Severe intraoperative hypertensive crisis during surgery for phaeochromocytoma/paraganglioma: analysis of pre-operative risk factors

Introduction

Phaeochromocytoma and paraganglioma (collectively PPGL) are catecholamine-secreting tumours of the adrenal gland and extra-adrenal autonomic tissue, respectively. Left untreated, these tumours can be fatal due to cardiovascular complications arising from significantly elevated plasma catecholamines (1). Additionally, approximately 10% of PPGL are malignant (2). To date, surgical resection is the only curative treatment modality. A unique intra-operative challenge associated with resection of PPGL relates to the surge of catecholamines released via the efferent circulation during dissection and tumour handling (3). This culminates in uncontrolled hypertension and subsequent complications such as cerebrovascular accident, irreversible myocardial ischaemia or left ventricular failure during the peri-operative period.

In the modern era, operative mortality rates of patients undergoing PPGL resection have dramatically reduced to approximately 0.5%, from a reported rate of 45% in the 1950s (4). This is largely attributed to the advent of pre-operative alpha-adrenoceptor blockade, despite continued advancements in diagnostics, anaesthetics and minimally-invasive surgery. As such, pharmacological alpha-blockade, in addition to beta-blockade for rebound tachycardia, remains the gold standard for pre-operative management in PPGL patients (5). However, these historical cornerstones of practice have recently come under new scrutiny; in an international multicentre study [2020], significantly more episodes of cardiovascular peri-operative morbidity were suffered by patients receiving pre-operative alpha-blockade compared to those who did not (4). Furthermore, a meta-analysis did not identify any difference in complication rates between the two groups (6). Determining when a patient is “optimally blocked” is also not straightforward (7). Potentially, the use of pre-operative adrenergic-blockade contributes to sustained post-adrenalectomy hypotension requiring vasopressor support. This may unnecessarily accumulate further risk and implicate resource allocation. It is foreseeable that in the next future, studies will concentrate on the correct selection of patients who are candidate for avoidance of adrenergic blockade (8).

In this setting, it is of paramount importance to clearly identify specific risk factors for severe intraoperative hypertensive crisis (SIHC) (9). While previous studies have identified some radiological and laboratory features that could predict SIHC, there is a paucity of literature exploring correlation with clinical features such as presenting symptoms and past medical history. The aim of this study is thus to explore the existence of such correlations. We present this article in accordance with the STROBE reporting checklist (10) (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-325/rc).

Methods

This study included patients who underwent resection of PPGL at Salford Care Organisation, Northern Care Alliance. Patients’ data was prospectively collected using EPR (Allscripts Sunrise, Philadelphia, USA). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Confidentiality and anonymity of the patients were maintained, without requirement for informed consent as per Data Protection and Caldicott Framework. As all variables reviewed formed part of routine data recording for United Kingdom service evaluation the study did not require formal ethical committee approval.

Patients and study design

Retrospective single centre study investigating correlation between preoperative data and SIHC.

Patients with a confirmed histological diagnosis of PPGL who underwent surgical excision between 1^st January 2012 and 31^st December 2020 were eligible for inclusion.

PPGL diagnosis was established preoperatively through biochemical tests (urine and plasma metanephrines) and typical imaging findings. Following diagnosis, PPGL patients universally underwent pharmacological stabilisation with Doxazosin or Phenoxybenzamine, according to standard practice guidelines. Alpha-blocker dosages are titrated upwards during weekly clinic assessment by a dedicated team of medical endocrinologists; attainment of sufficient alpha-blockade is guided by tachycardia, reduction from baseline blood pressure and patient reported indicators such as nasal congestion and postural hypotension. Blockade was considered adequate when a blood pressure of 130/80 mmHg and a heart rate of <90 beats/min was obtained. Beta-blocker were only introduced following optimal alpha-blockade to prevent the potentially dangerous actions of unopposed alpha-mediated vasoconstriction in conjunction with premature loss of beta-2-mediated vasodilatation. In the first period of the study (until 2013) patients were admitted several days prior to surgery for intravenous fluids. However, this practice ended in 2013 largely due to increasing capacity pressures and patients are instead counselled about sodium oral repletion and intensive oral hydration.

