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Acute intracerebral haemorrhage: Grounds for optimism in management
Journal of Clinical Neuroscience 19 (2012) 1622–1626
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Acute intracerebral haemorrhage: Grounds for optimism in management Candice Delcourt, Craig Anderson ⇑ Neurological and Mental Health Division, The George Institute for Global Health, PO Box M201, Missenden Road, New South Wales 2050, Australia Neurology Department, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia Stroke Medicine and Clinical Neuroscience, The University of Sydney, Missenden Road, Camperdown, New South Wales, Australia
a r t i c l e
i n f o
Article history: Received 22 December 2011 Accepted 2 May 2012
Keywords: Blood pressure Craniotomy Clinical trials Intracerebral haemorrhage Recombinant Factor VIIa
a b s t r a c t Spontaneous intracerebral haemorrhage (ICH) is one of the most devastating types of stroke, which has considerable disease burden in ‘‘non-white’’ ethnic groups where the population-attributable risks of elevated blood pressure are very high. Since the treatment of ICH remains largely supportive and expectant, nihilism and the early withdrawal of active therapy influence management decisions in clinical practice. However, approaches to management are now better defined on the basis of evidence that both survival and speed (and degree) of recovery are critically dependent on the location, size, and degree of expansion and extension into the intraventricular system of the haematoma of the ICH. Although no medical treatment has been shown to improve outcome in ICH, several promising avenues have emerged that include haemostatic therapy and intensive control of elevated blood pressure. Conversely, there is continued controversy over the role of evacuation of the haematoma of ICH via open craniotomy. Despite being an established practice for several decades, and having undergone evaluation in multiple randomised trials, there is uncertainty over which patients have the most to gain from an intervention with clear procedural risk. Minimally invasive surgery via local anaesthetic applied drill-puncture of the cranium and infusion of a thrombolytic agent is an attractive option for patients requiring critical management of the haematoma, not just in low resource settings but arguably also in specialist centres of western countries. With several ongoing clinical trials nearing completion, these treatments could enter routine practice within the next few years, further justifying the urgency of ‘‘time is brain’’ and that active management within well-organized, comprehensive acute stroke care units includes patients with ICH. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Intracerebral haemorrhage (ICH), estimated to affect over 1 million people worldwide each year,1,2 is the least treatable form of stroke and contributes substantially to the burden of cerebrovascular disease defined by various metrics such as premature mortality, disability, suffering, and economic and social burden. Although downward trends in rates of ICH are evident in Australia and several other Western countries, presumably due to improvements in both population-wide control of elevated blood pressure (BP) and targeted management of ‘‘hypertension’’, the condition remains a major ongoing health problem, particularly in developing countries where it accounts for between 20% and 50% of all strokes.1–4 Unfortunately, the management of ICH remains largely supportive and expectant. This contributes to ongoing nihilism and a low threshold to withdrawal of active care5 in such patients who are generally under the care of neurologists or physicians after being first deemed unsuitable by neurosurgeons after an initial alarmist ‘‘knee-jerk’’ referral from the emergency department as there was ⇑ Corresponding author. Tel.: +61 2 9993 4521; fax: +61 2 9993 4502. E-mail address: [email protected] (C. Anderson). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.05.018
‘‘blood on the CT head scan’’. Despite being an established practice for several decades, and having undergone evaluation in multiple randomised trials, controversy remains over the role of craniotomy in ICH. Apart from having the ability to decompress an infratentorial ICH and relieve obstructive hydrocephalus, there is uncertainty over which patients with hemispheric ICH have the most to gain from open evacuation of the haematoma, which has clear perioperative risk and involves cutting through healthy brain. Advances in the understanding of the pathophysiology of ICH (Fig. 1) and related prognostic factors6–8 has allowed the development and evaluation of treatments. The ICH score,6 which is comprised of several variables including age, initial level of consciousness, and neuroimaging parameters of location, volume and presence of intraventricular extension, is one of the most popular prognostic scales to aid patient care and research. However, it is recognition of the dynamic nature of the haematoma that has provided a clear mechanistic target for treatments, with early intensive BP lowering9 and haemostatic therapy10–12 holding considerable promise as standard therapies. In addition, thrombolytic clearing of intraventricular haemorrhage (IVH)13,14 and minimally invasive cranial puncture surgery15–17 are being explored with a clear imperative of improving the management for ICH. In this
1623
C. Delcourt, C. Anderson / Journal of Clinical Neuroscience 19 (2012) 1622–1626
Ha aemosta atic ther t rapyy BP P low werin ng thera apy
Critical phases in acute intracerebral haemorrhage Decompressive surgery – open or microsurgery Supportive care, care anti-oedema anti oedema treatment and mechanical ventilation Rehabilitation Long term BP lowering treatment Long-term
haematoma growth haematoma mass re bleeding re-bleeding cerebral oedema stroke recurrence 3-6 3 6 6 6-12 12 hours
12 hours h to t 1 week
k 1 to t 4 weeks
1 tto 6 months th
Fig. 1. Schema of potential therapeutic treatment targets according to critical stages of the natural history of intracerebral haemorrhage. BP = blood pressure.
