2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association – part. 1

Top 10 Take-Home Messages for the Management of Patients With Spontaneous Intracerebral Hemorrhage Guideline:

1. The organization of health care systems is increasingly recognized as a key component of optimal stroke care. This guideline recommends development of regional systems that provide initial intracerebral hemorrhage (ICH) care and the capacity, when appropriate, for rapid transfer to facilities with neurocritical care and neurosurgical capabilities.
2. Hematoma expansion is associated with worse ICH outcome. There is now a range of neuroimaging markers that, along with clinical markers such as time since stroke onset and use of antithrombotic agents, help to predict the risk of hematoma expansion. These neuroimaging markers include signs detectable by noncontrast computed tomography, the most widely used neuroimaging modality for ICH.
3. ICHs, like other forms of stroke, occur as the consequence of a defined set of vascular pathologies. This guideline emphasizes the importance of, and approaches to, identifying markers of both microvascular and macrovascular hemorrhage pathogeneses.
4. When implementing acute blood pressure lowering after mild to moderate ICH, treatment regimens that limit blood pressure variability and achieve smooth, sustained blood pressure control appear to reduce hematoma expansion and yield better functional outcome.
5. ICH while anticoagulated has extremely high mortality and morbidity. This guideline provides updated recommendations for acute reversal of anticoagulation after ICH, highlighting use of protein complex concentrate for reversal of vitamin K antagonists such as warfarin, idarucizumab for reversal of the thrombin inhibitor dabigatran, and andexanet alfa for reversal of factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban.
6. Several in-hospital therapies that have historically been used to treat patients with ICH appear to confer either no benefit or harm. For emergency or critical care treatment of ICH, prophylactic corticosteroids or continuous hyperosmolar therapy appears to have no benefit for outcome, whereas the use of platelet transfusions outside the setting of emergency surgery or severe thrombocytopenia appears to worsen outcome. Similar considerations apply to some prophylactic treatments historically used to prevent medical complications after ICH. Use of graduated knee- or thigh-high compression stockings alone is not an effective prophylactic therapy for prevention of deep vein thrombosis, and prophylactic antiseizure medications in the absence of evidence for seizures do not improve long-term seizure control or functional outcome.
7. Minimally invasive approaches for evacuation of supratentorial ICHs and intraventricular hemorrhages‚ compared with medical management alone‚ have demonstrated reductions in mortality. The clinical trial evidence for improvement of functional outcome with these procedures is neutral, however. For patients with cerebellar hemorrhage, indications for immediate surgical evacuation with or without an external ventricular drain to reduce mortality now include larger volume (>15 mL) in addition to previously recommended indications of neurological deterioration, brainstem compression, and hydrocephalus.
8. The decision of when and how to limit life-sustaining treatments after ICH remains complex and highly dependent on individual preference. This guideline emphasizes that the decision to assign do not attempt resuscitation status is entirely distinct from the decision to limit other medical and surgical interventions and should not be used to do so. On the other hand, the decision to implement an intervention should be shared between the physician and patient or surrogate and should reflect the patient’s wishes as best as can be discerned. Baseline severity scales can be useful to provide an overall measure of hemorrhage severity but should not be used as the sole basis for limiting life-sustaining treatments.
9. Rehabilitation and recovery are important determinants of ICH outcome and quality of life. This guideline recommends use of coordinated multidisciplinary inpatient team care with early assessment of discharge planning and a goal of early supported discharge for mild to moderate ICH. Implementation of rehabilitation activities such as stretching and functional task training may be considered 24 to 48 hours after moderate ICH; however, early aggressive mobilization within the first 24 hours after ICH appears to worsen 14-day mortality. Multiple randomized trials did not confirm an earlier suggestion that fluoxetine might improve functional recovery after ICH. Fluoxetine reduced depression in these trials but also increased the incidence of fractures.
10. A key and sometimes overlooked member of the ICH care team is the patient’s home caregiver. This guideline recommends psychosocial education, practical support, and training for the caregiver to improve the patient’s balance, activity level, and overall quality of life.

Preamble

Since 1990, the American Heart Association (AHA)/American Stroke Association (ASA) has translated scientific evidence into clinical practice guidelines with recommendations to improve cerebrovascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cerebrovascular care. The AHA/ASA sponsors the development and publication of clinical practice guidelines without commercial support, and members volunteer their time to the writing and review efforts.

Clinical practice guidelines for stroke provide recommendations applicable to patients with or at risk of developing cerebrovascular disease. The focus is on medical practice in the United States, but many aspects are relevant to patients throughout the world. Although it must be acknowledged that guidelines may be used to inform regulatory or payer decisions, the core intent is to improve quality of care and align with patients’ interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment; furthermore, the recommendations set forth should be considered in the context of individual patient values, preferences, and associated conditions.

