Indian Journal of Critical Care Case Report
Volume 2 | Issue 3 | Year 2023

Methylene Blue to the Rescue in Severe Vasoplegia after Oral Nimodipine in a Patient with Aneurysmal Subarachnoid Hemorrhage

Rupak Banerjee1, Lawni Goswami2, Debasis Rout3, Suresh Ramasubban4, Jayanta Sharma5

1-4Department of Critical Care Medicine, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India

5Department of Internal Medicine, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India

Corresponding Author: Rupak Banerjee, Department of Critical Care Medicine, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India, Phone: +91 9831298893, e-mail:

Received on: 20 April 2023; Accepted on: 14 May 2023; Published on: 23 June 2023


Aim and background: We report the first case in India of refractory vasoplegia from oral nimodipine after aneurysmal subarachnoid hemorrhage (aSAH) and its successful rescue with intravenous methylene blue.

Case description: A 53-year-old man presented with fever, headache, and neck pain from SAH due to the rupture of a suspected mycotic aneurysm. He was on peroral nimodipine postcoiling. After 1 hour, he developed severe hypotension, unresponsive to triple vasopressors. His low diastolic pressure pointed toward vasoplegia and after ruling out other causes with point-of-care ultrasound (POCUS), 200 mg of methylene blue was administered intravenously. The vasopressor requirement decreased immediately. No side effects were observed except chromaturia.

Conclusion: Nimodipine is recommended orally to reduce unfavorable outcomes from delayed cerebral ischemia. Mild hypotension is common, but in rare cases, it may lead to profound refractory vasoplegia. This case demonstrates the successful use of methylene blue as a potential rescue therapy.

How to cite this article: Banerjee R, Goswami L, Rout D, et al. Methylene Blue to the Rescue in Severe Vasoplegia after Oral Nimodipine in a Patient with Aneurysmal Subarachnoid Hemorrhage. Indian J Crit Care Case Rep 2023;2(3):75-77.

Source of support: Nil

Conflict of interest: None

Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.

Keywords: Delayed cerebral ischemia, Methylene blue, Oral nimodipine, Subarachnoid hemorrhage, Vasoplegia.


The unifying clinical definition of vasoplegia is lacking and remains mainly a diagnosis of exclusion. There are no evidence-based reversal agents for refractory vasoplegia following oral nimodipine. Since “Time Is Brain,” prompt administration of methylene blue after the exclusion of other causes by POCUS at bedside can be pragmatic and decrease long-term morbidity and mortality.


Vasoplegia is encountered in many clinical scenarios, including septic shock, anaphylaxis, postcardiopulmonary bypass surgery, severe burns, adrenal crisis, as well as calcium channel blocker overdose. It is characterized by significant hypotension, with normal to high cardiac output and low systemic vascular resistance1 despite high fluid, and catecholamines dosage. Intravenous nimodipine use can result in life-threatening hypotension and has a boxed warning from the manufacturer. Oral nimodipine (360 mg/day) is recommended as the standard of care for the prevention and treatment of delayed cerebral ischemia in aSAH.2 Profound vasoplegia following oral nimodipine is rare and under-recognized. Pathophysiology of this is complex and evidence regarding treatment is limited. We report a case of refractory vasoplegia after oral nimodipine that was unresponsive to triple vasopressors and was rescued by intravenous methylene blue with chromaturia observed as the only side effect. A literature search revealed an isolated case series describing four cases of vasoplegia after oral nimodipine successfully treated with methylene blue.3


A 53-year-old man presented with fever, headache, and neck pain for 7 days. Brain computed tomography (CT) done from outside facility was noncontributory. A lumbar puncture was done, and cerebrospinal fluid (CSF) was uniformly hemorrhagic. After correcting for red blood cells, his CSF still had an elevated white blood cell (WBC) count (neutrophilic predominance) and protein level, with a CSF to serum glucose ratio of <0.4. The CSF was negative for tuberculosis and multiplex polymerase chain reaction (PCR) based common pathogens. He was hemodynamically stable. The WBC and C-reactive proteins were marginally elevated. Intravenous ceftriaxone and vancomycin started. The CT brain and CT angiography done simultaneously revealed ruptured aSAH (Hunt and Hess grade III), with an aneurysm arising from the distal parietotemporal M3/M4 branch of the inferior division of the right middle cerebral artery. The clinical and CSF picture, along with the distal aneurysmal location, were suggestive of a mycotic origin. The transthoracic echocardiography was normal. Serology testing for hepatitis, syphilis, and retroviral disease was nonreactive.

