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Ann Thorac Surg 1995;59:481-485
© 1995 The Society of Thoracic Surgeons

Thyroid Hormones Homeostasis in Pediatric Patients During and After Cardiopulmonary Bypass

Institute of Clinical Physiology, National Research Council, Pisa, and Department of Pediatric Cardiac Surgery, Ospedale G. Pasquinucci, Massa, Italy

Accepted for publication October 18, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The concentrations of thyroid hormones were measured in 14 pediatric patients before, during, and after cardiopulmonary bypass. The ages of the patients ranged between 18 months and 14 years. Patients were kept normothermic, or moderate or deep hypothermia was induced depending on the specific pathologic condition involved. A marked reduction in the levels of total triiodothyronine, total thyroxine, free triiodothyronine, and thyroid-stimulating hormone, and in the ratio of free triiodothyronine to free thyroxine was detected during the time frame of the study. The minimum levels of each hormone were reached between 12 and 48 hours after cardiopulmonary bypass, indicating that changes in thyroid function and in the conversion of thyroxine to triiodothyronine are triggered by cardiopulmonary bypass and represent specific phenomena, and that these changes are progressively exacerbated during the postoperative period. The thyroid-stimulating hormone level was markedly reduced versus its baseline values (24% ± 0.13%), despite low levels of both total (40% ± 18%) and free (39% ± 20%) triiodothyronine: it returned to its preoperative level by the third postoperative day, but both the total (75% ± 10%) and free (74% ± 3%) triiodothyronine levels remained below their baseline values for 7 days postoperatively. Neither hemodilution nor hypothermia was responsible for the alteration observed. We conclude that pediatric patients undergoing cardiopulmonary bypass manifest changes in hormone metabolism similar to those seen in adult patients. These changes increase progressively during the postoperative period, and are still present 7 days postoperatively. The exact mechanism responsible for causing these changes is not thoroughly understood. Whether triiodothyronine replacement therapy is beneficial or deleterious remains controversial.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The unusual physiologic state imposed by hemodilution, hypothermia, and nonpulsatile flow during cardiopulmonary bypass (CPB) has been considered responsible for causing the changes in thyroid hormone metabolism in patients undergoing open heart surgical procedures [1]. Study findings indicate that this phenomenon simulates the euthyroid sick syndrome, and involves markedly decreased concentrations of total (TT₃) and free (FT₃) triiodothyronine, and low normal levels of total (TT₄) and free (FT₄) thyroxine and thyroid-stimulating hormone (TSH) [1, 2]. Because of this similarity to the euthyroid sick syndrome, the replacement of triiodothyronine (T₃) has recently been suggested as a possible new way to treat or prevent the low cardiac output that arises after CPB and cardiotomy [3]. However, conflicting opinions exist as to the advisability of T₃ replacement in this situation [4].

So far, investigations have mainly been restricted to adult patients and have been carried out during and a few hours after CPB. Only very few and incomplete data are available for pediatric patients [5, 6] and on the duration of these hormone changes [7]. The purpose of this study was to assess whether CPB disturbs thyroid function in children during open heart operations, and to evaluate the nature and duration of the phenomenon.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Between January 1993 and October 1993, 14 pediatric patients (9 male and 5 female) with congenital heart diseases underwent thyroid function evaluation before, during, and after CPB. The patients ranged in age from 18 months to 14 years (mean age, 6.2 years). The main clinical data for the patients studied are summarized in Table 1.

The hematologic thyroid profile was determined upon admission; after the induction of anesthesia; 5 minutes before heparin administration; 5 minutes after the start of CPB; immediately before the termination of CPB; 5 minutes after protamine administration; at 2, 6, 12, and 24 hours after operation; and at different intervals, in multiples of 12 hours, up to a maximum of 168 hours (7 days).

A standard technique was used to institute CPB, and involved bicaval drainage and ascending aorta perfusion. The circuit consisted of a properly calibrated roller pump, a membrane oxygenator, a cardiotomy reservoir, and polyvinyl chloride tubing throughout. The circuit was primed with Ringer's lactate solution and 5% plasma protein solution (Immuno AG, Vienna, Austria). Blood was added in 10 patients. When required, bicarbonate was added to the prime. Once constituted, the prime solutions were tested for their possible effect on the thyroid profile, before the start of CPB.

