Intracranial haemorrhage: therapeutic interventions and anaesthetic management
2014; Elsevier BV; Volume: 113; Linguagem: Inglês
10.1093/bja/aeu397
ISSN1471-6771
Autores Tópico(s)Acute Ischemic Stroke Management
ResumoSummaryIntracranial haemorrhage (ICH) is a devastating cause of stroke. Although the total incidence of ICH has remained stable worldwide, the proportion associated with the use of anticoagulant medications is increasing. Innovative interventions developed to improve patient outcomes often require peri-procedure anaesthetic management. This non-systematic review examines the pathophysiology of ICH at a clinical level, reports on novel therapeutic interventions, many of which are currently in clinical trials, and reviews the current published recommendations for the management of patients with ICH. Intracranial haemorrhage (ICH) is a devastating cause of stroke. Although the total incidence of ICH has remained stable worldwide, the proportion associated with the use of anticoagulant medications is increasing. Innovative interventions developed to improve patient outcomes often require peri-procedure anaesthetic management. This non-systematic review examines the pathophysiology of ICH at a clinical level, reports on novel therapeutic interventions, many of which are currently in clinical trials, and reviews the current published recommendations for the management of patients with ICH. Editor's key points•Intracranial haemorrhage (ICH) requires timely treatment to maximize functional outcome.•Efforts to reduce haematoma expansion, and thereby improve outcome, have involved recombinant factor VIIa (rFVIIa) and reduction in arterial pressure.•Reversal of anti-coagulation is an increasingly important consideration in ICH patients.•Multicentre trials are underway to improve management of these complex patients. •Intracranial haemorrhage (ICH) requires timely treatment to maximize functional outcome.•Efforts to reduce haematoma expansion, and thereby improve outcome, have involved recombinant factor VIIa (rFVIIa) and reduction in arterial pressure.•Reversal of anti-coagulation is an increasingly important consideration in ICH patients.•Multicentre trials are underway to improve management of these complex patients. Stroke is the fourth leading cause of death in the USA1World Health Organization (WHO). Fact sheet number 310: the top ten causes of death. 2014.Google Scholar and second only to ischaemic heart disease worldwide.2Go AS Mozaffarian D Roger VL et al.Heart disease and stroke statistics—2014 update: a report from the American Heart Association.Circulation. 2014; 129: e28-292Crossref PubMed Scopus (4482) Google Scholar While the majority of strokes are ischaemic in origin (see review by Anastasian in this issue),3Anastasian ZH Anaesthetic management of the patient with acute ischaemic stroke.Br J Anaesth. 2014; 113: ii9-ii16Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar 10–15% are due to intracranial haemorrhage (ICH).1World Health Organization (WHO). Fact sheet number 310: the top ten causes of death. 2014.Google Scholar, 4Australian Institute of Health and Welfare Stroke and its management in Australia: an update. Cardiovascular Disease Series no. 37. AIHW, Canberra2013Google Scholar ICH hs been traditionally divided into primary (spontaneous) and secondary. ICH is considered spontaneous if it results from rupture of small arteries and arterioles that have been damaged by chronic hypertension (60%) or amyloid angiopathy (30%),5Palm F Henschke N Wolf J et al.Intracerebral haemorrhage in a population-based stroke registry (LuSSt): incidence, aetiology, functional outcome and mortality.J Neurol. 2013; 260: 2541-2550Crossref PubMed Scopus (38) Google Scholar, 6Oureshi AI Turhim S Broderick JP Batjer HH Hondo H Hanley DF Spontaneous intracerebral hemorrhage.N Engl J Med. 2001; 344: 1450-1460Crossref PubMed Scopus (1322) Google Scholar, 7Skidmore CT Andrefsky J Spontaneous intracerebral hemorrhage: epidemiology, pathophysiology and medical management.Neurosurg Clin North Am. 2002; 13: 281-288Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar whereas secondary causes include trauma, aneurysms and vascular malformations, vasculitis, haemorrhagic conversion of infarct, and substance abuse. Primary ICH comprises 85% of all intracerebral haemorrhages,5Palm F Henschke N Wolf J et al.Intracerebral haemorrhage in a population-based stroke registry (LuSSt): incidence, aetiology, functional outcome and mortality.J Neurol. 