Expert Review of Neurotherapeutics
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
The clinical management of acute intracerebral hemorrhage Venkatesh Aiyagari To cite this article: Venkatesh Aiyagari (2015) The clinical management of acute intracerebral hemorrhage, Expert Review of Neurotherapeutics, 15:12, 1421-1432, DOI: 10.1586/14737175.2015.1113876 To link to this article: http://dx.doi.org/10.1586/14737175.2015.1113876
Published online: 13 Nov 2015.
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Date: 07 December 2015, At: 05:49
Review
The clinical management of acute intracerebral hemorrhage Downloaded by [University of California, San Diego] at 05:49 07 December 2015
Expert Rev. Neurother. 15(12), 1421–1432 (2015)
Venkatesh Aiyagari Department of Neurological Surgery and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA Tel.: +1 214 648 6410 Fax: +1 214 648 0341 venkatesh.aiyagari@utsouthwestern. edu
Intracerebral hemorrhage (ICH) is a stroke subtype with high mortality and significant disability among survivors. The management of ICH has been influenced by the results of several major trials completed in the last decade. It is now recognized that hematoma expansion is a major cause of morbidity and mortality. However, efforts to improve clinical outcome through mitigation of hematoma expansion have so far been unsuccessful. Acute blood pressure management has recently been shown to be safe in the setting of acute ICH but there was no reduction in mortality with early blood pressure (BP) lowering. Two large trials of surgical evacuation of supratentorial ICH have not shown improvement in outcome with surgery, thus minimally invasive surgical strategies are currently being studied. Lastly, a better understanding of the pathophysiology of ICH has led to the identification of several new mechanisms of injury that could be potential therapeutic targets. ● hematoma ● stroke ● neuroimaging ● medical management ● blood pressure ● edema ● hematoma expansion ● intracranial pressure ● hydrocephalus
KEYWORDS: cerebral hemorrhage
Stroke is a major public health problem. Worldwide, it is the second leading cause of death behind ischemic heart disease, accounting for 11.13% of all deaths.[1] Intracerebral hemorrhage (ICH) is the second most common stroke subtype (after ischemic stroke), accounting for 10–25% of all strokes.[2] However, the overall morbidity and mortality of ICH is higher than that of ischemic stroke. Less than half of patients with ICH survive 1 year (of whom only 20–30% live independently) and less than one-third survive 5 years.[2–4] Epidemiology
It is estimated that in the year 2010, the worldwide prevalence of stroke was 33 million, of which approximately half were first-time strokes.[5] Hemorrhagic strokes accounted for one-third (5.3 of 16.9 million events) of all incident strokes, however they were responsible for more than half (3.0 of 5.8 million) of all stroke deaths.[6] Similarly, the disabilityadjusted life years lost due to hemorrhagic stroke (62.8 million) were also much higher than those due to ischemic stroke (39.4 million).[6] The proportional frequency in low www.tandfonline.com
10.1586/14737175.2015.1113876
and middle-income countries is twice that of the high-income countries (22 vs 11%).[2] Notably, the incidence of hemorrhagic stroke and mortality from hemorrhagic stroke has decreased in high, low and middle-income countries.[6] In the US, stroke is the fourth leading cause of death.[1] Nearly 795,000 people experience a new or recurrent stroke each year of which 10% are ICH.[1] Data from the BASIC project showed that from the year 2000 to 2010, the age-, sex- and ethnicity-adjusted incidence of ICH decreased but there was no change in case fatality or long-term mortality.[7] However, other studies suggest a decline in short-term fatality.[8] Risk factors
Non-traumatic ICH is often classified as primary or secondary.[9] Primary ICH originates from the spontaneous rupture of small arteries and accounts for about 80% of cases of ICH. The major underlying risk factor for primary ICH is hypertension. Long standing hypertension leads to degenerative changes in the walls of small penetrating arteries supplying blood to the brain and these hemorrhages are most commonly seen in the basal
© 2015 Taylor & Francis
ISSN 1473-7175
1421
Review
Aiyagari
Downloaded by [University of California, San Diego] at 05:49 07 December 2015
