Patients’ characteristics

From January 2017 to December 2018, 15 patients (F/M 10/5, age 53 ± 12 years) with acromegaly underwent pituitary neurosurgery. The median diameter of the lesions was 13 (8–15; range 5–28) mm and was 8 (5–8) mm in microadenomas (n = 5) and 14 (13–15) mm in macroadenomas (n = 10), respectively.

In the pre-operative period, 6 out of 15 patients (40%) had been previously treated with medical therapy using somatostatin analogs (SSAs) (2 patients with lanreotide at the dose of 120 mg/28 days, 2 patients with octreotide at doses of 30 mg and 40 mg every 28 days, and 2 patients with pasireotide at the dose of 60 mg/28 days) for a duration of 9 ± 3 months. In all cases, ongoing treatment was discontinued one month before the surgery. One of the 2 patients on pasireotide had undergone a previous pituitary neurosurgery 53 months earlier and was re-operated due to the persistence of disease activity with remnant adenomatous tissue.

Before surgery, only 2 patients had good disease control during medical therapy (IGF-I / ULN < 1), while in other cases, disease was still active: in such patients, median IGF-I was 2.0 (1.4–2.9) xULN, and in 10 out of 13 patients (76.9%), IGF-I values were > 1.3xULN, with a median random GH of 3.9 (3.1–5.1) µg/L.

The characteristics of patients at baseline are shown in Table 1.

Table 1 Characteristics of patients at baseline. Data are expressed as mean ± standard deviation (SD) or median and interquartile range (IQR) or n (%). BMI: body mass index; GH: growth hormone; PRL: prolactin; IGF-I: insulin-like growth factor I; ULN: upper limit of normality; eGFR: estimated glomerular filtration rate (calculated through the CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration])Fluid balance in the postoperative period

The data regarding fluid input, output and balance are presented in Table 2. On the first postoperative day (POD1) 6 out of 15 patients (40%) had a negative fluid balance (-313 ± 210 ml) while on the second postoperative day (POD2) 11 out of 15 subjects (73.3%) presented a negative fluid balance (-565 ± 506 ml).

Table 2 Variations in fluids input and output in patients with and without postoperative polyuria. Data are expressed as mean ± standard deviation (SD).

One subject developed polyuria on POD1, while 3 subjects developed polyuria on POD2; in the end, only one subject with polyuria presented a positive fluid balance (+ 183 ml).

Subjects with polyuria did not exhibit a significant difference in terms of fluid balance compared to those who did not develop it, although a trend towards significance was observed regarding POD2 (p = 0.066). However, as expected, they did show a significantly higher urine output, considering the second postoperative day and both days combined.

Biochemical results in the perioperative and postoperative period

Copeptin levels at T0 were 3.85 (2.42–5.60) pmol/L and significantly increased at T1 (31.06 [10.33–57.84] pmol/L, p = 0.001) with subsequent rapid reduction; moreover, copeptin levels at T1 were significantly correlated with tumor diameter (r = 0.695, p = 0.004). On the other hand, no difference was observed between copeptin at T0 and at T2 (p = 0.140) and T3 (p = 0.650).

After surgery, GH levels rapidly decreased at T2 (1.90 [0.93–2.48] µg/L, p = 0.006 vs. T0) and at T3 (1.60 [0.48–1.98] µg/L, p = 0.005 vs. T0). Furthermore, median GH levels at T3 were significantly lower than those measured at T2 (p = 0.044).

No differences were observed during hospitalization regarding s-Na values and p-Osm; after surgery, however, u-Osm values were significantly lower than T0 at each time point (p < 0.05), both in subjects with and without polyuria. Moreover, u-Osm measured at T2 and USG evaluated at T3 were significantly lower in patients experiencing polyuria (Table 3). Finally, no patients with postoperative polyuria presented glycosuria.

Regarding the previously identified copeptin cut-off of 12.8 pmol/L [19], which showed good diagnostic accuracy for predicting acquired postoperative CDI, in the present sub-analysis only 4 out of 15 patients exhibited a copeptin value at T1 below this threshold. However, sequential assessment of fluid and electrolyte balance in the subsequent days ruled out the onset of either polyuria or CDI.

Table 3 Laboratory parameters at the different time points in patients with and without postoperative polyuria. T0: preoperative; T1: 1 h post-extubation; T2: morning of the first postoperative day; T3: morning of the second postoperative day; GH: growth hormone; s-Na: serum sodium; p-Osm: plasma osmolality; u-Osm: urine osmolality; USG: urine specific gravityCorrelations between biochemical results and fluid balance

Postoperative GH values did not significantly differ between those who developed polyuria and those who did not (p = 0.744 at T2, p = 0.391 at T3), but GH measured at T2 significantly correlated with a negative total fluid balance (r = -0.519, p = 0.048).

Copeptin levels at T1 were significantly higher in those who developed polyuria compared to those who did not (79.0 [52.1-239.4] pmol/L vs. 17.9 [8.8–32.7] pmol/L, p = 0.013) (Table 3); in particular a copeptin value at T1 > 39.9 showed excellent ability (Se 100%, Sp 90.9%, AUC 0.932, p < 0.001) in identifying individuals at risk of developing polyuria in the first 2 days after surgery (Fig. 1A).

Fig. 1

Receiver operating characteristics (ROC) analysis showing excellent accuracy for copeptin evaluated at 1 h post-extubation (A) and on the morning of the second postoperative day (B) in predicting the subsequent onset of polyuria in patients with acromegaly undergoing endoscopic endonasal resection

Similarly, copeptin evaluated at T3 ≤ 3.5 pmol/L was significantly associated with the development of both second-day polyuria (Se 100%, Sp 72.7%, AUC 0.758, p = 0.042) and total polyuria (Se 100%, Sp 72.7%, AUC 0.818, p = 0.004) (Fig. 1B). Accordingly, the copeptin T1 / T3 ratio was significantly higher in polyuric patients (25.9 [17.6–75.1] vs. 3.4 [1.7–6.8], p = 0.013) (Fig. 2). On the other hand, copeptin measured at T2 did not differ between the two groups (p = 0.948), nor did the T1 / T2 ratio, although there was a tendency towards significance (p = 0.057).

Fig. 2

Difference in the ratio between copeptin (pmol/L) values measured at 1 h post-extubation (T1) and on the morning of the first (T2) and the second (T3) postoperative day in patients with acromegaly undergoing pituitary neurosurgery based on the onset of polyuria or not. *p = 0.013

Acromegaly remission at the 1-year follow-up

Eleven out of 15 patients (73.3%) showed acromegaly remission at 12 months post-surgery. Disease remission was significantly correlated with GH values evaluated at T2 (r = -0.662, p = 0.007) but not at T3 (p = 0.182). In the ROC analysis, a GH value measured at T2 < 2 µg/L demonstrated excellent ability in predicting the long-term remission outcome (Se 90.9%, Sp 100%, AUC 0.955, p < 0.001).

Finally, a negative total balance was associated with disease remission at 12 months (p = 0.046), while no differences were observed regarding total diuresis and the likelihood of remission.