review, we explore current evidence for treatment of ICH and ongoing clinical trials of new treatments. 2. General management Current best practice guidelines recommend that all patients with ICH receive initial monitored care in an acute stroke unit or an intensive care unit.18 Antithrombotic agents should be discontinued, and the effects of anticoagulation should be promptly reversed with appropriate agents. Supportive management should include efforts to control raised intracranial pressure, and the maintenance of adequate airway, oxygenation, circulation, blood glucose level, body temperature, and hydration, as well as providing prophylaxis against deep vein thrombosis during immobilisation. For many aspects of management, however, there is uncertainty over whether the risks and costs associated with rapid and intensive normalisation of vital functions and physiological function justify the potential modest beneficial effects. Further research is needed in these areas. 2.1. Anticoagulant-associated ICH With the ageing of the population, an increased prevalence of atrial fibrillation and greater use of anticoagulation, there is potential for a rise in the rates of anticoagulant-associated ICH. A recent population-based study in Finland indicates a more positive outline, with modest declines in both the incidence of anticoagulant-associated ICH and its case-fatality evident over a 15 year period to 2008.19 Even so, of the nearly one in five ICH patients with anticoagulant-associated ICH, this study, like others, showed that over one-half were dead within 30 days of onset.20,21 There is hope that the new anticoagulants will have a better safety profile compared to warfarin in clinical practice: the randomised evidence indicates lower risks of ICH for dabigatran 150 mg twice daily (hazard ratio [HR] 0.4; 95% confidence intervals [CI] 0.27–0.6)22 apixaban 5 mg twice daily (HR 0.42; 95% CI 0.3–0.58),23 rivaroxaban 10 mg once daily (HR 0.67; 95% CI 0.47–0.93),24 probably related
to their different mode of action – inhibition of factors IIa and Xa – being more selective than that of warfarin. When ICH occurs in a patient taking a vitamin K antagonist, urgent reversal of anticoagulation and normalisation of the International Normalised Ratio (INR) (to 61.3) is generally recommended to stop ongoing ICH. In addition to intramuscular vitamin K, the administration of fresh frozen plasma (FFP) is the most popular treatment option because it is low cost and readily available. However, FFP exposes patients to the adverse effects of blood transfusion, which includes fever and anaphylaxis, and heart failure from volume overload. There are also delays in normalization of the INR related to the need to check ABO blood group compatibility, and there is uncertainty over its true beneficial effects given the time delay required to achieve thawing, administration and pharmacological effect. One study of anticoagulationassociated ICH indicates a median time of 30 hours (range 14–50) for normalisation of the INR.25 An attractive alternative therapy is therefore unactivated prothrombin-complex concentrates (PCC), which consists of several vitamin K-dependent coagulation factors (II, VII, IX, and X) and has the ability to rapidly normalise INR (<30 minutes of infusion).26 However, due to its high cost ($1000–$2000 per patient), limited access and unproven benefit, there is some reluctance on the part of haematologists/blood banks to release PCC for the treatment of ICH.27 While there are ongoing trials comparing FFP with PCC,26 none are powered to assess effects on hard clinical endpoints due to the obvious costs and logistical complexities to the funding and organisation of such a study. There are no antidotes to rivaroxaban, apixaban or dabigatran, although the latter can be removed through haemodialysis over several hours and there is potential for treatments under development to reverse the effects of these agents to be available for clinical use within the next few years. 2.2. Recombinant activated factor VII (rFVIIa) In the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial,11 80 lg/kg of the potenti pro-thrombotic agent rFVIIa administered
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C. Delcourt, C. Anderson / Journal of Clinical Neuroscience 19 (2012) 1622–1626
Fig. 2. (a) Baseline 15.8 mL basal ganglionic intracerebral haemorrhage (ICH) in a 73-year-old male at 3 hours after onset; (b) positive dual ‘‘spot sign’’ on associated CT angiography; (c) 96.4 mL ICH at 5 hours, with subsequent death at 12 hours (provided by Drs Andrew Demchuk and Dariush Dowlatshahi, University of Calgary).
