EDITORIAL
Time is brain also counts for ICH
Alejandro A. Rabinstein, MD Christopher D. Anderson, MD, MMSc
Correspondence to Dr. Rabinstein: [email protected] Neurology® 2015;84:970–971
Evidence from the ischemic stroke literature has taught us that “time is brain” if one is to save the ischemic penumbra. Although less recognized, the same principle applies to intracerebral hemorrhage (ICH), where different mechanisms of secondary brain damage also occur in the first few hours after symptom onset. For patients with ICH we have more limited and, at best, modestly efficacious treatment options. In this issue of Neurology®, Witsch et al.1 present their analysis of 282 patients with spontaneous ICH to determine if the delayed appearance of intraventricular hemorrhage (dIVH) on follow-up imaging influences acute mortality or long-term functional outcome. dIVH occurred in one-sixth of patients and more commonly among patients who had their first CT scan very soon after symptom onset (median time 1.1 hours vs 6 hours in patients with intraventricular hemorrhage [IVH] seen on the first CT scan and 7.4 hours in patients with no IVH at any point). Those with dIVH had much greater ICH expansion but smaller IVH volume compared with the initial IVH group. Even after controlling for the ICH score and hematoma expansion, IVH on the initial CT scan was associated with worse outcomes, whereas appearance of dIVH did not affect the clinical outcomes. Therefore, it appears that dIVH is more likely to be diagnosed in ICH patients who have their first CT scan very early after symptom onset (i.e., before hematoma expansion has fully developed) and represents a marker of subsequent expansion of the hemorrhage. IVH in general worsens prognosis, but based on this study dIVH per se would not be a useful therapeutic target. The results of this study contrast with those of Maas et al.,2 who reported that dIVH was associated with worse outcomes. Yet, because those data did not control for time to first CT scan, the results of that earlier study are difficult to interpret. In both studies, dIVH was strongly associated with larger hematoma expansion. Hematoma expansion is a common phenomenon in the first hours after the onset of ICH. Among patients presenting within 3 hours of onset, hematoma growth .33% occurs in one-quarter of patients within the first hour and in close to 40% within
the first 20 hours.3 In fact, more than 70% have some degree of hematoma expansion during the first day.4 Hematoma expansion is associated with worse functional outcomes and increased mortality from ICH4 although baseline hematoma volume remains the strongest determinant of outcome.5 Risk factors for a higher risk of hematoma expansion include shorter time from onset to first brain imaging, large hematoma volume at presentation, decreased level of consciousness, coagulopathy, hyperglycemia, and heavy drinking.6,7 Some, but not all, studies have shown association between hematoma expansion and severe acute hypertension or prior use of antiplatelet drugs.6 Presence of contrast extravasation (spot sign) on CT angiography reliably identifies patients at highest risk of hematoma growth.7 Development of perihematoma edema and IVH are additional mechanisms of secondary cerebral damage and could represent treatment targets. Edema grows rapidly during the first day, but continues to progress at a slower pace for 2 weeks.6 IVH is either present upon first imaging or develops within the first few hours. Taken in combination, the studies from Witsch et al.1 and Maas et al.2 confirm that IVH at presentation is solidly associated with worse shortand long-term outcomes. When controlling for timing of first CT scan, the study by Witsch et al.1 suggests that dIVH has no major prognostic implications and thereby does not identify an at-risk population to target for therapeutic intervention. In both studies, dIVH was primarily determined by intraparenchymal hematoma growth. Prevention of hematoma expansion as a therapeutic target remains elusive. Recombinant activated factor VII reduced hematoma growth but did not improve functional outcomes in the Factor Seven for Acute Hemorrhagic Stroke Trial (FAST).8 Meanwhile, more intensive blood pressure reduction was associated with a modest functional benefit in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT-2) despite no significant effect on hematoma expansion.9 Reversal of anticoagulation with prothrombin complex concentrate could reduce hematoma
