Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is an acute neurovascular emergency is a type of spontaneous SAH that results from rupture of an intracranial aneurysm. The early and late complications include rebleeding, neurogenic stunned myocardium, neurogenic pulmonary myocardium, vasospasm, electrolyte disturbances, seizures, and hydrocephalus. Delayed cerebral ischemia is associated with significant morbidity and mortality, and several pharmacological and nonpharmacological interventions have been tried to relieve it. Nimodipine is the only drug that has shown to improve outcome in patients with SAH. The survivors of aneurysmal SAH (aSAH) are often left with physical or functional disabilities affecting their quality of life. This makes aSAH one of the major areas of continuous research pertaining to its every aspect.
Keywords
Aneurysmal subarachnoid hemorrhage, Cerebral angiography, Endovascular coiling, Rebleeding, Triple-H therapy, Vasospasm
Outline
History 316
Introduction 316
Clinical Presentation and Diagnosis 317
Lumbar Puncture 318
Grading of Subarachnoid Hemorrhage 319
Initial Management Concerns in Neurocritical Care Unit 321
Rebleeding 321
Hydrocephalus 322
Vasospasm 322
Seizures 326
Neurogenic Stunned Myocardium 326
Neurogenic Pulmonary Edema 326
Electrolyte Disorders 326
Timing of Surgery 327
Clipping or Coiling 327
Evaluation of a Patient With Subarachnoid Hemorrhage for Anesthesia 328
Anesthetic Management 328
Temporary Clipping and Brain Protection Strategy 330
Intraoperative Aneurysm Rupture 330
Giant Aneurysms and Circulatory Arrest 331
Endovascular Management for Aneurysm Ablation 331
Postoperative Management of Patients 333
Conclusion 333
References 333
History
History of subarachnoid hemorrhage (SAH) dates back to Byrom Bramwell, who first described the symptoms of spontaneous meningeal hemorrhage. The term “spontaneous subarachnoid hemorrhage” was coined in 1924 by Charles P. Symonds. Successful clipping of internal carotid artery (ICA) aneurysm in a planned manner was first done by Walter Dandy. In the 1980’s, introduction of triple H therapy as a treatment for vasospasm and the British aneurysm nimodipine trial supporting the use of nimodipine revolutionized the management, never to look back again. In 1983, transluminal balloon angioplasty was introduced for treating vasospasm. Guido Guglielmi added endovascular coiling in 1991 as another armamentarium in the management of aneurysms.
Despite all the advancement, survivors are often left with physical or functional disabilities affecting their quality of life. This makes it one of the major areas of incessant scientific research with an ultimate aim to improve the outcome. Current era involves improvised diagnostic modalities, microneurosurgical techniques, advanced neuroradiological procedures, and management based on evidence-driven protocols.
Introduction
Aneurysmal SAH, an acute neurovascular emergency, is a type of spontaneous SAH that results from rupture of an intracranial aneurysm. The intracranial vessels have less muscle and elastic tissue in the tunica media and a thinner adventitia, predisposing them to development of an aneurysm. These are usually present at branching points in a vessel, where hemodynamic stress is the highest. Majority are located in anterior circulation (85–95%); the anterior communicating artery (ACom): 30%, the posterior communicating artery (PCom): 25%, and the middle cerebral artery (MCA): 20% being commonly involved ( Fig. 18.1 ). Posterior circulation accounts for 5–15% of aneurysms, involving basilar artery (10%) and vertebral artery (5%). Aneurysm may be graded according to its size as small (less than 15 mm), large (15–25 mm), and giant (>25 mm). The risk of rupture is high for aneurysms >7 mm in size.
Prevalence and Incidence
Prevalence of cerebral aneurysm is around 5%, and the ratio of ruptured: unruptured aneurysm is about 5:3 to 5:6. SAH comprises 6–8% of all strokes and accounts for 80% of all nontraumatic cases. The worldwide incidence of SAH is approximately 2–16 per 100,000 with wide variation among different regions of the world. Japan and Finland top the list, while low incidence has been reported for South and Central America. The actual incidence is may even be higher if 10–15% of patients who die before reaching hospital are also included. The average age of onset is ≥50 years, and the incidence increases with age. Women are affected 1.24 times more than men.
