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Abstract
Objective Surgery is the primary strategy for treating phaeochromocytoma (PCC), but it can lead to severe hypertension and heart failure. Although valsartan is effective in reducing high blood pressure, clinical data on the potential role of valsartan in PCC are currently limited. Therefore, the aim of this study was to investigate the effects of pretreatment with terazosin and valsartan on patients with PCC.
Methods In this retrospective cohort study, 50 patients who underwent laparoscopic resection of PCC were enrolled. During preoperative preparation, the patients (n=25) in the control group were treated with terazosin, while those (n=25) in the combination treatment group were treated with terazosin and valsartan. The levels of catecholamine hormones before and after surgery were determined, and the intraoperative blood pressure and the incidence of complications were compared between the two groups.
Results The results showed no significant differences in baseline patient characteristics or surgical conditions between the two groups (p>0.05). However, on the third day after surgery, the levels of catecholamine hormones in the two groups were significantly lower than those before surgery (p<0.05), while the levels in the combination treatment group were notably lower than those in the control group (p<0.05). The patients in the combination treatment group showed lower intraoperative blood pressure fluctuations and incidence of perioperative complications compared with the control group (p<0.05).
Conclusions Terazosin combined with valsartan can effectively improve perioperative haemodynamic instability and reduce postoperative complications in the preoperative management of PCC.
- basic sciences
- pharmacy design
- hypertension
- clinical pharmacy
- clinical trial medication
Data availability statement
No data are available.
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Introduction
Phaeochromocytoma (PCC) is a rare neuroendocrine tumour that derives from the adrenal medulla. According to statistics, the incidence of PCC is as high as 8 in every 100 000 people,1 and approximately 0.1–1% of PCC patients have hypertension.2 3 Laparoscopic surgery is a primary strategy for the treatment of PCC4; however, it carries a high risk of massive release of catecholamines into the circulatory system, leading to hypertension, arrhythmias, hypertensive encephalopathy, severe arterial spasms, metabolic acidaemia and even death.5 Studies have demonstrated that high levels of plasma norepinephrine and large tumour size were the risk factors for developing intraoperative and/or perioperative haemodynamic instability.6 7 Hypotension may be caused by a chronically low circulating blood volume and a sudden decrease in serum catecholamine levels of patients after tumour resection.8 Since 1956, preoperative medical management has been widely used to improve perioperative haemodynamic instability and reduce postoperative morbidity and mortality.9 α-Adrenergic blockade plays an important role in perioperative haemodynamics and surgical outcomes. However, maintaining haemodynamic stability and avoiding postoperative complications remain a challenge to be addressed.
Terazosin is a selective α1 adrenergic receptor blocker that acts on the α1 adrenoceptor and causes vasodilatation. Under the circumstance of no increase of α2 receptor presynaptic release of norepinephrine, severe tachycardia can be avoided.10 Terazosin has been widely used for the preoperative preparation of PCC11; however, perioperative complications are still common in PCC patients with treatment of terazosin only during preoperative preparation.12 Excessive production of catecholamines can increase the release of renin and may lead to the release of angiotensin,13 while angiotensin II exerts systemic effects and causes hypertension in patients.14 Thus, the use of angiotensin receptor blockers (ARB) could possibly promote blood pressure control, though the Endocrine Society Clinical Practice Guideline15 indicates that α-adrenergic receptor blockers are the primary option during perioperative management. However, it has been shown that the expression or activation of angiotensin II receptor reduces the growth of PCC, while angiotensin II contributes to the metastasis of breast cancer.16
This retrospective cohort study compared the efficacy and safety of pretreatment with terazosin and valsartan in PCC patients by comparing surgical conditions, catecholamine levels, intraoperative blood pressure changes, and the incidence of complications in the subjects. We hypothesised that terazosin combined with valsartan might improve perioperative haemodynamic instability and reduce postoperative complications in preoperative management of PCC.