See page 989 From the Department of Neurology (A.A.R.), Mayo Clinic, Rochester, MN; and the Department of Neurology (C.D.A.), Massachusetts General Hospital, Boston. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 970
© 2015 American Academy of Neurology
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
growth compared with fresh-frozen plasma,10 but the effect on functional outcome is less clear. Larger hematoma volume and presence of IVH on the initial CT scan are major nonmodifiable determinants of outcome in ICH. In addition, hematoma expansion worsens outcomes in ICH patients (regardless of whether it is associated with delayed IVH) and therefore represents a therapeutic target. Hematoma expansion and delayed IVH are much more common among patients who are first imaged very early after symptom onset and occur during the first few hours of the hospitalization. Therefore, ICH patients presenting very early to the emergency department should be carefully monitored in a stroke unit or a neurologic intensive care unit for the possibility of clinical worsening from these complications. Follow-up imaging within the first day may be justified in patients with risk factors for hematoma growth and is necessary in those who have neurologic decline. No treatment reduces hematoma expansion and improves functional outcomes. Yet prompt control of hypertension and correction of coagulopathy are recommended.11 More research is needed to identify more effective treatment interventions against hematoma growth. Ongoing randomized controlled trials evaluating early hemostatic therapy on patients with a spot sign on CT angiogram (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT] [ClinicalTrials.gov NCT00810888] and “Spot Sign” Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT] [ClinicalTrials.gov NCT01359202]), intensive blood pressure reduction with IV nicardipine (Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH-II] [ClinicalTrials.gov NCT01176565]), and prothrombin complex concentrate vs fresh-frozen plasma (International Normalized Ratio Normalization in Coumadin Associated Intracerebral Haemorrhage [INCH] [ClinicalTrials.gov NCT00928915]) promise to provide valuable information upon their completion. STUDY FUNDING No targeted funding reported.
DISCLOSURE A. Rabinstein reports no disclosures relevant to the manuscript. C. Anderson is supported by NIH–National Institute of Neurological Disorders and Stroke K23 NS086873-01 and the Anne B. Young Fellowship in Therapeutic Investigation sponsored by Biogen Idec, Inc. Go to Neurology.org for full disclosures.
REFERENCES 1. Witsch J, Bruce E, Meyers E, et al. Intraventricular hemorrhage expansion in patients with spontaneous intracerebral hemorrhage. Neurology 2015;84:989–994. 2. Maas MB, Nemeth AJ, Rosenberg NF, et al. Delayed intraventricular hemorrhage is common and worsens outcomes in intracerebral hemorrhage. Neurology 2013;80: 1295–1299. 3. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5. 4. Davis SM, Broderick J, Hennerici M, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175–1181. 5. LoPresti MA, Bruce SS, Camacho E, et al. Hematoma volume as the major determinant of outcomes after intracerebral hemorrhage. J Neurol Sci 2014;345:3–7. 6. Balami JS, Buchan AM. Complications of intracerebral haemorrhage. Lancet Neurol 2012;11:101–118. 7. Brouwers HB, Chang Y, Falcone GJ, et al. Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol 2014;71:158–164. 8. Mayer SA, Brun NC, Begtrup K, et al; FAST Trial Investigators. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127–2137. 9. Anderson CS, Heeley E, Huang Y, et al; INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355–2365. 10. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006;37:1465–1470. 11. Morgenstern LB, Hemphill JC III, Anderson C, et al; American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2010;41:2108–2129.
