(Revised from the previous guideline) Prophylactic antiseizure medication is not recom- mended (Class III; Level of Evidence B). (Unchanged from the previous guideline) Management of Medical Complications The frequency of medical complications after acute stroke is high, although there is substantially more information reported for ischemic stroke than ICH. In a trial of the safety and tolerability of NXY-059 (CHANT [Cerebral Hematoma and NXY Treatment]) in patients with sponta- neous ICH, at least 1 adverse event was reported in 88% of the placebo-treated patients, 40% of which were serious (ie, resulted in prolonged hospitalization, were immediately life threatening, or were fatal). The most common compli- cations were pneumonia (5.6%), aspiration (2.6%), respira- tory failure/distress (2%), PE (1.3%), and sepsis (1.7%).171 Approximately 50% of deaths after stroke are attributed to medical complications, usually after 7 days of hospitaliza- tion. Stroke patients who experience medical complications while in the hospital have increased mortality up to 4 years after the initial event. Dysphagia and aspiration are major risk factors for the development of pneumonia. Dysphagia is defined by swal- lowing impairment of the upper digestive tract and includes impairments in swallowing efficiency and safety, with delays in the timing of movements, reduced range of movements, and frank aspiration. Aspiration in this population is a sign of severe dysphagia and refers to abnormal entry of fluid, particulate exogenous substances, or endogenous secretions into the airways. In a retrospective study that included 90 Japanese ICH patients, 68% could not tolerate oral feed- In another German study of 208 ICH patients, 25% of patients required percutaneous endoscopic gastrostomy.173 In this study, GCS, occlusive hydrocephalus, mechanical venti- lation, and sepsis were independent risk factors for dyspha- gia and percutaneous endoscopic gastrostomy placement. In a prospective multicenter study, use of a formal screen- ing protocol for dysphagia (eg, water swallow test) for all patients admitted with ischemic stroke was associated with a significantly reduced risk of pneumonia compared with no The pneu- monia rate of sites with a formal dysphagia screen was 2.4% versus 5.4% of those without a screen, a 3% absolute risk reduction. Serious cardiac events and cardiac death after stroke may be caused by acute myocardial infarction (MI), heart failure, ventricular arrhythmias including ventricular tachycardia/ fibrillation, and cardiac arrest. Concurrent stroke and MI are not uncommon. Recent data from the prospective Austrian Stroke Unit Registry, which included 4984 ICH patients, found that 0.3% of patients had an MI over a median duration These patients not only experienced higher in- hospital mortality but also had greater complications, includ- ing pneumonia and progressive stroke. History of prior MI and severity of deficits on admission are associated with the occurrence of MI. In a meta-analysis of 65996 stroke patients with a mean follow-up of 3.5 years,176 the annual risk of MI was 2.2 %. For ICH patients, an elevated troponin level >0.4 ng/mL was found in 15% within 24 hours of admission and was associated with increased in-hospital mortality.21 In another study of 49 patients with supratentorial ICH, exclud- ing those who died within 12 hours or were moribund, 20% had elevated troponin levels, although this was not associated Heart failure can occur as the result of myocardial isch- emia, infarction, stress-induced cardiomyopathy, or uncon- trolled hypertension in the setting of acute ICH. Neurogenic pulmonary edema is an increase in interstitial and alveolar fluid in the setting of an acute central nervous system injury well documented in subarachnoid hemorrhage but prevalent in ICH as well.178 Neurogenic pulmonary edema presents abruptly and progresses quickly after the neurological insult. Radiographically, it is indistinguishable from cardiogenic pulmonary edema. Resolution usually occurs within several days. Intubation with mechanical ventilator support is often required for airway protection and maximum oxygen delivery. ICH patients may be at risk for acute respiratory distress syn- drome from multiple different origins179 ; however, at present, ways to prevent this have not been studied. When ICH patients develop acute respiratory distress syndrome, it is reasonable to use ventilation strategies used in non-neurological patients (such as low-tidal-volume ventilation)180 ; however, attention should be paid to avoid ICP elevations or inadequate cerebral oxygen delivery. Other medical complications in ICH patients include acute kidney injury, hyponatremia, gastrointestinal bleeding, impaired nutritional status, urinary tract infections, and post- stroke depression. Acute nephropathy (defined in a study by Oleinik et al181 as a rise in creatinine of at least 25% or 0.5 mg/ dL to a level of at least 1.5 mg/dL) occurred in 41 of 539 ICH patients (8%) admitted to a single institution over a 5-year period and was no more frequent in those who underwent which suggests that kidney injury was a result of overall medical status rather than this particular pro- cedure. Screening and monitoring are keys to detecting these events. Management at this time is focused on prevention and targeting these complications as they arise. Because of lim- ited information regarding ICH-specific issues related to ven- tilator-associated events, acute respiratory distress syndrome management, and acute kidney injury, these should be consid- ered areas for future study. The identification of preventive or treatment strategies for other medical complications will also require further studies focused on ICH patients. Management of Medical Complications: Recommendations A formal screening procedure for dysphagia should be performed in all patients before the initiation of oral intake to reduce the risk of pneumonia (Class I; Level of Evidence B). (New recommendation) Systematic screening for myocardial ischemia or infarction with electrocardiogram and cardiac enzyme testing after ICH is reasonable (Class IIa; Level of Evidence C). (New recommendation) Procedures/Surgery ICP Monitoring and Treatment Limited data exist regarding the frequency of elevated ICP and its management in patients with ICH.182 185 A recently reported Hemphill et al Management of Spontaneous ICH 2043 cohort study of 243 consecutive ICH patients described ICP episode of intracranial hypertension (defined as an ICP >20 In a randomized trial of intraventricular thrombol- ysis in 100 patients with intraventricular hemorrhage (IVH) and ICH smaller than 30 mm3 , ICP was >20 mmHg at the time of ventricular catheter (VC) insertion in 14 patients.184 