Methods
Study design and patient selection
In this retrospective cohort study, 50 patients who had undergone laparoscopic PCC resection in the Linyi People’s Hospital from June 2015 to June 2017 were enrolled. All patients were diagnosed as having PCC by biochemical tests and imaging examination that included 24 hour urinary catecholamine determination, blood catecholamine concentration determination, 24 hour urinary vanillin acid and urinary homovanillic acid determination, urinary metanephrine and normetanephrine determination, type B ultrasonic detection, and CT detection. The tumour tissues derived from the patients were collected for pathological diagnosis after surgery.
The inclusion criteria were: (1) pathological confirmation with PCC grade 2 or 3 (grade 0: blood pressure ≤140/90 mmHg, urinary norepinephrine <40.65 μg/24 hours, adrenaline <6.42 μg/24 hours, dopamine <330.59 μg/24 hours; grade 1: blood pressure ≤140/90 mmHg, urine norepinephrine >40.65 μg/24 hours or epinephrine >6.42 μg/24 hours or dopamine >330.59 μg/24 hours; grade 2: blood pressure ≤240/150 mmHg, urinary norepinephrine >50.25 μg/24 hours or epinephrine >8.31 μg/24 hours or dopamine >444.90 μg/24 hours; grade 3: blood pressure ≥240/150 mmHg, urinary norepinephrine >50.25 μg/24 hours or epinephrine >8.31 μg/24 hours or dopamine >444.90 μg/24 hours accompanied by cardiovascular and cerebrovascular accidents; (2) maximum tumour diameter <6 cm; (3) complete resection of the tumour. Grade 0 and 1 PCC refer to patients who have mild PCC symptoms and are easier to control than patients with grade 2 and 3, but these patients had limited significance for our study. Therefore, only patients with grade 2 to 3 PCC were included in this research.
The exclusion criteria were: (1) patients with paraganglioma, malignant PCC, severe injury in the lung or kidney; (2) patients with pathologically confirmed malignant PCC before the study. Baseline patient characteristics were collected and the surgical conditions and intraoperative blood pressure, catecholamine hormones levels and perioperative complications were analysed.
Baseline patient characteristics
In this study, 50 PCC patients who met the inclusion criteria were enrolled (table 1). The patients underwent laparoscopic resection of PCC from June 2015 to June 2017. Quantitative data were expressed as mean±SD.
Baseline patient characteristics and surgical conditions
The control group comprised 25 patients aged 39.69±10.12 years, with mean±SD body mass index (BMI) of 22.87±3.31 kg/m2, tumour size 44.63±12.55 mm, anaesthesia duration 193.64±35.27 min, operation duration 123.49±36.88 min, fluids given 3216.48±413.25 mL, blood loss 212.48±21.23 mL, and intraoperative urine volume 311.49±94.37 mL. Tumours were found located in the left side (n=9), right side (n=13) or both sides (n=3) in the patients. The patients in the control group received treatment with terazosin only in the preoperative management.
The combination treatment group comprised 25 patients aged 41.25±12.67 years old, with mean±SD BMI of 22.46±3.25 kg/m2, tumour size 42.56±11.27 mm, anaesthesia duration 188.62±42.56 min, operation duration 116.59±42.56 min, fluids given 3125.42±446.37 mL, blood loss 206.34±20.59 mL, and intraoperative urine volume 308.64±97.25 mL, who received combined treatment of terazosin and valsartan in the preoperative preparation. The tumour locations were found in the left side (n=10), right side (n=13) or both sides (n=2).
Preoperative management
During preoperative management, the patients in the control group orally received terazosin (1 mg/tablet) at the initial dose of 1 mg per day,17 which was gradually increased until the patients met the preoperative conditions, and the maximum dose of terazosin was between 1 mg and 5 mg per day. Patients who had a rapid heart rate (≥100 beats/min) were given 50 mg metoprolol (50 mg/tablet) a day, and the heart rate and blood pressure of all the patients were measured three times daily. The entire preoperative treatment lasted for 14 days.
