of the intraoperative findings during AVR. Another patient in this group required a concomitant mitral ring annuloplasty due to significant mitral regurgitation detected by intraoperative transesophageal echocardiography.
Troponin I release trend did not differ much between groups (Table 4 ). We did not observe significant differences between groups at any determination time. Mean serum troponin I was lower in the Celsior group at 12 h and almost equal at 24 h after surgery. Patients in Celsior group showed much less variability in their troponin I levels than those in the Abbott group who behaved more heterogeneously. In fact, the distribution of troponin I release in Celsior group followed a normal distribution, while Abbott group did not, showing a marked asymmetry with more patients in the superior outlier and extreme portions of the distribution at 12 h.
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The need for inotropics and norepinephrine was higher in the Celsior group, although without reaching statistical significance. Mean administered values of these drugs were greatly affected by the presence in this group of the only patient in the study with low cardiac output syndrome after surgery. This patient required IABP and pharmacologic support for 12 days. This patient had a preoperative EF of 32%, which was the lowest seen in both groups, had an ICU stay of 13 days and needed the highest amount of inotropic (17,107 mg/kg) and vasopressor (108 mg/kg) drugs among the patients in the study.
Two patients in the St. Thomas group developed severe respiratory infections and required long intubation periods and ICU stays (15 and 28 days). One of these patients was reoperated because of sternal instability. One patient in each group required a definitive pacemaker implant for complete AV blockade postoperatively. Preoperative prevalence of atrial fibrillation was similar in both groups and incidence of atrial fibrillation or atrial flutter during the postoperative period, in patients previously in sinus rhythm, was similar in both groups (Celsior, 55%; St. Thomas, 37%). In the Celsior group, two patients were reoperated in the early postoperative period due to excessive bleeding. One of them had a cardiac tamponade 8 days after surgery. All these patients had otherwise good postoperative courses.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Celsior was designed as a crystalloid cardioplegia, as all other solutions for solid-organ preservation. Its use in elective heart surgery gives us the opportunity to join the solutes of Celsior to the known benefits of blood cardioplegia, as oxygen and nutrient supply, better buffering power, etc. [16]. Nevertheless, the addition of blood in a proportion of 4:1 dilutes Celsior to an extent we did not know if the published benefits described in heart transplantation would stand in our group of patients. The clearest example was the need to increase the concentration of potassium in order to reach arrest concentrations. The aim of this prospective randomized study was to assess the safety and effectiveness of Celsior used as a bloodcardioplegic solution in elective cardiac surgery procedures, comparing the results obtained with those of a recognized cardioplegic solution, in this case the Abbott's St. Thomas’ Hospital No. 2 cardioplegic solution, which we routinely use as blood cardioplegia in our institution. We compared their performance in elective AVR operations. We chose AVR because it is a common, relatively short operation in which a homogeneous myocardial protection strategy can be adopted in most cases. However, ventricular hypertrophy and/or dilatation are common in these patients, making myocardial preservation a fundamental element for the success of the operation, possibly more than in any other heart surgery for the same ischemic times. Still, we did not expect to demonstrate significant benefits in preservation in our study. Classical preservation techniques have reached a level of safety and effectiveness in elective surgery in unjeopardized hearts. It would be necessary to screen a much higher number of patients to elucidate differences.
We decided not to include patients with known history of ischemic heart disease or previous coronary interventions. We decided this in order to assure an optimal and homogeneous delivery of the bloodcardioplegic solution through all myocardial territories during arrest. In this way, we tried to eliminate a possible bias that could have influenced the results.
During transplantation, ischemic times are usually longer than in any other type of heart surgery, reaching up to 250–300 min reasonably safely. Typically, hearts are young, healthy and well isolated with constant myocardial temperature at 4–10 °C. In this setting, Celsior has shown good preservation results [9–14]. But conditions concerning myocardial protection in our patients were quite different from those in heart transplantation. Besides being older and hypertrophied hearts, myocardial temperature during arrest was substantially higher. The sole maintenance of the heart inside the thorax over the esophagus made the myocardium to be always over 15 °C despite frequent administration of cardioplegia at 8 °C. Other possible factors of relevance are the minor but constant amount of normothermic blood that is not suctioned by the venous CPB cannula and gets to the right ventricle and the pulmonary circulation, the blood that reaches the coronary bed through the coronary sinus, and to some extent the non-coronary flow. Despite all these differences in our study with respect to the crystalloid use of Celsior in the transplant setting, we found Celsior to be a safe and effective solution as blood cardioplegia, with no mortality and no clear morbidity attributed to myocardial preservation.
