Perioperative Blood Pressure Management Recommendations in Pediatric Pheochromocytoma: A 10-Year Narrative Review

Rare diseases, which affect only a small number of individuals, often result in inadequate management, long-term impairment, and severe health outcomes, including mortality. Researchers studying these diseases, clinicians providing treatment, and patients themselves frequently face significant challenges. Researchers often struggle to gather a sufficient number of affected individuals for meaningful studies. Clinicians face difficulties in acquiring the specialized knowledge and expertise needed for effective treatment and are often hindered by the lack of standardized treatment guidelines. Moreover, patients and their families encounter significant obstacles, such as delayed diagnosis and limited access to essential medications [1‒5].

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors originating from chromaffin cells. Tumors within the adrenal glands are termed pheochromocytomas, while extra-adrenal ones are known as paragangliomas [6‒10]. Although PPGLs generally cause the excess production of catecholamines, such as dopamine, epinephrine, and norepinephrine, some paragangliomas do not secrete catecholamines and thus do not cause hypertension [11‒13]. Pheochromocytomas account for 80–85% of PPGLs, with an incidence of 2–8 cases per million population, while paragangliomas represent 15%, with an incidence of 0.5 cases per million population [6, 7, 14]. About one-fifth of PPGLs occur in children and adolescents, and PPGLs are responsible for 1.7% of hypertension cases in children [15, 16]. This literature review focuses only on pheochromocytomas in children.

Catecholamine release can have alpha (α)- and beta (β)-adrenergic effects. The α-adrenergic effects include intense vasospasm and hypertension, while the β-adrenergic effects include vasodilation, diaphoresis, and tachycardia [17]. Excess catecholamine may result in a potentially life-threatening hypertensive crisis and organ dysfunction if left untreated. The definitive treatment for pheochromocytoma involves tumor resection, but this carries the risks of hemodynamic instability and cardiovascular complications [1, 17, 18].

The success of blood pressure (BP) control generally determines the overall pheochromocytoma outcome [19, 20]. However, due to the condition’s rarity, the literature on BP management in pediatric pheochromocytoma cases is limited. Most studies reporting on pheochromocytoma in children are small retrospective case series from single centers. Moreover, randomized controlled trials (RCTs) and systematic reviews remain limited to adult populations [21]. Given the lack of pediatric guidelines, pheochromocytoma management in children relies heavily on adult protocols, although medication efficacy and safety profiles differ between the two populations. Hence, this literature review aimed to fill this knowledge gap in hypertension management in children based on updated studies and practices from the last 10 years, highlighting the importance of perioperative BP control. In addition, we review some practices applied before, during, and after tumor resection that affect pheochromocytoma outcomes. We also review the existing recommendations for long-term follow-up for the surveillance of tumor recurrence/metastasis after surgery, including the value of genetic testing in children with pheochromocytomas.

The literature was comprehensively searched, using various electronic databases, including MEDLINE (PubMed), Web of Science, Scopus, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), to identify eligible studies. Secondary searches were conducted on Google Scholar and other websites, and the reference lists of the included studies were hand-searched for additional relevant studies. The language was restricted to English. The selected electronic databases were searched for articles published in the last 10 years (June 2014 to May 2024). In the context of evidence-based medicine, the highest level of evidence possible was sought [22]. Nevertheless, due to the limited number of pediatric pheochromocytoma studies, all relevant article types were included while prioritizing studies with the highest level of evidence among those on the same issue/aspect of pheochromocytoma.

For this narrative review, best practices outlined by Sukhera [23], Ferrari [24], and Pautasso [25] were followed. These sources provided a framework for selecting and integrating relevant literature, ensuring a thorough and methodical approach. Furthermore, the Scale for the Assessment of Narrative Review Articles developed by Baethge et al. [26] was used to enhance the review’s rigor.