Risk Factors
The risk factors for development of SAH are:
- •
Increa Increasing age sing age
- •
Hypertension
- •
Positive family history
- •
Substance abuse (cigarette smoking, alcohol, cocaine)
- •
Oral contraceptives
- •
Associated conditions (autosomal polycystic kidney disease, type IV Ehlers-Danlos syndrome, connective tissue disorders, coarctation of aorta, familial intracranial aneurysm syndrome, arteriovenous malformation)
Aneurysms >7 mm in size are more prone to rupture, but in hypertensive smokers, even smaller aneurysms may rupture resulting in SAH. The American Heart Association (AHA)/American Stroke Association (ASA) recommends that hypertension should be treated and such treatment may reduce the risk of aneurysmal SAH (aSAH) (Class I; Level of Evidence B).
Natural History, Course, and Prognosis
Half of the patients with ruptured aneurysms if not treated may rebleed within 6 months and thereafter at the rate of 3% per year. The incidence of rebleeding is as high as 9–17% within 24 h with the first 6 h being most crucial. The mortality rates differ by region and vary from 32% in the United States, 43% in Europe, and 27% in Japan. This does not take into account those 12–15% of patients who die before receiving medical attention. Improvement in mortality seen has been largely due to improved survival among hospitalized patients. Old patients have a poor survival rate.
The modified Rankin scale when used to assess outcome shows 8–20% of patients to be persistently dependent. Patients having SAH and subsequent surgery are often left with profound changes in their cognition. Even patients with good neurological outcome continue to suffer a high degree of neurobehavioural deficits and are unable to resume their day-to-day activities. This neurocognitive dysfunction has been attributed to multiple factors like exposure of the brain to subarachnoid blood, associated hydrocephalus (HCP), global cerebral edema, vasospasm, or temporary clip application during the surgery.
Several initial factors associated with poor prognosis of the patient are higher Hunt-Hess grade, older age, presence of comorbid conditions, thick blood clots in brain, and rebleeding. In centers with high output of patients who have been treated for SAH, outcome may be better than that of other low-yield hospitals.
Clinical Presentation and Diagnosis
Sudden onset of severe headache, usually described as “worst headache of my life,” is experienced by about 80% of patients with SAH. In 10–43% of cases, sentinel headache or warning headache may precede the aneurysmal rupture. These are often minor hemorrhages for which the patient may not even seek medical attention. However, if diagnosed early, unruptured aneurysm can be timely managed before it ruptures.
Headache may be associated with nausea/vomiting, transient loss of consciousness, neck stiffness, photophobia, or focal neurologic deficits. Coma following SAH may be explained by increased intracranial pressure (ICP) and diffuse ischemia, seizures, HCP, or direct damage to brain tissue by hematoma.
Within 6–24 h, nuchal rigidity ensues, which can be elicited on examination. Patient is asked to flex the thigh to 90 degrees with his knee bent. If knee straightening causes pain (positive Kernig’s sign), then the patient has signs of meningismus. Positive Brudzinski sign manifested by involuntary hip flexion on flexing the patient’s neck also indicates meningismus. Focal neurologic deficit in the form of oculomotor palsy or hemiparesis may be present. In 20–40% of patients with SAH, ocular hemorrhage may also be found.
Diagnosis is generally carried out in two steps: first diagnosing SAH and then searching for its source.
Noncontrast computed tomography (NCCT) of the head can detect ≥95% of SAH cases, if performed within 48 h. It also tells about hematoma, HCP, infarct, and amount of blood in cisterns and fissures ( Fig. 18.2 ). Site of maximum blood density gives a clue about the location of the ruptured aneurysm. Blood concentrated in the anterior interhemispheric fissure suggests ACom aneurysm; in sylvian fissure, PCom or MCA aneurysm; and in prepontine cistern, probably rupture of basilar top or superior cerebellar artery (SCA) aneurysm.
Lumbar Puncture
If NCCT is negative, lumbar puncture (LP) can be done for diagnosing SAH. CT scan should be performed before LP to exclude significant intracranial midline shift, elevated ICP, obstructive HCP, or any obvious intracranial bleed. Any sudden decrease in ICP may cause an increase in transmural pressure (TMP) and may precipitate rebleeding. Care should be taken to use a small-gauge spinal needle and to remove minimal amount of cerebrospinal fluid (CSF). It is important to differentiate SAH from traumatic tap. Blood clears in subsequent samples if it is due to traumatic puncture but not in case of SAH. Xanthochromia is often negative within 2 h of the ictus and is seen in almost 100% cases by 12 h after the bleed. At 4 weeks it can still be detected in 40% of the patients making it a highly sensitive test. It is better appreciated by spectrophotometry. Red blood cell (RBC) count is usually >100,000 RBC/mm 3 , protein is increased, and glucose may be normal to decreased in CSF samples.
Magnetic resonance imaging (MRI) is not helpful for acute SAH but is useful after 4–7 days. However, fluid-attenuated inversion recovery, proton density, diffusion-weighted imaging (DWI), and gradient echo sequences can be used for diagnosis thus avoiding LP in CT-negative cases.