Neurology 84
March 10, 2015
971
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Time is brain also counts for ICH Alejandro A. Rabinstein and Christopher D. Anderson Neurology 2015;84;970-971 Published Online before print February 6, 2015 DOI 10.1212/WNL.0000000000001349 This information is current as of February 6, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/10/970.full.html
References
This article cites 11 articles, 5 of which you can access for free at: http://www.neurology.org/content/84/10/970.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Critical care http://www.neurology.org//cgi/collection/critical_care CT http://www.neurology.org//cgi/collection/ct Intracerebral hemorrhage http://www.neurology.org//cgi/collection/intracerebral_hemorrhage Outcome research http://www.neurology.org//cgi/collection/outcome_research
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Time is brain also counts for ICH
Alejandro A. Rabinstein, MD Christopher D. Anderson, MD, MMSc
Correspondence to Dr. Rabinstein: [email protected] Neurology® 2015;84:970–971
Evidence from the ischemic stroke literature has taught us that “time is brain” if one is to save the ischemic penumbra. Although less recognized, the same principle applies to intracerebral hemorrhage (ICH), where different mechanisms of secondary brain damage also occur in the first few hours after symptom onset. For patients with ICH we have more limited and, at best, modestly efficacious treatment options. In this issue of Neurology®, Witsch et al.1 present their analysis of 282 patients with spontaneous ICH to determine if the delayed appearance of intraventricular hemorrhage (dIVH) on follow-up imaging influences acute mortality or long-term functional outcome. dIVH occurred in one-sixth of patients and more commonly among patients who had their first CT scan very soon after symptom onset (median time 1.1 hours vs 6 hours in patients with intraventricular hemorrhage [IVH] seen on the first CT scan and 7.4 hours in patients with no IVH at any point). Those with dIVH had much greater ICH expansion but smaller IVH volume compared with the initial IVH group. Even after controlling for the ICH score and hematoma expansion, IVH on the initial CT scan was associated with worse outcomes, whereas appearance of dIVH did not affect the clinical outcomes. Therefore, it appears that dIVH is more likely to be diagnosed in ICH patients who have their first CT scan very early after symptom onset (i.e., before hematoma expansion has fully developed) and represents a marker of subsequent expansion of the hemorrhage. IVH in general worsens prognosis, but based on this study dIVH per se would not be a useful therapeutic target. The results of this study contrast with those of Maas et al.,2 who reported that dIVH was associated with worse outcomes. Yet, because those data did not control for time to first CT scan, the results of that earlier study are difficult to interpret. In both studies, dIVH was strongly associated with larger hematoma expansion. Hematoma expansion is a common phenomenon in the first hours after the onset of ICH. Among patients presenting within 3 hours of onset, hematoma growth .33% occurs in one-quarter of patients within the first hour and in close to 40% within
the first 20 hours.3 In fact, more than 70% have some degree of hematoma expansion during the first day.4 Hematoma expansion is associated with worse functional outcomes and increased mortality from ICH4 although baseline hematoma volume remains the strongest determinant of outcome.5 Risk factors for a higher risk of hematoma expansion include shorter time from onset to first brain imaging, large hematoma volume at presentation, decreased level of consciousness, coagulopathy, hyperglycemia, and heavy drinking.6,7 Some, but not all, studies have shown association between hematoma expansion and severe acute hypertension or prior use of antiplatelet drugs.6 Presence of contrast extravasation (spot sign) on CT angiography reliably identifies patients at highest risk of hematoma growth.7 Development of perihematoma edema and IVH are additional mechanisms of secondary cerebral damage and could represent treatment targets. Edema grows rapidly during the first day, but continues to progress at a slower pace for 2 weeks.6 IVH is either present upon first imaging or develops within the first few hours. Taken in combination, the studies from Witsch et al.1 and Maas et al.2 confirm that IVH at presentation is solidly associated with worse shortand long-term outcomes. When controlling for timing of first CT scan, the study by Witsch et al.1 suggests that dIVH has no major prognostic implications and thereby does not identify an at-risk population to target for therapeutic intervention. In both studies, dIVH was primarily determined by intraparenchymal hematoma growth. Prevention of hematoma expansion as a therapeutic target remains elusive. Recombinant activated factor VII reduced hematoma growth but did not improve functional outcomes in the Factor Seven for Acute Hemorrhagic Stroke Trial (FAST).8 Meanwhile, more intensive blood pressure reduction was associated with a modest functional benefit in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT-2) despite no significant effect on hematoma expansion.9 Reversal of anticoagulation with prothrombin complex concentrate could reduce hematoma
