CANADIAN STROKE BEST PRACTICE RECOMMENDATIONS. Hyperacute Stroke Care Evidence Tables Acute Subarachnoid Hemorrhage

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1 CANADIAN STROKE BEST PRACTICE RECOMMENDATIONS Acute Subarachnoid Hemorrhage Update 2015 Casaubon LK, Boulanger JM (Writing Group Chairs) on Behalf of the Stroke Hyperacute Stroke Writing Group 2015 Heart and Stroke Foundation

2 Table of Contents Search Strategy... 3 Published Guidelines... 4 Accuracy of Imaging, Lumbar Puncture & Clinical Decision Rules to Detect SAH Blood Pressure Management Treatment of Cerebral Vasospasm Surgical Interventions Prophylactic Seizure Treatment Reference List Acute Subarachnoid Hemorrhage

3 Search Strategy Identification Cochrane, Medline, and CINAHL and National Guideline Clearing House were searched Screening Titles and Abstracts of each study were reviewed. Bibliographies of major reviews or meta-analyses were searched for additional relevant articles Eligibility Excluded articles: Non-English, Commentaries, Case-Studies, Narratives, Book Chapters, Editorials, Non-systematic Reviews (scoping reviews), and conference abstracts. Included Articles: English language articles, RCTs, observational studies and systematic reviews/meta-analysis. Relevant guidelines addressing the topic were also included. Included A total of 17 Articles and 4 Guidelines Cochrane, Medline, CINAHL, and National Guideline Clearing House were search using the medical subject headings (*Aneurysm, Ruptured/ or *Subarachnoid Hemorrhage AND *Emergency Service, Hospital/ OR Assessment or Acute). Titles and abstract of each article were reviewed for relevance. Bibliographies were reviewed to find additional relevant articles. Articles were excluded if they were: non-english, commentaries, casestudies, narrative, book chapters, editorials, non-systematic review, or conference abstracts. Additional searches for relevant best practice guidelines were completed and included in a separate section of the review. A total of 17 articles and 4 guidelines were included and were separated into separate categories designed to answer specific questions. Acute Subarachnoid Hemorrhage

4 Published Guidelines Guideline Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G: European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis 2013;35: (Selected) Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Recommendations Recommendation for Diagnosis CT/CTA and MRI with multiple sequences are equally suitable for the diagnosis of SAH within 24 h (class II, level B) CT/CTA and multisequential MRI/MRA may confirm the underlying cause Lumbar puncture must be performed in a case of clinically suspected SAH if CT or MRI does not confirm the diagnosis (class II, level B); however, within the first 6 12 h the differentiation between genuine subarachnoidal blood and traumatic admixture of blood may be difficult DSA of all cerebral arteries should be performed if a bleeding source was not found on CTA and the patient has a typical basal SAH pattern on CT (class II, level B) If no aneurysm was found, CTA or DSA should be repeated as described below: SAH without aneurysm (class III, level C) Recommendation for Blood Pressure Management Until coiling or clipping, systolic blood pressure should be kept below 180 mm Hg; this may be already achieved by applying analgetics and nimodipine (GCP) If systolic pressure remains high despite these treatments further lowering of blood pressure should be considered (class IV, level C) If blood pressure is lowered the mean arterial pressure should be kept at least above 90 mm Hg (GCP) Recommendation for Seizure Management Antiepileptic treatment should be administered in patients with clinically apparent seizures (GCP) There is no evidence that supports the prophylactic use of antiepileptic drugs (class IV, level C) Recommendation on Other Pharmacological Prevention of Delayed Ischaemic Events Magnesium sulphate is not recommended for the prevention of DCI (class I, level A) Statins are under study Recommendation on Pharmacological Prevention of Delayed Ischemic Deficit with Nimodipine Nimodipine should be administered orally (60 mg/4 h) to prevent delayed ischaemic events (class I, level A) In case oral administration is not possible nimodipine should be applied intravenously (GCP) Class I Recommendations 1. Treatment of high blood pressure with antihypertensive medication is recommended to prevent ischemic stroke, Intracerebral hemorrhage, and cardiac, renal, and other end-organ injury. Oral nimodipine should be administered to all patients with asah. (It should be noted that this agent has been shown to Acute Subarachnoid Hemorrhage