Overall, however, ICP was not frequently elevated during monitoring and VC drainage in these patients. There is evidence for dif- ferential pressure gradients in at least some cases of ICH, so that ICP may be elevated in and around the hematoma but not distant from it.186 Because the usual causes of elevated ICP are hydrocephalus from IVH or mass effect from the hematoma (or surrounding edema), patients with small hematomas and limited IVH usually will not require treatment to lower ICP. Increased ICP also may be more common in younger patients and those with supratentorial ICH.185 Hydrocephalus is associ- ated with worsened outcome in acute ICH.187 189 patients with follow-up data who were randomized into the international Surgical Trial for Intracerebral Haemorrhage (STICH), 377 had IVH, and 208 of these had hydrocephalus (23% of all patients, 55% of those with IVH).190 ICP is measured by use of devices inserted into the brain parenchyma or cerebral ventricles. Fiber optic technology can be used in both types of devices. A VC inserted into the lat- eral ventricle allows for drainage of cerebrospinal fluid (CSF), which can help reduce ICP. A parenchymal ICP device is inserted into the brain parenchyma and allows for monitoring of ICP, but not CSF drainage. The absence of published stud- ies showing that management of elevated ICP has an effect on ICH outcome makes the decision whether to monitor and treat elevated ICP unclear in patients with ICH. Risks associated with ICP monitors include infection and intracranial hemor- rhage. The risk of hemorrhage or infection is thought to be higher with VC than with parenchymal catheters, although data on these rates are not derived from patients with ICH but principally from those with traumatic brain injury or aneurys- mal subarachnoid hemorrhage. In a 1997 series of 108 intrapa- renchymal devices, the rate of infection was 2.9% and the rate of intracranial hemorrhage was 2.1% (15.3% in patients with Two of 22 patients (9%) patients in the pla- cebo arm of a trial of intraventricular thrombolysis developed ventriculitis, but these patients had multiple intrathecal injec- tions, which could potentially increase the risk of infection.184 Before insertion of a monitoring device, the patient s coagula- tion status should be evaluated. Prior use of antiplatelet agents may justify platelet transfusion before the procedure, and the use of warfarin may require reversal of coagulopathy before placement. The decision to use a VC or a parenchymal cath- eter device should be based on whether there is a need to drain CSF to treat hydrocephalus or elevated ICP. Because of limited data regarding indications for monitor- ing and treatment of ICP in ICH, management principles for elevated ICP are usually generalized from those for traumatic brain injury, in which current guidelines recommend place- ment of an ICP monitor in patients with a GCS score of 3 to 8 and maintenance of an ICP <20 mmHg and a CPP of 50 to 70 mmHg, depending on the status of cerebral autoregula- Data from small, retrospectively analyzed cohorts of ICH patients suggest that rising ICP and declining CPP are associated with mortality.184,195,196 In 1 study of multimodality monitoring in 18 ICH patients, CPP <70 to 80 mmHg was associated with brain tissue hypoxia and poor outcome.195 Thus, ICP monitoring and subsequent treatment might be considered in ICH patients with a GCS score of 8 that is presumed related to hematoma mass effect, those with clinical evidence of transtentorial herniation, or those with significant IVH or hydrocephalus. Methods of treating elevated ICP are generally borrowed from traumatic brain injury guidelines as well. Basic princi- ples include elevation of the head of the bed to 30 , the use of mild sedation, and avoidance of collar-endotracheal tube ties that might constrict cervical veins.197 Mannitol or hypertonic saline may be used to treat acute ICP elevations, and hypertonic saline may be more effective.198 In patients with CSF outflow obstruction caused by hydrocephalus or a trapped ventricle, CSF drainage should be considered. Hematoma evacuation and decompressive craniectomy (DC) are options for treating ele- vated ICP and are discussed in the section on SurgicalTreatment of ICH. Salvage therapies might include barbiturate coma or mild hypothermia. Corticosteroids should not be used, because they are not effective in ICH and increase complications.199 Small case series have described the use of brain tissue oxygen and cerebral microdialysis monitoring in patients with Because of the small numbers of patients and limited data, no recommendation can be made regarding the use of these technologies at this time. ICP Monitoring and Treatment: Recommendations Ventricular drainage as treatment for hydrocephalus is reasonable, especially in patients with decreased level of consciousness (Class IIa; Level of Evidence B). (Revised from the previous guideline) Patients with a GCS score of 8, those with clinical evidence of transtentorial herniation, or those with significant IVH or hydrocephalus might be consid- ered for ICP monitoring and treatment. A CPP of 50 to 70 mmHg may be reasonable to maintain depend- ing on the status of cerebral autoregulation (Class IIb; Level of Evidence C). (Unchanged from the previ- ous guideline) Corticosteroids should not be administered for treat- ment of elevated ICP in ICH (Class III; Level of Evidence B). (New recommendation) Intraventricular Hemorrhage IVH occurs in 45% of patients with spontaneous ICH and is an independent factor associated with poor outcome.190,202,203 Pooled analysis of 13 studies found IVH in association with ICH increased the risk of death from 20% without to 51% IVH can be primary, confined to the ventricles, or secondary, originating as an extension of an ICH. Most IVH is secondary and related to hypertensive hemorrhages involving the basal ganglia and thalamus.202,205 Although the insertion of a VC should theoretically aid in drainage of blood and CSF from the ventricles, VC use alone may be ineffec- tive because of difficulty maintaining catheter patency and the slow removal of intraventricular blood.188 Thus, there has been recent interest in the use of thrombolytic agents as adjuncts to VC use in the setting of IVH. Animal studies and clinical series have reported that intra- ventricular administration of fibrinolytic agents, including urokinase, streptokinase, and recombinant tissue-type plas- minogen activator (rtPA), in IVH may reduce morbidity and mortality by accelerating blood clearance and clot lysis.206 214 Retrospective analysis of 42 consecutive patients with IVH, 88% attributable to primary ICH, who were treated with intra- ventricular urokinase found death occurred in 21 