The following terms were matched: (Child OR Adolescent OR Pediatric OR Paediatric) AND (Blood pressure OR Hypertension OR Hemodynamic OR Perioperative OR Preoperative OR Intraoperative OR Postoperative) AND (Management OR Treatment OR Therapy OR Drug OR Pharmacology) AND (Pheochromocytoma OR Paraganglioma OR Catecholamine-secreting tumor OR Adrenal tumor OR Endocrine tumor). Considering the rarity of the disease, while the primary focus remained on pediatric populations, data from adult populations were included if pediatric-specific information was limited: this is acknowledged within the text. The pathophysiology and diagnosis of pheochromocytoma are overviewed to provide readers with sufficient background. A summary of core studies from the last 10 years (2014–2024) with recommendations on perioperative BP management in PPGLs is available in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000542897) [19, 27‒40].

Catecholamines are hormones produced by the adrenal glands. Their main types are epinephrine, norepinephrine, and dopamine. Epinephrine is mainly synthesized by chromaffin cells in the medulla of the adrenal gland (>95% of total production) and functions as a hormone once released into the circulation [41‒44]. Conversely, norepinephrine mainly originates from sympathetic nerve endings as a neurotransmitter, with adrenomedullary chromaffin cells contributing less than 10% of the total norepinephrine production [45‒47]. Most pheochromocytomas secrete both epinephrine and norepinephrine, while dopamine-secreting pheochromocytomas are rare [48, 49]. Epinephrine-secreting pheochromocytomas commonly present with paroxysmal hypertension, palpitations, fainting, and hyperglycemia, while norepinephrine-secreting ones typically manifest with persistent hypertension, headaches, and sweating [50]. Meanwhile, patients with dopamine-secreting pheochromocytomas usually have a normal BP [51] (online suppl. Fig. 1).

The average age at presentation of pheochromocytoma in children is 11–13 years, with a male-to-female ratio of 2:1. The classic triad – diaphoresis, headaches, and palpitations – appears in up to 54% of cases. Pheochromocytoma is a more common cause of hypertension in children (1.7%) than in adults (0.2–0.6%). Sustained hypertension occurs in 60–90% of pediatric cases, whereas paroxysmal hypertension is more frequent in adults [6, 7, 28, 52, 53]. If pheochromocytoma is suspected despite normal BP readings, 24-h ambulatory BP monitoring can detect masked hypertension or abnormal dipping patterns [6, 53]. Pheochromocytoma in children is clinically suspected based on (1) signs and symptoms of catecholamine excess, (2) uncontrolled hypertension or unexplained variability in BP, (3) incidental tumors consistent with pheochromocytoma, (4) inappropriate response to medication or anesthesia, precipitating pheochromocytoma symptoms, (5) hereditary risk or syndromes associated with PPGLs, and (6) personal history of PPGL [6, 9, 18, 53‒64]. Online supplementary Figure 2 illustrates the common clinical findings in pheochromocytoma, while Figure 1 illustrates the general diagnostic approach for pediatric pheochromocytoma.

Considering patients with chronic kidney disease (CKD) stage 3 and above, including those with dialysis, plasma-free metanephrine and normetanephrine are superior to urinary metanephrines because of impaired catecholamine and metabolite elimination. This may also be linked with the heightened activity of adrenal and extra-adrenal N-methyl transferase, which is potentially influenced by elevated levels of glucocorticoids [65‒67].

Renal diseases are among the most common causes of hospital admissions, with early symptoms ranging from asymptomatic to a range of signs such as unexplained fevers, vague pain, anemia, gastrointestinal issues, abdominal masses, edema, hypertension, and metabolic acidosis [68‒72]. In pediatric renal outpatient clinics and hospital wards, the clinical spectrum of reported renal disorders includes acute glomerulonephritis (37.7%), nephrotic syndrome (26.1%), urinary tract infections (21.3%), acute kidney injury (17.9%), obstructive uropathy (1.9%), and CKD (1.2%) [73].

In contrast to the high prevalence of these renal diagnoses, hypertension is relatively rare, occurring in only 0.3–2.1% of pediatric outpatients and 1.1–6.7% of hospitalized children [74‒77]. A global meta-analysis reports a pooled prevalence of 4% (95% confidence interval [CI], 3.29–4.78%) for hypertension in the pediatric population [78]. Furthermore, PPGL accounts for just 2–4.5% of pediatric hypertension cases [79]. These findings underscore that pheochromocytoma is a particularly rare condition, presenting significant challenges in diagnosis and treatment for clinicians when compared to more commonly encountered renal diseases [80‒83].

