Management of vasospasm seems to be a favourite topic among CICM exmainers. It has come up several times in the past papers and vivas. The following is a list of representative SAQs:

A chapter of Oh's Manual (Ch. 51, pp 568) is the canonic resource for these topics. The gospel of subarachnoid management seems to be this 2012 Guidelines Statement from the AHA. Another good resource is available from Expert Reviews - it is an article from 2015 which lists and discusses all the successfull and unsuccessful trials in this area. The Dabus-Noguiera article quoted in LITFL also offers some opinions about the weirder therapies for AH, such as fasudil, colforsin, IABP, partial aortic occlusion, and so forth.

As far as non-journal study resources go, the LITFL review of vasospasm and DCI is a treatment with satisfying levels of detail; with its authors' interest in neurocritical care being well known, its value is significant as a distillate of his expertise.

For the purpose of this short summary, all these sources have been combined and remixed.

In brief:

Strong recommendations for management of SAH

  • Nimodipine (improves neurological outcome, and may or may not protect against vasospasm - but it should be given to all SAH patients. There is only evidence for the oral formulation - the IV infusion is not well-investigated.)
  • Surgical clipping or endovascular coiling of the ruptured aneurysm should be performed as early as feasible 
  • Maintenance of euvolemia is recommended to prevent vasospasm
  • Hypertension is recommended if the patient develops vasospasm.

These are a selection of the Class I recommendations made by the AHA.

 

Risk factors for vasospasm:

  • Fisher Grade 3 or 4 (see LITFL's article on SAH grading systems)
    • The thicker the blood in the basal cisterns, the greater the risk
  • Smoking
  • Cocaine use
  • Age under 50
  • SSRI and statin use
  • Rebleeding
  • Hypertension
  • Daily alcohol intake
  • Leukocytosis, WCC > 10.0
  • Hyperglycaemia
  • QTc > 450msec
  • LVH on ECG
  • ST depression on ECG

No difference in risk between clipping and coiling.

Prevention of Vasospasm

  • Nimodipine
      • The objective is to prevent symptomatic vasospasn, i.e. features of ischaemia and radiologically obvious strokes
      • The BRANT trial: patients receiving nimpodipine were 34% less likely to develop stroke. One ought to continue nimodipine for 21 days to get the optimal effect.
      • Owing to the difficulty in identifying patients who will go on to develop vasospasm, nimodipine is given to all SAH patients.
  • Nicardipine
      • Analogous to nimodipine, but with less RCT support behind its use
  • "Triple H therapy"
      • Largely discredited practice of forced hypervolemia, hypertension and haemodilution.
      • A Cochrane review of this "circulatory volume expansion therapy" (2004) did not find any benefit. However, there was only one RCT and one "quzi-randomised" trial. The numbers were simply too small to make a recommendation.
      • On purely theoretical physiological grounds, as well as from the standpoint of lacking evidence, this therapy was savagely shredded by Myburgh in an excellent review article (2005)
      • Hypertension is the only component broadly supported by a consensus of neurosurgeons.

 

 

Management of Vasospasm

  • Balloon angioplasty
  • Intra-arterial vasodilator injection (papaverine, verapimil, milrinone)

Experimental therapies

  • Statins - no benefit (STASH trial)
  • Intrathecal thrombolytics - some preventative benefit, but no large studies. A 2004 Japanese study found intrathecal urokinase decreased the incidence of vasospasm by almost 50%.
  • Endothelin 1 antagonists (eg. clazosentan) - no strong support, perhaps some subtle benefit (CONSCIOUS-1 trial)
  • Magnesium – no benefit (MASH-2 trial)
  • Tirilazad - a non-glucocorticoid aminosteroid that blocks lipid peroxidation - fiver RCTs; only one showed any benefit, and its efect was lost in the noise accoridng to a Cochrane meta-analysis.
  • Fasudil - a Rho kinase inhibitor that prevents the effects of extracellular calcium on smooth muscle contraction - promising on the basis of 8 RCTs, but still not fully supported by the evidence according to a 2012 meta-analysis.
  • Eicosapentaenoic acid - which also inhibits Rho kinase, like fasudil - promising results of one small study (the EVAS trial); thus far it still falls into the "experimental" category.