Apart from taking the same prescription as the control group, the patients in the combination treatment group also took valsartan (80 mg/tablet) orally. The initial dose was 80 mg a day, which was increased gradually until the patients met the preoperative conditions and the maximum dose was 80–160 mg per day. The preoperative treatment lasted for 14 days.
The following criteria were set as previously described18 to achieve an optimal preoperative condition: blood pressure ≤160/100 mmHg; no ST segment or T wave changes within 1 week before surgery; haematocrit <0.45; fewer than five premature ventricular contractions per minute.
Surgery
Adrenalectomy was performed on the patients through retroperitoneal incision of the 11th intercostal space under general anaesthesia by two experienced surgeons. The anaesthesia was induced by intravenously injecting propofol into the patients and maintained by inhaled sevoflurane. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (mABP) and central venous pressure (CVP) were monitored by invasive blood pressure monitoring technology, and the heart rate was measured by an electrocardiogram (ECG) monitor. Six percent hydroxyethyl starch was given to dilate the blood vessels.
Data extraction
Clinical data, including baseline patient characteristics and surgical conditions (ie, age, BMI, tumour size, tumour location, anaesthesia time, operation duration, fluids given, blood loss, and intraoperative urine volume), were compared between the two groups. A total of 10 mL blood specimens were collected from each patient, before and the third day after surgery, and maintained in heparin anticoagulant tubes and stored in ice until centrifugation. Plasma was obtained by centrifuging the specimens at 3000 rpm at 4℃ for 10 min and then preserved at −80℃. The concentrations of epinephrine, norepinephrine, metanephrine and normetanephrine were determined by enzyme-linked immunoassay assay (ELISA) kit (Labour Diagnostika Nord, Germany). Invasive blood pressure monitoring technology was used to monitor SBP, DBP, mABP and CVP. The catheter was placed in the blood vessel through puncture, and the outer end of the catheter was directly connected with a pressure sensor to determine the blood pressure value 10 min before surgery, at the time of endotracheal intubation and tumour resection, 10 min after tumour resection, and at the end of the surgery. We also recorded the incidence of intraoperative hypertensive crisis, sudden hypotension, microcirculation disorder, shock, and other perioperative complications.
Statistical analysis
The data were presented as mean±SD for continuous variables. Differences between the two groups were analysed by t-tests. Data were expressed as counts (%) for categorical variables, and the differences between the two groups were compared by χ2 test. Rank sum test was conducted for rank data comparison. Statistical analyses were performed by SPSS 20.0 software (SPSS Inc, Chicago, IL, USA), and p<0.05 was considered statistically significant.
Results
Baseline patient characteristics and surgical conditions
The baseline patient characteristics and surgical conditions are shown in table 1. In the present study, 50 PCC patients (25 patients treated with terazosin in the control group, and another 25 patients treated with terazosin and valsartan in the combination treatment group) were enrolled. No significant differences in age, BMI, tumour size, anaesthesia and operation duration, blood loss, and intraoperative urine volume between the two groups (p>0.05) (table 1) were identified. A crystal solution (0.9% sodium chloride solution, glucose sodium chloride solution) and colloidal solution (6% hydroxyethyl starch solution) were given to the patients for intraoperative vasodilation, and there was no significant difference in the amount of fluids given between the two groups.
Catecholamine hormones
To explore the effect of combined therapy of terazosin and valsartan on the catecholamine hormones, we carefully determined the concentrations of catecholamine hormones. No significant differences in the levels of epinephrine, norepinephrine, metanephrine or normetanephrine were identified between the two groups before surgery (p>0.05); however, a notable downregulation was observed in the two groups on the third day after surgery (p<0.05), with a lower tendency observed in the combination treatment group compared with the control group (p<0.05) (table 2).