Choice of surgical approach was guided by tumour location and size, with laparoscopic approach undertaken when deemed feasible. Standard general anaesthesia included arterial line for intraoperative haemodynamic monitoring and oesophageal manometry for cardiac output. All surgeries were performed following universally accepted oncological principles and specific PPGL principles such as minimizing manipulation and ligating the adrenal vein first, whenever possible. All surgeries were performed by a single, experienced surgeon and anaesthesia by small team of dedicated PPGL anaesthetists. Post-operatively, all patients are admitted to the critical care unit (CCU), as this is the only setting where vasopressors/inotropes can be administered in our institution.

Outcome measures and study variables

Primary outcome of this study was SIHC, defined as systolic blood pressure (SBP) >200 mmHg between anaesthesia induction and extubation.

Pre-operative data included age, sex, American Society of Anaesthesiologists (ASA) score, tumour features (location, dimensions), presenting symptoms, clinically significant presenting event [myocardial infarction (MI), stroke or syncope], plasma metanephrines, preoperative mean arterial pressure, familial tumour syndrome, Charlson Comorbidity Index and pressure, approach, catecholamine and sex score (PACS) risk score (11).

Intraoperative details included operative approach, intraoperative magnesium infusions, vasodilator and vasopressor utilisation, heart rate, intravenuous fluid infusion and ClassIntra.

Postoperative data included overall complications (graded with Clavien-Dindo Classification), major postoperative complications (Clavien-Dindo ≥ IIIB), comprehensive complication index (CCI), length of stay and vasopressor need at 24 hours.

Statistical analysis

Categorical variables are expressed as proportions and continuous variables are expressed as mean ± standard deviation (SD), or median [interquartile range (IQR)]. Hypothesis testing (Fischer or Chi-χ² test for categorical variables and T-test or Kruskal-Wallis for continuous variables; linear regression for continuous dependent variables) were performed using SPSS (IBM Version 27.0.1.0). Two-tailed P value <0.05 was considered statistically significant. Owing to limited sample size, multivariate analysis could not be performed.

Results

Patient demographics and clinical presentation

In total, 40 patients were included in the analysis. Table 1 summarises demographic and clinical characteristics of the cohort. The patients were mainly females (80%), overweight [median body mass index (BMI) 28.1 kg/m², IQR 26.1–32.1 kg/m²] with a median age of 58.5 years (IQR 36.75–78 years) and most had significant comorbidities (72.5% were considered ASAIII). Phaeochromocytoma was the diagnosis in 95% (n=38) of cases. In 22.2% (n=8) of patients, the diagnosis was entirely incidental while the rest had a number of presenting symptoms ranging from hypertension (60%) and palpitations (42.5%) to excessive sweating (30%) and headaches (30%). A minority of patients (15%) presented with a clinically significant event including MI (5%), stroke (5%) and syncope (5%).

Pre-operative management and operative approach

Pre-operatively, all patients underwent alpha-receptor blockade with 90% receiving phenoxybenzamine (median daily dose 90mg) and 10% Doxazosin (median daily dose 14mg). Following this, all patients except one underwent further beta-blockade with propranolol 90%, atenolol (2.5%) or bisoprolol (2.5%). All patients were deemed adequately blocked prior to surgery scheduling. There were no reported adverse incidents secondary to side effects of the preoperative pharmacological regimen.

SIHC and intraoperative care

At least one episode of SIHC was documented in 10% of cases. Univariate analysis is summarised in Table 2. All four patients with SIHC had initially presented with a clinically significant event while this was true for only 5.6% of patients without SIHC (P<0.001). In particular, presentation with MI was present in 50% vs. 0% of SIHC and non-SIHC patients, respectively (P=0.008). Patients with SIHC were also significantly more likely to harbour left-sided disease (100% vs. 33.33%; P=0.02). No significant association with SIHC was identified with regards to differences in other patient characteristics, including tumour size and metanephrine levels.

Regarding other haemodynamic parameters; 39/40 (97.5%) of patients had recorded at least one episode of SBP under 90 mmHg heart rate below 50 was seen in 50% of cases overall, while above 120 in one patient. Vasodilators (sodium nitroprusside, glyceryl nitrate or a combination) were administered intra-operatively in 90% of cases, while all required vasopressor (most commonly a combination of metaraminol and noradrenaline). Intravenous magnesium infusion was used routinely in all cases with an overall mean dose of 0.41 mmoL/kg (SD 0.29 mmoL/kg), while mean volume of fluid infusion was 3,450 mL.

