Review Article Address correspondence to Dr Andrew M Naidech, 710 N Lake Shore Drive 11th floor, Chicago, IL 60611, a-naidech@northwestern.edu Relationship Disclosure: Dr Naidech reports no disclosure Unlabeled Use of Products/Investigational Use Disclosure: Dr Naidech discusses the unlabeled/investigational use of desmopressin for the treatment of acute intracerebral hemorrhage * 2015, American Academy of Neurology Diagnosis and Management of Spontaneous Intracerebral Hemorrhage Andrew M Naidech, MD, MSPH, FANA ABSTRACT Purpose of Review: This article updates neurologists on recent insights and management strategies of intracerebral hemorrhage (ICH) Recent Findings: Blood pressure reduction likely improves outcomes in patients with intracerebral hemorrhage, although not by the expected mechanism of reducing hematoma growth One formulation of prothrombin complex concentrate for reversing severe bleeding associated with warfarin is now approved by the US Food and Drug Administration (FDA), and specific reversal therapies for the novel oral anticoagulants are in development Neurologic monitoring frequently detects ICH worsening that requires an intervention Platelet transfusion and pharmacologic platelet activation are promising and often used as part of patient management but have not yet been shown to improve patient outcomes Summary: Measurable progress continues toward establishing effective therapies to improve outcomes in patients with ICH Blood pressure reduction and reversal of medications that exacerbate bleeding are likely to improve outcomes Recommendations for neuromonitoring will help clinicians at the bedside attend to the most important abnormalities and optimize later quality of life This article reviews standards for diagnosis and severity of ICH, monitoring and treatment of complications in the hospital, available interventions, and the measurement of outcomes Continuum (Minneap Minn) 2015;21(5):1228–1298 INTRODUCTION Intracerebral hemorrhage (ICH) is the most deadly form of stroke and leaves many of its survivors with a persistent neurologic deficit Despite the high toll of the disease, the field continues to improve in diagnosis, targeted neuromonitoring, and patient management DIAGNOSIS ICH is less common than acute ischemic stroke but has a substantially higher acute mortality and a higher rate of early 1288 clinical decompensation1 and is more likely to cause subsequent disability.2 Consequently, misdiagnosis is potentially catastrophic The clinical presentation is often similar to ischemic stroke in that patients usually present with a focal neurologic deficit, but are more likely to have very elevated blood pressure; altered consciousness; and headache, nausea, or vomiting The etiology of ICH depends on the population ICH in younger populations is more likely due to chronic www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited October 2015 hypertension, and the hematoma is more likely to be in the basal ganglia or brainstem ICH in older populations is more likely to be lobar (This article does not consider traumatic ICH.) Many older patients with lobar hematomas will meet criteria for probable cerebral amyloid angiopathy (age at least 55 years, appropriate clinical history, evidence of multiple cerebral hemorrhages on MRI), a condition of amyloid deposition in cerebral vessels, and these patients are more likely to be harmed by anticoagulant medication.3 Ataxia may be the presenting symptom in patients with cerebellar hematomas, and these patients should be considered for early surgical decompression if there is concern for brainstem compression Imaging The diagnosis of ICH is established by an appropriate clinical history with corroborating imaging evidence of hemorrhage on CT or MRI scanning MRI scanning should be performed to help determine the etiology of ICH (Figure 2-1) Blood vessel imaging with magnetic resonance angiography (MRA), CT angiography (CTA), or conventional angiography should be considered if there is a question of a vascular malformation such as an aneurysm or arteriovenous malformation The yield of angiographic studies in patients with a history of hypertension and a typical appearance of ICH due to hypertension is very small Hematomas frequently expand after the diagnostic CT scan, particularly in patients who present soon after symptom onset; patients with hematoma expansion have a substantially worse outcome Thus, minimizing hematoma expansion