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Ann Thorac Surg 1995;60:745-747
© 1995 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery Nottingham City Hospital Hucknall Rd Nottingham Ng5 1pb England
To the Editor:
I was interested to read the article by Mainwaring and associates [1] concerning the changes in thyroid hormone concentrations during cardiopulmonary bypass in neonates. They quote a similar study my colleagues and I performed in infants [2], and comparison of the two articles raises several interesting points:
(1) In our study, the pump prime (containing Ringer's solution and fresh concentrated red cells) had an undetectable total thyroxine (T4) concentration, a total triiodothyronine (T3) concentration equivalent to 5% of the mean preoperative value for the 10 infants studied, and a thyroid-stimulating hormone (TSH) concentration equivalent to 6.2% of the mean preoperative value. These findings are in marked contrast to those of Mainwaring and associates, where total T3 concentrations were similar to preoperative levels and total T4 and TSH concentrations were 55% and 12% of preoperative levels.
The prime for this study comprised red blood cells, 5% albumin, and fresh frozen plasma, the latter presumably accounting for the differences and highlighting the potential effect on the metabolic response to cardiopulmonary bypass of a change in prime constituents, as has been noted in studies of other hormones and intermediary metabolites [3].
(2) At the onset of cardiopulmonary bypass, the pump prime instantly dilutes the child's blood volume up to fivefold in a 3-kg baby. Clearly, the concentration of any substance within the blood must be reduced at this instant, and although release from stores or a more active response might subsequently reverse this, without correcting for the effects of hemodilution at least in the initial stages, as Mainwaring and associates have failed to do, interpretation of early results is very difficult. Furthermore, with unknown changes in the plasma albumin concentration and with systemic heparinization, measurements of free T3 and free T4 concentration are much less useful as an index of thyroid hormone status than measurements of total T3 and total T4.
(3) Mainwaring and associates demonstrate, as we have done, an initial reduction in the TSH concentration with the onset of bypass, but recovery after 24 hours. In our study, more frequent sampling showed a more complex pattern but demonstrated changes in TSH concentration that complemented and predated the changes in T3 and T4 concentrations. I would therefore take issue with the conclusion that there is transient suppression of the pituitary-thyroid axis; rather, I think both our results show a remarkable responsiveness of the pituitary-thyroid axis, but suggest abnormal function at the hypothalamo-pituitary level instead.
(4) Finally, it is interesting to speculate on the effects of povidone-iodine skin preparation on thyroid function. Mainwaring and associates do not mention the type of skin preparation used, but it is well established that the skin of neonates allows significant transcutaneous iodine absorption, with plasma levels increasing as much as 14-fold after routine preparation [4]. Because high iodine concentrations are known to reduce plasma T4 levels and may also lead to renal impairment, the choice of skin preparation should be carefully considered in both neonates and small infants, particularly in view of the bypass-induced changes in thyroid hormone status.
References
Cardiac Institute Children's Hospital Health Center San Diego Ca 92123
Nichols Institute 33608 Ortega Highway San Juan Capistrano Ca 92690
To the Editor:
We thank Dr Mitchell for his comments regarding our article. Although our data are generally consistent with the data that he and his colleagues published [1], the interpretation of these data was remarkably different. We would like to take this opportunity to review the rationale for our conclusions.
As Dr Mitchell points out, the institution of cardiopulmonary bypass (CPB) in the neonate results in a ``dilutional'' effect of fourfold or fivefold. Whether this results in a rise or fall of constituents in the circulation depends on the composition of the CPB prime. In our study, the prime contained higher concentrations of free T4 and free T3, similar concentrations of total T3, and lower concentrations of total T4 and TSH as compared with the preoperative infant serum sample. After the institution of bypass, the concentrations of hormones (with the exception of free T3) were altered as expected based on the admixture of the patients' serum and the prime. Thus, free T4 concentrations rose, total T3 remained unchanged, and total T4 and TSH concentrations fell. Interestingly, free T3 concentrations, which one would anticipate would have increased upon institution of bypass, remained unchanged. This represents an unexpected finding, and we will present our theory on this momentarily.