After having established the diagnosis of SAH, the next step is to determine whether a ruptured aneurysm is the cause of it. The three methods of choice for detecting and delineating the anatomy of intracranial aneurysms are (1) catheter angiography by direct intra-arterial catheterization, (2) CT angiography after injection of contrast media, and (3) magnetic resonance angiography.
Digital subtraction angiography (DSA) provides information regarding cerebrovascular anatomy, aneurysm location and source of bleeding, aneurysm size/shape/orientation of dome and neck, relation to the parent/perforating arteries, and vasospasm ( Fig. 18.3 ). If cerebral angiography findings are negative, a repeat test should be performed 3–4 weeks later.
CT angiography (CTA) is able to detect aneurysms larger than 3 mm with a sensitivity and specificity comparable to that of DSA. CTA better defines aneurysmal wall calcification, intraluminal aneurysm thrombosis, and its relationship with bony landmarks ( Figs. 18.4 and 18.5 ). Advanced techniques like multisection CTA combined with matched mask bone elimination and dual-energy CTA can even detect smaller aneurysms.
Magnetic resonance angiography (MRA) can detect aneurysms 5 mm or larger with a high sensitivity of 85–100%. Its advantage is that it does not require iodinated contrast agent or ionizing radiation ( Fig. 18.6 ).
According to the 2012 guidelines, MRA and CTA may be considered when conventional angiography cannot be performed in a timely fashion. (Class II b, Level of Evidence B).
Grading of Subarachnoid Hemorrhage
Several scales for grading SAH are commonly used for assessing the risk of surgery, prognostication, and for communicating the condition of the patient among health care providers. Common ones are the Hunt and Hess grade, World Federation of Neurological Surgeons (WFNS) grade, and Fisher grade.
The Hunt and Hess classification includes 5 grades (1–5). Grade 1: asymptomatic or mild headache and slight nuchal rigidity; grade 2: moderate to severe headache, cranial nerve palsy (e.g., III, VI), nuchal rigidity, grade 3: mild focal deficit, lethargy, or confusion; grade 4: stupor, moderate to severe hemiparesis, early decerebrate rigidity; grade 5: deep coma, decerebrate rigidity, moribund appearance. If a patient suffers from hypertension, diabetes mellitus, severe atherosclerosis, or chronic obstructive pulmonary disease or has severe vasospasm on arteriography, one grade is added to the total score. The Hunt and Hess classification was modified to include grade 0: unruptured aneurysm and grade 1a: no acute meningeal/brain reaction, but with fixed neurodeficit. As the grade increases, the morbidity and mortality also increase. The World Federation of Neurological Surgeons (WFNS) score ranges from 1 to 5 and includes two parameters for assessment- Glasgow coma score (GCS) and major focal deficit. Grade 1: SAH patient with GCS 15 and no major focal deficit; grade 2: GCS 13–15 with no major focal deficit; grade 3: GCS 13–15 with major focal deficit; grade 4: GCS 7–12 with or without major focal deficit; Ggrade 5: GCS 3–6 with or without major focal deficit. A modified WFNS scale has also been proposed which requires further validation. Another commonly used scale is the Fisher scale, which is based on presence of blood in CT scan and was mainly proposed to predict cerebral vasospasm. Grade 1: no blood seen; grade 2: diffuse thin layer (<1 mm) of subarachnoid blood, grade 3: localized clot or thick (> 1 mm) subarachnoid blood; and grade 4: Intracerebral or intraventricular blood with diffuse or no subarachnoid blood. Based on this scale, the incidence of vasospasm was highest in grade 3 (37%) and lower in grade 4 (31%). Fisher scale has been further modified to take into account intraventricular and intracerebral or cisternal blood and has been found to be a better predictor of vasospasm. The modified Fisher scale is as follows: grade 0: no subarachnoid haemorrhage (SAH) or intraventricular haemorrhage (IVH), grade 1: focal or diffuse thin SAH (<1 mm), no IVH; grade 2 : thin focal or diffuse SAH (<1 mm), IVH present; grade 3: thick focal or diffuse SAH (>1 mm), no IVH; grade 4: thick focal or diffuse SAH (>1 mm), IVH present. The higher the grade, more is the risk of development of vasospasm. Ogilvy et al proposed a more comprehensive 5-point grading scale to predict surgical outcome, which includes Hunt and Hess grade IV or V, Fisher Scale score 3 or 4, aneurysm size > 10 mm, patient age > 50 years, and if the lesion is a giant (> or =25 mm) posterior circulation lesion. The “VASOGRADE” is a new validated scale used for delayed cerebral ischemia risk stratification after SAH. Patients are stratified into VASOGRADE-Green, VASOGRADE-Yellow, or VASOGRADE-Red on the basis of Fisher and WFNS scales. The yellow and red groups are at higher risk of development of DCI. The American Heart Association/American Stroke Association recommend that the initial severity of SAH should be determined rapidly by use of the Hunt and Hess or World Federation of Neurological Surgeons, because it is the most useful indicator of outcome after aSAH (Class I; Level of Evidence B).