within 4 hours of ICH onset significantly reduced ICH expansion to a similar 50% relative degree to that seen in the initial phase 2b trial,10 but with a discordant effect in this failing to translate into any improvement in survival or functional outcome at 90 days.11,12 Moreover, patients treated with rFVIIa had an increased risk of both venous and arterial thromboembolic complications, including ischaemic stroke and myocardial ischaemia. It is possible that rFVIIa may have significant beneficial effects for patients with a high likelihood of haematoma expansion and low risk of complications (that is, younger patients). Hence, the rationale behind targeting patients with a positive ‘‘spot sign’’ indicative of ongoing haemorrhage on the basis of active extravasation of contrast on CT angiography (Fig. 2),28–30 in the ongoing SPOT-IT31 and SPOTLIGHT trials.32 Even if one of these trials is positive, future use of rFVIIa is severely restricted by access, cost and limited patient eligiblility. 2.3. Early intensive control of hypertension Given the strong positive association between elevated BP levels and poor outcome from ICH, the rapid early control of BP is a logical strategy that is low cost and widely applicable. The pilot phase of the INTEnsive blood pressure Reduction in ACute intracerebral haemorrhage (INTERACT)9 trial and non-randomised Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)33 study evaluated intensive BP lowering treatment in ICH. Both demonstrated that the treatment is feasible and not hazardous to patients, which is contrary to the long-held neurological dogma that it is ‘‘dangerous’’ to alter BP and potentially, cerebral blood flow, during the acute phase of stroke. Moreover, in INTERACT, where intensive BP lowering (target systolic BP 140 mmHg) was compared with traditional management (target systolic BP 180 mmHg), there was a reduction in haematoma growth at 24 hours (14% compared to 26% between active and control groups), although the finding was not statistically significant after adjustment for minor imbalances in baseline characteristics related to initial haematoma volume and the time from ICH onset to brain CT scan. Nevertheless, the American Heart Association guidelines for the management of spontaneous ICH were updated in 200818 to recommend that in ‘‘patients presenting with a systolic BP of 150 to 220 mmHg, acute lowering of systolic BP to 140 mm Hg is probably safe (Class IIa; Level of Evidence: B)’’. Both studies are now in their main phases, as INTERACT234 and ATACH II,35 powered to assess the effects of treatment within 6 hours and 3 hours of onset of ICH, respectively, on substantive clinical out-
comes, with the former study nearing completion with results likely in 2013. 3. Surgical management 3.1. Standard open craniotomy for haematoma evacuation Craniotomy is the most widely studied intervention for the management of ICH. Although there have been no randomised trials specifically for patients with cerebellar haemorrhage, clinical observation indicates beneficial effects of decompression of the haematoma or shunting in those who are neurologically deteriorating or have brain stem compression and hydrocephalus from ventricular obstruction.15 However, the role for surgery in supratentorial ICH is not as clear-cut. The pivotal Surgical Treatment of Intracerebral Haemorrhage (STICH) trial36 assessed the effectiveness of early surgery (mean time from onset to treatment 30 hours; interquartile range [IQR] 16–49 hours) compared with initial conservative medical management. In the initial conservative group, 26% of patients underwent later evacuation (mean 60 hours, IQR 27–99 hours) because of re-bleeding, clinical deterioration, or a variety of other less frequent reasons. The likely modest differential treatment effect was therefore likely compromised by cross-over between randomised groups, contributing to the trial being neutral, and subsequent perception of an ‘‘inconclusive outcome’’. On the basis of the subgroup of patients with ICH within 1 cm of the cortex appearing to benefit from early surgery, the subsequent STICH II37 trial was launched targeting superficial hemorrhages, with results due in 2012. A Cochrane systematic overview with a meta-analysis of 10 randomised trials of routine medical treatment plus intracranial surgery compared with routine medical treatment alone indicates an overall benefit from surgical intervention in ICH. Surgery was associated with a statistically significant reduction in the odds of being dead or dependent at final follow-up (3 or 6 months) (odds ratio [OR] 0.71, 95% CI 0.58–0.88).38 Despite the evidence, many neurosurgeons remain reluctant to operate on ICH due to concern over risks and uncertain potential benefits. 3.2. Thrombolytic evacuation of intraventricular haemorrhage Ventricular drainage of cerebrospinal fluid is often performed for acute obstructive hydrocephalus, but careful drainage of intraventricular haemorrhage with instillation of a thrombolytic at low
C. Delcourt, C. Anderson / Journal of Clinical Neuroscience 19 (2012) 1622–1626