ganglia, thalamus, pons and cerebellum. Another common cause of primary ICH is cerebral amyloid angiopathy. This condition often leads to spontaneous lobar hemorrhages in elderly individuals. It is characterized by amyloid deposition and degenerative changes in the walls of blood vessels and is also associated with the ε2 and ε4 alleles of the apolipoprotein E gene. Secondary ICH is due to the presence of underlying vascular anomalies (such as arteriovenous malformations, dural arteriovenous fistulae, cerebral aneurysms, cavernoma, etc.), primary and metastatic brain tumors, hemorrhagic conversion of infarctions and bleeding diatheses (congenital, acquired or druginduced). Pathophysiology
Primary injury: An acute ICH acts as a rapidly expanding intracranial mass that directly disrupts neuronal architecture and causes injury by direct compress of the surrounding tissue. It is now well recognized that hematoma expansion can occur even after the patient has sought medical attention and therefore hematoma expansion can be a potential target for intervention. Among ICH patients scanned within 3 h of onset, 73% have some hematoma expansion when scanned at 24 h and significant hematoma expansion (>33% increase in volume) has been seen in nearly 40% of patients.[10,11] Hematoma growth is an independent predictor of mortality and functional outcome.[11] The precise mechanism of hematoma expansion is poorly understood but vascular injury from stretching of the neighbouring blood vessels has been implicated. Secondary injury: Secondary injury after an ICH can result from several mechanisms (Figure 1): a) events that occur consequent to the mass effect of the hematoma, for example, hydrocephalus, increased intracranial pressure leading to decreased cerebral perfusion and tissue shifts leading to
“herniation syndromes”, b) physiological response to the hematoma, for example, release of inflammatory mediators and thrombin leading to perihematomal edema and c) Release of clot breakdown products such as hemoglobin and iron. A detailed discussion of these pathways can be found in the referenced articles.[12–14] Several experimental therapies that target these mechanisms are currently being studied in clinical trials (Figure 1). Treatment Pre-hospital management
ICH is a true medical emergency where patients are at high risk of clinical deterioration in the first few hours after onset of symptoms. Emergency Medical Services (EMS) personnel attending to ICH patients should be able to recognize and manage airway compromise and cardiovascular instability and transport patients expeditiously to the nearest facility prepared to care for such patients.[15,16] Emergency department management Initial stabilization
In the emergency department, again, the initials focus is on stabilizing the airway-breathing-circulation.[17] It is generally accepted that patients with a Glasgow Coma Scale (GCS) Score of 33% increase in volume compared to baseline) is 33% in patients who present within 3 h of symptom onset, 11% in patients presenting between 3 and 6 h, 11% in patients presenting between 6 and 12 h and 20% in patients with an unknown time of onset (“Found down”).[19] The presence of contrast within the hematoma in a post contrast CT scan www.tandfonline.com
Review
Table 1. Features on a non-contrast head CT scan that suggest a secondary cause of intracerebral hemorrhage. ● ● ● ● ● ●
Significant subarachnoid haemorrhage “Non-hypertensive” or pure intraventricular location Calcification, dilated vessels or mass in/adjacent to ICH Hyperdense venous sinus or cortical vein Early significant edema Fluid level or irregular shape (indicative of a coagulopathy)
(“contrast extravasation”) or foci of enhancement within the hematoma (“spot sign”) on the source images of a CT angiogram (CTA), are both considered to reflect on-going bleeding from one or more blood vessels and are potent independent predictors of hematoma expansion.[20,21] The multicenter prospective Prediction of Haematoma Growth and Outcome in Patients with Intracerebral Haemorrhage Using the CT Angiography Spot Sign (PREDICT) study showed a strong association (relative risk: 2.3, 95% CI: 1.6–3.1) between spot sign and development of hematoma expansion of >6 ml or >33% from baseline ICH volume.[22] Recently, the “blend sign” on admission non-enhanced CT, defined as blending of hypoattenuating area and hyperattenuating region with a welldefined margin between the two, was also found to be valuable in predicting hematoma growth. The sensitivity, specificity, positive and negative predictive values of the blend sign for predicting hematoma growth were 39.3, 95.5, 82.7 and 74.1%, respectively.