The AHA/ASA strives to ensure that guideline writing groups contain requisite expertise and are representative of the broader medical community by selecting experts from a broad array of backgrounds, representing different sexes, races, ethnicities, intellectual perspectives, geographic regions, and scopes of clinical practice and by inviting organizations and professional societies with related interests and expertise to participate as endorsers. The AHA/ASA has rigorous policies and methods for development of guidelines that limit bias and prevent improper influence. The complete policy on relationships with industry and other entities (RWI) can be found at https://professional.heart.org/-/media/phd-files/guidelines-and-statements/policies-devolopment/aha-asa-disclosure-rwi-policy-5118.pdf?la=en.

Beginning in 2017, numerous modifications to AHA/ASA guidelines have been implemented to make guidelines shorter and enhance user-friendliness. Guidelines are written and presented in a modular knowledge chunk format; each chunk includes a table of recommendations, a brief synopsis, recommendation-specific supportive text, and, when appropriate, flow diagrams or additional tables. Hyperlinked references are provided to facilitate quick access and review. Other modifications to the guidelines include the addition of Knowledge Gaps and Future Research segments in some sections and a web guideline supplement (Online Data Supplement) for useful but noncritical tables and figures.

Joseph P. Broderick, MD, FAHA

Chair, AHA Stroke Council Scientific Statement Oversight Committee

1. Introduction

Approximately 10% of the 795 000 strokes per year in the United States are intracerebral hemorrhages (ICHs),¹ defined by brain injury attributable to acute blood extravasation into the brain parenchyma from a ruptured cerebral blood vessel. The clinical impact of ICH appears disproportionately high among lower-resource populations both in the United States and internationally. In US-based studies, ICH incidence has been reported to be ≈1.6-fold greater among Black than White people² and 1.6-fold greater among Mexican American than non-Hispanic White people.³ Internationally, ICH incidence is substantially higher in low- and middle-income versus high-income countries, both as a proportion of all strokes and in absolute incidence rates.^4,5

Several additional features of ICH make it a greater public health threat than conveyed by incidence numbers alone. ICH is arguably the deadliest form of acute stroke, with early-term mortality about 30% to 40% and no or minimal trend toward improvement over more recent time epochs.^6–9 Incidence of ICH increases sharply with age and is therefore expected to remain substantial as the population ages, even with counterbalancing public health improvements in blood pressure (BP) control.⁸ Another growing source of ICH is more widespread use of anticoagulants,¹⁰ a trend likely to counterbalance the reduced ICH risk associated with increasing prescription of direct oral anticoagulants (DOACs) relative to vitamin K antagonists (VKAs).¹¹

ICH thus remains in need of novel treatments and improved application of established approaches for every aspect of the disease: primary and secondary prevention, acute inpatient care, and poststroke rehabilitation and recovery. This guideline seeks to synthesize data in the ICH field into practical recommendations for clinical practice.

1.1. Methodology and Evidence Review

The recommendations listed in this guideline are, whenever possible, evidence based and supported by extensive evidence review. A search for literature derived from research principally involving human subjects, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline was conducted between October 2020 and March 2021. Additional trials published between March 2021 and November 2021 that affected the content, Class of Recommendation (COR), or Level of Evidence (LOE) of a recommendation were included when appropriate. For specific search terms used‚ readers are referred to the Online Data Supplement, which contains the final evidence tables summarizing the evidence used by the guideline writing group to formulate recommendations. In addition, the guideline writing group reviewed documents related to subject matter previously published by the AHA/ASA. References selected and published in the present document are representative and not all inclusive.

Each topic area was assigned a primary writer and a primary and sometimes secondary reviewer. Author assignments were based on the areas of expertise of the members of the guideline writing group and their lack of any RWI related to the section material. All recommendations were fully reviewed and discussed among the full guideline writing group to allow diverse perspectives and considerations for this guideline. Recommendations were then voted on, and a modified Delphi process was used to reach consensus. Guideline writing group members who had RWI that were relevant to certain recommendations were recused from voting on those particular recommendations. All recommendations in this guideline were agreed to by between 88.9% and 100% of the voting guideline writing group members.

1.2. Organization of the Writing Group

The guideline writing group consisted of vascular neurologists, neurocritical care specialists, neurological surgeons, an emergency physician, a hematologist, a rehabilitation medicine physician, a board-certified acute care nurse practitioner, a fellow-in-training, and a lay/patient representative. The writing group included representatives from the AHA/ASA, the American Association of Neurological Surgeons/Congress of Neurological Surgeons, and the American Academy of Neurology. Appendix 1 of this document lists guideline writing group members’ relevant RWI and other entities. For the purposes of full transparency, the guideline writing group members’ comprehensive disclosure information is available online.

1.3. Document Review and Approval

This document was reviewed by the AHA Stroke Council Scientific Statement Oversight Committee, the AHA Science Advisory and Coordinating Committee, and the AHA Executive Committee; reviewers from the American Academy of Neurology, the Society of Vascular and Interventional Neurology, and the American Association of Neurological Surgeons/Congress of Neurological Surgeons; and 53 individual content reviewers. Appendix 2 lists reviewers’ comprehensive disclosure information.