2013; 260: 2541-2550Crossref PubMed Scopus (38) Google Scholar and affects 4 million people globally, with a 30 day mortality of 40–50%.8Van Asch CJJ Luitse MJA Rinkel GJE van der Tweel I Algra A Klijn CJM Incidence, case fatality and functional outcome of intracerebral haemorrhage over time, according to age, sex and ethnic origin: a systematic review and meta-analysis.Lancet Neurol. 2010; 9: 167-176Abstract Full Text Full Text PDF PubMed Scopus (1662) Google Scholar, 9Broderick JP Adams Jr, HP Barsan W et al.Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association.Stroke. 1999; 30: 905-915Crossref PubMed Scopus (777) Google Scholar Of the survivors, only 20–25% are able to function independently at 6 months.10Feigin VL Barker-Collo S McNaughton H Brown P Kerse N Long-term neuropsychological and functional outcomes in stroke survivors: current evidence and perspectives for new research.Int J Stroke. 2008; 3: 33-40Crossref PubMed Scopus (59) Google Scholar, 11Broderick JP Connolly S Feldmann E et al.Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and Quality of Care and Outcomes Research Group.Stroke. 2007; 38: 2001-2003Crossref PubMed Scopus (816) Google Scholar A PubMed literature search from 1980 through 2014 was performed utilizing the following key words: intracerebral haemorrhage, anaesthesia, therapy, and guidelines. Recent articles and clinical trials were surveyed and are summarized in this review with particular attention to three areas: pathophysiology of ICH, recent therapeutic innovations, and published guidelines reflecting standard management. The two most prominent aetiologies of ICH include chronic hypertension and amyloidosis. Chronic hypertension leads to lipohyalinosis of cerebral arterioles, whereby there is breakdown of vasculature smooth muscle and intimal hyalinization, weakening the vessels, especially at their bifurcations.7Skidmore CT Andrefsky J Spontaneous intracerebral hemorrhage: epidemiology, pathophysiology and medical management.Neurosurg Clin North Am. 2002; 13: 281-288Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Amyloid angiopathy is defined by amyloid deposition in the media and adventitia of the arterioles, leading to fibrinoid necrosis. In contrast to hypertension-related haemorrhages, which occur most frequently in deep brain structures basal ganglia and thalamus, haemorrhages due to amyloid angiopathy are predominately lobar in nature. Clinical presentation of ICH depends on the location and volume of the haemorrhage. A large haematoma (>150 ml) may cause an abrupt increase in intracranial pressure (ICP), leading to the loss of cerebral perfusion pressure and direct brainstem compression resulting in death.12Xi G Keep RF Hoff JT Mechanisms of brain injury after intracerebral haemorrhage.Lancet Neurol. 2006; 5: 53-63Abstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar Abrupt onset of an altered level of consciousness or other symptoms of increased ICP, such as nausea and vomiting, with a new-onset focal neurological deficit, is a common clinical presentation. Symptoms as non-specific as mild numbness and tingling may be an early sign. Cerebellar haemorrhage can be characterized by ataxia, dysmetria, and nystagmus.13Ott KH Kase CS Ojemann RG Mohr JP Cerebellar hemorrhage: diagnosis and treatment: a review of 56 cases.Arch Neurol. 1974; 31: 160-167Crossref PubMed Scopus (192) Google Scholar Seizures are the presenting symptom in only 7% of patients.14Vespa PM O'Phelan K Shah M et al.Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome.Neurology. 2003; 60: 1441-1446Crossref PubMed Scopus (466) Google Scholar A clinical risk stratification ICH score developed by Hemphill and colleagues15Hemphill JC Bonovich DC Besmertis L Manley GT Johnston SC The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.Stroke. 