patients Another prospective study compared 48 patients with IVH (caused by ICH in 40 [83%]) treated with intraventricular rtPA to 49 matched control patients treated with VC alone.207 Mortality was reduced from 30% to 10% in the group treated with rtPA, with 2 patients in the rtPA group diagnosed with ventriculitis. In a small pro- spective trial, 16 patients with IVH and ICH <30 mm3 were randomized to VC or VC plus urokinase.214 Clearance of IVH was faster with urokinase. Mortality at 6 months was 14% with urokinase and 44% with VC alone (P=0.22), and there were no significant differences between groups in require- ment for permanent shunts or ventriculitis. Meta-analysis of 4 randomized and 8 observational studies of patients with IVH secondary to spontaneous ICH treated with VC (n=149) or VC with intraventricular fibrinolysis (n=167) found a sig- nificant decrease in mortality from 47% to 23% (pooled Peto OR, 0.32; 95% CI, 0.19 0.52), with the difference occurring principally in patients treated with urokinase.209 There was no difference in complications or need for permanent CSF diver- sion between subjects treated with intraventricular fibrinolytic agents andVC alone. Studies with rtPA have used various dose The largest trial of intraventricular fibrinolysis to date is the CLEAR-IVH trial (Clot Lysis: Evaluating Accelerated Resolution of IVH).184,217,218 CLEAR-IVH included 100 patients (22 placebo, 78 rtPA) with IVH attributable to spon- Overall, bacterial ventriculitis occurred in 3 patients with rtPA (4%) and 2 with placebo (9%). Patients treated with rtPA had significantly lower intracranial pressures, fewer VC obstructions that required replacement, and nonsignificantly shorter duration of VC requirement. There was symptomatic rebleeding in 9 rtPA patients (12%) and 1 patient given placebo (5%; P=0.33). Permanent CSF diversion was required in 14% of placebo and 6% of rtPA patients (P=0.27). Median 30-day modified Rankin scale score was 5 in both groups, and mortality was 19%, with no significant difference between placebo and rtPA. The phase 3 randomized CLEAR III trial is in progress. There are now reports of alternative procedures for IVH, such as endoscopic surgical evacuation and ventriculos- A comparison of 48 patients with IVH secondary to ICH and other causes and treated with endoscopic removal of IVH found 17% required permanent CSF diversion com- pared with 50% of 48 historical control patients treated with VC alone. Outcome on the modified Rankin scale was simi- lar. Two randomized trials have been reported comparing endoscopic removal of IVH with VC in patients with IVH secondary to primary ICH <30 mm3 In 1 of the studies, urokinase was also used in both treatment groups.223 Among the 46 patients treated with endoscopy compared with 44 treated with VC, mortality was not significantly different. One study reported improved outcome on the Glasgow Outcome Scale at 2 months with endoscopy but did not report the rate of permanent CSF diversion.223 The other suggested lower rates of permanent CSF diversion after endoscopy.221 Other reported management strategies for IVH include early ventric- endoscopic third ventriculostomy,225 or lumbar drainage.189 In a study comparing 16 patients treated with VC and lumbar drainage for ICH with IVH to 39 histori- cal control patients treated with VC alone, patients managed with VC plus lumbar drainage had a longer median duration of external CSF drainage but were significantly less likely to require permanent CSF diversion.189 IVH: Recommendations Although intraventricular administration of rtPA in IVH appears to have a fairly low complication rate, the efficacy and safety of this treatment are uncer- tain (Class IIb; Level of Evidence B). (Revised from the previous recommendation) The efficacy of endoscopic treatment of IVH is uncertain (Class IIb; Level of Evidence B). (New recommendation) Surgical Treatment of ICH (Clot Removal) The role of surgery for most patients with spontaneous ICH remains controversial. The theoretical rationale for hematoma evacuation revolves around the concepts of preventing her- niation, reducing ICP, and decreasing the pathophysiological impact of the hematoma on surrounding tissue by decreas- ing mass effect or the cellular toxicity of blood products. Randomized trials comparing surgery to conservative man- agement have not demonstrated a clear benefit for surgical intervention. Moreover, the generalizability of the results of these trials can be questioned, because patients at risk for her- niation were likely excluded and the largest and most recent studies had high rates of treatment group crossover from con- servative management to surgery. Since the last guidelines, 2 prospective randomized trials and 3 meta-analyses have been completed that compared surgery versus conservative treatment for ICH.226 229 Several other studies have examined minimally invasive approaches compared with craniotomy. Additionally, recent retrospective studies have suggested a possible role for craniectomy in ameliorating increased ICP caused by ICH.230 234 In addition, the current recommendations do not apply to intracranial hemorrhage caused by trauma or underlying structural lesions such as aneurysms and arteriove- nous malformations, because these patients were not included in the described ICH surgery trials. Craniotomy for Supratentorial Hemorrhage On the basis of inconclusive evidence from prior trials, STICH was undertaken to determine whether early surgery reduces mortality and improves neurological outcome compared with conservative management for supratentorial ICH when the treating neurosurgeon determined that uncertainty of preferred Hemphill et al Management of Spontaneous ICH 2045 treatment was present.235 In this trial, 1033 patients from 83 centers in 27 countries were randomized to early surgery (<24 hours of randomization) or initial conservative treatment. A favorable outcome on the 8-point extended Glasgow Outcome Scale at 6 months was used as the primary end point. Good outcome was dichotomized, with lower expectations set for those with worse prognosis. Twenty-six percent of the patients in the surgical arm achieved a favorable outcome compared with 24% in the medical arm. STICH found no overall statisti- cally significant difference in mortality or functional outcome between treatment groups. Notably, 26% of patients initially assigned to conservative management ultimately underwent surgery. Subgroup analysis suggested that patients with lobar hemorrhages within 1 cm of the cortical surface might ben- efit from surgery. Additional subgroup analysis suggested that the risk for a poor outcome was increased for patients who presented as comatose (GCS score 8). On the basis of these