Web viewaneurysm.[21,22] Preretinal or subhyaloid hemorrhages – large, smooth bordered and on the retinal surface – occur in up to 25% of patients.[23]

Update on the Management of Subarachnoid Hemorrhage

Katja E Wartenberg

Future Neurology. 2013;8(2):205-224.

Abstract and Introduction

Abstract

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease. Outcome after SAH is mainly determined by the initial severity of the hemorrhage. Neuroimaging, in particular computed tomography, and aneurysm repair techniques, such as coiling and clipping, as well as neurocritical care management, have improved during the last few years. The management of a patient with SAH should have an interdisciplinary approach with case discussions between the neurointensivist, interventionalist and the neurosurgeon. The patient should be treated in a specialized neurointensive care unit of a center with sufficient SAH case volume. Poor-grade patients can be observed for complications and delayed cerebral ischemia through continuous monitoring techniques in addition to transcranial Doppler ultrasonography such as continuous electroencephalography, brain tissue oxygenation, cerebral metabolism, cerebral blood flow and serial vascular imaging. Neurocritical care should focus on neuromonitoring for delayed cerebral ischemia, management of hydrocephalus, seizures and intracranial hypertension, as well as of medical complications such as hyperglycemia, fever and anemia.

Introduction

Subarachnoid hemorrhage (SAH) is an acute cerebrovascular event with profound effects on the CNS and several other organs. SAH occurs with an incidence of two to 22.5 cases per 100,000 individuals. [1,2] Risk factors include an age of ≥50 years (most common: 40–60 years), female sex[3,4] depending on the hormonal status[5] and African–American race.[6] Further risk factors include arterial hypertension, cigarette smoking, alcohol, cocaine or any other sympathomimetic agents, prior SAH from a separate aneurysm or a family history of SAH, multiple aneurysms, arteriovenous malformations, coarctation of the aorta, moyamoya disease, pituitary gland tumors, connective tissue disease associated with intracranial aneurysms such as autosomal dominant polycystic kidney disease, Ehlers–Danlos syndrome (type IV), Marfan syndrome, pseudoxanthoma elasticum and fibromuscular dysplasia.[3–20] Current developments in neurocritical care including advanced continuous neuromonitoring, a shift of focus to immediate real-time normalization of pathophysiological states and better recognition and management of complications following SAH have improved the level of care and clinical outcome.

Clinical Presentation & Diagnosis

Patients with SAH present with an explosive generalized headache as well as neck stiffness and back pain, photophobia, nausea and vomiting, loss of consciousness and seizures. Approximately 80% of patients describe the pain as "the worst headache of my life." More than 20% of patients experience 'sentinel headaches' that last for minutes or hours. These occur 2–8 weeks before SAH and may be accompanied by nausea and vomiting. These symptoms originate from minor leaking of blood from an

aneurysm.[21,22] Preretinal or subhyaloid hemorrhages – large, smooth bordered and on the retinal surface – occur in up to 25% of patients.[23] Seizures may be the presenting symptom in up to 20% of patients, mostly within the first 24 h after SAH.[24]

SAH is misdiagnosed in approximately 12% of cases. Reasons for an initial misdiagnosis include not obtaining an imaging study in 73% of the cases and/or not performing, or falsely interpreting, a lumbar puncture in 23% of cases. This often leads to delayed treatment until rebleeding or neurological deterioration has occurred, with increased morbidity and mortality.[4,25]

The clinical condition upon admission of a patient is most commonly rated with the Glasgow Coma Scale,[26] Hunt and Hess Scale[27] or the World Federation of Neurological Surgeons Scale (WFNS).[28] The reports about intra- and inter-observer agreements are sparse and highly variable. However, obtaining a score with either the Hunt and Hess Scale or WFNS on admission is recommended, as this is the single most useful predictor of long-term outcome.[29]

Noncontrast computed tomography (CT) remains the single most important test for the diagnosis of SAH (Figure 1). In the first 24 h, the sensitivity of a CT for SAH is 92–95%. [30–35] The sensitivity to detect blood on a head CT declines to 57–85% on day 5 and 6 and declines to 50% after 1 week. [32,36] With the newer generation of CT scanners, the sensitivity reaches 97–100% within the first 6 h and 87% 6 h or more after symptom onset.[33]

Figure 1.

Computed tomography showing a subarachnoid hemorrhage as thick blood clots in all basal and cisterns, interhemispheric and sylvian fissures, as well as enlargement of the temporal horns of the lateral ventricle (hydrocephalus).

Reproduced with permission from the Oxford University Press, NY, USA.219

The Fisher scale is a radiological scale based on the amount and distribution of blood on CT. The score corresponds to the likelihood of delayed cerebral ischemia (DCI) occuring (Figure 2). [37] A modification of the original Fisher scale, with particular attention to thick cisternal and ventricular blood, resulted in a more accurate prediction of symptomatic vasospasm (Figure 3).[38,39]

Figure 2.

Fisher scale on noncontrast computed tomography.

(A) Grade I: no subarachnoid blood, risk of symptomatic vasospasm 21%. (B) Grade II: diffuse deposition or vertical layers of blood <1 mm thick, risk of symptomatic vasospasm 25%. (C) Grade III: localized clot or vertical layers of subarachnoid blood >1 mm thick, risk of symptomatic vasospasm 37%. (D) Grade IV: subarachnoid blood of any thickness with intracerebral and/or ventricular hemorrhage, risk of symptomatic vasospasm 31%.37

Reproduced with permission from.220

Figure 3.

Modified Fisher scale on noncontrast computed tomography.

