10.1 Epidemiology and Diagnosis
Subarachnoid hemorrhage (SAH) causes significant morbidity and mortality. Roughly 1 in 10,000 adults suffers SAH caused by a ruptured cerebral aneurysm (aneurysmal SAH, aSAH) every year. Fifteen percent will die before reaching the hospital and another 20% in the hospital. A large number of survivors of SAH suffer at least moderate long-term disability, and only 50% recover sufficiently to return to work in their profession [1]. Poor outcome relates to early brain injury associated with the ictus as well as a plethora of delayed complications, including hydrocephalus, vasospasm, and delayed cerebral ischemia (DCI). Many of these complications can be ameliorated when diagnosed and treated early, which is why patients after subarachnoid hemorrhage should be monitored in intensive care units with experts treating this disease.
While trauma represents the most common cause of blood in the subarachnoid space, the etiology of non-traumatic SAH is dominated by aneurysmal rupture in 80% of presentations. Other etiologies include arteriovenous malformations (AVMs), amyloid angiopathy, vasculitis, and toxic and inflammatory vasculopathies. This chapter focuses on the treatment of aneurysmal subarachnoid hemorrhage, as these patients are at highest risk for developing complications and pose the most challenges to the treatment team.
Presentation is varied, although most cases share a sudden onset, with the majority of patients describing acute onset of severe headache, frequently characterized as the “worst headache of my life.” This is often associated with nausea, vomiting, neck pain, and brief loss of consciousness. More severe cases present with profound reduction of level of alertness, up to coma, and a variety of focal deficits.
As aneurysms of the cerebral arteries are acquired malformations that likely develop in response to chronic vascular injury, risk factors include increasing age, hypertension, tobacco use, alcohol abuse, and use of sympathomimetic drugs. There also appears to be a genetic component, as women carry increased risk, as do individuals with a family history of aneurysmal SAH in first-degree relatives and those affected by polycystic kidney disease and connective tissue diseases such as Ehlers-Danlos syndrome.
The initial study when SAH is suspected should be a non-contrast computed tomography (CT) of the brain, which has close to 100% sensitivity to detect SAH when completed within 6 h of onset of headache on a modern CT scanner and interpreted by skilled radiologist [2]. MRI including gradient recovery echo sequences has even higher sensitivity and can be helpful in unclear situations. Typical distributions of subarachnoid blood on CT scan include spread to the basal cisterns and major fissures and within the ventricles. False-negative CTs do occur, particularly when presentation is delayed. Lumbar puncture with spectrophotometric evaluation of cerebrospinal fluid (CSF) for xanthochromia remains standard of care for evaluation of patients with negative or equivocal CT scans [3]. Xanthochromia indicates the presence of hemoglobin breakdown products (mostly bilirubin and oxyhemoglobin), which is caused by the degeneration of red blood cells and develops within 4–6 h after the ictus. Once the diagnosis of SAH is confirmed, CT angiography (CTA) or digital subtraction angiography (DSA) can identify the underlying aneurysm. DSA remains the most sensitive study and has the advantage that coil embolization of amendable aneurysms can be performed during the initial angiography. CT angiography can be used alternatively if DSA is not immediately available.
10.2 Initial Management
Initial evaluation and management should focus on airway and hemodynamic stability. Patients who are unable to protect their airway should be intubated before CT imaging. Severe hypertension should be treated, as it may increase the risk of rebleeding [4]. Most commonly, a systolic blood pressure of less than 160 mmHg is targeted while avoiding hypotension. Short-acting intravenous agents should be used for blood pressure control, such as labetalol (5–20 mg) or hydralazine (5–20 mg). Nicardipine infusion (5–10 mg/h) is helpful to control refractory hypertension.