observations, the STICH II trial was undertaken.226,236 The STICH II trial addressed the question of whether early surgery would be beneficial for conscious patients with superficial lobar hemorrhage of 10 to 100 mm3 within 1 cm of the cortical surface and without IVH and who were admitted within 48 hours of ictus. Seventy-eight centers in 27 countries participated. The study randomized patients to early surgery (within 12 hours of randomization) plus medical manage- ment or medical management alone. The primary outcome was a prognosis-based dichotomized (favorable or unfavor- able) outcome of the extended Glasgow Outcome Scale. Forty-one percent of patients in the early surgery group had a favorable outcome compared with 38% in the medical arm; this difference was not statistically significant. A nonpre- specified subgroup analysis that included only patients with a poor prognosis (as defined by a specific equation used in STICH) showed that such patients were more likely to have a favorable outcome with early surgery; however, there was no advantage to early surgery for patients in the good prognosis category. A nonsignificant survival advantage was noted for the surgical arm. Twenty-one percent of patients random- ized to initial medical management ultimately underwent surgery, with the most common reason described as patient deterioration. The STICH II authors performed an updated meta-analysis of surgical trials reporting on 3366 patients.228 A significant advantage for surgery was shown when all patients were considered, but there was significant heteroge- neity in the data. Thus, early hematoma evacuation has not been shown to be beneficial in the 2 largest randomized tri- als, but high crossover rates of patients to surgical interven- tion, narrow patient-based inclusion criteria, and the focus of STICH and STICH II on early surgery leave unclarified whether surgery may benefit specific groups of patients with supratentorial ICH. Craniotomy for Posterior Fossa Hemorrhage Because of the narrow confines of the posterior fossa, dete- rioration can occur quickly in cerebellar hemorrhage caused by obstructive hydrocephalus or local mass effect on the brainstem. Several nonrandomized studies have suggested that patients with cerebellar hemorrhages >3 cm in diameter or patients in whom cerebellar hemorrhage is associated with brainstem compression or hydrocephalus have better out- comes with surgical decompression.237 239 Attempting to con- trol ICP via means other than hematoma evacuation, such as VC insertion alone, is considered insufficient, is not recom- mended, and may actually be harmful, particularly in patients with compressed cisterns.239 In contrast to cerebellar hemor- rhage, evacuation of brainstem hemorrhages may be harm- ful in many cases. Given the broad lack of clinical equipoise for surgical evacuation of cerebellar hemorrhages, especially those >3 cm in diameter occurring in potentially salvageable patients, it is unlikely that a randomized trial could be con- ducted to compare surgery versus conservative treatment. Craniectomy for ICH The potential of DC to improve outcomes for patients with ICH has not been well studied. On the basis of the results of the first STICH trial, several authors have suggested that outcomes could potentially be improved with DC for selected patients with high ICP and mass effect related to ICH.232 234,240 Patients in these studies tended to be those in coma (GCS score <8) and those who had significant midline shift, large hematomas, or ICP that did not normalize with medical man- agement. One study of DC without hematoma evacuation matched 12 consecutive patients with supratentorial ICH to control subjects via propensity score.232 Median hematoma , and median preoperative GCS score was 8. Three patients in the study group died compared with 8 in the control group, whereas 9 patients had a study-defined good outcome.Another study on DC without hematoma evac- uation included 5 patients with recalcitrant elevated ICP.234 This small cohort fared better than matched control subjects from the authors institutional prospective ICH database. A retrospective study of DC in addition to hematoma evacu- ation for both putaminal and lobar ICH found that patients with putaminal hemorrhage had greater reduction in midline shift and a trend toward better neurological outcome than matched control subjects.240 A systematic review of studies in which DC was performed in the setting of spontaneous ICH suggested that DC with hematoma evacuation might be safe and might improve outcomes.233 Minimally Invasive Surgical Evacuation of ICH Several recent randomized studies have compared minimally invasive aspiration to standard craniotomies and suggested better outcomes with less invasive approaches.227,231,241 243 A meta-analysis of 12 clinical trials suggested superiority of minimally invasive approaches over craniotomy, but meth- odological issues with this analysis have been raised.229,244 A recent randomized study of 465 patients compared needle aspiration of basal ganglia hemorrhages (25 40 mm3 ) to med- ical management alone. Although there was no significant impact on mortality, 3-month neurological outcome was bet- ter in the aspiration group.227 The Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for ICH Evacuation Trial II (MISTIE II) aimed to determine the safety of minimally invasive surgery plus rtPA in the setting of ICH. This study compared 79 surgical patients with 39 medical patients. The study demonstrated a significant reduc- tion in perihematomal edema in the hematoma evacuation group with a trend toward improved outcomes.231 A random- ized phase 3 clinical trial of minimally invasive hematoma evacuation (MISTIE III) is currently in progress. Timing of Surgery Timing of surgery for ICH remains controversial. Randomized prospective trials to date have reported on a wide time frame for surgery that ranges from 4 to 96 hours after symptom Subgroup analyses of patients in STICH II suggested a trend toward better outcome for patients operated on before 21 hours from ictus.226 An individual patient meta- analysis of 2186 patients from 8 trials of surgery for ICH found that surgery improved outcome if performed within 8 hours of Ultra-early craniotomy (within 4 hours from ictus) was associated with an increased risk of rebleeding in a study that involved 24 patients.248 Surgical Treatment of ICH: Recommendations Patients with cerebellar hemorrhage who are dete- riorating neurologically or who have brainstem compression and/or hydrocephalus from ventricu- lar obstruction should undergo surgical removal of the hemorrhage as soon as possible (Class I; Level of Evidence B). Initial treatment of these patients with ventricular drainage rather