Heparin was administered in a dosage of 3 mg/kg before CPB and a further dose (15 to 50 mg) was added to the prime solution. Flow was adjusted to obtain an adequate arterial pressure (40 to 70 mm Hg).

Different degrees of body temperature (normothermia, moderate hypothermia, and deep hypothermia) were used (35° to 19°C) depending on the specific pathologic condition involved. The bypass time ranged from 29 to 150 minutes (mean, 69 minutes) (see Table 1).

During the postoperative period, 5 patients received dobutamine (8 µg • kg^-1 • min^-1) and 1 also received dopamine (3 µg • kg^-1 • min^-1).

This study was approved by the Ethical Committee of the Ospedale Pediatrico Apuano and of the Institute of Clinical Physiology of the Italian National Research Council.

Hormone Assay Methods
The serum TT₄, TT₃, and TSH concentrations were measured by the fully automated immunoenzymometric assay AIA 600 system (Tosho, Tokyo, Japan). The serum FT₃ and FT₄ concentrations were measured using the gel equilibration procedure (Liso Phase RIA system; Tecno Genetics, Cassina de' Pecchi, Milan, Italy). To minimize the assay error, serum samples were assayed in different sessions (at least three times); the values given are the mean of all these assay results. In our laboratory, the normal ranges for the serum hormone concentrations are as follows: TT₄, 4.5 to 12 µg/dL; TT₃, 80 to 200 ng/dL; FT₄, 7.0 to 18.5 pg/mL; FT₃, 3.1 to 5.4 pg/mL; and TSH, 0.3 to 3.8 µUI/mL.

Statistical Analysis
Statistical analysis was carried out by a Macintosh IIsi personal computer using the Abacus Concepts Stat-View 4.0 and SuperANOVA programs (Abacus Concepts, Berkeley, CA). Repeated-measures analysis of variance was used to test the differences between hormone concentrations throughout the study; the Bonferroni test was used to compare the baseline values with the other values. The hormonal values are expressed as mean ± standard deviation in the text and mean ± standard error of the mean in the figures.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
During Cardiopulmonary Bypass and 2 Hours Postoperatively
The serum TT₃ and TT₄ concentrations (Fig 1) decreased significantly during CPB, and were 71% ± 20% (p < 0.01) and 64% ± 10% (p < 0.01) of the baseline values, respectively. Two hours after the operation, the TT₄ level showed a tendency toward returning to preoperative levels (90% ± 20%), but the TT₃ level was still well below the baseline values and tended to be less (64% ± 20%; p < 0.01) than the values obtained at the end of CPB.

View larger version (18K): [in this window] [in a new window]   Fig 1. . Time course of the total triiodothyronine (TT3) and total thyroxine (TT4) levels during and after cardiopulmonary bypass (CPB). The values (mean ± standard error of the mean) are expressed as the fraction of the baseline values. Statistical analysis performed using the analysis of variance test showed highly significant differences between the concentrations of both hormones throughout the study (p < 0.0001). (Bonferroni test: *p < 0.05; **p < 0.01.)

View larger version (17K): [in this window] [in a new window]   Fig 2. . Time course of free serum concentrations of the biologically active hormone triiodothyronine (FT3) and prohormone thyroxine (FT4) during and after cardiopulmonary bypass (CPB). Values (mean ± standard error of the mean) are expressed as the fraction of the baseline values. Statistical analysis performed using the analysis of variance test showed highly significant differences between the concentrations of both hormones throughout the study (p < 0.0001). (Bonferroni test: *p < 0.05; **p < 0.01.)

View larger version (14K): [in this window] [in a new window]   Fig 3. . Time course of the ratio of free triiodothyronine (FT3) to thyroxine (FT4) during and after cardiopulmonary bypass (CPB). Values (mean ± standard error of the mean) are expressed as the fraction of the baseline values. Statistical analysis performed using the analysis of variance test showed highly significant differences for the ratio throughout the study (p < 0.0001). (Bonferroni test: *p < 0.05; **p < 0.01.)