Post-operative course

During the postoperative period, 60% of patients were still on vasopressors 24 hours post-operatively despite a median 3,448 mL (Q1–Q3: 2,500–4,000 mL) of intravenous fluids given intraoperatively and 2,977 mL (Q1–Q3: 2,500–39,190 mL) in the postoperative period. The volume of peri-operative fluid was not a related to the mode of pharmacological adrenergic blockade.

Further univariate analysis identified female sex (P=0.04), preoperative normetanephrine levels (P=0.02) and PACS risk score as significantly associated to vasopressor dependency 24 hours after surgery.

There were no major postoperative complications (Clavine Dindo >3a) in the study cohort and median CCI was 0 (0, 2.2). Overall complications occurred in 27.5% and were associated with open surgery, either upfront or after conversion from laparoscopy (P=0.02) and vasopressor use at 24 hours post-skin closure (P=0.02), while no correlation with other patient or tumour characteristics was found. Specific complications can be found in Table S1.

Median length of stay was 3 days (IQR 2–4) in the CCU and 5 days in total (IQR 4–7). Length of stay in the CCU was associated with presentation with a clinically significant event (P=0.01), tumor size (P=0.02) and vasopressor use at 24 hours (P=0.04). Hospital stay was longer when patients developed a complication (P=0.01), had larger tumour size (P=0.02) and had higher metanephrine plasma levels (P=0.02).

Discussion

This study has investigated the association between SIHC and pre-operative factors and found a number of significant associations. In particular, SIHC was more likely in patients presenting with a clinically significant event (defined as MI, stroke or syncope) and especially MI. On the other hand, no patient presenting with different symptoms developed SIHC. Furthermore, also left-sided PPGL was strongly associated to the development of SIHC. These findings appear to be novel in the literature and may carry important implications.

In fact, the management of patients with phaeochromocytoma or paraganglioma is currently undergoing what appears as a phase of transition. Alpha-blockers were identified as a game-changing drug in the management of PPGL, positively affecting perioperative morbidity. However, some doubts on their optimal use still persist. Criteria were published in 1982 to provide guidance on achieving optimal pre-operative alpha-blockade (12), and these (or variations) are still routinely used by endocrinologists in conjunction with other surrogate markers of adequate blockade including development of nasal congestion (13). Nonetheless, whether interval clinical assessment alone, in patients undergoing alpha-blockade, is sufficient in obtaining optimal effect and thus improved haemodynamic stability intra-operatively, represents an uncertainty in current practice. In fact, recent studies have questioned whether adrenergic blockade provides a real benefit in today’s world, considered the significant improvements brought about in surgical and anaesthesiological practices. Groeben et al. conducted a large multicentre study including 21 centres and 1,860 PPGL patients (4). They recorded a very significant increase of cardiovascular complications in patients who underwent alpha-receptor blockade as opposed to those who did not. Furthermore, the incidence (5–7%) of severe hypertension (defined in that study as SBP >250 mmHg) did not differ between treated and un-treated patients.

In the present study, SIHC was seen in 10% of cases, which appears comparable to available data, including a recent large single-centre study using similar pre-operative sympathetic blockades. Kim et al. reported SBP >200 mmHg in 12.7% of 114 cases (14). Therefore, it appears that sudden and extremes of blood pressure variation are still commonplace despite best efforts of the pre-operative blockade regimen. Pharmacological preparation does not appear to alter this. Fortunately, there were no severe adverse events despite SIHC in this cohort. This may be because periods of hypertensive instability are transient rather than sustained. Temporary hypertension triggered by handling of PPGL during dissection may quickly normalise to the relatively stable baseline conferred by a disciplined pre-operative programme of alpha-blockade and skilled anaesthesiological management. In our study, the most significant association was found between SIHC and the severity of presenting symptoms. This finding interestingly links medical history and intraoperative events, highlighting the importance and central role that clinical aspects still carry, despite the fact that they may sometimes go un-regarded in today’s world of modern, technology-based medicine. It is plausible that such a presentation represents a surrogate of a more “haemodynamically aggressive” tumour. Similarly, left-sided PPGL seem to lead to SIHC more commonly than right–sided (no instance in this cohort). This is interesting as normally right-sided resections are associated with more difficult vein ligation due to the anatomical rapport with the liver and the short length of the vessel. Furthermore, analysis of baseline characteristics among right-sided and left-sided tumours, did not highlight any significant differences including size or metanephrine levels. Again, the finding may relate to, so far unknown, different biological predisposition to SIHC. In future, linking clinical manifestation, anatomy and biological basis will be an interesting frontier in the years to come. In fact, PPGL have been today sub-classified into three biological clusters based on underlying driving mutations (15). So far, each clusters’ behaviour has been defined in terms of biological aggressiveness, type of hormone secretion and partly in anatomy (adrenal vs. extra-adrenal) and symptoms (constant vs. episodic). However, it has not been clarified if significant haemodynamic events are more common in one cluster or the other and if there are further anatomical based behavioural differences. Future research investigating the association between molecular cluster, anatomical position, presenting symptoms and intraoperative hypertensive crisis is awaited with anticipation. Other studies have identified a number of factors that could impact on SIHC risk, including tumour size, pre-operative, urinary catecholamine levels, tumour necrosis, BMI and also surgical approach (16-19). These results were either not confirmed (possibly due to limited sample size) or not investigated in our study. However, we believe that at this moment they should not be considered conflicting but rather complementary and amenable to future integration.