than surgical evacuation is not recommended (Class III; Level of Evidence C). (Unchanged from the previous guideline) For most patients with supratentorial ICH, the usefulness of surgery is not well established (Class IIb; Level of Evidence A). (Revised from the previous guideline) Specific exceptions and potential subgroup considerations are outlined below in recommenda- tions 3 through 6. A policy of early hematoma evacuation is not clearly beneficial compared with hematoma evacu- ation when patients deteriorate (Class IIb; Level of Evidence A). (New recommendation) Supratentorial hematoma evacuation in deteriorating patients might be considered as a life-saving measure (Class IIb; Level of Evidence C). (New recommendation) DC with or without hematoma evacuation might reduce mortality for patients with supratentorial ICH who are in a coma, have large hematomas with significant midline shift, or have elevated ICP refrac- tory to medical management (Class IIb; Level of Evidence C). (New recommendation) The effectiveness of minimally invasive clot evacuation with stereotactic or endoscopic aspiration with or with- out thrombolytic usage is uncertain (Class IIb; Level of Evidence B). (Revised from the previous guideline) Outcome Prediction and Withdrawal of Technological Support Observational and epidemiological studies have identified a wide range of factors associated with outcome after acute ICH; identification of these factors led to the development of models to predict mortality and functional outcome. These prediction models include individual patient characteristics such as score on the GCS or NIHSS, age, hematoma volume and location, and the presence and amount of IVH.26,30,249 256 None of these prediction models, however, account for the impact of care limitations such as do-not-attempt-resuscitation (DNAR) orders or the withdrawal of technological support. Most patients who die of ICH do so during the initial acute hospitalization, and these deaths usually occur in the setting of withdrawal of support because of presumed poor Palliative care is an important aspect of care for patients with severe ICH and their families whether or not withdrawal of support is being pursued, and this is discussed in substantially more detail in the recently released American Heart Association scientific statement on Palliative and End- of-Life Care in Stroke. 259 Several studies, however, have identified withdrawal of medical support and other early care limitations, such as DNAR orders within the first day of hospi- talization, as independent predictors of outcome.260 262 By defi- nition, a DNAR order means that there should be no attempt at resuscitation should a cardiopulmonary arrest occur. In practi- cal use, however, DNAR orders are a proxy for overall lack of aggressive care when administered early after ICH, and the overall aggressiveness of ICH care at a hospital is associated with patient outcomes, even after controlling for specific indi- The decision to limit care early after ICH may therefore result in self-fulfilling prophecies of poor outcome, and studies show that current outcome predic- tion models are overly pessimistic because of the failure to account for these care limitations.264,265 Prognostication early after ICH is often desired by physicians, patients, and families, but existing prognostic models are biased by limitation-of-care decisions. Providers should therefore be cautious about offering precise prog- noses early after ICH, especially if the purpose of prog- nostication is to consider withdrawal of support or DNAR Aggressive, guideline-concordant therapy is thus recommended for patients with ICH who do not have advanced directives specifying that such care should not be undertaken. Outcome Prediction and Withdrawal of Technological Support: Recommendation Aggressive care early after ICH onset and postpone- ment of new DNAR orders until at least the second full day of hospitalization is probably recommended (Class IIa; Level of Evidence B). Patients with preex- isting DNAR orders are not included in this recom- mendation. Current prognostic models for individual patients early after ICH are biased by failure to account for the influence of withdrawal of support and early DNAR orders. DNAR status should not limit appropriate medical and surgical interventions unless otherwise explicitly indicated (Class III; Level of Evidence C). (Revised from the previous guideline) Prevention of Recurrent ICH Patients with ICH are at high risk of a recurrent event and of other major vascular disease.267 The cumulative risk of Hemphill et al Management of Spontaneous ICH 2047 ICH recurrence is 1% to 5% per year.267 269 In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), the hazard ratio (HR) for ICH recurrence among subjects with prior ICH relative to a first ICH in subjects with prior isch- Although the risk of ICH recurrence is highest in the first year after the ini- tial event, the ongoing risk extends for years, particularly in patients with lobar ICH.269,270 Risk Factors Hypertension, older age, and location of the initial hemor- rhage (deep versus lobar) are important risk factors for ICH High BP is associated with an increase in the recurrence of both deep and lobar hemorrhages.271 Increased risk in the elderly is attributed to a higher prevalence of cere- bral amyloid angiopathy (CAA) and increased use of anti- thrombotic medications with accumulating comorbidities.272 CAA is a recognized risk factor for recurrent ICH, particularly in lobar locations.271 Carriers of the apolipoprotein E 2 or patients with previous ICH before the present- and patients with a greater number of microbleeds (particularly microbleeds in lobar brain locations) on gradient echo MRI appear to be at higher risk for ICH recurrence.272,275 In whites, most of the initial and recurrent hemorrhages tend to be lobar, whereas deep hemorrhages (both initial and recur- rent) are more common in Asians.269,276 A history of ischemic stroke, particularly of the small-vessel lacunar type, which shares a common pathogenesis with ICH, might also be a pre- dictor of ICH recurrence.277,278 BP Management Among the preceding risk factors, only BP and the use of anti- thrombotic agents are modifiable. In PROGRESS, treatment with perindopril (4 mg daily) and indapamide reduced base- line BP by an average of 12 mmHg systolic and 5 mmHg dia- stolic and lowered the risks of first and recurrent ICH (adjusted respectively), as well as other vascular events.267,273,279 In that trial, the lowest risk of stroke recurrence was seen among patients with the lowest follow-up BP levels (median, 112 mmHg systolic and 72 mmHg diastolic) 280 ; those with prior ICH derived the greatest benefit, and the size of the benefit