Initial Management Concerns in Neurocritical Care Unit
The major complications of SAH include.
- •
Rebleeding
- •
Cerebral vasospasm leading to immediate cerebral ischemia and DCI
- •
HCP
- •
Seizures
- •
Cardiopulmonary dysfunction
- •
Electrolyte disturbances
Nonneurological complications of SAH (e.g., anemia, hypertension, hypotension, hyperglycemia, electrolyte disorders, cardiac insufficiency, and arrhythmias) develop in more than half of the patients and adversely affect outcome.
Rebleeding
Maximal frequency is on the first day (9–17%) with first 6 h being most crucial. Subsequently it reduces to 1–2% daily for the next 13 days. About 15–20% of patients with SAH rebleed within 14 days, 50% within 6 months, and then 3% per year. The overall incidence of rebleeding is 11%. Mortality from rebleeding is as high as 80%.
Risk increases with higher Hunt and Hess grade, larger size of the aneurysm, longer time to definitive treatment, previous sentinel headaches, ventriculostomy/lumbar spinal drainage, and systolic blood pressure >160 mmHg. Best method for preventing rebleeding is early clipping or coiling. Medical measures to prevent rebleeding include:
- •
Bed rest with head of bed elevated 30°, low external stimulation
- •
Control hypertension and maintain the patient’s normal blood pressure as the lower acceptable limit.
- •
Adequate sedation and analgesia for patient on ventilator
- •
Avoid rapid drainage of CSF (this will increase TMP)
- •
Maintain euvolemia
- •
Avoid seizures
- •
Avoid intramuscular medications/enema/nonsteroidal anti-inflammatory drugs
A Cochrane review on the use of antifibrinolytics for prevention of rebleeding showed significant decrease in rebleeding but increased cerebral ischemia as a result of which no improvement in outcome was observed.
The American Heart Association/American Stroke Association recommend that for patients with delay in obliteration of aneurysm carrying a significant risk of rebleeding, and no compelling medical contraindications, short-term (<72 h) therapy with tranexamic acid or aminocaproic acid is reasonable to reduce the risk of early aneurysm rebleeding (Class IIa; Level of Evidence B).
Blood pressure has to be adjusted in a way to prevent rebleeding, and at the same time cerebral perfusion pressure (CPP) should not be compromised. For this, AHA/ASA guidelines suggest to keep systolic blood pressure<160 mmHg.
Hydrocephalus
About 20–30% of patients develop acute HCP, and about 50% of these become chronic and require permanent CSF shunting. Blood interferes with CSF flow through the ventricular outflow tract and its reabsorption at arachnoid granulations. If external ventricular drainage is used in the acute state, caution should be taken not to lower ICP rapidly lest aneurysm may rupture. Similarly, lumbar drainage has also been found to be beneficial in vasospasm in few retrospective studies. Silting of arachnoid granulations and pia-arachnoid adhesions leads to development of chronic HCP and may require shunt placement. Presence of blood in ventricles is a high risk factor for its development.
Vasospasm
One of the most dreaded complications of SAH is vasospasm ,which peaks between 3 and 21 days and affects almost 70% of patients. The adventitia of intracranial arteries is thin as a result of which blood and its breakdown products enter the wall and reach tunica media causing vasoconstriction.
Clinical vasospasm also known as delayed ischemic neurological deficit (DIND) is clinically characterized by confusion/decreased level of consciousness with focal neurological deficit (speech/motor). It is seen in about 20–40% of the cases.
Radiographic vasospasm (angiographic vasospasm) is arterial narrowing demonstrated on cerebral angiography, often with slow filling of contrast, found in 30–70% of patients when done around the seventh day following SAH. Vasospasm appears as concentric narrowing, which can be focal/segmental/diffuse. It can be graded as mild (<25%), moderate (25–50%), or severe (>50%).
Symptomatic vasospasm : When DIND corresponds to a region of vasospasm seen on angiogram (20–30% of patients with SAH), vasospasm is said to be symptomatic.