is a primary goal of acute ICH treatment and the driving force behind aggressively lowering blood pressure and reversing coagulopathy After the diagnostic CT scan, at least one more brain imaging study should be performed in symptomatic patients to determine final hematoma size and assess for hematoma expansion KEY POINT h Obtaining an MRI is desirable to help determine the etiology of intracerebral hemorrhage and is particularly helpful for cerebral amyloid angiopathy Using MRI to improve diagnosis of intracerebral hemorrhage A, The patient presented with a small lobar intracerebral hemorrhage, seen as hyperdensity on noncontrast CT B, MRI revealed a second hematoma, seen as dark (hypointense) signal on gradient echo sequence in the left temporal lobe (arrow) Given the patient’s age, these findings made the diagnosis of amyloid angiopathy likely C, Later that month, noncontrast CT performed when the patient presented with right-sided weakness showed spontaneous hemorrhage in another location with intraventricular extension FIGURE 2-1 Continuum (Minneap Minn) 2015;21(5):1228–1298 www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited 1289 Intracerebral Hemorrhage KEY POINTS h The Intracerebral Hemorrhage Score is required documentation at comprehensive stroke centers for patients with intracerebral hemorrhage h Neuromonitoring encompasses a range of techniques and data Neuromonitoring may refer to repeated neurological assessments (eg, level of alertness, orientation) over time, to repeated noninvasive measures (such as processed scores from EEG data), to invasive monitors that display brain-specific measurements SEVERITY OF ILLNESS The Joint Commission has adopted the ICH Score as a standard severityof-illness scoring system for patients with ICH, and its documentation will be required at comprehensive stroke centers.4 Scores range from (least severe with low expected mortality) to (the worse possible score with death likely) Modifications to the ICH score that take into account more clinical or imaging variables may have slightly better predictive value for outcomes (Table 2-1) Do-not-resuscitate (DNR) status is a known confounder of outcomes in patients with ICH Unsurprisingly, in some (but not all) centers, patients with DNR status receive fewer interventions and have higher mortality rates than patients with a similar severity of injury This is not due to the withholding of any single beneficial intervention for ICH but may be owing to a pattern of less-aggressive care DNR status should be considered TABLE 2-1 Intracerebral Hemorrhage Scorea Variable ICH Score Points Hematoma volume Q30 mL Age Q80 years Glasgow Coma Scale or Glasgow Coma Scale 5Y12 Infratentorial hematoma location Intraventricular hemorrhage ICH = intracerebral hemorrhage a Modified with permission from Hemphill JC 3rd, et al, Stroke.4 B 2001 American Heart Association, Inc stroke.ahajournals.org/content/ 32/4/891.full 1290 with the patient and representatives while being mindful of its potential impact on subsequent care and outcomes NEUROMONITORING Many ‘‘neuromonitors’’ exist, ranging from repeated examinations such as level of consciousness2 and delirium screening to invasive monitors.5,6 As a general guide, all patients with acute ICH should be admitted to an intensive care unit setting to assess for neurologic deterioration, although some patients may be triaged to a stroke unit or step-down intensive care unit based on clinical severity and resource availability (Figure 2-2) The field of neuromonitoring has recently been exhaustively reviewed by the Neurocritical Care Society.7 Strong recommendations include the following: & Invasive blood pressure monitoring helps patients who are hemodynamically unstable and helps establish goals that take cerebral perfusion into account & Oximetry and capnography (measurement of carbon dioxide concentration in the blood) are helpful for mechanically ventilated patients There is enthusiasm, but still only preliminary data, for the use of brain oxygen tension monitors & Electroencephalography is recommended to detect subclinical seizures in patients with persistently altered consciousness (Case 2-1) & Blood glucose levels should be routinely measured & For patients whose body temperature is being actively managed (eg, cooling blankets, intravascular devices), shivering should be regularly monitored with a standard scale These recommendations may be reconsidered in light