The endocrinologic response of the neonate to CPB will be influenced by a host of factors. A partial list of possible factors would include age, weight, diagnosis, composition of CPB prime, type of operation, duration of CPB (cross-clamp and circulatory arrest duration), medications including anesthetic and steroids, inotropic infusions [2], and the postoperative condition of the patient. Our study was designed in an attempt to achieve as much uniformity as possible, recognizing that each patient would have a different clinical course. Given these variables, we observed a fairly reproducible pattern of thyroid hormone response. This response was characterized by an 80% reduction in free T3 and TSH levels. The simultaneous reduction in both free T3 and TSH levels can only be accounted for by suppression of the pituitary-thyroid axis.
The causes of the decreases in free T3 and TSH may be quite complex and separate. Upon institution of CPB, free T3 levels were unchanged instead of increased (as anticipated based on CPB prime concentrations). The failure of free T3 to increase may reflect compartmental shifts in that circulating T3 represents a small percentage of total body T3, and T3 exchanges rapidly between vascular and extravascular compartments [3, 4]. The subsequent fall in free and total T3 levels is attributable to decreased free T4 availability, dysfunction of the enzyme 5`-deiodinase (which converts T4 to T3 and has been implicated in the development of the euthyroid sick syndrome), and decreased secretion due to decreased TSH. However, the decrease in free T3 levels cannot be attributed to the effects of hemodilution, as Mitchell has suggested. The decrease in TSH levels may also have a multifactorial cause. The decreased TSH levels coincided with or were preceded by an increase in free T4 concentrations. This is precisely the expected response, because free T4 has a negative feedback regulation of TSH release. Levels of TSH could be affected by changes in thyrotropin-releasing hormone release from the hypothalamus, but this has yet to be studied in the neonate.
We do not agree with Mitchell that total hormone measurements would be more reflective of thyroid hormone status than free hormone measurements. In our study, we used equilibrium dialysis measurements to determine free T3 and free T4 levels. This methodology is highly accurate and measures free hormone levels directly [5]. Because free T3 is the principal form of biologically active thyroid hormone within the cell, free T3 levels are critical in evaluating the potential implications of thyroid hormone alterations on cardiac function. The methods used in Mitchell and associates' article measured total hormone levels, and therefore do not assess biologically active hormone concentrations. Inferences made concerning free hormone levels from total hormone measurements may be inaccurate due to changes in serum proteins and serum binding (which our study documents based on the change in ratios of free to total hormone levels postoperatively as compared with preoperatively). Because the assay techniques used in our study measure free hormone levels, there is no need to perform a mathematical correction for hemodilution (as Mitchell suggested). What one wants to know is the actual concentration of biologically active circulating thyroid hormone, and this is best answered by measuring free T3 using equilibrium dialysis techniques.
The issue of heparinization is important, as it can lead under certain circumstances to spuriously high measurements of free T4 [6]. Heparin induces lipase-dependent triglyceride lipolysis by raising nonesterified fatty acids concentrations in the assay as compared with the native serum sample. This requires serum triglyceride concentrations of 180 mg/dL or more [6]. Levels observed in normal neonates are usually less than 100 mg/dL [7]. Consequently, the initial increase in free T4 measurements is unlikely to have been spurious.
The transcutaneous iodine absorption could be another confounding variable. Iodine administration to normal individuals blocks the response of the thyroid gland to TSH stimulation. This would ordinarily result in reduced T4 levels with elevated serum TSH levels [8]. Although we did use iodine skin preparation in our patients, our data demonstrated decreased rather than increased serum TSH concentrations. Therefore, the effect of iodine could not account for the pattern of changes observed.
In summary, we are in substantial agreement with Dr Mitchell on many issues. We do not agree that free hormone concentrations are less important than total hormone concentrations. Measurements of free hormone concentrations are critical to the understanding of this complex endocrinologic system. Because free T3 will influence cardiac function, we believe that it is important to measure these levels directly. Our study demonstrated profound decreases in free T3 and TSH levels, and we continue to believe that the only conclusion that can be derived from our data is that there is suppression of the pituitary-thyroid axis.
References
This article has been cited by other articles:
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  S. D. Marks, C. Haines, I. M. Rebeyka, and R. M. Couch Hypothalamic-Pituitary-Thyroid Axis Changes in Children after Cardiac Surgery J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 2781 - 2786. [Abstract] [Full Text] [PDF]
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