Subarachnoid Hemorrhage Treatment & Management

The traditional treatment of subarachnoid hemorrhage (SAH) from a ruptured cerebral aneurysm included strict blood pressure control, with fluid restriction and antihypertensive therapy. This approach was associated with a high rate of morbidity and mortality from the ischemic complications of hypovolemia and hypotension.

Current recommendations advocate the use of antihypertensive agents when the mean arterial pressure (MAP) exceeds 130 mm Hg. Intravenous beta-blockers, which have a relatively short half-life, can be titrated easily and do not increase intracranial pressure (ICP). Beta-blockers are the agents of choice in patients without contraindications.

Most clinicians avoid the use of nitrates, such as nitroprusside or nitroglycerin, which elevate ICP. Hydralazine and calcium channel blockers have a fast onset and lead to a relatively lower increase in ICP than do nitrates. Angiotensin-converting enzyme inhibitors have a relatively slow onset and are not first-line agents in the setting of acute SAH.

Patients with signs of increased ICP or herniation should be intubated and hyperventilated. Minute ventilation should be titrated to achieve a PCO₂ of 30-35 mm Hg. Avoid excessive hyperventilation, which may potentiate vasospasm and ischemia.

Other interventions for increased ICP include the following:

• Osmotic agents (eg, mannitol), which can decrease ICP dramatically (50% 30 minutes post administration)

• Loop diuretics (eg, furosemide) also can decrease ICP

• The use of intravenous steroids (eg, dexamethasone [Decadron]) for decreasing ICP is controversial but is recommended by some authors

Patients must be admitted to the intensive care unit (ICU) with strict bed rest until the etiology of hemorrhage is determined. Patients should not be allowed out of bed for any reason. All patients should receive frequent neurologic evaluation. Use sedatives and analgesics cautiously to avoid masking the neurologic examination findings.

Additional medical management is directed to prevent and treat the following common complications of SAH:

• Rebleeding

• Vasospasm

• Hydrocephalus

• Hyponatremia

• Seizures

• Pulmonary complications

• Cardiac complications

Ideally, management of the complications of SAH should take place in a neurologic ICU or in an ICU similarly equipped. To minimize stimuli that may lead to an elevation of ICP, have the patient placed in a darkened, quiet, private room and given mild sedation if agitated. The head of the bed should be kept elevated at 30° to ensure optimal venous drainage.

Blood pressure must be maintained with consideration of the patient's neurologic status. Optimally, systolic blood pressure (SBP) of no more than 130-140 mm Hg should be the goal, unless clinical evidence of vasospasm is noted.

Indwelling catheters include an arterial line, central venous access, and Foley catheter. Seizure prophylaxis and calcium channel blockade are standard medical measures. Some centers favor volume expansion to treat vasospasm that develops days after the initial bleeding episode.

Surgical treatment to prevent rebleeding consists of clipping the ruptured berry aneurysm. Endovascular treatment ^[1] (ie, coiling) is an increasingly practiced alternative to surgical clipping. The neurosurgeon/neurointerventionalist must be involved early in the care of the patient with an aneurysmal SAH.

The initial management of patients with SAH is directed at patient stabilization. Assess the level of consciousness and airway, breathing, and circulation (ABCs).

Endotracheal intubation should be performed for patients presenting with coma, depressed level of consciousness, inability to protect their airway, or increased intracranial pressure (ICP). Rapid-sequence intubation should be employed, if possible, including the use of sedation, defasciculation, short-acting neuromuscular blockade, and agents to blunt an increase in ICP.

Intravenous access should be obtained, including central and arterial lines. A short-acting benzodiazepine, such as midazolam, should be administered prior to all procedures. Monitoring should include the following:

• Cardiac monitoring

• Pulse oximetry

• Automated and/or arterial blood pressure monitoring (arterial BP monitoring is indicated in high-grade SAH or when blood pressure is labile)

• End-tidal carbon dioxide, if applicable

• Urine output via placement of a Foley catheter

For more information, see the Medscape Reference article Emergent Management of Subarachnoid Hemorrhage.