Levels of catecholamine hormones
Intraoperative blood pressure
There was no significant difference in the levels of SBP, DBP, mABP and CVP 10 min before surgery between the two groups (p>0.05); however, a tendency to increase was observed during tracheal intubation with no significant difference between the two groups (p>0.05), and a significant upregulation was observed during tumour resection compared with 10 min before surgery (p<0.05) with a lower tendency observed in the combination treatment group compared with control group (p<0.05). A reduction of the four levels as above was observed in the two groups 10 min after the tumour resection, and the figures were lower than those 10 min before the surgery; meanwhile the blood pressure values in the combination treatment group were noticeably lower than those in the control group (p<0.05). Compared with the SBP, DBP and mABP levels in the two groups 10 min before surgery, a lower tendency was observed in the two groups at the end of the operation; meanwhile the four levels of blood pressure values in the combination treatment group were found to be significantly lower than in the control group (p<0.05). Furthermore, the patients in the combination treatment group tended to have lower intraoperative fluctuations of the four levels compared with those in the control group by detection; moreover, the fluctuations of patients in the combination treatment group showed a trend of first increasing and then decreasing over time, reaching the highest level at T2. (figures 1–4).
Comparison of intraoperative systolic blood pressure (SBP) fluctuations between the two groups. *P<0.05 compared with control group. △P<0.05 compared with T0.
Comparison of intraoperative diastolic blood pressure (DBP) fluctuations between the two groups. *P<0.05 compared with control group. △P<0.05 compared with T0.
Comparison of intraoperative mean arterial blood pressure (mABP) fluctuations between the two groups. *P<0.05 compared with control group. △P<0.05 compared with T0.
Comparison of intraoperative central venous pressure (CVP) fluctuations between the two groups. *P<0.05 compared with control group. △P<0.05 compared with T0.
Complications
During the treatment, two patients in the control group experienced an intraoperative hypertensive crisis compared to one patient in the combination treatment group. The incidence rate of sudden hypotension was 8.00% (2/25) in the control group compared with 4.00% (1/25) in the combination treatment group. In addition, patients may experience microcirculation disorder, which refers to changes in the physical and chemical properties of the blood; however, such a disorder could cause local tissue ischaemia and hypoxia or even necrosis. In this research, microcirculation disorders such as narrowing of the lumen of the coronary artery, slow blood flow, thrombosis (n=3), and shock (n=1) occurred in patients in the control group, while no microcirculatory disorder or shock was observed in the combination treatment group. Thus, the total incidence of complications in the combination treatment group was lower than in the control group (8.00% vs 32%; p<0.05) (online supplementary table 1).
Supplemental material
Discussion
PCC is a neuroendocrine tumour derived from chromaffin cells and produces excessive catecholamine. The annual incidence of PCC is 2 to 8 per million population; however, the mortality caused by PCC is significantly high.19 α-Receptor blockade has been routinely used in the preoperative preparation of PCC surgery.20 Advances in modern minimally invasive surgery and improved perioperative management have reduced the mortality rate of PCC to 0–3% and controlled the incidence of complications between 5–22%.21
Researchers suggest that preoperative preparation for PCC patients is critically important,22 as proper preoperative preparation helps to reduce the risk of developing perioperative haemodynamic instability and the incidence of cardiovascular complications. It is generally accepted that administering an α-receptor to patients for at least 14 days before surgery reduces the risk of vasoconstriction.23 However, a recent study has shown that the effectiveness of α-receptor blockade should be further determined.24 The results showed that the combined treatment of terazosin and valsartan in the preoperative preparation of PPC resection could lower the level of catecholamine and was related to improved haemodynamic instability and reduced incidence of complications in PCC patients.
