- Email: [email protected]
SERUM THYROID HORMONES CHANGES IN PATIENTS UNDERGOING CAESAREAN SECTION UNDER GENERAL OR REGIONAL ANAESTHESIA
Br.J. Anaesth. (1978), 50, 1053
SERUM THYROID HORMONES CHANGES IN PATIENTS UNDERGOING CAESAREAN SECTION UNDER GENERAL OR REGIONAL ANAESTHESIA S.
HALEVY,
M. LIU-BARNETT, P. L. Ross
AND
M. S. ROGINSKY
SUMMARY
Thyroid function in pregnancy at term has been studied thoroughly (Selenkow, Birnbaum and Hollander, 1973), but the influence of anaesthesia on thyroid function at the time of birth has not been investigated in either the mother or the newborn. Early animal experiments suggested that barbiturates, especially thiobarbiturates, depressed acutely the uptake of radioactive iodine (Wase and Greenspan, 1953; Wase, Repplinger and Foster, 1953; Wase and Foster, 1956; Mitskevich, 1957), and similar changes have been noted with cyclopropane, diethyl ether and thiopentone anaesthesia (Oyama, 1957, 1959). When thyroid uptake of iodine-131, or the release of 131 Ilabelled hormone were measured in humans, both an increase and a decrease were observed following general anaesthesia (Engstrom and Markardt, 1955; Goldenberg, Rosenbaum and Hayes, 1955; Goldenberg et al., 1956; Brown et al., 1964; Fore, Kohler and Wynn, 1966). In contrast, regional analgesia did not produce any significant changes in these measurements (Greene and Goldenberg, 1959). Conflicting results have been obtained on the effects of general anaesthesia on the plasma concentrations of serum thyroxine (T4) (Oyama, Shibata and Matsuki, 1969; Oyama et al., 1969a, b). The use of lignocaine for spinal anaesthesia was associated with a decrease in SIMON HALEVY,* M.D.; MAIDA LIU-BARNETT,* B.S., M.T.-A.S.C.P.J PATRICK L. Ross,:f PH.D.; MARTIN S.
ROGINSKY,§ M.D. ; Departments of Anesthesiology,* Psychiatry and Psychology^ and Medicine,§ State University of New York at Stony Brook, School of Medicine, Nassau County Medical Center, East Meadow, N.Y. 11554, U.S.A. Reprint requests to Dr Simon Halevy. 0007-O912/78/0050-1053 $01.00
serum T4 concentration (Oyama and Matsuki, 1971). In animal experiments, when pituitary thyrotrophic hormone (TSH) was measured following general anaesthesia, an increase or a biphasic response was noted (Mannisto, Saarinen and Ranta, 1976). However, in human studies thiopentone, halothane, diethyl ether and methoxyflurane were associated with unchanged TSH concentrations (Oyama, Matsuki and Kudo, 1972a). These inconsistent results have prevented any conclusions on the effects of anaesthesia on thyroid function in either the mother or the infant. Among the possible reasons for this are: the lack of a sensitive and precise method for the determination of thyroid function, and at the time of these studies the lack of complete tests of thyroid function. Furthermore, the effect of surgery on thyroid function in the absence of anaesthesia has not been explored sufficiently. We report some effects of anaesthesia on serum thyroid hormones in women undergoing Caesarean section. METHODS
Thirty-two unselected women undergoing Caesarean section at term were studied. The procedure for the study was approved by the Research and Medical Ethics Committee of the Nassau County Medical Center. None of the subjects had a history of thyroid or other endocrine disease. Eighteen patients received general anaesthesia, and 14 regional anaesthesia. General anaesthesia comprised induction with thiopentone 3.5 mg kg" 1 followed by suxamethonium l.Smgkg" 1 , endotracheal intubation and artificial ventilation with © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
The effects of anaesthesia on serum thyroid hormones were studied in 32 pregnant young women undergoing Caesarean section at term. Eighteen patients received general anaesthesia and 14 lumbar extradural blockade. Maternal serum concentrations of thyrotrophin (TSH), thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine (rT3) were measured using radioimmunoassay at 0, delivery and 24 h. There were no significant changes in TSH in the two groups. T4 concentrations decreased significantly at 24 h in the general anaesthesia group but regional anaesthesia produced a significant decrease only at the time of delivery. T3 concentrations decreased with both techniques. Reverse T3 increased markedly with general anaesthesia only at 24 h.
BRITISH JOURNAL OF ANAESTHESIA
1054
10 9 8 7 6 5 4 3 2
i I DELIVERY +24 h TIME OF SAMPLING
FIG. 1. Serum thyrotrophin (TSH) concentrations (mean + SEM) in patients undergoing Caesarean section under general or regional anaesthesia. 15 — 14
T
13
12
:
*
*T
10 8 7 6 5
RESULTS
TSH There were no significant changes in the concentrations of TSH at the three sampling times and there was no difference between the two groups (fig. 1).
* The human TSH kit (hTSH; Nuclear Medical Systems Inc.) uses anti-hTSH rabbit serum and a second antibody which is goat-anti-rabbit gamma globulin, together with hTSH 12sI-labelled thyrotrophin. The T4 and T3 kits (Diagnostic Products Corporation) and the rT3 (Serono Laboratories Inc.) were similar, using mI-labelled antigens, ANS (8 anilino-1-naphthalene sulphonic acid) and goatanti-rabbit gamma globulin. For RUT3, the kit was from Nuclear Medical Laboratories Inc. and used inorganic silicate as the binder. In this determination, the two hormones are used as reagents to demonstrate the number of available binding sites on serum thyroglobulin (TBG) by saturating serum TBG with the 12sI-labelled hormone.