In detail:

Vasospasm and Delayed Cerebral Ischaemia (DCI)

This is a much-spoken-of complication of subarachnoid blood. Generally speaking, 70% of patients will develop this complication.

Firstly, the definitions. They seem to overlap somewhat. And there are thousands of them; just see this table from Nature (2011). Some of the definitions quoted below are derived from proposals made by a multidisciplinary research group, published in Stroke in 2010; others were made by researchers who pined for a clinically relevant definition.

Definitions of vasospasm:

Vasospasm:

Symptomatic vasospasm:

Angiographic vasospasm

Delayed Cerebral Ischaemia (DCI):

- Frontera et al, 2009

Clinical deterioration caused by DCI

In brief, you know it's vasospasm when...

    • A focal neurological deficit develops (and persists for longer than an hour)
    • The GCS drops by 2 points (and stays that low for longer than an hour)
    • A new stroke occurs (on CT/MR)
    • No better explanation for any of the above.

Or, alternatively, there are no symptoms, and your patient is having a silent vasospasm. Therein lies the disadvantage of clinical examination.

There are several techniques of imaging which can be used to recognise vasospasm:

Conventional 4 vessel DSA (Digital Subtraction Angiography):

  • This is the gold standard for both diagnosis and management of vasospasm. One can confirm that vasospasm is occurring by a CT angiogram- or, if one were to go straight to DSA one could progress to some sort of definitive treatment. Verapimil and papaverine are the two most commonly used intra-arterial vasodilators.
  • However, this requires a skilled interventional radiologist. It exposes the patient to contrast and it it in vasive, with a (not insignificant - around 1%) risk of atheroma embolism or vessel dissection..
  • There is a small chance that this technique will lead to over-treatment: vessel narrowing may be detected, but this decrease in diameter may not reflect a decrease in flow, and may not warrant an injection of vasodilator.

On DSA assessment, the vasospasm may be graded:

  • no vasospasm
  • slight vasospasm, difficult to appreciate without control images
  • Moderate vasospasm, obvious narrowing but still more than 50% of expected diameter
  • Severe vasospasm, 50% or less of expected vessel diameter.

CTA/MRI:

  • Together, the two modalities can be very useful in non-invasive diagnosis of vasospasm. The sensitivity is said to be 79%, and specificity 93%.
  • The disadvantages are exposure to contrast and the need to confine an unstable ICU patient inside the Death Tunnel.
  • Another disadvantage is that coils and clips cause artefact, which impairs one's assessment of the arterial diameter, and they can play havoc with the MRI images.

Transcranial Doppler (TCD):

  • This is a totally non-invasive technique, which can be performed at the bedside, and that is its major advantage. Apparently, MCA flow velocities of more than 120cm/s are accurate in predicting ischaemia. Velocities over 200m/s practically scream "vasospasm". According to an old 1989 review, specificity is amazing, approaching 100%, but the sensisitivity is poor - only 58%.
  • Unfortunately, every observer will arrive at a different flow velocity.
  • Thus far, nobody can agree as to what slightly raised flow velocity means.
  • Transcranial Doppler may be more accurate when MCA velocity is indexed to the velocity of the carotid artery. If the velocity is more than 3 times faster, there is probably vasospasm going on.
     

SPECT/PET

  • These would be wonderful tools which would give us a glimpse of cerebral perfusion and metabolic resource utilisation. Unfortunately, nobody knows how to interpret them, and few centres can perfrom these studies. For lack of good validating evidence, they must for now remain experimental.

EEG

  • Can be used to obtain a picture of brain perfusion and metabolism and have
    shown variable correlation with vasospasm as assessed by more conventional
    methods.
  • Disadvantages: They are resource heavy not easily available, radiation exposure, patient
    transport are issues.

EEG:

  • The EEG can demonstrate findings which are strongly associated with vasospasm. Not only that, but it can detect areas of ischaemia. Most interestingly, it can do so early - i.e. before there are other fatures. However, deriving meaning from the squiggly lines requires a skilled interpreter. In the hands of such a guru, sensitivity and specificity for detecting vasospasm would be very high.