Pathophysiology
Alteration in contractions and relaxations of arterial smooth muscle cells secondary to imbalance of various factors is responsible for development of vasospasm. Oxyhemoglobin, a breakdown product of blood, causes release of endothelin I (vasoconstrictor) and decreases NO (vasodilator) secretion. Free radicals produce lipid peroxidation of membrane resulting in structural damage of vessel wall. Increase in interleukin (IL)-1B and IL-6 levels is also implicated in causing vasoconstriction. Thus, the interplay of various agents like oxyhemoglobin, superoxide anion, free radicals, platelet aggregating factor, endothelin I, and lipid peroxides gives rise to vasospasm. The failure in improving outcome of various pharmacological agents and interventions aimed at relieving vasospasm has led to research focusing on other factors that cause DCI. Lately, early brain injury, cortical spreading depression, and microthrombosis have been found to be involved in the pathogenesis of vasospasm. Cortical spreading depression are the depolarization waves in the gray matter that depresses the electroencephalographic (EEG) activity. These waves result in vasoconstriction, impairment of ion homeostasis, and recurrent tissue ischemia. So the new thought of therapeutic interventions targeting this early brain injury to prevent molecular damage and subsequent delayed ischemia has come up.
Diagnosis
Clinical
There may be alteration in consciousness, disorientation, and occurrence of new focal neurological deficit corresponding to the artery involved, usually around 3–14 days after SAH. We should rule out other causes of neurological deterioration like HCP, rebleeding, electrolyte disorders, seizures, and hypoxia before making diagnosis of vasospasm.
Digital Subtraction Angiography
It demonstrates arterial narrowing with slowing of contrast filling. The diameter of two daughter vessels is less than that of the parent artery in the presence of vasospasm. When compared to previous or later scans, this difference can be better appreciated. Advantage of DSA over other diagnostic modalities is that treatment can be directly instituted in the form of intra-arterial vasodilators or balloon angioplasty. However, it is invasive, runs the risk of vessel injury, is expensive, and repeated frequent studies are not possible.
CTA is a minimally invasive and less expensive alternative for angiography. CT perfusion study if done along with CTA increases its sensitivity. MRA is a noninvasive technique that requires neither contrast nor radiation exposure. Time of flight–MRA sequence is specific for diagnosis of vasospasm. Cost and long study period requiring patient cooperation are some of its limiting factors.
Transcranial Doppler
Vasospasm causes an increase in blood flow velocity, which can be measured by transcranial doppler (TCD). Normal MCA blood flow velocity is <120 cm/s, velocity ranging from 120 to 200 cm/s indicates mild vasospasm, and velocity >200 cm/s is taken as severe vasospasm. Also, an increase by 50 cm/s in 24 h indicates presence of vasospasm. However, it is important to differentiate between vasospasm and hyperemia (generalized raised flow velocity). These two can be differentiated by Lindegaard index, which is a ratio of flow velocities in ipsilateral MCA to extracranial ICA. Lindegaard ratio <3 denotes hyperdynamic circulation, 3–6 indicates mild-moderate vasospasm and >6 denotes severe vasospasm. Low pulsatility index is an independent predictor of symptomatic large vessel vasospasm.
Cerebral Blood Flow Study
In the presence of vasospasm, cerebral blood flow (CBF), cerebral metabolic rate and cerebral blood volume decreases, which can thus be diagnosed by various CBF studies. Single-photon emission CT, positron emission tomography, and xenon-enhanced CT provide quantitative measurement of CBF. These techniques are expensive, require patient transfer, and provide only a snapshot view.
CT perfusion, DWI, and perfusion-weighted studies of MRI can also detect early ischemia.
Electroencephalography
Amplitude of EEG decreases in the presence of vasospasm. Also, a decrease in alpha activity has been associated with onset of vasospasm.
Cerebral Microdialysis
Ischemia results in decreased glucose concentration and increased concentration of metabolites like lactate, glycerol, glutamate, and lactate–pyruvate ratio which can be measured and assessed for vasospasm. These changes often precede clinical onset of symptoms of DIND. Microdialysis has been found to be more specific for DIND when compared with TCD ultrasonography, and angiography.
Management of Vasospasm
Triple H Therapy
The triple “H” (hypertension, hypervolemia, hemodilution) therapy aims to increase CBF and cerebral perfusion and improve rheology of blood in patients with vasospasm following SAH. Once the aneurysm is clipped, it can be intensively instituted. For this purpose, systolic arterial pressure is increased [by administration of intravenous (IV) fluid or drugs], 160–200 mmHg in clipped aneurysms; central venous pressure is maintained at 8–12 mmHg (or pulmonary artery wedge pressure at 15–18 mmHg); and hematocrit is decreased to approximately 0.3–0.35. The various complications of triple H therapy are pulmonary edema, myocardial ischemia, congestive cardiac failure, electrolyte imbalance, dilutional coagulopathy, and rupture of unsecured aneurysm. However, prophylactic therapy is associated with increased cost and complications and does not improve early or late outcome.