dose may also improve outcomes.14 There are patients with intraventricular haemorrhage who remain in an obtunded state that is disproportionate to the size and location of ICH, often presumed related to chemical meningo-encephalitis. The Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) trial should provide randomised evidence that favours benefits of rapid clearage of intraventricular haemorrhage over the risks of surgery, bleeding and infection.14 3.3. Minimally invasive surgery with cranial puncture for haematoma evacuation Minimally invasive surgery to remove haematomas using mechanical clot disruption or endoscopic removal combined with the injection of a thrombolytic agent for clot dissolution is another attractive alternative to open craniotomy. As well as a reduction in operative time and surgical trauma, the procedure can be performed under local anesthesia by appropriately trained neurologists and intensivists rather than neurosurgeons. The approach is widely used in China, where improvements in disability, but not survival, have been demonstrated at 90 days.39,40 Preliminary results of the National Institutes of Health’s early phase Minimally Invasive Surgery plus rtPA for ICH Evaculation (MISTIE) trial41 shows that successful evacuation of the haematoma, albeit strongly dependent on an appropriate position of the catheter, can improve outcomes. However, a large international multicentre randomised trial is needed to demonstrate substantial clinical and cost-effective beneficial effects to bring about such a radical change in clinical practice. 4. Conclusions Despite its associated devastating outcomes, there is some cause for optimism that the management of ICH will improve. Better management of BP, more careful selection of patients who could respond to rFVIIa, and innovative surgical approaches which include use of thrombolytic therapy for IVH and minimally invasive ‘‘cranial puncture’’ surgery, offer considerable promise of a more active approach with effective therapy within the next few years. However, as chronically elevated BP is by far the strongest risk factor for ICH,42 and with some evidence of declines in rates but not of case fatality for ICH in recent decades,43 all clinicians should remain strong advocates for screening and treatment of hypertension, both in primary and secondary prevention. This is particularly important in countries which have large and rapidly ageing populations, such as China, where the prevalence of hypertension and rates of stroke, including ICH, are very high.44 References 1. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–60. 2. Zhang LF, Yang J, Hong Z, et al. Proportion of different subtypes of stroke in China. Stroke 2003;34:2091–6. 3. Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006;66:1182–6. 4. Sacco RL, Mayer SA. Epidemiology of intracerebral hemorrhage. In: Feldmann E, editor. Intracerebral Hemorrhage. Armonk, NY: Futura Publishing Co.; 1994. p. 3–23. 5. Zahuranec DB, Morgenstern LB, Sánchez BN, et al. Do-not-resuscitate orders and predictive models after intracerebral hemorrhage. Neurology 2010;75:626–33. 6. Hemphill 3rd JC, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–7. 7. Broderick JP, Brott TG, Duldner JE, et al. Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987–93. 8. Davis S, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175–81.
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9. Anderson CS, Huang Y, Wang JG, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391–9. 10. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777–85. 11. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127–37. 12. Mayer SA, Davis SM, Skolnick BE, et al. Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII? Stroke 2009;40:833–40. 13. Morgan T, Awad I, Keyl P, et al. Preliminary report of the clot lysis evaluating accelerated resolution of intraventricular hemorrhage (CLEAR-IVH) clinical trial. Acta Neurochir Suppl 2008;105:217–20. 14. Naff N, Williams MA, Keyl PM, et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke 2011;42:3009–16. 15. Longatti P, Martinuzzi A, Fiorindi A, et al. Neuroendoscopic management of intraventricular hemorrhage. Stroke 2004;35:e35–8. 16. Auer L, Deinsberger W, Niederkorn K, et al. Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study. J Neurosurg 1989;70:530–5. 17. Minimally Invasive Surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE). 2006. Available from: http://www.stroke-center.org/trials. 18. Morgenstern LB, Hemphill 3rd 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. 19. Huhtakangas J, Tetri S, Juvela S, et al. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study. Stroke 2011;42:2431–5. 20. Sjoblom L, Hardemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulation therapy: a Swedish multicenter study. Stroke 2001;32:2567. 21. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008;39:2993. 22. Connolly S, Ezekowitz M, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. 23. Granger C, Alexander J, McMurray J, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 24. Patel M, Mahaffey K, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 25. Pabinger I, Brenner B, Kalian U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008;6:622. 26. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 2006;37:256–62. 27. Lee SB, Manno EM, Layton KF, et al. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology 2006;67:1272–4. 