of locally available www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited October 2015 FIGURE 2-2 Algorithm of care for intracerebral hemorrhage from presentation through hospital discharge and follow-up CT = computed tomography; EEG = electroencephalogram; ICH = intracerebral hemorrhage; ICU = intensive care unit; MRI = magnetic resonance imaging resources and may not be possible in all settings Some monitoring systems are very resource intensive in terms of skilled labor and equipment INTRAVENTRICULAR HEMORRHAGE Intraventricular hemorrhage (IVH), the spread of blood into the ventricular system, is more common with hematoma locations that are closer to the ventricular system, such as the thalamus and caudate nuclei IVH is a common and serious complication of ICH that may lead to reduced consciousness, hydrocephalus, fever, and a worse outcome For patients with small to moderate Case 2-1 A 54-year-old woman presented with a new left-sided hemiparesis Her blood pressure was 140/80 mm Hg, and her history was significant for hypertension During the initial examination, the patient required stimulation to attend to the examiner and to follow voice commands When aroused, she was oriented to the hospital On physical examination, there was weakness of the left face, arm, and leg with moderate dysarthria and neglect to sensation There was no aphasia or ataxia CT scanning revealed a 15-mL right-sided lobar hematoma Initial laboratory studies were unremarkable Continued on page 1292 Continuum (Minneap Minn) 2015;21(5):1228–1298 www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited 1291 Intracerebral Hemorrhage KEY POINTS h Dissolving intraventricular clots with fibrinolytics is an attractive strategy for the treatment of intraventricular hemorrhage, and a phase trial is nearing completion h Anticoagulation should be emergently reversed in patients with intracerebral hemorrhage; the optimal agent is not clear, but most physicians prefer prothrombin complex concentrates over fresh frozen plasma at this time Continued from page 1291 The patient’s mental status initially waxed and waned, and the patient no longer followed commands the next day EEG monitoring was initiated due to encephalopathy, and a lateralized rhythmic pattern was seen on the same side as the hematoma After hours of EEG monitoring, a focal seizure on EEG without a clinical correlate was seen Levetiracetam 1000 mg IV was administered with resolution of electrographic seizures but intermittent rhythmic activity on EEG was still seen Her mental status improved, and she resumed following commands on bedside examination Comment Subclinical seizures are common after intracerebral hemorrhage (ICH) and may be reflected as a depressed mental status or a worsening neurologic examination Guidelines not support the use of prophylactic antiepileptic drugs (AEDs), particularly phenytoin However, AEDs are indicated for clinical or electroencephalographic seizures Patients with lobar hematomas, as in this patient, are at a particularly high risk for seizures New-onset seizures weeks to months after ICH are also common intraparenchymal hematomas and substantial amounts of IVH, intraventricular clot-busting therapy involves removing a small volume of CSF via the external ventricular drain with a syringe and replacing it with alteplase and sterile flush solution This is the rationale behind the phase Clot Lysis: Evaluating Accelerating Resolution of Intraventricular Hemorrhage (CLEAR-IVH) trial, currently in progress Preliminary results have been promising, although this therapy remains investigational pending the outcome of this ongoing phase clinical trial.8 MEDICAL MANAGEMENT Table 2-2 summarizes the general medical management of ICH Anticoagulation-Related Intracerebral Hemorrhage As subclinical atrial fibrillation is found more often, more patients will be prescribed anticoagulant medication.9 The traditional treatment for atrial fibrillation has been warfarin, and ICH is the most feared complication of anticoagulant treatment When patients taking warfarin experience severe bleeding, fresh-frozen plasma has been typically prescribed Recently, prothrombin complex con- 1292 centrates have been evaluated as a potentially more effective alternative, and one proprietary formulation (KCentra) has been recently approved by the US Food and Drug Administration (FDA) specifically for reversing bleeding related to warfarin.10 This is a general