Adrenalectomy is the recommended method to treat pheochromocytoma [31–33]. The important note is that patients are at risk of hemodynamically instability before, during and after surgery [32]. Therefore, appropriate preparation for the surgery is necessary to prevent complications [32].
In the Azahra hospital of Isfahan, endocrinologists tend to choose PhB to prepare the patients. It provides more preventive effects by irreversible binding to receptors, more immediate effects and a significant hypotensive effect [34]. Use of the drug, could greatly reduce intraoperative hemodynamic instability and patient’s death during surgery [35].
The initial PhB dose is once to twice daily, usually 10 mg, with an increase of 10–20 mg in divided doses every 2–3 days. Most commonly, the patient is ready for the surgery within the first 7–14 days after initiation of PhB. The final dose is most typically between 20–100 mg daily [36]. This was the chosen approach to prepare the patients in the Azahra hospital, too.
In our center, mean time of preoperative management was 19.7 ± 16.5 days with the median of 14.0 days. However, researchers have reported median duration of 27.4 days, 16 days, 35 days, 38.8 days and even 14 weeks. [10,30,37– 39]. Our study, like most previous studies, defined the duration of preoperative management from the time of beginning to surgery [29, 36, 37]. We didn’t find any difference between this duration and group of patients with and without hemodynamic alteration during surgery (P = 0.601), like the study Russel et al., Kiernan et al. and Hongju Liu et al. did. [38, 40, 41] Russel et al. reviewed 14 patients’ data who underwent adrenalectomy in a retrospective study from 1980 to 1993 and concluded that longer treatment with PhB can’t cause better perioperative BP stability. [40] In Hongju Liu et al.’s study, a total of 253 patients were grouped according to their tumor diameter: diameters of ≥ 8cm, 6 to 8 cm and < 6 cm. They showed that there was no difference in time of preparation for these 3 groups of patients. [41] It suggests that spending long days to prepare patients for the surgery is not necessary and helpful [38, 40, 41]. We should mention that all these studies, used imaging reports to do analyses on tumor size.
In a study, mean PhB dose was 29.4(20–40) mg/day [39]. In this study, Tian et al. studied 102 patients’ data who were diagnosed with pheochromocytoma and received surgical treatment from 2001 to 2018 in China. They took PhB from admission in hospital and they mentioned this mean dose. It was close to our study with the mean dose of 30.34 ± 14.22 mg/day (P = 0.635). There was no difference in PhB dose between groups of tumor size or groups of patients with and without hemodynamic instability during surgery in their study. In some other studies, mean doses were 55.0 ± 22.2 mg/day and 40 ± 23 mg/day [30, 43]. There was no difference in PhB dose between tumor sizes > 33.5mm and tumor sizes ≤ 33.5 groups in our study (P > 0.05). In the Hongju Liu et al.’s study, larger tumors needed more PhB dose [41]. Because pheochromocytoma is a rare disease and most studies are retrospective, we don’t know if determining the dose of the drug to prepare patients depends solely on measuring BP or some endocrinologists prefer to prescribe higher doses of PhB for larger tumors. They increase the dose of the drug until it is tolerable. Therefore, perhaps comparing the dose of the drug between different studies only indicates the prescriptions of each physician according to his/her experiences.
We couldn’t find any difference between HTC and no HTC groups when the tumor size was determined by pathology unlike when it was determined by imaging. Because pathology gives more accurate measure of tumor size Therefore, it seems that in our study, tumor size isn’t different in the 2 groups.
We also found that patients with admit SBPs more than 130mmHg, needed more doses of PhB were needed. A study, which Miahi R and colleagues did in 2008, showed that there was no correlation between this variable and dose of PhB [30]. Their study was a retrospective review of 60 patients with pheochromocytoma who underwent an adrenalectomy after adrenergic blockade using standardized protocol between 1998 and 2007. So we suggest a new item to pay attention managing pheochromocytoma. However, more studies are needed to confirm this finding.
We noticed that patients with higher levels of 24-h urine normetanephrine, needed more PhB. In the study which Miahi R et al. did [30], there was no significant correlation between the dose of PhB and levels of 24–h urine normetanephrine. Maybe this metabolite could be a predictor of more PhB needed to prepare patients for the surgery.
We also found that with more 24-h urine metanephrine levels, a bigger tumor can be expected, like the study Jennifer C Carr et al. did [42]. They studied 70 patients’ data retrospectively and concluded that urine normetanephrine, metanephrine and norepinephrine levels were correlated with bigger sizes of tumor.
Our study showed that despite adequate treatment with PhB and other prescriptions before surgery, HTC wasn’t uncommon (12 patients (23.1%)). So it’s of great importance to see why patients experienced HTC during adrenalectomy despite this management.