28. Wada R, Aviv RI, Fox AJ, et al. CT angiography ‘‘spot sign’’ predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007;38:1257–62. 29. Goldstein JN, Fazen LE, Snider R, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology 2007;68:889–94. 30. Delgado Almandoz JE, Yoo AJ, Stone MJ, et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke 2010;41:54–60. 31. http://www.STOPITSTUDY.org/index.html. 32. http://clinicaltrials.gov/ct2/show/NCT01359202. 33. Qureshi A. Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): rationale and design. Neurocrit Care 2007;6:56–66. 34. Delcourt C, Huang Y, Wang J, et al. The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2). Int J Stroke 2010;5:110–6. 35. Qureshi AI, Palesch YY. Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: design, methods, and rationale. Neurocrit Care 2011;15:559–76. 36. Mendelow A, Gregson B, Fernandes H, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005;365:387–97. 37. Mendelow A, Gregson B, Mitchell P, et al. Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol. Trials 2011;12:124. 38. Prasad K, Mendelow D, Gregson B. Surgery for primary supratentorial intracerebral haemorrhage. Cochrane Database Syst Rev 2008;4:CD000200. 39. Wang W, Jing B, Liu HM, et al. Minimally invasive surgery compared with conservative management. Int J Stroke 2009;4:11–6. 40. Zhou H, Zhang Y, Liu L, et al. Minimally invasive stereotactic puncture and thrombolysis therapy improves long-term outcome after acute intracerebral hemorrhage. J Neurol 2011;258:661–9. 41. Mitka M. Promising new procedure offers hope for patients with intracerebral hemorrhage. JAMA 2011;306:255–6.
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42. Ariesen M, Claus S, Rinkel G, et al. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke 2003;34:2060–6. 43. Van Asch CJ, Luitse MJ, Rinkel GJ, et al. 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;9:167–76. 44. Liu M, Wu B, Wang W, et al. Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol 2007;6:456–64.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Acute intracerebral haemorrhage: Grounds for optimism in management Candice Delcourt, Craig Anderson ⇑ Neurological and Mental Health Division, The George Institute for Global Health, PO Box M201, Missenden Road, New South Wales 2050, Australia Neurology Department, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia Stroke Medicine and Clinical Neuroscience, The University of Sydney, Missenden Road, Camperdown, New South Wales, Australia
a r t i c l e
i n f o
Article history: Received 22 December 2011 Accepted 2 May 2012
Keywords: Blood pressure Craniotomy Clinical trials Intracerebral haemorrhage Recombinant Factor VIIa
a b s t r a c t Spontaneous intracerebral haemorrhage (ICH) is one of the most devastating types of stroke, which has considerable disease burden in ‘‘non-white’’ ethnic groups where the population-attributable risks of elevated blood pressure are very high. Since the treatment of ICH remains largely supportive and expectant, nihilism and the early withdrawal of active therapy influence management decisions in clinical practice. However, approaches to management are now better defined on the basis of evidence that both survival and speed (and degree) of recovery are critically dependent on the location, size, and degree of expansion and extension into the intraventricular system of the haematoma of the ICH. Although no medical treatment has been shown to improve outcome in ICH, several promising avenues have emerged that include haemostatic therapy and intensive control of elevated blood pressure. Conversely, there is continued controversy over the role of evacuation of the haematoma of ICH via open craniotomy. Despite being an established practice for several decades, and having undergone evaluation in multiple randomised trials, there is uncertainty over which patients have the most to gain from an intervention with clear procedural risk. Minimally invasive surgery via local anaesthetic applied drill-puncture of the cranium and infusion of a thrombolytic agent is an attractive option for patients requiring critical management of the haematoma, not just in low resource settings but arguably also in specialist centres of western countries. With several ongoing clinical trials nearing completion, these treatments could enter routine practice within the next few years, further justifying the urgency of ‘‘time is brain’’ and that active management within well-organized, comprehensive acute stroke care units includes patients with ICH. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Intracerebral haemorrhage (ICH), estimated to affect over 1 million people worldwide each year,1,2 is the least treatable form of stroke and contributes substantially to the burden of cerebrovascular disease defined by various metrics such as premature mortality, disability, suffering, and economic and social burden. Although downward trends in rates of ICH are evident in Australia and several other Western countries, presumably due to improvements in both population-wide control of elevated blood pressure (BP) and targeted management of ‘‘hypertension’’, the condition remains a major ongoing health problem, particularly in developing countries where it accounts for between 20% and 50% of all strokes.1–4 Unfortunately, the management of ICH remains largely supportive and expectant. This contributes to ongoing nihilism and a low threshold to withdrawal of active care5 in such patients who are generally under the care of neurologists or physicians after being first deemed unsuitable by neurosurgeons after an initial alarmist ‘‘knee-jerk’’ referral from the emergency department as there was ⇑ Corresponding author. Tel.: +61 2 9993 4521; fax: +61 2 9993 4502. E-mail address: [email protected] (C. Anderson). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2012.05.018
