Exp. Clin. Endocrinol. Vol. 95, No. 2, 1990, pp. 217-223
J. A. Barth, Leipzig
Department of Surgery, Chiba Municipal Hospital, Chiba/Japan
T. CI-IIKENJI, M. MTZTJTANI and Y. KITSUKAWA
With 3 Figures Summary. Effects of anaesthesia on serum concentrations of thyroid hormónes during and soon
after abdominal surgery were examined in 29 patients undergoing cholecystectomy (n = 22) or removal of gastric cancer (n = 7. They were given one of the following anaesthetics in combination with nitrous oxide in oxygen: epidural bupivacaine, enflurane, pentazocine, ketamine, halothane, epidural bupivacaine and enflurane. Regardless of type of anaesthesia, T3 decreased significantly during and after surgery. T4 and rT3 increased markedly when either enflurane or halothane was given but not with the other anaesthetic agents; they then decreased toward pre-surgical levels after surgery. There was no correlation between changes in rT3 and those in cortisol or free fatty acids. TSH fluctuated little. These results show that the increases in rT3 and T4 during and soon after surgery are due not to surgical trauma but to inhalational anaesthetics such as enflurane and halothane.
Key words: Abdominal surgery - Anaesthesia - Reverse triiodothyronine - Thyroxine
Introduction
It is generally agreed that abdominal surgery causes a decrease in circulating T3 concentrations and a simultaneous reciprocal increase in rT3 values for several days after surgery (Burr et al., 1975; Hagenfeldt et al., 1979; Prescott et al., 1979; Wolfson et al., 1981). While the decrease in T3 concentrations is consistently noted, the increase in rT3 concentrations is not always found during or soon after surgery (Adami et al., 1978; Chan et al., 1978; Blichert-Toft et al., 1979; Hagenfeldt et al., 1979; Rutberg et al., 1985). In addition, no consistent change in intraoperative T4 concentrations has been described (Adami et al., 1978; Chan et al., 1978; Blichert-Toft et al., 1979; Hagenfeldt et al., 1979; Rutberg et al., 1985). On the other hand, in patients undergoing hysterec-
tomy, Brandt et al. (1976) observed decreases in T4 concentrations during epidural anaesthesia, but increases during general anaesthesia. Further, Hooper et al. (1978) found increased rT3 and T4 concentrations after induction of anaesthesia. These results suggest that variations in intraoperative thyroid hormone concentrations may be due to differences in the anaesthetics used. To test this assumption, we examined changes in iritraoperative thyroid hormone concentrations in patients undergoing upper abdominal surgery using a variety of anaesthetic agents.
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Anaesthesia, Not Surgical Stress, Induces Increases in Serum Concentrations of Reverse Triiodothyronine and Thyroxine during Surgery
218
Exp. Clin. Endocrinol. 95 (1990) 2
Materials and Methods Subj e cts and study protocol. Twenty-nine patients participated in three experimental protocols. None had evidence of endocrine disease or received any hormone preparations. Informed consent was obtained. The patients were premedicated with intramuscular hydroxyzine (50-75 mg) and atropine (0.5 mg) 1 h before surgery. Anaesthesia was induced with thiopental (3-4 mg/kg), diazepam (0.15-0.2 mg/kg) or both. Endotracheal intubation was performed with the aid of suxa-
methonium (1 mg/kg). Anaesthesia was maintained with nitrous oxide (2-3 1/mm) in oxygen (3-4 1/mm) using a semi-closed circuit system (GO) in combination with a main agent as described below. Pancuronium was given as required, and atropine and neostigmine at the end of surgery. Lactated Ringer's solution was infused at a rate of 8-12 mi/kg/h during surgery and continued at a rate of 2-3 ml/kg/h after surgery. Neither blood nor blood substitutes were given.