indication, and few patients with ICH were in the study leading to this approval Trials of novel oral anticoagulants (NOACs) in otherwise healthy patients with atrial fibrillation showed NOACs to be equivalent or superior to warfarin for stroke prevention and to be associated with lower rates of ICH.11,12 However, NOAC-associated ICH may be difficult to treat This is likely to be especially problematic for older people, who are more likely to have atrial fibrillation and more likely to die after ICH How best to reverse NOACs is not known, although a specific antidote for dabigatran is the subject of an ongoing clinical study The optimal timing of restarting anticoagulant medication after ICH is controversial, and few data exist to guide management (Case 2-2) A delay of week to months is considered reasonable, with early anticoagulation favored for patients with a high risk of thromboembolism, such as patients with www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited October 2015 TABLE 2-2 General Management of Intracerebral Hemorrhage Condition Recommendation Anticoagulant medication Normalization of international normalized ratio (INR) Blood pressure For patients with systolic blood pressure 9150 mm Hg and e220 mm Hg, consider lowering to 140 mm Hg For patients presenting with systolic blood pressure 9220 mm Hg, consider aggressive reduction of blood pressure with a continuous IV infusion of an antihypertensive and frequent blood pressure monitoring1 Fever Antipyretic medication; consider ice packs or devices for temperature control (preferably avoiding sedation, as appropriate) Cerebral edema Hypertonic saline and/or mannitol, usual goal 320 mOsm/L with weaning over several days Antiplatelet medication Consider desmopressin or platelet transfusion Hyperglycemia Routine protocol for glucose control Deep venous thrombosis prevention Consider mechanical prophylaxis; consider chemoprophylaxis after hematoma size stable for 2Y3 days IV = intravenous mechanical heart valves or patients with evidence of new cerebral ischemia on MRI, and deferred for patients with evidence of new hemorrhage on follow-up MRI scanning In the absence of clear guidelines and because of often competing therapeutic concerns (eg, anticoagulation to prevent cardioembolism, deferred anticoagulation to minimize the risk of recurrent ICH), this decision is often made after discussion among the consulting physicians Blood Pressure Reduction A prevailing theory has been that hematoma expansion indicates a physical tear in an artery or arteriole and that increased blood pressure leads to greater blood flow out of the tear into brain parenchyma Thus, aggressively reducing blood pressure might reduce hematoma expansion and improve functional outcomes The Intensive Blood Pressure Continuum (Minneap Minn) 2015;21(5):1228–1298 Reduction in Acute Cerebral Hemorrhage (INTERACT) trial suggested this hypothesis was valid, with less proportional hematoma growth in patients with more aggressive blood pressure reduction (target systolic 140 mm Hg or less).13 This formed the basis for INTERACT2, which enrolled nearly 2800 patients with acute ICH INTERACT2 did not achieve the primary end point of improved odds of ‘‘good outcome,’’ which was defined as moderately severe disability or better at 90 days Neither did aggressive blood pressure reduction have an effect on hematoma expansion.14 INTERACT2 did, however, find that aggressive blood pressure reduction was associated with: (1) improved functional outcomes when analyzed as an ordinal shift toward lower levels of disability; and (2) improved quality of life This implies that there may be another mechanism www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited 1293 Intracerebral Hemorrhage KEY POINT h Fever leads to worse outcomes in patients with intracranial hemorrhage; whether aggressive measures to abolish fever improves outcomes in these patients is not clear Case 2-2 A 75-year-old man presented with new-onset headache and right hemiparesis with onset 45 minutes prior to presentation to the emergency department His history was significant for hypertension and atrial fibrillation, for which he took warfarin Blood pressure was 185/95 mm Hg, and his temperature was 37.2-C (99.0-F) Physical examination confirmed the right hemiparesis with moderate sensory loss; he followed commands, uttered inappropriate words, and required stimulation to open his eyes (Glasgow Coma Scale score of 11) A