View larger version (14K): [in this window] [in a new window]   Fig 4. . Time course of thyroid-stimulating hormone (TSH) during and after cardiopulmonary bypass (CPB). Values (mean ± standard error of the mean) are expressed as the fraction of the baseline values. Statistical analysis performed using the analysis of variance test showed highly significant differences between the hormone concentrations throughout the study (p < 0.0001). (Bonferroni test: *p < 0.05; **p < 0.01.)

The TT₃ level showed the highest decline, and reached its lowest level 36 hours postoperatively (40% ± 18%; p < 0.01). On the sixth postoperative day, the TT₃ concentration was still significantly reduced compared with its baseline values (75% ± 10%; p < 0.05) (see Fig 1).

The FT₄ concentration tended to be slightly decreased 6 hours after operation and reached its minimum level 72 hours later (77% ± 10%) (see Fig 2).

The FT₃ concentration paralleled the TT₃ concentration, and greatly declined, reaching its lowest level 48 hours postoperatively (39% ± 20%; p < 0.01). Six days after operation, the serum concentration was still significantly reduced versus its baseline concentration (74% ± 3%; p < 0.01) (see Fig 2).

The FT₃/FT₄ ratio showed a progressive decline after CPB, reaching its minimum value (53% ± 12%; p < 0.01) between 12 and 24 hours after operation (see Fig 3). On the sixth postoperative day, the FT₃/FT₄ ratio was 73% ± 8% of its baseline value.

Between 6 and 12 hours postoperatively, the TSH level reached its lowest serum concentration (24% ± 13%; p < 0.05) (see Fig 4). The level started increasing 24 to 36 hours postoperatively and returned to its high pre-CPB level (well above the baseline value of the admission sample) 72 hours after operation (183% ± 90%).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
During CPB, as well as during systemic illnesses and surgical stress, adult patients suffer a low T₃ syndrome that involves a depression in the T₃ and FT₃ concentrations and a blunted TSH response to thyrotropin-releasing hormone (TRH) [1, 2]. The clinical importance of this low T₃ syndrome was elucidated by Hamilton and colleagues [9] in a large group of patients with advanced chronic heart failure. These investigators observed that the best predictor of mortality was a low FT₃/reverse T₃ ratio. Only very few and incomplete data are available for the pediatric age group [5, 6]. We therefore conducted an investigation in a group of pediatric patients undergoing open heart surgical procedures before, during, and after CPB up to a maximum of 7 days postoperatively.

In our study, the serum TT₃, TT₄, and TSH concentrations were found to decline significantly during CPB and remained low for several days; though the TSH level decreased significantly only after the termination of bypass versus the baseline values. Because the TT₃, TT₄, and TSH concentrations during CPB did not decrease in a proportional way, it can be assumed that this event was not simply the result of a dilutional effect. Interestingly, each hormone reached its minimum level between 12 and 48 hours after CPB, indicating that the phenomenon initiated by CPB was perpetuating itself and increasing in severity during the postoperative period when the variables usually evaluated to assess hemodilution (ie, hematocrit and plasma proteins concentration) had shown a return to the normal range. That a real modification in the thyroid hormone pattern (not one stemming from a dilutional effect) occurs is further confirmed by the measured reduction in the FT₄ and FT₃ concentrations, which, as reported, do not suffer from massive, nonphysiologic dilution [10].

The observed decline in the FT₃/FT₄ ratio, in the presence of a remarkably decreased FT₃ concentration but only a slightly reduced FT₄ concentration, may be explained by the operation of two different mechanisms: (1) a small reduction in the thyroidal production of T₄ (and probably T₃) and (2) a massive reduction in the peripheral conversion of T₄ to T₃.

The first hormone to show an increase was TSH (48 hours after the operation), followed by T₃ and T₄. It is probably by virtue of this increase in the TSH level that the physiologic homeostasis of thyroid function is reestablished.

As postulated by Wartofsky and Burman [11] for nonsurgical patients with the euthyroid sick syndrome, the hormone changes taking place after open heart operations might represent an adaptive response by which the organism reduces the energy expenditure. This hypothesis, and the observation that the hormone changes induced by CPB do not resolve with the end of bypass, but rather continue for at least several days, progressively worsening during the first 24 to 48 hours, compel us to carefully examine the advisability of replacement therapy. Previous studies in animals [12–14] and human subjects [3] have shown that T₃ replacement therapy causes a reverse in the transient ischemic events that follow the myocardial insult, thereby improving ventricular function by increasing aerobic metabolism by means of an increased synthesis of high-energy phosphates and correction of tissue lactic acidosis.

