CONTENTS
- Rapid Reference: Initial management 🚀
- Epidemiology, causes, & location
- Presentation
- Grading scales
- Diagnostic approach
- Management: Neurologic issues
- Management: Non-neurologic issues
- Podcast
- Questions & discussion
- Pitfalls
consultation
- Neurointerventional radiology & neurosurgery.
- Consider: aneurysm protection, external ventricular drain.
radiology
- CT angiography (CTA).
coagulation management
- Review of any anticoagulant medications the patient is taking (including aspirin).
- Coagulation labs:
- INR, PTT, fibrinogen.
- Other studies in specific situations (e.g., anti-Xa level, TEG).
- Reversal of medications:
- Treat endogenous coagulopathies:
blood pressure control 📖
- Usually target MAP below ~110 mm (but may be personalized).
- Treat pain immediately, before starting an antihypertensive.
- Have a low threshold to start an infusion (e.g., nicardipine or clevidipine).
- Once stable, add nimodipine if tolerated to prevent vasospasm (ideally 60 mg PO q4hr).
seizure prophylaxis & diagnosis 📖
- Prophylactic levetiracetam for all patients initially.
- Consider vEEG for comatose patients with possible seizures.
general supportive care
- Aggressive fever management, with physical cooling if needed. 📖
- Avoid hyponatremia (with aggressive treatment if this occurs) and hypotonic fluid. 📖
- If concern for ICP elevation or herniation, consider hypertonic therapy. 📖
- Target normocapnia (check blood gas & trend etCO2 if intubated).
- Follow magnesium with daily labs & replete PRN.
- DVT prophylaxis with sequential compression devices until the aneurysm is protected (chemical DVT prophylaxis is initially contraindicated). 📖
general
- Nontraumatic SAH causes ~3-5% of all strokes.(30516599, Louis 2021)
- The age range is broad. With an average age of ~50, SAH affects younger patients more often than most other stroke types.
- Stronger risk factors for aneurysmal SAH include:
- Hypertension, smoking, alcoholism.
- Personal/family history of SAH or other aneurysm.
- Genetic diseases (autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome, sickle cell disease, Marfan syndrome, fibromuscular dysplasia).
- Sympathomimetic use (e.g., cocaine, amphetamine).
causes of SAH
- Primary SAH:
- 85% are aneurysmal.
- 10% are perimesencephalic hemorrhages. 📖
- 5% are due to other vascular malformations:
- AVMs (arteriovenous malformations).
- dAVF (dural arteriovenous fistula).
- Arterial dissection.
- Moyamoya disease.
- Secondary SAH (tends to occur in the high cerebral convexity; see section below):(34618758)
- Trauma.
- RCVS (reversible cerebral vasoconstriction syndrome).
- PRES (posterior reversible encephalopathy syndrome).
- CVT (cerebral venous sinus thrombosis).
- CAA (cerebral amyloid angiopathy).
- Pituitary apoplexy.
- CNS vasculitis.
- Primary intracerebral hemorrhage with secondary extension to the subarachnoid space.
- Tumor.
- Coagulopathy.
- Sickle cell disease.
- Sympathomimetic abuse.
- Mycotic aneurysm (usually due to septic emboli from endocarditis; most often at distal MCA or vertebrobasilar system).(Torbey, 2019)
- Vertebral artery dissection that extends intracranially.
- Iatrogenic injury to cerebral vasculature.
causes of diffuse or basal SAH
- Aneurysm: Suggested by blood near the circle of Willis (e.g., blood in the basal cisterns, sylvian fissure, interhemispheric fissure, or interpeduncular fissure).
- Arterial dissection.
- Vascular malformation:
- AVM (Arteriovenous malformation).
- dAVF (Dural arteriovenous fistula).
- Vasculitis.
- Tumor.
- Pituitary apoplexy. (26046515)
causes of convexity SAH (near the cortex)
common
- Younger patients (<60): RCVS (reversible cerebral vasoconstriction syndrome). 📖
- Older patients (>60): CAA (cerebral amyloid angiopathy).
- TBI (traumatic brain injury). 📖
less common
- Dural arteriovenous fistulae (DAVF).
- CVT (cerebral venous sinus thrombosis or cortical vein thrombosis). 📖
rare
- PRES (posterior reversible encephalopathy syndrome). 📖
- Hyperperfusion syndrome. 📖
- Mycotic aneurysm due to endocarditis. 📖
- Tumor.
- Intracranial dissection.
- Cavernous malformations.
- Moyamoya disease. 📖
- PACNS (primary angiitis of CNS). 📖
- Coagulopathy.(26046515,31272323, 29274685; Andreas Charidimou)
perimesencephalic subarachnoid hemorrhage
basics
- Perimesencephalic SAH constitute 10% of all SAH (a.k.a., “prepontine SAH”). They result from bleeding from a venous origin, which is centered in the perimesencephalic area.
- Clinical characteristics of perimesencephalic SAH include:
- Initial neurologic examination is generally normal.
- The rate of rebleeding, symptomatic vasospasm, or hydrocephalus are extremely low.(Louis 2021)
- The overall prognosis is better than for aneurysmal SAH.
radiology
- Radiologic criteria for the pattern of perimesencephalic hemorrhage:(26046515; 33992453)
- (1) The center of the hemorrhage is located immediately anterior to the midbrain.