Rebleeding is the most dreaded early complication of SAH. The greatest risk of rebleeding occurs within the first 24 hours of rupture (4.1%). The cumulative risk of rebleeding is 19% at 14 days. The overall mortality rate from rebleeding is reported to be as high as 78%. Measures to prevent rebleeding include bed rest in a quiet room, analgesia, and sedation. Stool softeners are given to prevent Valsalva maneuvers with resultant peaks in SBP and ICP. Clipping or coiling aneurysms is the surgical approach to prevent rebleeding (see below).

Pain is associated with a transient elevation in blood pressure and increased risk of rebleeding. Analgesia is preferably achieved with a short-acting and reversible agent such as fentanyl. Sedation is used with caution to avoid distorting subsequent neurologic evaluation. The preferred agent is a short-acting benzodiazepine such as midazolam. Antifibrinolytics have been shown to reduce the occurrence of rebleeding. However, outcome likely does not improve because of a concurrent increase in the incidence of cerebral ischemia.

Clipping or coiling of aneurysms

Surgical treatment to prevent rebleeding is by clipping the ruptured berry aneurysm. Endovascular treatment ^[1] (ie, coiling) is an increasingly practiced alternative to surgical clipping. For more information, see the Medscape Reference article Subarachnoid Hemorrhage Surgery.

The choice between coiling and clipping usually depends on the location of the lesion, the neck of the aneurysm, and the availability and experience of hospital staff. At many institutions, higher-grade patients and those with significant medical comorbidities tend to be treated by coiling rather than clipping. Posterior circulation aneurysms are preferentially treated by coiling because of the significant morbidity and mortality associated with surgical clipping.

Koivisto et al did not show any difference between the 2 techniques at 1 year. ^[24] In contrast, the randomized prospective International Subarachnoid Aneurysm Trial (ISAT) found coiling to be significantly safer for the treatment of ruptured aneurysms that were deemed equally suitable candidates for either surgical or endovascular treatment. ^{[25, 26, 27]} The incidence of rebleeding was slightly higher in the coiled group, but the endovascularly treated group did so much better overall that the study was stopped after reviewing the 1-year outcome data.

Partially because of the ISAT study, endovascular treatment is becoming the first-line treatment for many aneurysms. However, a 2009 study expresses concerns regarding the generalizability of the ISAT and suggests that further analyses are needed. ^[28]

The data to establish long-term results of endovascular treatment are insufficient. In general, the incidence of recanalization is higher with coiling. Significant advances have been made with the introduction of new coated coils that either swell within the aneurysm or promote fibrous tissue formation and organization of the intra-arterial clot.

Other advances include the use of intracranial stents to promote coiling (especially in aneurysms with wide necks) and decrease inflow into the aneurysm in certain instances. The stents have also provided a novel approach to treating certain types of aneurysms that have historically been untreatable. At the moment, no long-term follow-up data exist to assess the efficacy of these new treatment modalities.

In a retrospective study, Chitale et al compared the safety and efficacy of stent-assisted coiling (SAC) and balloon-assisted coiling (BAC) in 84 patients with ruptured complex and wide-necked aneurysms in the setting of acute SAH. They concluded from their findings that SAC may be an acceptable alternative to BAC for the management of these types of aneurysms in the acute phase of SAH. According to the authors, the rates of hemorrhagic, thromboembolic, and overall procedural complications were not significantly different in the SAC and BAC groups: 6.8% vs 2.5% (P = .5), 11.4% vs 7.5% (P = .6), and 18.2% vs 10% (P = .3), respectively. In addition, they found that the rate of favorable outcomes did not differ significantly: 61% vs 77% (P = .1). ^[29]

Timing of intervention

The timing of surgery has been the subject of controversy for more than 40 years. Initially, the high complication rate related to early clipping of the aneurysm was thought to outweigh the risk of rebleeding, and a philosophy of delayed surgery was generally accepted. With the improvement of surgical technique, especially the routine adoption of microneurosurgical techniques, a major shift has occurred in favor of early surgery for patients with aneurysms of favorable grade.