5 Guideline Association E. Sander Connolly, Jr, Alejandro A. Rabinstein, J. Ricardo Carhuapoma, Colin P. Derdeyn, Jacques Dion, Randall T. Higashida, Brian L. Hoh, Catherine J. Kirkness, Andrew M. Naidech, Christopher S. Ogilvy, Aman B. Patel, B. Gregory Thompson, and Paul Vespa, on behalf of the American Heart Association Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Nursing, Council on Cardiovascular Surgery and Anesthesia, and Council on Clinical Cardiology Stroke. 2012; 43: Recommendations improve neurological outcomes but not cerebral vasospasm. The value of other calcium antagonists, whether administered orally or intravenously, remains uncertain.) Hypertension should be treated, and such treatment may reduce the risk of asah Tobacco use and alcohol misuse should be avoided to reduce the risk of asah.after any aneurysm repair, immediate cerebrovascular imaging is generally recommended to identify remnants or recurrence of the aneurysm that may require treatment. The initial clinical severity of asah should be determined rapidly by use of simple validated scales (eg, Hunt and Hess, World Federation of Neurological Surgeons), because it is the most useful indicator of outcome after asah. The risk of early aneurysm rebleeding is high and is associated with very poor outcomes. Therefore, urgent evaluation and treatment of patients with suspected asah is recommended. asah is a medical emergency that is frequently misdiagnosed. A high level of suspicion for asah should exist in patients with acute onset of severe headache. Acute diagnostic workup should include noncontrast head CT, which, if nondiagnostic, should be followed by lumbar puncture. DSA with 3-dimensional rotational angiography is indicated for detection of aneurysm in patients with asah (except when the aneurysm was previously diagnosed by a noninvasive angiogram) and for planning treatment (to determine whether an aneurysm is amenable to coiling or to expedite microsurgery). Between the time of asah symptom onset and aneurysm obliteration, blood pressure should be controlled with a titratable agent to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure. Surgical clipping or endovascular coiling of the ruptured aneurysm should be performed as early as feasible in the majority of patients to reduce the rate of rebleeding after asah. Complete obliteration of the aneurysm is recommended whenever possible. For patients with ruptured aneurysms judged to be technically amenable to both endovascular coiling and neurosurgical clipping, endovascular coiling should be considered. In the absence of a compelling contraindication, patients who undergo coiling or clipping of a ruptured aneurysm should have delayed follow-up vascular imaging (timing and modality to be individualized), and strong consideration should be given to retreatment, either by repeat coiling or microsurgical clipping, if there is a clinically significant (eg, growing) remnant. Low-volume hospitals (eg, _10 asah cases per year) should consider early transfer of patients with asah to high-volume centers (eg, _35 asah cases per year) with experienced cerebrovascular surgeons, endovascular specialists, and multidisciplinary neuro-intensive care services. Maintenance of euvolemia and normal circulating blood volume is recommended to prevent DCI. Induction of hypertension is recommended for patients with DCI unless blood pressure is elevated at baseline or cardiac status precludes it. asah-associated acute symptomatic hydrocephalus should be managed by cerebrospinal fluid diversion (EVD or lumbar drainage, depending on the clinical scenario). Acute Subarachnoid Hemorrhage

6 Guideline Recommendations Heparin-induced thrombocytopenia and deep venous thrombosis, although infrequent, are not uncommon occurrences after asah. Early identification and targeted treatment are recommended, but further research is needed to identify the ideal screening paradigms. Determination of aneurysm treatment, as judged by both experienced cerebrovascular surgeons and endovascular specialists, should be a multidisciplinary decision based on characteristics of the patient and the aneurysm. asah-associated chronic symptomatic hydrocephalus should be treated with permanent cerebrospinal fluid diversion. New Recommendations In addition to the size and location of the aneurysm and the patient s age and health status, it might be reasonable to consider morphological and hemodynamic characteristics of the aneurysm when discussing the risk of aneurysm rupture.class IIb, Level B Consumption of a diet rich in vegetables may lower the risk of asah. Class IIb, Level B After any aneurysm repair, immediate cerebrovascular imaging is generally recommended to identify remnants or recurrence of the aneurysm that may require treatment. Class I, Level B After discharge, it is reasonable to refer patients with asah for a comprehensive evaluation, including cognitive, behavioral, and psychosocial assessments. Class IIa, Level B CTA may be considered in the workup of asah. If an aneurysm is detected by CTA, this study may help guide the decision for the type of aneurysm repair, but if CTA is inconclusive, DSA is still recommended (except possibly in the instance of classic perimesencephalic SAH). Class IIb, Level C Magnetic resonance imaging (fluid-attenuated inversion recovery, proton density, diffusion-weighted imaging, and gradient echo sequences) may be reasonable for the diagnosis of SAH in patients with a nondiagnostic CT scan, although a negative result does not obviate the need for cerebrospinal fluid analysis. Class IIb, Level C DSA with 3-dimensional rotational angiography is indicated for detection of aneurysm in patients with asah (except when the aneurysm was previously diagnosed by a noninvasive angiogram) and for planning treatment (to determine whether an aneurysm is amenable to coiling or to expedite microsurgery). Class I, Level B Between the time of asah symptom onset and aneurysm obliteration, blood pressure should be controlled with a titratable agent to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure. Class I, Level B The magnitude of blood pressure control to reduce the risk of rebleeding has not been established, but a decrease in systolic blood pressure to 160 mm Hg is reasonable. Class IIa, Level C In the absence of a compelling contraindication, patients who undergo coiling or clipping of a ruptured aneurysm should have delayed follow-up vascular imaging (timing and modality to be individualized), and strong consideration should be given to retreatment, either by repeat coiling or microsurgical clipping, if there is a clinically significant (eg, growing) remnant. Class I, Level B Microsurgical clipping may receive increased consideration in patients presenting with large (>50 ml) intraparenchymal hematomas and middle cerebral artery aneurysms. Endovascular coiling may receive increased consideration in the elderly (70 y of age), in those presenting with poor-grade WFNS classification (IV/V) asah, and in those with aneurysms of the basilar Acute Subarachnoid Hemorrhage