[23] b) Can we identify an underlying secondary cause of hemorrhage? Hypertension is the most common cause of spontaneous ICH and the results of a prospective study of 206 patients of ICH who were all studied with catheter angiography indicated that in hypertensive patients more than 45 years old with a thalamic, putaminal or posterior fossa ICH, obtaining a cerebral angiogram to look for an underlying vascular malformation is extremely low yield (0 of 29 such patients).[24] However, a recent review of the literature suggests that the incidence of an underlying vascular lesion in patients with ICH is 14–53% and even for a typical basal ganglia hypertensive location, it is at least 4% [25] (Figure 2). Since hypertension is quite a common disease, a diligent search in all hypertensive patients with basal ganglia hemorrhages is likely to uncover a vascular lesion in a few patients. A CTA is a reasonable screening study for underlying vascular abnormalities. It has a high accuracy for detecting vascular lesions with a sensitivity and specificity of >95% compared with digital subtraction angiography (DSA) as the gold standard. The risks of radiation exposure and nephrotoxicity from intravenous contrast have been thought to be reasons to limit widespread use of CTA, however, recent studies indicate that the radiation exposure is not markedly different from a non-contrast head CT and the incidence of renal impairment is not higher than similar patients not exposed to intravenous contrast.[25,26] 1423
Review
Aiyagari
Downloaded by [University of California, San Diego] at 05:49 07 December 2015
A
B
C
Figure 2. Non-contrast CT scan of head showing a left thalamic hemorrhage in a 50-year-old hypertensive patient (A). The CT angiogram shows contrast enhancement within the hematoma (B). A digital subtraction angiogram confirms the presence of an underlying arteriovenous malformation (C).
The MRI scan is particularly helpful in differentiating primary ICH from hemorrhagic transformation of infarcts, detecting other underlying causes such as vascular malformations, tumors, cerebral venous thrombosis and cavernomas. Lastly, MRI can detect clinically silent cerebral microbleeds that may be seen in cerebral amyloid angiopathy or hypertensive cerebral vasculopathy. In a prospective study of 89 patients by Wijman et al., MRI scanning of patients with ICH led to a change in the diagnostic category in 14%, increased diagnostic confidence in 23% and changed management in 20% of patients.[27] Lummel et al. reported that MRI was able to pinpoint a probable bleeding cause in 39 of 60 patients who had no underlying lesion detected on digital subtraction angiography (DSA).[28] The DSA has a better spatial and temporal resolution than the CTA and is often the imaging modality of choice when there is a high suspicion of an underlying vascular malformation or a lesion found on a CTA needs to be better defined or treated 1424
endovascularly. If the suspicion for an underlying vascular lesion is high but the initial DSA and MRI do not reveal an underlying cause, the DSA should be repeated after about 2 weeks and if still negative, MRI and DSA should be repeated after resolution of the hematoma, usually after 1–4 months.[29] A recommended approach to imaging patients with ICH is illustrated in Figure 3. Subsequent management
Patients with an acute ICH should be initially monitored and managed in an intensive care unit or a dedicated stroke unit staffed by physicians and nurses who have neuroscience acute care expertise. Monitoring should include vital signs, neurological and cardiopulmonary assessments. Patients on intravenous antihypertensive infusions may need continuous intra-arterial BP monitoring. Monitoring of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) is suggested in patients with a GCS score of
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
The clinical management of acute intracerebral hemorrhage Venkatesh Aiyagari To cite this article: Venkatesh Aiyagari (2015) The clinical management of acute intracerebral hemorrhage, Expert Review of Neurotherapeutics, 15:12, 1421-1432, DOI: 10.1586/14737175.2015.1113876 To link to this article: http://dx.doi.org/10.1586/14737175.2015.1113876
Published online: 13 Nov 2015.