- (2) There may be extension to the basal part of the sylvian fissure, but there shouldn't be significant extension to the lateral sylvian fissure.
- (3) There is no complete filling of the anterior interhemispheric fissure.
- (4) There is no frank intraventricular hemorrhage (although some blood may be seen within the third and fourth ventricles).(29262441)
- (5) There is no parenchymal hematoma.
- If the above criteria are met, then a CT angiography alone may be sufficient to exclude the presence of aneurysm. If the criteria aren't met, then digital subtraction angiography should additionally be considered.(33992453)
clinical management
- Management is generally similar to that of a subarachnoid hemorrhage. Initially it may be difficult to differentiate an aneurysmal SAH from a perimesencephalic SAH. Until an aneurysmal SAH has been excluded, it may be wise to treat the patient as if they have an aneurysmal SAH.
- Once a perimesencephalic SAH has been definitively diagnosed, the patient may be treated similarly to a patient with aneurysmal SAH whose aneurysm has been protected (e.g., coiled).
headache is the hallmark symptom
- Most concerning is a thunderclap headache (usually defined as a severe headache that reaches maximal pain in <1 minute).(33992453)
- Typically the headache is characterized as “worst headache of life” – although this is neither sensitive nor specific.
- Headache may begin during exertion or anger.
- Headache persists for hours to days. 10-20% of patients may have had a milder sentinel headache which occurred days or weeks earlier.
- (Further discussion of thunderclap headache in the section below.)
meningismus
- May occur, often developing more gradually (e.g., photophobia, nuchal rigidity, neck pain).
- Can progress to low back pain and radicular pain once the blood settles in the lumbar cistern.
elevated ICP: emesis, reduced consciousness
- Elevated intracranial pressure may cause nausea/emesis, stupor, or coma.
- If these symptoms are due to hydrocephalus, this should prompt consideration for placement of an external ventricular drain. 📖
focal neurological signs
- These aren't typically a prominent feature, but can occur (e.g., due to mass effect of aneurysm, or dissection of blood into the parenchyma).
- Deficits may include hemiparesis, aphasia, abnormalities of pupils or extraocular movements.
- Oculomotor-CN3 palsy may result from aneurysmal compression. 📖 A frequent complaint associated with this is pulsatile tinnitus.
- CN6 palsy may result from elevated intracranial pressure.
other presentations
- Seizure is the presenting feature in up to 20% of patients.(34618758; Torbey 2019)
- NPE (neurogenic pulmonary edema) 📖 or cardiac arrhythmias.
- Sudden death (~10% die prior to receiving medical attention). A small subset of patients presenting after cardiac arrest have SAH.
definition
- Thunderclap headache is usually defined as a severe headache that reaches maximal pain in <1 minute. (33992453)
- A single thunderclap headache is generally more worrisome than a history of several similar headaches. (34618761)
causes of thunderclap headache
- More common:
- (#1) SAH (subarachnoid hemorrhage).
- (#2) RCVS 📖 (reversible cerebral vasoconstriction syndrome). A history of multiple thunderclap headaches recurring over several days is nearly pathognomonic for the diagnosis of RCVS.⚡️⚡️⚡️⚡️
- Acute hypertensive crisis.
- Cervical artery dissection (carotid or vertebral).
- CVT (cerebral venous thrombosis).
- ICH (intracerebral hemorrhage).
- Pituitary apoplexy.
- Ischemic stroke.
- Primary thunderclap headache.
- Rarer causes: (LaHue 2021)
- Spontaneous intracranial hypotension.
- Cerebral vascultiis.
- Sphenoid sinusitis.
- Aqueductal stenosis.
- Colloid cyst of the third ventricle.
- Giant cell arteritis.
- Cardiac cephalgia (pain referral related to myocardial ischemia).
diagnostic approach to thunderclap headache
- For patients with thunderclap headache, a reasonable diagnostic strategy might be to perform a STAT noncontrast CT scan followed immediately by a CTA of the head and neck. CT/CTA is fast, noninvasive, and safe (remember that contrast nephropathy doesn't exist 📖). This combination provides an immediate wealth of information about possible diagnostic possibilities (especially SAH, RCVS, arterial dissection, arteriovenous malformation, or intraparenchymal hemorrhage). For patients with SAH, immediate vascular imaging will help fast-track patients to prompt neurointervention, to prevent rebleeding.
- If CT/CTA leaves remaining confusion about the possibility of SAH, then lumbar puncture and/or MRI/MRA may be considered. MRI may be especially useful if there is concern regarding other underlying brain or cervical spine pathology, such as CNS vasculitis or malignancy.
- If CVT (cerebral venous thrombosis) is possible, then venous imaging should also be obtained (e.g., CT angiography plus CT venography).
- Traditionally, the approach to thunderclap headache has focused narrowly on ruling SAH in or out. As we learn more about other vascular pathologies (e.g., cervical arterial dissection and RCVS), it's becoming clear that simply evaluating for SAH isn't adequate for these patients. With ongoing improvements in CT scanning technology, a CT/CTA strategy may offer patients a rapid evaluation for numerous vascular pathologies – not just “rule-out SAH.”
