Neurogenic pulmonary edema (NPE) is a clinical condition that arises from various central nervous system (CNS) insults, including traumatic brain injury, intracranial hemorrhage, status epilepticus, meningitis, and brain tumors [1]. It is thought to occur due to a massive sympathetic discharge triggered by CNS insult, which leads to cardiopulmonary dysfunction [2]. In severe cases, the mortality rate ranges from 60% to 100% [3]. Although NPE was first reported over 100 years ago [4], there are few reports on specific treatment modalities for humans. We describe a case of a patient with a fulminant and prolonged course of NPE who required extracorporeal membrane oxygenation (ECMO) and was successfully treated with phenoxybenzamine and sildenafil. This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center and was exempted from both IRB review and patient consent.

A 5-year-old girl was admitted for the resection of a residual anaplastic ependymoma located on the posterior aspect of the medulla (Fig. 1). Her medical history included a craniotomy performed 1 year prior for tumor removal, followed by six cycles of chemotherapy, a session of high-dose chemotherapy with autologous stem cell transplantation, and radiation therapy. Her height was recorded at 106 cm (25th percentile), her weight at 16.5 kg (25th percentile), and her body mass index at 14.7 kg/m² (10th percentile).

Intraoperatively, the mass was found to be adherent to the posterior medulla. During the manipulation of the mass, the patient's heart rate (HR) and blood pressure (BP) exhibited unexpected fluctuations. The HR increased from 90 to 115 beats per minute, while the BP escalated from 110/50 to 170/90 mm Hg. As these episodes occurred, the resection was temporarily paused, and the episodes resolved spontaneously without intervention. Postoperatively, the patient's vital signs stabilized and were within normal limits, including an oxygen saturation of 100%.

At 7 hours postoperative, blood-tinged foamy sputum was suctioned from the endotracheal tube (E-tube). By 11 hours postoperative, the child exhibited progressive hypoxemia and respiratory failure, accompanied by a large volume of bloody secretion in the E-tube. A chest x-ray revealed bilateral airspace consolidation and an air bronchogram (Fig. 2). Her vital signs were as follows: a temperature of 37.4 °C, an HR of 186 bpm, a respiratory rate of 47 breaths/min, and a BP of 125/93 mm Hg. She exhibited labored breathing and an oxygen saturation of 74% despite receiving 100% supplemental oxygen. Despite using a conventional ventilator (CV), her oxygen saturation dropped to 44%, and her BP declined to 63/35 mm Hg. At 15 hours postoperative, she was switched to high-frequency oscillatory ventilation (HFOV); however, this failed to maintain adequate oxygenation, leading to her placement on veno-venous ECMO.

The patient did not have a history of a positive body fluid balance or recent transfusions. Coagulopathy was not found on the laboratory examinations. The patient’s echocardiogram did not show systolic or diastolic dysfunction. Since sepsis-associated acute respiratory distress syndrome could not be excluded, we used meropenem for 2 days and vancomycin for 4 days during ECMO application. However, all the infection surveillance showed negative results including a respiratory virus panel, tests for cytomegalovirus and Pneumocystis jirovecii, and bacterial culture. Given the absence of other diagnoses and the proximity of her surgery to the NPE trigger zone, NPE was considered the most likely diagnosis.

On postoperative day (POD) 1, the patient's BP fluctuated dramatically, ranging from 57/37 to 156/120 mm Hg within just a few minutes. We administered supportive care using sedatives, diuretics, and vasoactive drugs. By POD 4, the patient had stabilized, allowing for the removal of the ECMO and discontinuation of all vasopressors and vasodilators. On POD 9, the HFOV was switched to CV. However, subsequent attempts to wean the patient off the ventilator were unsuccessful, as her lungs became edematous with frothy secretions unless maintained on a high positive end-expiratory pressure (PEEP) above 10 cm H2O. Starting on POD 15, we initiated treatment with phenoxybenzamine, gradually increasing the dosage from 0.13 mg/kg/day to 2.22 mg/kg/day.

The patient's catecholamine level was measured before administering phenoxybenzamine and found to be within the normal range. Following the administration of phenoxybenzamine, we were able to reduce the PEEP to 5 cm H₂O and attempted extubation on POD 17. However, the patient experienced a recurrence of high BP and tachycardia as they were gradually awakened. Seven hours later, reintubation was necessary. Concurrently, the patient exhibited systolic BP fluctuations ranging from 120 to 160 mm Hg and a significant amount of bloody secretion in the E-tube. Despite increased ventilatory support, the patient developed bradycardia and hypotension, necessitating cardiopulmonary resuscitation. Circulation was restored after 13 minutes, and HFOV was subsequently reapplied.