SAH grading scales
World Federation of Neurological Surgeons scale | Hunt and Hess scale | Fisher scale | |||||
|---|---|---|---|---|---|---|---|
Grade | Glasgow Coma Score | Motor deficit | Grade | Neurologic findings | Grade | Subarachnoid blood on CT | Intraparenchymal/intraventricular blood on CT |
1 | 15 | Absent | 1 | Mild headache, nuchal rigidity | 1 | Absent | Absent |
2 | 13–14 | Absent | 2 | Moderate or severe headache, no deficit other than cranial nerve palsy | 2 | <1 mm thick diffuse layer | Absent |
3 | 13–14 | Present | 3 | Drowsiness, confusion, mild focal deficit | 3 | >1 mm thick diffuse layer or localized clots | Absent |
4 | 7–12 | Absent or present | 4 | Stupor, hemiparesis | 4 | Any | Present |
5 | 3–6 | Absent or present | 5 | Coma | |||
Patients with aSAH benefit from close collaboration between medical teams, including neurointensivists, neuroanesthesiologists, neurosurgeons and neuroradiologists, to facilitate prompt diagnosis, early securing of the aneurysm using the most appropriate method for the patient, and early recognition of complication to facilitate appropriate medical or interventional management. Patients should be transferred to a high-volume center that has diagnostic capabilities (CTA and DSA) and vascular neurosurgeons as well as interventional neuroradiologists as early as possible after initial stabilization and should be admitted to a dedicated intensive care unit. Outcomes are better for aSAH patients treated in high-volume centers that see >35 cases per year [5].
10.3 Treatment of Unsecured Aneurysms
Rebleeding risk is highest in the first 24–48 h after ictus [6]. Aneurysms should thus be secured as early as possible within the first 72 h. Both microvascular clipping and endovascular coil embolization are available to secure aneurysms. The International Subarachnoid Aneurysm Trial (ISAT) found that for aneurysms deemed appropriate for both clipping and coiling, coiling was associated with a lower complication rate and higher rates of independent survival both at short-term (1 year) and long-term (10 years) follow-up [7, 8]. Certain characteristics of aneurysm, such as a broad neck, location on the middle cerebral artery (MCA), or association with large intraparenchymal clot, make them more amenable to surgical clipping, while aneurysms of the basilar tip are preferentially coiled. Older patients with comorbidities and those with high-grade SAH may benefit from the lower complication rate associated with coiling. The appropriate treatment modality for an individual patient should be selected after multidisciplinary discussion involving the neurosurgeon, neurointerventionalist, and neurointensivist.
10.4 Management in the Intensive Care Unit
Patients with SAH are critically ill and prone to a variety of both early and delayed medical and neurologic complications, which benefit from monitoring and treatment in a dedicated, multidisciplinary, and collaborative intensive care unit. SAH is often associated with a profound systemic inflammatory response (SIRS), which may be triggered by early brain injury from the acute increase in intracranial pressure upon aneurysm rupture. An inflammatory cascade is initiated, which contributes to disruption of the blood-brain barrier, cerebral edema, and disturbed autoregulation, increases circulating catecholamines and inflammatory mediators, and may exacerbate delayed cerebral ischemia. SIRS after aSAH is associated with increased complications and poor outcome.
10.5 Early Complications
Rebleeding
Aneurysm rebleeding is associated with high mortality and is a risk factor for poor functional recovery. The risk is highest in the initial 24 h after symptom onset [6]. Rebleeding risk increases with longer time to definitive aneurysm treatment, severity of initial hemorrhage (loss of consciousness, poor neurological status at admission, need for external ventricular drain placement), previous sentinel headaches, persistent hypertension, and larger aneurysm size [4, 9–13]. Early definitive treatment of the aneurysm is the best way to prevent rebleeding. Definitive blood pressure goals to reduce the risk of rebleeding remain poorly defined. A goal systolic blood pressure <160 mmHg is a reasonable target. Short-acting, titratable infusions or intermittent bolus dose medications are recommended in the acute phase. Invasive hemodynamic monitoring via arterial cannulation is indicated while titrating medications but should not delay initiation of therapy. Goals of therapy should balance the risk of rebleeding with maintenance of cerebral perfusion pressure (CPP) in patients with elevated intracranial pressure (ICP).