Managing pheochromocytoma in children involves a multidisciplinary team including nephrologists, surgeons, anesthesiologists, endocrinologists, oncologists, geneticists, and intensivists. After diagnosis, the definitive treatment involves resecting the catecholamine-secreting tumor(s). Preparation for surgery can take longer (2–4 weeks) in children due to lower starting doses of medications to avoid side effects and increased sympathetic activity compared to adults [6]. The mortality rate for tumor resection has dropped significantly from >40% to 1–3% since the mid-twentieth century, largely due to improved perioperative BP management with α-adrenergic blockade. Advances in imaging modalities, minimally invasive surgery, hemodynamic monitoring, and shorter acting antihypertensive agents have also contributed to better outcomes [33, 84]. Appropriate BP management is crucial to prevent complications from catecholamine release, such as hypertensive crisis, stroke, arrhythmias, and postoperative hypotension [6, 7, 27, 28, 52, 54, 85‒98]. Approaches for each stage of pheochromocytoma are shown in Figure 2.

Commonly used anti-hypertensives in pediatric pheochromocytoma include α-adrenergic blockers, β-adrenergic blockers, calcium channel blockers (CCBs), and tyrosine hydroxylase inhibitors [6, 54, 99‒117]. Their mechanisms of action are shown in Figure 3, and detailed information on each drug group is given in Table 1.

Phenoxybenzamine is a nonselective and noncompetitive α-blocker [6, 52, 54, 88, 92]. Its lack of selectivity permits presynaptic α2 blockade, disrupting the norepinephrine negative feedback loop, which causes uncontrolled norepinephrine release from cardiac sympathetic neurons, leading to reflex tachycardia via β1 stimulation. Additionally, central α2 blockade induces side effects such as somnolence, headache, and nasal congestion [88]. Its extended duration of action may contribute to prolonged hypotension post-surgery [92]. Due to its limited application, phenoxybenzamine is often in short supply and costly for patients without health insurance coverage [118, 119].

Selective α1-blockers like prazosin, terazosin, and doxazosin are short-acting drugs that competitively inhibit only the α1 receptor [6, 52, 54, 88, 92]. They do not elicit reflex tachycardia and minimally penetrate the blood-brain barrier, resulting in minimal central effects [6, 88, 92, 120‒125] (online suppl. Fig. 3). However, their ability to lower BP might be limited because excessive catecholamine concentrations can overcome their competitive inhibition [126, 127]. Doxazosin, distinguished by its notably longer half-life, enables once-daily dosing and has been preferred in recent practice [92].

The Endocrine Society Clinical Practice Guidelines recommend α-blockers as first-line preoperative drugs to prevent cardiovascular complications [7]. Although no meta-analysis specifically addresses their use in pediatric populations, analyses in adults produced mixed results [128‒130]. Wang et al. [128] suggest that preoperative α-blockers do not guarantee more stable intraoperative hemodynamics or better perioperative outcomes. Zawadzka et al. [129] indicate that nonselective α-blockers are more effective in preventing intraoperative BP fluctuations while maintaining a comparable risk of intraoperative and postoperative hypotension and overall morbidity. Moreover, Schimmack et al. [130] suggest a lack of evidence for preoperative α-blockade, with no significant differences in mortality, cardiovascular complications, or intraoperative hemodynamic parameters between patients with or without α-blockade. Nevertheless, the certainty of the evidence is low due to the inferior quality of current studies.

β-blockers are usually given to counteract the reflex tachycardia induced by α-blockade. It is crucial to initiate β-blockers only after the initiation of α-blockers to prevent a hypertensive crisis due to unopposed vasoconstriction [6, 7, 52, 88, 131]. Cardioselective β1-receptor blockers (atenolol or metoprolol) are preferred over nonselective ones (propranolol) to minimize the risk of bronchoconstriction by β2-receptor blockade [6]. Labetalol, a combined selective α1- and nonselective β-blocker, is not recommended as initial therapy owing to its more potent β- than α-antagonistic activity, which may result in paradoxical hypertension or even a hypertensive crisis [6, 36, 132, 133].