See page 989 From the Department of Neurology (A.A.R.), Mayo Clinic, Rochester, MN; and the Department of Neurology (C.D.A.), Massachusetts General Hospital, Boston. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 970
© 2015 American Academy of Neurology
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
growth compared with fresh-frozen plasma,10 but the effect on functional outcome is less clear. Larger hematoma volume and presence of IVH on the initial CT scan are major nonmodifiable determinants of outcome in ICH. In addition, hematoma expansion worsens outcomes in ICH patients (regardless of whether it is associated with delayed IVH) and therefore represents a therapeutic target. Hematoma expansion and delayed IVH are much more common among patients who are first imaged very early after symptom onset and occur during the first few hours of the hospitalization. Therefore, ICH patients presenting very early to the emergency department should be carefully monitored in a stroke unit or a neurologic intensive care unit for the possibility of clinical worsening from these complications. Follow-up imaging within the first day may be justified in patients with risk factors for hematoma growth and is necessary in those who have neurologic decline. No treatment reduces hematoma expansion and improves functional outcomes. Yet prompt control of hypertension and correction of coagulopathy are recommended.11 More research is needed to identify more effective treatment interventions against hematoma growth. Ongoing randomized controlled trials evaluating early hemostatic therapy on patients with a spot sign on CT angiogram (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT] [ClinicalTrials.gov NCT00810888] and “Spot Sign” Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT] [ClinicalTrials.gov NCT01359202]), intensive blood pressure reduction with IV nicardipine (Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH-II] [ClinicalTrials.gov NCT01176565]), and prothrombin complex concentrate vs fresh-frozen plasma (International Normalized Ratio Normalization in Coumadin Associated Intracerebral Haemorrhage [INCH] [ClinicalTrials.gov NCT00928915]) promise to provide valuable information upon their completion. STUDY FUNDING No targeted funding reported.
DISCLOSURE A. Rabinstein reports no disclosures relevant to the manuscript. C. Anderson is supported by NIH–National Institute of Neurological Disorders and Stroke K23 NS086873-01 and the Anne B. Young Fellowship in Therapeutic Investigation sponsored by Biogen Idec, Inc. Go to Neurology.org for full disclosures.
REFERENCES 1. Witsch J, Bruce E, Meyers E, et al. Intraventricular hemorrhage expansion in patients with spontaneous intracerebral hemorrhage. Neurology 2015;84:989–994. 2. Maas MB, Nemeth AJ, Rosenberg NF, et al. Delayed intraventricular hemorrhage is common and worsens outcomes in intracerebral hemorrhage. Neurology 2013;80: 1295–1299. 3. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5. 4. Davis SM, Broderick J, Hennerici M, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175–1181. 5. LoPresti MA, Bruce SS, Camacho E, et al. Hematoma volume as the major determinant of outcomes after intracerebral hemorrhage. J Neurol Sci 2014;345:3–7. 6. Balami JS, Buchan AM. Complications of intracerebral haemorrhage. Lancet Neurol 2012;11:101–118. 7. Brouwers HB, Chang Y, Falcone GJ, et al. Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol 2014;71:158–164. 8. Mayer SA, Brun NC, Begtrup K, et al; FAST Trial Investigators. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127–2137. 9. Anderson CS, Heeley E, Huang Y, et al; INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355–2365. 10. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006;37:1465–1470. 11. Morgenstern LB, Hemphill JC III, Anderson C, et al; American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2010;41:2108–2129.
Neurology 84
March 10, 2015
971
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Time is brain also counts for ICH Alejandro A. Rabinstein and Christopher D. Anderson Neurology 2015;84;970-971 Published Online before print February 6, 2015 DOI 10.1212/WNL.0000000000001349 This information is current as of February 6, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/84/10/970.full.html
References
This article cites 11 articles, 5 of which you can access for free at: http://www.neurology.org/content/84/10/970.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Critical care http://www.neurology.org//cgi/collection/critical_care CT http://www.neurology.org//cgi/collection/ct Intracerebral hemorrhage http://www.neurology.org//cgi/collection/intracerebral_hemorrhage Outcome research http://www.neurology.org//cgi/collection/outcome_research
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
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