Submit your article to this journal
Article views: 37
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iern20 Download by: [University of California, San Diego]
Date: 07 December 2015, At: 05:49
Review
The clinical management of acute intracerebral hemorrhage Downloaded by [University of California, San Diego] at 05:49 07 December 2015
Expert Rev. Neurother. 15(12), 1421–1432 (2015)
Venkatesh Aiyagari Department of Neurological Surgery and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA Tel.: +1 214 648 6410 Fax: +1 214 648 0341 venkatesh.aiyagari@utsouthwestern. edu
Intracerebral hemorrhage (ICH) is a stroke subtype with high mortality and significant disability among survivors. The management of ICH has been influenced by the results of several major trials completed in the last decade. It is now recognized that hematoma expansion is a major cause of morbidity and mortality. However, efforts to improve clinical outcome through mitigation of hematoma expansion have so far been unsuccessful. Acute blood pressure management has recently been shown to be safe in the setting of acute ICH but there was no reduction in mortality with early blood pressure (BP) lowering. Two large trials of surgical evacuation of supratentorial ICH have not shown improvement in outcome with surgery, thus minimally invasive surgical strategies are currently being studied. Lastly, a better understanding of the pathophysiology of ICH has led to the identification of several new mechanisms of injury that could be potential therapeutic targets. ● hematoma ● stroke ● neuroimaging ● medical management ● blood pressure ● edema ● hematoma expansion ● intracranial pressure ● hydrocephalus
KEYWORDS: cerebral hemorrhage
Stroke is a major public health problem. Worldwide, it is the second leading cause of death behind ischemic heart disease, accounting for 11.13% of all deaths.[1] Intracerebral hemorrhage (ICH) is the second most common stroke subtype (after ischemic stroke), accounting for 10–25% of all strokes.[2] However, the overall morbidity and mortality of ICH is higher than that of ischemic stroke. Less than half of patients with ICH survive 1 year (of whom only 20–30% live independently) and less than one-third survive 5 years.[2–4] Epidemiology
It is estimated that in the year 2010, the worldwide prevalence of stroke was 33 million, of which approximately half were first-time strokes.[5] Hemorrhagic strokes accounted for one-third (5.3 of 16.9 million events) of all incident strokes, however they were responsible for more than half (3.0 of 5.8 million) of all stroke deaths.[6] Similarly, the disabilityadjusted life years lost due to hemorrhagic stroke (62.8 million) were also much higher than those due to ischemic stroke (39.4 million).[6] The proportional frequency in low www.tandfonline.com
10.1586/14737175.2015.1113876
and middle-income countries is twice that of the high-income countries (22 vs 11%).[2] Notably, the incidence of hemorrhagic stroke and mortality from hemorrhagic stroke has decreased in high, low and middle-income countries.[6] In the US, stroke is the fourth leading cause of death.[1] Nearly 795,000 people experience a new or recurrent stroke each year of which 10% are ICH.[1] Data from the BASIC project showed that from the year 2000 to 2010, the age-, sex- and ethnicity-adjusted incidence of ICH decreased but there was no change in case fatality or long-term mortality.[7] However, other studies suggest a decline in short-term fatality.[8] Risk factors
Non-traumatic ICH is often classified as primary or secondary.[9] Primary ICH originates from the spontaneous rupture of small arteries and accounts for about 80% of cases of ICH. The major underlying risk factor for primary ICH is hypertension. Long standing hypertension leads to degenerative changes in the walls of small penetrating arteries supplying blood to the brain and these hemorrhages are most commonly seen in the basal
© 2015 Taylor & Francis
ISSN 1473-7175
1421
Review
Aiyagari
Downloaded by [University of California, San Diego] at 05:49 07 December 2015