In this setting, the results of the current study may be useful both in clinical practice and in directing upcoming research (Figure 1). The implications in clinical practice may seem obvious but are nonetheless very significant, given that prolonged and severe hypertension during surgery predispose to severe complications such as cerebrovascular events, irreversible myocardial ischaemia and left ventricular failure due to high afterload. As such, the knowledge that the risk of SIHC is significantly higher in some patients with specific pre-operative characteristics despite satisfactory adrenergic blockade, while it may be negligible in others, could inform a more detailed anaesthetic planning and a tailored approach. Unfortunately, the relatively limited number of patients involved did not permit the development of an SIHC risk stratification tool or nomogram, which would be the next logical step. Further research on the matter could enhance current preoperative management. It is foreseeable that future studies will concentrate on the possibility of avoiding adrenergic blockade as a mandatory requirement before surgery. However, it is likely that some patients may still benefit of adrenergic blockade therapy while others will not. The selection of patients for this kind of study is thus very challenging, especially as the adverse events associated to poorly controlled SIHC may be extremely severe. In this setting the implications of our study may be even more relevant. Should patients with high SIHC risk be excluded and continued to be given adrenergic antagonism therapy? Or should they be involved as their SIHC risk is non-negligible even when blockade is used? We believe utmost caution should be exerted when considering a non-conventional preoperative pathway for the identified high-risk patients. An additional benefit of such risk stratification could be used in staff development, specifically for anaesthetic staff gaining experience in anaesthesia for such cases, where there are clear benefits in allowing the anaesthetist to gain confidence and experience with the more stable cases before encountering ones where extreme cardiovascular instability can be anticipated. Educationally, an enhanced understanding of risk also benefits anaesthetic training by nurturing confidence and acquisition of valuable experience with more stable cases before encountering patients in whom extreme cardiovascular instability can be anticipated.

Figure 1 Clinical and research implications of the study results. IHC, intraoperative hypertensive crisis.

This study also evaluated the patients’ postoperative course: the majority of patients became hypotensive and required vasopressors also 24 hours after index operation. The phenomenon of persistent hypotension resulting from abrupt loss of circulating catecholamines during the immediate aftermath of successful PPGL resection has been long-known and in the literature appears to be associated with female sex, preoperative catecholamine levels, open surgery and preoperative mean arterial pressure (11,20). Crucially, it is unknown how this phenomenon may be influenced by the pre-operative alpha-blockade regimen, although it is a logical assertion that phenoxybenzamine could have a significant impact, considering that it binds irreversibly to alpha-receptors and its half-life is approximately 24 hours (21). It is plausible that the high incidence of postoperative hypotension in our cohort may be linked to the preferential use of phenoxybenzamine and the routine use of concomitant beta-blockade. On ligation of the lesion’s efferent circulation, impairment of the ability to quickly increase cardiac output via either stroke volume or heart rate could result in a more pronounced hypotension. Almost the entirety (98.6%) of our patient cohort received beta-blockade when compared with rates of 59% and 74% in others (9). According to our data only normetanephrine levels were correlated with postoperative hypotension. This may be explained by the fact that tumours with high noradrenergic secretion tend to do so in a more constant fashion and thus exert more sustained effects (which are then reflected in a more sustained period of hypotension) (15). This result is also supported by similar data coming from Kim et al. (14). In contrast, metanephrine levels were associated with a higher incidence of (minor) postoperative complications. This finding, instead, may be due to the episodic and thus more disruptive nature of metanephrine output (15). Other factors influencing complications were open surgery (obviously) and tumour size. On the contrary, in our series preoperative blood pressure did not correlate to postoperative complications as recently pointed out in a larger study (22). In this study, intra-operative magnesium infusion, which inhibits the release of catecholamines from the adrenal medulla, did not appear to be a contributing factor in post-operative hypotension. The use of Magnesium as a primary anti-hypertensive agent has been demonstrated mainly in the obstetric population to treat pre-eclampsia but has been applied to phaeochromocytoma surgery for many years (23). There was no specific protocol for Mg⁺ infusion but most procedures done by same anaesthetist whose experience using Mg as membrane stabiliser developed over time.