REGIONAL
I
0
9
T4 There were no differences in the mean values of serum concentrations of T4 observed at the three sampling times between the subjects receiving general and those receiving regional anaesthesia. A significant decrease was observed at 24 h after delivery in the general anaesthesia group (P<0.02). In the regional anaesthesia group a sharp decrease was observed at
GENERAL
T
GENERAL
X
\
-
i 0
I
REGIONAL
i 1 DELIVERY + 24 h TIME OF SAMPLING
FIG. 2. Serum thyroxine (T4) concentrations (mean ± SEM) in patients undergoing Caesarean section under general or regional anaesthesia. 170 „ =
'60 150
I g
140 130
0 5
120 110
1
100
% 90 *" 80 70
i
• GENERAL ' REGIONAL
t 0
DELIVERY
24 h
TIME OF SAMPLING
FIG. 3. Serum triiodothyronine (T3) concentrations (mean ± SEM) in patients undergoing Caesarean section under general or regional anaesthesia.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
oxygen until delivery of the baby. Thereafter, anaesthesia was maintained with diazepam or pethidine, or both, nitrous oxide in oxygen and neuromuscular blockade was maintained with an infusion of suxamethonium. Regional analgesia combined a lumbar extradural block with lignocaine, bupivacaine or 2-chloroprocaine, or a combination of these agents. Venous blood samples for hormone analysis were collected just before anaesthesia, at the time of delivery and 24 h thereafter. All hormone measurements were made by radioimmunoassay techniques. Thyrotrophin (TSH), thyroxine (T4), L-3,3',5-triiodothyronine (T3), L-3, 3',5'-triiodothyronine (reverse T3, rT3) and the resin uptakes of T3 (RUT3) and rT3 (RUrT3) were measured in every sample using commercially available kits.* For rT3 resin uptake assay, the kit was the same as for RUT3 with replacement of 125 I-T3 with 125 I-rT3. All these methods have been tested for specificity, sensitivity, accuracy and reproducibility. Student's t tests were performed on basic and logarithmic data for paired samples, together with onesample tests on percentage changes; 5% was chosen as the level of statistical significance.
THYROID FUNCTION AND CAESAREAN SECTION 40 r •-O--
T
35 i
f
u _
30 -
1
J.
T
cr 25 i
0
±
lI
I
GENERAL REGIONAL
I •
DELIVERY +24 h
TIME OF SAMPLING
FIG. 4. Serum reverse triiodothyronine (rT3) concentrations (mean + SEM) in patients undergoing Caesarean section under general or regional anaesthesia.
the time of delivery (P< 0.01) but there was no further decrease at 24 h (fig. 2). T3 A significant decrease occurred with anaesthesia, continuing after anaesthesia (P< 0.01). There were no differences between the two groups at all times (fig. 3). rT3 A pattern similar to that for T3 was found for all samples except at 24 h with general anaesthesia (fig. 4). The significant decrease (P<0.01) in serum concentrations of rT3 with general anaesthesia from zero time to delivery was followed by a marked increase at 24 h (P< 0.01). Regional analgesia was associated with a sudden decrease (P<0.0l) at the time of delivery which continued for 24 h, similar to the changes occurring in T3. The significant differences in serum rT3 concentrations between the general and regional anaesthesia groups at 24 h reflected primarily this increase in rT3 with general anaesthesia at that time.
the effects of general and regional anaesthesia on this pituitary hormone. There was an early sudden decrease in serum T4 concentrations following regional anaesthesia and a later decrease after general anaesthesia. This decrease in serum T4, observed with both anaesthetic techniques, may have been produced by: an acute decrease in the secretion of T4 by the thyroid, an accelerated hepatic or renal catabolism of the circulating hormone, a redistribution of the hormone between the vascular, extracellular or intracellular compartments (Oyama, Shibata and Matsuki, 1969; Oyama et al., 1969a, b); or a perioperative expansion of the vascular space. The long half-life of T4 in the circulation and the absence of changes in thyrotrophic hormone make a decrease in T4 secretion unlikely to account for the observed changes. The absence of changes in the resin uptake of T3 or rT3 from times of sampling before to after delivery almost precludes the possibility of a decrease in the thyroid hormone-plasma binding proteins. Such a change could lead to a shift of thyroxine from the vascular space. Although no measurements of blood volumes have been carried out in this study, a decrease in this compartment at the time of delivery and in the postpartum period has been reported by other investigators. In addition, in this study the peri-operative hydration regimen was very similar and dilutional hypoproteinaemia and resulting decreased hormone concentration was unlikely to occur. Of considerable interest were the observations that the two thyroid hormones, T3 and rT3, which are derived primarily from the metabolic conversion of T4 in the liver and kidney (fig. 5), decreased throughout the study with one sample time exception. This suggests that both general and regional anaesthesia
CH 2 — CH — COOH
I
NH 2
DISCUSSION
We have demonstrated that changes in thyroid function occur at the time of delivery and in the period after delivery in women at term undergoing Caesarean section with general or regional anaesthesia. Our data are in agreement with studies showing that anaesthesia does not influence serum thyrotrophin concentrations (Charters, Odell and Thompson, 1969; Oyama, Matsuki and Kudo, 1972a, b ; Kirby, Clark and Johnston, 1973; Mannisto, Saarinen and Ranta, 1976). There were no significant differences between
3,5,3 -Triiodothyronine (T3) I
I
— /
\_o—/
\-CH2-CH-COOH
3 , 3 , 5 — Triiodorhyronine (Reverse T3, rT3) FIG. 5. Triiodothyronine and reverse triiodothyronine.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
20
T
1055
1056
It is possible that the hormone changes in maternal blood following anaesthesia occur also in the foetus. Indeed, the effect may be more pronounced since foetal liver and kidney function is immature at term. Recent reports noting a frequency of neonatal hypothyroidism as large as 1 in 4000 live births (La Franchi et al., 1977) suggest that a reduction in serum T3 following anaesthesia in the newborn may worsen neonatal hypothyroidism where this condition exists.
