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J Thorac Cardiovasc Surg 1999;117:1128-1135
© 1999 Mosby, Inc.
SURGERY FOR ADULT CARDIOVASCULAR DISEASE |
From the Departments of Anesthesiology,a Surgery,band Medicine,c Columbia University College of Physicians and Surgeons, New York, NY.
Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.
Received for publication May 8, 1998. Revisions requested July 8, 1998. Revisions received Feb 18, 1999. Accepted for publication Feb 19, 1999. Address for reprints: Samantha L. Mullis-Jansson, MD, 177 Fort Washington Ave, New York, NY 10032.
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Abstract |
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Introduction |
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1-5
Several studies evaluating the impact of T3 administration on low output states after cardiopulmonary bypass have yielded conflicting data. 6-9 The purpose of our study was to re-examine the impact of intravenous T3 administration on hemodynamic variables, inotropic support requirements, and morbidity/mortality after coronary artery bypass grafting (CABG).
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Methods |
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Outcome variables included perioperative hemodynamic data, pressor and inotropic requirements, morbidity, and mortality. Morbidity parameters included the prevalence of atrial fibrillation, pacemaker dependence, myocardial ischemia and infarction, and mechanical assistance (intra-aortic balloon pump or left ventricular assist device). Pharmacologic and hemodynamic data were collected before induction of anesthesia, on weaning from cardiopulmonary bypass, on arrival in the intensive care unit (ICU), and at frequent subsequent intervals until discharge from the ICU. Perioperative myocardial ischemia/infarction was diagnosed electrocardiographically by an independent cardiologist, blinded to the protocol, who applied creatine kinase MB fraction (>6%), aspartate aminotransferase (>100 mg/dL), and electrocardiographic criteria for myocardial infarction.
Preoperative and anesthetic management
Patients receiving ß-blockers or calcium channel blockers (or both) received these medications on the morning of the operation. Only patients who had been receiving stable dosages of these medications for at least 2 weeks before the operation were included in the study. Preoperative medication consisted of midazolam 0.05 to 0.1 mg/kg orally in the preoperative holding area 1 hour before the operation. On arrival in the operative suite and before the induction of anesthesia, routine monitoring was established, including placement of topical electrocardiographic electrodes, radial artery and thermodilution catheters (Swan-Ganz catheters; Baxter Healthcare Corp, Edwards Division, Santa Ana, Calif), and digital pulse oximetry. Hemodynamic monitoring included continuous measurement of heart rate, arterial and central venous pressure, cardiac output, and pulmonary artery pressure. Intravenous induction was effected with fentanyl (25 µg/kg), midazolam (0.05 mg/kg), and vecuronium (0.1 mg/kg). Inhalational anesthetics were not used. Anesthesia was maintained with a combination of intravenous fentanyl, midazolam, and vecuronium by continuous infusion. Operating room data were continuously recorded by the LifeLog automated record keeper (Modular Instruments, Malvern, Pa) and stored in a database located in a central file server. Data from the ICU and cardiac step-down units were collected on a portable computer and analysis was performed off-line.
Statistical analysis
All data were analyzed with the use of SAS system software (SAS Institute, Inc, Cary, NC). Data were presented as mean ± standard deviation. Preliminarily, continuous variables were compared by the paired and unpaired Student t test and analysis of variance (ANOVA), and discrete variables were analyzed by 
2 and Fisher's exact test. 10-12
To discern whether a treatment effect existed postoperatively (myocardial ischemia/infarction, pacemaker dependence, and atrial fibrillation), we used multiple logistic regression, controlling for other preoperative and demographic variables, such as age, gender, ejection fraction, and calcium channel and ß-blockade. These equations also generate odds ratios and 95% confidence intervals. The longitudinal data, such as heart rate, cardiac index, systemic vascular resistance, and dopamine and dobutamine administration, were studied with the use of a number of statistical methods: repeated-measures ANOVA (Proc Mixed) to discern group differences over time and Generalized Estimation Equations (the GEE method) for incorporating covariates into the model. Both methods allow for the covariance structure of the data to be estimated, due to the potential correlation among observations on the same individual between time points.
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Results |
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). Temporary or permanent pacemaker support was required in a greater proportion of patients in the placebo group (24.7%) than in the T3 group (13.6%, P = .013) and was also more common with increasing age and cardiopulmonary bypass time (Table V). Furthermore, 7 patients (4.1%) in the placebo group required temporary mechanical assistance after the operation (4 intra-aortic balloon pumps, 3 left ventricular assist devices), whereas no patient in the T3 group required such assistance. Finally, there were 2 deaths in the entire cohort of patients, both occurring in patients assigned to the placebo group.
