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Ann Thorac Surg 2000;69:334-335
© 2000 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of California, Los Angeles School of Medicine, Los Angeles, California, USA
Address reprint requests to Dr Buckberg, Division of Cardiothoracic Surgery, UCLA School of Medicine, Room 62-258 CHS, Box 951741, Los Angeles, CA 90095-1741
e-mail: gbuckber{at}surgery.medsch.ucla.edu
In this issue, Dr Treasure asks the fundamental question that has guided our entire research effort these past 20 years, "Is controlled reperfusion helpful?" Many areas of our work are quoted throughout this analysis, including an astounding editorial comment in the bibliography. There is concern for the clinical validity of our methods, and for Teoh’s suggestion of routine controlled reperfusion, based upon clinical metabolic analysis. Teoh’s report is the only reported clinical manuscript added to our 32 publications. Their clinical study in this issue analyzes 20 patients treated by a modified reperfusion protocol, and concludes that controlled reperfusion is not useful, and should be abandoned routinely.
The value of scientific work is its reproduction by others, and this evaluation is welcomed. These new experiments must start with a bias, for that is the reason for the study. To reject the initial hypothesis you must precisely reproduce the approach of others. The experimenter must then abandon this bias, and become an observer to see if the experiment is correct, or if nature (or the subject studied) has not been perturbed properly. Doctor Treasure states this clearly in his editorial, "Minimization; the platinum standard for trials?" [1] An additional philosophic concept was stated by Claude Bernard, a French physiologist who wrote in "The Introduction to Experimental Medicine," that "excessive faith in your preconceived ideas leads to distorted observations that often neglect important factors that do not further your aim" [2].
The absence of benefits from controlled reperfusion is apparent from the manuscript. Doctor Ferguson asked me to comment on this contradiction of our work, and to give my thoughts about the current status of warm substrate enriched cardioplegic reperfusion, a term that I find more accurate than hot shot. My response requires understanding the method used for protection to avoid ischemia, and determining if warm cardioplegic reperfusion delivered in this study matched the approach described in our cited multiple manuscripts.
The role of St. Thomas solution in blood to prevent ischemic damage is clear neither from the content of this paper, nor from its use of the bibliography, and the value of its antegrade reinfusion of each 30 minutes is not established. This contrasts to the antegrade or retrograde delivery administered more frequently clinically, based on experimental and clinical work. St. Thomas is a crystalloid solution and is mixed with blood and cooled by a circulating system. It is not clear if cardioplegic dilution resulted when a 4 to 1 blood to cardioplegia was used, nor whether this changed the basic crystalloid constituents evaluated without blood. It is important to know the precise limitations of protection, after cardioplegic delivery is introduced to reduce ischemic or reperfusion damage. One cannot determine this from the available blood St. Thomas information. This issue is the subject of my recent editorial, "Unproven Herbal Approaches vs Tested Scientific Study" [3].
The authors enumerated 32 of our publications, "according to Buckberg’s precise specifications." However, their reperfusion approach indicates these manuscripts were not carefully read. The detailed biochemical markers of damage show reperfusion injury. More importantly, the 5% to 10% mortality, despite short (< 60 minutes) aortic clamping in 40 valve patients, coupled with intraaortic balloon counterpulsation (IABP) use and longer intensive care unit stays establish a good starting point for controlled reperfusion.
Our clinical approach to limit reperfusion damage is cited [4], but was not followed. Reperfusion calcium is lowered to 0.2 to 0.3 mmol to limit Ca++ influx [5], not to 0.5 to 0.8 µmol/L as in this study. I presume the pharmacist added less citrate phosphate dextrose (CPD). High reperfusate K+ (20 mmol/L) is avoided to minimize a delay in resuming electromechanical activity. Our 8 to 10 mmol/L KCl dose also limits high potassium that may accelerate Ca++ entry after ischemia. These investigators used a 20 mmol/L dose and encountered the expected delay in coming off bypass. Reperfusion is at 150 mL/min for 3 minutes to further limit postischemic arrest after unclamping, and to keep the reperfusion pressure less than 50 mm Hg to reduce endothelial damage [5]. Instead, 1000 mL of high potassium solution for 5 minutes at approximately 75 mm Hg pressure. Osmolarity of 360 to 400 mOsm limits edema [6], yet the authors used 320 to 360 mOsm. The substrate dose was accurate, but the increased flow, pressure, K+, Ca++, and lower osmolarity disregarded our recommendations. The result in 20 patients receiving modified reperfusion in their study differs from our results, but that is not surprising because the methods they employ were not like ours. To validate our results I will summarize some clinical reports listed below, which follow our principles, but are not cited in their bibliography.