(A) Grade I: no or minimal subarachnoid blood, no intraventricular hemorrhage, risk of symptomatic vasospasm 24%. (B) Grade II: minimal subarachnoid blood with intraventricular hemorrhage, risk of symptomatic vasospasm 33%. (C) Grade III: diffuse or focal, thick subarachnoid blood, no intraventricular hemorrhage, risk of symptomatic vasospasm 33%. (D) Grade IV: diffuse or focal, thick subarachnoid blood with intraventricular hemorrhage, risk of symptomatic vasospasm 40%.38,39


MRI with proton-density-weighted, fluid-attenuated inversion recovery, diffusion-weighted imaging and gradient echo sequences can also be used to make the initial diagnosis of SAH or to detect a completely thrombosed aneurysm when the initial angiogram is negative.[40] However, the usefulness of MRI in the acute setting is often limited by logistics, the need for acute resuscitation and critical care management of the patient and motion artifacts.[29]

In any case, if the CT does not reveal subarachnoid blood and SAH is suspected, a lumbar puncture should always be performed. SAH can be determined by demonstrating xanthochromia (yellow-tinged appearance) after centrifugation, which differentiates SAH from a traumatic tap. Xanthochromia may take up to 12 h to appear after aneurysm rupture. Within 12 h, the erythrocyte count is elevated and does not diminish from tube one through to four. Red blood cells and xanthochromia disappear in approximately 2 weeks, unless hemorrhage recurs. Spectrophotometry is another method used to evaluate the cerebrospinal fluid for subarachnoid blood with a sensitivity of 100% and a specificity of only 29–92%.[41,42] 2D or 3D selective catheter cerebral angiography remains the gold standard for detecting intracranial aneurysms and delineating their anatomy (Figure 4). [29] With increasing availability and improving image quality of CT angiography (CTA) and magnetic resonance angiography (MRA) the need to perform an urgent catheter angiography has reduced over the past decades. The sensitivity of a 3D time-of-flight MRA ranges from 55 to 93%, and for aneurysms ≥5 mm it ranges from 85 to 100%. MRA assessment of the aneurysm neck and of the relationship to the originating artery is limited. [43–47] CTA is more readily obtainable and faster than MRA. This imaging modality carries a sensitivity of 77–100% for all aneurysms and 95–100% for aneurysms ≥5 mm. Vessel tortuosity and lack of experience restrict its usefulness.[48–52] Additional information such as aneurysm wall calcification, intraluminal thrombosis, relationship to bony landmarks and to intraparenchymal hemorrhage may be revealed by CTA. Decisions about the repair mode of the ruptured aneurysm may be solely based on information obtained by CTA.[53–56] Newer techniques including dual energy CTA at lower radiation dosages and multisection CTA combined with matched mask bone elimination are accurate in diagnosing intracranial aneurysms.[57,58]

Figure 4.

Detection of intracranial aneurysms.

(A) Selective catheter cerebral angiography with injection of the left internal carotid artery (arrow) and (B) computed tomography angiography demonstrating an aneurysm of the anterior communicating artery (arrow).


However, a four vessel cerebal angiogram (bilateral internal carotid and vertebral artery injections) is mandatory when CTA and MRA are negative for aneurysms. Furthermore, with cerebral angiography the adequacy of aneurysm repair is assessed during coiling or after surgical clipping. Vasospasm, local thrombosis or poor technique can lead to a false-negative angiogram. For this reason, patients with a negative angiogram should receive a follow-up study 1–2 weeks later. An aneurysm will be demonstrated in approximately 1–2% of these cases.[59]

General Emergency & Critical Care Management

In acute SAH, the sudden rise of intracranial pressure (ICP) up to levels of the mean arterial pressure (MAP) creates an arrest of cerebral circulation resulting in loss of consciousness [60] and the development of global cerebral edema as well as acute ischemic injury on neuroimaging (Figure 5). [61–64] Initial care

should focus on: stabilization of systemic oxygenation and hemodynamics to optimize cerebral perfusion and oxygen supply; control of ICP caused by hydrocephalus and/or global cerebral edema; blood pressure control; seizure control; and prevention of aneurysm rebleeding.

Figure 5.

Diffusion-weighted imaging of a patient with Hunt and Hess IV subarachnoid hemorrhage, obtained on admission, showing acute ischemic injury in the distribution of the bilateral anterior cerebral artery territory (arrows).

Reproduced with permission from Oxford University Press, NY, USA.219

The resuscitation goals for SAH are presented in . Recurrent hemorrhage occurs in 9–17% of patients in the first 72 h, 40–87% of those occur within the first 6 h. Patients with high-grade SAH, loss of consciousness at index bleed, larger aneurysms, sentinel bleeds, angiography within 3–6 h of symptom onset, delay to treatment and incomplete aneurysm repair are at a higher risk for recurrent hemorrhage.[65–68] The literature reports available are not sufficient for specific recommendations regarding blood pressure reduction and administration of antifibrinolytic therapy with tranexamic acid or aminocaproic acid prior to cerebral angiography or aneurysm repair. Lowering blood pressure to a systolic value of 140–160 mmHg with a titratable agent is recommended.[29] A MAP of 110 mmHg can be tolerated. However, care should be taken to adjust the MAP and cerebral perfusion pressure (CPP) to maintain cerebral blood flow (CBF).[29,56] A short course of antifibrinolytic therapy may be undertaken until aneurysm repair for a maximum of 72 h. This therapy should be discontinued 2 h prior to endovascular aneurysm repair. Thromboembolic events present a contraindication, and the patients should be monitored closely for deep venous thrombosis.[29,56,68] The use of steroids is not supported by any controlled trials.

Table 1. Acute management and resuscitation goals of subarachnoid hemorrhage.

Aspect of care Management

Blood pressure

Invasive monitoring

Goal: systolic <160 mmHg, diastolic <110 mmHg and mean blood pressure <110 mmHg, CPP >60 mmHg until aneurysm repair

Drugs: iv. urapidil 5–40 mg/h, iv. labetalol 5–150 mg/h, iv. nicardipine 5–15 mg/h, iv. clevidipine 1–32 mg/h, iv. esmolol 50–100 µg/kg/min, iv. metoprolol 1–5 mg/h, iv. hydralazine 1.5–7.5 mg/h, iv. clonidine 0.03–0.12 mg/h

Prevention of rebleeding

Aneurysm repair through coiling or clipping

Option: ε-aminocaproic acid 4 g iv., followed by 1 g/h for a maximum of 72 h, up to 4 h prior to angiogram

Fluid balance

Monitoring through cardiac output monitor measuring stroke volume variation (most accurate, only in fully mechanically ventilated patients), internal jugular or subclavian central line (CVP – less reliable), urine output and clinically

Isotonic fluids for fluid replacement only: 0.9% NaCl at 1.0–1.5 ml/kg/h

OxygenationGoal: oxygen saturation >90%

Intubation and mechanical ventilation if GCS <8

Fever control

Goal: temperature ≤37°C

Methods: iv. or p.o. acetaminophen or metamizol 500–1000 mg, if not successful: ice packs, cold wraps, surface or endovascular temperature control systems with management of shivering

