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Luis Roberto Salgado
The most important endocrinological response to surgical stress includes activation of the hypothalamic-pituitary-adrenal (HPA) and sympathetic systems. No major hormonal change occurs during anesthesia and surgical exploration. However, during anesthesia reversal, endotracheal extubation and in the immediate post-operative recovery period a strong activation of the HPA axis and adrenomedullary sympathetic system can be observed with substantial increases in plasma ACTH, cortisol and epinephrine (Udelsman 87). A limited number of papers that studied the responses of these systems to surgical stress had included patients with pituitary tumors (Arafah e trab com D.Cush), but no previous study had evaluated, in these patients, the influences on ACTH and cortisol secretion rates of the mechanical pituitary manipulation.
In this paper we report on the intraoperative ACTH and cortisol dynamics in patients submitted to transesphenoidal surgery (TS) for ACTH-secreting pituitary tumors as compared to those with other sellar tumors.
Twenty-one patients with pituitary tumors were evaluated before and after TS. All patients received identical sedative and anesthetic agents. Imaging of the pituitary tumors was obtained by magnetic resonance (MR) in all patients. Suggestive tumor tissue was visualized and resected by the neurosurgeon during surgery and histological examination and immunohystochemistry confirmed the diagnosis in all patients. Informed consent was obtained from all patients and the research protocol was approved by the Institutional Review Board.
They were divided in 2 groups according to their pre-operative HPA axis function and tumor type. Group I patients (n= 9; age = ; 3 males and 6 females) had GH-secreting and non-secreting adenomas. All patients had a normal cortisol response during an insulin tolerance test (ITT) obtained in the pre-operative period and these patients did not receive hydrocortisone (HC) during surgery or in the post-operatives days. Group II patients had ACTH-secreting pituitary tumors (n = 12; age = ; 2 males and 10 females). Ten patients had Cushing’s disease and 2 had Nelson’s syndrome. Group II patients received intravenous HC during surgery and in the first post-operative day, as follows: 200 mg during the day of surgery (PO-i)(50 mg immediatly before pituitary manipulation, 50 mg 10 minutes after pituitary tumor ressection and 50 mg b.i.d.) and 100 mg during the first post-operative day (PO-1) (50 mg b.i.d.).
Blood samples for cortisol and ACTH determination were obtained from all patients before anesthesia, immediatly before pituitary gland manipulation, 10 minutes after pituitary tumor resection and 30, 60, 90, 120 and 150 minutes after tumor removal. In Group I patients an additional blood sample was obtained 300 minutes after tumor removal.
Two Group II patients (one with Cushing’s disease and one with Nelson’s syndrome) were also studied using a similar protocol pre-operatively in a resting state. They received 200 mg of intravenous HC in a schedule similar to that during surgery and blood samples were obtained before and after HC injections at the same timing.
Serum cortisol and plasma ACTH were measured by an automated chemiluminescent enzyme immunoassay kit (IMMULITE, Diagnostic Products Corp., Los Angeles, CA) and the reference range was 5-25 m g/dL and 10-46 pg/mL for cortisol and ACTH, respectively. The inter- and intra-assay escrever por extenso (CV) for cortisol was 6.0% and 4.1%, respectively. For ACTH the CV inter-assay was 7.2% and the intra-assay CV was 2,9%.
Data were analyzed by the Mann-Whitney test, Wilcoxon test and 2-way ANOVA for repeated measures (on one dimension), and Kelss-Newman’s multiple range test. Results were reported as mean +/- SE. P-Values below 0.05 were considered statistically significant.
Mean ACTH and cortisol values observed in the preoperative evaluation were significantly smaller in group I (ACTH= 47.8 +/- 7.4 pg/mL and cortisol= 16.3 +/- 1.9 m g/dL) than in group II (ACTH = 82.5 +/- 15.6 pg/mL and cortisol = 32.3 +/- 4.5 m g/dL).
In group I, the mean ACTH value 10 minutes after pituitary tumor resection (ACTH = 69.8 +/- 11.7 pg/mL) was significantly greater than that in the pre-pituitary manipulation period (ACTH =29.2 +/- 8.2 pg/mL). This increase in ACTH level was observed after tumor resection and persisted for more than 150 minutes. The ACTH level fell into the normal range in all patients during PO-1 (figure 1). A significant increase in the cortisol level was observed 60 minutes after tumor resection, which persisted for at least 150 minutes.