If securing the aneurysm must be delayed for any reason, it is reasonable to consider a limited course (<72 h) of antifibrinolytics (epsilon aminocaproic acid or tranexamic acid) to stabilize the thrombus, unless medical contraindications exist [14]. Delayed (>48 h after ictus) or prolonged (>3 days) use of antifibrinolytic therapy increases risk of thromboembolic complications without offering additional benefit, as rebleeding risk drops after the first days, and should thus be avoided.
Hydrocephalus
Acute hydrocephalus occurs in up to 30% of aSAH patients, usually within the first few days [15]. Patients become symptomatic with signs of increased ICP, including nausea and decreased level of consciousness. Symptomatic patients should undergo urgent non-contrast head CT and, if ventriculomegaly is present, have an external ventricular drain (EVD) inserted without delay to provide CSF diversion. Up to 20% of patients after aSAH will develop chronic hydrocephalus and require placement of a permanent shunt [16, 17].
Seizures
Seizures or seizure-like activity is seen frequently in the acute phase of aSAH, especially with intraparenchymal hemorrhage and MCA aneurysms. However, the incidence of long-term epilepsy after SAH is low [18, 19]. As acute seizures increase rebleeding risk, it is reasonable to provide a short-term (e.g., 1 week) course of antiepileptics to patients deemed at high risk for seizure or who presented with ictal seizure [20]. While no large randomized controlled trials are available to guide choice of antiepileptic agent [21], small studies suggest that levetiracetam is associated with fewer complications and possibly better outcome than phenytoin [22–24]. Nonconvulsive seizures (NCS) are common in patients with high-grade aSAH and associated with poor outcome independent of treatment [25–27]. EEG monitoring can be used to detect NCS in comatose patients.
Neurogenic Stressed Myocardium
Signs of cardiac stress are frequently seen in the early days after aSAH and include a wide range of symptoms from EKG changes such as QT prolongation and ST changes, over-arrhythmias, and cardiac enzyme elevation all the way to reduced ejection fraction and cardiogenic shock. This syndrome of neurogenic stressed myocardium (NSM) is linked to early catecholamine surge and may be caused by injury to the central autonomic network in the medulla and hypothalamus with a resulting sympathetic hyperactivation that leads to myocyte contraction, ATP depletion, and cell death [28, 29]. NSM is characterized by ST changes and wall motion abnormalities that do not follow a vascular distribution, as well as relatively low troponin levels, which help differentiate NSM from acute coronary syndrome. Typical regional wall motion abnormalities in NMS affect the left ventricle in a global pattern, often with apical predominance and apical ballooning similar to stress-induced Takotsubo cardiomyopathy [29, 30]. In rare cases when suspicion for acute coronary syndrome remains even after echocardiography, cardiac perfusion imaging can be helpful to detect or exclude transmural myocardial ischemia. The presence of NSM after aSAH is associated with vasospasm, DCI, and poor outcome, likely because it is a marker of the severity of initial injury [31, 32]. It is important to be aware of NSM to limit unnecessary invasive workup for coronary disease in patients with typical EKG changes and to institute appropriate pharmacological support for patients who develop cardiac dysfunction leading to hypotension (i.e., inotropes to support left ventricular function over vasoconstrictors). Treatment of NSM is supportive, including inotropic support as needed. While subendocardial petechial hemorrhage and contraction band necrosis with focal myocyte death surrounding sympathetic nerve terminals can be present on autopsy, myocardial infarction is absent, and full recovery of cardiac function with complete resolution of symptoms can be expected within weeks [29, 30].
Neurogenic Pulmonary Edema
Flash pulmonary edema without cardiac dysfunction can occur after neurologic insults, including aSAH. It is characterized by rapid onset (within minutes to hours) of hypoxic respiratory failure, classically associated with bilateral pulmonary edema on chest X-ray. Neurogenic pulmonary edema (NPE) has been linked to acute intracranial pressure increase and insults to trigger zones in medulla or hypothalamus, similar to NSM. NPE is short-lived, and resolution typically occurs within 48–72 h. Longer duration of respiratory failure should raise suspicion for non-neurogenic causes, such as acute respiratory distress syndrome (ARDS), aspiration, pneumonia, or cardiogenic pulmonary edema [33–35]. Treatment of NPE is supportive and should include lung-protective ventilation strategies with positive end-expiratory pressure (PEEP) and low tidal volumes.
