2026 年 13 巻 p. 261-264
Neurogenic pulmonary edema is a rare but severe complication of acute central nervous system injury, such as subarachnoid hemorrhage, typically presenting with immediate onset. This report describes an uncommon case of delayed-onset neurogenic pulmonary edema following subarachnoid hemorrhage. A 68-year-old man with subarachnoid hemorrhage, caused by a ruptured left posterior communicating artery aneurysm, developed tachypnea and hypoxemia with bilateral pulmonary infiltrates 96 hours after symptom onset. Echocardiography was normal, ruling out cardiogenic causes, and neurogenic pulmonary edema was diagnosed. The patient improved rapidly with fluid restriction and diuretic therapy, and subsequently underwent successful aneurysm coil embolization. Neurogenic pulmonary edema is thought to result from an excessive sympathetic activation leading to pulmonary vasoconstriction, increased capillary pressure, and endothelial injury. Delayed cases may involve secondary sympathetic surges due to intracranial pressure fluctuations, vasospasm, or inflammatory injury. This case highlights the need for clinicians to consider delayed neurogenic pulmonary edema when respiratory deterioration occurs several days after subarachnoid hemorrhage to ensure timely diagnosis and life-saving management.
Complications of subarachnoid hemorrhage (SAH) include hydrocephalus, vasospasm, epileptic seizures, intracranial hypertension, and, extracranially, neurogenic pulmonary edema (NPE).1,2) NPE is defined as an acute-onset syndrome following significant central nervous system (CNS) injury, thought to result from catecholamine-mediated cardiopulmonary dysfunction.2) It has been associated with spinal cord injury, cerebrovascular disorders, traumatic brain injury, status epilepticus, and meningitis, all conditions linked to sympathetic nervous system overactivation.3) Here, we report the case of a 68-year-old man who developed delayed NPE four days after SAH onset.
A 68-year-old man presented with a sudden-onset headache accompanied by nausea. Computed tomography (CT) revealed SAH, classified as Hunt and Kosnik grade 2, World Federation of Neurosurgical Societies (WFNS) grade 2, and modified Fisher group 3. CT angiography did not clearly identify an aneurysm. After admission to the intensive care unit, repeated cerebral angiography on Day 1 and Day 3 revealed a microaneurysm at the left posterior communicating artery (Figure 1A). Endovascular treatment was planned after the vasospasm period. Daily chest radiographs obtained during hospitalization showed no evidence of pulmonary edema until approximately 96 hours after symptom onset (Figure 2A-C), when the patient developed worsening tachypnea. Additionally, an assessment of the administered medications showed no pharmacological agents associated with the development of pulmonary edema. The cumulative fluid balance from admission to Day 4 was +3,000 mL, with a mean daily intake of 1,900 mL (Table 1). A chest radiograph and chest CT at the same time demonstrated bilateral pulmonary infiltrates consistent with acute pulmonary edema (Figure 2D and E). Urgent bedside echocardiography revealed a nondilated left ventricle with normal systolic (ejection fraction >60%) and diastolic function. The atria were not dilated, mitral inflow Doppler confirmed sinus rhythm, and no valvular abnormalities or left ventricular thrombus were present. Cardiology consultation supported a noncardiogenic cause of pulmonary edema. Arterial blood gas analysis under oxygen supplementation (3 L/min) showed PaO2 of 75 mmHg, PaCO2 of 34.0 mmHg, and pH of 7.415. Suspecting NPE, the clinical team restricted daily fluid intake to 1,500 mL and administered diuretics cautiously to avoid volume during vasospasm management. At the onset of NPE, CT and magnetic resonance imaging (MRI) scans revealed no findings suggestive of new-onset hydrocephalus or increased intracranial pressure. Furthermore, there were no changes in the patient's neurological status, including the level of consciousness. Urine output was 2,800 mL on the first day of treatment and increased to 8,200 mL the following day. Over the next 3 days, the pulmonary edema progressively improved (Figure 2F-I), and coil embolization was successfully performed after the vasospasm period (Figure 1B and C).
(A, B) Preoperative internal carotid artery angiography and three-dimensional rotation angiography showing a microaneurysm (arrowhead) at the posterior communicating artery (arrow). (C) Postoperative internal carotid artery angiography confirming complete aneurysm obliteration.
(A, B, C) Chest radiographs on admission, Day 1, and Day 3 show no significant abnormalities. (D) Chest radiographs on Day 4 showing bilateral pulmonary edema. (E) Chest CT on Day 4 shows pulmonary edema with pleural effusion. (F, G) Chest radiographs on Day 5, and Day 6 showing bilateral pulmonary edema. (H, I) Chest radiographs on Day 7 and Day 12 demonstrating improvement of pulmonary edema.