7 Guideline Recommendations apex. Class IIb, Level C Stenting of a ruptured aneurysm is associated with increased morbidity and mortality. Class III, Level C Annual monitoring of complication rates for surgical and interventional procedures is reasonable. Class IIa, Level C A hospital credentialing process to ensure that proper training standards have been met by individual physicians treating brain aneurysms is reasonable. Class IIa, Level C Prophylactic hypervolemia or balloon angioplasty before the development of angiographic spasm is not recommended. Class III, Level B Transcranial Doppler is reasonable to monitor for the development of arterial vasospasm. Class IIa, Level B Perfusion imaging with CT or magnetic resonance can be useful to identify regions of potential brain ischemia. Class IIa, Level B Weaning EVD over 24 hours does not appear to be effective in reducing the need for ventricular shunting. Class III, Level B Routine fenestration of the lamina terminalis is not useful for reducing the rate of shunt-dependent hydrocephalus and therefore should not be routinely performed. Class III, Level B Aggressive control of fever to a target of normothermia by use of standard or advanced temperature modulating systems is reasonable in the acute phase of asah. Class IIa, Level B The use of packed red blood cell transfusion to treat anemia might be reasonable in patients with asah who are at risk of cerebral ischemia. The optimal hemoglobin goal is still to be determined. Class IIb, Level B Heparin-induced thrombocytopenia and deep venous thrombosis are relatively frequent complications after asah. Early identification and targeted treatment are recommended, but further research is needed to identify the ideal screening paradigms. Class I, Level B Revised Recommendations For patients with an unavoidable with delay in obliteration of aneurysm, a significant risk of rebleeding, and no compelling medical contraindications, short-term (<72 hours) therapy with tranexamic acid or aminocaproic acid is reasonable to reduce the risk of early aneurysm rebleeding. Class IIa, Level B Determination of aneurysm treatment, as judged by both experienced cerebrovascular surgeons and endovascular specialists, should be a multidisciplinary decision based on characteristics of the patient and the aneurysm. Class I, Level C For patients with ruptured aneurysms judged to be technically amenable to both endovascular coiling and neurosurgical clipping, endovascular coiling should be considered. Class I, Level B Low-volume hospitals (eg,<10 asah cases per year) should consider early transfer of patients with asah to high-volume centers (eg,>35 asah cases per year) with experienced cerebrovascular surgeons, endovascular specialists, and multidisciplinary neuro-intensive care services. Class I, Level B Maintenance of euvolemia and normal circulating blood volume is recommended to prevent DCI. Class I, Level B Induction of hypertension is recommended for patients with DCI unless blood pressure is elevated at baseline or cardiac status Acute Subarachnoid Hemorrhage

8 Guideline Diringer MN, Bleck TP, Claude HJ, III, Menon D, Shutter L, Vespa P, Bruder N, Connolly ES, Jr., Citerio G, Gress D, Hanggi D, Hoh BL, Lanzino G, Le RP, Rabinstein A, Schmutzhard E, Stocchetti N, Suarez JI, Treggiari M, Tseng MY, Vergouwen MD, Wolf S, Zipfel G: Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit Care 2011;15: (Selected) Recommendations precludes it. Class I, Level B Cerebral angioplasty and/or selective intra-arterial vasodilator therapy is reasonable in patients with symptomatic cerebral vasospasm, particularly those who are not rapidly responding to hypertensive therapy. Class IIa, Level B asah-associated acute symptomatic hydrocephalus should be managed by cerebrospinal fluid diversion (EVD or lumbar drainage, depending on the clinical scenario). Class I, Level B asah-associated chronic symptomatic hydrocephalus should be treated with permanent cerebrospinal fluid diversion. Class I, Level C Medical Measures to Prevent Rebleeding Early aneurysm repair should be undertaken, when possible and reasonable, to prevent rebleeding (High Evidence; Strong Recommendation). An early, short course of antifibrinolytic therapy prior to early aneurysm repair (begun at diagnosis; continued up to the point at which the aneurysm is secured or at 72 h post-ictus, whichever is shorter) should be considered (Low Evidence; Weak Recommendation). Delayed (>48 h after the ictus) or prolonged (>3 days) antifibrinolytic therapy exposes patients to side effects of therapy when the risk of rebleeding is sharply reduced and should be avoided (High Evidence; Strong Recommendation). Antifibrinolytic therapy is relatively contraindicated in patients with risk factors for thromboembolic complications (Moderate Evidence; Strong Recommendation). Patients treated with antifibrinolytic therapy should have close screening for deep venous thrombosis (Moderate Evidence; Strong Recommendation). Antifibrinolytic therapy should be discontinued 2 h before planned endovascular ablation of an aneurysm (Very Low Evidence; Weak Recommendation). When CTA and DSA are both available and CTA is of high technical quality, CTA should be performed preferentially if endovascular intervention is not planned at the time of angiography (Very Low Evidence; Weak Recommendation) Treat extreme hypertension in patients with an unsecured, recently ruptured aneurysm. Modest elevations in blood pressure (mean blood pressure <110 mmhg) do not require therapy. Pre-morbid baseline blood pressures should be used to refine targets; hypotension should be avoided (Low Evidence; Strong Recommendation). Seizures and Prophylactic Anticonvulsant Use Routine use of anticonvulsant prophylaxis with phenytoin is not recommended after SAH (low quality evidence strong recommendation). Routine use of other anticonvulsants for prophylaxis may be considered (very low quality evidence weak recommendation). If anticonvulsant prophylaxis is used, a short course (3 7 days) is recommended (low quality evidence weak recommendation). In patients who suffer a seizure after presentation, anticonvulsants should be continued for a duration defined by local Acute Subarachnoid Hemorrhage