Early surgery or coiling is generally recommended in patients with straightforward aneurysms of a favorable clinical grade. Evidence from clinical trials suggests that patients who undergo surgery within 72 hours have a lower rate of rebleeding and tend to fare better than those treated later. ^[30]

Poor-grade patients who fail to improve after stabilizing measures (including ventriculostomy placement) may not get treated in the acute period or may be preferentially treated by coiling. Delayed intervention is also recommended in patients with giant or complicated aneurysms.

A cost-utility analysis from the Netherlands reports that at age 80 years, the risks and benefits of aneurysm occlusion sway toward not performing the procedure. The authors suggest that in patients 80 years or older, aneurysm occlusion should be performed only if the predicted life expectancy of the patient leaves a margin for benefit. ^[31]

For prevention of vasospasm, maintenance of normovolemia, normothermia, and normal oxygenation are paramount. Volume status should be monitored closely, with avoidance of volume contraction, which can predispose to vasospasm.

Nimodipine

Oral nimodipine is the most studied calcium channel blocker for prevention of vasospasm after SAH. An American Heart Association/American Stroke Association guideline recommends its use for this purpose (class I, level of evidence A). ^[32] Calcium channel blockers have been shown to reduce the incidence of ischemic neurologic deficits, and nimodipine has been shown to improve overall outcome within 3 months of aneurysmal SAH. Calcium channel blockers and other antihypertensives should be used cautiously to avoid the deleterious effects of hypotension. ^{[33, 34]}

The mechanisms of nimodipine’s protective effect in vasospasm is unproved. However, it appears that nimodipine may prevent the ischemic complications of vasospasm by the neuroprotective effect of blockading the influx of calcium into damaged neurons.

In May 2013, the US Food and Drug Administration (FDA) approved a new oral nimodipine solution (Nymalize) for the treatment of patients with SAH. Nimodipine had been available previously only as a liquid-filled gel capsule. Intravenous (IV) administration of nimodipine meant for oral use has been reported to cause death, cardiac arrest, severe decreases in blood pressure, and other heart-related complications. The oral formulation has the potential to decrease or eliminate inadvertent IV administration of the drug. ^[35]

Thrombolytic therapy

Some evidence indicates that subarachnoid clot removal achieved via intracisternal injections of recombinant tissue plasminogen activator (rTPA) may dramatically reduce the risk of vasospasm. This is performed after the clipping of the aneurysm.

Thrombolytic therapy is associated with the theoretical risk of intracranial bleeding, and although the results of preliminary studies are favorable, rigorous clinical trials are needed to establish the safety and efficacy of this approach. Intracisternal antioxidants and anti-inflammatory agents are of uncertain value.

Aspiration and irrigation

Aspiration and irrigation of the subarachnoid clot at the time of aneurysmal clipping usually results in suboptimal removal of the clot and is associated with a significant risk of iatrogenic trauma to pial surfaces and small vessels.

Intraoperative sodium chloride lavage to clear blood products from the subarachnoid space may be of some benefit, but its effectiveness remains unproved.

CSF drainage

Some authors suggest that early CSF drainage via a ventricular drain may decrease the incidence of vasospasm. This intervention is performed after the aneurysm has been secured.

Use caution to prevent rapid or overly aggressive drainage of CSF, which may precipitate aneurysmal rebleeding. One author suggests draining the CSF if the intracranial pressure exceeds 20 mm Hg. The drain should be set at a height to drain at 20 mm Hg to avoid an excessive reduction in ICP.