Glucose control

Goal: 4.5–7.0 mmol/l (81–126 mg/dl)

Methods: continuous insulin infusion

Caution: avoid hypoglycemia

Option: adjust to cerebral glucose level if microdialysis is used

NutritionEnteral nutrition should be started and be at goal (25–30 kcal/kg/day) within 48 h of admission

DVT prophylaxis

Sequential compression devices

Heparin 5000 units sc. every 8 h or enoxaparin 30–40 mg sc. daily within 24 h after aneurysm repair, withhold 24 h before and after intracranial procedures

Aspiration prophylaxis Head-of-bed elevation 30°

Gastric protection Pantoprazole 20–40 mg iv. or p.o. daily

Laboratory Admission: electrolytes, CBC, coagulation, d-dimer, troponin I, creatine kinase, type and cross blood, urine analysis and toxicology screening

Daily: CBC, electrolytes, creatinine and blood gas

Other tests

ECG

Chest radiograph

Option: transthoracic echocardiography

Hyponatremia

Isotonic fluids: 0.9% NaCl at 1.0–1.5 ml/kg/h

Limit free-water intake

Options: 2–20% hypertonic saline solutions, NaCl tablets and fludrocortisone or hydrocortisone for negative fluid balance

Seizure prophylaxis

Anti-epileptic treatment for patients with initial seizure, focal intracerebral clot or focal cerebral edema prior to aneurysm clipping with levetiracetam 500–2000 mg iv. daily divided into two dosages

Maximum 3–7 days without evidence of seizures

Electroencephalography monitoring of patients with Hunt and Hess grade IV and V

Extraventricular drainage

Emergent EVD placement for all patients with Hunt and Hess grade IV and V, decreased mental status and hydrocephalus

Raising the EVD level or clamping dependent on EVD output as soon as possible

No antibiotic prophylaxis

CSF for cell count and differential, glucose, lactate and protein every other day; culture if cell count increases

Caution: many CSF drawings increase the risk of infections. Sterile conditions should be applied

Neurogenic stunned myocardium with pulmonary edema

Hemodynamic monitoring (PiCCO, Pulsion Medical Systems, Munich, Germany; Flo Trac, Edwards Lifesciences, Irvine, CA, USA; pulmonary artery catheter)

Goal MAP: 70–90 mmHg

Inotropic support: milrinone 0.25–20.75 µg/kg/min or dobutamine 3–15 µg/kg/min

Vasopressors: norepinephrine 0.03–00.6 µg/kg/min (first choice), phenylephrine 2–10 µg/kg/min or dopamine 5–30 µg/kg/min

Diuresis

Increase FiO2 and PEEP

Transthoracic echocardiography

Vasospasm prophylaxis and diagnosis

Nimodipine 60 mg p.o. every 4 h until SAH day 21

Option: simvastatin 40–80 mg p.o. or pravastatin 40 mg p.o. daily until SAH day 14

Avoid hypomagnesemia

Daily transcranial Doppler sonography including the Lindegaard index

Option: CT angiography, CT perfusion or MR perfusion imaging on SAH day 4–12 (mean 9) in high-risk patients (Hunt and Hess grade IV and V; modified Fisher grade III and IV)

Vasospasm therapy Consider Trendelenburg position (head down)

Caution: increased rates of ventilator-associated pneumonia

Infusion of 500–1000 ml 0.9% saline or 5% albumin over 15 min

Start vasopressors (norepinephrine, phenylephrine or dopamine) to raise systolic blood pressure to 160–220 mmHg (20 mmHg above current) until deficits resolve

Consider milrinone or dobutamine in patients with congestive heart failure or myocardial ischemia

Refractory vasospasm

• Angiographic angioplasty and/or intra-arterial papaverine, verapamil or nicardipine

• Hemodynamic monitoring with PiCCO or Flo Trac, augmentation for goal cardiac index ≥4.0 l/min/m2 and diastolic pulmonary artery pressure >14 mmHg with dobutamine or milrinone

CBC: Complete blood count; CPP: Cerebral perfusion pressure; CSF: Cerebrospinal fluid; CT: Computed tomography; CVP: Central venous pressure; DVT: Deep vein thrombosis; EVD: Extraventricular drainage; FiO2: Inspired fraction of oxygen; GCS: Glasgow Coma Scale; iv.: Intravenous; MAP: Mean arterial pressure, MR:Magnetic resonance tomography; NaCl: Sodium chloride; PEEP: Positive endexpiratory pressure; PiCCO: Pulse contour cardiac output monitoring; p.o.: By mouth; SAH: Subarachnoid hemorrhage; sc.:Subcutaneously.


The patients diagnosed with SAH should be treated at high volume centers (>35 cases per year) with appropriate specialty neurointensive care units (NICUs), neurointensivists, vascular neurosurgeons and interventional neuroradiologists.[29,69–71]

Treatment of Increased ICP

SAH is associated with intracranial hypertension caused by hydrocephalus, space-occupying intracerebral hemorrhage, and global and focal cerebral edema. Hydrocephalus occurs in 20–30% of patients after SAH.[72–74] The treatment of choice is insertion of an extraventricular drain (EVD),[29] which may result in a prompt clinical response such as improvement of consciousness. [75] The risk of infection ranges from 2.2 to 21.9% depending on the number of manipulations and sterile techniques used. If there is no improvement after 36–48 h and the ICP is low, a poor neurological state is likely due to primary brain injury related to the acute effects of hemorrhage. Weaning of the EVD should begin after ICP is controlled for 48 h, either by trials of intermittent clamping or raising the EVD level with ICP monitoring. Clamping the EVD and subsequent weaning within 24 h, as opposed to a gradual increase in EVD level, resulted in a decreased length of stay in the intensive care unit, but did not reduce the need for a ventriculoperitoneal shunt.[76] Serial lumbar puncture[77] or placement of a lumbar drain[78] present alternatives to prolonged or repeated EVD placement if the basal cisterns are open. Approximately 18–26% of all SAH patients require a ventriculoperitoneal shunt for persistent hydrocephalus. [73,79]

Space-occupying intraparenchymal hemorrhages should be treated by craniotomy and surgical decompression. Decompressive craniectomy is indicated in patients with life-threatening cerebral edema with and without intracerebral hemorrhage, due to infarction or recurrent hemorrhage, and should be performed rapidly to avoid herniation.[80]