CCBs such as amlodipine and nifedipine are recognized adjunctive therapies to α-blockers. However, their use as monotherapy is discouraged except for cases with mild hypertension or significant side effects with α-blockers [6, 88, 92, 132]. CCBs function by relaxing vascular smooth muscle and reducing peripheral vascular resistance by inhibiting norepinephrine-induced calcium influx in vascular smooth muscle cells [88, 134, 135]. Unlike α-blockers, CCBs do not cause drug-induced orthostatic hypotension or reflex tachycardia. They also confer protective effects on the heart by preventing catecholamine-mediated coronary vasospasm and myocarditis [136, 137].

From a pediatric perspective, CCBs are often the initial choice for managing hypertension in children due to their favorable side effect profile, ease of dosing, and lack of need for lab monitoring during dose titration, unlike angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Typically, treatment begins with a CCB, particularly amlodipine, while evaluating secondary causes of hypertension [54]. Pacak et al. [132] stated that in some institutions, nicardipine, amlodipine, and nifedipine are the primary preoperative treatments of choice in normotensive patients with pheochromocytoma, with nifedipine controlled-release tablets being preferred for their efficacy and extended duration of action [92].

Metyrosine use is associated with intraoperative hemodynamic stability, decreased blood loss, and a reduced need for vasopressors and fluids [138, 139]. Typically used as an adjunct for α-blockers, it reduces the need for high-dose α-blockers and is advantageous for patients who cannot tolerate their side effects [6, 36, 91, 125, 140]. In a retrospective cohort study by Ludwig et al. [91], metyrosine was used in 40% of pediatric cases, with only 16% experiencing intraoperative hemodynamic instability compared to 50% of those who did not receive the medication. Metyrosine can be administered to patients with severe symptoms unresponsive to other medications, particularly those with biochemically active and metastatic tumors [36, 132].

Metyrosine, acting centrally, may induce extrapyramidal symptoms in approximately 10% of patients [141]. Other potential adverse effects include orthostatic hypotension, sedation, fatigue, anxiety, diarrhea, dry mouth, reduced salivation, and neuromuscular manifestations like jaw tightening and tremors [6, 52, 54, 142, 143]. Furthermore, its high cost and limited availability (some countries require pre-orders through specialty pharmacies) pose significant barriers to its widespread use [105].

Patients with pheochromocytoma have an approximate 15% decrease in intravascular volume [144]. Therefore, antihypertensive agents with vasodilatory properties, such as α-adrenoceptor blockers, can cause hypotension as the vascular space expands, with the remaining intravascular volume often being insufficient [145]. Volume expansion through fluid and salt intake is crucial to counteract orthostatic hypotension resulting from catecholamine excess and anticipated α-adrenergic blockade [6, 27, 38, 52, 54, 87, 88, 91, 98]. Adequacy of intravascular volume can be assessed and monitored in the clinical setting by palpating the volume of the radial pulse [38]. The included studies in Table 2 show a consensus in favor of advocating for a high-fluid and high-salt diet [6, 27, 38, 52, 54, 98].

In children with pheochromocytoma, high catecholamine levels in the blood can stimulate α-adrenergic receptors, leading to arterial vasoconstriction and intravascular volume contraction. Therefore, a high-salt, high-fluid diet is prescribed before admission [146]. However, no established international guidelines specify the exact amounts of salt and fluid based on body weight. Consequently, it is critical to conduct a case-by-case evaluation as an excess of salt and fluid may exacerbate hypertension in children with pheochromocytoma, particularly those with underlying renal or cardiovascular conditions.

An important consideration in implementing the high-salt and -fluid diet is the CKD pathophysiology. CKD is associated with increased extracellular fluid (ECF) volumes caused by salt and fluid retention as a direct consequence of sodium sensitivity, contributing to hypertension. In children with CKD, a link exists between the excess ECF volume and left ventricular hypertrophy, and around 14.4% of children with CKD are more prone to adverse cardiovascular events. Consequently, limiting salt intake is advised in all CKD stages as a rational and essential tool to correct fluid overload and hypertension [147‒150]. CKD patients generally retain a reasonable sodium balance until their renal function declines severely. In progressing CKD, as the number of working nephrons diminishes, the sodium balance demands increased sodium excretion per nephron. This protective mechanism may reduce salt retention and ECF expansion. However, sudden and extreme salt restriction can pose dangers such as renin-aldosterone axis stimulation, catecholamine generation, and dyslipidemia. Therefore, additional caution must be exercised when administering salt and fluid to pheochromocytoma patients with kidney or cardiovascular impairment as fluid overflow could lead to acute decompensation [151‒153].