9 Guideline Recommendations practice (low quality evidence weak recommendation). Continuous EEG monitoring should be considered in patients with poor-grade SAH who fail to improve or who have neurological deterioration of undetermined etiology (low quality evidence strong recommendation). Cardiopulmonary Complications Monitoring Baseline cardiac assessment with serial enzymes, electrocardiography, and echocardiography is recommended, especially in patients with evidence of myocardial dysfunction (Low quality evidence; Strong Recommendation). Monitoring of cardiac output may be useful in patients with evidence of hemodynamic instability or myocardial dysfunction. (Low quality evidence; Strong Recommendation). Treatment In case of pulmonary edema or evidence of lung injury, the goal of therapy should include avoiding excessive fluid intake and judicious use of diuretics targeting euvolemia (Moderate quality evidence; Strong recommendation). Standard management of heart failure is indicated with the exception that CPP/MAP should be maintained as appropriate for the neurological condition. (Moderate quality evidence; Strong recommendation). Monitoring Intravascular Volume Status Monitoring of volume status may be beneficial (Moderate quality evidence; weak recommendation). Vigilant fluid balance management should be the foundation for monitoring intravascular volume status. While both non-invasive and invasive monitoring technologies are available, no specific modality can be recommended over clinical assessment (Moderate quality evidence; weak recommendation). Central venous lines should not be placed solely to obtain CVP measures and fluid management based solely on CVP measurements is not recommended (Moderate quality evidence; strong recommendation). Use of PACs incurs risk and lacks evidence of benefit. Routine use of PACs is not recommended (Moderate quality evidence; strong recommendation). Managing Intravascular Volume Status Intravascular volume management should target euvolemia and avoid prophylactic hypervolemic therapy. In contrast, there is evidence for harm from aggressive administration of fluid aimed at achieving hypervolemia (high quality evidence; strong recommendation). Isotonic crystalloid is the preferred agent for volume replacement (Moderate quality evidence; weak recommendation). In patients with a persistent negative fluid balance, use of fludrocortisone or hydrocortisone may be considered (moderate quality evidence; weak recommendation). Glucose Management Acute Subarachnoid Hemorrhage

10 Guideline Recommendations Hypoglycemia (serum glucose <80 mg/dl) should be avoided (High quality evidence-strong recommendation). Serum glucose should be maintained below 200 mg/dl (Moderate quality evidence-strong recommendation). If microdialysis is being used, serum glucose may be adjusted to avoid low cerebral glucose (Very low quality evidence-weak recommendation). Monitoring for Delayed Cerebral Ischemia (DCI) and Triggers for Intervention Monitoring for neurological deterioration, and specifically DCI, should take place in an environment with substantial multidisciplinary expertise in the management of SAH (Moderate quality evidence strong recommendation). Patients at high risk for DCI should be closely monitored throughout the at risk period. This is best accomplished in an ICU setting where additional monitoring and treatment can be rapidly implemented (Very low quality evidence-strong recommendation). Oral nimodipine (60 mg every 4 h) should be administered after SAH for a period of 21 days (High quality evidence strong recommendation). Imaging of vascular anatomy and/or perfusion can be used to confirm a diagnosis of DCI in monitored good-grade patients who show a change in neurologic exam or TCD variables (Strong quality evidence strong recommendation). A strategy for detection and confirmation of DCI should be employed. This should first and foremost involve frequent repeat neurological assessment by qualified providers. Intermittent screening or more continuous monitoring methods may additionally be used. TCD may be used for monitoring and detection of large artery vasospasm with variable sensitivity. Thresholds of mean blood flow velocities <120 cm/s for absence and >200 cm/s and/or MCA/ICA ratio >6 for presence are reasonable (Moderate quality evidence strong recommendation). DSA is the gold standard for detection of large artery vasospasm (High quality evidence strong recommendation). High quality CTA can be used for screening for vasospasm, and due to its high specificity may reduce the need for DSA studies (Low quality evidence weak recommendation). CTP findings of elevated MTT > 6.4 s may be additive to CTA findings in predicting DCI (Low quality evidence weak recommendation). EEG, PbtO 2 monitoring, and CMD may all be useful physiological monitors for DCI detection. Data from probes should be interpreted in light of its limited field of view and location in relation to pathology. The relative value of these monitors individually versus as part of a multi-modality monitoring strategy is not known (Low quality evidence weak recommendation). In high risk patients who have a clinical picture strongly suggestive of DCI, and in whom elective screening CTA/CTP or DSA has already demonstrated vasospasm/dci, it is reasonable to initiate medical therapy without further investigations (Moderate quality evidence-strong recommendation). Acute Subarachnoid Hemorrhage

11 Guideline Recommendations In patients where there is clinical uncertainty regarding the cause of neurological deterioration, DSA is indicated if an endovascular intervention is planned (Moderate quality evidence strong recommendation). In sedated or poor-grade SAH patients, clinical deterioration may be difficult to assess, and TCD, continuous EEG, PbtO 2 monitoring, and/or CMD are options for monitoring for vasospasm and DCI (Low quality evidence-weak recommendation). Elective screening with CTP/CTA or DSA on may provide additional information (Low quality evidence-weak recommendation). High Volume Centers Patients with SAH should be treated at high volume centers (Moderate quality evidence strong recommendation). High volume centers should have appropriate specialty neurointensive care units, neurointensivists, vascular neurosurgeons and interventional neuroradiologists to provide the essential elements of care (Moderate quality evidence strong recommendation American Association of Neuroscience Nurses. Care of the patient with aneurysmal subarachnoid hemorrhage. Glenview (IL): American Association of Neuroscience Nurses; 2009 Dec. 30 p. Patient Care Preaneurysm Securement Assessment Upon admission of the patient to the intensive care unit (ICU), hourly neurologic exam checks (including a complete neurologic exam, National Institutes of Health Stroke Scale, Glasgow Coma Scale, and hemodynamic monitoring) are performed and compared to baseline to detect early deterioration because of aneurysmal rebleed, acute hydrocephalus, ischemia related to inadequate cerebral perfusion (from early cerebral vasospasm or other causes), or other medical complications. Airway and Oxygenation Intubation and mechanical ventilation may be indicated for patients with decreased mental status, compromised airways, or acute lung injuries from subarachnoid hemorrhage (SAH; e.g., neurogenic pulmonary edema), aspiration, or a Glasgow Coma Scale motor score of withdrawal. Modes of ventilation vary, especially in patients who have pulmonary complications following SAH. The goal is to maintain adequate oxygenation and ventilation without compromising both intracranial and cerebral perfusion pressures. Positive end expiratory pressure of 5 cm H2O may be used cautiously in the asah patient; however, it does decrease blood pressure (BP) and may lead to cerebral ischemia (Level 2; Muench et al., 2005). Pressure-controlled ventilation should be considered if the patient has significant aspiration or early acute respiratory distress syndrome. Patients recovering from asah are critically ill patients at risk for many common secondary injuries such as atelectasis and pneumonia. Hourly monitoring of breath sounds and frequent deep breathing should be encouraged. Coughing is discouraged in the SAH patient before aneurysm securement because of the increased risk of aneurysm rupture with the increased intracranial pressure (ICP) and BP that occurs during coughing. BP Management The exact relationship between aneurysmal rebleed and BP remains to be identified; however, most clinicians agree that to prevent rebleed, BP control is achieved before aneurysm securement. Systolic BP is kept between 90 and 140 mm Hg before Acute Subarachnoid Hemorrhage