Risk factors for vasospasm

 

The classical risk factors are as follows:

  • Thick subarachnoid blood: As Fisher (of the Fisher scale) had found in a series of 47 patients, anything thicker than 1mm all but guarantees vasospasm. This is probably the most important risk factor.
  • Smoking (OR = 4.7) - probably as a result of some sort of vascular endothelial confusion.
  • Cocaine use (OR = 6.4) - even though being intubated prevented them from snorting it.
  • Youth (under 50 years of age = almost twice the risk of the over-50s) - likely owing to the higher elasticity and thus greater "spasmability" of young blood vessels; this is supported by the finding that old crusty vessels are protective from vasospasm, presumably with the atheroma acting as some sort of naturally secreted stent.
  • SSRI and statin use (OR =2.0 and 2.75) - nobody knows why

A recent analysis of 370 patients has added several more risk factors:

  • Rebleeding (OR = 1.16)
  • Hypertension (OR = 1.92)
  • Daily alcohol intake (OR = 1.23)
  • Leukocytosis, WCC > 10.0 (OR = 1.31 - for infarction, rather than angiographic vasospasm)
  • Hyperglycaemia(OR = 1.32 - for infarction, rather than angiographic vasospasm)
  • QTc > 450msec (OR = 1.52)
  • LVH on ECG (OR = 2.71)
  • ST depression on ECG (OR = 1.29)

Also: there is no difference in incidence of vasospasm between the clipped group and the coiled group.

That's important to know.

 

Pathophysiology of vasospasm

One could (and perhaps one day will) devote a massive excess of attention to this fascinating area.

For now, I will limit myself to quoting LITFL's article by Oliver Flower, which mentions the following:

  • oxyHb contacts intraluminal wall of vessel
  • calcium dependent and independent pathways
  • free radical mechanisms
  • imbalance in vasoactive agents: NO, endothelin, arachadonic acid
  • neuronal mechanisms leading to increased vascular tone, endothelial tone and apoptosis

The reference for this is likely an article by Kolias and Belli from 2008 (Journal of Neuroscience Research).

Prevention and management of vasospasm

Nimodipine for the prevention of vasospasm

The BRANT trial from England has demonstrated a massively decreased risk of SAH-induced stroke in patients receiving nimpodipine - they were 34% less likely to develop stroke. One ought to continue nimodipine for 21 days to get the optimal effect. The usue of nimodipine undergoes a more thorough dissection in the following chapter (Evidence for the use of nimodipine in SAH)

Nicardipine for the prevention of vasospasm

This -drug the other calcium channel blocker for vasospasm - also appears to have some sort of cerebral vessel selectivity. Trials from the 1990s support its use as a means of preventing vasospasm; however there was no heroic stroke reduction, and both the treatment and placebo groups had the same outcomes at 3 months. In more recent research focus has shifted to using it intrathecally, or intrarterially, or as a slow-release implant. A 2013 meta-analysis of RCTs (5 of them) has finally found some outcome benefit, but only after combining all the intravenius intrathecal and intraarterial data, which seems like a strange strategy.

The rise and fall of "Triple H therapy"

Since its debut in 1990, "Triple H" therapy for subarachnoid haemorrhage has been used in ICUs worldwide as a means of protecting the SAH patients from vasospasm-induced stroke.

Hypertension, hypervolaemia, hemodilution. In order to prevent hypoperfusion injury, the prevailing theory was that the blood pressure should be high, the blood volume should be hyperexpanded, and the hematocric should be low (to decrease blood viscosity). This theory seems to have arisen from the simple relationships of fluid dynamics, where pressure gradients and fluid viscosity are the governing determinants of flow rate.