SAH severity is expressed using various scores as shown below. The Hunt & Hess score is easier to apply and more widely utilized than the WFNS (World Federation of Neurosurgical Societies) score. A weakness of these scores is that the patient's mental status may initially be obtunded by hydrocephalus, followed by rapid improvement after insertion of a ventricular drain. Thus, neurologic status after initial resuscitation and hydrocephalus management may be more important than the patient's initial presentation.
Conventionally, clinical grades 1-3 are often referred to as “good grade” SAH, whereas grades 4-5 are referred to as “poor grade” SAH. This can be a bit misleading, because many patients with “good grade” SAH are quite sick and have a substantial mortality.
performance of noncontrast CT scan for SAH diagnosis
- Noncontrast CT is the standard initial test for possible subarachnoid hemorrhage.
- The sensitivity is nearly 100% within six hours of headache onset, after which time blood starts looking a bit more grey, so the sensitivity may decrease slightly.
- Pseudo-subarachnoid pattern may occur in patients with severe anoxic brain injury – more on this here: 📖
after SAH is found, what else should you look for on CT scan?
- Distribution of blood may suggest an etiology (more on this below).
- Intraparenchymal hemorrhage may be seen in some patients.
- Hydrocephalus may be seen, which is an important finding since it's an indication for an EVD (external ventricular drain).
- Global cerebral edema may occasionally be seen after severe SAH. This usually occurs in patients with loss of consciousness, potentially reflecting a self-limited period of intracranial circulatory arrest.(Louis 2021)
typical CT appearance of aneurysmal SAH in various locations (34618758)
- AComm (anterior communicating artery) or ACA (anterior cerebral artery) aneurysms:
- Subarachnoid blood in the interhemispheric fissure.
- Focal frontal lobe intracerebral hematoma.
- MCA (middle cerebral artery) aneurysms:
- Subarachnoid blood along the Sylvian fissure.
- Focal anterior temporal lobe intracerebral hematoma (which may be dramatic, overshadowing the subarachnoid blood).(29262441)
- Posterior circulation aneurysms:
- Blood in the prepontine area, fourth ventricular outlet, and foramen magnum.
- Causes of SAH depending on location (diffuse/basal vs. convexity): 📖
- CT angiography (CTA) is highly sensitive and specific (~95%) for aneurysm detection, but may miss very small aneurysms.
- CTA has numerous potential roles:
- (1) For patients who have a SAH, CTA is essential to evaluate for underlying vascular anomalies (e.g., aneurysms, arteriovenous malformations).
- (2) For patients who do not have a SAH, CTA is useful to evaluate for the possibility of Reversible Cerebral Vasoconstriction Syndrome (RCVS) 📖 or cervical artery dissection.
- (3) For patients with a thunderclap headache and possible SAH, the finding of an aneurysm may indicate the need for further diagnostic testing (e.g., with lumbar puncture).
- Based on increasing appreciation of the prevalence of RCVS among patients with thunderclap headache, such patients may benefit from CTA regardless of whether the noncontrast CT scan is positive for SAH.
- Broader use of CTA may also be bolstered by evidence that contrast dye is not nephrotoxic.📖
- A potential drawback of CTA is that it may reveal asymptomatic unruptured aneurysms in ~2% of the population. Thus, it must be borne in mind that detecting an aneurysm without subarachnoid blood is not diagnostic of an aneurysmal subarachnoid hemorrhage. However, detecting unruptured aneurysms may provide an opportunity to advise patients regarding practices that could reduce their risk of aneurysmal rupture in the future (e.g., blood pressure control, tobacco cessation, avoidance of excessive alcohol use, and avoidance of sympathomimetics).
A traumatic tap is common and often cannot be differentiated from SAH in part because most clinical laboratories do not have validated spectrophotometry. -Maher M et al. (31964292)
background
- Traditionally, lumbar puncture (LP) has been used to evaluate for SAH in patients with negative noncontrast head CT scan who have high suspicion for SAH (primarily if the CT scan was obtained >6 hours after headache onset). In this context, erythrocytes or xanthochromia would support a diagnosis of SAH.
- Xanthochromia refers to the yellow hue noted on CSF that occurs due to RBC breakdown. It develops within 2-4 hours after the acute hemorrhage and should be present after 12 hours. This can be very helpful to make the diagnosis of SAH when the RBC count has downtrended between the first and last tube.
- The only way an LP can be entirely reassuring is if there are zero RBCs and there is no xanthochromia.
lumbar puncture suffers from numerous drawbacks:
- LP is an invasive procedure with risks of infection and hematoma.
- LP can be technically challenging in some patients.
- LP is contraindicated in patients with coagulopathy or those taking antiplatelet agents or therapeutic anticoagulation.
- LP is time-consuming, delaying the diagnosis of SAH.
- The performance of LP is far from perfect, with sensitivity and specificity in the 85% range.
- It's unclear how to optimally differentiate between SAH and a traumatic LP (falling numbers of RBCs from tube #1 to tube #4 can be seen with both a traumatic tap and a SAH; various articles disagree about optimal RBC cutoffs for tube #4).
Due to uncertainty in the interpretation of LP results, LP for the diagnosis of SAH is controversial.(34030777) The routine use of LP is gradually falling out of favor, primarily for two reasons:
- (1) With ongoing, perpetual improvements in CT scanning technology, fewer hemorrhages will be missed by CT scan. The seminal Perry study showing that CT scan sensitivity decreased after six hours was performed between 2000-2009.(21768192) CT scanners have improved a lot in the past fifteen years, so this data probably doesn't apply to modern scanners.