12 Guideline Recommendations aneurysm securement (Level 3; Suarez, Tarr, & Selman, 2006). There are a variety of vasoactive agents used to maintain BP within an acceptable range. Choice of vasoactive agent and BP target range varies depending upon institutional policy (i.e., policy and procedures) and managing clinician preference. Some institutions require clinicians to follow systolic BP, and other institutions follow mean arterial pressure. Typically, BP is maintained within the target range using an initial bolus followed by commencement of an intravenous (IV) drip that is titrated to maintain BP within the target range (Level 2; Kraus, Metzler, & Coplin, 2002). Use of sublingual agents that may cause a rapid drop in BP is not recommended. BP should be lowered in a controlled manner as a sudden drop in BP increases the risk of cerebral ischemia. Hypotension occurring before aneurysm securement places the patient recovering from asah at risk for ischemia. Hypotension should be treated with rapid IV fluid replacement beginning with isotonic saline (0.9%) and colloids as necessary. For persistent hypotension, IV vasopressors should be instituted. Intracranial Pressure Monitoring When a patient shows symptoms of increasing ICP, or is at increased risk of increased ICP because of large blood load, an external ventricular catheter or subarachnoid bolt is inserted. This can be done in the operating room (during surgical clipping or as a separate surgical procedure) or emergently at the bedside to decrease ICP. Poor clinical grade on admission, acute neurologic deterioration, or progressive enlargement of ventricles on CT scan are clear indications for the use of an external ventricular device (Level 2; Mayberg et al., 1994; Rordorf et al., 1997; Suzuki et al., 2000). Newer data suggest that external ventricular drainage does not include likelihood of aneurysm rehemorrhage when drainage is performed at moderate pressures (<10 cm H2O) (Level 2; Fountas et al., 2006). Aseptic technique is essential during external ventricular drain or subarachnoid bolt insertion because an infection can occur, especially if the drain is left in for an extended period of time. Cultures are to be routinely performed, and antibiotics are initiated if any signs of infection are present. Some clinicians and institutions use prophylactic antibiotics for asah patients with an external ventricular drain, although there is no literature supporting this practice. Although all of these catheters allow monitoring of ICP, the external ventricular catheter permits cerebral spinal fluid (CSF) drainage to control ICP and clear blood from the CSF. The external ventricular catheter is associated with a higher infection rate than other catheters (Level 2; Lozier et al., 2002). Care related to CSF management varies by institution and clinician preference. Continuous drainage of CSF from an external ventricular drain (EVD) at a specified level (above the external auditory meatus or foramen of Monroe as per institutional policy) prevents ICP from rising above that level and allows for continuous clearance of bloody CSF from the ventricles and subarachnoid space (see Guide to the Care of the Patient with Intracranial Pressure Monitoring: AANN Reference Series for Clinical Practice). In febrile patients (temperature 38.3ºC or as per institutional policy), fever reduction should be achieved with administration of acetaminophen every 4 6 hours to achieve normothermia (Level 3; Suarez, Tarr, & Selman, 2006). Surface or intravascular cooling is instituted to maintain temperature <38.3ºC if medications are not effective (Level 3; Suarez, Tarr, & Selman, 2006). It is important to control fever in this population as it is associated with poorer recovery from asah (Level 2; Commichau, Scarmeas, & Mayer, 2003; Fernandez et al., 2007). Surveillance cultures may be obtained daily in patients receiving cooling therapy, otherwise cultures should be obtained per Society of Critical Care Medicine guidelines (Level 3; O'Grady et al., 1998). In patients receiving surface cooling, monitor and treat shivering with warm compresses to the hands and sedation or paralytics as needed. Induced hypothermia is not routinely recommended (Level 2; Bederson et al., 2009) Acute Subarachnoid Hemorrhage

