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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.54 no.3 Campinas May/June 2004
Thyroid function profile in infants submitted to cardiac surgery with cardiopulmonary bypass*
Aspectos de la función tiroidea en lactantes sometidos a cirugía cardíaca con circulación extracorpórea
Paula Maria da Cruz, M.D.I; Carmem Narvaes Bello, TSA, M.D.II; Miguel Lorenzo Barbero Marcial, M.D.III; José Otávio Costa Auler Júnior, TSA, M.D.IV
IMestre em Medicina pela Faculdade
de Medicina da Universidade de São Paulo (Área de Concentração:
Anestesiologia); Médica pertencente ao Corpo Clínico do Hospital São
Joaquim da Real e Benemérita Sociedade Portuguesa de Beneficência
IIDoutora em Medicina pela FMUSP; Médica Assistente do Departamento de Anestesiologia do HCFMUSP
IIIDiretor da Unidade Cirúrgica de Cardiologia Pediátrica do Instituto do Coração do HCFMUSP
IVProfessor Titular da Disciplina de Anestesiologia da FMUSP; Diretor da Divisão de Anestesiologia do HCFMUSP
BACKGROUND AND OBJECTIVES: Cardiac surgery
with cardiopulmonary bypass (CPB) is related to euthyroid disease or hypothalamic-pituitary-thyroid
system depression. Abnormal hemodynamic status induced by CPB is responsible
for several endocrine-metabolic changes, triggering complex systemic inflammatory
response. This study aimed at evaluating triiodothyronine (T3), tetraiodothyronine
(T4) and thyrotrophin (TSH) behavior in infants submitted to cardiac
surgery with CPB.
METHODS: Participated in this study 15 infants. Blood samples for T3, T4 and TSH evaluation were collected in four moments: M1 - after anesthetic induction; M2 - at surgery completion; M3 - six hours after surgery completion; M4 - 24 hours after M1. To complete this study the following parameters were evaluated: mean blood pressure (MBP), central blood temperature (ºC), tissue oxygenation and acid-base attributes (M1, CPB, M2, M3 and M4).
RESULTS: The patients' means aged, weigh, height and body surface were 3.9 months; 4.708 kg; 0.65 m and 0.3 m2 respectivety. Plasma T3 (p < 0.0001), T4 (p < 0.0001) and TSH (p = 0.0021) concentrations have significantly varied throughout the study with T3 concentrations progressively decreasing. Lowest T3 and T4 values were coincident with highest Ht and Hb values, discarding hemodilution effects. Highest serum TSH concentrations have shown a possible hypothalamic-pituitary-thyroid system reaction to hypothermia and of massive iodine absorption (topic use of antiseptic solutions). "Low T3 Syndrome" aspects were identified in all studied moments.
CONCLUSIONS: There have been changes in serum T3, T4 and TSH concentrations in infants submitted to cardiac surgery with cardiopulmonary bypass.
Key Words: ANESTHESIA, Pediatric; HORMONES: thyroid; SURGERY, Cardiac
JUSTIFICATIVA Y OBJETIVOS: La cirugía
cardíaca con circulación extracorpórea (CEC) relacionase a la
enfermedad eutiroidea o a la depresión del eje hipotálamo-hipofisário-tiroideo.
El estado hemodinámico incomún impuesto por la CEC es responsable
por diversas alteraciones endócrino-metabólicas, acarreando compleja
respuesta inflamatoria sistémica. Esta investigación tuvo como objetivo
analizar el comportamiento de la triiodotironina (T3), tetraiodotironina
(T4) y tireotrofina (TSH) en lactantes sometidos a cirugía cardíaca
MÉTODO: Fueron estudiados 15 lactantes. Las muestras de sangre para pesquisa de T3, T4 y TSH fueron obtenidas en 4 momentos designados: M1 - después de la inducción de la anestesia; M2 - después del final de la cirugía; M3 - 6 horas después del final de la cirugía y M4 - 24 horas después del M1. Para complementar esta investigación, fueron estudiadas las variaciones de los siguientes parámetros: presión arterial media (PAM), temperatura sanguínea central (ºC), atributos de la oxigenación del tejido y del equilibrio ácido-base (M1, CEC, M2, M3 y M4).
RESULTADOS: Las medias de edad, peso, altura y superficie corpórea de los pacientes fueron 3,9 meses; 4,708 kg, 0,65 m y 0,3 m2respectivamente. Las concentraciones plasmáticas de T3 (p < 0,0001), T4 (p < 0,0001) y TSH (p = 0,0021) variaran significativamente durante el período estudiado, siendo que las de T3 declinaran progresivamente. Las menores tasas de T3 y T4 coincidieran con las mayores de Ht y Hb, descartando los efectos de la hemodilución. Las mayores concentraciones séricas de TSH demostraran la probable reacción del eje hipotálamo-hipofisário-tiroideo a los efectos de la hipotermia y de la absorción maciza por el yodo (uso tópico de soluciones anti-sépticas). Fueron identificados aspectos de la "Síndrome del T3 bajo" en todos los momentos estudiados.