2001; 32: 891-897Crossref PubMed Google Scholar identified level of consciousness at presentation, infratentorial and intraventricular haemorrhage, haemorrhage volume >30 ml, and age >80 yr as independent factors predictive of outcomes (Table 1). More specifically, mortality was significantly correlated with increasing ICH score, with no mortality if ICH score= 0 and 100% mortality with ICH score=6 (Fig. 1). This score, or variants of it, has been extensively utilized in multiple clinical trials of ICH therapies.Table 1Determination of the ICH score. GCS score indicates GCS score on initial presentation (or after resuscitation); ICH volume, volume on initial CT calculated using ABC/2 method; and IVH, presence of any IVH on initial CT. Reproduced from15Hemphill JC Bonovich DC Besmertis L Manley GT Johnston SC The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.Stroke. 2001; 32: 891-897Crossref PubMed Google Scholar, with permissionComponentICH score pointsGCS score 3–42 5–121 13–150ICH volume (ml) ≥301 ≤300IVH Yes1 No0Infratentorial origin of ICH Yes1 No0Age (yr) ≥801 ≤800Total ICH score0–6 Open table in a new tab The pathophysiology of ICH is now recognized as a cascade of phenomena. First, there is the insult of the initial haemorrhage. The initial haemorrhage volume, in conjunction with level of consciousness, has long been established as an important predictor of mortality.16Broderick JP Brott TG Duldner JE et al.Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality.Stroke. 1993; 24: 987-993Crossref PubMed Scopus (1412) Google Scholar Secondly, haematoma expansion occurs in 30% of ICH patients and is correlated not only with mortality but also with decreased incidence of recovery to independent function.17Davis SM Broderick J Hennerici M et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (856) Google Scholar, 18Dowlatshahi D Demchuk AM Flaherty ML et al.VISTA Collaboration. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes.Neurology. 2011; 76: 1238-1244Crossref PubMed Scopus (383) Google Scholar Finally, the extent of perihaematoma brain oedema is significantly correlated with continued neuronal damage and post-haemorrhage mortality.19Staykov D Wagner I Volbers B et al.Natural course of perihemorrhagic edema after intracerebral hemorrhage.Stroke. 2011; 42: 2625-2629Crossref PubMed Scopus (112) Google Scholar Therapeutic interventions throughout this cascade of events are limited and the subject of ongoing investigations of safety and efficacy. Surgical evacuation of the haematoma can be beneficial in decreasing ICP and minimizing the effects of haematoma expansion and perihaemorrhagic oedema. The decision to bring a patient to the operating theatre for acute evacuation of an ICH depends on the location and the size of the haemorrhage. A Cochrane database meta-analysis reported an overall benefit of surgery compared with conservative therapy [odds ratio (OR) 0.71; P<0.001; 95% confidence interval (CI)=0.58–0.88];20Prasad K Mendelow AD Gregson B Surgery for primary supratentorial intracerebral haemorrhage.Cochrane Database Syst Rev. 2008; (CD000200)Google Scholar however, patients with an ICH in deep brain structures and those with intraventricular haemorrhage leading to hydrocephalus did worse with early surgery, while those with superficial ( 9, haematoma volume of 20–60 ml, or surgical evacuation within 8 h of ictus.22Gregson BA Broderick JP Auer LM et al.Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage.Stroke. 2012; 43: 1496-1504Crossref PubMed Scopus (163) Google Scholar Cerebellar haemorrhage is the one subgroup in which surgical evacuation is recommended if the patient has a large haematoma (>3 cm), is deteriorating neurologically, or has brainstem compression or hydrocephalus.23Morgenstern LB Hemphill III, JC Anderson C et al.Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2010; 41: 2108-2129Crossref PubMed Scopus (1230) Google Scholar Decompressive craniectomy, utilized as a treatment for malignant intracranial hypertension and brain oedema in traumatic brain injury and middle cerebral artery thromboembolic stroke, has not been prospectively studied in ICH. A review of several case–control studies suggests that patients with GCS<8 and haematoma volume <60 ml who underwent decompressive craniectomy in conjunction with haematoma evacuation had a favourable outcome in 41% of cases with an overall mortality of 28%.24Takeuchi S Wada K Nagatani K et al.Decompressive hemicraniectomy for spontaneous intracerebral hemorrhage.Neurosurg Focus. 