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Ann Thorac Surg 1996;61:1328-1329
© 1996 The Society of Thoracic Surgeons
DR RICHARD D. WEISEL (Toronto, Ont, Canada): I appreciate the opportunity to discuss this elegant study from the group at Cornell University in New York. Your study was recently published in the New England Journal of Medicine and is a beautifully designed and executed trial comparing T3 to placebo therapy for patients undergoing coronary artery bypass grafting. You found improvement in cardiac index early postoperatively. However, you were careful to avoid claiming a clinical benefit from perioperative T3 treatment. Your caution was emphasized in the accompanying editorial, which suggested no clinical benefit to the perioperative use of T3. What is your current indication for T3 use? Would patients who have poor ventricular function and are at high risk for a low output syndrome coming off bypass benefit from perioperative T3 treatment?
You were surprised to find a significant reduction in the incidence of superventricular arrhythmias in the T3-treated patients. You have not been able to identify the reason for the reduced incidence of arrhythmias. In previous studies from our institution, we found that cardioplegic interventions intended to improve atrial protection did not reduce the incidence of perioperative arrhythmias. However, cardioplegic interventions that reduced perioperative ischemic injury (creatine kinase-MB release) and improved early postoperative ventricular function reduced the prevalence of postoperative atrial arrhythmias from 42% to 18% (p < 0.01). In your study T3 improved postoperative ventricular function and decreased the prevalence of atrial arrhythmias from 46% to 24% (p < 0.01). Therefore, do you believe T3 improved perioperative protection and in this way reduced postoperative arrhythmias? Do you have any creatine kinase-MB measurements in your patients that would indicate whether there was a difference in perioperative ischemic injury?
Finally, do you believe that T3 should be used prophylactically to prevent postoperative arrhythmias?
DR KLEMPERER: Thank you very much, Dr Weisel. It is true that in the New England Journal of Medicine article we did downplay the conclusions somewhat with regard to whether T3 should be used routinely. Although we did observe hemodynamic benefits, these were not of sufficient magnitude to significantly alter reliance on traditional pharmacologic agents. At our institution we have a rather aggressive policy toward giving inotropes and vasodilators to maintain cardiac parameters, and we did not find that the use of perioperative T3 therapy was capable of modifying this reliance. Our results did not support the routine use of T3 as a vasoactive agent after cardiac operations, even in patients at high risk for low cardiac output syndrome. Those are the group of patients we tried to identify. Our study did not have the power to identify whether there was a subgroup of patients who would have clinical benefit from T3 therapy.
Interpreting our results with respect to postoperative atrial fibrillation will mandate, first, an understanding of why postoperative atrial fibrillation occurs. There really is no satisfactory explanation at this time, although your comments regarding ischemia-reperfusion and postoperative hemodynamics are attractive. Triiodothyronine has been shown in numerous experimental settings to attenuate ischemia-reperfusion injury of the ventricle. Perhaps atrial injury is characterized by arrhythmias at later time points and T3 may be modifying this. I do not have a biological explanation. Experimental evidence suggests that T3 may also alter myocyte adrenergic receptor expression. Modification of neural injury, relevant to vagal input in this setting, is also under investigation in the laboratory. We have plans to conduct another clinical trial designed specifically to investigate the effects of T3 on postoperative arrhythmias with atrial fibrillation as a primary end point. This would include analysis of creatine kinase-MB measurements. We do not have those data for this study, although there were no electrocardiographic differences with respect to perioperative myocardial infarctions.
Should T3 be used routinely to decrease postoperative atrial arrhythmias? I do not think we can say that definitively at this time. This will require further evaluation, both in the clinic and the laboratory, but it is certainly an area that should attract interest to explore further.
DR DIMITRI NOVITZKY (Tampa, FL): I congratulate you for this outstanding work. For many years I have been involved studying the acute effects of T3 on the cardiovascular system. I would like to mention several points about the ``low free T3 state.'' While working at The University of Cape Town, we experienced a loss of approximately 20% of brain-dead organ donors as a result of hemodynamic instability. This prompted us to look at this problem in the laboratory. In baboons after induction of brain death a significant endocrine derangement takes place; the most relevant aspect of which was a rapid plasma free T3 reduction; however, thyroid-stimulating hormone levels remained unchanged. Triiodothyronine replacement allowed the rescue of unstable brain-dead organ donors depending up to 40 µg • kg-1 • min-1 of dopamine. After T3 therapy the inotropic support was rapidly reduced, the electrocardiogram normalized, and the previously existing arrhythmias no longer were observed. After transplantation, the observed cardiac function of these hearts procured from initially unstable donors was excellent.