Statins

Statin therapy has been proposed as a means of preventing vasospasm and delayed cerebral ischemia. Statins may improve cerebral vasomotor reactivity through cholesterol-dependent and cholesterol-independent mechanisms. ^{[36, 37]} The use of statins in SAH is controversial. Several small studies have shown promise. Two meta-analyses have shown contradicting results. Sillberg et al concluded that statin therapy reduces vasospasm and cerebral ischemia, ^[38] while Vergouwen et al found no benefit of statin therapy. ^[39] Until more data are available, the use of statins cannot be routinely recommended. ^[40]

The Simvastatin in Aneurysmal Subarachnoid Hemorrhage (STASH) study, a multicenter randomized controlled clinical trial, will be investigating the effects of 40 mg of simvastatin in patients with SAH. The trial is currently recruiting participants. The planned sample size is 1600 patients, which should be powerful enough to answer the controversy surrounding statin therapy in SAH.

Triple H therapy

Treatment for symptomatic vasospasm has traditionally involved the induction of hypertension, hypervolemia, and hemodilution, or triple H therapy. This therapy should be reserved for patients with aneurysms secured by surgical clipping or endovascular techniques in order to reduce the risk of rebleeding.

The efficacy of triple H therapy remains subject to debate. A review of controlled studies showed no positive effect of triple H therapy or its components on increasing cerebral blood flow. ^[41]

Aggressive hypertensive therapy with inotropes and vasopressors (eg, dobutamine) can be initiated, if warranted. Hypervolemia may be achieved by using packed erythrocytes, isotonic crystalloid, and colloid and albumin infusions in conjunction with vasopressin injection. Corticosteroids may be of some benefit; however, such treatment remains controversial. Hemodilution or transfusion is used to maintain the hematocrit at 30-35% in order to optimize blood viscosity and oxygen delivery.

Initiation of triple H therapy requires placement of a pulmonary artery catheter in order to guide volume expansion and inotropic or vasopressor therapy. Central venous pressure (CVP) should be maintained at 10-12 mm Hg. Pulmonary artery wedge pressure (PAWP) should be maintained at 14-20 mm Hg.

Transluminal balloon angioplasty

Transluminal balloon angioplasty is recommended for treatment of vasospasm after failure of conventional therapy. One study reported improved neurologic outcome in 70% of patients with symptomatic vasospasm after transluminal angioplasty. Case series reports have indicated that angioplasty appears to be effective in treating vasospasm of large proximal vessels. ^[42]

Angioplasty is not effective in direct treatment of vasospasm of more distal vessels; however, distal blood flow may be increased as a result of increased proximal vessel diameter. The potential complications of angioplasty include vessel rupture, dissection, or occlusion, as well as intracerebral hemorrhage.

Papaverine, magnesium, and investigational agents

Intra-arterial injection of papaverine has been reported to improve outcome, but more data are needed before its routine use can be recommended. The beneficial effects of papaverine infusion appear to be short-lived compared with those of angioplasty.

Magnesium is a neuroprotective agent that acts as an N-methyl-D-aspartate (NMDA) receptor antagonist and a calcium channel blocker. It has been used to reduce cerebral ischemic events in SAH patients. Magnesium levels should be carefully monitored. Studies of magnesium treatment in SAH have yielded disparate results. A small, randomized, placebo-controlled pilot study by Westermaier et al found that maintaining serum magnesium concentrations of 2-2.5 mmol/L reduced the occurrence of cerebral ischemic events following aneurysmal SAH. ^[43]

A meta-analysis showed that magnesium reduced the risk of delayed cerebral ischemia and poor outcome in aneurysmal SAH. ^[44] However, a larger multicenter phase III trial by Wong et al found no significant difference at 6 months between patients treated with magnesium IV or placebo. ^[45]

Several new agents have been investigated for the use in SAH, especially to ameliorate vasospasm. In a randomized, double-blind, placebo-controlled, pilot trial, methylprednisolone did not decrease vasospasm but improved functional outcomes. ^[46] Tirilazad, a nonglucocorticoid 21-aminosteroid, has not shown consistent benefit. ^[47] Intra-arterial colforsin is under investigation to improve vasospasm. ^[48]

Treatment for acute hydrocephalus includes external ventricular drainage, depending on the severity of clinical neurologic dysfunction or CT scan findings. Rapid lowering of intracranial pressure during intraventricular catheter placement is associated with a higher risk of rebleeding and should be avoided. Resolution of hydrocephalus may be assessed periodically by blocking CSF drainage while monitoring ICP.