ACKNOWLEDGEMENT
This work was supported by Meadowbrook Education and Research Foundation, Nassau County Medical Center, East Meadow, New York. REFERENCES
Brown, P. S., Clark, C. G., Crooks, J., Elston, R. C , Parbrook, E. O., and Thorburn, A. R. (1964). Thyroid and adrenocortical responses to surgical operation. Clin. Sci., 27, 447. Burr, W. A., Black, E. G., Griffiths, R. S., Hoffenberg, R., Meinhold, H., and Wenzel, K. W. (1975). Serum triiodothyronine and reverse triiodothyronine concentrations after surgical operation. Lancet, 2, 1277. Charters, A. C , Odell, W. D., and Thompson, J. C. (1969). Anterior pituitary function during surgical stress and convalescence. Radioimmunoassay measurement of blood TSH, LH, FSH and growth hormone. J. Clin. Endocrinol. Metab., 29, 63. Chopra, I. J. (1974). A radioimmunoassay for measurement of 3, 3', 5'-triiodothyronine (reverse T3). J. Clin. Invest., 54, 583. Chopra, U., Smith, S. R., Reza, M., and Solomon, D. H. (1975). Reciprocal changes in serum concentrations of 3, 3', 5'-triiodothyronine (reverse T3) and 3, 3'-5-triiodothyronine (T3) in systemic illnesses. J. Clin. Endocrinol. Metab., 41, 1043. Engstrom, W. W., and Markardt, B. (1955). The effects of serious illness and surgical stress on the circulating thyroid hormone. J. Clin. Endocrinol. Metab., 15, 953. Fore, W., Kohler, P., and Wynn, J. (1966). Rapid redistribution of serum thyroxine during ether anesthesia. J. Clin. Endocrinol. Metab., 26, 821. Goldenberg, I. S., Lutwak, L., Rosenbaum, P. J., and Hayes, M. A. (1956). Thyroid activity during operation. Surg. Obstet. Gynecol, 102, 129. Rosenbaum, P. J., and Hayes, M. A. (1955). Patterns of thyroid-adrenocortical response after operation. Ann. Surg., 142, 786. Greene, N. M., and Goldenberg, I. S. (1959). The effect of anesthesia on thyroid activity in humans. Anesthesiology, 20, 125. Kirby, R., Clark, F., and Johnston, I. D. A. (1973). The effect of surgical operation of moderate severity on thyroid function. Clin. Endocrinol., 2, 89. La Franchi, S. H., Murphey, W. H., Buist, N. R. M., Larsen, P. R., and Foley, T. P. (1977). Neonatal hypothyroidism detected by the Oregon regional screening program. Pediatr. Res., 11, 427. Mannisto, P. T., Saarinen, A., and Ranta, T. (1976). Anesthetics and thyrotropin secretion in the rat. Endocrinology, 99, 875. Mitskevich, M. S. (1957). Glands of Internal Secretion in the Embryonic Development of Birds and Mammals, p. 177. Moscow: Acad. Sci. U.S.S.R. Oyama, T. (1957). Effects of anesthesia on thyroid function of rats. Anesthesiology, 18, 719. (1959). Effect of di-ethyl ether anesthesia on thyroid function of rats. Endocrinology, 65, 56. Matsuki, A. (1971). Serum levels of thyroxine in man during spinal anesthesia and surgery. Anesth. Analg. (Cleve.), 50, 309.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
may interfere with mono-deiodination of T4 to its metabolic products T3 and rT3. However, other explanations, such as hormone redistribution and circulatory changes, may be possible. In addition, these data suggest that regional and general anaesthesia differ in their effect on the overall metabolic transformation of T4 in the period after anaesthesia. The increase in rT3 which was seen only at 24 h after general anaesthesia remains unexplained. An increase in rT3 when T3 decreases has been observed in a variety of clinical situations (Chopra et al., 1975). Our data are in agreement with the study of Burr and others (1975) who demonstrated a decrease in serum T3 after surgery. Since the major source of T3 in plasma is from the peripheral mono-deiodination of thyroxine and both surgery and anaesthesia may decrease this process, no conclusion can be reached from this study concerning which of the two factors was primarily responsible for the observed effect. Burr and colleagues (1975) also reported an increase in serum reverse T3 following surgery, but without specific reference to the type of anaesthesia. We observed an increase in serum rT3 concentrations only after 24 h with general anaesthesia. The peripheral metabolism of T4 by mono-deiodination can yield rT3 as well as T3 (Chopra, 1974). During surgery, systemic illness, fasting and in the newborn there is stimulation of the rT3 pathway of T4 catabolism coincidental with a decrease in the T3 catabolic pathway similar to that observed with general anaesthesia in the present study. No increase in rT3 occurred when T3 concentrations were decreased during regional anaesthesia. It is known that this latter anaesthetic technique has minimal effects on hepatic and renal function. Therefore, the "expected" change in the T3/rT3 ratio at 24 h after general anaesthesia can be explained by a direct hepatic or renal effect of the systemically administered anaesthetic agent. These effects of general anaesthetics are well documented in the literature. The observation of an alteration in the T3/rT3 ratio may provide another index of alterations in hepatic and renal function produced by general anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
