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Ann Thorac Surg 2003;76:1227-1233
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Myocardial protection with intermittent cold blood during aortic valve operation: antegrade versus retrograde delivery

^a Bristol Heart Institute, University of Bristol, Bristol, United Kingdom

^* Address reprint requests to Mr Ascione, Consultant Senior Lecturer, Cardiothoracic Surgery, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
e-mail: r.ascione{at}bristol.ac.uk

Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

 
BACKGROUND: Intermittent antegrade cold blood cardioplegia is superior to warm blood cardioplegia in patients who have aortic valve operation. This study compared the cardioprotective efficacy of intermittent antegrade and retrograde cold blood cardioplegia with emphasis on metabolic stress in the left and right ventricles.

METHODS: Thirty-nine patients who had elective aortic valve replacement were prospectively randomly selected to receive intermittent antegrade or retrograde cold blood cardioplegia. Left and right ventricular biopsies were collected 5 minutes after institution of cardiopulmonary bypass and 20 minutes after cross-clamp removal and were used to determine metabolic changes. Metabolites (adenine nucleotides, amino acids, and lactate) were measured using high-powered liquid chromatography and enzymatic techniques. Serial measurement of troponin I release was also used as a marker of myocardial injury.

RESULTS: Preoperative characteristics were similar between groups. There was no in-hospital mortality, and no differences were observed in postoperative complications. Preischemic concentration of taurine was significantly higher in left ventricular biopsies, whereas adenosine triphosphate tended to be lower in the left ventricle. At reperfusion adenosine triphosphate levels were significantly lower than preischemic levels in right but not left ventricles irrespective of the route of delivery. The alanine-glutamate ratio was significantly elevated in both ventricles. Myocardial injury as assessed by troponin I release was also significantly increased in both groups.

CONCLUSIONS: Retrograde and antegrade intermittent cold blood cardioplegic techniques are associated with suboptimal myocardial protection. Metabolic stress was more pronounced in the right than the left ventricle irrespective of the cardioplegic route of delivery used.

	Introduction

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Patients with significant aortic valve stenosis develop left ventricular hypertrophy (LVH) as an adaptive response to increased left ventricular wall stress [1]. Myocardial hypertrophy increases myocardial metabolic demand, reduces coronary vasodilator reserve especially in the subendocardial layers, and renders the heart more vulnerable to ischemia during cardiac operations [2, 3]. In view of the fact that most of the myocardial protection techniques have been investigated and developed in the setting of coronary operation, it is not surprising that the choice of optimal cardioplegia in patients presenting with LVH remains controversial [4–8]. Differences between the two pathologies suggest that cardioplegic techniques developed for ischemically diseased heart might not be suitable for hypertrophic hearts [9]. In support of this is our recent study showing that antegrade delivery of intermittent cold blood cardioplegia was superior to warm blood cardioplegia in patients with LVH who had aortic valve operation [10]. This was the opposite of what we found in patients who had coronary revascularization [11, 12].

Retrograde blood cardioplegia is an established method of myocardial protection and has been advocated during aortic valve replacement [4, 6, 13]. However, the efficacy of using retrograde cardioplegia alone for myocardial protection remains controversial, especially regarding protection of the right ventricle [14, 15]. In this study we examined the efficacy of antegrade versus retrograde route of delivery of intermittent cold blood cardioplegia in protecting hypertrophic hearts during valve operation in terms of myocardial metabolic derangements in both left and right ventricles, global myocardial injury, and early clinical outcome.

	Material and methods

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Patient selection
Eligibility for operation was based on medical history, echocardiography, and most recent angiogram. The endpoints of the study were myocardial metabolic changes, myocardial injury and clinical outcome.

Thirty-nine patients with LVH who had aortic valve replacement for isolated valve stenosis were prospectively randomized to antegrade (n = 21) or retrograde (n = 18) intermittent cold blood cardioplegia. The randomization codes were concealed in numbered sealed opaque envelops. The treatment allocation for a patient was determined by opening the next envelope the evening before the operation.

Exclusion criteria included coronary artery disease, significant aortic regurgitation, left ventricular ejection fraction less than 30%, insulin-dependant diabetes mellitus, and previous heart operation. The United Bristol Healthcare Trust Ethical Committee approved the study, and all patients gave informed consent.

Operative procedure
Anesthetic technique and surgical procedure have been reported previously [9]. Briefly, propofol infusion at 3 mg/kg per hour was combined with remifentanyl infusion at 0.5 to 1 µg/kg per minute. Neuromuscular blockade was achieved by 0.1 to 0.15 mg/kg pancuronium bromide or vecuronium, and the lungs were ventilated to normocapnia with air and oxygen (45% to 50%). Mean arterial pressure of 60 mm Hg or above was maintained with increments of metaraminol 0.5 to 1.0 mg or volume. Heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 480 seconds or above before commencement of cardiopulmonary bypass. Additional 3000 IU of heparin was administered if required.