On the other hand, this same therapy might aggravate the reduction in TSH secretion, possibly inhibiting the increase in TSH and consequently abnormally prolonging the duration of the low T3 syndrome. A similar behavior was observed in a randomized prospective study that assessed the response of hypothyroxinemic patients with severe nonthyroidal illnesses to T₄ therapy [15].

Beside hemodilution, nonpulsatile flow and hypothermia have also been considered factors responsible for triggering the thyroid hormone changes occurring during CBP [1, 16]. Low serum total and free T₃ and T₄ concentrations, with inappropriately low serum TSH concentrations, have been observed in nonsurgical patients suffering from severe hypothermia [17]. Robuschi and associates [1] also postulated that hypothermia per se could be responsible for the blunted response of TSH to TRH during CPB.

In our study, different degrees of hypothermia were used during CPB, depending on the specific pathologic condition involved, with 6 patients operated on in a normothermic state (35°C). No substantial differences were observed in the overall hormone behavior in terms of the patients operated on in a normothermic state (Fig 5) versus those operated on under conditions of mild or deep hypothermia (Fig 6). The only minor difference was an acceleration in the early recovery of patients operated on in a normothermic state, but the CPB time was significantly shorter in these patients, which may also explain this observation.

View larger version (16K): [in this window] [in a new window]   Fig 5. . Time course of the serum concentrations of the biologically active hormone triiodothyronine (FT3) and prohormone thyroxine (FT4) in patients operated on in a normothermic (35°C) state (see Table 1). Values (mean ± standard error of the mean) are expressed as fraction of the baseline values.

View larger version (16K): [in this window] [in a new window]   Fig 6. . Time course of the serum concentrations of the biologically active hormone triiodothyronine (FT3) and prohormone thyroxine (FT4) in patients operated on in a hypothermic state (19° to 28°C) (see Table 1). Values (mean ± standard error of the mean) are expressed as fraction of the baseline values.

Comparison of our findings regarding thyroid function after CPB in pediatric patients is difficult because of the sparse data reported so far for this age group. Belgorosky [6] and Zucker [5] and their associates conducted an investigation in pediatric patients to assess the hormone changes taking place during CPB. Both studies were carried out before, during, and after CPB, but the period of observation postoperatively was only 48 and 24 hours, respectively, for the two studies. However, some differences do exist between our results and those reported by Belgorosky and colleagues [6], who found no changes in the TSH levels after operation.

Zucker and co-workers [5], on the contrary, observed a reduction in the TT₄, TT₃, and TSH concentrations after operation, with each hormone showing a tendency to decrease in concentration 24 hours postoperatively. Had the period of observation been longer, these investigators would probably have observed the same changes as we did.

In conclusion, based on the data revealed by our study, pediatric patients undergoing open heart surgical procedures display hormone changes similar to those observed in adult patients. These hormone changes are not exclusively confined to the CPB period, but tend to become more pronounced postoperatively. The hormone concentrations start increasing during the second and third postoperative day, but the low T₃ and FT₃ concentrations persist 6 days postoperatively. The exact mechanism responsible for causing these hormone changes has not yet been recognized. Further studies are necessary to shed more light on this phenomenon and its causes, especially before hormone replacement therapy can be considered in this setting.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Giuliano Kraft, Michela Leoncini, and Fatima Bongiorni for their excellent technical assistance.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Biagini, Divisione di Cardiochirurgia, Ospedale G. Pasquinucci, Via Aurelia Sud, Località Montepepe, 54100 Massa (MS), Italy.