13 Guideline Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage Cruickshank A, Auld P, Beetham R et al. Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann Clin Biochem 2008;45(Pt 3): (Selected) Recommendations Reporting and interpretation of net bilirubin absorbance (NBA) and net oxyhaemoglobin absorbance (NOA) of absorbance units (AU) of Cerebrospinal fluid (CSF) bilirubin spectrophotometry : NBA AU and NOA 0.02 AU. Report as: Bilirubin and oxyhaemoglobin not increased. No evidence to support SAH. NBA AU and NOA >0.02 AU but <0.1 AU. Report as: Bilirubin not increased. Small amount of oxyhaemoglobin detected. No evidence to support SAH. NBA AU and NOA 0.1 AU. Report as: Oxyhaemoglobin is present in sufficient concentration to impair the ability to detect bilirubin. SAH not excluded. When NBA >0.007 AU and NOA 0.02 AU or NOA >0.02 AU but with no visible oxyhaemoglobin peak: a) Serum bilirubin 20 mmol/l and CSF protein 1.0 g/l. Report as: Increased CSF bilirubin. Consistent with SAH. (This would be an unusual pattern within the first week after an event.) (b) Serum bilirubin >20 mmol/l and CSF protein 1.0 g/l. Apply formula to calculate an adjusted NBA (Appendix 2). If adjusted NBA > AU then report as: Increased CSF bilirubin. Consistent with SAH. (This would be an unusual pattern within the first week after an event.) If adjusted NBA AU then report as: Increased CSF bilirubin but probably totally accounted for by increase in serum bilirubin. Not supportive of SAH. (c) CSF protein >1.0 g/l, whatever the serum bilirubin. Report as: Increased CSF bilirubin. This finding may be consistent with: SAH; an increased bilirubin accompanying the increased CSF protein; or other source of CSF blood. Interpret result with caution in relation to SAH especially if within first week of event. NBA >0.007 AU and NOA >0.02 AU with visible oxyhaemoglobin peak Report as Bilirubin and oxyhaemoglobin increased. Consistent with SAH. Acute Subarachnoid Hemorrhage

14 Accuracy of Imaging, Lumbar Puncture & Clinical Decision Rules to Detect SAH Perry et al Canada Prospective cohort Backes et al Netherlands Retrospective study NA NA 2131 patients >15 years, admitted to 10 institutions ( ), presenting with nontraumatic acute headache peaking within 1 hour, presenting within 14 days of symptom onset. Mean age was 44.1 years. 60.5% were women and 26.2% arrived by ambulance. 205 patients admitted with suspicion of SAH to a single facility from Median age was 48 years, 67% women. 3 candidate rules were evaluated. The reference standard was any one of following items: positive findings on unenhanced CT, xanthochromia in CSF or the presence of RBCs in CSF with positive results on cerebral angiogram. All investigations were performed at the discretion of the treating physician. In cases where patients were discharged from hospital without both a CT and lumbar puncture, were evaluated using the proxy Outcome Assessment Tool, which included a structured interview conducted by telephone at 1 and 6 months and a review of medical records As part of standard protocol, all patients received a CT scan. A lumbar puncture was performed when plain CT was negative. CSF was inspected visually and by spectrophotometry The accuracy (sensitivity/specificity) of clinical decision-making rules to identify SAH were compared with the reference standard The accuracy of CTs performed 6 hours and > 6 hours after ictus, to identify nontraumatic SAH was evaluated. 132 patients (6.2%) were identified with SAH. 80% of eligible patients received a CT, 45% underwent lumbar puncture. The Ottawa SAH rule was developed, with the addition of 2 variables to one of the existing clinical decision rules, which produced the most accurate model. The best model to identify SAH included: age 40 years, the presence of neck pain or stiffness, witnessed LOC, onset during exertion, limited neck flexion and thunderclap headache yielding a sensitivity of 100% (95% CI 97.2%-100%), specificity of 15.3% (95% CI 13.8%-16.9%) and c statistic of 0.60 (95% CI ) 137 patients received a CT 6 hours after ictus and 113 received a CT> 6 hours after ictus. SAH was identified in 68 who received a CT within 6 hours of symptom onset and in 37 patients who received a CT beyond 6 hours of symptoms. Of the 69 patients who received a CT within 6 hours with a negative or inconclusive finding, CSF was positive in 1 case. Of the 76 patients who received a CT >6 hours with a negative or inconclusive finding, CSF was positive in 5 cases. Acute Subarachnoid Hemorrhage

15 The sensitivity and specificity of CT to identify SAH when performed within 6 hours were 98.5% (95% CI 92.1%-100%) and 100% (95% CI 94.8%-100%) Perry et al Canada Prospective cohort Perry et al Canada Prospective cohort NA NA 3,132 consecutive alert (GCS=15) patients >15 years, admitted to 11 institutions ( ), presenting with nontraumatic acute headache or with syncope associated with headache who underwent emergency head CT, using third generation scanners as part of their diagnostic investigation. Patients were excluded if onset of headache was > 14 days, history of recurrent headaches, focal neurological deficits; papilloedema or history aneurysm, ventricular shunt, or brain neoplasm 1999 alert (GCS score=15) patients aged 16 years admitted to 6 university-affiliated hospitals ( ) with non-traumatic acute headache peaking within an hour of syncope associated with headache. Radiologists who were blinded to the study and data forms but who had routine clinical information, interpreted all CT scans. The reference standard was presence of subarachnoid blood identified on unenhanced CT, visible xanthochromia in the cerebrospinal fluid; or red blood cells (>5 106/L) in the final tube of cerebrospinal fluid collected and an aneurysm identified on cerebral angiography. All patients received routine care/imaging/investigations as per standard hospital protocols. Data associated with 26 possible predictors of SAH were also collected by study personnel. The sensitivity (SN), specificity (SP), + predictive value (PPV), - predictive value (NPP), + likelihood ratio) +LR) and likelihood ratio (-LR) of CT to identify SAH were calculated. Results were stratified by time to CT ( 6 or >6 hours). SAH (diagnosed by unenhanced CT, xanthochromia in CSF or the presence of RBCs in CSF with positive results on cerebral angiogram Clinical decision making rules to determine the need for investigation were developed models based on the results of univariate analyses. The sensitivity and specificity of CT to identify SAH when performed beyond 6 hours were 90.0% (95% CI 76.3%-97.2%) and 100% (95% CI 95.1%-100%) Most patient in the entire cohort were young (mean age <45 years), 60.3% were women, mean pain score (0-10 scale) was % of patients had a CT scan within 6 hours of symptom onset, 49% underwent lumbar puncture after negative CT results. 240 patients (7.7%) were diagnosed with SAH. Overall: SN=93%, SN=100%, PPV=100%, NPP=99.4%, +LR=, -LR=0.07. (all 95% CIs were tight) For 953 patients who were scanned within 6 hours, SN, SP, PPV, and NPV were all 100% For 2,179 patients who were scanned > 6 hours: SN=85.7%, SP=100%, PPV=100%, NPV=99.2%, +LR=, -LR= patients (6.5%) were diagnosed with SAH. All but 9 were identified by the radiologist s final report. 7 patients had xanthochromia, 2 had RBS in CSF+ positive angiogram. Mean age was 43 years, 60.4% were female, 78.5% reported the worst headache of their lives. Patients with SAH were younger, more likely to describe worse pain, to have suffered OC, complained of neck pain/stiffness, vomited, arrived by ambulance and had higher blood pressure. Acute Subarachnoid Hemorrhage