  • Hypertension was supposed to improve the flow though the spasming vessels by overcoming the normal mechanisms of cerebral autoregulation, and forcefully driving an increase in cerebral blood flow by the sheer effect of the pressure gradient. Of course, the vessels of the brain have some degree of control over what is happening to their diameter, and normally cerebral autoregulation of bloodflow will compensate for systemic increases in mean arterial pressure. The key idea was that induced hypertension would eventually “break” this compensation. Ideally, one would continue this treatment for the same duration as the nimodipine (i.e. for about 21 days).
    Ultimately, this component of Triple H therapy ended up being the only one broadly supported by a recent multidisciplinary consensus conference. Among a group of neurocritical care specialists and neurosurgeons, hypertension "was considered reasonable by most participants", even though there was a great variety in opinion regarding how hight he blood pressure should be, which blood pressure variable to aim for (MAP vs SBP?) and which agents we should use to achieve it.
    If pushed, most would agree that the "correct" blood pressure is the pressure at which your neurological deficits disappear.
  • Hypervolaemia was supposed to increase the circulating fluid volume, thereby allowing enhanced filling of the cerebral circulation. One is puzzled as to how this is supposed to work, given the known distribution of blood volume (with more than 70% of it tending to slosh around in the venous capacitance vessels rather than arteries). It certainly doesn't seem to do what it's supposed to, according to empirical evidence.
  • Haemodilution is supposed to improve laminar flow though the cerebral vessels by decreasing the viscosity of the blood. This may actually be relevant in patients with polycythaemia, or patients who have a subarachnoid haemorrhage in addition to an actual hyperviscosity syndrome.

Myburgh has offered this strategy a nice overview in CCR(2005) and couldn’t recommend it on the balance of evidence. Cerebral autoregulation thresholds are too variable among patients, he says, and probably vary regionally among different parts of the cerebral circulation.

Do the experts agree? No of course they do not. Myburg’s opinion is contradicted by Dhar et al, whose prospective physiological study found that Triple H therapy (all three independently) improve cerebral oxygen delivery to vulnerable regions. The debate about this is ongoing. Thus far, the 2009 iteration of the Stroke  guidelines for management of SAH has concluded that induced hypertension as part of Triple H therapy is a “reasonable approach”, even though the enthusiastic evidence for its use is far from satisfactory.

The most recent spoonfulls of evidence added into this cauldron have been generally unsupportive of "Triple H" therapy. In 2010, a review of the literature found no evidence to support the use of the full package, or any of its components individually. In 2014, the Japanese have confirmed a lack of improvement in clinical outcdomes in a prospective multicentre study. With such a heterogeneously lumpy porridge of evidence, it is little wonder that a 2014 survey of management protocols has found "striking variability in the practice patterns of European physicians", with 44% of responders using "Triple-H" therapy in spite of the patchiness of the evidence in support of it.

Intrathecal thrombolysis

Spilled blood causes vasospasm(it is thought), so one might think that causing a premature breakdown of this blood is beneficial in the prevention of vasospasm. The injection of urokinase followed by some unusual head movements was viewed as a good idea by some Japanese investigators, and had yielded a 50% decrease in vasospasm and associated complications. It is still viewed as an "experimental" therapy.

Statins for subarachnoid haemorrhage

There was some interest in the idea that statin therapy might somehow decrease the morbidity from subarachnoid haemrorrhage . The STASH trial has compared placebo to an 80mg dose of simvastatin, and was forced to conclude that the findings "do not support a beneficial effect of simvastatin in patients with SAH "

Magnesium infusion

Given the smooth-muscle-relaxing effects of magnesium cations, its application to cerebral vasospasm seems no great logical leap. The MASH-2 trial from 2012 was a multi-center investigation of 64mmol of MgSO4 per day, randomised among 606 patients, which somberly concluded that "intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage".

Endothelin receptor antagonists

Clazosentan (a relative of bosentan) is an endothelin-1 receptor antagonist, and it has been investigated in the aptly named Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) trial. The complications of clazosentan therapy (such as anaemia and hypotension) were "manageable". Its use, at least in in severe and moderate vasospasm, demonstrated "a trend toward improvement", as opposed to actual improvement. In short, these drugs only merit the most lukewarm of recommendations.