ganglia, thalamus, pons and cerebellum. Another common cause of primary ICH is cerebral amyloid angiopathy. This condition often leads to spontaneous lobar hemorrhages in elderly individuals. It is characterized by amyloid deposition and degenerative changes in the walls of blood vessels and is also associated with the ε2 and ε4 alleles of the apolipoprotein E gene. Secondary ICH is due to the presence of underlying vascular anomalies (such as arteriovenous malformations, dural arteriovenous fistulae, cerebral aneurysms, cavernoma, etc.), primary and metastatic brain tumors, hemorrhagic conversion of infarctions and bleeding diatheses (congenital, acquired or druginduced). Pathophysiology
Primary injury: An acute ICH acts as a rapidly expanding intracranial mass that directly disrupts neuronal architecture and causes injury by direct compress of the surrounding tissue. It is now well recognized that hematoma expansion can occur even after the patient has sought medical attention and therefore hematoma expansion can be a potential target for intervention. Among ICH patients scanned within 3 h of onset, 73% have some hematoma expansion when scanned at 24 h and significant hematoma expansion (>33% increase in volume) has been seen in nearly 40% of patients.[10,11] Hematoma growth is an independent predictor of mortality and functional outcome.[11] The precise mechanism of hematoma expansion is poorly understood but vascular injury from stretching of the neighbouring blood vessels has been implicated. Secondary injury: Secondary injury after an ICH can result from several mechanisms (Figure 1): a) events that occur consequent to the mass effect of the hematoma, for example, hydrocephalus, increased intracranial pressure leading to decreased cerebral perfusion and tissue shifts leading to
“herniation syndromes”, b) physiological response to the hematoma, for example, release of inflammatory mediators and thrombin leading to perihematomal edema and c) Release of clot breakdown products such as hemoglobin and iron. A detailed discussion of these pathways can be found in the referenced articles.[12–14] Several experimental therapies that target these mechanisms are currently being studied in clinical trials (Figure 1). Treatment Pre-hospital management
ICH is a true medical emergency where patients are at high risk of clinical deterioration in the first few hours after onset of symptoms. Emergency Medical Services (EMS) personnel attending to ICH patients should be able to recognize and manage airway compromise and cardiovascular instability and transport patients expeditiously to the nearest facility prepared to care for such patients.[15,16] Emergency department management Initial stabilization
In the emergency department, again, the initials focus is on stabilizing the airway-breathing-circulation.[17] It is generally accepted that patients with a Glasgow Coma Scale (GCS) Score of 33% increase in volume compared to baseline) is 33% in patients who present within 3 h of symptom onset, 11% in patients presenting between 3 and 6 h, 11% in patients presenting between 6 and 12 h and 20% in patients with an unknown time of onset (“Found down”).[19] The presence of contrast within the hematoma in a post contrast CT scan www.tandfonline.com
Review
Table 1. Features on a non-contrast head CT scan that suggest a secondary cause of intracerebral hemorrhage. ● ● ● ● ● ●
Significant subarachnoid haemorrhage “Non-hypertensive” or pure intraventricular location Calcification, dilated vessels or mass in/adjacent to ICH Hyperdense venous sinus or cortical vein Early significant edema Fluid level or irregular shape (indicative of a coagulopathy)
(“contrast extravasation”) or foci of enhancement within the hematoma (“spot sign”) on the source images of a CT angiogram (CTA), are both considered to reflect on-going bleeding from one or more blood vessels and are potent independent predictors of hematoma expansion.[20,21] The multicenter prospective Prediction of Haematoma Growth and Outcome in Patients with Intracerebral Haemorrhage Using the CT Angiography Spot Sign (PREDICT) study showed a strong association (relative risk: 2.3, 95% CI: 1.6–3.1) between spot sign and development of hematoma expansion of >6 ml or >33% from baseline ICH volume.