To ensure optimal intravascular volume, patients should be admitted 1–2 days before surgery to administer preoperative fluids [6, 36]. Minimally invasive laparoscopic tumor resection by transperitoneal or retroperitoneal approaches is the preferred surgical method because it reduces pain, hastens recovery, and shortens hospital stays [6, 7, 52, 54, 88, 154‒156]. Laparoscopic adrenalectomy (LA) is feasible for tumors under 6 cm [7, 133]. However, larger or more complex tumors may require laparotomy [6, 7, 10]. In patients with bilateral disease or hereditary PPGLs, adrenal cortex-sparing surgery can prevent the need for lifelong steroid replacement therapy [6, 7, 52, 54, 155]. Clear dissection planning between the tumor margin and adrenal gland is crucial to prevent PPGL recurrence [131]. The surgical approach should be guided by tumor size, surgeon expertise, and institutional guidelines, aiming to achieve surgical resection with minimal morbidity and no severe operative events [154, 157].

Most such tumors are excised under general anesthesia [158]. The three pivotal intraoperative steps are endotracheal intubation, tumor manipulation, and tumor ligation [158, 159]. During the initial two phases, catecholamine release is expected, increasing the risk of hypertension and arrhythmias. Conversely, in the last phase, diminished catecholamine secretion may precipitate symptomatic hypotension [158]. Risk factors for intraoperative hemodynamic instability encompass anesthetic agents, tumor characteristics (size and location), associated genetic syndromes, elevated preinduction plasma catecholamine levels, significant postural BP drop following α-blockade initiation, preinduction mean arterial pressure >100 mm Hg, and the choice of surgical approach [160, 161].

Intraoperative hypertension is typically managed with short-acting and potent vasodilators, while β-blockers are used for tachyarrhythmia [6, 52, 54, 88, 155, 158, 162‒171] (Table 3). Preferred choices for hypertension include sodium nitroprusside and nitroglycerine, while esmolol is favored for tachyarrhythmia [6, 52, 164, 170]. If intraoperative hypotension arises, hypotensive agents are initially ceased and potential hemorrhage or myocardial dysfunction is considered [88]. The primary treatment involves an intravenous (IV) bolus of crystalloids; colloids or blood products can be added if there is significant bleeding [6, 54]. If hypotension persists, IV norepinephrine can be administered, while vasopressin is typically reserved for refractory cases. Special caution is needed when administering intraoperative fluids to avoid cardiopulmonary complications, especially in cases of catecholamine-induced cardiomyopathy [6, 155, 172].

Important considerations in anesthesia, beyond standard monitoring, include invasive BP monitoring via intra-arterial catheters and ensuring adequate IV access, often through a central venous catheter [88, 139, 142, 158, 161, 173]. Advanced hemodynamic monitoring is essential, using techniques such as transesophageal Doppler and pulse contour analysis [174, 175]. Swan-Ganz catheters are indicated for patients with pheochromocytoma-induced cardiomyopathy, with transesophageal echocardiography as an alternative [161, 176].

Laparoscopic tumor resection usually results in minimal postoperative problems. However, patients need intensive care unit monitoring due to potentially severe complications [173]. Close monitoring of BP, heart rate, and plasma glucose levels is essential for the first 24–⁠48 h to mitigate hemodynamic instability [6, 54, 88, 177, 178]. Hypoglycemia can occur due to rebound hyperinsulinemia, which may lead to neurologic impairments if not promptly treated. In drowsy or unresponsive patients, electrolyte and endocrine abnormalities should be investigated.