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Discussion |
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13-15 Concurrently, Novitzky and colleagues 16 reported that T3 exerted significant beneficial effects when administered to pigs subjected to myocardial ischemia and cardiopulmonary bypass. In subsequent years, other basic science and clinical investigations supported the premise that thyroid hormone metabolism was altered in advanced heart failure and that T3 administration improved myocardial performance after cardioplegic arrest and ischemic injury. 17-19 In one clinical study, T 3 was found to decrease the prevalence of atrial fibrillation after CABG surgery. 22 Despite these encouraging results, other studies have failed to demonstrate significant improvements in clinical outcome indices in patients treated with T3 . 21,22 For this reason, T3 has not become a routine component of pharmacologic management of patients with heart failure or those undergoing cardiopulmonary bypass. In an effort to reconcile the issues raised by these conflicting reports, we performed a clinical trial designed to closely examine the effect of T3 on both physiologic parameters and clinically relevant outcome variables in patients undergoing CABG. In our study, patients receiving T3 on crossclamp removal and for 6 subsequent hours demonstrated significantly better myocardial function after the operation than patients receiving placebo, resulting in lesser requirements for inotropic support. Interestingly, these benefits were not diminished by preoperative ß-blocker therapy. Although preoperative ß-blocker therapy did not influence the overall prevalence of perioperative myocardial ischemia, T3 administration dramatically reduced the rate of this complication. This effect on the prevalence of perioperative ischemia is consistent with data obtained in animal models of myocardial ischemia. The requirement for mechanical assistance, an indicator of profound myocardial dysfunction, was significantly reduced in patients receiving T3, underscoring the potential clinical utility of this agent. Notably, although the clinically relevant beneficial effects of T3 administration on perioperative inotropic support and myocardial infarction were experienced by patients of both sexes, improvements in cardiac index were not observed in women. An explanation for the differences between the genders remains to be found.
Atrial fibrillation remains a common postoperative complication in patients undergoing CABG surgery, occurring in 5% to 40% of patients and contributing significantly to length of hospital stay and costs. 23 A variety of factors have been identified as predictors of perioperative atrial fibrillation: These include advanced age, male gender, preoperative hypertension, the requirement for intra-aortic balloon pump support, postoperative pneumonia, and the need for extended postoperative ventilatory support. 24-26 Others have suggested that the presence of significant disease in the vessels supplying the sinoatrial and atrioventricular nodes is a strong predictor of postoperative atrial arrhythmias. 27 In our study, although increased age conferred a higher risk for postoperative atrial fibrillation, neither gender, cardiopulmonary bypass time, nor T3 therapy appeared to affect the incidence of this arrhythmia. Finally, in patients receiving T3, there was a dramatic decrease in the need for postoperative pacemaker support (13.6% vs 24.7%) during the first 48 hours after cardiopulmonary bypass, confirming clinically the experimentally established chronotropic effects of this agent. Of the 6 patients who eventually required permanent pacemaker insertion, only 1 was a member of the T3 group.
In conclusion, our single-center study has confirmed the positive inotropic and chronotropic effects of T3 administered perioperatively in patients undergoing CABG and has furthermore identified clinically relevant benefits in these patients, including reduced rates of myocardial ischemia, pacemaker dependence, and mechanical assistance. Although female patients did not have the same improvement in hemodynamic indices after T3administration as their male counterparts, they experienced similar reductions in postoperative inotropic requirements and complication rates. The mechanisms by which T 3 exerts these beneficial effects is currently a matter of speculation and warrants a multicenter investigation to confirm that T3 treatment reduces perioperative myocardial infarction, lessens the need for mechanical support, and increases survival.
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Appendix: Discussion |
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Decreased levels of serum T3 have been consistently demonstrated after cardiopulmonary bypass. Depression of T3 levels exceeds that predicted from hemodilution and cardiopulmonary bypass and is added to the list of interventions possibly associated with euthyroid-sick syndrome.
Far more controversial is the question of whether restoring the serum T3 levels to normal results in a hemodynamic advantage. Novitzky and his colleagues have consistently demonstrated an improved hemodynamic performance after T3 administration, but a Duke study of 211 patients showed minimal effects. Klemper studied T3 administration compared with placebo in 142 patients and found mild hemodynamic improvement but no change in important clinical outcomes. Your study demonstrates a major hemodynamic and survival effect. The effect is much stronger than those previously demonstrated and raises some interesting questions. Dr Wechsler has 4 questions to which I will add 2.
1. Do you believe that the dose of 1 µg/kg as a bolus and then over the next 6 hours differed significantly enough from doses used in prior studies to account for your observations?
2. Did you require specific objective hemodynamic indices to be obtained before initiating the drug? Could the vasodilator effect of T3and the accompanying increased inotropic therapy have increased the cardiac index to account for the differences?
3. Your statistical method used predominantly univariate comparisons between significant end points. Do you think the data would hold up if subjected to a logistic regression analysis or multivariate analysis that would eliminate data points that served as surrogates for one or another?