1.4. Scope of the Guideline

This guideline addresses the diagnosis, treatment, and prevention of ICH in adults and is intended to update and replace the AHA/ASA 2015 ICH guideline.¹² This 2022 guideline is limited explicitly to spontaneous ICHs that are not caused by head trauma and do not have a visualized structural cause such as vascular malformation, saccular aneurysm, or hemorrhage-prone neoplasm. These hemorrhages without a demonstrated structural or traumatic cause are often referred to as primary ICH (see further comment on this terminology in Section 2.1, Small Vessel Disease Types). This guideline thus does not overlap with AHA/ASA guidelines or scientific statements on the treatment of arteriovenous malformations,¹³ aneurysmal subarachnoid hemorrhage,¹⁴ or unruptured saccular aneurysms.^13,15 This guideline does, however, address imaging approaches to ICH that help differentiate primary ICH from these secondary causes.

This guideline aims to cover the full course of primary ICH (Figure 1), from the location and organization of emergency care (Section 3), initial diagnosis and assessment (Section 4), and acute medical and surgical interventions (Sections 5.1, 5.2, and 6) to further inpatient care of post-ICH complications (Sections 5.3–5.5), goals of care assessment (Section 7), rehabilitation and recovery (Section 8), and secondary prevention of recurrent ICH (Section 9). Because of the substantial differences in pathogenesis and course between ICH and ischemic stroke, the writing group sought, when possible, to base its recommendations on data derived specifically from ICH patient groups. Some aspects of inpatient medical care and post-ICH rehabilitation are likely to be similar between patients with ICH and patients with ischemic stroke, however. Readers are therefore referred to relevant AHA/ASA guidelines and scientific statements for ischemic stroke in these overlapping areas.^16,17Table 1 is a list of associated AHA/ASA guidelines and scientific statements that may be of interest to the reader.

Another area where this ICH guideline interfaces with prior ischemic stroke guidelines is the challenging area of antithrombotic agent use in patients after ICH who are at risk for both recurrent ICH and ischemic stroke (Section 9.1.3, Management of Antithrombotic Agents). This guideline does not attempt to reassess the extensive literature on assessment of future ischemic stroke risk and instead refers the reader to existing AHA guidelines on primary and secondary ischemic stroke prevention.^18,19

This ICH guideline has a new section on assessment of ICH risk in individuals with no prior ICH but with neuroimaging findings such as cerebral microbleeds or cortical superficial siderosis suggestive of a hemorrhage-prone microvasculopathy. This topic, which was also previously discussed in an AHA scientific statement on the wider area of silent cerebrovascular disease,²⁰ does not fall strictly under the heading of ICH management. This guideline writing group nonetheless included the section (9.2, Primary ICH Prevention in Individuals With High-Risk Imaging Findings) because of its close relationship to the considerations used for secondary prevention of recurrent ICH (Section 9.1, Secondary Prevention) and the high frequency with which these small hemorrhagic lesions are detected as incidental findings on magnetic resonance imaging (MRI) performed for other indications. Evidence on how to interpret and act on incidental hemorrhagic lesions remains limited but is likely to grow with the widespread incorporation of blood-sensitive MRI methods into research studies and clinical practice.

1.5. COR and LOE

Recommendations are designated with both a COR and an LOE. The COR indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit in proportion to risk. The LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 2).

2. General Concepts

2.1. Small Vessel Disease Types

Despite our use of the term primary ICH to distinguish from ICH with a demonstrated structural cause (Section 1.4, Scope of the Guideline), these seemingly spontaneous hemorrhages are not truly primary but rather represent the consequence of defined underlying (and often co-occurring) vascular pathologies. The 2 common cerebral small vessel pathologies that account for the overwhelming majority of primary ICH are arteriolosclerosis and cerebral amyloid angiopathy (CAA). Each is a common age-related pathology, appearing at autopsy at moderate to severe extents in 30% to 35% of individuals enrolled in a longitudinal study of aging.²¹ Arteriolosclerosis (also referred to as lipohyalinosis) is detected as concentric hyalinized vascular wall thickening favoring the penetrating arterioles of the basal ganglia, thalamus, brainstem, and deep cerebellar nuclei (collectively referred to as deep territories). Its major associated risk factors are hypertension, diabetes, and age. CAA is defined by deposition primarily of the β-amyloid peptide in the walls of arterioles and capillaries in the leptomeninges, cerebral cortex, and cerebellar hemispheres (lobar territories). The primary risk factors for CAA are age and apolipoprotein E genotypes containing the ε2 or ε4 alleles.

ICH occurs in a relatively small subset of those brains with advanced arteriolosclerosis or CAA, typically in deep territories for arteriolosclerosis and lobar territories for CAA, the brain locations favored by the underlying pathologies. Small, often asymptomatic cerebral microbleeds in these compartments are substantially more common, occurring in >20% of population-based individuals >60 years of age scanned with sensitive T2*-weighted MRI methods.^22,23 The presence of multiple strictly lobar ICHs, microbleeds, or cortical superficial siderosis (chronic blood products over the cerebral subpial surface) has been pathologically validated as part of the Boston criteria to detect CAA-related hemorrhage with reasonably high specificity and sensitivity.²⁴ Microbleeds associated with arteriolosclerosis tend to occur in deep territories but can appear in lobar territories as well.

