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Use of Nimodipine in Subarachnoid Hemorrhage: A Review

Epidemiology and Etiology

Subarachnoid hemorrhage (SAH) is a stroke typified by bleeding into the subarachnoid space of the brain. Classically, this bleeding originates from aneurysms in the intracranial arteries of the Circle of Willis.1 Aneurysms are often described as weak areas or blister-like abnormalities in the wall of the blood vessel. High pressure and shear stress can cause these abnormal areas to grow, further weakening the vessel lumen until the lesion ruptures. When this occurs, blood escapes into the subarachnoid space, creating a diffuse bleeding pattern. Additionally, intracerebral and intraventricular hemorrhage may occur concomitantly, depending on the size, location, and extent of bleeding of the aneurysm. SAH may also occur as the result of trauma, though it is usually not related to aneurysm development nor is it typically associated with the various complications that ensue after aneurysmal bleeding. The focus of this review will be on aneurysmal SAH.

SAH is more common in women than in men (usually an approximate 60% to 70% incidence in women). The majority of patients with SAH are between 40 and 60 years of age, in contrast to the average age of patients with intracerebral hemorrhage (ICH) or ischemic stroke.1 Considerable variability in the presentation of SAH occurs around the globe. Individuals in Finland and Japan have the highest rate of SAH (20 to 23 per 100,000 people).2 Individuals in the United States also have a high rate of SAH (15 per 100,000 people). This variability may be caused by genetic factors that predispose individuals to develop intracranial aneurysms and subsequent SAH. Many individuals develop intracranial aneurysms, though many are never identified. The rate at which aneurysms grow and the factors that cause aneurysms to generate symptoms, even before rupture, are still being defined.

Several modifiable risk factors also are associated with the development of aneurysmal subarachnoid hemorrhage.3 Hypertension is the primary risk factor for SAH. Nearly 50% of patients with SAH have a prior medical history of hypertension.3 Poor control of blood pressure is typical for these patients. Individuals who smoke also have a higher risk of SAH. Recreational use of stimulants, such as cocaine or methamphetamine is also associated with SAH, though scattered cases of other commonly used stimulants, such as phentermine and phenylpropanolamine, have been reported.3-5 The use of an oral anticoagulation or heavy ethanol use may be associated with SAH as well.

Patients with SAH commonly present with a familiar refrain of symptoms. The chief symptom is a headache that the majority of patients describe as the “worst headache of my life.” This is often misdiagnosed as migraine or sinus infection in some individuals; but, the character of the headache is described as vastly different by patients. Signs of meningeal irritation or evolving hydrocephalus may also be evident (e.g., photophobia, stiff neck, nausea, vomiting).1 Patients with a more severe presentation may also exhibit confusion, seizures, or cranial nerve dysfunction, with the most severe patients presenting in a comatose or moribund state.

Outcomes of SAH can be poor, depending on their time to presentation, the size of the hemorrhage, and treatment of SAH complications during hospitalization. Nearly 10% of individuals with SAH die immediately, while another 15% to 25% will die during their hospital stay.1 Neurologic outcomes typically correlate with the severity of illness upon presentation. Scoring systems in the early stages of SAH can give practitioners some idea of prognosis and the likelihood of complications (Table 1). Patients with a Hunt-Hess classification of 1 or 2 (less severe symptoms) or low World Federation of Neurological Surgeons (WFNS) score generally have a good outcome compared with patients who have more severe presenting symptoms. Other scoring systems may also be used in this setting, including the Fisher score. This score focuses on the amount of blood and hematoma in the brain seen on computed tomography (CT) scan and better predicts the risk of vasospasm than other scoring systems, like the Hunt-Hess Scale.