Apart from head-of-bed elevation, sedation, temperature control, administration of isotonic fluids, maintaining CPP >60 mmHg and an arterial partial pressure of carbon dioxide of 35 mmHg, bolus administration of hypertonic saline may be the preferred treatment for ICP crisis. Hypertonic saline (23.5%) given for ICP control resulted in an increase in CBF in ischemic regions and in brain tissue oxygenation, as well as in a decrease in ICP.[81,82]

Multimodal monitoring including ICP, MAP, CPP, partial pressure of cerebral tissue oxygen, cerebral lactate, pyruvate, glucose, glycerol and glutamate by microdialysis and reactivity indices may help to determine the optimal CPP threshold. The pressure reactivity index is calculated as the correlation coefficient between ICP and MAP to reflect cerebral autoregulation states. If autoregulation is disturbed, MAP changes are directly transmitted passively through a nonreactive vasculature to ICP (Figure 6). The optimal CPP is defined as the CPP at the lowest pressure reactivity index observed within a range of CPP (usually 50–90 mmHg).[83]

Figure 6.

Relationship between extremes of cerebral perfusion pressure and intracranial pressure in states of reduced intracranial compliance.

In the vasodilatory cascade zone, CPP insufficiency and intact pressure autoregulation leads to reflex cerebral vasodilation and increased ICP: the treatment is to raise CPP. In the autoregulation breakthrough zone, pressure and volume overload, which overwhelms the brain's capacity to autoregulate, leads to increased cerebral blood volume and ICP: the treatment is to lower CPP.

CPP: Cerebral perfusion pressure; ICP: Intracranial pressure.

Reproduced with permission from.221

Volume Status

Intravascular volume status should be monitored since reduced intravascular volume may cause cerebral ischemia and infarction.[84–87] Although placement of a central venous catheter is recommended for large volume access and monitoring, central venous pressure was found to be an unreliable marker of intravascular volume.[88,89] Assessment of fluid status should not be based solely on central venous pressure, but should include clinical examination of the patient, records of input and output, hourly urine output and stroke volume variation in intubated patients. Routine placement of pulmonary artery catheters is not recommended.[56] In general, intravenous fluid management for patients with SAH should target euvolemia.[29,56] Prophylactic hypervolemia may be harmful.[90–93] Isotonic fluids such as 0.9% saline at 1–1.5 ml/kg/h can be used. Supplemental 250 ml boluses of crystalloid (0.9% saline) or colloid (5% albumin) solution can be given every 2 h. However, crystalloids are preferred. [56] Hypertonic saline solutions are an alternative to normal saline for patients suffering from refractory intracranial hypertension or symptomatic intracranial mass effect. Hypotonic fluids should be avoided. [29]

Treatment of Seizures

The frequency of seizures in SAH has been reported to be 1–7% at onset. Approximately 5% of patients experience seizures during hospitalization and 7% will develop epilepsy during the first year after discharge.[94,95] The most important trigger for seizure is focal pathology such as large subarachnoid clots, intracerebral or subdural hematoma and cerebral infarction. A seizure at the onset of SAH does not predict an increased risk for epilepsy.[94] Routine use of phenytoin or fosphenytoin may worsen functional and cognitive outcome after SAH[96,97] and is no longer recommended.[29,56] If seizure prophylaxis with other anti-epileptic drugs is warranted to prevent rebleeding, they should be administered for only 3–7 days.[56]

Comatose patients may have nonconvulsive seizures or status epilepticus (8–19%).[98–100] Therefore, continuous electroencephalography is recommended in poor-grade SAH patients in stupor or coma. The effect of treatment of nonconvulsive seizures in these patients is less clear.[56]

Aneurysm Repair

Clipping within 48–72 h of ictus and safer microsurgical techniques result in permanent aneurysm obliteration in over 90% of patients, confirmed by intra- or post-operative angiograms as well as in low morbidity and mortality (5–15%) excluding giant aneurysms.[17,30,101,102] The complication rate of clipping is highest during the repair of large or basilar artery aneurysms. [103–105] Aneurysms on the middle cerebral artery may be more amendable to surgery.[106,107]

With the introduction of Guglielmi Detachable Coils (Target Therapeutics, CA, USA; soft thrombogenic detachable platinum coils) for endovascular therapy of aneurysms in 1991, [108,109] coil embolization became an important alternative to craniotomy and aneurysm clipping. Obliteration of small-necked aneurysms is achieved in 80–90% of cases. The complication rate is up to 9% including perforation and cerebral ischemia.[110] The ISAT trial enrolled 2134 good-grade patients with mostly small aneurysms (<10 mm) in the anterior circulation in a randomized fashion to undergo aneurysm clipping or coiling. [95,111] At 1 year, death and dependency was 23.5% after coiling and 30.9% after clipping (absolute risk reduction of death and dependence at 1 year 7.4% with coiling), which may be attributed to decreased brain retraction injury or intraprocedural rebleeding with coiling compared with clipping. The risk of epilepsy is decreased with coiling after 1 year (14 vs 24%). The main concern about endovascular therapy is an increased rate of rebleeding after several years due to coil compaction and aneurysm regrowth at the residual neck (recurrent hemorrhage 7% after coiling vs 2% with clipping after 1 year). [95,111]

The decision between surgical clipping and endovascular coiling should be made by a team of neurological, surgical and interventional cerebrovascular experts and should be based on clinical and radiological characteristics such as: clinical status of the patient; anticipated surgical ease or difficulty based on anatomical location; anatomy of the access vessels (tortuosity, extent of arteriosclerotic change); width of aneurysm neck in comparison with the dome and the parent artery (wide neck aneurysms are difficult to completely obliterate with coils, coils may migrate and be a source for emboli); and presence of an intracerebral hematoma with mass effect.[29,104]

Recent advances in technique including the balloon remodeling technique that holds the coils in the aneurysm cavity, liquid polymer coils and embolic agents make treatment of broad neck aneurysm feasible. The skills of the treating interventionalist or neurosurgeon, as well as the institution, may have a great impact on outcome. Regardless of the methods, aneurysms should be treated as early as possible to prevent rebleeding. Delayed follow-up imaging to determine the status of the aneurysm over time is reasonable, but deserves further study.[29]

Delayed Cerebral Ischemia

DCI is defined as the development of new focal neurological signs and/or deterioration in level of consciousness, lasting for more than 1 h, or the appearance of new infarctions on CT or MRI. The underlying pathophysiology is thought to be vasospasm and other causes are excluded. [112,113] This definition has been found to be more meaningful than symptomatic vasospasm (new focal deficit and/or decrease in level of consciousness due to vasospasm), especially in patients with severe SAH whose neurological deterioration may be unrecognized. Arterial narrowing can be demonstrated angiographically in 50–70% of patients and leads to delayed ischemia in 19–46% after SAH (angiographic

vasospasm, see Figure 7). The development of DCI starts on day 3 after SAH, is maximal at 5–14 days and resolves on day 21. The presence of thick subarachnoid blood seen on admission CT and severe intraventricular hemorrhage are strongly associated with higher risk for vasospasm (Figures 2 & 3). [37–

39,114,115] Prevention and management of DCI is listed in .