In group II, mean ACTH values were also significantly greater 10 minutes after pituitary tumor resection (297.8 +/- 75.1 pg/mL) than in the pre-manipulation period (ACTH= 115.4 +/- 26.2 pg/mL). This occurred despite the administration of 50 mg of HC before pituitary manipulation. No differences in mean ACTH concentration were found within the first 5 hours after tumor resection either in the 6 patients with complete tumor resection (proved later by the remission of hypercortisolism in 5 patients with Cushing disease or ACTH normalization in a patient with Nelson’s syndrome) (mean ACTH = 153.9 +/- 46.4 pg/mL) or in other 6 patients not cured by surgery (mean ACTH = 161.2 +/- 71.2 pg/mL) (p= 1.0). Only in PO-1 a significant decrease in ACTH level was observed in these patients (9/12 had a normal ACTH level). Both patients with ACTH-secreting tumors (one with Cushing’s disease and other with Nelson’s syndrome) studied in a resting state pre-operatively were cured by surgery. They showed a clear decrease in ACTH concentration after HC administration pre-operatively. This was not observed intra-operatively. ACTH levels after tumor resection in patients with Nelson’s syndrome followed the same pattern as observed in patients with Cushing’s disease and statistical results were the same when they were excluded from the sample.
Increased ACTH and cortisol secretion during anesthesia reversal, endotracheal extubation and early recovery has been well docummented in some reports dealing with major surgical procedures (Arafah, Udelsman, Estep 62). They are considered the main periods of stress to the patient. We noted a robust ACTH release in our patients with non-secreting tumors during TS during these periods.
It is well known that in normal subjects in a resting state steroid administration supresses ACTH. We found that HC may partially suppress ACTH secretion in patients with ACTH-secreting pituitary tumors. On the other hand, in conditions of stress (surgery) corticotrophs may secrete high amounts of ACTH in spite of the excess of circulating steroids as in group II patients, suggesting that during stress the behavior of the human HPA system may not conform to the specifications of a rigid negative feedback mechanism (Step).
An abrupt decline in ACTH level should be expected within 15-30 min (approximately one half-life)(referencia 6 doFaff 95) if tumor resection was complete and corticotrophs were totally suppressed. However, even in those 6 patients cured by surgery (including 1 patient with Nelson’s syndrome) persistently high ACTH levels could be seen at least 5 hours after tumor resection. This suggests that peri-tumoral normal corticotrophs may not be totally suppressed in patients with Nelson’s syndrome or Cushing’s disease. We observed a rise in ACTH levels during the first post-resection hours in patients with Cushing’s disease who were cured by TS. Graham et al did not observe a significant reduction in ACTH levels for hours after complete tumor resection. Mechanical pituitary manipulation may justify the early rise in ACTH levels, as showed in the present study, but it could not explain the maintenance of high ACTH levels for hours (ACTH half-life = 8-15 minutes). Its not clear which ACTH-releasing factor could be leading to this abnormally set feedback mechanism during surgical stress. Several substances secreted during surgical stress may induce ACTH release such as CRH, vasopressin, angiotensin-II, catecholamines and interleukin-1 and 6 ( Udelsman 87, Salem 94 e trab da Martha). Some of these substances could be acting as a potent ACTH-releasing factors. Durijk et al ( 97 ) showed that administration of a supra-physiological dose of HC (80 mg) suppressed the lipopolysaccharide-induced interleukin-1B, interleukin-6 and tumor necrosis factor (TNF) alfa production, whereas administration of a physiological dose (20 mg) of HC suppressed only TNF-alfa production. In the present study, a similar supra-physiological dose of HC was administered in patients with ACTH-secreting tumors and it is possible that all 3 citokines were suppressed during surgical stress. At least in these cases, the persistent ACTH release could not be exclusively due to these citokines. ACTH and cortisol hypersecretion occurred in the post-operative period of neck exploration procedures despite the absence of increased circulating CRH (Udelsman 87). Udelsman and col (1987) showed significant increase in epinephrine and in plasma renin activity during this period and they should be considered pottentially important ACTH-releasing factors. However, plasma elevations of catecholamines during acute glucocorticoid deficiency after surgical treatment for Cushing’s disease (abstract ICE 96) are not enough to induce an adequate increase in ACTH levels. We noted (umpublished data) that in a patient with cortisol-secreting adrenal adenoma there was no ACTH increase after surgery, suggesting that in this situation corticotrophs were completely suppressed or that some ACTH-releasing factors secreted during TS were not released during adrenalectomy. Persistent ACTH secretion during the immediate post-operative period in patients with ACTH-secreting pituitary tumors may be induced by so far unknown ACTH-releasing factors.
Peri-tumoral normal corticotrophs are not completely suppressed in patients with Cushing's disease. This is also true during the immediate post-operative stress period and with the administration of high doses of glucocorticoids. ACTH-releasing factors other than the traditional ones may be responsable in these patients for the persistent ACTH release during TS. In patients with ACTH-secreting pituitary tumors the behavior of the human HPA system during TS does not conform to the specifications of a negative feedback mechanism, as can be seen in patients without ACTH-secreting tumors. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfer in the maintenance of high ACTH-levels during the early post-operative period.