The underlying small vessel types of ICH have several practical implications for the formulation of ICH guidelines. They establish a hemorrhage-prone environment in which use of antithrombotic agents creates increased risk of ICH.²⁵ It is important to note, however, that the small vessel pathologies that underlie ICH are also associated with increased risk of ischemic stroke,²⁶ highlighting the complexity and importance of balancing the risks versus benefits of antithrombotic treatment. Among the cerebral small vessel diseases, CAA inferred by the Boston criteria appears to confer substantially greater risk for recurrent hemorrhage than arteriolosclerosis (recurrent ICH rates in a pooled analysis of 7.39%/y after CAA-related ICH versus 1.11%/y after non–CAA-related ICH).²⁷

2.2. Mechanisms for ICH-Related Brain Injury

ICH is understood to injure surrounding brain tissue through the direct pressure effects of an acutely expanding mass lesion and through secondary physiological and cellular pathways triggered by the hematoma and its metabolized blood products.²⁸ Direct pressure effects can include both local compression of immediately surrounding brain tissue and more widespread mechanical injury caused by increased intracranial pressure (ICP), hydrocephalus, or herniation. Early HE, possibly driven by mechanical shearing of surrounding vessels by the initial hematoma,²⁹ is common and a consistent predictor of worse ICH outcome.³⁰

Secondary physiological and cellular injury mechanisms postulated to be triggered by ICH include cerebral edema, inflammation, and biochemical toxicity of blood products such as hemoglobin, iron, and thrombin.²⁸ Although it is plausible that the underlying small vessel disease type may affect the mechanism and severity of ICH-related brain injury, there is currently no strong evidence for substantial differences between the acute course of arteriolosclerosis-related and CAA-related ICH other than differences attributable to ICH location.

Several of the major medical therapies for ICH such as BP lowering and reversal of anticoagulation are aimed at limiting HE. The search for effective medical treatments for protecting tissue from secondary post-ICH injury, like the search for effective neuroprotectants for ischemic stroke, has to date been unsuccessful. Surgical hematoma evacuation through craniotomy, minimally invasive approaches, or ventriculostomy is aimed at both preventing further pressure-related injury and protecting against secondary physiological and cellular injury. One complexity that arises in the interpretation of results of surgical ICH trials is the possibility that mortality might be prevented without improvement in functional outcome, an issue addressed explicitly in the current guidelines.

2.3. Limits to Generalizability

A key limitation that runs through all sections of this guideline is that much of the data come from high-resource countries and from more affluent demographic groups within those countries. The potential limitations of generalizability to lower-resource settings and populations noted to be disproportionately at risk of ICH (Section 1, Introduction), highlight the need for future guidelines based explicitly on data from these underserved and underrepresented groups.

3. Organization of Prehospital and Initial Systems of Care

Synopsis

Much of the data for prehospital care and stroke systems of care are derived from studies of stroke of all types (including ICH). Furthermore, it is generally not possible for prehospital clinicians to distinguish between patients with ICH and those with other types of stroke. As a result, the recommendations for prehospital care of patients with hemorrhagic stroke are essentially identical to those recommended for any patient with stroke: early recognition, expedient transport to the most appropriate facility, and prenotification before hospital arrival to expedite the in-hospital stroke response. Although it can be difficult to measure the precise time to onset of ICH treatment, it is reasonable to infer that earlier diagnosis will be closely linked to earlier treatment. To facilitate rapid diagnosis and treatment of ICH, we recommend public health measures to educate the public, build and maintain organized systems of care, and ensure appropriate training of first responders.