Patients with persistent hemodynamic instability may require postoperative ventilator support. Hypotension may stem from tumor resection, the prolonged effects of α-receptor blockers, IV antihypertensive medications during surgery, and adrenergic receptor downregulation [6, 179]. Sudden hypotension may result from reduced plasma volume, surgical bleeding, and anesthetic-induced vasodilation. Postoperative hypertension may develop, usually resolving within weeks unless residual lesions or metastatic disease exist [54, 85, 177]. For hypertension, pain, fluid overload, return of autonomic reflexes, and inadvertent renal artery ligation should be considered. Persistent hypertension may indicate incomplete tumor resection or metastatic disease [85, 88, 177].

IV fluid should be initially administered aggressively if postoperative hypotension occurs. If ineffective, vasopressors like norepinephrine, rarely epinephrine, and vasopressin can be given to restore normal BP. Pure α-adrenoceptor agonists like phenylephrine are avoided due to the potential residual effects of preoperative α-adrenoceptor blockade. Hypotension management primarily aims to ensure that sufficient tissue perfusion is restored and maintained [85].

Prabhu et al. [180] reported a case of a 14-year-old boy with bilateral pheochromocytoma who underwent nephrectomy due to a nonfunctioning kidney and presented with severe hypertension and end-organ damage. Following the excision of the second tumor, a precipitous fall in BP was successfully managed with an infusion of noradrenaline, dopamine, crystalloid, and colloid. In a retrospective study by Romero et al. [38] in a pediatric population, 20% of patients experienced postoperative hypotension, with each episode lasting <24 h. All patients were given vasopressor infusions, and one received a crystalloid infusion. Both studies indicate that post-tumor resection hypotension can occur and may persist despite crystalloid and/or colloid administration. Preparedness to manage the inevitable BP drop with vasopressors is essential to ensure a transient episode without serious complications.

Nine UK centers retrospectively collected information on patients who underwent adrenalectomy for pheochromocytoma between 2012 and 2020, revealing independent risk factors for postoperative hypotension. Multivariable analysis revealed that female sex (odds ratio [OR] 1.85), preoperative catecholamine level (OR 3.11), open surgery (OR 3.31), and preoperative mean arterial BP (OR 0.59) were independently associated with postoperative hypotension, forming a clinical risk score (area under the receiver operating characteristic curve: 0.69, C-statistic: 0.69). Based on the assessment of the clinical risk score, low-risk and high-risk patients had a 25% and 68% risk of postoperative hypotension, respectively [181].

Walz et al. [39] prospectively studied 42 children (mean age: 15.6 ± 3.1 years) who underwent surgery between 2001 and 2016 at a single institution in Germany. A total of 70 tumors (mean size: 2.7 cm) were removed (45 pheochromocytomas and 25 paragangliomas). All operations were performed using minimally invasive techniques (retroperitoneoscopic, laparoscopic, extraperitoneal). The mean postoperative hospital stay length was 3.3 ± 1.8 days (range: 0–8 days).

In a meta-analysis comparing the efficacy and safety of LA versus open adrenalectomy (OA) for pheochromocytomas in the adult population, 12 out of 14 included studies reported length of stay as an outcome, involving 690 patients (369 LA and 321 OA) in total. The results showed a shorter hospital stay for the LA group, with a weighted mean difference of −3.21 days (95% CI: −4.30 to 2.12, p < 0.001) compared to the OA group based on data from the identified studies [182].

At the Institute of Urology, University of Southern California, adrenalectomies were performed on 3 patients aged 2–13 years using the da Vinci Xi surgical system (Intuitive Surgical, Sunnyvale, CA, USA). The median postoperative hospital stay was 2 days. However, 1 patient experienced a prolonged recovery due to an unexpected drug reaction (range 1–6 days). Overall, typical postoperative recovery seems comparable to or better than previous reports for minimally invasive adrenalectomies [183].

A review of seven studies involving 108 children diagnosed with PPGLs reported that most of the postoperative period was uneventful [21, 28, 37, 91, 154, 157, 184]. However, in cases with complications, while some resolved over time, others proved to be life-threatening. Among cardiovascular complications, persistent and/or severe hypotension was observed, while non-cardiovascular complications included acute pulmonary edema, mechanical intestinal obstruction, renal atrophy, severe bleeding, insulin resistance, and severe apneic episodes [20, 27, 36, 85, 91, 154, 157, 184, 185].