2013; 34: E5Crossref PubMed Scopus (56) Google Scholar Comparative data in patients who had only medical management or had haematoma resection without decompressive craniectomy suggest a mortality of 91% and favourable outcome in only 5% of patients.16Broderick JP Brott TG Duldner JE et al.Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality.Stroke. 1993; 24: 987-993Crossref PubMed Scopus (1412) Google Scholar, 22Gregson BA Broderick JP Auer LM et al.Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage.Stroke. 2012; 43: 1496-1504Crossref PubMed Scopus (163) Google Scholar Since both the extent of ICH expansion and the development of significant peri-haemorrhagic oedema are correlated with initial haematoma volume, some have rationalized that evacuation of the haematoma might diminish the damage resulting from these processes.12Xi G Keep RF Hoff JT Mechanisms of brain injury after intracerebral haemorrhage.Lancet Neurol. 2006; 5: 53-63Abstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar Recent trials have suggested that there may be benefit from minimally invasive (endoscopic) clot removal as a stand-alone treatment or in combination with thrombolysis of the clot in some patient populations.25Vespa P McArthur D Miller C et al.Frameless stereotactic aspiration and thrombolysis of deep intracerebral hemorrhage is associated with reduction of hemorrhage volumes and neurological improvement.Neurocrit Care. 2005; 2: 274-281Crossref PubMed Scopus (107) Google Scholar, 26Mould WA Carhuapoma JR Muschelli J et al.Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema.Stroke. 2013; 44: 627-634Crossref PubMed Scopus (259) Google Scholar MISTIE III, a multicentre randomized trial (phase III) is underway to investigate the outcome and safety of clot lysis with rtPA (NCT01827046). Intraventricular haemorrhage, often secondary to an ICH in the basal ganglia or thalamus, occurs in 45% of ICH patients.27Tuhrim S Horowitz DR Sacher M Godbold JH Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage.Crit Care Med. 1999; 27: 617-621Crossref PubMed Scopus (354) Google Scholar Intraventricular (IVH) volume has been established as an independent predictor of poor outcome in ICH patients, independent of hydrocephalus,27Tuhrim S Horowitz DR Sacher M Godbold JH Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage.Crit Care Med. 1999; 27: 617-621Crossref PubMed Scopus (354) Google Scholar, 28Young WB Lee KP Pessin MS et al.Prognostic significance of ventricular blood in supratentorial hemorrhage: a volumetric study.Neurology. 1990; 40: 616-619Crossref PubMed Google Scholar, 29Hanley DF Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage.Stroke. 2009; 40: 1533-1538Crossref PubMed Scopus (177) Google Scholar perhaps because of the toxic effects of intraventricular blood on the brainstem and other periventricular structures.30Dey M Stadnik A Awad IA Thrombolytic evacuation of intracerebral and intraventricular hemorrhage.Curr Cardiol Rep. 2012; 14: 754-760Crossref PubMed Scopus (13) Google Scholar The presence of IVH increases the mortality of ICH to between 50% and 80%.31Steiner T Diringer MN Schneider D et al.Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII.Neurosurgery. 2006; 59 (discussion 773–4): 767-773Crossref PubMed Scopus (7) Google Scholar The Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Haemorrhage (CLEAR) trial (phase III) is now enrolling patients to evaluate the use of endoscopically directed recombinant tissue plasminogen activator (rTPA) to lyse clot in IVH and determine if this improves outcome (NCT 00784134). Haematoma expansion usually occurs within the first 24 h after the initial haemorrhage, and occurs in up to 30% of patients.17Davis SM Broderick J Hennerici M et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (856) Google Scholar For each 10% increase in haematoma volume, there is a 5% increase in the hazard ratio for mortality, and each 1 ml in volume increase leads to a 7% decrease in the likelihood of the patient being able to function independently.17Davis SM Broderick J Hennerici M et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (856) Google Scholar, 32Delcourt C Huang Y Arima H et al.Hematoma growth and outcomes in intracerebral hemorrhage: the INTERACT 1 study.Neurology. 