Cardiopulmonary bypass was established by using an aortic cannula and a two-stage venous cannula in the right atrium. A standard circuit was used—a Bard tubing set, which included a 40-micron filter, a Stockert roller pump, and a hollow fiber membrane oxygenator (Monolyth, Sorin Biomedica, Midhurst, UK). The prime composition in the extracorporeal circuit was 1000 mL of Hartmann's solution, 500 mL of Gelofusine, 0.5 g/kg mannitol, 7 mL of 10% calcium gluconate, and 6000 IU of heparin. Nonpulsatile flow was used, and flow rates throughout bypass was 2.4 L/m² per minute. Systemic temperature was actively cooled down to 32°C. The left ventricle was vented in all patients through the right superior pulmonary vein.

Myocardial protection was achieved by using antegrade or retrograde cold (6 to 8°C) blood cardioplegia, with added K⁺ and Mg²⁺ to give a final concentration of 20 mmol/L K⁺ and 5 mmol/L Mg²⁺. The cold blood cardioplegic solution was similar in the two groups; it was a mixture of the patient's blood withdrawn from the cardiopulmonary bypass circuit and St. Thomas' I cardioplegic solution (4 blood:1 St Thomas' I) [7, 11]. After cross-clamping and opening of the ascending aorta, the cardioplegia was administered in the antegrade group directly into the coronary ostia as a 1-L bolus (700 mL in the left followed by 300 mL in the right ostia) at a pressure of 150 mm Hg (total delivery time approximately 3 minutes). Infusions of 200 mL for each ostium were repeated at 15-minute intervals. In the retrograde group, a retrograde coronary sinus cardioplegic catheter (Edwards LifeScience, Irvine, CA) was introduced through a purse-string suture into the right atrium and guided into the coronary sinus. The catheter was inserted for 1.5 cm in the coronary sinus, and its position was checked by manual palpation, pressure, and by the type of peculiar wave pressure. Finally, the appropriate delivery of cardioplegia was also confirmed visually at time of administration by checking the cardiac venous system. After cross-clamping, a bolus of 1 L of cardioplegic solution was infused into the coronary sinus at an infusion pressure of no more than 50 mm Hg. Repeated doses of 400 mL were delivered at 15-minute intervals.

Clinical data
Perioperative clinical outcome data were collected prospectively in the Patient Analysis and Tracking System (Dendrite Clinical Systems Ltd, London, UK). Heart rate and rhythm were monitored continuously and displayed on a monitor that included an automated detector of arrhythmia during the first 72 hours postoperatively (Solar 8000 Patient Monitor; Marquette Medical Systems, Milwaukee, WI). Twelve-lead electrocardiographic recordings were performed preoperatively, 2 hours postoperatively, and then daily thereafter until discharge. Clinical diagnostic criteria for perioperative myocardial infarction were new Q waves of greater than 0.04 ms, a reduction in R waves greater than 25% in at least two leads, or both. Biochemical diagnostic criteria for perioperative myocardial infarction were peak troponin I concentrations higher than 3.7 µg/L and a troponin I concentration greater than 3.1 µg/L 12 hours postoperatively or greater than 2.5 µg/L at 24 hours postoperatively [16, 17].

Collection of ventricular biopsy specimens
Transmural biopsies of the left ventricular apical or anterolateral free wall and the right ventricular free wall (4 to 12 mg wet weight) were taken using a Trucut needle (Baxter Healthcare Corporation, Northbrook, IL). Two biopsies were collected from each ventricle; the first biopsy was taken 5 minutes after institution of cardiopulmonary bypass before aortic cross-clamping (control), the second after 20 minutes of reperfusion following removal of the aortic cross-clamp. Each specimen was frozen immediately in liquid nitrogen until processing analysis of metabolites. A research technician blind to the operative technique performed the analyses.

Extraction and measurement of metabolites in biopsy specimens
The procedure used to extract the metabolites was similar to that described previously [10, 11]. In brief, frozen biopsy specimens were crushed under liquid nitrogen, and the resultant powder was extracted with perchloric acid. An aliquot was taken for protein determination, and the rest of the extracts were centrifuged at 1500 x g for 10 minutes at 4°C. The supernatant was neutralized and processed to determine metabolites. Protein determination was carried out using a protein determination kit from Sigma (Poole, Dorset, United Kingdom). Bovine plasma albumin (Sigma) was used as a standard. Therefore the data were expressed per protein content. Adenine nucleotides and amino acids were measured using high-powered liquid chromatography as previously reported [18]. Lactate was determined by using a kit from Sigma (Poole, Dorset, United Kingdom)

Troponin i assay
Blood concentration of myocardial troponin I was determined preoperatively and 1, 4, 12, 24, and 48 hours postoperatively. The assay was performed using ACCESS Immunoassay System (Beckman Instruments, Inc. Chaska, MN).