Study I. Twenty-two patients undergoing elective cholecystectomy were studied (Table 1). bupivacaine, 15-30 ml; (B) enflurane, 0.5-3%; (C) intravenous pentazocine, 80-105 mg (50-80 mg at the time of induction); (D) drip infusion of 0.1% ketamine, 100-125 mg (60-75 mg at the time of induction); (E) halothane, 0.2-1.5%; (F) epidural bupivacaine and enflurane (A + B). Peripheral venous blood samples were taken immediately before premedication, 1 h after skin incision (or at the completion of any surgery that required less than 1 h) and 2 h after surgery. Table 1 Clinical data of 22 patients undergoing cholecystectomy (Study I)
Group GO
+ A B C D E F (Epidural (Enfiurane) (Pentazocine) (Ketamine) (Halothane) (Epidural bupivacain bupivacain)
Sex (female/male) Age (yr)
Duration of surgery (mm) Estimated blood
(n=5)
(n==5)
(n=3)
(n=3)
(n=3)
2/3
1/4
2/1
1/2
1/2
+ Enflurane) (n==3) 1/2
57 ± 13 99 ± 11
51 ± 8 81 ± 3
46 ± 8 67 ± 20
38 ± 3 63 + 15
50 + 16 89 + 19
84 ± 29
130 ± 27
131 ± 31
142 ± 43
149 ± 41
186 + 44
147 ± 40
44± 9
loss (ml)
mean ± SD; GO = nitrous oxide + oxygen Study II. Three male and 1 female patient admitted for elective surgery for gastric cancer were studied. Ages were between 36 and 74 years (mean 61). Two patients received GO + A anaesthesia and the other two GO + B. Sequential blood samples were taken up to 4 h during surgery as well as 1 h before and 2 h afterward. Study III. Three male patients undergoing gastric cancer operation were included. Ages ranged from 63 to 71 years. They received GO + A for the first 1 h followed by GO + B. Blood samples were taken before surgery, at the end of GO + A and 1 h after the start of GO + B. Assays. Serum hormone concentrations were determined by radioimmunoassay with kits from the following sources in Tokyo: TSH, Daiichi Radioisotope; total T4, total T3 and rT3, Dainabot; free T4 and free T3, Amersham; cortisol, Baxter. Serum free fatty acids (FFA) were measured by a Hitachi 705 automated analyzer. The intra-assay and inter-assay coefficients of variation were less than 10% in each assay.
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They were divided into six groups according to the chief anaesthetic agent given: (A) epidural 0.5%
T. CHjxEJI et al., Response of rT3 and T4 to Anaesthesia
219
Data analysis. Differences within groups were assessed with the paired Student's t-test. For determination of differences between groups, comparison with the GO + A group was made using unpaired t-test incorporating the Bonlerroni method (Godfrey, 1985). Data are presented as mean
± SD.
Study I. TSH concentrations did not change significantly during the course of the study in any group (data not shown). Total T4 concentrations in the GO + A group decreased by 9% 1 h after skin incision (Fig. 1), whereas those in the GO + B, GO + E and GO + F groups increased by 43, 24 and 19%, respectively. All returned to presurgical values 2 h after surgery. Total T3 concentrations decreased in all groups by 15-25% 1 h after skin incision and by 25-35% 2 h after surgery. Most of the changes were statistically significant. Free T4 and T3 concentrations showed qualitatively similar changes to total T4 and T3. Concentrations of rT3 increased by 91% in the GO + B group and by about 50% in the GO + E and GO + F groups 1 h after skin incision. A 30% increase in the first as well as a 10% increase in the last two groups was still present 2 h after surgery. No significant change in rT3 concentrations was detected in the other groups. There was no correlation between the change in rT3 and the change in cortisol or FFA concentrations either 1 h after skin incision or 2 h after surgery (data not shown). Studies II and III. TSH concentrations were virtually unchanged, as in Study I (data not shown). Total T4 concentrations in the two patients of the GO + B group increased by an average of 64% 1 h after skin incision and then decreased gradually, approaching pre-surgical values 2 h after surgery (Fig. 2), whereas those in the GO + A group remained almost unchanged. Despite insignificant changes during GO + A anaesthesia, total T4 concentrations showed a 24% increase 1 h after the start of GO + B anaesthesia (Fig. 3). Total T3 concentrations in all four patieiits decreased progressively by 25, 32 and 36% 1 and 3 h after skin incision and 2 h after surgery, respectively (Fig. 2). Changing anaesthesia from GO + A to GO + B had no effect on the rate of decrease (Fig. 3). Free T4 and T3 concentrations varied in a similar manner to those of total T4 and T3. Concentrations of rT3 in the GO + B group increased by more than 50% 1 h after skin incision, remained there during the next 2 h and decreased slowly thereafter, reaching levels 30% above the pre-surgical values 2 h after surgery (Fig. 2). The concentrations of the GO + A group did not change much. Concentrations of rT3 showed no significant change during GO + A anaesthesia but a 50% increase during GO + B anaesthesia (Fig. 3). There was no correlation between the changes in rT3 concentrations and the changes in cortisol or FFA throughout the studies (data not shown). Discussion
Intraoperative increases in T4 and rT3 concentrations were observed in the present study only when enflurane or halothane was used. A decrease in T3 was consistently
noted regardless of the anaesthetic used. Each patient received the same drugs for premedication, and neither diazepam (Sowers et al., 1977) nor thiopental (BlichertToft et al., 1979) had any apparent effect on thyroid hormone concentrations. Furthermore, changing anaesthesia from GO + A to GO + B significantly increased T4 and rT3 concentrations (Study III). These results clearly showthat enflurane and halothane are responsible for the increases. Although the observations were made mainly on cases with cholecystectomy, a moderately severe insult to the body (Study I), findings with gastric cancer surgery, a greater insult (Study II), were essentially the same, supporting the assumption that these increases are unrelated to surgical trauma.