Recommendation-Specific Supportive Text

1. Early symptom recognition is essential for timely ICH care. In the United States, ≈67% of adults know the signs and symptoms of stroke and the need to call EMS; stroke knowledge increased almost 15 percentage points between 2009 and 2017.³³ Public education campaigns can improve stroke knowledge,^35,50 increase the use of EMS for stroke,³¹ and use of EMS is associated with shorter time to diagnosis.³² In the largest cluster randomized controlled study of >75 000 subjects, an educational intervention reduced time to hospital arrival in women (median, 328 minutes versus 559 minutes) but not men.³⁴ Although some smaller studies have demonstrated modest benefits, others have shown no or only transient benefits.^51–54 Knowledge of stroke warning signs varies by race, sex, ethnicity, age, education, and urbanicity,³³ which may contribute to disparities in outcomes. Public education campaigns should make every attempt to address underserved groups and those with the largest opportunities to improve awareness.
2. No existing clinical decision scale can differentiate ICH from other diseases with high sensitivity or specificity in the absence of neuroimaging. Prehospital scales such as FAST (Face, Arm, Speech, Time to call 911), LAPSS (Los Angeles Prehospital Stroke Scale), CPSS (Cincinnati Prehospital Stroke Scale), and ROSIER (Recognition of Stroke in the Emergency Room) are available and typically are validated in all stroke rather than ICH specifically.⁴¹ Differences include whether they focus on sensitivity or specificity and whether they screen for stroke severity as well as presence. For dispatch, a group found that a specific dispatch stroke assessment tool was associated with shorter time to diagnosis,³⁷ and a clinical trial found that a dispatch stroke screen reduced time to both hospital arrival and stroke unit admission (although only 5% had ICH).³⁶ One group analyzed ICH specifically³⁹ and found an association between documented stroke scale use and ICH recognition. The sensitivity for ICH was 84%, and stroke scale documentation was independently associated with ICH recognition and shorter door–to–computed tomography (CT) times (20 minutes versus 47 minutes). Most studies of stroke scale use in practice inadequately account for false-negative cases, thereby likely artificially boosting performance. One group developed a clinical prediction rule to classify stroke subtypes, including ICH, in the prehospital setting; however, neither the sensitivity nor positive predictive value was published.⁴⁰
3. One group found that in a large national cohort of patients with stroke, EMS use compared with arrival to hospital by other means is independently associated with earlier emergency department (ED) arrival (adjusted odds ratio [OR], 2.00 [95% CI, 1.93–2.08]), quicker ED evaluation (adjusted OR, 1.89 [95% CI, 1.78–2.00]), and more rapid treatment for ischemic stroke (adjusted OR, 1.44 [95% CI, 1.28–1.63]).^32,42 For ICH specifically, a large multicenter cohort study found that time from symptom onset to ED was 63 minutes versus 227 minutes in patients who used EMS versus those who did not use EMS, and time to hospital admission was 167 minutes versus 537 minutes.⁵⁵ Thus, persistent efforts to ensure activation of the 9-1-1 or a similar emergency system by patients or other members of the public for suspected stroke are warranted.
4. Many observational studies in patients with stroke (including both ischemic and ICH) have found that use of prehospital notification to the destination ED is associated with faster time to neuroimaging and shorter time to alteplase in ischemic stroke.^56–59 For example, a large registry found that after adjustment for covariates, EMS use (with prenotification) was associated with faster door-to-CT times than both private transport and EMS without prenotification.⁴⁴ In the AHA Get With The Guidelines–Stroke registry, EMS personnel provided prearrival notification to the destination ED for 67% of transported patients with stroke.⁴³ EMS prenotification was associated with shorter door-to-imaging times and shorter symptom onset–to–needle times. One group found that for ICH, early stroke team activation was associated with faster door-to-CT times (24 minutes versus 48 minutes) and faster time to hemostatic medication when used (63 minutes versus 99 minutes).⁶⁰
5. Many regions have developed stroke systems of care and stratify hospitals according to their ability to deliver intravenous thrombolytics or endovascular therapy for ischemic stroke. Triage algorithms suggest routing patients on the basis of the results of prehospital stroke severity scales. These scales often indicate high severity in the case of ICH, which would direct patients with potential ICH preferentially to advanced stroke centers such as a comprehensive stroke center. Whether patients with ICH benefit from the higher level of care versus earlier temporizing at regional facilities remains to be seen and should be studied. One observational study found that Canadian provinces that had implemented stroke systems of care had reduced mortality for the entire cohort (including ICH, ≈10% of the cohort; adjusted incidence rate ratios, 0.85 [95% CI, 0.79–0.92]).⁴⁵
6. Most studies of MSUs have focused on time to thrombolysis for stroke, and subgroup analyses of those diagnosed with ICH are small and underpowered. One group randomized their geographic region to weeks on/off for MSU availability and found that those patients treated in MSUs had faster times from symptom onset to laboratory results and to CT.⁴⁷ No MSU diagnosis of ICH (or lack of ICH) required revision during follow-up. Another study in 2 regions of Germany found similar reductions in time to CT.⁴⁶ The MSU reduced the use of interfacility transfer to zero for ICH because those with ICH were taken to a comprehensive stroke center as the initial hospital. Forty-one percent of the MSU patient group and none of the standard care group received BP management in the field after diagnosis, suggesting that MSU led to earlier initiation of treatment. Issues of logistics, feasibility, and cost currently appear to restrict MSU use to certain regions and facilities, and all studies are currently underpowered to evaluate any association with clinical outcome after ICH.
7. No clinical trials of different EMS response strategies were found to have been conducted in ICH. Some have been published in traumatic brain injury (TBI). One large clinical trial of TBI found that in patients with Glasgow Coma Scale (GCS) score <9, survival was lower in the advanced life support than basic life support stage.⁴⁹ In patients with TBI, it may be that prehospital intubation costs time that can outweigh any benefit and that bag-mask ventilation is adequate to both oxygenate and ventilate most patients during transport. Observational studies have noted that prehospital ND is relatively common after ICH.^48,61,62 This suggests a value for EMS clinicians trained in performing initial and serial neurological examinations using a stroke screening tool^63–66 and with the ability to provide expedient care, including airway support, for a patient who deteriorates during transport. Therefore, it is reasonable for advanced life support–trained clinicians to respond to patients with suspected stroke.