Blood pressure

Invasive monitoring






Fluid balance

Monitoring through cardiac output monitor measuring stroke volume variation (most accurate, only in fully mechanically ventilated patients), internal jugular or subclavian central line (CVP – less reliable), urine output and clinically




Fever control



Glucose control Goal: 4.5–7.0 mmol/l (81–126 mg/dl)





DVT prophylaxis





Laboratory

Admission: electrolytes, CBC, coagulation, d-dimer, troponin I, creatine kinase, type and cross blood, urine analysis and toxicology screening


Other tests

ECG

Chest radiograph


Hyponatremia




Seizure prophylaxis Anti-epileptic treatment for patients with initial seizure, focal intracerebral clot or focal cerebral edema prior to aneurysm clipping with levetiracetam 500–2000 mg iv. daily divided into two dosages












Inotropic support: milrinone 0.25–20.75 µg/kg/min or dobutamine 3–15 µg/kg/min


Diuresis





Option: simvastatin 40–80 mg p.o. or pravastatin 40 mg p.o. daily until SAH

day 14




Vasospasm therapy

Consider Trendelenburg position (head down)










Figure 7.

Cerebral angiogram demonstrates vasospasm.

(A) Vasospasm of the basilar artery (arrow), (B) the right vertebral artery (arrow) and (C) branches of the left posterior cerebral artery (arrow).


Monitoring for DCI

Observation in a NICU with expertise in performing frequent neurological examinations (options: Glasgow Coma Scale exam hourly, NIH Stroke Scale 6 hourly[116]) and daily transcranial Doppler ultrasonography are simple and helpful monitoring tools.[29,56] Decreased level of consciousness and focal signs such as aphasia or hemiparesis in a good-grade SAH patient should prompt the clinician to take immediate action such as a confirmatory test.[29,56]

Transcranial Doppler ultrasonography is a noninvasive method used to diagnose vasospasm in the larger cerebral arteries with high specificity and variable sensitivity, dependent on the operator and other systemic conditions.[117,118] A mean flow velocity (Vm) greater than 120 cm/s in the middle cerebral artery is concerning for vasospasm, Vm above 200 cm/s is considered to be predictive, but dynamic changes of the Vm, such as a twofold increase, may be more sensitive for the diagnosis of vasospasm. [117,119] The Lindegaard index (Vm of the middle cerebral artery in relation to Vm in the extracranial internal carotid artery) above 6 also indicates the presence of arterial vasospasm.[119–121] If DCI due to vasospasm is suspected, a vascular imaging study, such as CT with CTA and/or CT perfusion, MRI with MRA or the gold standard, a cerebral angiogram, should be performed.[29,56] CTA was found to have a high negative predictive value of 95–100%, a good correlation with cerebral angiography and a tendency to overestimate the degree of arterial narrowing.[122,123] CT perfusion gives additional information on cerebral perfusion status with mean transit time and CBF. Both correlate well with cerebral angiography; mean transit time >6.4 s is more sensitive and CBF is more specific for vasospasm.[124,125] These imaging tests should be repeated if the clinician is uncertain about the change in clinical status being caused by DCI, if an endovascular intervention is considered and if the risks of the planned therapy may outweigh the benefits.[56]

Poor-grade patients in stupor or coma require different monitoring techniques to identify DCI. Multimodal monitoring may be helpful in these patients by providing direct and real-time information about partial brain tissue oxygen pressure (by polarographic technique through Clark electrode) and metabolism (cerebral lactate, pyruvate, glucose, glycerol and glutamate by microdialysis), cerebral perfusion (MAP - ICP = CPP, CBF by thermal diffusion microprobe) and depression of brain activity by continuous electroencephalography or intracortical electrodes. Quantitative continuous electroencephalography analysis demonstrated sensitive and specific detection of DCI by reductions in α-variability or α/δ ratio.[126,127] Clusters of spreading depolarizations seen on cortical electroencephalography were associated with DCI.[128] These are currently being investigated in the DISCHARGE-1 Phase III study. Partial brain tissue oxygen pressure monitoring allows for early detection of DCI showing a decrease in the cerebral oxygenation.[129] Elevations of glycerol, glutamate and lactate/pyruvate ratios as markers of ischemia were correlated with reductions of CBF on PET and DCI.[130–132] When used, these parameters should be interpreted taking into account their limited region of capture and their location in relation to blood clots and other pathology. Moreover, screening for

perfusion deficits and arterial narrowing with CTA and CT perfusion may be reasonable in poor-grade patients.[56]

Prevention of DCI

Aside from high vigilance for symptoms of DCI, several pharmacological interventions have been investigated for their potential to prevent DCI.