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Results
GO +A 16
GO+B
GO+C
GO-t-D
GO+E
GO+F
*** t
14
IL
12 10 8
L
6 4 2
e
3
o
1.4 1.2 1.0
* *
0.8
0.6 0.4 0.2 O
4
3
*
*
**
*
2
o 800
600 -
400 200 O
Fig. 1 Serum total and free thyroid hormone concentrations (mean ± SD) in 22 cholecystectomy patients before (PRE, open bars), 1 h after skin incision (1 H, stippled bars) and 2 h after surgery (POST, hatched bars). Patients were divided into 6 groups according to anaesthetic used in combi..
nation with nitrous oxide + oxygen (GO): GO + A, epidural bupivacain; GO + B, eiif1urane; GO + O, pentazocine; GO + D, ketamine; GO + E, halothane; GO + F, epidural bupivacaine + enilurane. n = 5 (GO + A, GO + B) or 3 (GO + O, GO + D, GO + E, GO + F). *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0005, compared with pre-surgical values in the same group; t < 001, compared with the GO + A group.
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2
221
T. CHIxmJJ et al., Response of rT3 and T4 to Anaesthesia
GO+A J GO+B 14
12
10.
86-
4. o1
3-
3
2
O
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2
o
1.0
0.8
0.6 01
o
600 E
a.
400-
p-
200 PRE
2
1
HOURS
Fig. 3
Fig. 2 Fig. 2
Serum total and free thyroid hormone concentrations before (PRE), during and 2 h after
(POST) surgery in 4 gastric cancer patients. Each symbol represents one patient given either GO + A (O D) or GO + B (. ) anaesthesia. See Fig. 1 for explanation of GO + A and GO + B. Fig. 3
Serum total and free thyroid hormone concentrations before (PRE) and during surgery
under 1 h of GO + A followed by GO + B in 3 gastric cancer patients. Each symbol represents one patient. *p < 0.05, **p < 0.01, compared with pre-surgical values. See Fig. 1 for explanation of
GO+Aand GO+B.
222
Since there was no change in TSR concentrations, the pituitary may not be involved in the increase in T4 concentrations. There are reports suggesting halothane releases T4 from hepatic stores (Oyama et al., 1969; Harland et al., 1974) and the rise in T4 concentrations may therefore be due to displacement, probably from the liver. The sharp rise in free T4 concentrations suggests qualitative and quantitative alterations in T4-binding proteins. This study confirms an intraoperative decrease in total and free T3 concentrations (Kehiet et al., 1979). Although the mechanism for the surgery-induced decrease in T3 remains obscure, the suggestion that it is due to increased conversion of T4 to rT3 (Brandt et al., 1976) is unlikely to be correct, because the decrease in T3 is not necessarily accompanied by increased rT3 concentrations. Intraoperative or immediate postoperative increases in rT3 and T4 concentrations thus have been shown to occur only with enflurane or halothane and not when other anaesthetic agents are used. This explains the divergent findings in previous studies (Adami et al., 1978; Chan et al., 1978; looper et al., 1978; Blichert-Toft et al., 1979; Hagenfeldt et al., 1979). TSR (looper et al., 1978) and glucocorticoids (Chopra et al., 1975) increase rT3 concentrations but these hormones played no part in the increase in this study. Presurgical caloric restriction, which causes increased rT3 (O'Brian et al., 1980), was not responsible either, because all the patients in Study I were well nourished and had no caloric restriction before surgery. Lack of correlation between changes in rT3 and FFA concentrations showed that the increase in rT3 was not an artifact caused by increased FFA concentrations in sera (O'Connell et al., 1982). Although the detailed mechanism of the rT3 increase requires further study, one possibility is the greater conversion of extra T4, because the increase in rT3 was paralleled by an increase in T4. It is also possible that the inhalational anaesthetics release rT3 along with T4 from tissue stores. Abdominal surgery is well known to induce a decrease in T3 values and a simultaneous reciprocal increase in rT3 values postoperatively until the 4th or 5th day of convalescence (Burr et al., 1975; Hagenfeldt et al., 1979; Prescott et al., 1979; Wolfson et al., 1981). The present observation that the increased rT3 values during surgery decreased toward pre-surgical values 2 h after surgery suggests that the postoperative increase in rT3 is not affected by the anaestheties used during surgery. It is therefore quite likely that the reciprocal changes in T3 and rT3 seen during surgery differ from those during the postoperative course in terms of the mechanism involved.
Re!erences An.&jri, H.-O.; JoliANssox, H.; THOREN, L; WIDE, L.; AxERSTEOM, G.: Serum levels of TSH.