was directly related to the degree of BP lowering, with no clear evidence of a lower threshold below which the benefit attenuated or even reversed, as is seen for ischemic stroke or coronary artery disease. Results of the Secondary Prevention of Small Subcortical Strokes (SPS3) study have shown that the greatest benefit of more intensive BP lowering is on the prevention of ICH in patients with established small-vessel stroke disease and that lowering target SBP to <130 mmHg significantly reduced the risk of ICH (risk reduction, 60%; which suggests that ICH patients should have their BP lowered to or beyond the targets currently rec- ommended in other high-risk groups (<130 mmHg systolic and 80 mmHg diastolic in the presence of diabetes mellitus, heart failure, or chronic kidney disease).282 Other factors, such as BP variability, the presence of obstructive sleep apnea,283,284 obesity, and other lifestyle modifications, should also be considered despite the lack of systematic data regarding their effect on ICH recurrence. Frequent alcohol use (>2 drinks per and illicit drug use have been linked to elevated BP and and should be avoided in ICH patients. Tobacco use is also associated with increased ICH risk287 291 and should be discontinued. The optimal timing for initiating BP lowering after ICH to prevent recurrence is unknown. In INTERACT2, rapid reduction of SBP to <140 mmHg within a few hours was safe, which indicates that such treatment can be safely initiated as soon as possible after ICH onset.134 Management of Antithrombotic Drugs The rising use of anticoagulant agents in an aging population is associated with increased risk of ICH and its recurrence.292 There is a marked paucity of prospective population-based data on the risk of ICH recurrence and mortality after reini- tiation of warfarin. In a cohort of 284 consecutive patients with warfarin-related ICH in the Registry of the Canadian Stroke Network, mortality rates were lower in those who restarted warfarin in the hospital: 31.9% versus 54.4% at 30 the rates of bleeding events were not increased.293 In a ret- rospective cohort study of 2869 ICH patients, of whom 234 had warfarin-associated ICH, the HR for recurrent ICH with resumption of warfarin was 5.6 (95% CI, 1.8 17.2) during a In another study of 48 patients with warfarin-associated ICH, of 23 patients who began taking warfarin again, 1 had a recurrent ICH and 2 subsequently had traumatic intracranial hemorrhage, whereas none who did not restart warfarin had recurrent intracranial bleeding. However, 5 patients in the nonrestarted group devel- oped thromboembolism (2 with stroke) compared with none in the group who restarted warfarin.295 Using a Markov deci- sion model and estimates for 1-year risk of ICH recurrence of 15% after lobar ICH versus 2.1% for deep ICH, Eckman found that withholding anticoagulation improved quality-adjusted life-year expectancy by 1.9 quality-adjusted life-years after lobar ICH and 0.3 quality-adjusted life-years after deep ICH, which led to the conclusion that anticoagula- tion should be avoided after lobar ICH but can be considered in patients with deep hemorrhage if the risk of thromboem- bolism is particularly high. CAA is an important cause of warfarin-associated lobar ICH in the elderly. The presence of microbleeds might increase the risk of ICH recurrence in warfarin users, although there are no prospective data. In a pooled analysis of ICH and ischemic stroke or transient isch- emic attack patients, microbleeds were more frequent in war- farin users with ICH than in nonwarfarin users (OR, 2.7; 95% CI, 1.6 4.4; P<0.001) but were not more frequent in warfarin users with ischemic stroke or transient ischemic attack (OR, OR, 0.01), and the presence of microbleeds was associated with a higher risk of subsequent ICH (OR, 12.1; 95% CI, 3.4 The optimal timing for resumption of anticoagulation after ICH, if necessary, is uncertain, and no randomized trial data are available to guide the decision. Several observational studies of patients with anticoagulant-related ICH found low rates of cardioembolic events while not receiving anti- coagulation therapy or recurrent ICH when anticoagulation but the results are limited by relatively small sample sizes and short durations of follow-up. A larger study of 234 patients with warfarin-related ICH followed up for a median of 34 weeks found that the risk of rebleeding with early resumption of anticoagulation exceeded the risk of thromboembolism from withholding it, whereas later, the opposite was true.294 A survival model based on these data found that the total risk of ischemic plus hemorrhagic stroke was minimized when anticoagulation was reinitiated after 10 weeks, and the authors suggested a delay of at least 1 month after ICH.294 In practice, the timing often depends on the indication for anticoagulation. In patients with pros- thetic heart valves, early resumption of anticoagulation may be necessary because of the high risk of embolism. Although there are conflicting reports regarding the risk of ICH recur- rence with antiplatelet use, particularly in patients with lobar or percutaneous left atrial appendage closure303 might be safer alternatives to warfarin in some patients with atrial fibrillation. Antiplatelet agents do not appear to dramatically increase the risk of and therefore appear to be gener- ally safe for use after ICH, including ICH caused by CAA. Although dabigatran, rivaroxaban, and apixaban are reported to convey a lower risk of ICH than warfarin in atrial fibrilla- their usefulness as alternatives to warfarin after ICH remains to be determined. Meta-analyses suggest that aspirin use is associated with modest increases in ICH incidence305 but the absolute ICH risk in unselected populations appears to be small relative to the absolute numbers of MIs and ischemic A small observational study found that antiplatelet use was common after ICH and did not appear to be associated with an increase in the risk of ICH recurrence in 127 survivors of lobar hemorrhage (HR, 0.8; 95% CI, 0.3 2.3; P=0.73) and 80 survivors of deep hemorrhage (HR, 1.2; 95% There are conflicting reports regarding the use of statins in patients with ICH.308 312 In the Stroke Prevention With Aggressive Reduction in Cholesterol Levels (SPARCL) study, the benefit of high-dose atorvastatin in reducing recurrent ischemic stroke was offset in part by an increased risk of ICH. Secondary analysis found that statin treatment, increasing age, and having ICH as the qualifying stroke for study enrollment were factors associated with later ICH However, a meta-analysis of 31 randomized controlled trials that included 91 588 statin-treated patients found no significant association between statin use and ICH all-cause