Statistical analysis
Categorical variables were analyzed using either the Fischer exact test or the ² test where appropriate. Comparison between continuous variables was made using analysis of variance or t test where appropriate. All statistical analyses were performed with the aid of a computerized software package (Statview for Windows; SAS Institute Inc, Cary, NC).

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

 
Clinical outcome
Preoperative patient characteristics are shown in Table 1, whereas intraoperative and postoperative data are shown in Table 2. There were no in-hospital deaths. No differences were observed between groups in terms of postoperative complications.

View larger version (29K): [in this window] [in a new window]   Fig 1. Baseline (preischemic) concentrations of important metabolites in the normal right ventricle (hatched bars) compared with the hypertrophic left ventricle (open bars). Mean ± standard error. *p less than 0.05 compared with right ventricular biopsy. (ADP = adenosine diphosphate; Ala = alanine; AMP = adenosine monophosphate; ATP = adenosine triphosphate; Glu = glutamate.)

View larger version (14K): [in this window] [in a new window]   Fig 2. Concentrations (nmol/mg protein) of myocardial metabolites in ventricular biopsies from left and right ventricles of patients in the antegrade group, collected before ischemia (solid bars) and after reperfusion (open bars). Mean ± standard error *p less than 0.05 compared with corresponding value in control biopsy. (Ala/Glu = alanine-glutamate ratio; ATP = adenosine triphosphate.)

View larger version (17K): [in this window] [in a new window]   Fig 3. Concentrations (nmol/mg protein) of myocardial metabolites in ventricular biopsies from left and right ventricles of patients in the retrograde group, collected before ischemia (solid bars) and after reperfusion (open bars). Mean ± standard error *p less than 0.05 compared with corresponding value in control biopsy. **p less than 0.05 versus control and left ventricle. (Ala/Glu = alanine-glutamate ratio; ATP = adenosine triphosphate.)

Myocardial injury
There was a considerable time-dependent postoperative release of troponin I in both groups (Fig 4). However, the release of troponin I tended to be higher in the retrograde group throughout the study, although this did not reach statistical significance (eg, p = 0.08 for 1 hour postoperatively). This trend was also seen when considering the total release more than 2 days postoperatively (4.45 ± 0.8 versus 6.8 ± 0.72 ng/mL for antegrade and retrograde, respectively).

View larger version (17K): [in this window] [in a new window]   Fig 4. Time-dependent postoperative release of troponin I (ng/mL) in both groups. Values are mean ± standard error. (Pre-op = preoperative.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

Myocardial ischemia provokes changes in the intracellular concentration of metabolites (eg, decrease in ATP, increase in lactate and alanine-glutamate ratio) and ions (eg, H⁺ and Na⁺). If coronary flow is restored quickly, then metabolic and ionic homeostasis are reestablished and recovery occurs. However, reperfusion after prolonged ischemia can lead to irreversible damage caused by Ca²⁺ loading and generation of reactive oxygen species. Strategies to protect the myocardium involve manipulations that are aimed at reducing the extent of metabolic and ionic changes during ischemia and early reperfusion. Therefore, cardioplegic techniques that confer the best metabolic preservation tend to be most protective [9–12].

Cardiac muscle adapts to changes in the body (eg, substrate availability and physiologic demands) by modifying muscle function, altering the synthesis and degradation rates of specific proteins, and altering the use of substrates [20]. When the heart is chronically overloaded, it enlarges and major remodeling of structure and function occurs. This may determine occurrence of hypertrophy. In hearts with aortic stenosis, LVH leads to increases in left ventricular end-diastolic volume and pressure, myocardial work, and oxygen demand [21]. The metabolic state of severely hypertrophied myocardium is anaerobic [22]. This is likely to make the heart more vulnerable to ischemia and reperfusion injury, a situation seen during open-heart operation. The right ventricle, however, generally is not affected by these compensatory mechanisms, as it is not chronically overloaded [22].

Methods of retrograde delivery have been tested mostly during coronary operations. The rationale is that retrograde delivery provides a relatively uniform distribution of cardioplegia even in the presence of severe coronary artery disease, which can affect uniform distribution with antegrade delivery [15], and that it is effective in the presence of aortic regurgitation. One of the major findings of this study is that both routes of delivery produced significantly more metabolic stress in the right ventricle than the left ventricle. One possible explanation is that many anomalies or variations have been identified in the venous anatomy of the heart, which might affect the perfusion of the right ventricular free wall and septum during retrograde delivery [15]. With regard to antegrade delivery, the observed difference might be due to the smaller volume of cardioplegia administered into the right coronary ostium at induction. A further explanation for the worse protection of the right ventricle with retrograde delivery could be its baseline metabolic status. It has been suggested that overload hypertrophy (volume or pressure) occurring in the left ventricle may induce changes in the metabolism of the myocardium, which may in turn lead to persistent modifications in mitochondrial function [23]. This is in agreement with our finding of relatively higher ATP and lower taurine levels in the normal right ventricle compared with the hypertrophied left ventricle at baseline. In keeping with these findings is the higher level of taurine found in the hypertrophied hearts of rats and of patients who died of congestive heart failure [24]. Whether changes in myocardial taurine during ischemia is important for protection remains controversial [19, 25].