Table 1. Selected Scales Used to Categorize the Severity of Subarachnoid Hemorrhage39
Scale Hunt and Hess Fisher World Federation of Neurological Surgeons
1 Asymptomatic or minimal headache No subarachnoid blood GCS 15, no motor deficit
2 Moderate-to-severe headache, nuchal rigidity, possible cranial nerve palsy Diffuse deposition or thin layer of blood < 1 mm thick GCS 13 – 14, no motor deficit
3 Drowsy, confused, mild focal neurologic deficit Localized clots and/or layer of blood > 1 mm thick GCS 13 – 14, with motor deficit
4 Stupor, moderate-to-severe hemiparesis, early decerebrate rigidity No or diffuse subarachnoid blood; presence of intracerebral or intraventricular hemorrhage GCS 7 – 12, with or without motor deficit
5 Deep coma, decerebrate posturing, moribund   GCS 3 – 6, with or without motor deficit
GCS = Glasgow Coma Scale

Initial Stabilization

Patients who present with possible SAH should have rapid diagnostic testing to confirm the diagnosis. In addition to a detailed neurologic exam, CT scans may be used to identify areas where blood is present in the brain.6 CT angiography and/or digital subtraction angiography are often used to illuminate the brain vasculature and often permit clinicians to visualize the precise location and morphology of existing aneurysms. In centers where CT scans or angiography are not immediately available, lumbar puncture may be considered instead in order to confirm the SAH diagnosis.

Severity of illness scores for SAH are different than many other critically ill patients. Scores, such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sepsis-related Organ Failure Assessment (SOFA), do not tend to correlate well to the unique risks for poor outcome attendant with SAH. Several scoring systems are employed in an effort to categorize the severity and subsequent risks of SAH (Table 1). Each scale has advantages and disadvantages and may exhibit some degree of inter-rater variability. Combination of individual scales may aid practitioners in better projecting risks of morbidity and mortality; but each scale may also be used on its own, depending on provider preference.

Acutely, patients with SAH are at risk of rebleeding. Rigorous blood pressure control should be instituted as quickly as possible.6 While the ideal blood pressure after SAH is not well defined, goals from intracerebral hemorrhage studies are often extrapolated to SAH in the emergent setting. Typically short-acting intravenous antihypertensives, such as nicardipine or labetalol, are used to reduce the systolic blood pressure (SBP). The current treatment threshold for goal SBP is less than 140 mm Hg, though many practitioners are awaiting the results of ongoing clinical trials for confirmation that this is the most appropriate goal.7 Reduction to goal SBP within 1 to 2 hours is ideal. Clinicians may be wary of rapid reduction of blood pressure in the context of chronic hypertension (as in hypertensive emergency). However, little evidence exists suggesting that these concerns apply to patients with acute, severe intracerebral hemorrhage.8 Blood pressure reduction should continue until later in the course of care when the risk for rebleeding is mitigated. Additionally, if the aneurysm is secured, blood pressure goals can be liberalized to maximize cerebral perfusion.

Reversal of coagulopathy should also be considered. Patients who present with concomitant oral anticoagulant use or antiplatelet use are at risk of expanding the SAH because of the relative lack of physiologic hemostatic mechanisms. Rebleeding caused by the lack of hemostasis is associated with dramatically worse outcomes for patients with SAH. Antifibrinolytic agents (aminocaproic acid or tranexamic acid) have been investigated in this setting, but lack efficacy and may increase the risk of stroke.9 The advent of newer oral anticoagulants has broadened the scope of procoagulant or reversal agents necessary. A complete review of anticoagulant reversal is beyond the scope of this activity, but readers can refer to guidelines on the topic.10 Regardless of the agent, the ideal reversal therapy could be given quickly, have prompt and durable reversal action, and have minimal contribution to the procoagulant response in areas aside from the bleeding aneurysm.