1057
THYROID FUNCTION AND CAESAREAN SECTION
SCHILDDRUSENHORMONSERUM UND VERANDERUNGEN IN PATIENTEN WAHREND EINES KAISERSCHNITTS UNTER ALLGEMEINER ODER LOKALER ANASTHESIE ZUSAMMENFASSUNG
Die Wirkung von Schilddrusenhormonserum auf Anasthesie wurde in 32 schwangeren jungen Frauen mit termingerechtem Kaiserschnitt untersucht. Achtzehn Patienten erhielten die allgemeine Anasthesie und 14 eine lumbale extradurale Blockade. Mutterliche Serumkonzentrationen von Thyrotrophin (TSH), Thyroxin (T4), Trijodothyronin (T3) und reverses Trijodothyronin (rT3) wurden mit Radioimmunotest um 0,0 Stunden/Geburt gemessen und 24 Stunden danach. In beiden Gruppen gab es keine bedeutenden Anderungen von TSH. In der allgemeinen Anasthesiegruppe zeigten die T4 Konzentrationen nach 24 Studen eine bedeutende Verminderung, aber die lokale Anasthesie zeigte nur zur Geburtszeit eine bedeutende Verminderung. T3 Konzentrationen verringerten sich bei beiden Techniken. rT3 verstarkte sich bemerkenswert nur nach 24 Stunden bei der allgemeinen Anasthesie. CAMBIOS EN LAS HORMONAS TIROIDES DEL SUERO EN PACIENTES SOMETIDOS A CESAREA BAJO ANESTESIA GENERAL O REGIONAL SUMARIO
VARIATIONS DES HORMONES DE LA THYROIDE DANS LE SERUM SUR DES FEMMES SUBISSANT UNE OPERATION CESARIENNE SOUS ANESTHESIE GENERALE OU SOUS ANESTHESIE REGIONALE RESUME
Les effets de Panesthesie sur les hormones de la thyroide se trouvant dans le serum ont ete etudies sur 32 jeunes femmes enceintes devant subir une operation cesarienne une fois arrivees a terme. Dix-huit d'entre elles ont ete placees sous anesthesie generale et 14 ont subi un blocage lombaire extradural. Les concentrations de thyrotrophine (TSH), de thyroxine (T4), de triiodothyronine (T3) et de triiodothyronine inversee (rT3) dans le serum maternel ont ete mesurees par essai de radioresistances a 0, au moment de Paccouchement, et 24 h apres. II n'y a eu aucun changement sensible dans la TSH des deux groupes. Les concentrations de T4 ont baisse d'une maniere significative apres 24 h dans le groupe soumis a une anesthesie generale, mais Panesthesie regionale n'a produit une diminution sensible qu'au moment de Paccouchement. Les concentrations de T3 ont diminue avec les deux techniques. Les concentrations de T3 inversee ont notablement augmente avec Panesthesie generale, mais seulement 24 h apres.
86
Se estudiaron los efectos ejercidos por anestesia sobre las hormonas tiroides del suero en 32 mujeres jovenes embarazadas sometidas a cesarea al final de su periodo de embarazo. Dieciocho pacientes recibieron anestesia general y 14 bloqueo extradural lumbar. Las concentraciones en el suero materno de tirotropina (TSH), tiroxina (T4),triyodotironina (T3) y triyodotironina inversa (rT3) fueron medidas valiendose de pruebas radioimmunologicas tomadas a 0, durante el parto y 24 horas despues. No se produjeron cambios significativos en el TSH de los dos grupos. Las concentraciones de T4 disminuyeron significativamente al cabo de 24 horas en el grupo de anestesia general, pero la anestesia general produjo una significativa disminucidn solamente en el momento del parto. Las concentraciones de T3 disminuyeron con ambas tecnicas. El T3 inverso aumento notablemente con la anestesia general solo al cabo de 24 horas.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
Oyama, T., Matsuki, A., and Kudo, T. (1972a). Effect of halothane, methoxyflurane anaesthesia and surgery on plasma thyroid-stimulating hormone (TSH) levels in man. Anaesthesia, 27, 2. (1972b). Effect of ether, thiopentone anaesthesia and surgery on plasma thyroid-stimulating hormone (TSH) levels in man. Br.J. Anaesth., 44, 841. Shibata, S., and Matsuki, A. (1969). Thyroxine distribution during ether and thiopental anesthesia in man. Anesth. Analg. (Cleve.), 48, 1. Kudo, T. (1969a). Thyroxine distribution during halothane anesthesia in man. Anesth. Analg. (.Cleve.), 48, 715. (1969b). Serum endogenous thyroxine levels in man during anaesthesia and surgery. Br. J. Anaesth., 41, 103. Selenkow, H. A., Birnbaum, M. D., and Hollander, C. S. (1973). Thyroid function and dysfunction during pregnancy. Clin. Obstet. Gynecol., 16, 66. Wase, A. W., and Foster, W. C. (1956). Thiopental and thyroid metabolism. Proc. Soc. Exp. Biol. Med., 91, 89. Greenspan, J. (1953). Effect of sodium 5-allyl-5(1 methylbutyl) 2-thiobarbiturates on uptake of I 1 3 1 by rat thyroid. Proc. Soc. Exp. Biol. Med., 84, 154. Repplinger, E., and Foster, W. C. (1953). The effect of anesthetic agents on thyroid activity of the rat. Endocrinology, 53, 630.