Limitations of the present study are that we did not use weight-adjusted doses of cardioplegia and that we did not measure myocardial temperature. These methods would have increased the scientific value of our findings. In conclusion, this work suggests that the myocardial protection is suboptimal with both antegrade and retrograde intermittent cold blood cardioplegia. Myocardial damage is more pronounced in the right ventricle than the left ventricle irrespective of the route of delivery used.

	Acknowledgments

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This work was supported by grants from the British Heart Foundation.

	Discussion

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion References

 
DR MARSHALL L. JACOBS (Philadelphia, PA): Could you tell us a little bit about your perfusion strategy? Did you use global hypothermia of mild or moderate degree? Did you use total bypass with caval tourniquets and exclusion? And how was the heart vented? What I am getting at really is the question of whether you think subtle rewarming or incomplete cooling of the right ventricle would be sufficient to account for the difference in your observations.

DR LOTTO: We used a single double-stage cannula in the right atrium, and we vented the right superior pulmonary vein in our patients, and we went down to 32 degrees of a systemic perfusate and we did not use any ice slush on the heart, and that was actually true in both groups.

DR JACOBS: You say you did not use topical coolant?

DR LOTTO: No, we did not.

DR JACOBS: Did you measure myocardial temperature in the right and left ventricles?

DR LOTTO: No, we did not.

DR RICHARD N. GATES (Orange, CA): Several years ago in the laboratory at UCLA we did some similar experiments looking at antegrade and retrograde distribution of cardioplegia using microspheres. Correlating our laboratory with your clinical findings, we, too, noted that both the right and left ventricles received theoretically acceptable cardioplegia flow per milligram of tissue for an arrested heart using either antegrade or retrograde. We also found that flow in the left ventricular sections compared to the right ventricular sections was three to four times higher. If we placed a purse-string suture around the coronary sinus and then delivered the cardioplegia, that difference went away, and left and right ventricular perfusion was equal. It has been our clinical practice since that time to place a purse-string suture about the coronary sinus for all cases where the right atrium is to be opened as well as for cases where the right ventricle is hypertrophied.

So my question is, do you have any experience in using a non-purse-stringed coronary sinus in patients who have significant pulmonary hypertension with right ventricular hypertrophy or conditions where right ventricular hypertrophy is present? In such cases have you had good protection with simple non-purse-stringed retrograde delivery?

DR LOTTO: Thank you for your comments. No, we do not have results on the technique of purse-stringing the coronary sinus. I want to make a comment on the retrograde delivery. We used a bimanual technique in order to position the cannula, and actually we are aware that several studies showed the presence of a different distribution of the venous system into the coronary sinus, and that can account for differences into the left and the right ventricles.

The other question in this study that arose is that the right ventricle is not hypertrophied, and from a previous study that was published in the European Journal of Cardiothoracic Surgery, we know that cold blood cardioplegia is effective in protecting the hypertrophic heart, but we do not know if it is as effective in protecting the so-called normal right heart.

DR PEDRO J. DEL NIDO (Boston, MA): One thing is surprising about your data: there has been a lot of work showing that the coronary venous blood from the right ventricle returns directly to the right atrium, but it does not go to the coronary sinus very much; however, you also found a deficit even when you used antegrade-delivered cardioplegia directly into the right coronary artery. That finding implies that either the 300 mL that you delivered is not enough or just the heat transferred to the right ventricle, which is the anteriormost structure, is causing it to warm up and be less protected. Of all the possible strategies, have you changed your patient management after you saw those data? In other words, have you altered the way that you manage right ventricular protection?

DR LOTTO: The way we are looking into the protection of the heart is more towards the temperature of the cardioplegia delivery. In fact, at the moment, at the Bristol Heart Institute we are starting the possibility of using a final hot shot in order to try to wash out the metabolites that might accumulate in the heart.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Attilio A. Lotto Raimondo Ascione Massimo Caputo Alan J. Bryan Gianni D. Angelini Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lotto, A. A. Articles by Suleiman, M-S. Search for Related Content PubMed PubMed Citation Articles by Lotto, A. A. Articles by Suleiman, M-S. Related Collections Myocardial protection