T3, rT3, T4 and T3-resin uptake in surgical trauma. Acta Endocrinol. 88 (1978) 482-489, BLIcliEscr-T0FT, M.; CHRISTENSEN, V.; ENOQUIST, A.; FOG-MOLLER, F.; KEmET, H ; MADSEN,
S. N.; SKOVSTED, L.; TiboR, J.; OLGAARD, K.: Influence of age on the endocrine-metabolic response to surgery. Ann. Surg. 190 (1979) 761-770. BRANDT, M. R.; KEBIET, H.; SKOVSTED, L ; HANSEN, J. M.: Rapid decrease in plasma-triiodo-
thyronine during surgery and epidural analgesia independent of afferent neurogenic stimuli and of cortisol. Laneet 2 (1976) 1333-1336. Buia, W.. A.; GRIFFrL'Hs, R. S.; BLACH, E. G.; H0FFENBEHO, R.; MEINHOLD, H.; WENZEL,
K. W.: Serum triiodothyronine and reverse triiodothyronine concentrations after surgical pperation. Lancet 2 (1975) 1277-1279. Cix, V.; WANG, C.; YBUxa, R. T. T.: Pituitary.thyroid responses to - surgical stress. Acta Endocrinol. 88 (1978) 490-498
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Exp. Clin. Endocrino!. 95 (1990) 2
T. CHrKsNJI et al., Response of rT3 and T4 to Anaesthesia
223
CHOPBA, I. J.; Wiiirs, D E ; ORGIAzzr, J.; SoLoMor, D. H.: Opposite effects of dexamethasone on serum concentrations of 3,3', 5'-triiodothyronine (reverse T3) and 3,3', 5-triiodothyronine (T3). J. Clin. Endocrinol. Metabol. 41 (1975) 911-920. GODFREY, K.: Comparing the means of several groups. New Eng!. J. Med. 313(1985) 1450-1456. HAGENFELDT, I; MELAIÇDER, A.; THORELL, J.; TIBELIN, S.; WEsTGEEN, U.: Active and inac-
tive thyroid hormone levels in elective and acute surgery. Acta Chir. Scand. 145 (1979) 77-82. Hin, W. A.; Honpov, P. W.; STRANG, R.; FITZGERALD, B.; RICHABDS, J. R.; HOLLOWAY, K B.: Release of thyroxine from the liver during anaesthesia and surgery. Br. J. Anaesth. 46 (1974) 818-820. HoorEa, M. J.; RAI'CLIFFE, J. G.; RATOLIFFE, W. A.; MARSHALL, J.; YouNG, R. E.; NGAEI, G.;
control by TSR. Clin. Endocrino!. 8 (1978) 267-273. KEBIET, H.; 1ÇiuFER, P. V.; WERKE, J.: Thyrotropin, free and total triiodothyronine, and thyroxine in serum during surgery. Clin. Endocrinol. 10 (1979) 131-136. O'BJL&N, J. T.; BYBEE, D. E.; BURMAN, K. D.; OsnuRFR, R. C.; K5IAzEK, M. R.; WART0T5-
xy, L.; GEoRGEs, L. P.: Thyroid hormone homeostasis in states of relative caloric deprivation. Metabolism 29 (1980) 721-727. O'CoiuLL, M.; ROBBINS, D. C.; BOGARDUS, C.; BURGER, A. G.; DANFORTH, E., Jr.: The inter-
action of free fatty acids in radioimmunoassays for reverse triiodothyronine. J. Clin. Endocrinol. Metabo!. 55 (1982) 577-582. OYAMA, T.; SHIBATA, S.; MATSUKI, A.; KUD0, T.: Thyroxine distribution during halothane anesthesia in man. Anesth. Analg. 48 (1969) 715-719. PREscoTT, R. W. G.; YEO, P. P. B.; WATSON, M. J.; JomrsTolcE, I. D. A.; RATCLIFFE, J. G.; EVERED, D. C.: Total and free thyroid hormone concentrations after elective surgery. J. Clin. Pathol. 32 (1979) 321-324. RUTBERG, H.; ANDERBERG, B.; HAKAIÇSON, E.; JORFELDT, L.; K&GEDAL, B.; TEGLER, L.:
Influence of extradural blockade on serum thyroid hormone concentrations after surgery. Acta Chir. Scand. 151 (1985) 97-103. SowERs, J. R.; RAJ, R P ; HERSHMAN, J. M.; CAELSON, H. E.; MCCALLUM, R. W.: The effect
of stressful diagnostic studies and surgery on anterior pituitary hormone release in man Acta Endocrinol. 86 (1977) 25-32. WoLYsoN, M. S.; RAOUF, A. A.; O'GomuAN, P.; MAESDEN, P.: Rapid adaptation of pituitary
responsiveness to TRH in the post-surgical state. The role of free T3. Clin. Endocrinol. 15 (1981) 579-584. (Accepted 13 April 1989)
Author's address: Dr. Tomu CHTFENJI, Department of Surgery, Chiba Municipal Hospital, 827 Yahagi, Chiba 280, Japan
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Ciuu, D. H.: Evidence for thyroidal secretion of 3,3', 5'-triiodothyronine in man and its
J. A. Barth, Leipzig
Department of Surgery, Chiba Municipal Hospital, Chiba/Japan
T. CI-IIKENJI, M. MTZTJTANI and Y. KITSUKAWA
With 3 Figures Summary. Effects of anaesthesia on serum concentrations of thyroid hormónes during and soon
after abdominal surgery were examined in 29 patients undergoing cholecystectomy (n = 22) or removal of gastric cancer (n = 7. They were given one of the following anaesthetics in combination with nitrous oxide in oxygen: epidural bupivacaine, enflurane, pentazocine, ketamine, halothane, epidural bupivacaine and enflurane. Regardless of type of anaesthesia, T3 decreased significantly during and after surgery. T4 and rT3 increased markedly when either enflurane or halothane was given but not with the other anaesthetic agents; they then decreased toward pre-surgical levels after surgery. There was no correlation between changes in rT3 and those in cortisol or free fatty acids. TSH fluctuated little. These results show that the increases in rT3 and T4 during and soon after surgery are due not to surgical trauma but to inhalational anaesthetics such as enflurane and halothane.