Intra-arterial vasodilators

Nicardipine (as above) has been used intra-arterially to selectively dilate the spasming vessels. Similarly, papaverine ( phosphodiesterase inhibitor) and verapimil (another calcium channel blocker) have been used with some effect, and remain in routine use today. The most recent Critical Care Guidelines on the Endovascular Management of Cerebral Vasospasm have found papaverine to be the most extensively studied agent, and the one with the greatest amount of support behind it; less data exists in support of verapimil and nicardipine. Milrinone has also showed some promise, both as an intrarterial agent and as an inthrathecal irrigation; there may be an additive effect with nimdipine in the setting of refractory vasospasm.

Balloon angioplasty

If one does not wish to expose the patient to intraarterial vasodilators, one may instead address the spasm in a very direct and brutally mechanical way, but dilating the spasmed vessel with a balloon. The abovementioned guidelines statement had identified 27 studies. There seems to be some disagreement as to which is better (intraarterial papaverine vs. balloonoplasty studies have a substantial degree of heterogeneity in their reported outcomes). There is no disagreement, however, about the risks - balloons have a known association with arterial rupture and fatal haemorrhage.

References

Oh's Intensive Care manual

Chapter   51   (pp. 568)  Acute  cerebrovascular  complications by Bernard  Riley  and  Thearina  de  Beer

LITFL offer this reference as a follow-on to their chapter:

Dabus, Guilherme, and Raul G. Nogueira. "Current Options for the Management of Aneurysmal Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: A Comprehensive Review of the Literature." Interventional Neurology 2.1 (2013): 30-51.

Frontera, Jennifer A., et al. "Defining Vasospasm After Subarachnoid Hemorrhage What Is the Most Clinically Relevant Definition?." Stroke 40.6 (2009): 1963-1968.

Vergouwen, Mervyn DI, et al. "Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group."Stroke 41.10 (2010): 2391-2395.

Etminan, Nima, et al. "Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis." Journal of Cerebral Blood Flow & Metabolism 31.6 (2011): 1443-1451.

Brathwaite, Shakira, and R. Loch Macdonald. "Current Management of Delayed Cerebral Ischemia: Update from Results of Recent Clinical Trials." Translational stroke research 5.2 (2014): 207-226.

Mir, D. I. A., et al. "CT Perfusion for detection of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis." American Journal of Neuroradiology 35.5 (2014): 866-871.

Scheglov, Dmitry V., et al. "Endovascular Treatment of Vasospasm Related to Acute Subarachnoid Hemorrhage from Ruptured Aneurysms." Neurovascular Events After Subarachnoid Hemorrhage. Springer International Publishing, 2015. 223-229.

Serrone, Joseph C., et al. "Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions." Expert review of neurotherapeutics 0 (2015): 1-14.

Rinkel, Gabriel JE, et al. "Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage." The Cochrane Library (2004).

Connolly, E. Sander, et al. "Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association." Stroke 43.6 (2012): 1711-1737.

Macdonald, R. Loch, et al. "Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1) randomized, double-blind, placebo-controlled Phase 2 dose-finding trial." Stroke39.11 (2008): 3015-3021.

Mees, Sanne M. Dorhout, et al. "Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial." The Lancet380.9836 (2012): 44-49.

Zhang, Shihong, et al. "Tirilazad for aneurysmal subarachnoid haemorrhage."The Cochrane Library (2010).

Liu, Guang Jian, et al. "Systematic assessment and meta-analysis of the efficacy and safety of fasudil in the treatment of cerebral vasospasm in patients with subarachnoid hemorrhage." European journal of clinical pharmacology 68.2 (2012): 131-139.

Kirkpatrick, Peter J., et al. "Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial." The Lancet Neurology 13.7 (2014): 666-675.

Yoneda, Hiroshi, et al. "A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm: the EVAS study."World neurosurgery 81.2 (2014): 309-315.

Teasdale, G. M., et al. "A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies." Journal of neurology, neurosurgery, and psychiatry 51.11 (1988): 1457.

Connolly, E. Sander, et al. "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association." Stroke 43.6 (2012): 1711-1737.

Myburgh, J. A. "Triple h” therapy for aneurysmal subarachnoid haemorrhage: real therapy or chasing numbers." Crit Care Resusc 7.3 (2005): 206-212.