- (2) There is increasing recognition that many patients with thunderclap headache have RCVS, a diagnosis that requires CT angiography. Thus, patients presenting with thunderclap headache may benefit from CT angiography even if the LP is negative. Such patients may be better served by receiving both a CT and CTA immediately. If both the CT and CTA are negative, then SAH can generally be safely excluded.(30881537) However, some centers may still complete an MRI to be entirely certain, especially in more subacute presentations.
In some patients, LP may be required to exclude CNS infection (e.g., patients presenting with a more gradual-onset headache, or other features suggestive of infection).
MRI/MRA overall has similar performance compared to CT +/- CTA. However, MRI is limited by logistic constraints as the initial diagnostic test.
diagnosis of subarachnoid hemorrhage:
- FLAIR is sensitive in the acute phase of SAH, showing sulcal hyperintensity.(31485117)
- Sequences that detect hemosiderin (GRE and SWI) may be better than CT scan for subacute or chronic SAH.(30516599) These sequences become more sensitive for SAH detection over a period of days, rendering MRI a potentially attractive option for patients who present late and have a negative CT scan.
- MRI sensitivity increases from ~94% in the acute phase to ~100% in the subacute phase.(11160469)
detection of underlying pathology:
- MRI can be useful to detect subtle underlying pathology (e.g., arteriovenous malformations, infections, malignancy, or inflammatory disorders).(30516599)
- For patients with SAH near the base of the brain and no defined source of bleeding, cervical spine MRI may be useful to evaluate for a spinal source of bleeding.
interventional role
- Following initial SAH diagnosis, angiography may allow for interventional embolization of aneurysms, to prevent rebleeding. This can be done via coils, stent-assisted coiling (usually deferred in the acute setting due to the need for dual antiplatelet therapy), or newer WEB devices (woven mesh devices designed to minimize the need for stents).
- For patients with post-SAH vasospasm, angiography may allow for local infusion of vasodilators and angioplasty.
diagnostic role
- For patients with a SAH and no evidence of an aneurysm on CT angiography, an invasive angiogram may be performed to further exclude the presence of aneurysms or other vascular causes of bleeding.
- Invasive angiography is generally regarded as the gold standard for detection of aneurysms or cerebral vasospasm. However, the sensitivity of invasive angiography still isn't perfect (perhaps ~85-90%).
angiography-negative SAH
- About 10% of SAH patients are not initially found to have an aneurysm or other vascular process despite invasive angiography.
- Most of these patients have perimesencephalic hemorrhage. 📖
- Roughly 2% of those with no identified aneurysm will subsequently be found to have an aneurysm on repeat angiogram.(34184178, Torbey, 2019) The initial angiogram may occasionally be negative due to vasospasm or local thrombosis, which prevents contrast from entering the aneurysm.(Torbey, 2019)
- These patients may continue to be managed under the assumption that they have an unidentified aneurysm that ruptured.
- MRI brain and cervical spine (with and without contrast) can be completed in between angiograms, to continue to search for other underlying pathologies.
Differential diagnosis and approach need to be tailored to an individual patient, but common concerns include the following:
common causes of neuroworsening
- Aneurysm rebleeding:
- Risk highest early on.
- Deterioration is often rapid & dramatic.
- Hydrocephalus, elevated intracranial pressure (ICP).
- Early hydrocephalus is very common, immediately following SAH.
- Late hydrocephalus may occur as well, due to dysfunction of arachnoid granulations in reabsorbing CSF.
- DCI (delayed cerebral ischemia):
- May occur after 3-14 days, peak ~7-10 days.
- Deterioration is often gradual and somewhat subtle.
- Seizures or NCSE (nonconvulsive status epilepticus).
- Shock or hypotension (with subsequent inadequate cerebral perfusion pressure).
- Takotsubo cardiomyopathy.
- Central adrenal insufficiency.
- Medication effect (e.g., sedation).
- Infection: (e.g., ventriculitis following ventricular drain placement).
- High fever (e.g., central fever).
- Metabolic derangements (e.g., hypoglycemia, hyponatremia, hypercapnia, uremia).
evaluation may include:
- Review of data:
- Review recent electrolytes.
- Review fever curve.
- Review glucose trends.
- Review ICP trends (if available).
- Review medication history (focusing on neuroactive medications).
- Obtain laboratory studies as appropriate:
- STAT fingerstick glucose.
- Repeat electrolytes (if not recently measured).
- Consider blood gas measurement if hypercapnia or hypocapnia are suspected clinically (e.g., based on a review of trends in end tidal CO2 level and minute ventilation).
- Consider sampling fluid from an external ventricular drain to evaluate for ventriculitis.
- Bedside examination:
- Neurological examination.
- POCUS evaluation of the optic nerve sheath diameter to evaluate for ICP (if no ICP monitor is in place).
- Studies to consider:
- CT scan is useful to evaluate for hydrocephalus, intracranial hemorrhage, or aneurysm rebleeding.
- CT scan + CT angiography may be useful if delayed cerebral ischemia is possible.