Recent evidence casts a doubt on the usefulness of its different components. In a systematic review conducted by Dankbaar et al., authors found no beneficial effect of triple H therapy on increasing CBF. However, among the three H, hypertension has been found to be most effective. The recent guidelines recommend maintenance of euvolemia and normal circulating blood volume for prevention of DCI. In patients who develop DCI, hypertension should be induced provided cardiac status permits it (Class I, Level of evidence B). A randomized controlled study (RCT) was carried out to assess the effect of induced hypertension on CBF in patients with delayed cerebral ischemia after aneurysmal SAH. The induced hypertension failed to augment overall CBF as measured by CT perfusion, however in areas with lowest perfusion, a small effect of improved CBF was seen. Based on the results, further large RCT needs to be carried out.
Various drugs utilized for induction of hypertension are dopamine, phenylephrine, dobutamine, and noradrenaline. Although none has been strongly proved to be superior over the others, norepinephrine and phenylephrine are commonly used.
Calcium Channel Blockers
Calcium channel blockers (CCB) stop calcium influx through L-type voltage-gated calcium channels, and this forms the basis of multiple trials studying the role of various CCBs in vasospasm. Dihydropyridines, a group of CCBs, mainly affect arterial vascular smooth muscle, and among these nimodipine specifically is lipid soluble and thus is able to cross the blood–brain barrier.
British aneurysm nimodipine trial studied 554 patients with SAH (all grades), all of whom were started on oral nimodipine within 96 h of hemorrhage. Incidence of cerebral infarction in treatment group was 22% vs. 33% in placebo group. Although angiographic improvement may not be seen with nimodipine, it improves neurological outcome by improving microcirculation and has other neuroprotective effects. It also causes reduced platelet aggregation and increased fibrinolytic activity. Based on Class I evidence, nimodipine 60 mg should be administered four times a day to all patients with aSAH for a period of 21 days from the day of haemorrhage. IV nimodipine is equal in efficacy to oral nimodipine, but because of more side effects and cost factor, IV administration may be limited to patients with deranged enteral absorption or metabolism. CCB therapy may cause hypotension, which may be deleterious and must be treated. In an experimental study, selective intra-arterial and intrathecal route were found superior in relieving vasospasm in rabbits than IV or oral routes. Similarly angiographic improvement was observed in 82.2% of patients and immediate clinical improvement in 68.3% of the patients with no adverse drug effect in patients with SAH in whom nimodipine was administered intrarterially. Another CCB, nicardipine when given IV showed improvement in angiographic vasospasm but failed to show improvement in clinical outcome. Nicardipine pellets have also been implanted in cerebral cisterns during clipping, and it was seen that it prevents vasospasm and improves the clinical outcome. Intra-arterial nicardipine titrated to relief of vasospasm was associated with significant intraoperative blood pressure decrease requiring intraoperative vasopressor therapy, and a tendency toward re-treatment when used as initial monotherapy for vasospasm. Fasudil is a rho-kinase inhibitor and also blocks calcium channels. Liu et al. conducted a meta-analysis studying the efficacy of fasudil in the management of vasospasm. They found that fasudil decreased the incidence of angiographic vasospasm, clinical vasospasm, and cerebral infarction and improved overall outcome. Thus it is recommended that oral nimodipine should be administered to all patients with aSAH (Class I; Level of Evidence A). Role of other CCBs is uncertain.
Statins
Statins are 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors increase nitric oxide synthase levels, which in turn causes smooth muscle relaxation and vasodilation. It also decreases oxidative stress, reduces inflammation, and inhibits thrombogenesis. Patients already on statin prior to SAH, should continue with the treatment. Earlier studies involving pravastatin and simvastatin showed promising results regarding decrease in vasospasm and DCI. However, still usefulness of starting statins after SAH was unclear as different meta-analyses had given conflicting conclusion and suggested conduction of more randomized controlled trials. STASH is a double-blinded phase III randomized trial evaluating the effects of 40 mg simvastatin in patients with acute aSAH. The authors did not detect any benefit in long-term or short-term outcome.