After initial clinical stabilization, neurosurgeons often elect to embolize the aneurysm. This may be accomplished by various means, though the predominant methods in contemporary practice are surgical clipping and neuroendovascular coiling.11 Various factors weigh in the decision to clip or coil an aneurysm including aneurysm size, aneurysm morphology, neck to dome ratio, patient risk factors, and time after ictus. The large International Subarachnoid Aneurysm Trial (ISAT) endeavored to compare the efficacy and durability of clipping and coiling in a large multinational population.11 In the end, clipping and coiling are essentially equivalent, though there may be some distinct advantages to endovascular coiling, such as a potential increased rate of survival free of disability at one year. For individual patients with SAH, it is ideal to be treated at a high volume center with neurosurgeons facile with both techniques so that the clinician can make an individualized choice for treatment. Readers are referred to helpful Web sites for a patient-level description of the different methods of embolizing aneurysms.13,14

From a pharmacologic standpoint, there are distinct differences to consider between clipping and coiling.1,15 Clipping involves a craniotomy, therefore general anesthesia is required. In order to deploy the aneurysm clip, the neurosurgeon often has to cross-clamp the target artery temporarily, which may result in acute cerebral vasospasm. Topical or intra-arterial calcium channel blockers may be necessary to reverse this vasospasm. Conversely, neuroendovascular coiling introduces foreign material to the endogenous coagulation system. When contained within the aneurysm, this results in embolization of the defect (i.e., treatment success). On rare occasions, however, the thrombosis may extend out of the aneurysm neck and into the lumen of the blood vessel. In addition, parts of the coil may also extend out of the aneurysm neck, leading to thrombosis. For these reasons, most patients undergoing coiling receive an intravenous heparin bolus (usually 50 to 80 units/kg) to maintain some level of anticoagulation while embolizing the aneurysm and to prevent acute thrombosis.16

Medical Complications of SAH

Various medical complications arise from SAH as the patient convalesces.17 The risk of rebleeding is perhaps the most deleterious. In patients who have undergone clipping or coiling, the risk of rebleeding is negligible. However, in situations where no aneurysm is identified (so called angiography-negative SAH), continued rigorous blood pressure control is necessary to mitigate the risk of rebleeding. In addition, patients with posterior circulation aneurysm rupture or concomitant intraventricular hemorrhage may present with hydrocephalus, which may require drainage of cerebrospinal fluid with a ventriculostomy.15 Seizures may occur in 10% of patients with SAH, though routine antiepileptic drug prophylaxis does not appear to be helpful and may be harmful depending on the agent selected.1,6 Fever is also common and may lead to clinical worsening and excesses in treatment.17 Fever increases cerebral metabolic rate of oxygen consumption (CMRO2), which increases demand in the brain. Increases in temperature may also exacerbate elevations in intracranial pressure and often leads to treatment with both antipyretics and nonpharmacologic cooling therapies. SAH patients commonly exhibit systemic inflammatory response for the first week or 2 after ictus, which, combined with frequent fever, often leads to excesses in antimicrobial use. It is estimated that 50% of patients with SAH, who receive antimicrobials do so because of noninfectious fever. Venous thromboembolism also occurs in approximately 9% to 11% of patients and it may be associated with history of smoking and a delay in pharmacologic prophylaxis.18

Hyponatremia occurs in approximately 13% to 33% of patients with SAH, though this estimate is likely low based on current practical definitions of hyponatremia by neurocritical care practitioners.17,19 Hyponatremia in the context of neurologic injury is often implicated in worsening of cerebral edema. Whether reductions in serum sodium occur as the result of cerebral salt wasting syndrome or the syndrome of inappropriate antidiuretic hormone (SIADH) is controversial and not well defined. It is possible that a combination of the 2 disorders is present for many patients with SAH. Clinicians should maintain serum sodium concentrations within the normal range (or even at the high end of this range) in order to prevent exacerbations in cerebral edema. The optimal range for sodium levels in neurocritical care patients has yet to be established.