- EEG may be considered to exclude nonconvulsive status epilepticus.
acute hydrocephalus: basics
- Acute hydrocephalus occurs in ~20% of patients, within minutes to days after hemorrhage.(30516599)
- Causes of hydrocephalus may include:(Torbey, 2019)
- Bleeding into the ventricular system.
- Obstruction of the fourth ventricle by blood.
- Impaired reabsorption of CSF at the arachnoid granulations.
- The best predictor of hydrocephalus is a poor clinical grade SAH.
- Deterioration may occur gradually, as patients appear increasingly lethargic. Clinical features may include:
- Reduced consciousness, nausea/vomiting, hypertension, and abducens nerve palsies.
- Impaired upgaze.
- Serial CT scan can help clarify the diagnosis. If CT scans are not readily available (e.g., patient is too unstable to travel to the scanner), other tests may also be considered (e.g., ocular ultrasonography). 📖
acute hydrocephalus: management
- Hydrocephalus may resolve spontaneously in about a third of patients, but those experiencing symptoms from their hydrocephalus will need intervention.
- External ventricular drain (EVD) is the treatment of choice. Historically, there was some concern that drain placement could eliminate a tamponade effect of the CSF on the aneurysm, and thereby promote rebleeding. This does not seem to be the case.(Nelson, 2020) However, before aneurysm protection is in place, the drain will often be managed gingerly (e.g., kept open at a level of 20 cm water, to prevent excess drops in intracranial pressure). Practice varies between institutions, with the neurosurgical team usually managing the ventricular drain.
- Lumbar drain insertion is another option for the management if the patient has communicating hydrocephalus. However, some patients may have obstructive hydrocephalus (due to obstruction of the ventricular system by blood, or a parenchymal hemorrhage) – in which case lumbar drainage is contraindicated.
- Indications for external ventricular drain include:(36333038)
- Radiologic evidence of acute obstructive hydrocephalus.
- Clinical evidence of symptomatic hydrocephalus (e.g., reduced levels of consciousness).
ICP (intracranial pressure) elevation
- Management is generally similar to the treatment of ICP in general. 📖
- For patients who are initially presenting with SAH: there should be a low threshold to administer empiric hypertonic therapy due to concerns regarding elevated ICP or herniation. 📖 (Albin 2022)
- Elevated ICP may persist even after placement of an external ventricular drain.
chronic shunt-dependent hydrocephalus
- Some patients may fail to wean off external ventricular drainage, necessitating a chronic CSF shunt.
rebleeding epidemiology
- Rebleeding occurs in ~15% of patients. When it occurs, the mortality rate is enormous (~50%).
- Most rebleeding occurs within the first six hours following admission.(30516599) If the aneurysm is not secured, the risk of rebleeding will continue to gradually increase over time (e.g., ~1% daily increase over the first month).(Shutter 2019)
- Risk factors for rebleeding include:
- Poor grade SAH.
- Large aneurysm, greater delay before aneurysm treatment.
- History of a sentinel bleed.
- History of hypertension; diastolic blood pressure >90 mm on admission.
- Antiplatelet medications or another coagulopathy.
- Intraparenchymal or intraventricular component of the hemorrhage.(35985353)
rebleeding prevention #1/4: anticoagulation reversal
- (See the approach at the top of this chapter: 📖)
rebleeding prevention #2/4: blood pressure control
- There is no solid data on Bp targets:
- Adequate blood pressure to perfuse the brain is needed (with hypotension being particularly dangerous).
- Excess blood pressure could potentially encourage aneurysmal rebleeding.
- Adequate analgesia is always essential, both for comfort and for blood pressure control. Pain should be rapidly treated prior to initiation of antihypertensives, as analgesia alone will often reduce the blood pressure.
- Guidelines recommend typically targeting a SBP <160 (American Heart Association) or MAP <110 mm (Neurocritical Care Society). However, these targets may be personalized when the patient's baseline blood pressure is known. If the patient is conscious, blood pressure may be correlated with mental status (e.g., if reducing the blood pressure causes a mental status deterioration, then antihypertensives may be held to determine if the mental status will improve at a slightly higher pressure).
- Continuous antihypertensive infusions may be useful initially (e.g., nicardipine or clevidipine).
- After the aneurysm has been clipped or coiled, blood pressure targets may be liberalized (e.g., allowing the SBP to rise up to <200 mm). Permissive hypertension may theoretically reduce the likelihood of symptomatic vasospasm.
rebleeding prevention #3/4: aneurysm treatment
- Promptly securing the aneurysm (either via surgical clipping or endovascular occlusion) reduces the risk of rebleeding. (Nelson, 2020) This should be achieved as soon as possibly, usually not later than 72 hours.(36333038)
- The ISAT and BRAT trials demonstrated that endovascular coiling generally yields superior outcomes compared to neurosurgery.(16139655, 22054213) Ongoing advances in neurointerventional radiology are continuing to improve patient outcomes following aneurysm coiling.
- In most centers, neurointerventional radiology and neurosurgery discuss the aneurysm’s amenability to coiling vs. clipping, which will depend on the aneurysm’s configuration, size, anatomy, presence of a neck, and location. Interventional radiology is typically favored, except for a few situations:(33992453)
- Aneurysms with an associated hematoma that requires surgical drainage.
- Aneurysms with a broad neck that isn't amenable to coiling.