Nimodipine, a dihydropyridine calcium channel blocker, was found to improve neurological outcome after SAH based on neuroprotection rather than an effect on the vasculature. Oral nimodipine (60 mg every 4 h) should be administered from day 1 to day 21.[29,56,133]

Magnesium, a physiologic calcium antagonist, blocks voltage-gated calcium channels, reduces the release of glutamate and entry of calcium into cells. Its vasodilatative effect and safety in SAH was repeatedly confirmed. The IMASH trial enrolled 327 patients randomized to receive magnesium or placebo within 48 h of symptom onset for 10–14 days. A difference in primary outcome, defined as favorable outcome at 6 months according to the extended Glasgow Outcome Scale, could not be demonstrated.[134] Only one trial with 107 patients showed a reduction of DCI, defined as ischemic infarction by 29% in the magnesium group (64 mmol/day for 14 days), which did not result in a better long-term outcome or reduced mortality at 6 months.[135] These findings were confirmed by a meta-analysis including a total of 875 patients.[136] Therefore, administration of additional magnesium is not recommended at this point. However, hypomagnesemia should be treated. [56]

Statins have been evaluated in small randomized, controlled trials for safety, their neuroprotective effect and their potential to decrease the incidence of DCI after SAH. In a recent meta-analysis, a reduction of DCI and a small effect on mortality could be shown; the remainder of the results were heterogeneous.[137] A multicenter trial studying the effect of simvastatin 40 mg daily for 21 days on DCI versus placebo, STASH, is ongoing.[301] As the use of statins is safe in SAH, patients already on statins prior to SAH should continue their medication, and starting statins may be considered in patients presenting with SAH.[56]

Clot removal and intrathecal administration of recombinant tissue plasminogen activator or urokinase during craniotomy to promote fibrinolysis, as well as head shaking aimed at clot dissolution, are still under investigation.[138,139] Endothelin receptor antagonists such as clazosentan reduced the incidence of angiographic vasospasm, but did not affect clinical outcome.[140]

Management of DCI

The treatment of DCI involves hemodynamic and endovascular management. Hemodynamic augmentation encompasses aggressive volume expansion with crystalloid or colloid solutions, as well as elevation of blood pressure and cardiac output in order to improve CBF through arteries in spasm and without autoregulatory capacity. This management strategy is often referred to as the 'triple H therapy': hypervolemia, hypertension and hemodilution, and is considered the standard therapy of DCI. However, only limited data are available about its effect.[141–146] Most of these small studies report hypervolemia

and/or administration of vasopressors, such as dopamine or norepinephrine, to be safe with variable effects on CBF and DCI. Phenylephrine was found to be safe to elevate the MAP by 20–35% in the setting of DCI.[147] In the presence of cardiac dysfunction, dobutamine or milrinone infusions are alternatives to maintain sufficient cardiac output, as measured by cardiac index.[148–150] However, dobutamine may lower the MAP and require an increase in vasopressor dosage. The available evidence mostly supports the use of dobutamine.[56] Hemodilution is not recommended because of a reduction of oxygen delivery to the brain.[151] If DCI is suspected, saline bolus administration and a trial of stepwise-induced hypertension with a vasopressor or inotropic drug should be undertaken, with periodic neurological assessments of the patient to define the MAP target. If nimodipine administration leads to temporary hypotension, the dosing intervals may be changed or the drug discontinued. [29,56] If DCI is refractory to maximal induced hypertension and hypervolemia, or limited by complications such as congestive heart failure, myocardial ischemia or pulmonary edema, cerebral balloon angioplasty and/or administration of intra-arterial papaverine, nicardipine or verapamil may lead to reversal of neurological deterioration. Intracranial pressure and arterial blood pressure should be monitored during administration of intra-arterial vasodilators. The timing of endovascular therapy should take into account the level and tolerance of hemodynamic augmentation, prior evidence of vasospasm and the availability of endovascular procedures.[29,56,152–155]

Electrolyte Disturbances

Hyponatremia occurs in 20–40% of SAH patients. Hypomagnesemia (40%), hypokalemia (25%) and hypernatremia (20%) are also common after SAH.[156–159] Hyponatremia is usually caused by inappropriate secretion of antidiuretic hormone and free-water retention and/or excessive renal sodium excretion due to increased atrial natriuretic factor, so called 'cerebral salt wasting syndrome'. [159,160] Intravascular volume depletion and sodium loss may increase the risk of DCI and infarction. [84,85] In 124 WFNS grade IV and V patients, hyponatremia (serum sodium <135 mmol/l) developed in 63% of patients, caused by cerebral salt wasting syndrome in 55%. Late-onset hyponatremia (between SAH day 4 and 9) correlated with a higher occurrence of cerebral infarction in this patient population. Nevertheless, hyponatremia did not have an association with poor outcome at 3 months (Glasgow Outcome Scale: 1–3).[161]

Fludrocortisone and hydrocortisone were studied for the prevention of hyponatremia in SAH. [162–166] If started early, the corticosteroids are effective in the prevention of natriuresis and hyponatremia. However, their use was complicated by hyperglycemia and hypokalemia.

Administration of large-volume isotonic crystalloids and restriction of free-water intake should be applied to counteract potential hypovolemia and to prevent inappropriate water retention. Hypertonic saline (3%) may be used to correct hyponatremia.[56,167]

Conivaptan is an arginine vasopressin receptor antagonist (V1A/V2) approved for the treatment of euvolemic and hypervolemic hyponatremia.[168] Initial reports of its use in neurocritical care patients with hyponatremia have yielded promising results.[169] Caution should be taken to avoid hypovolemia with the use of conivaptan.[56]

Treatment of Medical Complications

In addition to the direct effects of the initial hemorrhage and secondary neurological complications, SAH also predisposes to medical complications that may have a detrimental impact on outcome [159] and increase the length of stay in the NICU and in the hospital.[170]

Fever

Fever (≥38.3°C) is the most common of all medical complications in SAH patients (41–72%). [159,171–176] It was found to be associated with an increased risk of symptomatic vasospasm, [173] an increased length of stay in both the NICU and hospital,[170] poor outcome (modified Rankin Scale [mRS]: 4–6), dependence in activities of daily living and cognitive impairment at 3 months.[159,173,174] In SAH patients, the temperature should be monitored in short intervals. Normothermia should be the target in every SAH patient (). In a case–control study of advanced fever control with surface or endovascular cooling devices in 40 SAH patients, advanced fever control resulted in a lower daily fever burden and better outcomes at 12 months (mRS: 4–6 in 21%) compared with conventional fever management of 80 SAH patients (mRS: 4–6 in 46%; p = 0.03).[176] With a new occurrence of fever, infections need to be sought for and treated. Fever control should be attempted with antipyretics as the first-line therapy, followed by surface cooling or intravascular devices along with treatment for shivering.[29,56]



Blood pressure

Invasive monitoring






Fluid balance Monitoring through cardiac output monitor measuring stroke volume variation (most accurate, only in fully mechanically ventilated patients), internal jugular or subclavian central line (CVP – less reliable), urine output and clinically




Fever control



Glucose control

Goal: 4.5–7.0 mmol/l (81–126 mg/dl)