16 Sensitivity (SN) and specificity (SP) were calculated. 3 rules were developed whereby patients should be investigated if any of the variables are present. Rule 1: age 40 yrs, neck pain or stiffness, witness LOC, onset with exertion (SN=100%, SP=28.4%) Cortnum et al Denmark Retrospective study Perry et al Canada Prospective cohort study NA NA 499 patients admitted to a single institution from with suspected/verified SAH 220 patients aged 16 years admitted to 6 university-affiliated hospitals ( ) with non-traumatic acute headache or syncope associated with a headache, peaking within 1 hour, and presenting within 14 The medical records were reviewed together with CT scan, angiography, and results from cerebral spinal fluid analysis by 2 members of the neurosurgical staff. Clinical history, examination findings, and time from onset of symptoms until CT scan (days) were also recorded. All patients received a CT scan. If the scan was positive, an angiography was performed. If the scan was negative, a lumbar puncture was performed. All enrolled patients had cerebrospinal fluid collected as part of their care, to exclude SAH. Fluid was examined for cell count and visible xanthochromia and spectrophotometry. 4 different definitions of positive spectrophotometry Sensitivity and specificity of CT to identify SAH. (Lumbar puncture was the referenced standard) Detection of xanthochromia using spectrophotometry Rule 2: arrival by ambulance, age 45 yrs, vomiting at least once and DBP>100 mm Hg (SN=100%, SP=36.5%) Rule 3: arrival by ambulance, SBP>160 mm Hg, neck pain/stiffness age yrs. (SN=100%, SP=38.8%) SAH was excluded in 203 patients based on the results of CT and lumbar puncture. 296 patients had confirmed SAH. Of these 295 were based on positive CT results. In a single patient, diagnosis was based on lumbar puncture performed on day 6. Overall CT scanning had a sensitivity of 99.7% (95% CI %) and a specificity of 100% ( %). 2 SAHs were identified, one with red blood cells without xanthochromia and one with visible xanthochromia in CSF. The sensitivity and specificities using the 4 definitions of xanthochromia were 100% (n=3) and 0% (n=1) for sensitivity and 26% (n=2), 83% (n=1) and 89% (n=1). The sensitivity and specify associated with visual Acute Subarachnoid Hemorrhage

17 days of symptom onset. Mean age: 42 years Patients were excluded if onset of headache was > 14 days, history of recurrent headaches, focal neurological deficits; papilloedema or history aneurysm, ventricular shunt, or brain neoplasm were used. The reference standard was presence of subarachnoid blood identified on unenhanced CT, visible xanthochromia in the cerebrospinal fluid; or red blood cells (>5 106/L) in the final tube of cerebrospinal fluid collected and an aneurysm identified on cerebral angiography. inspection were 50% and 97%, respectively Blood Pressure Management Dorhout Mees et al Netherlands Cochrane Review NA 16 RCTs (3361 patients) including patients of any age and either gender with SAH documented by either computerised tomography (CT) scan or cerebrospinal fluid examination were included. Mean ages of the patients ranged from 44 to 56 years. In 11 of the 13 trials of calcium antagonists versus placebo, the aneurysm was treated by surgical clipping; in six trials, the aneurysm was clipped in all patients, in the other five trials 30% to 60% of patients had their aneurysm clipped. Treatment contrasts were any calcium antagonist, (including magnesium sulphate) vs. control (n=13), or with a second calcium antagonist (magnesium sulphate) vs. control in addition to a calcium antagonist (n=3). Treatment was initiated within 4 days of SAH onset in 13 trials and within 10 days in 3 trials. Duration of treatment was 21 days (n=14), 9 days (n=1) and 30 days (n=1). Total daily doses of nimodipine were 360 mg (n=5), 540 mg (n=1), continuous infusion at 2 mg/hr (n=1), 2.1 mg/kg (n=1). Primary outcome: Poor outcome (death or dependence on help for ADLs), assessed within six months. Secondary outcomes: Case fatality, secondary ischemia, rebleeding within six month of SAH, adverse events Duration of follow-up was hospital LOS (n=1), 21 days (n=3), 1 month (n=2), 2-3 months (n=7), 3-6 months (n=2) and up to 3 years (n=1) (Any) treatment was associated with a significant reduction in the risk of poor outcome: RR= 0.81, 95% CI , p= Results from 9 trials included. The addition of magnesium to nimodipine was associated with a borderline reduction in the risk of poor outcome at 3 months: RR= 0.75, 95% CI , p=0.05. Results from 3 trials included. (Any) treatment was not associated with a reduction in case fatality: RR= 0.86, 95% CI , p= Results from 11 trials included. (Any) treatment was associated with a significant reduction in the risk of secondary ischemia: RR= 0.66, 95% CI , p< Results from 11 trials included. (Any) treatment was associated with a significant reduction in the risk of rebleeding during clinical course: RR= 0.75, 95% CI , p= Acute Subarachnoid Hemorrhage