CT scan revealed a 34-mL left parietal lobe hematoma with scant intraventricular hemorrhage His Intracerebral Hemorrhage (ICH) Score was recorded as (1 point for a Glasgow Coma Scale of 11, point for hematoma volume of greater than 30 mL, point for intraventricular hemorrhage [IVH]) The patient’s blood pressure was reduced to 140 mm Hg systolic Warfarin was reversed with prothrombin complex concentrate Fever developed on day and was treated with acetaminophen Altered mental status prompted EEG monitoring, which was discontinued after 48 hours when no epileptiform abnormalities were seen Repeat CT scanning demonstrated minimal hematoma growth, and an MRI revealed no other foci of intracerebral hemorrhage The patient was discharged to a rehabilitation facility At month, he was awake, alert, and able to ambulate with a device Plans were being made to return home with outpatient physical and occupational therapy Warfarin was restarted Comment When to restart anticoagulation in patients with ICH is not well defined One month is generally considered a reasonable time frame in patients considered to be a low risk for recurrent ICH accounting for a slight benefit from aggressive blood pressure reduction other than reduction in hematoma growth INTERACT2 has been influential, particularly given the lack of other available interventions to improve outcomes after ICH Patients with ICH and a long history of hypertension may have an autoregulatory curve that is shifted to the right (ie, have cerebral vessels that effectively regulate cerebral blood flow at hypertensive blood pressures but autoregulate less effectively at normal blood pressure) However, blood pressure reduction (down to a systolic blood pressure of 140 mm Hg) does not seem to cause perihematomal ischemia or neurologic decline.14,15 Small areas of ischemia distant from the hematoma have been reported with aggressive blood pressure reduction.16,17 1294 Fever and Temperature Control Temperature should be routinely measured in patients with ICH Where available, a core measure using a bladder catheter is preferred; however, protocols to reduce the use of indwelling bladder catheters to minimize infection risk may make this difficult in awake patients Fever (ie, elevated core temperature) has been repeatedly linked to worse outcomes in patients with ICH.18 Fever has many deleterious effects, including increased brain and muscle metabolism that may, in turn, have additional adverse consequences Documented associations between fever and worse outcome have led clinicians to attempt to reduce fever, which has been more difficult and, thus far, less rewarding than initially hoped.19 Antipyretics are routinely given but are typically insufficient to abolish fever A www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited October 2015 variety of cooling devices are available, some external and some intravascular Cold saline also acutely reduces core temperature and is a common intervention for temperature reduction after cardiac arrest.20,21 Devices generally are effective in reducing temperature in patients with fever that persists despite antipyretic medication, but shivering is a common result that may prevent fever control Shivering can be reliably assessed at the bedside, and a variety of off-label medications (eg, buspirone, fentanyl, meperidine) and interventions (such as counterwarming with warm air) have been proposed to minimize shivering; none are FDA-approved for this indication.22Y24As of yet, high-quality data on whether interventions to reduce fever improve outcomes after ICH are lacking, although several studies are under way Cerebral Edema Cerebral edema is common after ICH In general, the volume of cerebral edema is proportional to the volume of the hematoma, with larger hematomas leading to more edema This is particularly important in patients with hematomas large enough to cause midline shift and altered consciousness The exact cause of cerebral edema is not clear; ischemia around the hematoma does not seem to be a proximate cause Cerebral edema is commonly visualized as hypodensity surrounding the hematoma on CT or hyperintensity on T2-weighted MRI, and usually peaks several days after ICH onset Treatment usually consists of hyperosmolar therapy with hypertonic saline, mannitol, or both Mannitol can be given via peripheral IV but may lead to volume depletion with repeated dosing because it is an osmotic diuretic Hypertonic saline