DVT prophylaxis





Laboratory

Admission: electrolytes, CBC, coagulation, d-dimer, troponin I, creatine kinase, type and cross blood, urine analysis and toxicology screening


Other tests ECG

Chest radiograph


Hyponatremia




Seizure prophylaxis

Anti-epileptic treatment for patients with initial seizure, focal intracerebral clot or focal cerebral edema prior to aneurysm clipping with levetiracetam 500–2000 mg iv. daily divided into two dosages












Inotropic support: milrinone 0.25–20.75 µg/kg/min or dobutamine 3–15

µg/kg/min


Diuresis





Option: simvastatin 40–80 mg p.o. or pravastatin 40 mg p.o. daily until SAH day 14




Vasospasm therapy Consider Trendelenburg position (head down)










Hyperglycemia

Hyperglycemia on admission or persistent hyperglycemia throughout the hospital stay was associated with DCI as well as a poor short- and long-term outcome (Glasgow Outcome Scale: 1–3; mRS: 4–6) after SAH in several investigations.[131,159,177–181] Depending on the definition, hyperglycemia occurs in 30–100% of SAH patients.[159,178,179,182]

A small trial of 55 patients with SAH confirmed the feasibility and safety of continuous insulin infusion for glucose values exceeding 7 mmol/l (126 mg/dl) with glucose assessments performed every 2 h. [183] The first randomized trial of intensive glucose control (target glucose 80–120 mg/dl = 4.4–6.7 mmol/l) versus standard insulin therapy (target glucose 80–220 mg/dl = 4.4–12.2 mmol/l) in 78 SAH patients showed a decreased rate of infection from 42 to 27% in the intensive group. Mortality at 6 months and the frequency of vasospasm were comparable in the two groups.[184] Retrospective studies reflecting the changes in clinical practice, such as the introduction of insulin protocols, demonstrated that good glycemic control (mean glucose burden >7.8 mmol/l [140 mg/dl] and <1.1 mmol/l [20 mg/dl]) significantly reduced the likelihood of a poor outcome at 3–6 months.[185] Hypoglycemia (<60 mg/dl = 3.3 mmol/l) was identified as a powerful independent predictor of mortality at discharge. [186] Hypoglycemia resulting from tight glycemic control was linked to an increased risk of DCI and infarction. [187] This may be seen as a decrease of cerebral glucose as well as an increase in the lactate/pyruvate ratio and glycerol as markers for cell stress when utilizing microdialysis.[180,188–190] Clinical signs of systemic and cerebral hypoglycemia may not be obvious in poor-grade SAH patients. Therefore, hypoglycemia should be avoided while applying tight glucose control. If microdialysis is used, the serum glucose level can be titrated according to the cerebral glucose measurements.[29,56]

Anemia

Anemia treated with blood transfusions is associated with an increased risk of delayed infarction, mortality and poor functional outcome at 3 months after SAH,[159,191] as well as brain tissue hypoxia (partial brain tissue oxygen pressure ≤15 mmHg) and metabolic distress (lactate/pyruvate ratio ≥40). [192]

In a safety study, 44 SAH patients were randomized to hemoglobin targets of 10 g/dl (6.2 mmol/l) or 11.5 g/dl (7.1 mmol/l).[193] Achieving the higher hemoglobin target by transfusion of packed red blood cells was found to be safe and feasible.[193] It remains uncertain whether anemia after SAH reflects general illness severity, impacts outcome directly or whether the treatment for anemia – blood transfusions – contributes to a poor outcome.[191,194,195] To minimize the frequency of anemia, the number of blood drawings should be reduced. Maintenance of hemoglobin levels between 8 and 10 g/dl (5.0–6.2 mmol/l) is recommended.[56] The optimal hemoglobin level in SAH patients still needs to be determined.[29]

Neurogenic Stunned Myocardium & Pulmonary Edema

SAH may be further complicated by cardiac dysfunction and pulmonary edema due to a catecholamine surge, resulting in neurogenic 'stunned myocardium' or 'neurogenic stress cardiomyopathy' and neurogenic pulmonary edema. Cardiac dysfunction is accompanied by transient electrocardiographic abnormalities, troponin leaks, reversible wall motion abnormalities on echocardiogram, hypotension and reduction of cardiac output. Neurogenic pulmonary edema is caused by an increased permeability of the pulmonary vasculature and may occur isolated or in conjunction with neurogenic cardiac injury. Hypotension, reduced cardiac output and impaired oxygenation may impair cerebral perfusion in the setting of increased ICP or DCI.[196–198] Troponin I elevations are found in approximately 35% of SAH patients[199,200] and cardiac arrhythmias in 35%.[159] A recent meta-analysis showed that cardiac abnormalities on an ECG, echocardiography and troponin measurements are linked to DCI, poor outcome and mortality after SAH (discharge 6 months follow-up period).[201] Thus, baseline evaluation with serial cardiac enzymes and an ECG is recommended. Patients with evidence of depressed myocardial function and pulmonary edema should receive echocardiography and monitoring of cardiac output. Standard management for heart failure is applied, with particular focus on cerebral perfusion status. In pulmonary edema, lung protective ventilation and euvolemia are the targets of therapy. [56]

Prognosis

The mortality rate was reduced from 50 to 25–35%.[202–204] Mortality rates are higher in women than in men.[205–207] Of the two-thirds of patients who survive, approximately 50% are permanently disabled, mainly due to neurocognitive deficits (20%), anxiety and depression, which occur in up to 80% of patients. Many patients do not return to work or retire early, and their relationships are affected. [208,209] Older age, poor clinical grade upon presentation, rebleeding, larger aneurysm size, global cerebral edema, DCI and medical complications impact on functional outcome after SAH. Of all these factors, the clinical condition upon arrival in the hospital appears to be the single most important risk factor for a poor outcome.[61,159,210,211] The poor-grade patients (Hunt and Hess or WFNS grade IV and V), 18–24% of the entire SAH population, present the greatest challenge to the neurointensivist. They have worse long-term functional outcomes and higher mortality rates.[159,212,213] However, early and aggressive treatment of patients with severe SAH resulted in unexpected improvements in the long-term outcome. [67,203,214–216] Of 26 patients with poor-grade SAH with neurocognitive testing at 1 year, half of the patients, mainly young and highly educated individuals, all employed in full-time jobs prior to SAH, had mild cognitive deficits and were able to live a normal life.[213]

Of equal importance, it should be noted that mortality rates are substantially higher and good long-term functional outcomes less common at centers that treat less than 18 patients with SAH per year. [69–71,217]

Conclusion

SAH is a devastating cerebrovascular disease. Improved NICU management and repair techniques reduced the impact of DCI on long-term functional outcome after SAH. The initial severity expressed in Hunt and Hess or WFNS grades became the major determinant of the long-term clinical and functional status of the patient. CTA facilitates screening for the ruptured aneurysm at the time of SAH diagnosis and helps to plan the most appropriate repair procedure; coiling or clipping. All treatment decisions should be made in a multidisciplinary team approach of neurointensivists, neurosurgeons and interventional neuroradiologists. The patients should be treated at high-volume centers with expertise and NICUs in place.