In our study, larger tumors resulted a significant increase in the HTC during surgery (a larger maximal diameter of > 33.5mm reported by imaging, P = 0.023). It was consistent with other studies [22, 38, 44–47]. However, HTC during operation was not correlated with catecholamine levels alone. This may suggest that the intraoperative manipulation of larger tumors causes release of larger amounts of catecholamines than are recorded at baseline, which is consistent with Kiernan et al.’s conclusion of their study [38]. In another study, H Bruynzeel et al. analyzed data of 73 patients who underwent operation from 1995 to 2007 in a retrospective pattern. They concluded that larger tumor size is a risk factor for hemodynamic instability during surgery. (> 4cm, r = 0.27, P < 0.05) [22] In a retrospective study which Anouk Scholten and colleagues did, 61 pheochromocytoma resections between 2000 and 2010 was done. They concluded that tumor size is an independent risk factor for HTC during surgery (> 3cm, r = 0.39, P = 0.002) [46].
There was no difference in type of surgery between groups of patients with and without HTC during surgery. It is consistent with Davies et al.’s study [47]. They compared 24 patients’ data which 12 patients underwent open and 12 patients underwent laparoscopic surgery. They concluded that there was no statistically significant difference between the two groups. However, Kiernan and colleagues studied 91 patients’ records and concluded that open surgery was associated with HTC during surgery [38].
As mentioned earlier, we had 12 patients with HTC during surgery. Four of them (33.3%), received PhB less than 20 mg/day. All of them had our criteria of preparation for the surgery but 6 of them (50%) had right before surgery SBP > 130mmHg. For 4 patients, we couldn’t find a reason. However, 3 of them (75%) had tumor sizes greater than 50mm. The other one’s tumor size was 34mm. It’s considerable that all 52 patients were totally prepared and then were sent to operating room and these BPs before surgery, were detected by anesthesiologists.
As mentioned above, all BPs before surgery in patients with HTC were greater than patients without this crisis. A study which Buitenwerf E et al. did, showed that a preoperative SBP < 130 mmHg is associated with less hemodynamic instability during surgery [49]. They did a randomized controlled trial from 2012 to 2017 in Netherlands on a total of 144 patients and concluded this result about preoperative SBP but they didn’t mention SBP on admission. It shows that maybe lowering these BPs, could be helpful in preventing HTC during surgery. So increased dose of PhB to decrease these BPs to SBPs < 130mmHg can be a significant predictor of improved intraoperative hemodynamic stability. This conclusion is parallel with the study which Livingstone M et al. did [8]. They reviewed 100 pheochromocytoma resections from 1992 to 2013 and concluded that increased preoperative dose of PhB over the last 10 years’ practice have likely contributed to the improvements in perioperative outcomes.
This issue that if taking anti-hypertensive drugs aside from α- and β- blocker, including ACEIs and ARBs or Amlodipine could predict a HTC during surgery was analyzed. We found that patients taking amlodipine to control BP were at more risk for HTC during surgery. Amlodipine, a long acting calcium channel blocker, is mainly used to supplement α- blockers in patients with poor BP control, to obviate the need of increasing the dosage of α-blockers, to replace α-blockers when cause severe side effects and to prevent α-blocker-induced sustained hypotension in patients with only intermittent hypertension. Calcium channel blockers don’t cause hypotension or orthostatic hypotension when patient is normotensive [50]. We didn’t find a study to focus on this variable. We suggest more and clinical trial studies to evaluate this drug and its effect on HTC during surgery but our recommendation is to reduce the use of amlodipine and instead, more α–blocker be used as possible as it can be used while preparing the patients for adrenalecomy and more hydration and high sodium diet be administered to prevent probable hypotension of patients.
There were several limitations in our study. First, this was a retrospective study spanning a 9–year period and any retrospective study is limited by the quality and inaccuracy in data reporting. Second, the analysis of HTC during surgery was limited by the small number of patients who experienced this crisis during surgery. (12 patients, 23.1%) Third, the fact that it was a single – center study. Fourth, because of incomplete data recording, we couldn’t record patients Body Mass Index (BMI) and therefore, it may have affected some of our data analyses. Finally, our center was a COVID-19 referral center when the epidemic started, so most surgeries couldn’t be done and caused a limitation in sample of our study.
Despite these limitations, we could find some analyses that few studies had mentioned, like taking amlodipine and its predictor value of HTC during surgery. One of strength of the study was the relatively good number of patients. We used both imaging and pathology reports to analysis tumor sizes. Also it’s worth to mention that this study is the only study which is done in Iran and therefore its data can be helpful for next studies.