Key words: Abdominal surgery - Anaesthesia - Reverse triiodothyronine - Thyroxine
Introduction
It is generally agreed that abdominal surgery causes a decrease in circulating T3 concentrations and a simultaneous reciprocal increase in rT3 values for several days after surgery (Burr et al., 1975; Hagenfeldt et al., 1979; Prescott et al., 1979; Wolfson et al., 1981). While the decrease in T3 concentrations is consistently noted, the increase in rT3 concentrations is not always found during or soon after surgery (Adami et al., 1978; Chan et al., 1978; Blichert-Toft et al., 1979; Hagenfeldt et al., 1979; Rutberg et al., 1985). In addition, no consistent change in intraoperative T4 concentrations has been described (Adami et al., 1978; Chan et al., 1978; Blichert-Toft et al., 1979; Hagenfeldt et al., 1979; Rutberg et al., 1985). On the other hand, in patients undergoing hysterec-
tomy, Brandt et al. (1976) observed decreases in T4 concentrations during epidural anaesthesia, but increases during general anaesthesia. Further, Hooper et al. (1978) found increased rT3 and T4 concentrations after induction of anaesthesia. These results suggest that variations in intraoperative thyroid hormone concentrations may be due to differences in the anaesthetics used. To test this assumption, we examined changes in iritraoperative thyroid hormone concentrations in patients undergoing upper abdominal surgery using a variety of anaesthetic agents.
Downloaded by: University of Pittsburgh. Copyrighted material.
Anaesthesia, Not Surgical Stress, Induces Increases in Serum Concentrations of Reverse Triiodothyronine and Thyroxine during Surgery
218
Exp. Clin. Endocrinol. 95 (1990) 2
Materials and Methods Subj e cts and study protocol. Twenty-nine patients participated in three experimental protocols. None had evidence of endocrine disease or received any hormone preparations. Informed consent was obtained. The patients were premedicated with intramuscular hydroxyzine (50-75 mg) and atropine (0.5 mg) 1 h before surgery. Anaesthesia was induced with thiopental (3-4 mg/kg), diazepam (0.15-0.2 mg/kg) or both. Endotracheal intubation was performed with the aid of suxa-
methonium (1 mg/kg). Anaesthesia was maintained with nitrous oxide (2-3 1/mm) in oxygen (3-4 1/mm) using a semi-closed circuit system (GO) in combination with a main agent as described below. Pancuronium was given as required, and atropine and neostigmine at the end of surgery. Lactated Ringer's solution was infused at a rate of 8-12 mi/kg/h during surgery and continued at a rate of 2-3 ml/kg/h after surgery. Neither blood nor blood substitutes were given.