The critical care length of stay and total length of stay in hospital appears to correlate only with tumour size. It is unclear why tumour size could independently affect CCU and hospital length of stay but this may be related to a generally more advanced disease and thus a technically more difficult surgery (prone to more blood loss, etc.) or to more pronounced systemic effects of the tumour.

Limitations of the study include its retrospective and monocentric nature which limit generalizability of the results. However, the fact that all patients were operated by the same experienced surgeon could regarded as a meaningful factor in minimising bias due to different surgical conducts, which may represent a relevant confounding factor, especially in the case of PPGL where surgical manipulation may determine large physiological derangements. The sample size may also appear a major limitation and in fact it did not allow for multivariate analysis or prediction score/nomogram development. Furthermore, appropriate assessment of postoperative complication could be underpowered. However, it was sufficient to highlight some interesting patterns. The relatively high percentage of patients who underwent upfront or converted laparotomy could have been a bias as it has been reported as a risk factor for SIHC. However, it appeared to have no particular effect in our cohort. Other limitations regarding the surgical approach in this cohort are the absence of robotic-assisted surgery (24,25). Robotic surgery has been shown to potentially reduce postoperative complications and it would be interesting to evaluate its effect on SIHC. Similarly, the retroperitoneal approach is less frequently used but is a valid alternative technique especially in patients with obesity and its impact on SIHC should be investigated in the future (26). Further limitations include the definition of SIHC. Although the authors recognise that SIHC should be viewed as a spectrum of states, and that a threshold of 180/120 is widely recognised as representing the threshold for a hypertensive crisis (3). However, the choice of SBP >200 mmHg as a cut-off to define a hypertensive crisis in the specific setting of ongoing surgery, is supported by a body of literature: in a large retrospective study composed of over 200,000 patients receiving anaesthesia for elective surgery, patients with baseline SBP greater than 200 mmHg suffered significantly elevated rates of in-hospital mortality or raised troponin when compared to patients with lower baseline blood pressures (27), while in a validated European haemodynamic instability scoring system of patients undergoing general anaesthesia, SBP >200 mmHg attained the highest score in the maximum SBP domain (28); in fact, SBP >200 mmHg was used as a threshold by many other authors previously investigating on the subject and identified as a risk factor for intraoperative bleeding and cardiovascular complications(18,19,29).

Despite the cited limitations, we believe this study contributes to our knowledge on PPGL resection and may help paving future clinical and research directions by identifying the presence of severe presenting symptoms and laterality as major determinants in SIHC risk.

Conclusions

SIHC occurs in a minority of patients despite optimal preoperative alpha-lytic therapy. The risk of SIHC appears to be tightly associated with the presence of a clinically significant presenting event, and in particular with MI. SIHC may also be more frequent in patients with left-sided tumours. Patients with one or more of these features should be regarded as deserving a cautious pre- and intra- operative anaesthesiological planning. Their participation to studies on alpha-lytic therapy should be carefully considered.

Acknowledgments

Special acknowledgements to Dr. Tara Kearney (Consultant Endocrinologist, Salford Care Organisation) and the endocrine and ICU teams at Salford Care Organisation, Northern Care Alliance.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-325/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-325/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-325/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-325/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Confidentiality and anonymity of the patients were maintained, without requirement for informed consent as per Data Protection and Caldicott Framework. As all variables reviewed formed part of routine data recording for United Kingdom service evaluation the study did not require formal ethical committee approval.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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