Although rarely discussed, renal complications are presumed to be correlated with pheochromocytoma in adults. A possible correlation between pheochromocytoma and CKD arose from a multicenter study involving 472 adult patients with PPGLs, of whom 78.4% had pheochromocytoma. The study reported that hypertension persisted in 26.3% of patients despite successful resection, possibly attributable to other risk factors such as older age, higher body mass index, lower left ventricular ejection fraction, and intraoperative hemodynamic instability [186].

Despite the well-documented presence of hypertension across CKD stages, several studies have challenged the belief that it can cause significant kidney damage, providing conflicting results regarding the relationship between hypertension and renal complications, especially CKD [187‒195]. This necessitates long-term follow-up of pheochromocytoma cases with persistent hypertension following tumor resection.

A large meta-analysis of the hypertensive population supports the concept that hypertension is not correlated with kidney damage. A meta-analysis of 10 RCTs of 26,521 patients with nonmalignant hypertension showed no benefit of antihypertensive medications in reducing the risk of developing renal dysfunction (relative risk = 0.97; 95% CI, 0.78–1.21; p = 0.77) [190].

The same concept is also supported by studies involving long-term follow-up of kidney transplant recipients and donors. All patients with kidney failure and essential hypertension who had bilateral nephrectomies then received kidney transplantations from normotensive donors became normotensive and showed evidence of reversal of hypertensive damage to the heart (left ventricular hypertrophy) and retinal vessels after transplantation. This suggests that the primary defect associated with hypertension might lie in the native kidneys [191]. Another study reported a group of recipients with no family history of hypertension who received a kidney from a “hypertensive” family. This specific group required more anti-hypertensives in the long-term follow-up than those receiving a kidney from a “normotensive” family (OR 5.0, 95% CI, 1.4–1.78; p = 0.017) [192].

Among kidney donors, nonmalignant hypertension developed in 4%, 10%, and 51% at 5, 10, and 40 years post-donation. Hypertension is associated with reduced estimated glomerular filtration rate (eGFR); however, the association is weak, with hazard ratios (95% CI) of eGFR <60, <45, and <30 mL/min per 1.73 m² at last follow-up being 1.44 (1.21–1.72; p < 0.0001), 1.89 (1.42–2.52; p < 0.0001), and 2.26 (1.24–4.25; p = 0.009), respectively. This indicates hypertension is common post-donation, and the link between hypertension and CKD is weak [193].

Simultaneously, the belief that hypertension might be associated with CKD is supported by a study showing that living kidney donations were independently associated with a 19% higher risk of hypertension (adjusted hazard ratio, 1.19; 95% CI, 1.01–1.41; p = 0.04) compared to healthy non-donors. Although kidney donors experienced an increase in eGFR post-donation (+0.4 and +0.6 mL/min per year for white and black kidney donors, respectively), the eGFR plateaued after incident hypertension (0 and −0.2 mL/min per year, respectively). This suggested hypertension could be a risk factor in post-donation eGFR because it is associated with cessation of the increase in eGFR after donation [194].

Follow-up at 6 weeks, between 6 months and 1 year post-surgery, and then annually is recommended. During these visits, detailed history-taking, BP monitoring, and serum or urine metanephrine testing should be performed to monitor recurrence. Imaging is performed intermittently and if symptoms develop or serum/urine metanephrines are elevated. Additionally, in cases with kidney function impairment before surgery, long-term follow-up including CKD parameters such as creatinine level, eGFR, albuminuria, or proteinuria is recommended [196, 197].

Metachronous tumors necessitate longer follow-up, especially in hereditary cases with succinate dehydrogenase subunit B mutations. Despite a high overall survival rate (95.5–100%), the event-free survival rate is significantly lower (39–88.8%) and declines over time. This underscores the need for adequate monitoring and interventions to improve quality of life. In addition, one study indicated higher rates of recurrent primary tumors and metastatic disease in pediatric populations than in adults [28, 37, 154, 157, 198‒201] (online suppl. Table 2).