Symptomatic cases of hydrocephalus may be managed by temporary lumbar CSF drainage, serial LPs, or placement of a permanent ventricular shunt. Ventriculostomy placement is associated with an increased risk for rebleeding, along with known infectious risk; therefore, patients with dilated ventricles but no compromise of level of consciousness should be treated conservatively, with close monitoring of mental status and prompt intervention in case their clinical status declines.

Nevertheless, ventriculostomy, when done correctly, is a relatively low-risk procedure that can result in dramatic and immediate clinical improvement in about two thirds of patients. If the patient's grade improves enough as a result of ventriculostomy, the patient may become a candidate for early surgery.

When grading patients clinically, great care must be taken to note possibly reversible deficits related to hydrocephalus, which may be contributing to the patients' poor condition. According to a study of 47 patients with poor-grade aneurysm without CT evidence of irreversible brain destruction who underwent ventriculostomy, early control of the ICP and aggressive management appeared to be the appropriate treatment in this subset of patients.

Hyponatremia

Hyponatremia following subarachnoid hemorrhage occurs in 10-34% of cases. Elevated levels of atrial natriuretic factor (ANF) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been implicated.

Administration of isotonic fluid can prevent volume contraction but not hyponatremia. Use of slightly hypertonic sodium chloride (1.5% sodium chloride) at rates above maintenance requirements usually is efficacious for SAH-induced hyponatremia. Avoid fluid restriction in patients with SAH.

Seizures

Agents used for seizure prophylaxis include the following:

• Phenytoin, the agent of choice, can achieve rapid therapeutic concentrations when loaded intravenously, and it does not cause alterations in consciousness

• Phenobarbital produces a sedative effect, which may mask the neurologic evaluation; phenobarbital is used less frequently than phenytoin

• Long-term anticonvulsants are not recommended in patients without prior seizure activity or risk factors such as hematoma, infarct, or middle cerebral artery aneurysm

Some studies argue that anticonvulsant therapy can be limited safely to the immediate perioperative period in patients with no parenchymal clot, ischemic infarct, or postoperative hematoma.

Acute pulmonary edema and hypoxemia

Acute pulmonary edema and hypoxia are almost universal in severe subarachnoid hemorrhage. The pulmonary edema in SAH is believed to be neurogenic in origin and unrelated to triple H therapy; however, the latter is associated with an increased risk of fluid overload.

SAH-induced hypoxemia likewise is believed to be partially neurogenic in origin because it is out of proportion to what would be expected from cardiac insufficiency or fluid overload.

Treatment of acute pulmonary edema may include the use of gentle diuresis, dobutamine, and positive end-expiratory pressure.

Cardiac dysfunction

Cardiac dysfunction is common in subarachnoid hemorrhage, particularly in the first 48 hours, but it is typically benign. The perioperative therapy to prevent secondary cerebral ischemia (hypervolemia, hypertension) may exacerbate myocardial ischemia.

Conversely, therapy for myocardial ischemia, such as nitrates, may increase intracranial pressure, lower cerebral perfusion pressure, and exacerbate cerebral ischemia.

Screening is generally not recommended in the general population. Even in special populations, such as patients with polycystic kidney disease, studies have failed to show any benefit to screening. ^[49] In patients who have had 2 or more first-degree relatives with radiographically proven intracranial aneurysms, screening with CT or MR angiography may be considered on an individual basis. ^[50]

In general, the screening of patients with previous SAH cannot be recommended. However, screening can save costs and increase quality-adjusted life-years (QALYs) in the subset of patients who are at relatively high risk of both aneurysm formation and rupture. In addition, in patients with fear of recurrence, screening may increase QALYs at acceptable costs. ^[51] Nevertheless, more data are needed to help identify patients who can benefit from screening.