Pheochromocytoma crisis managed with veno-arterial extracorporeal membrane oxygenation: a case report

Introduction

Background

Pheochromocytoma is a rare and usually benign tumor derived from the adrenal gland chromaffin cells, which produce catecholamines (1). Its annual incidence is estimated to be 2–8 cases per million inhabitants (2), with no differences in gender distribution. Pheochromocytoma is often asymptomatic, and the diagnosis may be established incidentally (3) or during screening for familial syndromes (4). Due to an improved understanding of the pathogenesis of these tumors, the diagnosis is suspected in patients with clinical features related to catecholamine excess, typically paroxysmal and/or uncontrolled hypertension and adrenergic symptoms including anxiety, dizziness, as well as the classic triad of headaches, diaphoresis, and palpitations (1). However, an acute life-threatening complication may be the first presentation. Pheochromocytoma crisis (PCC) is a rare, severe endocrine emergency causing the sudden and massive release of catecholamines, which can lead to hemodynamic instability, myocardial depression with cardiogenic shock and multi-organ dysfunction (5), while acute pulmonary edema or acute respiratory distress syndrome (ARDS) as the primary manifestation is rare (6). PCC associated mortality rate can reach 30% (7).

The management in the intensive care unit (ICU) includes organ support until surgery is performed. Mechanical circulatory support, such as veno-arterial extracorporeal membrane oxygenation (VA-ECMO), provides temporary life support for patients in refractory cardiogenic shock when the heart and lungs fail to maintain adequate circulation despite conventional therapies (8). It ensures oxygenation and perfusion while allowing time for recovery or transition to further interventions. In case of PCC, VA-ECMO has been described as beneficial (9-11). VA-ECMO, together with intra-aortic balloon pump (IABP) are cardiac life-supporting devices. The former, which is applied to patients with severe cardiogenic shock and cardiac arrest (12), increases the afterload because of its reversed vascular flow, whereas the latter reduces it. From a physiologic viewpoint, IABP assists VA-ECMO by reducing afterload and left ventricle wall tension and oxygen demands, so IABP combined with VA-ECMO is expected to reduce mortality (13).

Rationale and knowledge gap

The clinical application of mechanical support in cardiopulmonary insufficiency caused by PCC is still uncertain. There is no clear consensus on how to achieve hemodynamic stabilization of the patient and about the optimal timing for surgery.

Objective

We report a case of cardiogenic shock requiring VA-ECMO and IABP support, unveiling a diagnosis of pheochromocytoma, and treated with adrenalectomy. We present this case in accordance with the CARE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-148/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A 48-year-old woman, with a history of anxiety disorder and a hospitalization for Takotsubo syndrome 3 months before, was admitted to San Bortolo Hospital. On admission to the emergency department (ED), she complained of headache, dizziness, widespread paresthesias, hyposthenia, dysphagia and chest tightness. The physical examination revealed normal verbal and motor response, mydriasis and severe tachypnea. She had hypertension (165/110 mmHg), sinus tachycardia (150 rpm), generalized vasoconstriction, desaturation to 80% on pulse oximetry and hyperglycemia. Severe metabolic acidosis and hypoxemia [pH 6.9, PaCO₂ 46 mmHg, PaO₂ 49 mmHg, base excess (BE) −21.3, lactates 12.5 mmol/L] were detected. Consequently, rapid sequence intubation was performed and deep sedation together with mechanical ventilation [tidal volume 7 mL/kg predicted body weight (PBW), respiratory rate 18/min, positive end expiratory pressure (PEEP) 10 cmH₂O, FiO₂ 50%] were initiated. Laboratory results showed leukocytosis (15×10⁹/L), spontaneous international normalized ratio (INR) 1.7 and activated partial thromboplastin time (aPTT) ratio 2.3, D-dimer 26,780 µg/L, troponin I 5,878 ng/L, creatinine 1.79 mg/dL, myoglobin 70,267 µg/L, and elevated liver enzymes. A transthoracic echocardiography (TTE) highlighted a severe systolic dysfunction of the left ventricle [estimated ejection fraction (EF) 20%] with basal and medial akinesia consistent with recurrence of Takotsubo syndrome.