CONCLUSIONES: Fueron observadas alteraciones en las concentraciones séricas de T3, T4 y TSH en lactantes sometidos a la cirugía cardíaca con circulación extracorpórea.
Cardiac surgery with cardiopulmonary bypass (CPB) is related to euthyroid disease or hypothalamic-pituitary-thyroid system depression. Abnormal hemodynamic status induced by CPB is responsible for several endocrine-metabolic changes, triggering complex systemic inflammatory response 1. Euthyroid disease, evidenced by transient thyroidal hormones peripheral metabolism unbalance, is interpreted as an organic defense mechanism aiming at decreasing baseline metabolism, but it may also mean poor prognosis 2-4. In the lab it is manifested in two ways 5:
1. "Low T3 Syndrome": presence of decreased T3 serum concentrations and high reverse T3 concentrations (T3r) in the presence of normal T4 and TSH. This phenomenon is caused by lower desiodinase type 1 - 5 activity, which is the enzyme normally responsible for generating T3 as from T4 and for the production of diiodothyronines as from T3r (inactive metabolite). As result, T3 is not satisfactorily produced while serum T3r rates are increased. The situation is further worsened by further alternative metabolic pathway action through desiodinase type 1 - 5, which generates T3r (but not T3) as from T4. Serum T3r rates are then increased by higher production and inadequate clearance.
2. "Low T3 and T4 Syndrome": more severe, caused by deficient TSH stimulation and followed by the decrease or inefficacy of thyroid hormone carrying proteins. In this case, serum T3r concentrations are virtually not changed because type 1 - 5 desiodinase (alternative pathway) does not find enough substrate, which is T4.
Euthyroid disease has already been documented in adults submitted to cardiac surgery with CPB; however pediatric patients have uncertain behavior due to immaturity 6.
This study aimed at evaluating T3, T4 and TSH behavior in infants submitted to cardiac surgery with CPB.
After the Ethics Committee approval, 15 infants, physical status ASA III, IV and V, submitted to cardiac surgery for cyanotic and non-cyanotic disease correction were prospectively evaluated. Exclusion criteria were children with congenital thyroidal metabolism disorders, hypothalamic-pituitary-thyroid system disorders, having received iodine contrast (cardiac catheterization) or with parents with thyroid dysfunction. Blood samples for T3, T4 and TSH evaluation were collected in four moments: M1 - after anesthetic induction; M2 - at surgery completion; M3 - 6 hours after surgery completion; M4 - 24 hours after M1. The following parameters were also evaluated: in moments M1, CPB (maximum hypothermia determined by the surgical team), M2, M3 and M4, the behavior of the following variables: mean blood pressure (MBP), central blood temperature (esophageal thermometer, ºC), hematocrit (Ht), hemoglobin (Hb), oxygen partial pressure (PaO2), oxygen arterial saturation (SpO2), blood pH (pH), excess bases (EB) and bicarbonate ion (HCO3-).
General anesthesia was induced with fentanyl, midazolam and pancuronium 7. Antiseptic technique consisted of extensive topic application of anti-germ solution (1% active iodine, 100 mL), followed by refined ethyl alcohol and Povidine® (10% active iodine). Children were submitted to perfusion with pediatric membrane oxygenator under assisted hypothermia (28 to 20 ºC) and non-pulsatile blood flow generated by the CPB pump roller system (1.5 L.min-1). Perfusate (600 to 700 mL ) aimed at maintaining hematocrit above 30% through the administration of blood products 8. T3 and T4 were dosed by the radioimmunoassay method and TSH was dosed by the immunoradiometric method.
Normal values: T3 - 0.8 to 2 ng.mL -1; T4 - 4.5 to 12.5 µg.dL -1; TSH - 0.3 to 4.5 mUl.mL -1.
Means along time were evaluated by profile analysis and quantitative variables by Dunnet and Bonferroni's test, considering significant p < 0.05.
T3, T4 and TSH concentrations varied significantly along time (p < 0.05). Highest T3 (although slightly below normal reference values) and T4 means were obtained in M1. Lowest T3 and T4 means were found in M4. Highest TSH concentrations were obtained in M2 and lowest TSH concentrations were obtained in M3. Numeric results are shown in table I, while hormonal concentrations along time are shown in figure 1, 2 and 3.
All other parameters have also varied significantly along time (p < 0.05), except for Ht and Hb (Table II). Lowest MBP, central blood temperature, Ht, Hb, pH, EB and HCO3- means were obtained at CPB. Highest Ht and Hb concentrations were found in M4.