Knowledge Gaps and Future Research

• Data on whether and what types of public health campaigns that help the public recognize stroke early translate into faster time to ICH diagnosis, treatment, and better outcomes are lacking. Future studies could ideally target which aspects of these campaigns are most useful in improving outcomes and in which populations.
• Data on which prehospital strategies translate to improved outcomes are limited; many studies are observational and confounded by local processes that select which teams go to which patients according to dispatch, severity, geography, and resources. Future studies may best target comparing a “scoop and run” approach (with minimal time/care on scene) to one sending a higher level of care (such as an MSU) to the scene. It is unknown whether prehospital basic life support or advanced life support yields better ICH outcomes. Data on the impact of MSUs on ICH are also limited.
• Much of the data for prehospital care and stroke systems of care were derived from studies of suspected stroke (including ICH), diagnosed stroke of all types (including ICH), or ischemic stroke. As a result, the recommendations for prehospital care are typically based on those for ischemic stroke or all strokes. Future research should evaluate whether particular systems of care are specifically beneficial to ICH, as well as the impact of regionalized large vessel occlusion stroke care on ICH outcomes and the impact of EMS bypass of primary stroke centers for suspicion of large vessel occlusion.
• Existing tools to stratify or diagnose ICH in the prehospital setting are limited. It remains unclear which, if any, tool is best or whether stroke scales that incorporate severity, rather than just stroke presence, are useful for ICH prehospital assessment. Further study of test characteristics of existing stroke severity scores in identifying patients with ICH is needed, whether the destination of patients with potential ICH should be the same as that for patients with large vessel occlusion strokes, or whether centers that do not have neurosurgical capabilities should be bypassed.
• Studies are needed to examine the potential benefit of mobile CT scanners to identify and treat ICH earlier. It will be important to determine whether other potential treatments targeted specifically to ICH improve outcome when provided earlier in the clinical course.

4. Diagnosis and Assessment

4.1. Diagnostic Assessment of Acute ICH Course

4.1.1. Physical Examination and Laboratory Assessment

Synopsis

Routine laboratory work provides important information about coagulation status and organ function that must be addressed rapidly in the setting of a spontaneous ICH (Table 3). A rapid assessment of laboratory data such as complete blood count and coagulation profile can help to diagnose coagulopathy attributable to medications or underlying medical conditions such as hematologic malignancies.⁷² This could lead to targeted therapies that can improve outcome. For surgical patients, coagulation status is important to determine whether external ventricular drainage (EVD) or craniotomy can be performed safely. Electrolyte disturbances, renal dysfunction, and acute cardiac syndromes can confound the clinical picture and require treatments that should be initiated urgently on hospital arrival.

Recommendation-Specific Supportive Text

1. Complete blood count and coagulopathy studies (prothrombin time/partial thromboplastin time/INR) can help determine hemorrhage type, including spontaneous ICH attributable to extreme thrombocytopenia (eg, platelets <10 000, although platelet counts below higher thresholds also may contribute to ICH), anticoagulant-related hemorrhage, or coagulopathy secondary to malignancy or liver failure. Anticoagulant-related hemorrhages are associated with increased hematoma volume and expansion, as well as increased morbidity and mortality.^84–86 Admission anemia is associated with hemorrhagic expansion and poor outcomes^73,74 and thrombocytopenia is associated with higher mortality for patients taking antiplatelets.⁷⁵ In patients taking warfarin, admission INR value may predict outcome. One study showed a dose response of INR level in warfarin-related hemorrhage associated with poor outcome,⁸⁸ whereas another showed no association.⁸⁹ Elevated troponin on admission for patients with ICH is associated with increased in-hospital mortality for both medical and surgical ICH patient populations.^{67,69,90–92} The association of admission troponin with functional outcomes and 30-day mortality was reported in 1 study⁶⁷ but not in another study after adjustment for confounding factors.⁷¹ Renal failure on admission also is associated with poor functional outcomes,^71,76,77,79 in-hospital mortality,⁸⁰ and 12-month mortality.^76,79 Admission hyperglycemia is associated with unfavorable short- and long-term outcomes,⁷⁰ short-term mortality,^68,78,81 and long-term mortality after ICH.⁶⁸ Additional lifestyle risk factors that should be assessed include tobacco smoking, diet, alcohol, and waist-to-hip ratio.⁹³