The total body computed tomography (CT) scan revealed the presence of a minor right fronto-insular subdural hematoma, a left adrenal mass (55 mm × 52 mm × 60 mm) with colliquative-necrotic alterations (as depicted in Figure 1), suggestive for pheochromocytoma, and pelvic intraperitoneal fluid. Due to the adrenergic storm, there was severe haemodynamic instability, which required continuous infusions of either short-acting beta-blocker and alfa-lytic, and epinephrine.

Figure 1 An axial CT scan image showing a left sided adrenal mass (55 mm × 52 mm × 60 mm) with heterogeneous enhancement pattern. CT, computed tomography.

During the first hours after ICU admission, a rapid progression to a multi-organ failure was observed, including increased need of inotropes and vasopressors (epinephrine, levosimendan), worsening respiratory mechanics and hypoxemia [PaO₂/FiO₂ (P/F) <100], worsening liver and renal functions, progressive coagulopathy, and thrombocytopenia. Therefore, on the same day, continuous renal replacement therapy (CRRT) in venovenous hemodiafiltration (CVVHDF) setting and Theralite^® high cut-off (HCO) dialyzer (Gambro, Hechingen, Germany, cut-off 45 kDa, 2.1 m²) were initiated because of the severe metabolic acidosis, worsening oliguria and hypermyoglobinemia. Nevertheless, the day after the patient was deemed to need IABP and VA-ECMO supports, implanted respectively in the left femoral artery and in the right femoral vessels.

VA-ECMO cannulation was done percutaneously under echocardiography guidance by a cardiovascular surgeon wearing full personal protective equipment. Blood was drained from the right common femoral vein and reinfused through the right femoral artery [25 Fr multi-stage Maquet inflow (Hechingen, Germany) and 19 Fr Euroset outflow cannulas (Hechingen, Germany) were used, respectively]. Cannulas positioning was verified by cardiac ultrasonography. A smaller arterial catheter (6 Fr) was placed distally to the entry site of the arterial cannula to prevent lower limb ischemia. Platelets, D-dimer, fibrinogen, aPTT, INR and antithrombin were monitored every 6 hours. The anticoagulation of the VA-ECMO circuit, although initiated only 48 hours later due to the severe coagulopathy, was achieved with unfractionated heparin on continuous infusion and titrated on aPTT time and thromboelastography R-time. The hemoglobin threshold for red blood cell transfusion was <8 g/dL (or ≤9 g/dL when hypoxemia persisted); platelet transfusions were discouraged except for severe thrombocytopenia (<50×10⁹/L) or thrombocytopenia of more than 100×10⁹/L with bleeding. IABP was set at 1:2 mode, VA-ECMO initial settings were 2,500 revolutions per minute [RPM, resulting in 2 litres per minute (LPM) blood flow], sweep gas 2 LPM (furtherly increased up to a 4.5 LPM), FiO₂ 100%, titrating parameters until reaching mean arterial pressure (MAP) of 70 mmHg and SpO₂ of 92%. Rotaflow^® centrifugal pump (Hechingen, Germany) and PLS-i oxygenators (Maquet Cardio-pulmonary Hirrlingen^®, Hechingen, Germany) were used. Ventilatory settings were modified to achieve ultra-protective ventilation (tidal volume 4 mL/kg PBW, respiratory rate 10/min, PEEP 8 cmH₂O, FiO₂ 35%). A wide-spectrum antibiotic therapy with Piperacillin-Tazobactam was also started after the worsening of the abdominal distension, with multiple episodes of melena and ultrasonographic evidence of intra-abdominal free-fluid. On day 4, after the electroencephalogram (EEG) evidence of a generalized status epilepticus, anticomitial therapy with levetiracetam was initiated, furtherly combined with lacosamide. A few days later, a brain magnetic resonance (MR) and consequently a lumbar punction were performed for the suggestion of an infective meningoencephalitis (no micro-organism was isolated); contextually the antibiotic therapy was escalated to meropenem and linezolid.