CT: computed tomography
The Cumulative Fluid Balance from Admission to Day 4
| Fluid balance (mL) | Day 0 | Day 1 | Day 2 | Day 3 | Day 4 |
|---|---|---|---|---|---|
| Intake volume | 1,100 | 1,800 | 2,500 | 2,200 | 1,900 |
| Output volume | 1,200 | 900 | 1,600 | 1,100 | 1,700 |
| Balance | −100 | +900 | +900 | +1,100 | +200 |
NPE is a life-threatening, but often underrecognized, complication of acute CNS injury, including SAH.1,2,4) It is characterized by the rapid onset of pulmonary edema following a significant neurological insult, in the absence of primary cardiac dysfunction. Although its pathophysiology is not fully understood, the widely accepted "catecholamine surge" hypothesis proposes that this sudden, massive sympathetic discharge following CNS injury leads to intense systemic and pulmonary vasoconstriction, increasing pulmonary capillary hydrostatic pressure.5) This rise in pressure may cause mechanical stress and endothelial disruption ("blast theory"), resulting in the leakage of protein-rich fluid.5,6) Thus, NPE represents a mixed hydrostatic and permeability-mediated pulmonary edema. Current evidence supports a multifactorial model, in which sympathetic activation, hemodynamic stress, endothelial injury, and inflammatory signaling interact synergistically. Vasoactive mediators such as endothelin-1, nitric oxide, and inflammatory cytokines further promote capillary leak and endothelial dysfunction.3,5)
Although most NPE can arise acutely-within minutes to hours after the initial neurological insult-delayed presentations, including those occurring several days after SAH, as in this case, have been sporadically reported (Table 2).7-9) Previous studies have identified several risk factors associated with the development of NPE in the context of SAH. These include a high Hunt and Kosnik grade, female sex, and specific aneurysm locations, particularly within the posterior circulation or posterior fossa.7-9) The mechanisms underlying such delayed presentations remain speculative, but likely reflect a complex, evolving process beyond the initial sympathetic surge. Secondary sympathetic activation appears central; fluctuations in intracranial pressure, cerebral vasospasm, or delayed cerebral ischemia can trigger recurrent autonomic surges days after the initial event. These repeated episodes may reproduce the hemodynamic and microvascular changes necessary to induce pulmonary edema after a latent interval. Additionally, the initial CNS injury may "prime" the pulmonary endothelium through oxidative stress and inflammatory activation.10) Progressive accumulation of inflammatory mediators and reactive oxygen species can compromise alveolar-capillary integrity, producing delayed fluid extravasation often described as a "two-hit" model.11,12) Systemic inflammation following SAH, including activation of the hypothalamic-pituitary-adrenal axis and release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha, may further impair pulmonary endothelial function and promote delayed edema formation. In this case, several patient-specific factors likely synergized to produce the delayed onset of NPE. First, the onset of respiratory deterioration at 96 hours coincided with the high-risk period for cerebral vasospasm. As discussed, vasospasm can serve as a potent trigger for a secondary autonomic surge days after the initial hemorrhage. Second, the cumulative fluid balance of +3,000 mL from admission to Day 4 likely acted as a crucial mechanical contributing factor. According to the "two-hit" model, the initial SAH may have primed the pulmonary endothelium via systemic inflammation and oxidative stress. The subsequent intravascular volume load, while potentially tolerable for a healthy pulmonary vasculature, may have significantly increased pulmonary capillary hydrostatic pressure. When combined with a secondary, vasospasm-induced sympathetic surge, this hydrostatic stress likely overwhelmed the already compromised alveolar-capillary barrier, precipitating the clinical manifestation of NPE. Additionally, while posterior fossa and posterior circulation aneurysms are established risk factors for NPE, the specific involvement of a posterior communicating artery aneurysm and its anatomical proximity to the brainstem autonomic centers may have further predisposed this patient to recurrent sympathetic discharges. Recognition of delayed-onset NPE is critical. Respiratory decline several days after SAH is often misattributed to more common complications such as pneumonia, aspiration, or cardiac dysfunction. Maintaining a high index of suspicion for NPE, especially in patients with progressive intracranial hypertension or vasospasm, is essential for timely recognition and appropriate management. Core elements of effective treatment include optimization of oxygenation, prudent fluid management to avoid volume overload while supporting vasospasm therapy, and rigorous stabilization of intracranial and systemic hemodynamics. Given the mixed hydrostatic and permeability pathophysiology, interventions that mitigate sympathetic overactivation and minimize pulmonary vascular pressures may also be beneficial, although supporting evidence remains limited.
Summary of Previous Cases of Delayed-Onset Neurogenic Pulmonary Edema
| Case | Age | Sex | H&K grade | Location | Treatment | Duration from onset (days) |
|---|---|---|---|---|---|---|
| BA-SCA: basilar artery-superior cerebellar artery; DACA: distal anterior cerebral artery; F: female; H&K grade: Hunt and Kosnik grade; M: male; Pcom: posterior communicating artery; VA-PICA: vertebral artery-posterior inferior cerebellar artery | ||||||
| Fisher et al. (7) | 28 | F | 4 | BA-SCA | Clipping | 4 |
| Miyamori et al. (8) | 40 | F | 5 | VA-PICA | Clipping | 2 |
| Imai (9) | 64 | M | 4 | DACA | Coiling | 2 |
| Present | 68 | M | 2 | Pcom | Coiling | 4 |
In conclusion, delayed-onset NPE likely reflects a multifactorial process involving secondary sympathetic surges, evolving endothelial injury, inflammatory pathways, and systemic or treatment-related factors. Clinicians should remain vigilant for NPE even several days after SAH, particularly in patients with recurrent intracranial hypertension or vasospasm. Early recognition and prompt supportive care are vital to prevent progression to respiratory failure and to improve outcomes.
We are grateful to Dr. Yuki Tokonami (Department of Cardiology, Hamamatsu University School of Medicine), Dr. Daiki Sato, and Dr. Ei Kishimoto (Department of Respiratory Medicine, Hamamatsu University School of Medicine) for their specialized clinical assessment. Their expertise was instrumental in performing the differential diagnosis of the respiratory findings and in confirming the definitive diagnosis of neurogenic pulmonary edema in this case.
All authors have no conflict of interest.
This study was approved by the appropriate Institutional Review Board (IRB: 21-064), and it adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patients.