Interestingly, we found no significant differences in all intraoperative and postoperative variables concerning myocardial preservation with the exception of the proportion of patients presenting with spontaneous sinus rhythm after myocardial ischemia and the need for at least one electric defibrillation, with the differences in both cases favorable to Celsior. We observed no differences either in the amount of K+ added to the cardioplegic solution to achieve electromechanical quiescence anytime during surgery or in serum K+ concentration after aortic opening.
Reperfusion arrhythmias are commonly seen after cardioplegic arrest and are one manifestation of ischemia-reperfusion injury [21,22]. There are many mechanisms believed to trigger these arrhythmias like heterogeneous reperfusion, oxidative stress by oxygen free radicals, alteration of electrolyte concentration across cell membranes, low ATP levels, etc. [21,23]. Fast return to sinus rhythm after cardioplegic arrest is generally considered an indicator of fine myocardial protection. This variable has been used in laboratory and clinical studies comparing different methods of myocardial protection during cardioplegic arrest [24,25]. It has been described that prevalence and duration of reperfusion arrhythmias increases as it does the duration of cardioplegic arrest [25], the mass of ischemic tissue and the duration and intensity of ischemia without cardioplegia [22]. These data suggest that differences observed in our study may reflect a better myocardial protection during the cardioplegic arrest with Celsior, allowing a faster return to a normal sinus rhythm after coronary flow restoration at the end of surgery. In contrast, some studies comparing Celsior with other solutions in heart transplantation have reported a higher incidence of reperfusion arrhythmias [3,10,15]. These studies did not find differences in the energy status of the grafts after ischemia and attributed this trend in the incidence of arrhythmias to changes in electrolyte concentrations, with higher K+ gradients across the cell membrane, triggering arrhythmias as in hypokalemia. We must remark that these studies compared Celsior as crystalloid solution with intracellular-like solutions that prevented this flux across the membrane and helped to maintain a physiologic electrolyte concentration.
We found no significant differences in postoperative outcome between groups as it is reflected by all variables studied. Although it did not achieve statistical significance, a higher need for inotropic drugs in the Celsior group was observed. A similar finding has been reported in a clinical transplantation study [9], where a greater need of catecholamines and vasodilators in Celsior-preserved grafts was found compared to UW solution. The grafts showed an adequate response to drugs and a progressive restoration of myocardial function over time. The authors attributed these observations to myocardial stunning. Similar results have been published in a recent experimental study comparing Celsior and UW solution in rabbits [15]. None of these studies used Celsior as blood cardioplegia. In our study, patients with Celsior-preserved hearts received inotropic and vasopressor support in a higher proportion of cases and in a higher amount, but they required it during a similar number of days and stayed fewer days in the ICU than patients in the control group. Although it is important to remark that none of these variables achieved statistical significance when compared, these studies showing similar results may give a word of caution in this respect.
In conclusion, our study shows that Celsior cardioplegia is effective and seems to be safe in elective cardiac surgery when it is administered as a conventional bloodcardioplegic solution. We found, even at relatively short cross-clamp times, a significantly higher rate of spontaneous sinus rhythm after aortic cross-clamping and a reduced proportion of patients requiring electric defibrillation for reperfusion arrhythmias, findings that could traduce a better myocardial protection during cardioplegic arrest. We found no mortality, although an expected mortality of 5% was calculated for both groups. We also did not find complications during surgery regarding cardioplegic arrest or CPB weaning. There was only one perioperative acute myocardial infarction in the Abbott group and troponin I release after surgery behaved quite similarly in both groups. Patients in the Celsior group were discharged 1 day before on average compared with those in the Abbott group.
However, special considerations must be taken. This study was performed in previously unjeopardized hearts in which a very standardized operation was performed. The procedures were carried out with relatively short ischemic times and using an optimal preservation strategy in hearts without significant coronary flow impairments. Therefore, more clinical studies with longer ischemic times and larger cohorts of patients being randomized are required to verify if Celsior brings a better myocardial protection against ischemia-reperfusion injury than other cardioplegic solutions. It will be of great interest to evaluate Celsior using different protective strategies and in longer and more demanding interventions from the myocardial preservation point of view as multivalvular, CABG and combined procedures. The possibility of lengthening the periods between consecutive cardioplegia administrations in long procedures or even safely completing an entire operation with only one administration is also to be determined.
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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