Although the adrenergic support was still necessary, thanks to the VA-ECMO a slow, but progressive, improvement of the cardiac performance was observed, as confirmed by a routine TTE detection of an improved EF of 45%, which allowed the removal of the IABP device on day 5. Concurrently, a rectosigmoidoscopy and a total body CT scan revealed the evidence of bowel necrosis. Therefore, a multidisciplinary discussion involving endocrinology, cardiology, anesthesiology critical care medicine and general surgery was carried out. Finally, on day 6, in a context of general clinical improvement and specific imaging findings, our time-based decision was to carry the patient to the operating room (OR), where she underwent laparotomy, adrenal tumorectomy and left hemicolectomy with colostomy (Figure 2). Once returned to the ICU, the VA-ECMO support was successfully removed. Given adequate clinical and laboratory response throughout the days following the surgery, neuromuscular blockade, deep sedation, and adrenergic support were progressively discontinued. Concurrently, parenteral nutrition was initiated, and the bowel motility was recovered. On day 9 the patient was extubated and two days later CRRT was suspended.

Figure 2 Surgical resections of left colon and left adrenal gland together with the mass.

A multimodal rehabilitation process was implemented and after 15 days since ICU admission the patient was discharged to general surgery ward in good general conditions and eleven days later, she was finally discharged from hospital. The final histological examination confirmed the diagnosis of pheochromocytoma. After discharge, the patient was referred to a specialized center where she underwent further endocrinologic evaluations, genetic testing, and regular follow-up. The timeline of clinical case progression is shown in Figure 3.

Figure 3 Timeline of clinical case progression. ICU, intensive care unit; CRRT, continuous renal replacement therapy; IABP, intra-aortic balloon pump; VA, veno-arterial; ECMO, extracorporeal membrane oxygenation.

Discussion

In this paper, we have outlined the beneficial role that VA-ECMO and IABP can play as a bridge therapy to surgery in the treatment of pheochromocytoma.

First and foremost, the diagnosis was not straightforward. The patient’s medical history was largely uninformative, except for a history of hypertension. The physical examination suggested a primarily neurological issue, with consequent marked secondary activation of the sympathetic autonomic system resulting in shock with lactic acidosis and hypoxemia. The multi-organ failure picture prompted us to perform a total body CT scan, ultimately revealing the presence of the adrenal tumor, enabling us to diagnose pheochromocytoma. Specifically, a PCC was then suspected, as confirmed by the ultrasonographic detection of Takotsubo syndrome (14) with severe impairing of systolic function, and the presentation of acute pulmonary edema, despite both conditions as primary manifestations are rare (6,14). Urinary metanephrines were not measured as we deemed the severe clinical presentation along with imaging findings sufficient for the diagnosis of PCC. Additionally, the measurement would likely have been biased by the circulating exogenous catecholamines administered during hypotensive phases.

After reaching the diagnosis, the focus shifted to the treatment. Regardless of their size, secreting adrenal tumors typically warrant surgical intervention (15). Unfortunately, no guideline or expert consensus are available to recommend when the PCC patient should undergo surgery; moreover, a clear indication of emergency surgery for PCC is lacking. Since there is no precise timing for the surgery, we focused on ensuring the patient stability before proceeding to take the patient to the OR: the decision-making processes that led us to make the clinical choices required extensive reasoning regarding the physiological aspects underlying the hemodynamic homeostasis of the human body. According to multidisciplinary practice 2021 guidelines (2), major preoperative preparations included blood pressure adjustment with selective and non-selective α-blockers, recovery of the blood volume, and managing glucose abnormalities, although no consensus is available in literature regarding the MAP target for optimal tissue perfusion and adequate urine output. The main issue related to PCC is the excess of catecholamines that can cause direct damage to the myocardium through the activation of the renin-angiotensin-aldosterone system (RAAS), causing increased oxygen consumption and decreased myocardial oxygen delivery, leading to coronary artery spasms, endothelial injury, arrhythmias, and eventually cardiac dysfunction (16).