Endothelin-1 Receptor Antagonists
Endothelin receptor antagonists competitively block endothelin-1 receptors A and B and thus may decrease the vasospasm. In a phase II trial, TAK-044 (endothelin A/B receptor antagonist) when administered to patients with vasospasm, showed a trend toward decreased ischemic defects but there was no change in the 3-month Glasgow outcome scale. Clazosentan is an endothelin A receptor antagonist. In a dose finding trial (CONSCIOUS-1 trial), clazosentan reduced the incidence of angiographic vasospasm in a dose-dependent manner but was associated with increased rates of pulmonary complications, hypotension, and anemia. In a subsequent trial (CONSCIOUS-2), clazosentan failed to improve outcome in patients treated with surgical clipping for ruptured aneurysm. Furthermore, CONSCIOUS-3 trial was undertaken to assess whether clazosentan reduced vasospasm-related morbidity and all-cause mortality in patients with aSAH treated by endovascular coiling. It was stopped prematurely following completion of CONSCIOUS-2, and although there was reduction in vasospasm-related morbidity/all-cause mortality, no improvement was seen in clinical outcome. A recent meta-analysis does not favor use of endothelin receptor antagonists in patients with aSAH. It increases the risk of lung complications, pulmonary edema, hypotension, and anemia.
Magnesium Sulfate
It is a calcium antagonist, blocks calcium channels, and causes vasodilation. It is an N -methyl d -aspartate receptor antagonist, decreases glutamate release, and has neuroprotective effects. Hypomagnesemia is present in almost 38% of patients with SAH and is associated with poor WFNS grade at admission. Initial MASH study suggested a decrease in DCI and poor outcome when magnesium was started within 4 days after SAH and continued until 14 days after occlusion of the aneurysm.
Subsequently MASH II trial, a phase III randomized multicenter study enrolled 1204 patients with aSAH, who received either magnesium or placebo within 4 days of SAH. The primary outcome variable assessed was poor outcome at 3 months after hemorrhage. Authors found no beneficial effect of IV magnesium on outcome and thus do not recommend its routine administration.
Angioplasty
Usually used for vasospasm refractory to medical management. It can be balloon angioplasty or pharmacological angioplasty.
Balloon angioplasty is performed in patients with proximal vessel vasospasm. Although it is quite safe in the hands of experienced intervention neuroradiologists, various complications described are thrombosis at an angioplasty site, vessel rupture, hemorrhagic infarction due to reperfusion of an infarcted area, and rebleeding from an unprotected aneurysm following vessel dilatation.
Pharmacological angioplasty: Intra-arterial vasodilators are used when:
- 1.
narrowed segment does not allow passage of the balloon catheter;
- 2.
technically difficult to reach artery;
- 3.
distal or perforating vessels are affected, which cannot be treated by this modality; and
- 4.
there are risks of angioplasty.
Various agents used for this purpose are CCBs (already discussed), papaverine, and milrinone.
Milrinone
Milrinone is a phosphodiesterase III inhibitor with ionotropic and vasodilator effects. Fraticelli et al. studied 22 patients with angiographically proven vasospasm. Intra-arterial milrinone was infused (8 mg over 30 min) in the main artery, with a maximum total dose of 24 mg. Along with it, IV milrinone was continued up to day 14 after SAH. They found effective reversal of vasospasm without causing hypotension. Other than intra-arterial and IV route, it also has been used for cisternal irrigation.
Papaverine
It causes vasodilation by inhibiting cyclic AMP (cAMP) and cyclic GMP (cGMP) phosphodiesterases in smooth muscles causing increased intracellular levels of cAMP and cGMP. It is administered into the affected vascular territory, in concentration of 0.3% at a rate of 3 mL/min (maximum 300 mg per vascular territory). Intra-arterial papaverine is effective in increasing angiographical diameter, decreasing prolonged circulation time, and improving CBF and oxygenation. Another alternative route is cisternal injection intraoperatively, after the aneurysm is clipped. The various side effects reported are hypotension, increased ICP, transient neurological deficits (mydriasis, brainstem depression), seizures, thrombocytopenia, and paradoxical exacerbation of vasospasm. The vasodilatory effect is short lived and requires repeated administration.
Balloon Angioplasty
It is performed to dilate proximal segments of large intracranial vessels. It directly treats stenotic cerebral vessels by widening the narrowed segment and causes functional impairment of smooth muscle in the vessel wall. Various complications include vessel occlusion, dissection, and rupture, dislodging of aneurysm clips, and thrombus formation. It can be combined with intra-arterial vasodilator therapy for treating both proximal and distal vasospasm.
Cerebral angioplasty and/or selective intra-arterial vasodilator therapy is reasonable in patients with symptomatic cerebral vasospasm, particularly those who are not rapidly responding to hypertensive therapy (Class IIa; Level of Evidence B).