He underwent an uneventful endovascular coiling procedure, was extubated in the operation theatre, and shifted to the intensive care unit. Postcoiling, he was on the standard operating procedure (nurse-led neuromonitoring, oral nimodipine, intravenous heparin, and induced hypertension with supplementary transcranial Doppler as required) as per institutional protocol. After 1 hour, he became lethargic, tachycardic, and profoundly hypotensive (80/44 mm Hg, mean arterial pressure <60 mm Hg), necessitating fluid boluses and the use of high doses of noradrenaline, adrenaline, and phenylephrine. Since sepsis was considered a primary differential diagnosis, pan cultures, and inflammatory markers were sent. Antimicrobial therapy was escalated, and hydrocortisone was initiated. Nimodipine was withheld. Given the profoundness and rapidity of hypotension, a comprehensive POCUS examination was done, which revealed normal cardiac output and good biventricular function without any cardiac tamponade, pneumothorax, hypovolemia, or raised intracranial pressure. Due to the absence of other plausible causes, hypotension in the presence of adequate volume and cardiac function, a diagnosis of refractory vasoplegia secondary to nimodipine was made by exclusion. A blood sample for glucose-6-phosphate dehydrogenase (G6PD) level was sent. We administered intravenous methylene blue 200 mg over 30 minutes as a salvage therapy. He came off vasopressors within 15 minutes, with spontaneously dissolving chromaturia (Fig. 1) as the only side effect.

Fig. 1: Chromaturia following methylene blue


Delayed cerebral ischemia accounts for significant morbidity and mortality4,5 and is a major cause of secondary neurologic injury after aSAH. To prevent and treat it, nimodipine should be initiated within 96 hours at a dose of 60 mg every 4 hours and be continued for 21 days.5 Though mild hypotension requiring dose reduction or concomitant vasopressor use is not uncommon,2,6 profound vasoplegia following oral nimodipine is rare. The mechanism of vasoplegia (Flowchart 1) includes dysregulation of vasodilatory and vasoconstrictive properties of vascular smooth muscle cells.7 Nitric oxide (NO) accumulation leading to activation of cyclic guanosine monophosphate (cGMP) and thereby inhibiting calcium entry inside the cell is thought to be the main mechanism for vasodilatation. Nimodipine, a voltage-gated L-type calcium channel blocker, crosses the blood-brain barrier owing to lipophilicity8 and preferentially acts on cerebral vessels. It has a terminal elimination half-life of 8–9 hours, but the initial elimination is rapid (1–2 hours), necessitating dosing every 4 hours. Risk factors for vasoplegia include intravenous heparin, use of long-acting angiotensin converting enzyme inhibitors,9 and inflammatory milieu10 with the release of interleukines11 in subarachnoid hemorrhage. Nimodipine may cause a disbalance of calcium signaling and eventually increase NO release and consequent vasodilatation. Among the other noncatecholamine-based therapies for vasoplegia, hydroxocobalamin, and angiotensin II were not available in our institution. Vasopressin was avoided due to the fear of a decrease in cerebral blood flow and possibly creating additional vasospasm.12 Since there is a lack of data regarding the superiority of one therapy over the other, we treated our patient with methylene blue. Acting as a NO scavenger, it inhibits endothelial NO synthase activity and thereby decreases cGMP-regulated vasodilatation by NO. The rapid increase in blood pressure along with down titration of vasopressors within minutes of methylene blue administration in the context of its pharmacokinetic properties indirectly suggests that cessation of vasopressors was not just due to the tapering effect of the drug. However, at clinically relevant concentrations, it can cause headache, encephalopathy, severe pulmonary hypertension, hemolysis (in G6PD deficiency), and serotonin syndrome (with concomitant selective serotonin reuptake inhibitor, monoamine oxidase inhibitor use) for which the treating team should remain vigilant.

Flowchart 1: Pathophysiology of vasoplegia: physiologic contraction of vascular smooth muscle occurs in response to intracellular calcium, which causes vasoconstriction. Inflammatory mediators can lead to adrenoreceptor desensitization, an immediate increase in vasoconstrictive mediators with subsequent depletion, and the production of NO. NO leads to an increase in cGMP, which inhibits calcium in cells, leading to muscle relaxation. NO also activates adenosine triphosphate-sensitive potassium channels (KATP), leading to hyperpolarization and inhibited vasoconstriction


Severe refractory hypotension following nimodipine should alert the physician about vasoplegia mediated via impaired NO signaling. The potential benefits of nimodipine should not undermine its potential for life-threatening adverse effects, and prompt intervention may be taken to preserve cerebral perfusion. Evidence for methylene blue in nimodipine-induced vasoplegia is limited but promising and commands more research.


Rupak Banerjee

Lawni Goswami

Debasis Rout

Suresh Ramasubban

Jayanta Sharma


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