This study was supported, in part, by a National Research Council–04 Committee Grant and by the ARMED Foundation.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Robuschi G, Medici D, Fesani F, et al. Cardiopulmonary bypass: a low T4, T3 syndrome with blunt thyrotropin response to thyrotropin releasing hormone. Horm Res 1986;23:151–8.[Medline]
2. Holland FW, Brown PS Jr, Weintraub BD, Clark RE. Cardiopulmonary bypass and thyroid function: a euthyroid sick syndrome. Ann Thorac Surg 1991;52:46–50.[Abstract]
3. Novitzky D, Cooper DKC, Barton CI, et al. Triiodothyronine as an inotropic agent after open heart surgery. J Thorac Cardiovasc Surg 1989;98:972–7.[Abstract]
4. Gotsche LSB-H, Weeke J. Changes in plasma free thyroid hormones during cardiopulmonary bypass do not indicate triiodothyronine substitution. J Thorac Cardiovasc Surg 1992;104:273–7.[Abstract]
5. Zucker AR, Charnow B, Fields AI, Hung W, Burman K. Thyroid function in critically ill children. J Pediatr 1985;107:552–4.[Medline]
6. Belgorosky A, Weller G, Chaler E, Iorcansky S, Rivarola MA. Evaluation of serum total thyroxine and triiodothyronine and their serum fractions in nonthyroidal illness secondary to congenital heart diseases. Studies before and after surgery. J Endocrinol Invest 1993;16:499–503.[Medline]
7. Chu SH, Huang TS, Hsu RB, Wang SS, Wang CJ. Thyroid hormone changes after cardiovascular surgery and clinical implication. Ann Thorac Surg 1991;52:791–6.[Abstract]
8. Westgren U, Burger A, Ingemansson S, Melander A, Tibblin S, Wahlin E. Blood levels of 3,5,3`-triiodothyronine and thyroxine: differences between children, adults and elderly subjects. Acta Med Scand 1976;200:493–5.[Medline]
9. Hamilton MA, Warner Stevenson L, Luu M, Walden JA. Altered thyroid hormone metabolism in advanced heart failure. J Am Coll Cardiol 1990;16:91–5.[Abstract]
10. Ekins R. Measurement of free hormones in blood. Endocr Rev 1990;91:562–672.
11. Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: the euthyroid sick syndrome. Endocr Rev 1982;3:164–217.[Abstract/Free Full Text]
12. Novitzky D, Matthews N, Shawley D, Cooper DKC, Zhudi N. Triiodothyronine in the recovery of stunned myocardium in dogs. Ann Thorac Surg 1991;51:10–7.[Abstract]
13. Dyke CM, Yeh T, Lehman JD, et al. Triiodothyronine-enhanced left ventricular function after ischemic injury. Ann Thorac Surg 1991;52:14–9.[Abstract]
14. Novitzky D, Human PA, Cooper DKC. Inotropic effect of triiodothyronine (T3) following myocardial ischemia and cardiopulmonary bypass: an experimental study in pigs. Ann Thorac Surg 1988;45:50–5.[Abstract]
15. Brent GA, Hershman J. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986;63:1–8.[Abstract/Free Full Text]
16. Bremner WF, Taylor KM, Baird S. Hypothalamo-pituitary-thyroid axis function during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1978;75:392–9.[Abstract]
17. Bacci V, Schussler A, Kaplan TB. The relationship between serum triiodothyronine and thyrotropine during systemic illness. J Clin Endocrinol Metab 1982;54:1229–35.[Abstract/Free Full Text]
18. Taylor KM, Wright GS, Bain WH, Caves PK, Beastall GS. Comparative studies of pulsatile and nonpulsatile flow during cardiopulmonary bypass. III. Response of anterior pituitary gland to thyrotropin-releasing hormone. J Thorac Cardiovasc Surg 1978;75:579–84.[Abstract]
19. Wilber JF, Utiger RD. Thyrotropin incorporation of 14C-glucosamine by isolated rat adenohypophisis. Endocrinology 1969;84:1316–21.[Abstract/Free Full Text]
20. Vale W, Grant G, Amoss M, Blackwell R, Guillemin R. Culture of enzymatically dispersed anterior pituitary cells: functional validation of the methods. Endocrinology 1972;91:562–72.[Abstract/Free Full Text]

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This Article Abstract 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): Vittorio Vanini Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murzi, B. Articles by Biagini, A. Search for Related Content PubMed PubMed Citation Articles by Murzi, B. Articles by Biagini, A.