mortality were significantly reduced with statin A Markov analysis evaluating the risks and ben- efits of statin therapy in patients with prior ICH concluded that if statin use does increase the risk of ICH, avoidance of statins should be considered in patients with ICH, particu- larly those with lobar ICH.311 Concordant with these con- clusions, statin use and age were independently associated with the presence and number of microbleeds, especially in cortical locations, in ICH patients.313 In contrast, continued statin use after ICH was associated with early neurologi- cal improvement and reduced 6-month mortality in a small There are no data on whether the reported propensity for ICH with statin use is dose depen- dent. It remains unclear whether statins should be continued or discontinued in ICH patients. Prevention of Recurrent ICH: Recommendations When stratifying a patient s risk for recurrent ICH may affect management decisions, it is reasonable to consider the following risk factors for ICH recur- rence: (1) lobar location of the initial ICH; (2) older age; (3) presence and number of microbleeds on gra- dient echo MRI; (4) ongoing anticoagulation; and (5) presence of apolipoprotein E 2 or 4 alleles (Class IIa; Level of Evidence B). (Revised from the previous guideline) BP should be controlled in all ICH patients (Class I; Level of Evidence A). (Revised from the previ- ous guideline) Measures to control BP should begin immediately after ICH onset (Class I; Level of Evidence A). (New recommendation) A long-term goal of BP <130 mmHg systolic and 80 mmHg diastolic is reasonable (Class IIa; Level of Evidence B). (New recommendation) Lifestyle modifications, including avoidance of alco- hol use greater than 2 drinks per day, tobacco use, and illicit drug use, as well as treatment of obstruc- tive sleep apnea, are probably beneficial (Class IIa; Level of Evidence B). (Revised from previous guideline) Avoidance of long-term anticoagulation with warfa- rin as a treatment for nonvalvular atrial fibrillation is probably recommended after warfarin-associated spontaneous lobar ICH because of the relatively high risk of recurrence (Class IIa; Level of Evidence B). (Unchanged from the previous guideline) Anticoagulation after nonlobar ICH and antiplate- let monotherapy after any ICH might be considered, particularly when there are strong indications for these agents (Class IIb; Level of Evidence B). (Revised from the previous guideline) The optimal timing to resume oral anticoagula- tion after anticoagulant-related ICH is uncertain. Avoidance of oral anticoagulation for at least 4 weeks, in patients without mechanical heart valves, might decrease the risk of ICH recurrence (Class IIb; Level of Evidence B). (New recommendation) If indicated, aspirin monotherapy can probably be restarted in the days after ICH, although the optimal timing is uncertain (Class IIa; Level of Evidence B). (New recommendation) The usefulness of dabigatran, rivaroxaban, or apixa- ban in patients with atrial fibrillation and past ICH to decrease the risk of recurrence is uncertain (Class IIb; Level of Evidence C). (New recommendation) There are insufficient data to recommend restric- tions on the use of statins in ICH patients (Class IIb; Level of Evidence C). (Unchanged from the previous guideline) Hemphill et al Management of Spontaneous ICH 2049 Rehabilitation and Recovery Knowledge of differences in the natural history of recovery patterns and prognosis for residual disability and function- ing between ICH and ischemic stroke is complicated by the lower rate of ICH compared with ischemic stroke and the lumping of subarachnoid hemorrhage and ICH together in many studies. There are also problems associated with the insensitivity of many of the outcome measures used in rehabilitation to allow detection of clinically meaning- ful differences between groups. Even so, there is grow- ing evidence that patients with ICH make slightly greater and faster gains in recovery than patients with ischemic In general, recovery is more rapid in the first few weeks but may continue for many months after ICH,28,316 with approximately half of all survivors remaining dependent on others for activities of daily living.30 However, patients vary in their speed and degree of recovery, and there is no hard rule as to when recovery ends. Cognition, mood, motivation, and social support all influence recovery, and it is difficult to separate intrinsic from adaptive recovery. A simple prognostic score that uses age, ICH volume and location, level of con- sciousness at admission, and pre-ICH cognitive impairment has been shown to predict independence at 90 days.30 Such scores are useful across all patients, but prognostic imaging techniques may also be useful with lesions in specific func- Given that ICH is often located in lobar regions and complicated by intraventricular extension, some patients with specific cognitive deficits or delayed recovery that is dis- proportionate to the size of the lesion may require specialized therapy in rehabilitation.27 The provision of stroke rehabilitation services has received considerable attention in recent years. In part this represents a need to tailor services to ensure optimal recov- ery for patients, and in part it is attributable to fiscal pres- sures on costly health services. Given strong evidence for the benefits of well-organized, multidisciplinary inpatient (stroke unit) care in terms of improved survival, recovery, and returning home compared with care provided in conven- tional nondedicated stroke wards,319 efforts have been made to extend this service model of coordinated care into the community. Specifically, early supported hospital discharge and home-based rehabilitation programs have been shown to whereas home-based therapy for stable patients has been shown to produce comparable outcomes to conventional outpatient rehabilitation.320 Comprehensive stroke units that include rehabilitation services demonstrate improved outcomes compared with other models of stroke The majority of studies do not differentiate ICH patients from those with ischemic stroke. However, a recent random- ized trial in 364 patients in China was specific to ICH, in which a 3 stage in-hospital rehabilitation program was com- pared to standard ward and medical care. Improvement was significantly greater for the rehabilitation group, measured by Fugl-Meyer and Barthel scales over 6 months, with the greatest improvement evident in the first month after stroke.322 A similar result was seen in an Australian trial of very early mobilization in 72 patients, but the number of ICH patients was too small to make any sensible comparisons to those with The success of rehabilitation depends on caregiver train- ing and