Seizures
Seizure-like activity early in course of SAH may be experienced in around 26% of patients and about 3–7% may have delayed onset. Seizures may provoke rebleeding from an unsecured aneurysm. Risk factors are MCA aneurysm, thick blood clot, intracerebral hematoma, rebleeding, infarction, poor neurological grade, and hypertension. The prophylactic anticonvulsant therapy may be associated with adverse drug effects, worse cognitive outcome, and even vasospasm. However, routine long-term therapy is not recommended in these patients, a short course during early days after ictus is justified.
Neurogenic Stunned Myocardium
After SAH, ischemia of hypothalamus causes intense sympathetic surge and catecholamine release, which may lead to myocardial injury and even sudden death. The term “neurogenic stunned myocardium” is characterized by chest pain, dyspnea, hypoxemia, left ventricular systolic dysfunction, cardiogenic shock with pulmonary edema, and elevated cardiac markers occurring after SAH. Electrocardiographic (ECG) changes may be present ranging from t wave inversion, Q-T prolongation, S-T segment changes, ectopics, to arrhythmias, seen in more than 50% of the patients. ECG manifestations in patients with SAH and Takotsubo cardiomyopathy are similar and on echocardiogram apical sparing can be appreciated in SAH.
Cardiac troponin I (cTI) levels have been found to be increased (≥0.3 ng/mL) in about 31% of the patients. Cardiac injury is more in patients with increased SAH severity. With peak cTI levels >0.5 μg/L, the risk of DCI exceeds 50%; with levels >2.0 μg/L, the risk of pulmonary edema exceeds 30%; and with levels >10.0 μg/L, the risk of developing hypotension is more than 40%. cTI elevation after SAH is associated with an increased risk of cardiopulmonary complications, DCI, and death or poor functional outcome at discharge. Peak levels are seen between 1 and 5 days post SAH. At the same level of myocardial impairment on echocardiogram, cardiac troponin levels will be much lower in SAH than in patients with myocardial infarction.
Cardiac output may be measured intraoperatively in patients with hemodynamic instability or regional wall motion abnormalities. Aneurysm clipping attains priority over other cardiac interventions, and management of cardiovascular abnormalities is usually supportive.
Neurogenic Pulmonary Edema
Wide-ranged incidence of about 2–42.9% has been reported for neurogenic pulmonary edema (NPE) with an estimated mortality of about 10%. More than 20% of patients have symptomatic pulmonary involvement after SAH. Abrupt increase in ICP causes sympathetic stimulation and release of catecholamines, which in turn leads to increase in systemic and pulmonary pressures resulting in development of transudative pulmonary edema, which is noncardiogenic in origin. NPE may manifest as early as within minutes to hours following a cerebral event or may present 12–24 h following it. Following SAH, patient may develop acute dyspnea, tachypnea, and hypoxia with pink, frothy sputum. On auscultation, bilateral crackles and rales can be heard. Chest X-ray will show bilateral infiltrates. Davison et al. proposed the following diagnostic criteria for NPE: (1) bilateral infiltrates, (2) PaO 2 /FiO 2 ratio <200, (3) no evidence of left atrial hypertension, (4) presence of central nervous system injury (severe enough to have caused significantly increased ICP), and (5) absence of other common causes of acute respiratory distress syndrome or ARDS (e.g., aspiration, massive blood transfusion, sepsis). Symptoms often resolve spontaneously within 24–48 h if raised ICP is taken care of. Patients should not be allowed to become hypoxic, lest secondary brain damage may occur.
Electrolyte Disorders
Sodium and magnesium imbalance occurs commonly in patients with SAH, but any electrolyte disorder can actually exist. The incidence of hyponatremia and hypernatremia ranges from 10% to 30% and 19–22%, respectively. Hyponatremia often occurs following SAH as a result of vomiting, diuresis, and loss of oral intake. Cerebral salt wasting syndrome is most common cause of hyponatremia following SAH, seen in poor-grade patients, ruptured ACom artery aneurysms, and HCP. Excessive secretion of ANP and BNP after SAH causes loss of sodium and water from the body. Syndrome of inappropriate antidiuretic hormone is another cause of hyponatremia seen in these patients. Both hypernatremia and hyponatremia are associated with poor outcome. Class IIa evidence favors use of fludrocortisone acetate and hypertonic saline for preventing and correcting hyponatremia. Early inhibition of natriuresis with fludrocortisone before onset of hyponatremia even prevents symptomatic vasospasm. Rapid correction entails risk of osmotic demyelination and should be borne in mind.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