‘‘blood on the CT head scan’’. Despite being an established practice for several decades, and having undergone evaluation in multiple randomised trials, controversy remains over the role of craniotomy in ICH. Apart from having the ability to decompress an infratentorial ICH and relieve obstructive hydrocephalus, there is uncertainty over which patients with hemispheric ICH have the most to gain from open evacuation of the haematoma, which has clear perioperative risk and involves cutting through healthy brain. Advances in the understanding of the pathophysiology of ICH (Fig. 1) and related prognostic factors6–8 has allowed the development and evaluation of treatments. The ICH score,6 which is comprised of several variables including age, initial level of consciousness, and neuroimaging parameters of location, volume and presence of intraventricular extension, is one of the most popular prognostic scales to aid patient care and research. However, it is recognition of the dynamic nature of the haematoma that has provided a clear mechanistic target for treatments, with early intensive BP lowering9 and haemostatic therapy10–12 holding considerable promise as standard therapies. In addition, thrombolytic clearing of intraventricular haemorrhage (IVH)13,14 and minimally invasive cranial puncture surgery15–17 are being explored with a clear imperative of improving the management for ICH. In this
1623
C. Delcourt, C. Anderson / Journal of Clinical Neuroscience 19 (2012) 1622–1626
Ha aemosta atic ther t rapyy BP P low werin ng thera apy
Critical phases in acute intracerebral haemorrhage Decompressive surgery – open or microsurgery Supportive care, care anti-oedema anti oedema treatment and mechanical ventilation Rehabilitation Long term BP lowering treatment Long-term
haematoma growth haematoma mass re bleeding re-bleeding cerebral oedema stroke recurrence 3-6 3 6 6 6-12 12 hours
12 hours h to t 1 week
k 1 to t 4 weeks
1 tto 6 months th
Fig. 1. Schema of potential therapeutic treatment targets according to critical stages of the natural history of intracerebral haemorrhage. BP = blood pressure.
review, we explore current evidence for treatment of ICH and ongoing clinical trials of new treatments. 2. General management Current best practice guidelines recommend that all patients with ICH receive initial monitored care in an acute stroke unit or an intensive care unit.18 Antithrombotic agents should be discontinued, and the effects of anticoagulation should be promptly reversed with appropriate agents. Supportive management should include efforts to control raised intracranial pressure, and the maintenance of adequate airway, oxygenation, circulation, blood glucose level, body temperature, and hydration, as well as providing prophylaxis against deep vein thrombosis during immobilisation. For many aspects of management, however, there is uncertainty over whether the risks and costs associated with rapid and intensive normalisation of vital functions and physiological function justify the potential modest beneficial effects. Further research is needed in these areas. 2.1. Anticoagulant-associated ICH With the ageing of the population, an increased prevalence of atrial fibrillation and greater use of anticoagulation, there is potential for a rise in the rates of anticoagulant-associated ICH. A recent population-based study in Finland indicates a more positive outline, with modest declines in both the incidence of anticoagulant-associated ICH and its case-fatality evident over a 15 year period to 2008.19 Even so, of the nearly one in five ICH patients with anticoagulant-associated ICH, this study, like others, showed that over one-half were dead within 30 days of onset.20,21 There is hope that the new anticoagulants will have a better safety profile compared to warfarin in clinical practice: the randomised evidence indicates lower risks of ICH for dabigatran 150 mg twice daily (hazard ratio [HR] 0.4; 95% confidence intervals [CI] 0.27–0.6)22 apixaban 5 mg twice daily (HR 0.42; 95% CI 0.3–0.58),23 rivaroxaban 10 mg once daily (HR 0.67; 95% CI 0.47–0.93),24 probably related