SERUM THYROID HORMONES CHANGES IN PATIENTS UNDERGOING CAESAREAN SECTION UNDER GENERAL OR REGIONAL ANAESTHESIA S.
HALEVY,
M. LIU-BARNETT, P. L. Ross
AND
M. S. ROGINSKY
SUMMARY
Thyroid function in pregnancy at term has been studied thoroughly (Selenkow, Birnbaum and Hollander, 1973), but the influence of anaesthesia on thyroid function at the time of birth has not been investigated in either the mother or the newborn. Early animal experiments suggested that barbiturates, especially thiobarbiturates, depressed acutely the uptake of radioactive iodine (Wase and Greenspan, 1953; Wase, Repplinger and Foster, 1953; Wase and Foster, 1956; Mitskevich, 1957), and similar changes have been noted with cyclopropane, diethyl ether and thiopentone anaesthesia (Oyama, 1957, 1959). When thyroid uptake of iodine-131, or the release of 131 Ilabelled hormone were measured in humans, both an increase and a decrease were observed following general anaesthesia (Engstrom and Markardt, 1955; Goldenberg, Rosenbaum and Hayes, 1955; Goldenberg et al., 1956; Brown et al., 1964; Fore, Kohler and Wynn, 1966). In contrast, regional analgesia did not produce any significant changes in these measurements (Greene and Goldenberg, 1959). Conflicting results have been obtained on the effects of general anaesthesia on the plasma concentrations of serum thyroxine (T4) (Oyama, Shibata and Matsuki, 1969; Oyama et al., 1969a, b). The use of lignocaine for spinal anaesthesia was associated with a decrease in SIMON HALEVY,* M.D.; MAIDA LIU-BARNETT,* B.S., M.T.-A.S.C.P.J PATRICK L. Ross,:f PH.D.; MARTIN S.
ROGINSKY,§ M.D. ; Departments of Anesthesiology,* Psychiatry and Psychology^ and Medicine,§ State University of New York at Stony Brook, School of Medicine, Nassau County Medical Center, East Meadow, N.Y. 11554, U.S.A. Reprint requests to Dr Simon Halevy. 0007-O912/78/0050-1053 $01.00
serum T4 concentration (Oyama and Matsuki, 1971). In animal experiments, when pituitary thyrotrophic hormone (TSH) was measured following general anaesthesia, an increase or a biphasic response was noted (Mannisto, Saarinen and Ranta, 1976). However, in human studies thiopentone, halothane, diethyl ether and methoxyflurane were associated with unchanged TSH concentrations (Oyama, Matsuki and Kudo, 1972a). These inconsistent results have prevented any conclusions on the effects of anaesthesia on thyroid function in either the mother or the infant. Among the possible reasons for this are: the lack of a sensitive and precise method for the determination of thyroid function, and at the time of these studies the lack of complete tests of thyroid function. Furthermore, the effect of surgery on thyroid function in the absence of anaesthesia has not been explored sufficiently. We report some effects of anaesthesia on serum thyroid hormones in women undergoing Caesarean section. METHODS
Thirty-two unselected women undergoing Caesarean section at term were studied. The procedure for the study was approved by the Research and Medical Ethics Committee of the Nassau County Medical Center. None of the subjects had a history of thyroid or other endocrine disease. Eighteen patients received general anaesthesia, and 14 regional anaesthesia. General anaesthesia comprised induction with thiopentone 3.5 mg kg" 1 followed by suxamethonium l.Smgkg" 1 , endotracheal intubation and artificial ventilation with © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
The effects of anaesthesia on serum thyroid hormones were studied in 32 pregnant young women undergoing Caesarean section at term. Eighteen patients received general anaesthesia and 14 lumbar extradural blockade. Maternal serum concentrations of thyrotrophin (TSH), thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine (rT3) were measured using radioimmunoassay at 0, delivery and 24 h. There were no significant changes in TSH in the two groups. T4 concentrations decreased significantly at 24 h in the general anaesthesia group but regional anaesthesia produced a significant decrease only at the time of delivery. T3 concentrations decreased with both techniques. Reverse T3 increased markedly with general anaesthesia only at 24 h.
BRITISH JOURNAL OF ANAESTHESIA
1054
10 9 8 7 6 5 4 3 2
i I DELIVERY +24 h TIME OF SAMPLING
FIG. 1. Serum thyrotrophin (TSH) concentrations (mean + SEM) in patients undergoing Caesarean section under general or regional anaesthesia. 15 — 14
T
13
12
:
*
*T
10 8 7 6 5
RESULTS
TSH There were no significant changes in the concentrations of TSH at the three sampling times and there was no difference between the two groups (fig. 1).
* The human TSH kit (hTSH; Nuclear Medical Systems Inc.) uses anti-hTSH rabbit serum and a second antibody which is goat-anti-rabbit gamma globulin, together with hTSH 12sI-labelled thyrotrophin. The T4 and T3 kits (Diagnostic Products Corporation) and the rT3 (Serono Laboratories Inc.) were similar, using mI-labelled antigens, ANS (8 anilino-1-naphthalene sulphonic acid) and goatanti-rabbit gamma globulin. For RUT3, the kit was from Nuclear Medical Laboratories Inc. and used inorganic silicate as the binder. In this determination, the two hormones are used as reagents to demonstrate the number of available binding sites on serum thyroglobulin (TBG) by saturating serum TBG with the 12sI-labelled hormone.