[22] Recently, the “blend sign” on admission non-enhanced CT, defined as blending of hypoattenuating area and hyperattenuating region with a welldefined margin between the two, was also found to be valuable in predicting hematoma growth. The sensitivity, specificity, positive and negative predictive values of the blend sign for predicting hematoma growth were 39.3, 95.5, 82.7 and 74.1%, respectively.[23] b) Can we identify an underlying secondary cause of hemorrhage? Hypertension is the most common cause of spontaneous ICH and the results of a prospective study of 206 patients of ICH who were all studied with catheter angiography indicated that in hypertensive patients more than 45 years old with a thalamic, putaminal or posterior fossa ICH, obtaining a cerebral angiogram to look for an underlying vascular malformation is extremely low yield (0 of 29 such patients).[24] However, a recent review of the literature suggests that the incidence of an underlying vascular lesion in patients with ICH is 14–53% and even for a typical basal ganglia hypertensive location, it is at least 4% [25] (Figure 2). Since hypertension is quite a common disease, a diligent search in all hypertensive patients with basal ganglia hemorrhages is likely to uncover a vascular lesion in a few patients. A CTA is a reasonable screening study for underlying vascular abnormalities. It has a high accuracy for detecting vascular lesions with a sensitivity and specificity of >95% compared with digital subtraction angiography (DSA) as the gold standard. The risks of radiation exposure and nephrotoxicity from intravenous contrast have been thought to be reasons to limit widespread use of CTA, however, recent studies indicate that the radiation exposure is not markedly different from a non-contrast head CT and the incidence of renal impairment is not higher than similar patients not exposed to intravenous contrast.[25,26] 1423
Review
Aiyagari
Downloaded by [University of California, San Diego] at 05:49 07 December 2015
A
B
C
Figure 2. Non-contrast CT scan of head showing a left thalamic hemorrhage in a 50-year-old hypertensive patient (A). The CT angiogram shows contrast enhancement within the hematoma (B). A digital subtraction angiogram confirms the presence of an underlying arteriovenous malformation (C).
The MRI scan is particularly helpful in differentiating primary ICH from hemorrhagic transformation of infarcts, detecting other underlying causes such as vascular malformations, tumors, cerebral venous thrombosis and cavernomas. Lastly, MRI can detect clinically silent cerebral microbleeds that may be seen in cerebral amyloid angiopathy or hypertensive cerebral vasculopathy. In a prospective study of 89 patients by Wijman et al., MRI scanning of patients with ICH led to a change in the diagnostic category in 14%, increased diagnostic confidence in 23% and changed management in 20% of patients.[27] Lummel et al. reported that MRI was able to pinpoint a probable bleeding cause in 39 of 60 patients who had no underlying lesion detected on digital subtraction angiography (DSA).[28] The DSA has a better spatial and temporal resolution than the CTA and is often the imaging modality of choice when there is a high suspicion of an underlying vascular malformation or a lesion found on a CTA needs to be better defined or treated 1424
endovascularly. If the suspicion for an underlying vascular lesion is high but the initial DSA and MRI do not reveal an underlying cause, the DSA should be repeated after about 2 weeks and if still negative, MRI and DSA should be repeated after resolution of the hematoma, usually after 1–4 months.[29] A recommended approach to imaging patients with ICH is illustrated in Figure 3. Subsequent management
Patients with an acute ICH should be initially monitored and managed in an intensive care unit or a dedicated stroke unit staffed by physicians and nurses who have neuroscience acute care expertise. Monitoring should include vital signs, neurological and cardiopulmonary assessments. Patients on intravenous antihypertensive infusions may need continuous intra-arterial BP monitoring. Monitoring of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) is suggested in patients with a GCS score of