According to hormonal means obtained, it is possible to consider that early on (M1) there were already lab aspects of "Low T3 Syndrome", and several factors may have contributed for such:
a) Malnutrition - congenital heart diseases in general course with significant caloric deprivation originated from inadequate diet, nutrients malabsorption or high metabolic consumption 9. Hypercatabolic state, when present, is the result of excessive catecholamines production and not of thyroid hormones hyperactivity. Malnutrition directly affects T4 conversion into T3 and, in the presence of liver failure, there are changes in T3 and T4 transport due to the lack of plasma carrying proteins TBG (Thyroid-Binding Globulin) and TBPA (Thyroid-Binding Pre-Albumin) 10,11. Thyroid hormonal activity depression is also common 12;
b) Preoperative fasting - exaggerated infant fasting, or worse, in infants with decreased nutritional reserves, promotes circulating fatty acids release which interferes with thyroid hormones transportation by proteins. Adults submitted to 24-hour food suppression have developed "Euthyroid Sick Syndrome", characterized by lower tissue T4 conversion with progressive generation of T3r. Oral glucose normalizes serum T3 13;
c) Preoperative medication - some drugs, such as furosemide, directly affect biochemical binding of T3 and T4 to TBG, TBPA and albumin by the competition mechanism 14.
Highest serum TSH concentrations (although within normal limits) were obtained in M2, suggesting that there has been more pituitary stimulation at cardiac surgery completion. However, lab aspects of "Low T3 Syndrome" still remained.
Topic application of iodinated products (anti-germ and iodine tincture) in children results in massive iodine absorption by the skin not necessarily with previous integrity disruption. Contamination is proven by increased serum and urinary concentrations of this ion 15-17.
Metabolism is affected in two ways:
a) Lower hormone synthesis by the thyroid (Wolf-Chaikoff effect) because of thyroid-peroxidase inhibition and consequent blockade of organification (or iodination) of thyroglobulin (substance generator of thyroid hormones in glandular parenchyma);
b) Lower peripheral conversion of T4 into T3 (euthyroid disease) - since iodine excretion is exclusively achieved by renal clearance, this type of intoxication, in addition to impairing neonate and infant renal function (whose glomerular filtration rate is already physiologically decreased), may lead to prolonged thyroid hypofunction 18. Primary transient hypothyroidism is configured and characterized by significant plasma TSH increase together with decrease in T3, T4 and their free fractions 12.
Another aspect to be considered is the interference of drugs.
Steroids, used to attenuate CPB-induced inflammatory response, directly reach three metabolic sites: biochemical binding of hormones to carrying proteins (increased free hormones), tissue T4 conversion, and pituitary TSH secretion decrease, in this case not followed by increased T3 and T4, but by the opposite 12,13.
Dopamine depresses pituitary activity leading to lower TSH production even after stimulation with exogenous TRH (thyrotrophin release factor), with lab installation of secondary or transient pituitary hypothyroidism 12.
Heparin releases lipases and, as a consequence, triglycerides hydrolysis into non-esterified free fatty acids, impairing the binding of hormones to plasma proteins 19. Heparin also prevents the binding of hormones to specific protein sites. Increased blood fatty-acids due to its use, however, seems to be of little relevance in neonate and infant cardiac surgeries 20.
Increased free hormones (T3F and T4F) during CPB 21 have been attributed to the administration of sodium bicarbonate which, like heparin, changes the biochemical affinity of hormones to circulating proteins. Possible prolonged metabolic acidosis may also affect intracellular conversion of T4 into T3 22.
Systemic inflammatory response, undesirable event inherent to CPB, interferes with thyroid hormones secretion through the release of immune system chemical mediators. The presence of cytokines during pediatric surgeries has been reviewed by Saatvedt et al. 23 who have observed persistent reverse correlation between serum IL-6 and IL-3 rates. IL-6 and tumor necrosis factor, released during CPB-induced hypoperfusion, possibly due to intestinal bacterial translocation, decrease T3 generation as from T4 and decrease serum TSH 24,25 (depressing effect on pituitary).
Non-pulsatile blood flow, directly responsible for transient anterior pituitary secreting hypofunction, also affects the hypothalamic-pituitary-thyroid system, decreasing the amount of serum cortisol. Exogenous TSH administration does not increase TSH during CPB, thus establishing one more factor contributing for secondary transient hypothyroidism 26,27.
T3/Ht ratio has allowed for the investigation of hemodilution effects, but lowest T3 concentrations were paradoxically found after CPB 28. We have considered a possible influence of inadvertent thyroid hormones administration in the perfusate through blood transfusion, but this was considered irrelevant due to hemodilution 29,30 (half-lives of T3, T4 and TSH present in one red-cell concentrate unit are respectively: 1 to 2 days; 8 days and 54 minutes). Proteins scavenging observed in adult surgeries (with the use of Cell Saver), however, has been substantial and also seems to explain the increase in T4F after CPB in pediatric surgeries 31.