requires a central venous catheter but can be used indefinitely A target serum osmolality of approximately 320 mOsm/L (to avoid nephrotoxicity), Continuum (Minneap Minn) 2015;21(5):1228–1298 or resolution of clinical symptoms, is the usual target of therapy Evidencebased protocols for discontinuation of hyperosmolar therapy have not been developed; the usual practice is to permit serum osmolality to decrease by up to 10 mEq/L/d as long as there are no symptoms of recurrent cerebral edema For more information, refer to the article ‘‘Management of Intracranial Pressure’’ by W David Freeman, MD, FSNS, FAAN, in this issue of Continuum KEY POINT h Cerebral edema is common after intracerebral hemorrhage and generally reflects the volume of the underlying hematoma Antiplatelet Medication and Platelet-Activating Therapy Clinical interventions to improve platelet activity are analogous to correcting coagulopathy in patients with ICH As anticoagulants lead to reduced blood clotting, aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) lead to platelet inhibition that reduces the formation of a platelet plug at the site of bleeding The use of aspirin and NSAIDs can be detected on rapid point-of-care testing in patients with acute ICH.25 When detected, reduced platelet activity is associated with more IVH, more hematoma growth, increased mortality at 14 days, and worse functional outcomes at 3-month follow-up.26,27 Interventional trials to improve platelet activity are under way Platelet transfusion was a logical step to improve platelet activity and improves pointof-care assay results A prospective, randomized controlled trial of platelet transfusion (PATCH) is under way in Europe.28 Pending these data, platelet transfusion for ICH has become commonplace in some centers.29 However, platelet transfusion has potential adverse events, such as infection, volume overload, and limited supply Desmopressin has been prescribed for more than decades to improve platelet activity in patients known to take aspirin In a recent phase 2a trial, it improved platelet activity in patients with acute ICH.30,31 www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited 1295 Intracerebral Hemorrhage KEY POINTS h Immediate neurosurgical consultation is particularly indicated for cerebellar hemorrhage, large lobar hemorrhage, hydrocephalus, midline shift, and a decrease in consciousness on serial neuromonitoring h Neuro-QOL, the Patient-Reported Outcomes Measurement Information System, and National Institutes of Health Toolbox are web-based outcome measures developed by the National Institutes of Health Statins ("-Hydroxy"-Methylglutaryl-CoA Reductase Inhibitors) Controversy has surrounded the use of statin drugs in patients at high risk for ICH, particularly lobar ICH.32 This was buttressed by data showing an association between aggressively lowering cholesterol and a higher risk of ICH.33 More recent data suggest statins may be associated with no harm and perhaps better outcomes after ICH.34,35 Withholding or reducing the dose in patients with ICH and very low density lipoprotein cholesterol seems prudent Otherwise, discontinuation of statins does not appear to be necessary in most ICH patients SURGICAL MANAGEMENT A working relationship with neurosurgical colleagues is crucial to maximizing outcomes for patients with ICH Particular consideration should be given to the following: & Patients with cerebellar hematomas since these patients are at a high risk for brainstem compression & Large lobar hematomas since these are most accessible & Ventricular drainage for patients with hydrocephalus or IVH & Patients with midline shift, as this may be surgically correctable & A decrease in consciousness on serial neuromonitoring, as this may indicate an expanding intracranial hematoma Other than patients who are highly likely to clinically benefit from surgical decompression (eg, large cerebellar hematomas, hemispheric hematomas causing tissue shift, and neurologic decline in patients with good rehabilitation potential), the best way to select patients for surgical decompression is less clear In patients without a clear need for emergent surgical decompression, two 1296 clinical trials of early surgery (via craniotomy) versus expectant management found no difference in outcomes.36 Hematoma evacuation by means of stereotaxis is currently being investigated in the Minimally Invasive Surgery Plus rt-PA for Intracerebral Hemorrhage