Although significant efforts of medical management were made, an adequate control of hemodynamic status was not achieved. Therefore, after cardiac surgery consultation, an IABP was implanted in an attempt to increase the diastolic blood pressure and coronary artery blood flow together with decreasing afterload and myocardial oxygen consumption (17). Unfortunately, despite the introduction of IABP, an improvement of the heart failure condition was not observed, with ongoing hemodynamic instability. Therefore, on the same day, after multidisciplinary discussion, an extra-corporeal support with VA-ECMO was introduced. Indeed, in cases of biventricular failure, the VA-ECMO is the first choice for patients in cardiogenic shock and impaired oxygenation, as it provides full cardiopulmonary support (17). However, the increase in afterload due to VA-ECMO is associated with risks of worsening myocardial ischemia, delayed recovery of myocardium, left ventricular thrombus, and pulmonary edema (18). To prevent these consequences, we took advantage of the presence of IABP and its left ventricle unloading properties (19). The decision was challenging due to the presence of subdural hematoma, as identified with the CT scan performed upon ICU admission, which is a well-known relative contraindication to the placement of the support (as shown in Table 1). Despite the associated risks, in our opinion, at that moment VA-ECMO represented the only chance of survival for the patient. During the next few days, extracorporeal supports led to a gradual recovery of cardiac function, as revealed by daily echocardiographic monitoring, allowing the reduction of pharmacological support and enabling the removal of the IABP support. Despite the well-known limitations of ultrasounds related to the operator expertise, the echocardiography is the best option for cardiac function monitoring in ECMO-patients, as traditional methods (Swan-Ganz, PiCCO^TM, Hechingen, Germany) are unreliable and used as adjuncts (20). On the other side, a progressive worsening of the abdominal picture was detected, with the evidence of bowel necrosis. In fact, it is well known that the use of high doses of vasopressors and IABP are both closely associated with the onset of intestinal ischemia. In particular, non-occlusive intestinal ischemia is a pathological condition, occurring in the setting of critical illness, secondary to the use of vasoactive drug leading to severe splanchnic vasoconstriction, metabolic derangement and culminating in multiple organ dysfunction (21). We then took advantage of the achievement of subtle hemodynamic stability to allow the patient to be transferred to the OR, considering the urgent need not only to perform the adrenalectomy, but also the left hemicolectomy, after the evidence of bowel necrosis. In our patient, the tumor was successfully removed with the intra-operative assistance of VA-ECMO. During the surgery, blood pressure and oxygen saturation were stable, with no intractable hypotension after tumor resection, indicating that patients with PCC could benefit from adrenal resection assisted by VA-ECMO.

The use of ECMO support during PCC has also been considered by other authors. Sauneuf et al. (7) used ECMO as a rescue therapy in 14 out of 34 patients (41%) with PCC, two of whom underwent urgent surgery on ECMO support. Despite higher severity scores at admission in the ECMO group, 90-day mortality was not significantly different between patients managed with versus without ECMO, which confirms our hypothesis that mechanical support could stabilize the patient, buying time to manage the crisis through catecholamine level control, blood pressure stabilization, and eventually preparation for definitive surgical treatment. In accordance with our work, a few case reports have highlighted the utility of ECMO during PCC as a tool to stabilize the patient (22), even in combination with IABP (23). In both cases, in contrast with our patient, the pheochromocytoma was surgically removed subsequently, after optimizing the antihypertensive medical therapy. In another cases (24,25), the ECMO played a crucial role as an advanced intra-operative support during the urgent adrenalectomy, as it occurred in our patient. In a review of 62 PCC cases, the favorable prognosis linked to early VA-ECMO intervention was demonstrated by improved cardiac function and an in-hospital survival rate of 87% (26), although this strategy must be cautiously considered because of the high risk of surgical site bleeding in a fully heparinized patient, and ECMO-related complications. In contrast with most studies highlighting the utility of VA-ECMO in patients with PCC, the decision to carry the patient to the OR before weaning from extracorporeal mechanical support, along with the presence of intestinal necrosis, made the timing-based decision of surgical intervention more critical and the procedure itself more delicate. The simultaneous presence of acute kidney injury (AKI), seizures and cerebral hemorrhage represents novel elements not reported in other studies, adding complexity and making our case report more challenging.

Conclusions

Our study highlighted the critical issues associated with the diagnosis and particularly with the management of patients with pheochromocytoma presenting with PCC. Surgical treatment is needed, but its timing is crucial and not straightforward since the patient may be too unstable to undergo surgery, yet delaying the procedure could lead to multi-organ failure and ultimately death. In this setting, VA-ECMO and IABP can play a role in achieving sufficient hemodynamic stability, thus enabling the adrenalectomy to be performed safely.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-148/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-148/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-148/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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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