Cardiac abnormalities are also quite common for patients with SAH. At least 50% of patients with SAH will exhibit abnormalities on electrocardiogram20; the severity and clinical relevance varies from patient to patient. Electrocardiographic phenomenon, such as inverted T-waves, ST depression, sinus tachycardia, and pathologic Q waves may occur, but are often clinically innocuous.21 QTc prolongation may increase the risk of torsades de pointes and may also be a surrogate for the development of cerebral vasospasm.21,22 Clinicians should be mindful of medications that may also prolong the QTc interval and avoid use when possible and monitor closely when use is necessary. The most severe cardiac complication associated with SAH is stress-induced cardiomyopathy. This occurs in 10% to 15% of patients and is typified by apical stunning, troponin leak, and, in some individuals, acute heart failure.20 This heart failure severely complicates care, particularly in the context of cerebral vasospasm, and increases mortality. The cardiomyopathy reverses over time and many patients return to their normal baseline cardiac function during the subsequent months after ictus. Cardiac monitoring of all patients with SAH is prudent, though patients with preexisting cardiac disease require much closer scrutiny of potential complications.

Cerebral Vasospasm

While numerous medical complications accompany aneurysmal SAH, perhaps the most anticipated complication that drives therapy in the acute setting is cerebral vasospasm. Vasospasm occurs in as many as 70% of individuals with SAH, with approximately 20% to 30% of those who experience vasospasm developing delayed neurologic deficits.15 The time course for vasospasm is relatively predictable, with the risk of development in 2 to 3 days and peaking at 7 to 10 days after ictus. Patients with cerebral vasospasm require hemodynamic augmentation to ensure adequate cerebral perfusion.6,15 Historically, Triple H therapy (i.e., hemodilution, hypervolemia, and hypertension) was employed. While permissive or induced hypertension is still a cornerstone of therapy in contemporary practice, hypervolemia (and to a lesser extent, hemodilution) is no longer a treatment goal.23 Maintenance of a euvolemic state during hemodynamic augmentation is similarly effective when compared with hypervolemia, but is associated with less pulmonary edema. Inotropic agents may also be considered as a method to optimize cerebral perfusion. Alternative strategies, such as super-selective intra-arterial vasodilator infusions or cerebral artery angioplasty, may be helpful in reversing vasospasm.24

The pathophysiology of vasospasm is multifactorial and is still not completely defined.25 It is clear that several factors weigh in the development of vasospasm, including nitric oxide scavenging, oxygen-containing free radical stress, the release of endogenous vasoconstrictors, and a vigorous immune response. As the blood from the initial hemorrhage resides in the subarachnoid space, an immune response to the brain occurs to aid in clearance of the material identified as foreign. This immune response, while normal physiology, creates something akin to a chemical meningitis state, propagating inflammation and cell breakdown. The blood is lysed to be cleared, which liberates hemoglobin (specifically, iron). Iron scavenges nitric oxide, creating intense vasoconstriction. In addition, iron is a scaffold for the Fenton reaction and perpetuates oxygen-containing free radical stress, adding to the already evolving ischemic damage. Other factors, such as endothelin, are present in elevated quantities after SAH, which further augment the vasoconstriction.

Multiple agents and treatment strategies have been employed for the purposes of preventing cerebral vasospasm and the subsequent ischemic damage. Nearly all agents have failed to provide benefit, including agents with a wide range of actions, including the following: lipid peroxidation inhibitors (tirilazad), oral or intravenous vasodilators (nicardipine, clazosentan), indirect calcium channel blockers (magnesium), prophylactic fluid augmentation (albumin, hypervolemia), and nitric oxide-preserving agents (statins).26-31 The only pharmacologic agent to demonstrate benefit for the treatment of patients with SAH is oral nimodipine.32-33 Nimodipine does not appear to prevent radiographic vasospasm, though it is clear that patients who receive nimodipine for 21 days after SAH have a lower rate of death and dependency compared with those receiving placebo. The precise reason for this effect is not well-defined, though it may be the result of neuroprotective effects of blocking calcium channels and/or vasodilation of small, perforating vessels that cannot be visualized by conventional cerebral blood flow monitoring techniques. Despite, numerous clinical trials, in an effort to add options for clinicians to prevent complications associated with vasospasm, oral nimodipine remains the standard of care in contemporary practice.26-31