Hypothermia activates the hypothalamic-pituitary-thyroid system promoting sympathetic nervous system hyper-reactivity with the release of catecholamines in the plasma 32. Experimental studies in rats have shown increased plasma TSH 30 minutes after exposure to cold, due to intensive pituitary stimulation with higher TRH production 33. TRH secretion in these conditions is independent of the amount of TRH previously present in the hypothalamus during normothermal situations 34,35. Fundamental thyroid metabolic changes in neonates are based on abrupt fetal exposure to the extra-uterine environment, with sudden circulating TSH increase three hours after birth. Chronic exposure to cold is also related to increased T3 and T4 12,13.
A comparative study with children (1.5 to 13 months) submitted to CPB under normothermia or hypothermia (±18 ºC) has shown major TSH increase in the second group, suggesting that this phenomenon is not restricted to birth, but is a consequence of anterior hypothalamus pre-optic area cooling 36.
The interpretation of M2 results shows lower T3 and T4 rates together with increased TSH, and it should be highlighted that the effects of acute contamination with iodine and of hypothermia were possibly preponderant. This way, in this study, it was observed that neuraxis was not depressed, suggesting that it has actively responded to these factors.
Progressive T3 and T4 decrease would not be related to hemodilution effects, since highest Ht and Hb means were found in M4. Plasma THS decrease in M3 seems to be related to the exposure to hormonal secretion depressing agents, such as dopamine, and/or the release of inflammatory response substances (cytokines). However, even in these two situations, there were lab evidences of "Low T3 Syndrome".
In our study, cardiac surgery with CPB for congenital heart disease correction in infants has promoted significant changes in T3, T4 and TSH behavior during the studied period. This way, there are several etiologies promoting thyroid metabolic changes during pediatric cardiac surgeries. The major cause of intraoperative primary hypothyroidism, surely promoted by acute and massive iodine absorption by the skin as a consequence of the use of anti-septics 16,37, could have been totally abolished since there are other non-iodinated compounds that are also effective. Cases of reoperation in a short period of time may mean further and even more severe contamination. Excess iodine in the body may lead to prolonged thyroid hypofunction state called Wolff-Chalkoff effect 12-14 (or thyroid peroxidase block), a long time described in adults. This means that during this period, excessive iodine is not incorporated to thyroglobulin molecule present in glandular parenchymal colloidal substance. This organic phenomenon prevents the disproportional production of circulating T3 and T4 and consequent systemic metabolic unbalance (hyperthyroidism). Effects of this unbalance in infants are not known, but it is known that it persists while all uptaken and retained iodine in the thyroid is not excreted. Initial result is decreased glandular T3 and T4 production with simultaneous serum TSH increase 13,17.
Some studies have shown that hypothermia is an independent factor promoting, per se, expressive pituitary response with increased circulating TSH 32-34. In this case, this is an additional effect similar to iodine contamination.
There are however other agents during pediatric cardiac surgeries with CPB, which may simultaneously promote transient secondary hypothyroidism (that is, pituitary response depression) 17,29,30. Among them, few may be abolished or at least attenuated, since they are inherent to intraoperative and anesthetic techniques, such as the use of drugs as steroids, dopamine, heparin, furosemide, sodium bicarbonate, non-pulsatile blood flow and hemodilution 1,8,12,14,19,22,24,27. One has to consider, however, that in normal physiological conditions, pituitary responds to massive iodine absorption (with increased TSH production), provided there is no situation maintaining it hypofunctioning, such as those intervening during the perioperative period.
The conclusion, then, is that during infant cardiac surgery, thyroid function is the result of all effects acting sometimes on the direct production of hormones by the gland and increasing circulating TSH (primary hypothyroidism), sometimes on the hypothalamic-pituitary-thyroid axis decreasing TSH (secondary hypothyroidism) 20, and sometimes on peripheral thyroid hormones metabolism. These manifestations, if transient, determine the presence of euthyroid disease 13,31, characterized by reversible but sometimes prolonged thyroid function disorders with extremely relevant postoperative effects 2-5. In this study it was not possible to investigate the real magnitude of pituitary response to exogenous iodine contamination, although increased serum TSH has prevailed.
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Dr. José Otávio Costa Auler Júnior
Divisão de Anestesiologia do Instituto do Coração do HC FMUSP
Av. Dr. Enéas de Carvalho Aguiar, 44
05403-000 São Paulo, SP
Submitted for publication June 10, 2003
Accepted for publication October 1, 2003
* Received from Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo, SP