REGIONAL
I
0
9
T4 There were no differences in the mean values of serum concentrations of T4 observed at the three sampling times between the subjects receiving general and those receiving regional anaesthesia. A significant decrease was observed at 24 h after delivery in the general anaesthesia group (P<0.02). In the regional anaesthesia group a sharp decrease was observed at
GENERAL
T
GENERAL
X
\
-
i 0
I
REGIONAL
i 1 DELIVERY + 24 h TIME OF SAMPLING
FIG. 2. Serum thyroxine (T4) concentrations (mean ± SEM) in patients undergoing Caesarean section under general or regional anaesthesia. 170 „ =
'60 150
I g
140 130
0 5
120 110
1
100
% 90 *" 80 70
i
• GENERAL ' REGIONAL
t 0
DELIVERY
24 h
TIME OF SAMPLING
FIG. 3. Serum triiodothyronine (T3) concentrations (mean ± SEM) in patients undergoing Caesarean section under general or regional anaesthesia.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
oxygen until delivery of the baby. Thereafter, anaesthesia was maintained with diazepam or pethidine, or both, nitrous oxide in oxygen and neuromuscular blockade was maintained with an infusion of suxamethonium. Regional analgesia combined a lumbar extradural block with lignocaine, bupivacaine or 2-chloroprocaine, or a combination of these agents. Venous blood samples for hormone analysis were collected just before anaesthesia, at the time of delivery and 24 h thereafter. All hormone measurements were made by radioimmunoassay techniques. Thyrotrophin (TSH), thyroxine (T4), L-3,3',5-triiodothyronine (T3), L-3, 3',5'-triiodothyronine (reverse T3, rT3) and the resin uptakes of T3 (RUT3) and rT3 (RUrT3) were measured in every sample using commercially available kits.* For rT3 resin uptake assay, the kit was the same as for RUT3 with replacement of 125 I-T3 with 125 I-rT3. All these methods have been tested for specificity, sensitivity, accuracy and reproducibility. Student's t tests were performed on basic and logarithmic data for paired samples, together with onesample tests on percentage changes; 5% was chosen as the level of statistical significance.
THYROID FUNCTION AND CAESAREAN SECTION 40 r •-O--
T
35 i
f
u _
30 -
1
J.
T
cr 25 i
0
±
lI
I
GENERAL REGIONAL
I •
DELIVERY +24 h
TIME OF SAMPLING
FIG. 4. Serum reverse triiodothyronine (rT3) concentrations (mean + SEM) in patients undergoing Caesarean section under general or regional anaesthesia.
the time of delivery (P< 0.01) but there was no further decrease at 24 h (fig. 2). T3 A significant decrease occurred with anaesthesia, continuing after anaesthesia (P< 0.01). There were no differences between the two groups at all times (fig. 3). rT3 A pattern similar to that for T3 was found for all samples except at 24 h with general anaesthesia (fig. 4). The significant decrease (P<0.01) in serum concentrations of rT3 with general anaesthesia from zero time to delivery was followed by a marked increase at 24 h (P< 0.01). Regional analgesia was associated with a sudden decrease (P<0.0l) at the time of delivery which continued for 24 h, similar to the changes occurring in T3. The significant differences in serum rT3 concentrations between the general and regional anaesthesia groups at 24 h reflected primarily this increase in rT3 with general anaesthesia at that time.
the effects of general and regional anaesthesia on this pituitary hormone. There was an early sudden decrease in serum T4 concentrations following regional anaesthesia and a later decrease after general anaesthesia. This decrease in serum T4, observed with both anaesthetic techniques, may have been produced by: an acute decrease in the secretion of T4 by the thyroid, an accelerated hepatic or renal catabolism of the circulating hormone, a redistribution of the hormone between the vascular, extracellular or intracellular compartments (Oyama, Shibata and Matsuki, 1969; Oyama et al., 1969a, b); or a perioperative expansion of the vascular space. The long half-life of T4 in the circulation and the absence of changes in thyrotrophic hormone make a decrease in T4 secretion unlikely to account for the observed changes. The absence of changes in the resin uptake of T3 or rT3 from times of sampling before to after delivery almost precludes the possibility of a decrease in the thyroid hormone-plasma binding proteins. Such a change could lead to a shift of thyroxine from the vascular space. Although no measurements of blood volumes have been carried out in this study, a decrease in this compartment at the time of delivery and in the postpartum period has been reported by other investigators. In addition, in this study the peri-operative hydration regimen was very similar and dilutional hypoproteinaemia and resulting decreased hormone concentration was unlikely to occur. Of considerable interest were the observations that the two thyroid hormones, T3 and rT3, which are derived primarily from the metabolic conversion of T4 in the liver and kidney (fig. 5), decreased throughout the study with one sample time exception. This suggests that both general and regional anaesthesia
CH 2 — CH — COOH
I
NH 2
DISCUSSION
We have demonstrated that changes in thyroid function occur at the time of delivery and in the period after delivery in women at term undergoing Caesarean section with general or regional anaesthesia. Our data are in agreement with studies showing that anaesthesia does not influence serum thyrotrophin concentrations (Charters, Odell and Thompson, 1969; Oyama, Matsuki and Kudo, 1972a, b ; Kirby, Clark and Johnston, 1973; Mannisto, Saarinen and Ranta, 1976). There were no significant differences between
3,5,3 -Triiodothyronine (T3) I
I
— /
\_o—/
\-CH2-CH-COOH
3 , 3 , 5 — Triiodorhyronine (Reverse T3, rT3) FIG. 5. Triiodothyronine and reverse triiodothyronine.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
20
T
1055
1056
It is possible that the hormone changes in maternal blood following anaesthesia occur also in the foetus. Indeed, the effect may be more pronounced since foetal liver and kidney function is immature at term. Recent reports noting a frequency of neonatal hypothyroidism as large as 1 in 4000 live births (La Franchi et al., 1977) suggest that a reduction in serum T3 following anaesthesia in the newborn may worsen neonatal hypothyroidism where this condition exists.