Bederson, Joshua B., et al. "Guidelines for the management of aneurysmal subarachnoid hemorrhage a statement for healthcare professionals from a special Writing Group of the Stroke Council, American Heart Association."Stroke 40.3 (2009): 994-1025.

Muizelaar, J. Paul, and Donald P. Becker. "Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage. Direct effect on cerebral blood flow." Surgical neurology 25.4 (1986): 317-325.

Dhar, Rajat, et al. "Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage: Clinical article." Journal of neurosurgery 116.3 (2012): 648-656.

Pickard, J. D., et al. "Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial."BMJ: British Medical Journal 298.6674 (1989): 636.

Origitano, Thomas C., et al. "Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic hemodilution (" triple-H" therapy) after subarachnoid hemorrhage." Neurosurgery 27.5 (1990): 729-740.

Marshall, Scott A., Paul Nyquist, and Wendy C. Ziai. "The role of transcranial Doppler ultrasonography in the diagnosis and management of vasospasm after aneurysmal subarachnoid hemorrhage." Neurosurgery Clinics of North America21.2 (2010): 291-303.

Greenberg, E. D., et al. "Diagnostic accuracy of CT angiography and CT perfusion for cerebral vasospasm: a meta-analysis." American Journal of Neuroradiology 31.10 (2010): 1853-1860.

Sloan, M. A., et al. "Sensitivity and specificity of transcranial Doppler ultrasonography in the diagnosis of vasospasm following subarachnoid hemorrhage." Neurology 39.11 (1989): 1514-1514.

Rivierez, M., et al. "Value of electroencephalogram in prediction and diagnosis of vasospasm after intracranial aneurysm rupture." Acta neurochirurgica 110.1-2 (1991): 17-23.

Kawamoto, Shunsuke, et al. "Effectiveness of the head-shaking method combined with cisternal irrigation with urokinase in preventing cerebral vasospasm after subarachnoid hemorrhage." Journal of neurosurgery 100.2 (2004): 236-243.

Vergouwen, Mervyn DI, et al. "Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial." Journal of Cerebral Blood Flow & Metabolism 29.8 (2009): 1444-1453.

Macdonald, R. Loch, et al. "Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) Randomized, Double-Blind, Placebo-Controlled Phase 2 Dose-Finding Trial."Stroke 39.11 (2008): 3015-3021.

Bakker, Nicolaas A., et al. "International subarachnoid aneurysm trial 2009: endovascular coiling of ruptured intracranial aneurysms has no significant advantage over neurosurgical clipping." Neurosurgery 66.5 (2010): 961-962.

Fisher, C. M., J. P. Kistler, and J. M. Davis. "Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning." Neurosurgery 6.1 (1980): 1-9.

LITFL offer this reference as a follow-on to their chapter:

Dabus, Guilherme, and Raul G. Nogueira. "Current Options for the Management of Aneurysmal Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: A Comprehensive Review of the Literature." Interventional Neurology 2.1 (2013): 30-51.

Frontera, Jennifer A., et al. "Defining Vasospasm After Subarachnoid Hemorrhage What Is the Most Clinically Relevant Definition?." Stroke 40.6 (2009): 1963-1968.

Vergouwen, Mervyn DI, et al. "Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group."Stroke 41.10 (2010): 2391-2395.

Etminan, Nima, et al. "Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis." Journal of Cerebral Blood Flow & Metabolism 31.6 (2011): 1443-1451.

Brathwaite, Shakira, and R. Loch Macdonald. "Current Management of Delayed Cerebral Ischemia: Update from Results of Recent Clinical Trials." Translational stroke research 5.2 (2014): 207-226.

Mir, D. I. A., et al. "CT Perfusion for detection of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis." American Journal of Neuroradiology 35.5 (2014): 866-871.

Lasner, Todd M., et al. "Cigarette smoking-induced increase in the risk of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage." Journal of neurosurgery 87.3 (1997): 381-384.

Conway, James E., and Rafael J. Tamargo. "Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage."Stroke 32.10 (2001): 2338-2343.

Charpentier, Claire, et al. "Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage." Stroke30.7 (1999): 1402-1408.

Singhal, A. B., et al. "SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage." Neurology 64.6 (2005): 1008-1013.