Loop, at the Cleveland Clinic [7], studied greater than 800 high-risk coronary patients, including valve repair and replacement, and found patients treated without our protocol were 95% more likely to have a morbid event, as compared to patients treated according to our protocol. This was despite a shorter cross-clamp time (66 vs 81 minutes) in patients not treated with our protocol. A cost analysis of Cleveland Clinic data showed a $2,200.00 per patient savings, and further cost savings would occur by including outlier patients with prolonged intensive care unit and hospital times.
Kirklin evaluated substrate enhanced controlled reperfusion in greater than 2300 coronary artery bypass graft patients, and quantified the reduced mortality to approximately 2% after greater than 60 to 180 minutes of ischemia [8]. In approximately 1500 patients receiving integrated blood cardioplegic protection (including warm or cold, antegrade or retrograde, and intermittent or continuous delivery) mortality was 1.6% with greater than 50% in the high-risk category [9]. The integrated method was used in 82 consecutive high-risk patients with prolonged aortic clamping during complex valve procedures (mitral repair, 186 minutes, Ross procedure, 217 minutes) and a less than 3% IABP use and less than 2% mortality occurred [10].
Our warm reperfusion protocol was established in 1986, in the Supplement quoted in the bibliography. It evolved experimentally and was administered to patients. This contrasts to cardiac operation, as there is no protection of the heart after acute coronary occlusion, and total recovery is dependent upon warm reperfusion. This method was tested in a 156 patient international study and again in Germany [11, 12]. Return of immediate contractility after greater than 6 hours of coronary occlusion occurred in 87%, no deaths in 90 nonshock patients, and a 10% mortality in acute myocardial infarction patients in shock.
Each of these aforementioned precise applications of our controlled reperfusion analysis was based upon a method that appears in their bibliography. Perhaps deviation from these established protocols implies this investigating team thought that markedly reducing reperfusion calcium, avoiding hyperkalemia, restricting the dose, limiting hypertensive reperfusion, and counteracting edema, was unhelpful in the modified reperfusate they delivered to the 20 patients. This disregard however did not detract recommending abandonment of routine controlled warm substrate enriched blood cardioplegic reperfusion.
To answer Dr Ferguson’s second question, regarding the value of warm substrate enriched blood cardioplegic reperfusion, I believe surgical ischemia is needed to enhance visualization during operation. Consequently, reperfusion damage can occur from blood flow interruption (valve removal and suture placement, coronary revascularization) [13]. We codified some fundamental factors that limit damage, including the value of lowering Ca++, and avoiding early electromechanical activity. This was only one alteration of our multiple aspect reperfusion approaches.
The ischemic heart is vulnerable to sudden calcium influx immediately after unclamping; usually 2 to 3 synchronous beats occur, followed by ventricular fibrillation after normal blood reperfusion. Unprotected calcium entry (ie, normal Ca++) may cause hypercontracture with subsequent sarcolemmal damage. Initial cardioplegic reperfusion maintains arrest and prevents this hypercontracture, allowing a brief interval where ionic balances can recover more normally during immediate reoxygenation. Recovery of spontaneous rhythm is common. Other methods of limiting reperfusion calcium damage include calcium channel blockers and sodium/hydrogen ion exchange inhibitors. In the future, more comprehensive approaches (ie, reducing neutrophils, oxygen radical scavengers, etc) will be added as new information unfolds.
The cardiac surgeon must be aware that reperfusion injury after ischemia may be controlled by warm substrate enriched modified cardioplegic reperfusion before restoring regular blood flow by aortic unclamping. This control provides an important tool for our armamentarium. The 3 to 5 minutes to accomplish this task is a small price, compared to the morbidity and mortality from low output syndrome and subsequent exorbitant expenditure of myocytes and dollars. More information is needed before following the conclusion to abandon routine warm blood cardioplegic reperfusion after this 20 patient study. My observations underline potential dangers from imposing Procrustean ideas on complex reperfusion phenomena.
I borrow again from Claude Bernard who said, "men who have excessive faith in their theories and ideas are not only ill prepared for making discoveries. They also make very poor observations. Of necessity, they observe with a preconceived idea and when they devise an experiment, they can see, in its results, only confirmation of their theory. In this way, they distort observation and often neglect very important facts" [2].
References
This article has been cited by other articles:
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  J. M. Albes, M. Gross, U. Franke, J. Wippermann, T. U. Cohnert, R. Vollandt, and T. Wahlers Revascularization during acute myocardial infarction: risks and benefits revisited Ann. Thorac. Surg., July 1, 2002; 74(1): 102 - 108. [Abstract] [Full Text] [PDF]
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 L. B. Becker, M. L. Weisfeldt, M. H. Weil, T. Budinger, J. Carrico, K. Kern, G. Nichol, I. Shechter, R. Traystman, C. Webb, et al. The PULSE Initiative: Scientific Priorities and Strategic Planning for Resuscitation Research and Life Saving Therapies Circulation, May 28, 2002; 105(21): 2562 - 2570. [Full Text] [PDF]
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