to their different mode of action – inhibition of factors IIa and Xa – being more selective than that of warfarin. When ICH occurs in a patient taking a vitamin K antagonist, urgent reversal of anticoagulation and normalisation of the International Normalised Ratio (INR) (to 61.3) is generally recommended to stop ongoing ICH. In addition to intramuscular vitamin K, the administration of fresh frozen plasma (FFP) is the most popular treatment option because it is low cost and readily available. However, FFP exposes patients to the adverse effects of blood transfusion, which includes fever and anaphylaxis, and heart failure from volume overload. There are also delays in normalization of the INR related to the need to check ABO blood group compatibility, and there is uncertainty over its true beneficial effects given the time delay required to achieve thawing, administration and pharmacological effect. One study of anticoagulationassociated ICH indicates a median time of 30 hours (range 14–50) for normalisation of the INR.25 An attractive alternative therapy is therefore unactivated prothrombin-complex concentrates (PCC), which consists of several vitamin K-dependent coagulation factors (II, VII, IX, and X) and has the ability to rapidly normalise INR (<30 minutes of infusion).26 However, due to its high cost ($1000–$2000 per patient), limited access and unproven benefit, there is some reluctance on the part of haematologists/blood banks to release PCC for the treatment of ICH.27 While there are ongoing trials comparing FFP with PCC,26 none are powered to assess effects on hard clinical endpoints due to the obvious costs and logistical complexities to the funding and organisation of such a study. There are no antidotes to rivaroxaban, apixaban or dabigatran, although the latter can be removed through haemodialysis over several hours and there is potential for treatments under development to reverse the effects of these agents to be available for clinical use within the next few years. 2.2. Recombinant activated factor VII (rFVIIa) In the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial,11 80 lg/kg of the potenti pro-thrombotic agent rFVIIa administered
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Fig. 2. (a) Baseline 15.8 mL basal ganglionic intracerebral haemorrhage (ICH) in a 73-year-old male at 3 hours after onset; (b) positive dual ‘‘spot sign’’ on associated CT angiography; (c) 96.4 mL ICH at 5 hours, with subsequent death at 12 hours (provided by Drs Andrew Demchuk and Dariush Dowlatshahi, University of Calgary).
within 4 hours of ICH onset significantly reduced ICH expansion to a similar 50% relative degree to that seen in the initial phase 2b trial,10 but with a discordant effect in this failing to translate into any improvement in survival or functional outcome at 90 days.11,12 Moreover, patients treated with rFVIIa had an increased risk of both venous and arterial thromboembolic complications, including ischaemic stroke and myocardial ischaemia. It is possible that rFVIIa may have significant beneficial effects for patients with a high likelihood of haematoma expansion and low risk of complications (that is, younger patients). Hence, the rationale behind targeting patients with a positive ‘‘spot sign’’ indicative of ongoing haemorrhage on the basis of active extravasation of contrast on CT angiography (Fig. 2),28–30 in the ongoing SPOT-IT31 and SPOTLIGHT trials.32 Even if one of these trials is positive, future use of rFVIIa is severely restricted by access, cost and limited patient eligiblility. 2.3. Early intensive control of hypertension Given the strong positive association between elevated BP levels and poor outcome from ICH, the rapid early control of BP is a logical strategy that is low cost and widely applicable. The pilot phase of the INTEnsive blood pressure Reduction in ACute intracerebral haemorrhage (INTERACT)9 trial and non-randomised Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)33 study evaluated intensive BP lowering treatment in ICH. Both demonstrated that the treatment is feasible and not hazardous to patients, which is contrary to the long-held neurological dogma that it is ‘‘dangerous’’ to alter BP and potentially, cerebral blood flow, during the acute phase of stroke. Moreover, in INTERACT, where intensive BP lowering (target systolic BP 140 mmHg) was compared with traditional management (target systolic BP 180 mmHg), there was a reduction in haematoma growth at 24 hours (14% compared to 26% between active and control groups), although the finding was not statistically significant after adjustment for minor imbalances in baseline characteristics related to initial haematoma volume and the time from ICH onset to brain CT scan. Nevertheless, the American Heart Association guidelines for the management of spontaneous ICH were updated in 200818 to recommend that in ‘‘patients presenting with a systolic BP of 150 to 220 mmHg, acute lowering of systolic BP to 140 mm Hg is probably safe (Class IIa; Level of Evidence: B)’’. Both studies are now in their main phases, as INTERACT234 and ATACH II,35 powered to assess the effects of treatment within 6 hours and 3 hours of onset of ICH, respectively, on substantive clinical out-