Pheochromocytomas present management challenges due to their rarity in pediatric secondary hypertension cases [6, 52, 54]. Current guidelines rely on limited data from single centers, highlighting the need for multicenter studies to formulate robust management protocols tailored to this unique patient population [6, 7, 52, 54]. Key areas requiring further investigation include the comparative efficacy and safety of preoperative nonselective versus selective α-blockers, other medications (alone or in combination as adjuvants), or no preoperative medication.

The obligatory α-adrenergic blockade, more extensively studied in adults, lacks formal evaluation in children [6, 52, 54]. Furthermore, to our knowledge, no systematic reviews and meta-analyses have compared the efficacy and safety profile of selective and nonselective α-blockade in pediatric populations. Furthermore, a more tailored and specific definition of a high-salt diet instead of a one-size-fits-all approach is imperative. The absence of standardized sodium intake protocols based on body weight poses significant risks, particularly for younger and/or smaller patients [6, 28, 38, 52, 54, 87, 88, 91, 98].

Meta-analyses in adults highlight complexities in interpreting treatment outcomes due to variations in preoperative goals, drug dosages, and study endpoints [128‒130]. These challenges are compounded by retrospective study designs and inadequate adjustments for confounding variables. Thus, future research should focus on standardizing management protocols (e.g., whether the control group should not receive any preoperative antihypertensive drug), selecting appropriate study endpoints (e.g., defining the parameter and threshold for hemodynamic instability), ensuring adequate sample sizes for enough power to detect statistical differences, and conducting high-quality prospective cohort studies and RCTs. In this context, well-designed long-term multicenter studies are needed to advance knowledge and improve clinical outcomes of pediatric pheochromocytoma.

Future studies in pheochromocytoma should prioritize key areas based on recent research insights. Additionally, an important consideration is that 3% of pheochromocytoma cases are malignant [131]. First, enhanced genetic testing protocols are needed to encompass a broader spectrum of susceptibility genes, as evidenced by the European-American Pheochromocytoma-Paraganglioma-Registry study, where 80% of pediatric patients with PPGLs had germline mutations [201]. Given the high incidence of genetic mutations in pediatric PPGL cases and their association with metastasis and multifocality, more attention to specific genetic markers is warranted [200‒202]. Using genetic testing and surveillance programs, an increasing proportion of patients with PPGLs are diagnosed before symptoms appear [7, 8]. Tracking disease progression, treatment responses, and long-term survival is essential to optimize the efficacy and safety of PPGL treatments, particularly in patients with high-risk mutations or aggressive tumors. This approach translates to a better quality of life, particularly for children who have their whole future ahead of them.

Pheochromocytoma, although rare, is an important cause of secondary hypertension in the pediatric population. Surgical intervention is the definitive treatment and requires appropriate perioperative management to mitigate hemodynamic instability and avert lethal cardiovascular complications arising from tumor manipulation. Antihypertensive agents should be promptly administered upon suspicion of diagnosis, with α-blockers serving as the primary therapy. To counteract reflex tachycardia, β-blockers may be introduced thereafter. Additional adjunctive antihypertensive agents may be considered if target BP is not achieved with standard therapy. The patient should be fluid- and salt-replete to counter volume contraction from chronic, excessive catecholamine exposure.

Lifelong routine biochemical and imaging surveillance is essential post-tumor excision, particularly in those with identified mutations, to monitor recurrence and metastatic risk. Genetic testing is imperative for all pheochromocytoma patients, even those with solitary presentations lacking familial history or metastatic evidence. Determining underlying mutations has implications for tailoring treatment strategies and prognosis. Future research should prioritize well-designed prospective studies, preferably multicenter, to enhance sample size considering the disease’s rarity. Finally, RCTs comparing the efficacy, safety, and optimal dosing of antihypertensive medications would greatly improve the quality of scientific evidence, given the current absence of such studies in the pediatric population.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

C.G.A. and N.N. designed the article, searched for literature, and wrote the primary draft of the manuscript. H.I.L. wrote and revised the pathophysiology, diagnostic approach, and overall management sections. C.G.A. and N.N. were responsible for data visualization. C.G.A. and H.I.L. provided critical revision of the manuscript. C.G.A. and N.N. revised the final version of the manuscript. All the authors approved the final version of the manuscript.