10.6 Late Complications
10.6.1 Delayed Cerebral Ischemia
Delayed cerebral ischemia (DCI) is a common and feared detrimental complication after aSAH, affecting a third of patients. It is defined as any focal or global neurologic deterioration that lasts longer than an hour without an obvious alternative cause [36]. DCI can lead to cerebral infarction, disability, and death and is a main driver of poor functional outcome after aSAH [37].
DCI has traditionally been attributed to vasospasm, a narrowing of the larger intracerebral vessels that appears in 70% of aSAH patients between 4 and 14 days after ictus. The assumption is that vasospasm can become severe enough to compromise local cerebral perfusion and cause ischemia. However, there is a dissonance between the occurrences of vasospasm in 70% and DCI in 30% of patients after aSAH. DCI can present in the absence of vasospasm on DSA. More importantly, drugs such as clazosentan reduce vasospasm but do not improve outcome after aSAH, whereas nimodipine improves outcome without affecting vasospasm [38], supporting that vasospasm is likely not the only cause of DCI and that not all vasospasm leads to DCI [39]. Alternative causes of DCI include cortical spreading depolarizations [40], a depolarization wave in the gray matter that results in EEG depression and can cause spreading vasoconstriction and ischemia [41]; microthrombosis of small vessels, which is seen in areas of ischemia on autopsy [42]; and microvascular constriction. DCI is more common in younger patients, in smokers, and in those with higher WNFS and Fisher scores. Early brain injury, global cerebral edema, NPE, and NMS all are associated with the development of DCI [43].
Diagnosis and Monitoring
DCI is a clinical diagnosis and requires frequent neurologic examination. Most practitioners assess neurologic status every hour, while some suggest that patients at low risk for DCI can safely be assessed less frequently (i.e., every 2–4 h) [39]. The gold standard for diagnosis of vasospasm is digital subtraction angiography (DSA). Given the invasive nature of DSA, however, it is poorly suited for daily screening. Daily monitoring of blood flow velocities in the large intracerebral vessels using noninvasive transcranial Doppler ultrasonography (TCD) provides an estimate of vessel dimension and can be helpful in predicting vasospasm and recognizing it early. The correlation of TCD velocities with vasospasm is best established for the middle cerebral artery (MCA) territory. Mean flow velocities (MFV) of > 200 cm/s are usually seen as evidence of vasospasm, while MFV < 120 cm/s make vasospasm unlikely. The Lindegaard ratio divides MFV in the MCA by MFV in the extracranial carotid artery, which is not affected by vasospasm, thus controlling for increases in MFV that are caused by elevated cardiac output. A Lindegaard ratio of > 3 suggests vasospasm. In the hands of experienced operators, the sensitivity of MFV elevation for vasospasm and its negative predictive value are high, making TCDs a good screening tool to detect patients at low risk for DCI, who may be eligible for early transfer from the ICU. Unfortunately, specificity of TCDs is low [44]. Some practitioners use CT angiography and CT perfusion studies to identify vasospasm and brain tissue at risk of ischemia, which correlates with DCI [45]. However, these studies cause significant additional exposure to contrast dye and radiation and should not be used for routine screening.
It is especially challenging to detect DCI in patients with high-grade aSAH, who do not have a reliable neurologic exam that can be followed. Multimodal monitoring, including continuous EEG and monitoring of intracranial pressure and arterial blood pressure, holds some promise for prediction and early detection of DCI in this population. Early studies suggest that the electroencephalographic alpha/delta ratio may predict DCI [46, 47], whereas the cerebral pressure reactivity index (calculated as a correlation coefficient between arterial blood pressure and intracranial pressure) may indicate a compromised cerebral autoregulation and predict poor prognosis [48, 49]. These monitoring techniques should currently be used within research protocols to obtain more definitive data.