comes, with the former study nearing completion with results likely in 2013. 3. Surgical management 3.1. Standard open craniotomy for haematoma evacuation Craniotomy is the most widely studied intervention for the management of ICH. Although there have been no randomised trials specifically for patients with cerebellar haemorrhage, clinical observation indicates beneficial effects of decompression of the haematoma or shunting in those who are neurologically deteriorating or have brain stem compression and hydrocephalus from ventricular obstruction.15 However, the role for surgery in supratentorial ICH is not as clear-cut. The pivotal Surgical Treatment of Intracerebral Haemorrhage (STICH) trial36 assessed the effectiveness of early surgery (mean time from onset to treatment 30 hours; interquartile range [IQR] 16–49 hours) compared with initial conservative medical management. In the initial conservative group, 26% of patients underwent later evacuation (mean 60 hours, IQR 27–99 hours) because of re-bleeding, clinical deterioration, or a variety of other less frequent reasons. The likely modest differential treatment effect was therefore likely compromised by cross-over between randomised groups, contributing to the trial being neutral, and subsequent perception of an ‘‘inconclusive outcome’’. On the basis of the subgroup of patients with ICH within 1 cm of the cortex appearing to benefit from early surgery, the subsequent STICH II37 trial was launched targeting superficial hemorrhages, with results due in 2012. A Cochrane systematic overview with a meta-analysis of 10 randomised trials of routine medical treatment plus intracranial surgery compared with routine medical treatment alone indicates an overall benefit from surgical intervention in ICH. Surgery was associated with a statistically significant reduction in the odds of being dead or dependent at final follow-up (3 or 6 months) (odds ratio [OR] 0.71, 95% CI 0.58–0.88).38 Despite the evidence, many neurosurgeons remain reluctant to operate on ICH due to concern over risks and uncertain potential benefits. 3.2. Thrombolytic evacuation of intraventricular haemorrhage Ventricular drainage of cerebrospinal fluid is often performed for acute obstructive hydrocephalus, but careful drainage of intraventricular haemorrhage with instillation of a thrombolytic at low
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dose may also improve outcomes.14 There are patients with intraventricular haemorrhage who remain in an obtunded state that is disproportionate to the size and location of ICH, often presumed related to chemical meningo-encephalitis. The Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) trial should provide randomised evidence that favours benefits of rapid clearage of intraventricular haemorrhage over the risks of surgery, bleeding and infection.14 3.3. Minimally invasive surgery with cranial puncture for haematoma evacuation Minimally invasive surgery to remove haematomas using mechanical clot disruption or endoscopic removal combined with the injection of a thrombolytic agent for clot dissolution is another attractive alternative to open craniotomy. As well as a reduction in operative time and surgical trauma, the procedure can be performed under local anesthesia by appropriately trained neurologists and intensivists rather than neurosurgeons. The approach is widely used in China, where improvements in disability, but not survival, have been demonstrated at 90 days.39,40 Preliminary results of the National Institutes of Health’s early phase Minimally Invasive Surgery plus rtPA for ICH Evaculation (MISTIE) trial41 shows that successful evacuation of the haematoma, albeit strongly dependent on an appropriate position of the catheter, can improve outcomes. However, a large international multicentre randomised trial is needed to demonstrate substantial clinical and cost-effective beneficial effects to bring about such a radical change in clinical practice. 4. Conclusions Despite its associated devastating outcomes, there is some cause for optimism that the management of ICH will improve. Better management of BP, more careful selection of patients who could respond to rFVIIa, and innovative surgical approaches which include use of thrombolytic therapy for IVH and minimally invasive ‘‘cranial puncture’’ surgery, offer considerable promise of a more active approach with effective therapy within the next few years. However, as chronically elevated BP is by far the strongest risk factor for ICH,42 and with some evidence of declines in rates but not of case fatality for ICH in recent decades,43 all clinicians should remain strong advocates for screening and treatment of hypertension, both in primary and secondary prevention. This is particularly important in countries which have large and rapidly ageing populations, such as China, where the prevalence of hypertension and rates of stroke, including ICH, are very high.44 References 1. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–60. 2. Zhang LF, Yang J, Hong Z, et al. Proportion of different subtypes of stroke in China. Stroke 2003;34:2091–6. 3. Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006;66:1182–6. 4. Sacco RL, Mayer SA. Epidemiology of intracerebral hemorrhage. In: Feldmann E, editor. Intracerebral Hemorrhage. Armonk, NY: Futura Publishing Co.; 1994. p. 3–23. 5. Zahuranec DB, Morgenstern LB, Sánchez BN, et al. Do-not-resuscitate orders and predictive models after intracerebral hemorrhage. Neurology 2010;75:626–33. 6. Hemphill 3rd JC, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–7. 7. Broderick JP, Brott TG, Duldner JE, et al. Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987–93. 8. Davis S, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175–81.
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