Knowledge Gaps and Future Research

• Further studies are necessary to determine whether platelet or coagulation activity assays may identify a subgroup of patients who benefit from platelet transfusion, desmopressin acetate, tranexamic acid (TXA), or other acute therapies for ICH.
• Although changes in traditional coagulation factors or diluted thrombin time may indicate the presence of DOAC medications, these studies are not reliable enough to determine the level of anticoagulation at the time of presentation with DOAC-related ICH. Specific factor Xa inhibition levels have been developed for the factor Xa inhibitors and thrombin-based assays for dabigatran, but these studies are not widely available and often are not able to be run in an emergency setting quickly enough for decision-making. Specific reliable measurements of these anticoagulants could determine which patients may benefit from reversal of anticoagulation.
• Viscoelastic hemostatic assays, including thromboelastography and rotational thromboelastography, allow measurement of both cellular and plasma components of clot formation and fibrinolysis, unlike traditional coagulation tests (prothrombin time/partial thromboplastin time/INR) that reflect an in vitro coagulation pathway. These laboratory values predict significant bleeding and need for transfusions in trauma patients but have not been shown to improve outcome or mortality. Viscoelastic assays detect coagulation abnormalities that do not always appear on traditional coagulation tests in patients with ICH. It is unclear whether the results of these studies correlate with patient outcome. Understanding the significance of these studies in patients with ICH is an area of emerging and active research.
• Interpretation of admission ECG and troponin values can be challenging in patients with ICH because these can be either secondary to neurocardiogenic changes or attributable to true myocardial ischemia, which is important in the early evaluation and management of patients with ICH. Interpretation and management of early electrocardiographic changes in patients with ICH is an area of future study.

4.1.2. Neuroimaging for ICH Diagnosis and Acute Course

Synopsis

Brain imaging is essential to distinguish ICH from ischemic stroke and determine ICH volume (often estimated in practice with the ABC/2 formula¹⁰⁹). CT is the most widely used imaging modality to confirm (or rule out) the presence of ICH because of its widespread availability, rapidity, high diagnostic accuracy, and ease. However, MRI with echo-planar gradient echo or susceptibility-weighted sequences also can detect hyperacute ICH with high accuracy.^94,95,110 Brain imaging during the acute phase of ICH can provide prognostic information and aid in monitoring the evolution of ICH. HE tends to occur early after ICH (typically within 24 hours of ICH onset) and is associated with poor outcome and mortality.^30,97,98,111 Identification of a spot sign on CTA or contrast-enhanced CT^104,107,108 or certain imaging features on NCCT such as heterogeneous densities within the hematoma or irregularities at its margins^106,112 may help to identify patients at risk for HE. These markers could influence the triage, monitoring intensity, and outcome prognostication for such patients. Repeating the CT after the initial scan to evaluate for development of HE, hydrocephalus, or perihematomal edema can be useful, particularly in patients whose neurological status deteriorates and in those with impaired level of consciousness in whom examination is limited.

Recommendation-Specific Supportive Text

1. A prospective, multicenter, observational study of 62 patients presenting within 6 hours of spontaneous ICH reported that the sensitivity, specificity, predictive value, and accuracy of detecting ICH on MRI by experienced readers were 100%.⁹⁴ A similar study in 200 patients in which MRI was done first followed by CT found that MRI and CT were equivalent for detecting acute ICH and that MRI was more accurate for detecting chronic ICH.⁹⁵ A prospective, single-center study in patients with spontaneous ICH reported that MRI was slightly more sensitive than CT for detecting small IVH‚ where MRI sensitivity was 100% compared with 97% for CT.⁹⁶
2. HE occurs early after ICH and is an independent predictor of ND, mortality, and poor functional outcome.^30,111 A prospective, observational study in 103 patients with spontaneous ICH who had a baseline CT within 3 hours of ICH onset and a repeat CT at 1 and 20 hours after baseline scan found that substantial HE occurred in 26% of patients on the 1-hour scans and in an additional 12% of patients on the 20-hour scans.⁹⁷ HE was associated with ND. In another study, the frequency of HE was greatest among those who underwent the initial CT scan within 3 hours of ICH onset and progressively declined as the time to initial scan was prolonged; 15% of patients exhibited HE between 6 and 12 hours and 6% between 12 and 24 hours. HE after 24 hours was extremely rare (0%).⁹⁸ However, delayed IVH has been reported in 21% of patients with no initial IVH, and infrequently beyond 24 hours,⁹⁹ delayed IVH is more likely to be associated with delayed HE, is independently associated with mortality and poor outcomes, and often requires emergency surgical intervention. Incorporating new IVH appearance and IVH expansion into the definition of HE appears to improve prediction of poor neurological outcome.^113,114 In patients with ICH with stable examination and preserved level of consciousness, follow-up CT scans at ≈6 and 24 hours after onset appear adequate to exclude HE and document final ICH volume.
3. This recommendation pertains to indications for repeat imaging to detect other downstream effects of recent hemorrhage that may occur beyond the first 24-hour period. Evidence derived from patients with mild TBI, defined as a GCS score ≥13, suggested that routine repeat head CT in neurologically stable patients is of low yield and often unnecessary,^100,115 whereas other evidence indicated that routine serial neuroimaging may have some value in patients with moderate or severe TBI.¹⁰¹ However, these studies included few subjects with ICH (most patients had subarachnoid, subdural, or epidural hemorrhages), and the physiological differences between traumatic and nontraumatic hemorrhage limit the generalizability of these data to primary ICH. A single-center observational study in 239 patients with spontaneous ICH admitted to a neurological intensive care unit (ICU) with a standardized order set, including serial CT at 6, 24, and 48 hours and hourly neurological assessments, found that 35% of patients required emergency neurosurgical interventions after admission; 46% were instigated by imaging findings versus 54% by a change in neurological examination,¹⁰² suggesting that routine serial imaging might be of supplemental value to neurological assessments. Beyond the first 24 hours, serial imaging is generally guided by the clinical picture of the patient.
4. Although benefits of therapies that target HE have currently not been demonstrated, stratification of patients at risk of HE can influence the triage and intensity of monitoring of these patients and their prognosis. A prospective, multicenter, observational study reported that HE was more frequent in patients with a CTA-positive spot sign than in those without it, although the negative and positive predictive values of the spot sign were not robust.¹⁰⁴ Mortality and poor modified Rankin Scale (mRS) score at 90 days were greater in patients with CTA-positive spot sign. Subsequent meta-analyses^106–108 also suggested that CTA-positive spot sign can predict HE and mortality, although interpretation of these analyses is limited by high heterogeneity of the included studies. A meta-analysis of individual data from 5435 patients reported that the addition of the spot sign provided small improvement in the discrimination of an HE prediction model composed of simple clinical variables (ICH volume, time from ICH onset to imaging, and use of antithrombotic drugs).¹⁰³ The sensitivity and positive predictive values of the spot sign to predict HE are time dependent; they are highest between 0 and 2 hours of ICH onset–to–scan time and decrease as time lapses.¹⁰⁵ CTA also can detect some structural causes of secondary ICH (Section 4.2, Diagnostic Assessment for ICH Pathogenesis). Although CTA does not appear to commonly trigger acute renal injury,¹¹⁶ this risk remains a relevant consideration in obtaining this study.
5. Previous studies have suggested that signs on NCCT of heterogeneous density within the hematoma or irregularities at its margins (also described in the literature as hypodensities, fluid level, swirl, black hole, blend, island, or satellite signs) can serve as alternatives to the spot sign to predict HE¹¹² (Figures S1 and S2 in the Data Supplement). A meta-analysis of 25 studies including 10 650 patients reported that these NCCT markers are associated with HE and poor functional outcome, although there was substantial heterogeneity and pooled estimates were unadjusted for confounding variables.¹⁰⁶