- Associated cerebral edema that may benefit from leaving a craniectomy flap off, to accommodate swelling.
rebleeding prevention #4/4: antifibrinolytics
- The ULTRA RCT of early tranexamic acid failed to show benefit in clinical outcomes (with a trend that actually seemed to favor placebo).(33357465) This is a large, modern, multicenter RCT which should guide our practice.
- Tranexamic acid may be considered for occasional patients with challenging coagulopathies (e.g., hyperfibrinolysis revealed on thromboelastography) or in those whose aneurysm management needs to be delayed (e.g., patients requiring long distance inter-hospital transfer).
basics
- Nonconvulsive seizures or status epilepticus may occur in ~10% of patients, especially comatose patients.
- Seizure may be most frequent at the onset of SAH.(34308493)
- Risk factors for seizure include:
- Greater overall disease severity (e.g., thick SAH on CT scan, lower GCS, poor Hunt and Hess grade).
- Rebleeding.
- Parenchymal abnormalities: intracerebral hemorrhage, cerebral infarct.
- Hydrocephalus requiring an external ventricular drain.
- Craniotomy, surgical aneurysm clipping.
- (Sources disagree about the relationship of seizures with age.)
management
- Continuous video EEG should be considered for patients with persistent coma after initial resuscitation, or clinical concern for possible seizure. (More on the indications for continuous EEG monitoring: 📖.)
- Seizure prophylaxis should be considered initially:
- 🛑 Phenytoin has been associated with poor outcomes, so phenytoin should not be used. Phenytoin is notable among antiepileptics for its broad range of side effects, so phenytoin is not a favored antiepileptic agent in general.
- Levetiracetam is generally the preferred agent for seizure prophylaxis, based on its safety profile.(33896527)
- Seizure prophylaxis is often continued for roughly ~3-7 days. For patients who don't have a seizure, prophylaxis can be discontinued after seizure has been excluded (either via EEG or clinical examination) and the aneurysm has been secured. Epilepsy develops in ~2% of patients, requiring ongoing antiseizure medication.(33992453)
- Patients with seizure should be treated in the usual fashion, including longer durations of antiepileptic therapy (e.g., several months of maintenance therapy). 📖
basics
- Vasospasm occurs in about a third of patients. It is the leading cause of morbidity among patients who survive their initial SAH.(30516599)
- Vasospasm usually occurs 3-14 days after SAH, with a peak risk around days 7-10. It generally resolves by day 21.
- Risk factors:
- High volume of subarachnoid blood is the primary risk factor (see the table below).
- Intraventricular hemorrhage.
- Younger age.
- Aneurysmal etiology of the SAH (spontaneous SAH in the absence of an aneurysm rarely causes delayed cerebral ischemia).(35985353)
- Only about half of patients with vasospasm (~25% of all patients) have tissue ischemia with neurological deterioration (termed “symptomatic vasospasm” or “delayed cerebral ischemia”).(35985353) If vasospasm does not cause neurological deterioration, then it can often be observed without treatment.
- Clinically, patients with delayed cerebral ischemia may deteriorate gradually with nonspecific symptoms (e.g., lethargy or behavioral changes, with or without focal neurological deficits).
prevention of delayed cerebral ischemia
- (1) Nimodipine 💊 (a dihydropyridine calcium channel blocker):
- If possible, nimodipine should be given to all patients with aneurysmal SAH, for up to 21 days.(34308493)
- Class I evidence supports an improvement in clinical outcomes (although, curiously, nimodipine hasn't been shown to affect angiographic vasospasm – it's possible that it affects smaller caliber vessels).
- The usual dose of nimodipine is 60 mg q4hrs for 21 days, but this may be reduced in patients with borderline hypotension (e.g., to 30 mg q2hr or q4hr).
- (2) Maintenance of euvolemia.
- (3) Maintenance of normal magnesium levels (check levels daily and replete aggressively if low).
surveillance for delayed cerebral ischemia
(1) Serial neurological examinations.
(2) Transcranial doppler (TCD).
- May be used to surveil for the development of vasospasm. 📖
(3) Continuous EEG
- (1) One of the earliest signs of cerebral ischemia is loss of fast frequency (e.g., alpha frequencies; figure below).(35493831) Quantitative EEG may be used to detect trend changes in alpha activity over time. Alpha-delta ratio and alpha variability have been used to predict the onset of vasospasm, up to three days before the onset of vasospasm.(9546487; 34510093)
- Alpha power: Reduction in alpha frequencies be a sign of ischemia.
- Alpha/delta ratio: ischemia tends to reduce alpha frequencies and increase delta frequencies (figure below). Thus, the alpha/delta ratio may be especially useful. Reductions in alpha/delta ratio suggest vasospasm, especially if reduction occurs focally in one hemisphere.(Albin 2022)
- Relative alpha variability: Measurement of the normal fluctuation in alpha-activity over time. Decreased relative alpha variability may be a reflection of delayed cerebral ischemia.
- (2) Worsening focal slowing or late-appearing epileptiform abnormalities (e.g., epileptiform discharges, periodic/rhythmic activity) may predict delayed cerebral ischemia.(LaRoche 2018; Albin 2022)
diagnosis of delayed cerebral ischemia
some general concepts
- New onset of focal neurological findings that correlates with vasospasm in the suspected vascular territory is the hallmark of diagnosing delayed cerebral ischemia. This can sometimes be extremely difficult to determine, particularly when patients are comatose.