2012; 79: 314-319Crossref PubMed Scopus (179) Google Scholar Risk factors for expansion include initial haemorrhagic volume, early presentation for medical care after symptom onset, use of antithrombotic and antiplatelet medications,33Broderick JP Diringer MN Hill MD et al.Determinants of intracerebral hemorrhage growth: an exploratory analysis.Stroke. 2007; 38: 1072-1075Crossref PubMed Scopus (273) Google Scholar and the presence of the 'spot sign', a marker of continued bleeding on computed tomography angiography (CTA)34Goldstein JN Fazen LE Snider R et al.Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage.Neurology. 2007; 68: 889-894Crossref PubMed Scopus (276) Google Scholar, 35Wada R Aviv RI Fox AJ et al.CT angiography 'spot sign' predicts hematoma expansion in acute intracerebral hemorrhage.Stroke. 2007; 38: 1257-1262Crossref PubMed Scopus (503) Google Scholar, 36Brouwers HB Greenberg SM Hematoma expansion following acute intracerebral hemorrhage.Cerebrovasc Dis. 2013; 35: 195-201Crossref PubMed Scopus (184) Google Scholar (Fig. 2). Although it has a positive predictive value of 61%, many patients without a spot sign go on to suffer significant haematoma expansion.37Demchuk AM Dowlatshahi D Rodriguez-Luna D et al.Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.Neurology. 2012; 11: 483Google Scholar Additionally, genetic factors play a role in that presence of the apolipoprotein E ε2 allele increases the risk of secondary haematoma expansion in lobar ICH.38Brouwers HB Biffi A Ayres AM et al.Apolipoprotein E genotype predicts hematoma expansion in lobar intracerebral hemorrhage.Stroke. 2012; 43: 1490-1495Crossref PubMed Scopus (67) Google Scholar Clinical trials aimed at reducing haematoma expansion have focused on either utilization of recombinant factor VIIa (rFVIIa) or reduction in arterial pressure. Although a phase II trial confirmed a reduction in haematoma volume, morbidity, and mortality after rVIIa treatment,39Mayer SA Brun NC Begtrup K et al.Recombinant activated factor VIII for active intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1152) Google Scholar a phase III trial failed to demonstrate any outcome benefit.40Mayer SA Brun NC Begtrup K et al.Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2008; 358: 2127-2137Crossref PubMed Scopus (974) Google Scholar Although currently it is not recommended to treat patients without a history of anticoagulant use with rVIIa, ongoing trials in the USA and Canada [(STOP-IT (NCT00810888) and SPOTLIGHT (NCT01359202)] are designed to evaluate the safety and efficacy of rVIIa in preventing haematoma expansion utilizing refined selection criteria based on the CTA spot sign. Since the expansion of volume of an intracranial haematoma is associated with increased mortality, several studies have attempted to minimize the ultimate size of the haematoma by reducing arterial pressure. The INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) trial assessed the effect of a reduction in systolic arterial pressure to 4 h, possibly reducing any potential benefit.42Hill MD Muir KW Interact-2: Should blood pressure be lowered acutely after intracerebral hemorrhage?.Stroke. 2013; 44: 2951-2952Crossref PubMed Scopus (24) Google Scholar Over 50% of the patients were from China, which may make it difficult to generalize the results to other populations, although the authors' subgroup analysis did not find any difference between this group and the rest of the study population. A post hoc analysis of systolic arterial pressure variability in this study population revealed a significant association between increased variability and poor outcome,43Mannning L Hirakawa Y Arima H et al.Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomized controlled trial.Lancet Neurol. 2014; 13: 364-373Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar suggesting that avoiding wide swings in arterial pressure may benefit ICH patients. The Antihypertensive Treatment in Acute Cerebral Haemorrhage (ATACH2) trial is utilizing a single agent, nicardipine, to rapidly reduce systolic arterial pressure to 110–140 mm Hg within 4 h. Preliminary data suggest a decrease in both haematoma expansion and in-hospital mortality (www.atach2.com, NCT01176565). Although INTERACT2 failed to reach statistical significance and ATACH2 is not complete, the results suggest that rapid reduction in blood pressure in ICH patients in whom ICP is not a concern, will not cause harm and may be of benefit. Secondary injury due to the development of peri-haemorrhagic oedema is another target for clinical therapy in ICH. Perihaematoma oedema can develop within 3 h of haemorrhage, but peaks 10–20 days after the initial haemorrhage,44Zazulia AR Diringer MN Derdeyn CP et al.Progression of mass effect after intracerebral hemorrhage.Stroke. 