Study I. Twenty-two patients undergoing elective cholecystectomy were studied (Table 1). bupivacaine, 15-30 ml; (B) enflurane, 0.5-3%; (C) intravenous pentazocine, 80-105 mg (50-80 mg at the time of induction); (D) drip infusion of 0.1% ketamine, 100-125 mg (60-75 mg at the time of induction); (E) halothane, 0.2-1.5%; (F) epidural bupivacaine and enflurane (A + B). Peripheral venous blood samples were taken immediately before premedication, 1 h after skin incision (or at the completion of any surgery that required less than 1 h) and 2 h after surgery. Table 1 Clinical data of 22 patients undergoing cholecystectomy (Study I)
Group GO
+ A B C D E F (Epidural (Enfiurane) (Pentazocine) (Ketamine) (Halothane) (Epidural bupivacain bupivacain)
Sex (female/male) Age (yr)
Duration of surgery (mm) Estimated blood
(n=5)
(n==5)
(n=3)
(n=3)
(n=3)
2/3
1/4
2/1
1/2
1/2
+ Enflurane) (n==3) 1/2
57 ± 13 99 ± 11
51 ± 8 81 ± 3
46 ± 8 67 ± 20
38 ± 3 63 + 15
50 + 16 89 + 19
84 ± 29
130 ± 27
131 ± 31
142 ± 43
149 ± 41
186 + 44
147 ± 40
44± 9
loss (ml)
mean ± SD; GO = nitrous oxide + oxygen Study II. Three male and 1 female patient admitted for elective surgery for gastric cancer were studied. Ages were between 36 and 74 years (mean 61). Two patients received GO + A anaesthesia and the other two GO + B. Sequential blood samples were taken up to 4 h during surgery as well as 1 h before and 2 h afterward. Study III. Three male patients undergoing gastric cancer operation were included. Ages ranged from 63 to 71 years. They received GO + A for the first 1 h followed by GO + B. Blood samples were taken before surgery, at the end of GO + A and 1 h after the start of GO + B. Assays. Serum hormone concentrations were determined by radioimmunoassay with kits from the following sources in Tokyo: TSH, Daiichi Radioisotope; total T4, total T3 and rT3, Dainabot; free T4 and free T3, Amersham; cortisol, Baxter. Serum free fatty acids (FFA) were measured by a Hitachi 705 automated analyzer. The intra-assay and inter-assay coefficients of variation were less than 10% in each assay.
Downloaded by: University of Pittsburgh. Copyrighted material.
They were divided into six groups according to the chief anaesthetic agent given: (A) epidural 0.5%
T. CHjxEJI et al., Response of rT3 and T4 to Anaesthesia
219
Data analysis. Differences within groups were assessed with the paired Student's t-test. For determination of differences between groups, comparison with the GO + A group was made using unpaired t-test incorporating the Bonlerroni method (Godfrey, 1985). Data are presented as mean
± SD.
Study I. TSH concentrations did not change significantly during the course of the study in any group (data not shown). Total T4 concentrations in the GO + A group decreased by 9% 1 h after skin incision (Fig. 1), whereas those in the GO + B, GO + E and GO + F groups increased by 43, 24 and 19%, respectively. All returned to presurgical values 2 h after surgery. Total T3 concentrations decreased in all groups by 15-25% 1 h after skin incision and by 25-35% 2 h after surgery. Most of the changes were statistically significant. Free T4 and T3 concentrations showed qualitatively similar changes to total T4 and T3. Concentrations of rT3 increased by 91% in the GO + B group and by about 50% in the GO + E and GO + F groups 1 h after skin incision. A 30% increase in the first as well as a 10% increase in the last two groups was still present 2 h after surgery. No significant change in rT3 concentrations was detected in the other groups. There was no correlation between the change in rT3 and the change in cortisol or FFA concentrations either 1 h after skin incision or 2 h after surgery (data not shown). Studies II and III. TSH concentrations were virtually unchanged, as in Study I (data not shown). Total T4 concentrations in the two patients of the GO + B group increased by an average of 64% 1 h after skin incision and then decreased gradually, approaching pre-surgical values 2 h after surgery (Fig. 2), whereas those in the GO + A group remained almost unchanged. Despite insignificant changes during GO + A anaesthesia, total T4 concentrations showed a 24% increase 1 h after the start of GO + B anaesthesia (Fig. 3). Total T3 concentrations in all four patieiits decreased progressively by 25, 32 and 36% 1 and 3 h after skin incision and 2 h after surgery, respectively (Fig. 2). Changing anaesthesia from GO + A to GO + B had no effect on the rate of decrease (Fig. 3). Free T4 and T3 concentrations varied in a similar manner to those of total T4 and T3. Concentrations of rT3 in the GO + B group increased by more than 50% 1 h after skin incision, remained there during the next 2 h and decreased slowly thereafter, reaching levels 30% above the pre-surgical values 2 h after surgery (Fig. 2). The concentrations of the GO + A group did not change much. Concentrations of rT3 showed no significant change during GO + A anaesthesia but a 50% increase during GO + B anaesthesia (Fig. 3). There was no correlation between the changes in rT3 concentrations and the changes in cortisol or FFA throughout the studies (data not shown). Discussion
Intraoperative increases in T4 and rT3 concentrations were observed in the present study only when enflurane or halothane was used. A decrease in T3 was consistently
noted regardless of the anaesthetic used. Each patient received the same drugs for premedication, and neither diazepam (Sowers et al., 1977) nor thiopental (BlichertToft et al., 1979) had any apparent effect on thyroid hormone concentrations. Furthermore, changing anaesthesia from GO + A to GO + B significantly increased T4 and rT3 concentrations (Study III). These results clearly showthat enflurane and halothane are responsible for the increases. Although the observations were made mainly on cases with cholecystectomy, a moderately severe insult to the body (Study I), findings with gastric cancer surgery, a greater insult (Study II), were essentially the same, supporting the assumption that these increases are unrelated to surgical trauma.