ACKNOWLEDGEMENT
This work was supported by Meadowbrook Education and Research Foundation, Nassau County Medical Center, East Meadow, New York. REFERENCES
Brown, P. S., Clark, C. G., Crooks, J., Elston, R. C , Parbrook, E. O., and Thorburn, A. R. (1964). Thyroid and adrenocortical responses to surgical operation. Clin. Sci., 27, 447. Burr, W. A., Black, E. G., Griffiths, R. S., Hoffenberg, R., Meinhold, H., and Wenzel, K. W. (1975). Serum triiodothyronine and reverse triiodothyronine concentrations after surgical operation. Lancet, 2, 1277. Charters, A. C , Odell, W. D., and Thompson, J. C. (1969). Anterior pituitary function during surgical stress and convalescence. Radioimmunoassay measurement of blood TSH, LH, FSH and growth hormone. J. Clin. Endocrinol. Metab., 29, 63. Chopra, I. J. (1974). A radioimmunoassay for measurement of 3, 3', 5'-triiodothyronine (reverse T3). J. Clin. Invest., 54, 583. Chopra, U., Smith, S. R., Reza, M., and Solomon, D. H. (1975). Reciprocal changes in serum concentrations of 3, 3', 5'-triiodothyronine (reverse T3) and 3, 3'-5-triiodothyronine (T3) in systemic illnesses. J. Clin. Endocrinol. Metab., 41, 1043. Engstrom, W. W., and Markardt, B. (1955). The effects of serious illness and surgical stress on the circulating thyroid hormone. J. Clin. Endocrinol. Metab., 15, 953. Fore, W., Kohler, P., and Wynn, J. (1966). Rapid redistribution of serum thyroxine during ether anesthesia. J. Clin. Endocrinol. Metab., 26, 821. Goldenberg, I. S., Lutwak, L., Rosenbaum, P. J., and Hayes, M. A. (1956). Thyroid activity during operation. Surg. Obstet. Gynecol, 102, 129. Rosenbaum, P. J., and Hayes, M. A. (1955). Patterns of thyroid-adrenocortical response after operation. Ann. Surg., 142, 786. Greene, N. M., and Goldenberg, I. S. (1959). The effect of anesthesia on thyroid activity in humans. Anesthesiology, 20, 125. Kirby, R., Clark, F., and Johnston, I. D. A. (1973). The effect of surgical operation of moderate severity on thyroid function. Clin. Endocrinol., 2, 89. La Franchi, S. H., Murphey, W. H., Buist, N. R. M., Larsen, P. R., and Foley, T. P. (1977). Neonatal hypothyroidism detected by the Oregon regional screening program. Pediatr. Res., 11, 427. Mannisto, P. T., Saarinen, A., and Ranta, T. (1976). Anesthetics and thyrotropin secretion in the rat. Endocrinology, 99, 875. Mitskevich, M. S. (1957). Glands of Internal Secretion in the Embryonic Development of Birds and Mammals, p. 177. Moscow: Acad. Sci. U.S.S.R. Oyama, T. (1957). Effects of anesthesia on thyroid function of rats. Anesthesiology, 18, 719. (1959). Effect of di-ethyl ether anesthesia on thyroid function of rats. Endocrinology, 65, 56. Matsuki, A. (1971). Serum levels of thyroxine in man during spinal anesthesia and surgery. Anesth. Analg. (Cleve.), 50, 309.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
may interfere with mono-deiodination of T4 to its metabolic products T3 and rT3. However, other explanations, such as hormone redistribution and circulatory changes, may be possible. In addition, these data suggest that regional and general anaesthesia differ in their effect on the overall metabolic transformation of T4 in the period after anaesthesia. The increase in rT3 which was seen only at 24 h after general anaesthesia remains unexplained. An increase in rT3 when T3 decreases has been observed in a variety of clinical situations (Chopra et al., 1975). Our data are in agreement with the study of Burr and others (1975) who demonstrated a decrease in serum T3 after surgery. Since the major source of T3 in plasma is from the peripheral mono-deiodination of thyroxine and both surgery and anaesthesia may decrease this process, no conclusion can be reached from this study concerning which of the two factors was primarily responsible for the observed effect. Burr and colleagues (1975) also reported an increase in serum reverse T3 following surgery, but without specific reference to the type of anaesthesia. We observed an increase in serum rT3 concentrations only after 24 h with general anaesthesia. The peripheral metabolism of T4 by mono-deiodination can yield rT3 as well as T3 (Chopra, 1974). During surgery, systemic illness, fasting and in the newborn there is stimulation of the rT3 pathway of T4 catabolism coincidental with a decrease in the T3 catabolic pathway similar to that observed with general anaesthesia in the present study. No increase in rT3 occurred when T3 concentrations were decreased during regional anaesthesia. It is known that this latter anaesthetic technique has minimal effects on hepatic and renal function. Therefore, the "expected" change in the T3/rT3 ratio at 24 h after general anaesthesia can be explained by a direct hepatic or renal effect of the systemically administered anaesthetic agent. These effects of general anaesthetics are well documented in the literature. The observation of an alteration in the T3/rT3 ratio may provide another index of alterations in hepatic and renal function produced by general anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