1999; 30: 1167-1173Crossref PubMed Scopus (323) Google Scholar and increases morbidity and mortality.45Gebel JM Jauch EC Brott TG et al.Relative edema volume is a predictor of outcome in patients with spontaneous intracerebral hemorrhage.Stroke. 2002; 33: 2636-2641Crossref PubMed Scopus (291) Google Scholar Several trials are aimed at reducing oedema and direct neurotoxicity due to haemoglobin, thrombin, and iron. Thrombin, a serine protease, has been demonstrated to promote both early and delayed oedema formation by disrupting the blood–brain barrier, inducing apoptosis, potentiating glutamate, and activating microglia.46Lee KR Colon GP Betz AL Keep RF Kim S Hoff JT Edema intracerebral hemorrhage: the role of thrombin.J Neurosurg. 1996; 84: 91-96Crossref PubMed Scopus (321) Google Scholar Perihaematoma oedema is reduced in ICH associated with thrombolysis therapy when compared with spontaneous ICH,47Gebel JM Brott TG Sila CA et al.Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage.Stroke. 2000; 31: 596-600Crossref PubMed Scopus (88) Google Scholar and was reduced in the MISTIE II trial of minimally invasive lysis with rtPA.24Takeuchi S Wada K Nagatani K et al.Decompressive hemicraniectomy for spontaneous intracerebral hemorrhage.Neurosurg Focus. 2013; 34: E5Crossref PubMed Scopus (56) Google Scholar Additionally, haemoglobin and iron may increase brain oedema, and although the iron chelator deferoxamine reduced ICH-induced brain oedema in animals,48Nakamura T Keep RF Hua Y Schallert T Hoff JT Xi G Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage.Neurosurg Focus. 2006; 104: 305-312Google Scholar a human trial was halted because of an increased incidence of acute respiratory distress syndrome (NCT1662895). The inflammatory response, neutrophil infiltration, cytokine and complement activation, and production of tissue matrix metalloproteases all play a role in tissue oedema. While early studies of corticosteroid therapy failed to show benefit and led to increased complications,49Poungvarin N Bhoopat W Viriyavejakul A et al.Effects of dexamethasone in primary supratentorial intracerebral hemorrhage.N Engl J Med. 1987; 316: 1229-1233Crossref PubMed Scopus (279) Google Scholar several current ongoing trials are directed towards reducing oedema and improving patient outcomes. Hypothermia was found to potentially limit ICH perihaemorrhagic oedema in two retrospective case-controlled studies.50Kollmar R Staykov D Dorfler A et al.Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage.Stroke. 2010; 41: 1684-1689Crossref PubMed Scopus (126) Google Scholar, 51Kollmar R Juettler E Huttner H et al.Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial.Int J Stroke. 2012; 7: 168-172Crossref PubMed Scopus (56) Google Scholar Accordingly, a prospective, multicentre, randomized controlled phase II trial is currently underway (NCT01607151). Similarly, a small trial of fingolimid, a sphingosine-1-phosphate receptor ligand with anti-inflammatory properties approved in the treatment of multiple sclerosis, showed a short-term reduction in perihaematoma oedema and improvement in NIH stroke scale when administered to patients for the first 72 h after ICH.52Fu Y Hao J Zhang N et al.Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study.JAMA Neurol. 2014; 71: 1092-1101Crossref PubMed Scopus (205) Google Scholar Trials to assess whether this improvement might be sustainable are necessary. While research is directed towards the discovery of treatments to improve the outcome of ICH, the use of anticoagulants for the prevention of thromboembolic stroke and coronary stent thrombosis has increased both the incidence and severity of ICH. Atrial fibrillation is associated with 15–25% of ischaemic strokes,53Marini C De Santis F Sacco S et al.Contribution of atrial fibrillation to incidence and outcome of ischemic stroke.Stroke. 2005; 36: 1115
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