Use of Nimodipine to Treat SAH

Nimodipine is the only FDA-approved medication for the prevention of delayed neurologic deficits after the successful treatment of SAH. The typical dose is 60 mg (oral or enteral) every 4 hours for 21 days.6,15 Therapy should occur as soon as it is reasonable after initial stabilization and, at the latest, within 96 hours of hemorrhage.32,33 As a dihydropyridine calcium channel blocker, the drug presents a contradictory concern in the context of SAH management. While nimodipine is beneficial for the treatment of SAH, the hypotension that often occurs with calcium channel blockers conflicts with the typical therapeutic goals of hemodynamic augmentation. For patients with SAH-associated stunned myocardium, hypotension also often becomes evident with nimodipine administration, further complicating the hemodynamic management in this specific population. Practitioners may elect to split the dose to 30 mg every 2 hours or even give less drug per day (e.g., 30 mg every 4 hours) to mitigate the hypotension, though little evidence exists suggesting that this dosing strategy is effective. In patients with vasospasm, concomitant use of vasopressors, such as norepinephrine, may also be considered so that induced hypertension can be maintained while also giving nimodipine. Other practitioners may just elect to hold nimodipine doses until the blood pressure is likely to tolerate another dose or may discontinue the nimodipine altogether to prioritize hypertension and hemodynamic augmentation.

Administration of nimodipine also presents specific issues for patients who are critically ill. The nimodipine capsules available in the United States consist of a tough, flexible outer skin and a small amount of peppermint oil-based solution containing 30 mg of nimodipine. Patients who can take medication by mouth are required to swallow 2 large capsules with each dose. Patients who cannot swallow or who are intubated and have enteral access require a different approach. In the past, a common practice was for nurses to extract the nimodipine liquid from the capsule in order to administer the liquid enterally via a feeding tube. This practice was fraught with difficulty and safety concerns. First, the tough outer skin of the capsule makes it difficult to puncture with a needle, often leading to needlesticks.34 Second, extraction of the liquid from the capsule with a needle is highly inefficient and leads to dosing errors.34 Finally, and most importantly, instances of inadvertent intravenous administration of nimodipine have been reported.35-37 This may lead to extreme hypotension, myocardial ischemia, and/or death. As a result, the U.S. Food and Drug Administration (FDA) added a black-box warning to the prescribing information to warn against this practice. The use of alternative methods of liquid extraction (use of scissors or razors) also likely leads to inefficient extraction and dosing errors because of the viscosity of the nimodipine solution. Soaking the capsules is also inappropriate because the capsule readily takes on water (nearly doubling in size after 5 minutes in water), diluting the nimodipine solution.

The following 2 primary strategies are reasonable for pharmacists to consider when dispensing enteral nimodipine: First, the pharmacy may elect to manufacture unit doses of nimodipine by performing the nimodipine extraction for the nurse. Batch manufacturing by a pharmacy technician results in precise dosing and can be done in oral syringes that cannot be used with needles, thereby reducing the likelihood of inadvertent intravenous administration.34,38 Second, a commercial nimodipine solution is available for use (i.e., Nymalize 60 mg/20 mL). The solution is available in bulk bottles or as unit-dose cups. The benefits of this product are obvious when considering that the risk for inadvertent intravenous administration is extremely low and the preparation time for pharmacy is brief. In addition, the solution is grape-flavored; so it is possible to administer to patients who would rather use this formulation by mouth as an alternative to swallowing 2 large capsules. In centers with extremely high volume or relatively low volume or where pharmacy extraction and manufacturing is undesirable, the commercial solution may be preferred. The use of the commercial product or pharmacy extraction of nimodipine is an institution-specific decision based on resources, convenience, and cost. Regardless of the decision, it is clear that the dispensing of nimodipine capsules to the bedside for extemporaneous extraction by nurses or other health care providers is ill-advised and potentially dangerous.