1057
THYROID FUNCTION AND CAESAREAN SECTION
SCHILDDRUSENHORMONSERUM UND VERANDERUNGEN IN PATIENTEN WAHREND EINES KAISERSCHNITTS UNTER ALLGEMEINER ODER LOKALER ANASTHESIE ZUSAMMENFASSUNG
Die Wirkung von Schilddrusenhormonserum auf Anasthesie wurde in 32 schwangeren jungen Frauen mit termingerechtem Kaiserschnitt untersucht. Achtzehn Patienten erhielten die allgemeine Anasthesie und 14 eine lumbale extradurale Blockade. Mutterliche Serumkonzentrationen von Thyrotrophin (TSH), Thyroxin (T4), Trijodothyronin (T3) und reverses Trijodothyronin (rT3) wurden mit Radioimmunotest um 0,0 Stunden/Geburt gemessen und 24 Stunden danach. In beiden Gruppen gab es keine bedeutenden Anderungen von TSH. In der allgemeinen Anasthesiegruppe zeigten die T4 Konzentrationen nach 24 Studen eine bedeutende Verminderung, aber die lokale Anasthesie zeigte nur zur Geburtszeit eine bedeutende Verminderung. T3 Konzentrationen verringerten sich bei beiden Techniken. rT3 verstarkte sich bemerkenswert nur nach 24 Stunden bei der allgemeinen Anasthesie. CAMBIOS EN LAS HORMONAS TIROIDES DEL SUERO EN PACIENTES SOMETIDOS A CESAREA BAJO ANESTESIA GENERAL O REGIONAL SUMARIO
VARIATIONS DES HORMONES DE LA THYROIDE DANS LE SERUM SUR DES FEMMES SUBISSANT UNE OPERATION CESARIENNE SOUS ANESTHESIE GENERALE OU SOUS ANESTHESIE REGIONALE RESUME
Les effets de Panesthesie sur les hormones de la thyroide se trouvant dans le serum ont ete etudies sur 32 jeunes femmes enceintes devant subir une operation cesarienne une fois arrivees a terme. Dix-huit d'entre elles ont ete placees sous anesthesie generale et 14 ont subi un blocage lombaire extradural. Les concentrations de thyrotrophine (TSH), de thyroxine (T4), de triiodothyronine (T3) et de triiodothyronine inversee (rT3) dans le serum maternel ont ete mesurees par essai de radioresistances a 0, au moment de Paccouchement, et 24 h apres. II n'y a eu aucun changement sensible dans la TSH des deux groupes. Les concentrations de T4 ont baisse d'une maniere significative apres 24 h dans le groupe soumis a une anesthesie generale, mais Panesthesie regionale n'a produit une diminution sensible qu'au moment de Paccouchement. Les concentrations de T3 ont diminue avec les deux techniques. Les concentrations de T3 inversee ont notablement augmente avec Panesthesie generale, mais seulement 24 h apres.
86
Se estudiaron los efectos ejercidos por anestesia sobre las hormonas tiroides del suero en 32 mujeres jovenes embarazadas sometidas a cesarea al final de su periodo de embarazo. Dieciocho pacientes recibieron anestesia general y 14 bloqueo extradural lumbar. Las concentraciones en el suero materno de tirotropina (TSH), tiroxina (T4),triyodotironina (T3) y triyodotironina inversa (rT3) fueron medidas valiendose de pruebas radioimmunologicas tomadas a 0, durante el parto y 24 horas despues. No se produjeron cambios significativos en el TSH de los dos grupos. Las concentraciones de T4 disminuyeron significativamente al cabo de 24 horas en el grupo de anestesia general, pero la anestesia general produjo una significativa disminucidn solamente en el momento del parto. Las concentraciones de T3 disminuyeron con ambas tecnicas. El T3 inverso aumento notablemente con la anestesia general solo al cabo de 24 horas.
Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on July 7, 2015
Oyama, T., Matsuki, A., and Kudo, T. (1972a). Effect of halothane, methoxyflurane anaesthesia and surgery on plasma thyroid-stimulating hormone (TSH) levels in man. Anaesthesia, 27, 2. (1972b). Effect of ether, thiopentone anaesthesia and surgery on plasma thyroid-stimulating hormone (TSH) levels in man. Br.J. Anaesth., 44, 841. Shibata, S., and Matsuki, A. (1969). Thyroxine distribution during ether and thiopental anesthesia in man. Anesth. Analg. (Cleve.), 48, 1. Kudo, T. (1969a). Thyroxine distribution during halothane anesthesia in man. Anesth. Analg. (.Cleve.), 48, 715. (1969b). Serum endogenous thyroxine levels in man during anaesthesia and surgery. Br. J. Anaesth., 41, 103. Selenkow, H. A., Birnbaum, M. D., and Hollander, C. S. (1973). Thyroid function and dysfunction during pregnancy. Clin. Obstet. Gynecol., 16, 66. Wase, A. W., and Foster, W. C. (1956). Thiopental and thyroid metabolism. Proc. Soc. Exp. Biol. Med., 91, 89. Greenspan, J. (1953). Effect of sodium 5-allyl-5(1 methylbutyl) 2-thiobarbiturates on uptake of I 1 3 1 by rat thyroid. Proc. Soc. Exp. Biol. Med., 84, 154. Repplinger, E., and Foster, W. C. (1953). The effect of anesthetic agents on thyroid activity of the rat. Endocrinology, 53, 630.