Angiotensin plays an important role in the formation and development of PCC hypertension syndrome, and angiotensin II receptor blocker is a first-line antihypertensive drug.25 In our study, we found no significant difference in anaesthesia time, operation duration, amount of fluids given, blood loss, and intraoperative urine in the two groups under controlled factors (ie, age, BMI, tumour size and location). Therefore, we conclude that the use of valsartan did not affect the outcome of the PCC operation; however, as the characteristics of the subjects included in the study were different, the effects of baseline patient characteristics on the surgical condition remain to be further investigated. Another study26 showed that the operation duration of PCC patients who had 2 mg terazosin a day before surgery was approximately 40 min, which was shorter than that in our study; however, such a difference could be explained by individual differences, sample capacity or other possible factors.
PCC patients typically have hypertension, sweating, palpitation and headache, and their bodies secrete a large amount of catecholamines, including epinephrine, norepinephrine, metanephrine and normetanephrine. Hypersecretion of catecholamines may lead to hypertension, arterial spasms and/or metabolic acidaemia. In this study, PCC patients were classified into grades 0, 1, 2, and 3 according to their levels of blood pressure, urinary catecholamine indicators and whether they had a history of cardiovascular; finally, grade 2 or 3 patients were included. According to Maloberti et al,27 hypersecretion of catecholamines can also cause increased myocardial oxygen consumption. In this study, we found that the level of catecholamines was lower in the combination treatment group than in the control group, indicating that the combined use of terazosin and valsartan could more effectively inhibit catecholamines—which is consistent with a previous study28 in which valsartan was shown to inhibit vasoconstriction and catecholamine release.
Moreover, tumour removal can lead to the release of a large amount of catecholamines into the blood circulation, thereby causing paroxysmal or persistent hypertension.29 After tumour resection, the concentration of catecholamines in the blood greatly reduces, which could cause a sharp drop in blood pressure. Low blood volume could lead to hypotension or even shock, which might result in low systemic microcirculatory function and serious damage to vital organs. The purpose of preoperative preparation is to control blood pressure and heart rate,30 and it is generally accepted that α-adrenergic blockade is a primary option in the preoperative management of PCC.31 In the present study, the patients’ levels of SBP, DBP, mABP and CVP in the perioperative preparation were more stable in the combination treatment group than in the control group, and the incidence of complications in the combination treatment group was lower than in the control group, suggesting that the treatment of terazosin combined with valsartan could better maintain perioperative haemodynamic stability and reduce postoperative complications. Valsartan can block the excitation of the sympathetic nerve and prevent vasoconstriction if used in combination with angiotensin II, therefore reducing cardiac load and lowering blood pressure by inhibiting ventricular remodelling and aldosterone secretion, eliminating sodium, and storing potassium.32 Thus, α-adrenergic blockade combined with ARB may be a new therapeutic strategy for the preoperative preparation of PCC.
Compared with treatment using terazosin alone, the combined treatment of terazosin and valsartan is safer and more effective in the preoperative management of PCC and can better improve perioperative haemodynamic instability and reduce postoperative complications; thus, such a therapeutic strategy may provide a new direction in the preoperative management of PCC. However, our study has some limitations: for example, there is a lack of long-term follow-up data, and no multiple regression analyses were performed to analyse the influencing factors of hypertension. Moreover, further studies are required to determine the prognostic evaluation and factors affecting the therapeutic effects.
What this paper adds
What is already known on this subject
Surgery is the primary strategy for treating phaeochromocytoma (PCC), but it can lead to severe hypertension and heart failure.
Although valsartan is effective in reducing high blood pressure, clinical data on the potential role of valsartan in PCC are currently limited.
Therefore, the aim of this study was to investigate the effects of pretreatment with terazosin and valsartan on patients with PCC.
What this study adds
Terazosin combined with valsartan can effectively improve perioperative haemodynamic instability in the preoperative management of PCC.
Terazosin combined with valsartan can effectively reduce postoperative complications in the preoperative management of PCC.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
References
Footnotes
EAHP Statement 4: Clinical Pharmacy Services.
Contributors Substantial contributions to conception and design: QJ. Data acquisition, data analysis and interpretation: FL, XZ, YW, CL, YC. Drafting the article or critically revising it for important intellectual content: QJ.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.