- Exclusion of alternative causes of neurologic deterioration will make it more likely that clinical deterioration is truly caused by vasospasm.
- Neurological improvement following augmentation of blood pressure may support the diagnosis of symptomatic vasospasm (see below).
CT angiography +/- CT perfusion
- CT angiography can be performed rapidly and noninvasively, with high sensitivity and specificity.
- CT scanning simultaneously may exclude alternative diagnoses (e.g., hydrocephalus).
- CT perfusion may supplement CT angiography by providing information about tissue perfusion, thereby improving sensitivity for distal vasospasm.(Nelson, 2020) Mean transit time (MTT) and cerebral blood flow (CBF) both correlate well with angiography. Mean transit time >6.4 seconds is more sensitive, and reduced cerebral blood flow (<30%) is more specific for vasospasm.(Torbey, 2019)
MRI
- An MRI showing areas of ischemic tissue could be used to support a diagnosis of symptomatic vasospasm – however, if ischemia is evident on MRI then it is likely that the window of opportunity to intervene may have been missed already.
invasive angiography
- Gold standard test for large-vessel vasospasm. However, this is invasive and may not be readily available.
- The primary advantage of angiography is the ability to provide immediate therapy (see below).
management of delayed cerebral ischemia
initial interventions
- Treat hypovolemia if present.
- Aggressive treatment of any hypomagnesemia.
- MAP elevation to ~20 mm above baseline using norepinephrine or phenylephrine may increase cerebral blood flow.
- If possible, neurological exams should be followed, to determine if this causes clinical improvement.
- Brain vessels lack alpha-1 receptors, so vasoconstriction due to norepinephrine or phenylephrine should theoretically be limited to systemic vessels (thereby preferentially increasing cerebral perfusion).(33992453)
- If an external ventricular drain is in place, opening the drain to a lower pressure may reduce the intracranial pressure, thereby improving the cerebral perfusion pressure.(33992453)
neurointerventional radiology
- Interventional radiology therapy with intra-arterial vasodilator administration and/or angioplasty may be helpful.
other potential interventions
- Intrathecal nicardipine infusion has been used for refractory vasospasm, although no high-quality randomized data are available regarding this.(30607826)
- Systemic milrinone infusion is supported by a reasonable amount of experience, albeit in the absence of high-level evidence.(32217799)
(treatments that aren't helpful)
- Unfortunately, trials involving statins, magnesium, or endothelin-1 antagonists have not shown benefit.(24837690, 22633825, 22403047)
- 🛑 Historically, “Triple H” therapy has been used to treat vasospasm (Hypertension, Hemodilution, and Hypervolemia). Of these three H's, only hypertension is beneficial. Hemodilution and hypervolemia are potentially dangerous and should not be utilized.(34308493)
- Potential indications for intubation may include:
- Inability to protect the airway.
- Rapidly deteriorating mental status.
- Status epilepticus.
- Refractory agitation, with a need for intubation in order to expedite a safe diagnostic work-up.
- Intubation should be performed with efforts to avoid elevating the intracranial pressure or causing hemodynamic instability. (more on this here)
basics
- SAH may be painful, with ongoing meningeal irritation causing headache.
- NSAIDs should generally be avoided due to risks of coagulopathy and renal dysfunction.
potential analgesics
- Scheduled acetaminophen may be helpful (e.g., 1 gram q6hrs).
- Gabapentin may be useful for the pain of meningeal irritation (within a dosing range of ~300-900 mg TID).(25403765)
- Migraine therapies are often useful as well, including antiemetics such as metoclopramide or prochlorperazine, in combination with magnesium infusions and/or diphenhydramine.
- Valproic acid 500 mg IV over 15 minutes may be beneficial in refractory patients.
- Opioid should be minimized since they are not effective for meningeal pain (e.g., by using PRN boluses for breakthrough pain only).
takotsubo (stress) cardiomyopathy
- This is very common in patients with SAH, especially more severe SAH.
- More on takotsubo cardiomyopathy: 📖
neurogenic pulmonary edema
- Differential diagnosis usually centers around:
- Aspiration pneumonitis or pneumonia.
- Cardiogenic pulmonary edema primarily due to takotsubo cardiomyopathy.
- Iatrogenic volume overload.
- Treatment of neurogenic pulmonary edema is supportive. This is generally a self-limited process, with sympathetic tone normalizing over a period of days. Avoid aggressive diuresis, which may increase the risk of vasospasm.
- More on neurogenic pulmonary edema: 📖
- Central fever (a.k.a., neurogenic fever) is common in SAH. However, central fever remains a diagnosis of exclusion, following evaluation for infection. Evaluation may include cultures of blood, sputum, and cerebrospinal fluid (for patients with external ventricular drains).(Nelson 2020)
- Regardless of the etiology, fever should always be treated aggressively to reduce secondary brain injury (e.g., using acetaminophen +/- physical cooling). In one case-control study, advanced fever control correlated with better outcomes after one year.(20190667)
- Additional information:
prior to aneurysm protection
- Chemical DVT prophylaxis is contraindicated.