Yin, L., et al. "Predictors analysis of symptomatic cerebral vasospasm after subarachnoid hemorrhage." Early Brain Injury or Cerebral Vasospasm. Springer Vienna, 2011. 175-178.

Hussein, Haitham M., et al. "Intracranial Vascular Calcification is Protective from Vasospasm after Aneurysmal Subarachnoid Hemorrhage." Journal of Stroke and Cerebrovascular Diseases (2014).

Inagawa, T., K. Yahara, and N. Ohbayashi. "Risk Factors Associated with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage."Neurologia medico-chirurgica (2014).

Inagawa, T., K. Yahara, and N. Ohbayashi. "Risk Factors Associated with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage."Neurologia medico-chirurgica (2014).

Kolias, Angelos G., Jon Sen, and Antonio Belli. "Pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage: putative mechanisms and novel approaches." Journal of neuroscience research 87.1 (2009): 1-11.

Haley Jr, E. Clarke, Neal F. Kassell, and James C. Torner. "A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage: a report of the Cooperative Aneurysm Study." Journal of neurosurgery 78.4 (1993): 537-547.

Rosenquist, Ashley, et al. "921: Safety of intrathecal nicardipine for vasospasm due to aneurysmal subarachnoid hemorrhage." Critical Care Medicine 41.12 (2013): A231.

Huang, Ren-qiang, et al. "Nicardipine in the treatment of aneurysmal subarachnoid haemorrhage: a meta-analysis of published data.Acta Neurologica Belgica 113.1 (2013): 3-6.

Kasuya, H. "Clinical trial of nicardipine prolonged-release implants for preventing cerebral vasospasm: multicenter cooperative study in Tokyo." Early Brain Injury or Cerebral Vasospasm. Springer Vienna, 2011. 165-167.

Pandey, Paritosh, et al. "A Simplified Method for Administration of Intra-Arterial Nicardipine for Vasospasm With Cervical Catheter Infusion." Neurosurgery 71 (2012): ons77-ons85.

Tagami, Takashi, et al. "Effect of Triple-H Prophylaxis on Global End-Diastolic Volume and Clinical Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage." Neurocritical care (2014): 1-8.

Dankbaar, Jan W., et al. "Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review." Crit Care 14.1 (2010): R23.

Lennihan, Laura, et al. "Effect of Hypervolemic Therapy on Cerebral Blood Flow After Subarachnoid Hemorrhage A Randomized Controlled Trial." Stroke 31.2 (2000): 383-391.

Diringer, Michael N., et al. "Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference." Neurocritical care 15.2 (2011): 211-240.

Velly, Lionel J., et al. "Anaesthetic and ICU management of aneurysmal subarachnoid haemorrhage: A survey of European practice." European journal of anaesthesiology (2014).

Kimball, Matthew M., Gregory J. Velat, and Brian L. Hoh. "Critical care guidelines on the endovascular management of cerebral vasospasm." Neurocritical care 15.2 (2011): 336-341.

Kirkpatrick, Peter J., et al. "Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial." The Lancet Neurology (2014), Volume 13, Issue 7, Pages 666 - 675

Mees, Sanne M. Dorhout, et al. "Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial." The Lancet 380.9836 (2012): 44-49.

Nishiguchi, Mitsuhisa, et al. "Effect of vasodilation by milrinone, a phosphodiesterase III inhibitor, on vasospastic arteries after a subarachnoid hemorrhage in vitro and in vivo: effectiveness of cisternal injection of milrinone." Neurosurgery 66.1 (2010): 158-164.

Anand, Saurabh, Gaurav Goel, and Vipul Gupta. "Continuous intra-arterial dilatation with nimodipine and milrinone for refractory cerebral vasospasm." Journal of neurosurgical anesthesiology 26.1 (2014): 92-93.

Wartenberg, Katja Eliriede, and Stephan A. Mayer. "Intracerebral hemorrhage."The Stroke Book (2013): 204.

Wartenberg, Katja E., et al. "Impact of medical complications on outcome after subarachnoid hemorrhage*." Critical care medicine 34.3 (2006): 617-623.