The Pharmacist’s Role

Pharmacists play a key role in the interdisciplinary care of patients with SAH. Initial selections of appropriate therapies to promptly reverse coagulopathy and hypertension immediately after the ictus are essential. Pharmacists can play a role in navigating the cerebral vasospasm treatment process, particularly when employing judicious isotonic or hypertonic fluid resuscitation, vasopressors, and, in some cases, intra-arterial vasodilators. Supportive care issues, such as venous thromboembolism prophylaxis, headache treatment, prevention and treatment of infection, and evaluation and treatment of fever are also rich with pharmacotherapy decisions. Patients with acute SAH exhibit altered (and in many cases augmented) pharmacokinetic parameters, resulting in an increased volume of distribution and accelerated clearance of medications. Pharmacists should be cognizant of these changes and adjust dosing and monitoring accordingly. Finally, administration of nimodipine can be associated with adverse events and potentially devastating errors. Pharmacists should play a large role in determining the appropriate formulations and ensuring safe administration of nimodipine in all patients with SAH.

Summary

SAH is a potentially devastating event, not only because of the initial hemorrhage, but also because of the medical complications. Cerebral vasospasm is the most common complication and is usually anticipated; it may lead to permanent neurologic deficits or death. Treatment of cerebral vasospasm is, typically, moderately successful with hemodynamic augmentation or super-selective vasodilation. Prevention of vasospasm and clinical sequelae is a cornerstone of treatment throughout the course of SAH. The only FDA-approved medication to prevent the complications associated with vasospasm is oral nimodipine. While nimodipine is effective for preventing delayed neurologic deficits, its use is complicated by practical limitations, such as hypotension and administration difficulties. Centers should consider the FDA black-box warning against inadvertent intravenous administration of nimodipine gel extracted from capsules and abolish bedside extraction of nimodipine for patients who require enteral administration of the drug. Pharmacy extraction and manufacturing or use of the commercially available liquid nimodipine product is recommended to ensure safe and pharmaceutically appropriate dispensing and administration.