18 In the three trials of magnesium sulphate versus placebo in addition to nimodipine, aneurysms were treated with surgical clipping (52% to 66% of all patients) as well as endovascular coiling (24% to 28% of all patients). There were two trials of nicardipine vs. placebo. In one, 180 mg per day were given for 21 days. In the other, i.v. nicardipine 0.15 mg/kg/hr was given for 14 days. Another trial studied AT877 (90 mg i.v. per day for 14 days). One study assessed magnesium sulphate vs. control in the absence of another calcium antagonist. In 3 trials patients were randomized to receive magnesium sulphate or placebo in addition to nimodipine. Results from 8 trials included. Treatment of Cerebral Vasospasm Pharmacological Interventions Kirkpatrick et al UK Simvastatin in Aneurysmal Subarachnoid Haemorrhage (STASH) RCT CA: þ Blinding: Patient þ Assessor þ ITT: þ 803 patients from 35 centres with confirmed SAH, aged years, presenting within 96 hours of symptom onset. Patients taking statin drugs at the time of stroke, or contraindicated medications, those with suspected drug or alcohol abuse and those with poor prospects for survival, were excluded. Patient were randomized to receive 40 mg simvastatin or placebo, as soon as possible, for 3 weeks Primary outcome: mrs at 6 months Secondary outcomes: Death at 6 months, delayed ischemic deficits (deterioration of 2 points on the Glasgow Coma Scale), delayed ischemic deficits requiring intensive care, sepsis, discharge destination and SF-36 At discharge there was no significant difference in the proportion of patients who experienced a good outcome (mrs 0-2) 59% (simvastatin) vs. 62% (placebo), adj OR=1.08, 95%CI , p=0.61. At 6 months, there was no significant difference in the proportion of patients who experienced a good outcome (mrs 0-2) 72% vs. 72% (adj OR=0.97, 95% CI , p=0.81), or death 10% vs. 9%, p In subgroup analysis of the primary outcome, age, World Federation of Neurological Science grade or Fisher grade on admission, the presence or absence of a motor deficit, the presence or Acute Subarachnoid Hemorrhage

19 absence of hydrocephalus, ventilator vs. no ventilator, aneurysm location or days to initiation of treatment were found to be significant effect modifiers. There were no significant differences between groups for any of the secondary outcomes. 18% of patients in each group experienced a serious adverse event. Baharoglu et al Cochrane review Netherlands NA 10 RCTs (n=1,904) including patients with clinical symptoms and signs of SAH resulting from a ruptured aneurysm. Trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) vs. control administered within 2 weeks of SAH. Duration of treatment ranged from >72 hours (n=1) to 6 weeks. In all other studies patients were treated for at least 10 days. Primary outcomes: Poor outcome (death, vegetative state, or severe disability, assessed using the Glasgow Outcome Scale or the Modified Rankin Scale) at the end of follow-up (3 month minimum) or all-cause mortality at 3 months. Secondary outcome: Rebleeding, cerebral ischaemia, and hydrocephalus There were 41 withdrawals from the simvastatin group and 50 from the placebo group. Treatment with antifibrinolytic drugs was not associated with the reduced risk of a poor outcome at the end of scheduled follow-up: RR= 1.02, 95% CI 0.91 to 1.15 (n=4 trials) or death from all causes: RR= 1.00, 95% CI 0.85 to 1.18 (n=10 trials). Treatment with antifibrinolytic therapy did significantly reduced the risk of rebleeding: RR=0.65, 95% CI 0.44 to 0.97; 78 per 1000 people (n=10 trials), but did significantly increase the risk of cerebral ischaemia: RR= 1.41, 95% CI 1.04 to 1.91; 83 per 1000 people (n=6 trials). There was no effect of treatment on the risk of hydrocephalus at the end of follow-up (RR= 1.11, 95% CI 0.90, n=5 trials). Vergouwen et al Systematic review & metaanalysis Netherlands NA 5 randomized, placebocontrolled trials (n=2601 patients) examining the effect of endothelial receptor antagonists in patients following asah. The 3 CONSCIOUS trials + 2 other RCTs were included. The age eligibility for the trials varied from >18 yrs. to 65, 70 and 75 yrs. Patients were randomized to receive: an escalating dose of TAK-044 (50 mg) for 10 days (n=1) or clazosentan at varying doses (n=4). Doses varied from 0.2 mg/kg/day, 1 mg/hr, 5 mg/hr and 15 mg/hr. The treatment period for all clazosentan trials was 14 days. Primary outcome: Poor outcome (defined as a Glasgow Outcome Scale of 1-3, or the Extended GOS score of 1-4) at 3 months. Secondary outcomes: Occurrence of angiographic vasospasm, new cerebral infarction, vasospasm related infarction and case fatality The risk of a poor outcome was not reduced significantly with endothelial receptor antagonist treatment (RR=1.06, 95% CI ). ARR was 2%, 95% CI -2% to 5%. Treatment with endothelial receptor antagonists significantly reduced the risk of angiographic vasospasm (RR=0.58, 95% CI ). ARR= - 29%, 95% CI -39% to -18%. The results from 2 trials were included. Treatment did not significantly reduce the risk of vasospasm-related infarction (RR=0.76, 95% CI Acute Subarachnoid Hemorrhage