- Pneumatic compression devices should be used for DVT prophylaxis.
after aneurysm protection
- When to initiate DVT prophylaxis:
- Heparin-induced thrombocytopenia is relatively common in this context, with some series reporting rates of 6%.(30516599) The use of low-molecular-weight heparin may be preferable in patients with adequate renal function, because low-molecular-weight heparin causes less heparin-induced thrombocytopenia than unfractionated heparin.
Hyponatremia following aneurysmal SAH is very common, and often a presage to the start of cerebral vasospasm.
potential causes of hyponatremia after SAH
- Cerebral salt wasting.
- SIADH (syndrome of inappropriate ADH secretion).
- Hypovolemia – including cerebral salt-wasting syndrome.
- Adrenal insufficiency due to hypothalamic/pituitary axis dysfunction.
- Pseudohyponatremia (due to mannitol, uncontrolled hyperglycemia, or hypertriglyceridemia from propofol infusion).
- Multifactorial combination of the above etiologies.
investigation
- Evaluate volume status.
- Check serum osmolality and cortisol level.
- Check urine sodium and urine osmolality.
management
- 🛑 Because hypovolemia can precipitate vasospasm, fluid restriction or diuretics should generally be avoided among patients who are within the vasospasm window.
- 🔑 Hypertonic therapy is the front-line therapy for all hyponatremic SAH patients (e.g., 3% saline or ampules of hypertonic bicarbonate, depending on the patient's acid/base status).(18216309)
- Worsening hyponatremia represents a threat to the brain, so this requires a prompt and definitive therapy.
- Hypertonic therapy will be effective regardless of the etiology of the hyponatremia (unlike, for example, isotonic saline – which may work for patients with isolated hypovolemia, but will exacerbate hyponatremia among patients with SIADH).
- Other identifiable problems should be treated as well. However, treating these issues will not lead to prompt and reliable resolution of hyponatremia, so these treatments should not be utilized as the sole therapy for hyponatremia:
- Evaluate and treat for adrenal insufficiency as appropriate. (more on the investigation and treatment of adrenal insufficiency here).
- If there is evidence of hypovolemia, this may be treated with additional administration of isotonic crystalloid (e.g., Plasmalyte). If patients appear to have ongoing salt wasting that requires persistent and large-volume crystalloid resuscitation, then the addition of fludrocortisone may be trialed in efforts to simplify their fluid management, at a dose of 0.1-0.2 mg PO BID. (more on cerebral salt wasting below).
- Sodium levels should be frequently monitored, until stable improvement has been achieved.
cerebral salt wasting syndrome
- Following SAH, some patients develop cerebral salt wasting, which is marked by a combination of:
- (1) Hyponatremia.
- (2) Polyuria causing volume depletion.
- (3) Urine with high osmolality and high sodium concentration.
- The existence of cerebral salt wasting is controversial.(32611661) In particular, it's difficult to sort out this phenomenon from SIADH (which will cause a nearly identical laboratory profile). Different authors have provided drastically different estimations regarding the prevalence of SIADH versus cerebral salt wasting (e.g., some authors state that cerebral salt wasting is common, whereas one series of 100 patients failed to diagnose a single case).(24248182)
- Cerebral salt wasting does seem to be a real clinical phenomenon. The most likely pathophysiology may be aldosterone deficiency, which occurs in some patients with SAH.(12030914, 32501957, 9014912) This would explain the efficacy of exogenous fludrocortisone or hydrocortisone for these patients (as both medications possess mineralocorticoid effects).(17585086, 18268175)
- Treatment of cerebral salt wasting may thus involve a combination of approaches:
- (1) Hyponatremia may be treated with hypertonic therapy (e.g., 3% NaCl).
- (2) Hypovolemia may be managed with simultaneous administration of isotonic fluid and fludrocortisone, as needed to achieve euvolemia. The use of fludrocortisone is recommended by AHA/ACC and NCS guidelines as a strategy to limit natriuresis. The dose range may be 0.1-0.3 mg PO BID.(34618758) Fludrocortisone can cause hypokalemia, which may require appropriate potassium repletion.
- Numerous articles claim that the treatment of SIADH involves water restriction +/- diuresis, such that the treatment of SIADH is “opposite” to that of cerebral salt wasting syndrome. This is dangerously misleading. In fact, both SIADH and cerebral salt wasting can be managed with hypertonic therapy – allowing prompt initiation of hypertonic therapy without knowing the precise etiology.(18216309)
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To keep this page small and fast, questions & discussion about this post can be found on another page here.
- When evaluating a patient with thunderclap headache, be careful of falling into the binary trap of simply excluding SAH. There are other important causes of thunderclap headache (e.g., RCVS).
- Hyponatremia in the context of SAH should be treated promptly with hypertonic saline (with or without additional treatments). Simply providing isotonic fluid or fluid restriction can exacerbate hyponatremia in some patients.
Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.
Guidelines
- Connolly et al. 2012 – AHA/ACC guideline on subarachnoid hemorrhage.
- Diringer et al. 2011 – Neurocritical Care Society guidelines on subarachnoid hemorrhage.
Review of seminal studies by The Bottom Line
- ULTRA (2021) – TXA failed to show benefit in subarachnoid hemorrhage.
- Bradford (2013) – Hypermagnesemia didn't improve vasospasm.
References
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