This prompted us to look at the cardiac function in clinical conditions exhibiting the low free T3 state. This endocrine condition is also present during and after open heart operations on cardiopulmonary bypass. Triiodothyronine administration to animals subjected to cardiopulmonary bypass and cardioplegic arrest resulted in excellent metabolic and hemodynamic recovery of the heart, whereas hearts from control animals had a markedly depressed level of high-energy phosphates, accumulation of tissue lactate, and depressed myocardial contractility.
In a small, prospective, randomized, blinded study administering T3 to low-risk patients undergoing open heart operations we found in the T3 group a significant reduction of the systemic vascular resistance, improvement of the cardiac output, and less requirement of inotropic and diuretic requirements. No difference in surgical mortality was observed.
Exploring various therapeutic regimens we have found that the optimal therapeutic T3 loading dose is 2 to 3 µg/kg administered at the time of release of the aortic cross-clamp, followed by a T3 infusion of 0.5 µg • kg-1 • 24 h-1 for 24 to 72 hours. Using this therapeutic regimen we administered T3 to 160 high-risk patients with a mean preoperative estimated mortality of 32% (Parsonnet and STS Risk Assessment models). Using this pharmacologic T3 dosage we have not observed any change in oxygen consumption; however, the most remarkable observation was the reduction of the surgical mortality by 72%. With the same T3 regimen we have also observed beneficial T3 therapy in patients who became cardiopulmonary bypass--dependent despite high inotropic and intraaortic balloon pump support. After the T3 loading dose rapid hemodynamic recovery was observed, allowing discontinuation of cardiopulmonary bypass in all 13 patients within 20 to 30 minutes.
In my estimation T3 therapy in open heart operations is safe and efficacious; however, this therapeutic modality should be only indicated for high-risk patients undergoing open heart operations. In those with a low estimated mortality T3 therapy is not justified. Further prospective, multicenter, randomized trials are required.
DR HUSAIN NAGAMIA (Brandon, FL): I compliment Dr Klemperer on a very elegant study. My question is, Did you identify any patients who were actually hypothyroid in your group of patients, and did they benefit more than the others?
DR KLEMPERER: I will address both questions briefly. Thank you, Dr Novitzky, for your comments; I look forward to seeing your report on using the higher T3 dose. We have also found, experimentally, that T3 enhances cardiac performance without excess oxygen demand. Similarly, there was a poster presented yesterday, by DiPiero and colleagues from the University of Pennsylvania, that also showed that T3 increases cardiac contractility in an energetically efficient manner.
We did identify a few patients who had been in the hospital preoperatively and had the euthyroid sick syndrome, as opposed to classic chronic hypothyroidism. We could not distinguish any difference in the effects of T3 supplementation in these patients versus the rest of the cohort.
DR LAWRENCE I BONCHEK (Lancaster, PA): I think it has been the experience of all of us that in routine coronary bypass the major factor that prolongs hospital stay is atrial arrhythmias. Why do you think there was no difference in the length of hospital stay in your two groups?
Second, I would ask about your cost/benefit ratio, because T3 is relatively expensive. There are some improvements in postoperative recovery, but if you do not shorten length of stay then you really do not improve cost/benefit, I would imagine. Did you specifically look at costs in the two groups?
Finally, I would like to discourage the hypothesis that reperfusion injury is responsible, because we do coronary bypass without cardioplegia and with very brief intervals of cross-clamping that I doubt have any negative effect on the atrium in terms of ischemic injury. Although I have not taken the opportunity to write it up, we have looked carefully at our incidence of atrial fibrillation and it is not really lower than the statistics in the literature for cardioplegia use.
DR KLEMPERER: Thank you. I think you have identified one of the more difficult findings in our work. We did not see any changes in length of stay, which one may have expected with a nearly 50% decrease in the incidence of atrial fibrillation. However, these were a high-risk group of elderly patients with significant comorbid illnesses, and the lengths of stay were long overall. It is possible that a larger study, with greater power, perhaps even double the size based on a preliminary power analysis, would detect differences in length of stay.
The comments regarding ischemia-reperfusion injury are interesting and again emphasize that the etiology of postoperative atrial fibrillation is not clear. We did not perform a formal cost analysis in this study. Triiodothyronine has traditionally been a relatively expensive agent. I do not know if that will be true in the future. Still, an article in the September 1995 ACC Current Journal Review estimated that the additional cost per patient incurred when atrial fibrillation occurs after a routine cardiac operation is approximately $8,000, which is not trivial.
Related Article
Ann. Thorac. Surg. 1996 61: 1323-1327.
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