The duration of monitoring in the ICU can be individualized. Many programs will watch all patients after aSAH in the ICU throughout the phase of high vasospasm risk (14 days) and perform a second DSA before discharge to confirm successful occlusion of the aneurysm and absence of additional aneurysms and exclude significant vasospasm. Others recommend that those at low risk for DCI (age > 65 years, WFNS grades 1–3, Fisher grades 1–2) and without evidence of vasospasm by TCD velocities and CT perfusion imaging can be considered for transfer from the ICU as soon as 5–7 days after the SAH [39].
Prevention
Prevention and treatment of vasospasm and DCI are among the most challenging tasks in critical care after aSAH. Despite a multitude of promising preclinical studies, few pharmacological interventions have proven to be beneficial in clinical trials. The calcium channel blocker nimodipine given enterally (60 mg every 4 h) or intravenously (1–3 mg/h, not available in the USA) improves outcome after aSAH without affecting vasospasm [50]. The rho-kinase inhibitor fasudil (available only in Asia) may have some benefit as well [51]. Unfortunately, large randomized trials have failed to confirm promising results from pilot studies for several other drugs. There is no evidence of improved outcome in patients receiving magnesium (IMASH [52]), statins (STASH [53]), or the endothelin receptor antagonist clazosentan (CONSCIOUS-2 [54]).
Patients with decreased intravascular volume have a higher risk to experience DCI and cerebral infarctions. However, prophylactic hypervolemic therapy does not improve outcome while increasing cardiopulmonary complications [55]. Current best practice is to maintain euvolemia in all patients with aSAH, which is frequently done by close monitoring of fluid intake/output and replacement of any excessive fluid loss. Beyond maintaining an even fluid balance, no single best method for determining volume status and defining euvolemia has been established. Most practitioners rely on a combination of fluid balance, daily weights, and various invasive and noninvasive measures of preload and fluid responsiveness, including pulmonary wedge pressure, global end-diastolic volume measured by transpulmonary thermodilution, and echocardiographic measures of preload such as left ventricular end-diastolic volume and pressure and dynamic changes in vena cava diameter. Dye and isotope dilution studies, if available, provide highly reliable measures of circulating blood volume and can be useful to establish euvolemia in complex clinical situations [56–59].
Treatment
Rescue measures should be initiated once signs of DCI occur. Triple-H therapy consisting of induced hypertension, hypervolemia, and hemodilution, used to be the mainstay of rescue therapy for DCI. However, only induced hypertension actually augments cerebral blood flow, whereas the other components do not. Triple-H therapy is therefore no longer recommended and has been abandoned in favor of induced hypertension [55]. Most practitioners will use vasopressors such as norepinephrine to increase mean arterial blood pressure (MAP) in a stepwise fashion (20–30%) until symptoms improve or MAP of 120–130 mmHg is reached. No single vasopressor is clearly superior. Blood pressure should be monitored continuously by arterial line. Unfortunately, the first randomized trial to investigate whether induced hypertension can improve outcome (HIMALAIA) was recently stopped early due to slow enrollment and was unable to show a clear benefit of blood pressure augmentation for functional outcome [60]. In the absence of more definitive studies, blood pressure augmentation remains the best medical treatment option available for DCI.
Patients who do not rapidly improve after hypertension is induced should be referred for urgent DSA and possible balloon or pharmacological angioplasty of large vessel vasospasm. Several different vasodilator drugs, including nicardipine, verapamil, and milrinone, have been used for super-selective intra-arterial infusion to relieve cerebral vasospasm. Vasodilatory effects are short-lived, and no large controlled trials have investigated whether angioplasty improves outcome after aSAH. In the absence of alternative treatment options, balloon or pharmacological angioplasty should be considered when medical therapy fails to improve DCI [61].