DCI is monitored with neurological exams and/or transcranial Doppler sonography. However, DCI is not recognized in poor-grade patients with standard monitoring techniques. Vascular and perfusion imaging studies may be helpful, as well as continuous multimodality neuromonitoring tools such as continuous electroencephalography, brain tissue oxygenation, cerebral metabolism and CBF. Controlled induced hypertension is the mainstay of medical management of DCI, followed by balloon angioplasty and/or intra-arterial vasodilators in refractory cases. The targets of intensive care management are euvolemia, normoglycemia avoiding hypoglycemia, normonatremia, normothermia, normal ICP and sufficient CPPs considering the states of failed autoregulation.

Future Perspective

The majority of the recommendations for the management of patients with SAH are based on the consensus opinions of experts in the field.[29,56] There are many open-ended questions such as the efficacy of antifibrinolytic therapy and the optimal blood pressure goal to prevent rebleeding prior to aneurysm repair, the efficacy of intensive glucose control and its target range, the impact of maintained normothermia on outcome after SAH, the optimal hemoglobin target after SAH and during DCI and the optimal therapy regimen for neurogenic stunned myocardium. New endovascular techniques such as intra-aortic balloon pumps and counterpulsation entered the field of DCI management. Current prevention of DCI and neuroprotection trials include intracisternal application of thrombolytic therapy to decrease the clot burden, and consequently the incidence of delayed cerebral ischemia, early placement of lumbar drainage to reduce subarachnoid blood, intrathecal application of magnesium sulfate, intraoperative implantation or intraventricular use of nicardipine prolonged-release implants (pellets), transfusion of packed red blood cells, administration of erythropoetin as well as randomized, controlled outcome studies of statins and human albumin. The common aim of the reduction of blood clots in the subarachnoid space or the local and systemic application of neuroprotective agents is the reduction of delayed cerebral ischemia along with an improvement of clinical outcome. Most of these trials are designed as safety studies. The STASH trial (recruiting) and the ALISAH II trial (under review) are Phase III trials aimed at improving outcome.[218,301] The best monitoring technique and triggers for neuroimaging and intervention for DCI in poor-grade SAH patients needs to be studied. With the

application of multimodality monitoring, including intracortical electroencephalography electrodes, more light is shed into the pathophysiology of secondary injury after SAH such as spreading depolarizations, a wave along the cortex characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression), seen as a cause or a sign of DCI. Physiological derangements are noted and interpreted. The role of spreading depolarizations in DCI and potential therapy targets for physiological derangements detected by multimodality monitoring now need to be clarified and defined.

Sidebar

Executive Summary

Clinical Presentation & Diagnosis

Thunderclap headache, followed by nausea and vomiting, is the typical feature of subarachnoid hemorrhage (SAH).

The sensitivity of SAH detection by computed tomography approaches 100% within the first 6 h.

Cerebral angiography remains the gold standard to demonstrate the ruptured aneurysm, although computed tomography angiography can detect aneurysms with comparable sensitivity.

The modified Fisher scale provides a more accurate prediction of the probability of vasospasm.

General Emergency & Critical Care Management

Emergency management should focus on the restoration of airway, breathing and circulation with attention to blood pressure and seizure control and the treatment of intracranial hypertension.

An external ventricular drain is indicated for the emergency management of hydrocephalus and monitoring of intracranial pressure. Up to 26% of patients require a ventriculoperitoneal shunt.

Multimodal monitoring may help to determine the optimal cerebral perfusion pressure threshold.

Euvolemia is the target for volume status.

The patients diagnosed with SAH should be treated at high-volume centers (>35 cases per year).

Aneurysm Repair

The treatment modalities coiling and clipping depend on the clinical condition of the patient and the anatomy of the aneurysm.

A case discussion among experts should determine the appropriate treatment modality and the patient should be treated in a specialized neurointensive care unit.

Delayed Cerebral Ischemia

Monitoring for delayed cerebral ischemia with frequent neurological exams and/or transcranial Doppler sonography is mandatory in good-grade patients. A change in clinical examinations or an increase in mean flow velocities >200 cm/s or in the Lindegaard ratio >6 should trigger a vascular imaging study. A clinical examination in an awake patient is often more helpful, as the sensitivity of the diagnosis of vasospasm by transcranial Doppler sonography is rather low.

Poor-grade patients require different monitoring techniques in addition to transcranial Doppler sonography

Medical treatment of delayed cerebral ischemia consists of induced hypertension and/or augmentation of cardiac output. Balloon angioplasty and intra-arterial vasodilators are endovascular treatment options.

Electrolyte Disturbances

Hyponatremia, hypomagnesemia, hypokalemia and hypernatremia are also common after SAH and should be corrected.

Treatment of Medical Complications

Intensive care management should target normothermia and normoglycemia avoiding hypoglycemia, treatment of myocardial dysfunction and pulmonary edema.

Prognosis

With further reduction of mortality by improved repair techniques and critical care management, the long-term outcome after SAH has improved, especially in poor-grade patients.

Older age, poor clinical grade upon presentation, rebleeding, larger aneurysm size, global cerebral edema, delayed cerebral ischemia and medical complications impact functional outcome after SAH.

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Papers of special note have been highlighted as:

* of interest

** of considerable interest

Website

301. The STASH trial. www.stashtrial.comReviewWartenberg

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Web viewaneurysm.[21,22] Preretinal or subhyaloid hemorrhages – large, smooth bordered and on the retinal surface – occur in up to 25% of patients.[23]