4. I did not note in your table whether there was a significant difference in patients being operated on under reoperative conditions between the 2 groups. Was there a difference? I would like to add 2 questions to Dr Wechsler's:
One point that stood out in your presentation was the large difference in enzyme leak. Was there a difference in Q-wave myocardial infarction between the 2 groups? If not, how do you account for postoperative creatine kinase release? As I understand your protocol, the drug is given after the crossclamp is removed. Do you hypothesize some protective effect, perhaps an influence on reperfusion, that decreases ischemic injury?
Dr Mullis-Jansson. To answer the first question in relationship to the dosage of the T3: dosages that had been given in the past ranged from approximately 0.4 µg/kg all the way up to 2 to 3 µg/kg, given as a bolus. In the groups that had the 2- to 3-µg/kg boluses, there were difficulties in terms of maintaining pressure in relationship to vasodilatory responses. Klemper's group used a 0.8-µg/kg bolus. I do not think the 0.2-µg/kg difference between our study and Klemper's study would account for the difference in the results of the study. One explanation for the difference in the result may be in relationship to the percentage of patients in Klemper's study who had preoperative left ventricular dysfunction. We had a higher percentage of patients with ejection fractions less than 40% than did Klemper. About 45% of our patients had an ejection fraction less than 40%, and that may indeed explain that there may be a selective beneficial effect in patients with more morbid preoperative left ventricular function than the patients with normal left ventricular function.
Dr Schaff. The second question was whether the differences in hemodynamics might be accounted for by vasodilatation caused by the T 3 and in subsequent inotropic use to make up for that decrease in peripheral vascular resistance.
Dr Mullis-Jansson. We certainly did not see that. In fact, the only end point in which we saw a statistical difference in systemic vascular resistance was at the immediate postpulmonary/cardiopulmonary bypass measurement. In all subsequent measurements there was no difference between the groups, so I do not believe this is an afterload-reducing effect.
Dr Schaff. What about the difference in creatine kinase release? Is there a myocardial protective effect when the drug is given after the crossclamp release?
Dr Mullis-Jansson. I cannot explain it. The diagnosis of myocardial infarction was made by a cardiologist who was blinded to the protocol. The cardiologist was given the data in terms of each of the patients, and that included 5 days of electrocardiograms and all the enzyme data that were obtained on the patients for 3 days after the operation. The diagnosis was made on that basis.
Dr Karl H. Krieger (New York, NY). One further question. Atrial fibrillation is a major problem after CABG surgery, particularly when considering length of stay. Dr Klemper's study noted a statistically significant decrease in atrial fibrillation; his rate, I think, was cut in half in patients who received T3. In your study you showed a decreased incidence, corroborating his study, but the difference did not reach statistical significance. Can you propose a mechanism by which T3 would affect atrial fibrillation in the postoperative period?
Dr Mullis-Jansson. In the animal model the beneficial effects seem to be in relationship to decreasing the effects of ischemia on sinoatrial and atrioventricular node function. In the past, one of the proposed mechanisms for atrial fibrillation after CABG surgery has been to cause an insult to the sinoatrial or atrioventricular node. Perhaps T3 in some way protects this nodal mechanism such that the incidence of postoperative arrhythmias will be lower.
Dr Ahmad Rajaii Khorasan (Neptune, NJ). The dramatic difference in your survival results and the need for left ventricular assist devices in the 2 groups raises a question about the other important factors that can influence these outcomes: for example, the extent of coronary disease, pump time, number of CABGs, and so on. Please comment on the distribution of these variables in the 2 groups.
Dr Mullis-Jansson. In terms of those demographic parameters, the groups were equivalent. There was no difference in the ischemic crossclamp time or cardiopulmonary bypass time or in the number of grafts that were done. The patients seemed to be equivalent in the 2 groups. We could find no difference. In fact, other papers have suggested that some of the differences may be in relationship to those parameters, such as preoperative incidence of hypertension or advanced age (age is certainly a predictor of increased morbidity and mortality). Our groups, however, were equivalent.
Dr Patrick L. Ergina (Montreal, Quebec, Canada). I have a question that was alluded to initially. I noticed that you wanted to keep the mean arterial pressures fairly high. When you treated those patients with pressors, which many people believe have an inotropic effect to combat the effect seen on your slide of decreased systemic vascular resistance on the T3 group, did you look at that specifically as a possible confounding variable? You used norepinephrine bitartrate (Levophed), but you did not document its use.
Dr Mullis-Jansson. Right. We do use norepinephrine bitartrate (Levophed), although that is not shown in our illustrations. The dosages of norepinephrine bitartrate (Levophed) between the 2 groups were equivalent.
Dr Ergina. My second question concerns pacing. Pacing was more prevalent in the placebo group, and you noted that there were more ischemic changes in 1 group. How did you approach the paced electrocardiograms?
Dr Mullis-Jansson. In this study there was only 1 patient who was asystolic and in whom we could not get any type of rhythm strip. In the other patients, the temporary pacemaker was turned off before the 12-lead electrocardiogram was performed, and then the cardiologist read the 12-lead electrocardiogram with the patient's own native rhythm, albeit a slow one. He read it from that rhythm and rate.
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