Evacuation (MISTIE) trial.37 ANALYSIS OF OUTCOMES DATA The most common outcome metric for ICH is the modified Rankin Scale (mRS), a global functional scale from (no symptoms) to (dead) The mRS has a high inter-rater reliability when validated questionnaires are used for its assessment, so different raters will generally record the same result.38 A variety of scores for health-related quality of life are also available and are generally correlated with the mRS The National Institutes of Health (NIH) has recently released novel outcome measures: Neuro-QOL is a series of questionnaires specifically developed and validated in patients with neurologic diseases.39 The Patient-Reported Outcomes Measurement Information System has more general instruments, many of which ‘‘cross-walk’’ to NeuroQOL measures The NIH Toolbox is a set of performance measures in motor, cognitive, sensory, and self-reported emotional health.40 These low-cost, web-based tools make it possible for more centers to comprehensively obtain state-of-the-art outcomes and examine how their processes might maximize health-related quality of life (www.assessmentcenter.net) CONCLUSION Care of patients with acute ICH has been improved by better description of severity and complications, evolutions in monitoring and control of vital signs, and measurable improvements in outcomes with specific interventions The www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited October 2015 next several years are likely to see further advancements that improve functional outcomes and quality of life for survivors of ICH REFERENCES Hemphill JC, Greenberg SM, Anderson CS, et al American Heart 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WNL.54.2.354 19 Lord A, Karinja S, Lantigua H, et al Therapeutic temperature modulation for fever after intracerebral hemorrhage Neurocrit Care 2014;21(2):200Y206 doi:10.1007/s12028-013-9948-5 www.ContinuumJournal.com Copyright © American Academy of Neurology Unauthorized reproduction of this article is prohibited 1297 Intracerebral Hemorrhage 20 Mayer SA, Kowalski RG, Presciutti M, et al Clinical trial of a novel surface cooling system for fever control in neurocritical care patients Crit Care Med 2004;32(12):2508Y2515 doi:10.1097/01.CCM.0000147441.39670.37 31 Naidech AM, Maas MB, Levasseur-Franklin KE, et al Desmopressin improves platelet activity in acute intracerebral hemorrhage Stroke 2014;45(8):2451Y2453 doi:10.1161/ STROKEAHA.114.006061 21 Diringer MN; Neurocritical Care Fever Reduction Trial Group Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system Crit Care Med 2004;32(2):559Y564 doi:10.1097/ 01.CCM.0000108868.97433.3F 32 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between statin use and intracerebral hemorrhage: a systematic review and meta-analysis Eur J Neurol 2014; 21(2):192Y198 doi:10.1111/ene.12273 35 Flint AC, Conell C, Rao VA, et al Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition JAMA Neurol 2014;71(11):1364Y1371 doi:10.1001/ jamaneurol.2014.2124 26 Naidech AM, Bendok BR, Garg RK, et al Reduced platelet activity is associated with more intraventricular hemorrhage Neurosurgery 2009;65(4):684Y688 doi:10.1227/ 01.NEU.0000351769.39990.16 36 Mendelow AD, Gregson BA, Rowan EN, et al Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial Lancet 2013;382(9890):397Y408 doi:10.1016/S0140-6736(13)60986-1 27 Naidech AM, Jovanovic B, Liebling S, et al Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage Stroke 2009;40(7):2398Y2401 doi:10.1161/STROKEAHA.109.550939 37 United States National Institutes of Health Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III Clinical Trials web site www.clinicaltrials.gov/ct2/ results?term=NCT01827046&Search=Search Accessed July 30, 2015 28 de Gans K, de Haan RJ, Majoie CB, et al PATCH: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial BMC Neurol 2010;10:19 doi:10.1186/1471-2377-10-19 38 Saver JL, Filip B, Hamilton S, et al Improving the reliability of stroke disability grading in clinical trials and clinical practice: the Rankin Focused Assessment (RFA) Stroke 2010;41(5):992Y995 doi:10.1161/ STROKEAHA.109.571364 29 Ziai WC, Mirski MA The slippery slope of platelet transfusion for intracerebral hemorrhage Neurocrit Care 2012;17(1): 154Y155 doi:10.1007/s12028-012-9694-0 39 Cella D, Lai JS, Nowinski CJ, et al Neuro-QOL: brief measures of health-related quality of life for clinical 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