10.6.2 Hyponatremia
Hyponatremia is very common after aSAH and may be associated with worse outcome [62]. It can be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or by cerebral salt wasting. While SIADH usually presents with euvolemia or hypervolemia and cerebral salt wasting with hypovolemia/volume contraction, urine and serum osmolarity and sodium concentrations are similar in both conditions. The two disorders can be difficult to distinguish in the clinical setting where patients routinely receive intravenous fluids [63, 64]. Moreover, both conditions can coexist in the same patient, leading to fluid and salt loss aggravated by disproportional water retention. Fluid restriction, the treatment of choice for SIADH, can be detrimental when applied to an individual with cerebral salt wasting, as it will worsen hypovolemia and can exacerbate vasospasm and DCI. It should therefore not be used in patients with aSAH. Similarly, the vaptans (vasopressin receptor antagonists), which are used to treat chronic SIADH [65], can force significant diuresis and cause hypovolemia and should be used only with very careful monitoring, if at all. In contrast, infusion of hypertonic saline can be safely used to replace sodium and fluid in cerebral salt wasting, or force appropriate diuresis in SIADH, correcting hyponatremia in both conditions [66]. Fludrocortisone can be given additionally to increase sodium and water retention, although it may be most effective when initiated before cerebral salt wasting begins [67].
10.6.3 Anemia
Anemia develops frequently after aSAH, caused by inflammatory suppression of erythropoietin, iatrogenic blood loss from frequent lab draws, and red blood cell dilution from aggressive fluid treatment. While the presence of anemia associates with injury severity and poor outcome after aSAH, it is unclear if transfusion, which itself is associated with complications, can improve outcome. A high transfusion threshold (maintaining hemoglobin levels above 9–10 g/dL) is recommended to optimize cerebral oxygen delivery in patients with vasospasm and DCI [68–70].
10.7 Thromboprophylaxis
As SAH patients are often immobilized for a prolonged time and have a high inflammatory state, they are at high risk for venous thromboembolic disease (VTE). Mechanical means of thromboprophylaxis such as sequential compression devices should always be used. Pharmacological prophylaxis appears safe once the aneurysm is secured, even in the presence of an external ventricular drain [71, 72].
10.8 Mobilization
Early mobilization is recommended for critically ill patients, as it reduces ventilator days and delirium and hastens return to functional independence [73]. Patients after aSAH have traditionally been subjected to prolonged bedrest out of concern that mobilization may increase the risk of rebleeding and compromise cerebral blood flow and exacerbate vasospasm-associated ischemia. It is reasonable to prescribe bedrest until the aneurysm is secured to minimize straining and the risk of rebleeding. However, early mobilization once the aneurysm is secured appears safe and may preferentially benefit patients with higher-grade bleeds [74]. An individualized approach should be used when patients have vasospasm to avoid orthostatic changes that may compromise cerebral blood flow.
10.9 Guidelines
The American Heart Association [75] and European Stroke Organisation [76] have published fairly recent guidelines for the management of patients with SAH, which include the critical care phase. Similarly, the Neurocritical Care Society published a consensus statement with recommendations for critical care management of SAH [77]. This chapter generally follows these recommendations. When regional/local recommendations deviate, we recommend the reader to use their best judgment to decide which approach is the best fit for their patients’ individual circumstances.
Key Points
Initial evaluation and management of patients with suspected aneurysmal subarachnoid hemorrhage (aSAH) should focus on airway and hemodynamic stability. Patients who are unable to protect their airway should be intubated before CT imaging. Severe hypertension should be treated, as it may increase the risk of rebleeding.
Rebleeding risk from a ruptured aneurysm is highest in the first 24–48 h after ictus. Aneurysms should thus be secured as early as possible within the first 72 h.
Acute hydrocephalus is a frequent early complication after aSAH. Patients who develop signs of increased ICP should have an external ventricular drain (EVD) inserted if ventriculomegaly is present on non-contrast head CT.
Signs of cardiac stress are frequently seen in the early days after aSAH. This syndrome of neurogenic stressed myocardium (NSM) is linked to early catecholamine surge and often correlates with severity of the SAH. Treatment of NSM is supportive, including inotropic support as needed.
Prevention and treatment of vasospasm and delayed cerebral ischemia (DCI) are among the most challenging tasks in critical care after aSAH. The calcium channel blocker nimodipine improves outcome after aSAH without affecting vasospasm. Current best practice is to maintain euvolemia in all patients with aSAH. Induced hypertension, using vasopressors to increase blood pressure until symptoms improve, is the initial treatment of choice for DCI. Patients who do not rapidly improve after hypertension is induced should be referred for urgent balloon or pharmacological angioplasty of large vessel vasospasm.