Downloaded by: University of Pittsburgh. Copyrighted material.
Results
GO +A 16
GO+B
GO+C
GO-t-D
GO+E
GO+F
*** t
14
IL
12 10 8
L
6 4 2
e
3
o
1.4 1.2 1.0
* *
0.8
0.6 0.4 0.2 O
4
3
*
*
**
*
2
o 800
600 -
400 200 O
Fig. 1 Serum total and free thyroid hormone concentrations (mean ± SD) in 22 cholecystectomy patients before (PRE, open bars), 1 h after skin incision (1 H, stippled bars) and 2 h after surgery (POST, hatched bars). Patients were divided into 6 groups according to anaesthetic used in combi..
nation with nitrous oxide + oxygen (GO): GO + A, epidural bupivacain; GO + B, eiif1urane; GO + O, pentazocine; GO + D, ketamine; GO + E, halothane; GO + F, epidural bupivacaine + enilurane. n = 5 (GO + A, GO + B) or 3 (GO + O, GO + D, GO + E, GO + F). *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0005, compared with pre-surgical values in the same group; t < 001, compared with the GO + A group.
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T. CHIxmJJ et al., Response of rT3 and T4 to Anaesthesia
GO+A J GO+B 14
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Fig. 2 Fig. 2
Serum total and free thyroid hormone concentrations before (PRE), during and 2 h after
(POST) surgery in 4 gastric cancer patients. Each symbol represents one patient given either GO + A (O D) or GO + B (. ) anaesthesia. See Fig. 1 for explanation of GO + A and GO + B. Fig. 3
Serum total and free thyroid hormone concentrations before (PRE) and during surgery
under 1 h of GO + A followed by GO + B in 3 gastric cancer patients. Each symbol represents one patient. *p < 0.05, **p < 0.01, compared with pre-surgical values. See Fig. 1 for explanation of
GO+Aand GO+B.
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Since there was no change in TSR concentrations, the pituitary may not be involved in the increase in T4 concentrations. There are reports suggesting halothane releases T4 from hepatic stores (Oyama et al., 1969; Harland et al., 1974) and the rise in T4 concentrations may therefore be due to displacement, probably from the liver. The sharp rise in free T4 concentrations suggests qualitative and quantitative alterations in T4-binding proteins. This study confirms an intraoperative decrease in total and free T3 concentrations (Kehiet et al., 1979). Although the mechanism for the surgery-induced decrease in T3 remains obscure, the suggestion that it is due to increased conversion of T4 to rT3 (Brandt et al., 1976) is unlikely to be correct, because the decrease in T3 is not necessarily accompanied by increased rT3 concentrations. Intraoperative or immediate postoperative increases in rT3 and T4 concentrations thus have been shown to occur only with enflurane or halothane and not when other anaesthetic agents are used. This explains the divergent findings in previous studies (Adami et al., 1978; Chan et al., 1978; looper et al., 1978; Blichert-Toft et al., 1979; Hagenfeldt et al., 1979). TSR (looper et al., 1978) and glucocorticoids (Chopra et al., 1975) increase rT3 concentrations but these hormones played no part in the increase in this study. Presurgical caloric restriction, which causes increased rT3 (O'Brian et al., 1980), was not responsible either, because all the patients in Study I were well nourished and had no caloric restriction before surgery. Lack of correlation between changes in rT3 and FFA concentrations showed that the increase in rT3 was not an artifact caused by increased FFA concentrations in sera (O'Connell et al., 1982). Although the detailed mechanism of the rT3 increase requires further study, one possibility is the greater conversion of extra T4, because the increase in rT3 was paralleled by an increase in T4. It is also possible that the inhalational anaesthetics release rT3 along with T4 from tissue stores. Abdominal surgery is well known to induce a decrease in T3 values and a simultaneous reciprocal increase in rT3 values postoperatively until the 4th or 5th day of convalescence (Burr et al., 1975; Hagenfeldt et al., 1979; Prescott et al., 1979; Wolfson et al., 1981). The present observation that the increased rT3 values during surgery decreased toward pre-surgical values 2 h after surgery suggests that the postoperative increase in rT3 is not affected by the anaestheties used during surgery. It is therefore quite likely that the reciprocal changes in T3 and rT3 seen during surgery differ from those during the postoperative course in terms of the mechanism involved.
Re!erences An.&jri, H.-O.; JoliANssox, H.; THOREN, L; WIDE, L.; AxERSTEOM, G.: Serum levels of TSH.