References

  1. Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. New Engl J Med. 2006;354(4):387-396.
  2. Linn FH, Rinkel GJ, Algra A, van Gijn J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke. 1996;27(4):625-629.
  3. Qureshi AI, Suri MF, Yahia AM, et al. Risk factors for subarachnoid hemorrhage. Neurosurgery. 2001;49(3):607-612; discussion 12-13.
  4. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343(25):1826-1832.
  5. Bain JA, Dority JS, Cook AM. Subarachnoid hemorrhage in a patient taking phentermine for weight loss. J Am Pharm Assoc (2003). 2014;54(5):548-551.
  6. Diringer MN, Bleck TP, Claude Hemphill J, 3rd, et al; and the Neurocritical Care Society. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211-240.
  7. Anderson CS, Heeley E, Huang Y, et al; and the INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. New Engl J Med. 2013;368(25):2355-2365.
  8. Ohwaki K, Yano E, Nagashima H, et al. Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement. Stroke. 2004;35(6):1364-1367.
  9. Baharoglu MI, Germans MR, Rinkel GJ, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2013;8:CD001245.
  10. Holbrook A, Schulman S, Witt DM, et al; American College of Chest Physicians. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e152S-e184S.
  11. Brisman JL, Song JK, Newell DW. Cerebral aneurysms. New Engl J Med. 2006;355(9):928-939.
  12. Molyneux A, Kerr R, Stratton I, et al; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360(9342):1267-1274.
  13. The Neurologic & Orthopedic Hospital of Chicago. Aneurysm coiling animation. https://www.youtube.com/watch?v=QR7sKMYCqec. Accessed December 15, 2015.
  14. Norton Healthcare. Unassisted Aneurysm Coiling Technique. Aneurysm coiling animation on Vimeo Web site. https://vimeo.com/17642453. Accessed December 15, 2015.
  15. Bederson JB, Connolly Jr ES, Batjer HH, et al; American Heart Association. Guidelines for the management of aneursymal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009;40(3):994-1025.
  16. Wanke I, Doerfler A, Dietrich U, et al. Endovascular treatment of unruptured intracranial aneurysms. AJNR Am J Neuroradiol. 2002;23(5):756-761.
  17. Wartenberg KE, Mayer SA. Medical complications after subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21(2):325-338.
  18. Serrone JC, Wash EM, Hartings JA, et al. Venous thromboembolism in subarachnoid hemorrhage. World Neurosurg. 2013;80(6):859-863.
  19. Audibert G, Steinmann G, de Talancé N, et al. Endocrine response after severe subarachnoid hemorrhage related to sodium and blood volume regulation. Anesth Analg. 2009;6:1922-1928.
  20. Hessel EA 2nd. The brain and the heart. Anesth Analg. 2006;103(3):522-526.
  21. van der Bilt I, Hasan D, van den Brink R, et al. Cardiac dysfunction after aneurysmal subarachnoid hemorrhage: relationship with outcome. Neurology. 2014;4:351-358.
  22. Ibrahim GM, Macdonald RL. Electrocardiographic changes predict angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2012;8:2102-2107.
  23. Lennihan L, Mayer SA, Fink ME, et al. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2000;31(2):383-391.
  24. Weant KA, Ramsey CN 3rd, Cook AM. Role of intraarterial therapy for cerebral vasospasm secondary to aneurysmal subarachnoid hemorrhage. Pharmacotherapy. 2010;30(4):405-417.
  25. Harrod CG, Bendok BR, Batjer HH. Prediction of cerebral vasospasm in patients presenting with aneurysmal subarachnoid hemorrhage: a review. Neurosurgery. 2005;56(4):633-654; discussion 633-654.
  26. Kirkpatrick PJ, Turner CL, Smith C, et al; and the STASH Collaborators. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666-675.
  27. Haley EC Jr, Kassell NF, Apperson-Hansen C, et al. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg. 1997;83(3):467-474.
  28. Lanzino G, Kassell NF, Dorsch NW, et al. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg. 1999;90(6):1011-1017.
  29. Dorhout Mees SM, Algra A, Wong GK, et al; and the writing groups of MASH-I, IMASH, MASH-II, MASH, and FAST-MAG Collaborators. Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis. Stroke. 2015;46(11):3190-3193.
  30. Suarez JI, Martin RH, Calvillo E, et al; and the ALISAH Investigators. The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes. Stroke. 2012;43(3):683-690.
  31. Macdonald RL, Higashida RT, Keller E, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43(6):1463-1469.
  32. Petruk KC, West M, Mohr G, et al. Nimodipine treatment in poor-grade aneursym patients. J Neurosurg. 1988;68(4)505-517.
  33. Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298(6674):636-642.
  34. Oyler DR, Stump SE, Cook AM. Accuracy of nimodipine gel extraction. Neurocrit Care. 2015;22(1):89-92.
  35. U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: Serious medication errors from intravenous administration of nimodipine oral capsules. FDA Web site. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm220386.htm. Accessed June 3, 2014.
  36. Institute for Safe Medication Practices (ISMP). Take steps to avoid inadvertent IV administration of nimodipine.July 28, 2005. ISMP Web site. https://www.ismp.org/newsletters/acutecare/articles/20050728_1.asp. Accessed June 6, 2014.
  37. Institute for Safe Medication Practices (ISMP). The Following Are Excerpts From the Newsletter August 11, 1999: Safety Briefs: NIMOTOP (nimodipine) capsule given IV to a patient who could not swallow instead of via naso-gastric tube.. ISMP Web site. https://www.ismp.org/newsletters/acutecare/archives/Aug99.asp#Aug25,1999. Accessed June 6, 2014.
  38. Green AE, Banks S, Jay M, Hatton J. Stability of nimodipine solution in oral syringes. Am J Health Syst Pharm. 2004;61(14):1493-1496.
  39. Rosen DS, Macdonald RL. Subarachnoid hemorrhage grading scales: a systematic review. Neurocrit Care. 2005;2(2):110-118.

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