On POD 28, we initiated treatment with sildenafil at a dose of 1 mg/kg/day, which was gradually increased to 8 mg/kg/day over the following 10 days. Following the administration of phenoxybenzamine and sildenafil, the patient did not experience recurrent pulmonary edema. Consequently, she was extubated and placed on continuous positive airway pressure (CPAP) on POD 38. Six days after extubation, she was successfully weaned off CPAP and transferred to a general ward. One week later, she was able to be discharged home with phenoxybenzamine and sildenafil in an alert and communicative state. After discharge, she was readmitted several times due to recurrent suspicious pneumonia. She was tapered off phenoxybenzamine and sildenafil over the course of 1 year after discharge. Since then, she has been followed up for 2 years, and she is now able to run in room air without neurologic sequelae or dyspnea.

NPE is known to be triggered by stimulating specific areas of the brain, particularly in the hypothalamus and medulla oblongata. This stimulation can be due to global hypoperfusion resulting from a sudden increase in intracranial pressure (IICP) or a localized ischemic event within the trigger zone [5]. Symptoms of NPE can appear quickly, within minutes to hours after a neurological insult, or they may emerge 12–24 hours following a CNS injury [6,7]. In our patient, a fulminant NPE developed 7 hours after manipulation of the trigger zone, with no signs of intracranial hemorrhage or IICP evident on computed tomography scans. We hypothesize that inflammatory or ischemic insults evolved over these 7 hours, causing persistent alterations in the trigger zones. The patient experienced recurrent fluctuations in BP for over 2 weeks until we initiated treatment with phenoxybenzamine.

The primary treatment for NPE involves supportive care for the pulmonary edema and addressing the underlying neurological condition [1]. In this case, supportive measures such as oxygenation and maintaining body fluid balance achieved partial success. However, attempts to reduce the high PEEP (above 10 cm H₂O) consistently failed, exacerbating the pulmonary edema. The predominant initial mechanism of NPE is thought to be an overactivation of central α-adrenergic discharge [8]. Animal studies have shown that sympathetic denervation can prevent NPE [9,10], and phenoxybenzamine has been found to inhibit increases in pulmonary-artery and systemic pressures [11]. We believe that phenoxybenzamine was effective in our patient by blocking a hydrostatic pressure surge in the pulmonary vasculature, potentially triggered by pulmonary vasoconstriction or an increased venous return due to systemic vasoconstriction following a catecholamine surge [1]. To our knowledge, there are no existing reports of phenoxybenzamine being used to treat NPE in humans; only two pharmaceutical treatments have been documented. Chlorpromazine, an α-adrenergic blocker, was effective in one case of NPE [12], although it primarily affects the CNS and is typically used in psychiatric settings [13]. Phentolamine, another α-adrenergic blocker, was successfully used in an NPE patient who was weaned off the medication within 3 days [7]. In contrast, the patient discussed in this report experienced prolonged BP fluctuations, necessitating a medication with a longer duration of action.

Despite the significant role of α-adrenergic blockers, they may not be sufficient to prevent NPE. According to the "blast theory," a massive neural outflow leads to transiently high capillary pressure, damaging the capillary-alveolar membrane and resulting in the leakage of protein-rich plasma into the interstitial and alveolar spaces [14]. When applying the blast theory to this patient, we concluded that controlling her pulmonary capillary pressure was inadequate to prevent capillary rupture, despite stabilization of her systemic BP with phenoxybenzamine. To manage the intermittent and abrupt increases in her pulmonary vascular pressure, we administered sildenafil. Inhaled nitric oxide has proven effective for brain-dead organ donors but is unsuitable for long-term management [15]. Sildenafil has been documented as a treatment for high-altitude pulmonary edema, where elevated pulmonary-artery or capillary pressure causes a noninflammatory leak across the alveolar-capillary barrier [16]. It has also been shown to prevent high-altitude pulmonary edema [17]. We hypothesized that sildenafil's effect in preventing pressure-related leakage would be analogous in cases of NPE. We believe that the patient’s clinical improvement was not merely a result of the natural progression of the disease. This is supported by the fact that she exhibited recurrent pneumonia-like symptoms and haziness on her chest x-rays when we attempted to taper the medications during the early phase of outpatient follow-up.

In this case, we report a fulminant NPE case that was successfully treated with phenoxybenzamine and sildenafil. These medications may be considered for NPE patients who exhibit fluctuating BP and/or a prolonged, fulminant disease course when other treatment options are unavailable. Further research involving more patients is needed to clarify the clinical indications for, and the choice of, pharmaceutical treatments for NPE, as well as to understand their mechanisms of action.