T3, rT3, T4 and T3-resin uptake in surgical trauma. Acta Endocrinol. 88 (1978) 482-489, BLIcliEscr-T0FT, M.; CHRISTENSEN, V.; ENOQUIST, A.; FOG-MOLLER, F.; KEmET, H ; MADSEN,
S. N.; SKOVSTED, L.; TiboR, J.; OLGAARD, K.: Influence of age on the endocrine-metabolic response to surgery. Ann. Surg. 190 (1979) 761-770. BRANDT, M. R.; KEBIET, H.; SKOVSTED, L ; HANSEN, J. M.: Rapid decrease in plasma-triiodo-
thyronine during surgery and epidural analgesia independent of afferent neurogenic stimuli and of cortisol. Laneet 2 (1976) 1333-1336. Buia, W.. A.; GRIFFrL'Hs, R. S.; BLACH, E. G.; H0FFENBEHO, R.; MEINHOLD, H.; WENZEL,
K. W.: Serum triiodothyronine and reverse triiodothyronine concentrations after surgical pperation. Lancet 2 (1975) 1277-1279. Cix, V.; WANG, C.; YBUxa, R. T. T.: Pituitary.thyroid responses to - surgical stress. Acta Endocrinol. 88 (1978) 490-498
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CHOPBA, I. J.; Wiiirs, D E ; ORGIAzzr, J.; SoLoMor, D. H.: Opposite effects of dexamethasone on serum concentrations of 3,3', 5'-triiodothyronine (reverse T3) and 3,3', 5-triiodothyronine (T3). J. Clin. Endocrinol. Metabol. 41 (1975) 911-920. GODFREY, K.: Comparing the means of several groups. New Eng!. J. Med. 313(1985) 1450-1456. HAGENFELDT, I; MELAIÇDER, A.; THORELL, J.; TIBELIN, S.; WEsTGEEN, U.: Active and inac-
tive thyroid hormone levels in elective and acute surgery. Acta Chir. Scand. 145 (1979) 77-82. Hin, W. A.; Honpov, P. W.; STRANG, R.; FITZGERALD, B.; RICHABDS, J. R.; HOLLOWAY, K B.: Release of thyroxine from the liver during anaesthesia and surgery. Br. J. Anaesth. 46 (1974) 818-820. HoorEa, M. J.; RAI'CLIFFE, J. G.; RATOLIFFE, W. A.; MARSHALL, J.; YouNG, R. E.; NGAEI, G.;
control by TSR. Clin. Endocrino!. 8 (1978) 267-273. KEBIET, H.; 1ÇiuFER, P. V.; WERKE, J.: Thyrotropin, free and total triiodothyronine, and thyroxine in serum during surgery. Clin. Endocrinol. 10 (1979) 131-136. O'BJL&N, J. T.; BYBEE, D. E.; BURMAN, K. D.; OsnuRFR, R. C.; K5IAzEK, M. R.; WART0T5-
xy, L.; GEoRGEs, L. P.: Thyroid hormone homeostasis in states of relative caloric deprivation. Metabolism 29 (1980) 721-727. O'CoiuLL, M.; ROBBINS, D. C.; BOGARDUS, C.; BURGER, A. G.; DANFORTH, E., Jr.: The inter-
action of free fatty acids in radioimmunoassays for reverse triiodothyronine. J. Clin. Endocrinol. Metabo!. 55 (1982) 577-582. OYAMA, T.; SHIBATA, S.; MATSUKI, A.; KUD0, T.: Thyroxine distribution during halothane anesthesia in man. Anesth. Analg. 48 (1969) 715-719. PREscoTT, R. W. G.; YEO, P. P. B.; WATSON, M. J.; JomrsTolcE, I. D. A.; RATCLIFFE, J. G.; EVERED, D. C.: Total and free thyroid hormone concentrations after elective surgery. J. Clin. Pathol. 32 (1979) 321-324. RUTBERG, H.; ANDERBERG, B.; HAKAIÇSON, E.; JORFELDT, L.; K&GEDAL, B.; TEGLER, L.:
Influence of extradural blockade on serum thyroid hormone concentrations after surgery. Acta Chir. Scand. 151 (1985) 97-103. SowERs, J. R.; RAJ, R P ; HERSHMAN, J. M.; CAELSON, H. E.; MCCALLUM, R. W.: The effect
of stressful diagnostic studies and surgery on anterior pituitary hormone release in man Acta Endocrinol. 86 (1977) 25-32. WoLYsoN, M. S.; RAOUF, A. A.; O'GomuAN, P.; MAESDEN, P.: Rapid adaptation of pituitary
responsiveness to TRH in the post-surgical state. The role of free T3. Clin. Endocrinol. 15 (1981) 579-584. (Accepted 13 April 1989)
Author's address: Dr. Tomu CHTFENJI, Department of Surgery, Chiba Municipal Hospital, 827 Yahagi, Chiba 280, Japan
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Ciuu, D. H.: Evidence for thyroidal secretion of 3,3', 5'-triiodothyronine in man and its