support; however, the likely configuration of services in any region will depend on available resources and fund- ing options. A key portion of rehabilitation should include education for the patient and caregiver regarding secondary stroke prevention and means to achieve rehabilitation goals. Rehabilitation programs should consider lifestyle changes, depression, and caregiver burden as important issues to address with the patient and caregivers. Rehabilitation and Recovery: Recommendations Given the potentially serious nature and complex pattern of evolving disability and the increasing evi- dence for efficacy, it is recommended that all patients with ICH have access to multidisciplinary rehabilita- tion (Class I; Level of Evidence A). (Revised from the previous guideline) Where possible, rehabilitation can be beneficial when begun as early as possible and continued in the community as part of a well-coordinated ( seam- less ) program of accelerated hospital discharge and home-based resettlement to promote ongoing recov- ery (Class IIa; Level of Evidence B). (Unchanged from the previous guideline) Future Considerations As documented above, the acute treatment of spontaneous ICH remains under intense investigation. Thanks largely to acute lowering of BP can now be considered safe and potentially effective for improving outcome in most instances of ICH. Ongoing and future studies in this area, such as ATACH II,324 will seek to solidify the evidence for efficacy of BP lowering and refine the BP ranges and targets that should be applied in practice. These studies will also address other outstanding questions, such as whether the spot sign or other neuroimaging findings identify patients more likely to benefit from BP lowering.325 Although current evidence does not establish a general strategy of early surgery for supratentorial ICH, studies will continue to seek subgroups of patients who benefit. Another major focus in future years will be determining whether minimally invasive surgery231 can provide the advantages of hematoma removal with less surgical trauma and there- fore greater net benefit to patients. Another rational but still unproven approach to acute ICH treatment is neuroprotec- tion of surrounding brain tissue from the toxic effects of the hematoma. The translation of biological data on neuro- protection from animals to human ICH patients may face the same difficulties encountered by the ischemic stroke neuroprotection field, such as identifying the correct animal model system and a clinically relevant time frame for treat- Emerging methods such as prehospital administra- tion of candidate neuroprotectants327 should increase the range of feasible treatment approaches and time windows for acute ICH. As targeted treatments for acute ICH continue to be ana- lyzed, it is important to note that many of the gains seen in Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other J. Claude Hemphill III University of California, San Francisco NIH/NINDS* None None None None None None Steven M. Greenberg Massachusetts General Hospital Avid Radiopharmaceuticals ; NIH ; NINDS ; None None None None None None Craig S. Anderson The George Institute for Global Health, University of Sydney; Royal Prince Alfred Hospital The National Health and Medical Research (NHMRC) of Australia None Takeda China*; Covidien*; Bayer* None None Pfizer*; The Medicines Company* None Kyra Becker University of Washington School of Medicine NINDS None None None None None None Bernard R. Bendok Northwestern Medical Faculty Foundation NIH None None None None None None Mary Cushman University of Vermont NIH/NHLBI ; NIH/NINDS None None None None None None Gordon L Fung University of California San Francisco Medical Center None None None None None None None Joshua N. Goldstein Massachusetts General Hospital CSL Behring ; NIH*; NINDS None None None None CSL Behring* None R. Loch Macdonald Independent Medical Practitioner Brain Aneurysm Foundation*; Canadian Institutes of Health Research*; Heart and Stroke Foundation of Canada*; Physicians Services Incorporated Foundation* None None None Edge Therapeutics* Actelion Pharmaceuticals* None Pamela H. Mitchell University of Washington NIH None None None None None None Phillip A. Scott University of Michigan NIH/NINDS None None None None None None Magdy H. Selim Harvard Medical Faculty Physicians NIH/NINDS None None None None Daiichi-Sankyo* None Daniel Woo University of Cincinnati NINDS None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. Disclosures ICH outcome have resulted from improved hospital care. Improvements in hospital care tend to be incremental rather than revolutionary but can sum to substantial benefits to patients and remain a key part of future ICH research. Acute ICH treatment, like acute ischemic stroke treatment, is fundamentally limited in its ability to reduce stroke-related disability; for this reason, it is improved ICH prevention and recovery that has the greatest potential for reducing overall disease burden. In the area of ICH prevention, BP control can be considered as established treatment.273,328 There remains no disease-modifying treatment for prevention of CAA-related ICH; however, this is a major goal for ongoing and future tri- als. Another important question to be addressed is the possible role of the newer direct OACs in patients at increased ICH risk and the identification of the subgroup that might derive the greatest benefit from the reduced tendency of these agents to trigger intracranial bleeding.72,73,304 Finally, there are no spe- cific treatments or therapies established for enhancing post- ICH recovery, which highlights a tremendous opportunity for improving outcome from this devastating form of stroke. Hemphill et al Management of Spontaneous ICH 2051 References 1. Zahuranec DB, Gonzales NR, Brown DL, Lisabeth LD, Longwell PJ, Eden SV, Smith MA, Garcia NM, Hoff JT, Morgenstern LB. Presentation of intracerebral haemorrhage in a community. 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Diabetologia. 2010;53:429 434. doi: 10.1007/s00125-009-1617-z. Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Sepideh Amin-Hanjani University of Illinois at Chicago NIH/NINDS (Site PI on MISTIE 3 trial)* None None None None None None Charlotte Cordonnier Lille University Hospital (France) None None None None None None None Matthew L. Flaherty University of Cincinnati Academic Health Center NINDS (Coinvestigator on NINDS-funded grants NS030678, (Principal Investigator, NINDS 2P50NS044283, STOP-IT Study ) Novo Nordisk (Principal Investigator of NINDS-funded STOP-IT Study, study drug supplied by Novo Nordisk)* CSL Behring* None Sense Diagnostics, LLC CSL Behring* None Eric E. 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