Knowledge Gaps and Future Research

• Routine serial CT after the initial scan, regardless of neurological status, to evaluate for ICH expansion, development of hydrocephalus, or brain swelling is not uncommon in clinical practice. Although the usefulness of this practice has been studied extensively in patients with ICH attributable to TBI, there is a paucity of studies in patients with nontraumatic, spontaneous ICH. Future research should evaluate the cost/benefit implications of serial imaging after ICH and clarify the patient characteristics and conditions under which serial imaging should be considered.
• The utility of NCCT signs to predict HE, alone or as part of prediction scores based on clinical variables, and guide decision-making on the triage and monitoring of patients with ICH at high risk for HE is appealing, particularly in low-resource settings where immediate performance and interpretation of CTA are challenging. However, the prognostic yield and clinical relevance of these NCCT signs and scores are yet to be adequately examined in prospective large studies. An important goal of future research is to refine the utility of NCCT signs (defined by standardized criteria) and HE scores to maximize their diagnostic and predictive capabilities and validity.

4.2. Diagnostic Assessment for ICH Pathogenesis

Synopsis

Heterogeneous disease entities such as arteriolosclerosis/lipohyalinosis, CAA, or vascular malformations may lead to acute brain parenchymal bleeding.¹²⁶ Clinicians should investigate the cause of ICH because it may influence acute and preventive treatment strategies and prognosis. Among individuals <70 years of age who did not have typical hypertension-related deep territory ICH, an underlying macrovascular cause (arteriovenous malformations, aneurysm, dural arteriovenous fistula, cavernoma and cerebral venous thrombosis) is present in 1 of 4 to 1 of 7 patients, depending on age category.¹¹⁸ However, there is substantial heterogeneity in clinical practice in how, when, and in whom an underlying macrovascular cause is explored.¹²⁷ CTA and MRA appear to have >90% sensitivity and specificity after ICH for the detection of intracranial vascular malformations in highly selected populations compared with catheter intra-arterial DSA.¹²⁸ Catheter intra-arterial DSA remains the gold standard to search for macrovascular causes of ICH and appears to have the highest diagnostic yield as an adjunct or alternative to CT-based or magnetic resonance–based vascular imaging in (1) patients <70 years of age with lobar ICH, (2) patients <45 years of age with deep or posterior fossa ICH, (3) patients 45 to 70 years of age with deep or posterior fossa ICH and the absence of both history of hypertension and signs of small vessel disease on imaging, (4) all patients with ICH with CT or magnetic resonance evidence of a macrovascular lesion, and (5) patients with primary IVH.^{117,118,120,129,130} CT or magnetic resonance venography should be included with CTA or MRA when clinical factors or ICH location suggests possible cerebral venous thrombosis.¹³¹ For patients without evidence of macrovascular causes, MRI can be used to search for markers of ongoing diseases such as CAA, deep perforating vasculopathy, cavernous malformation, or malignancy.

Recommendation-Specific Supportive Text

1. In the DIAGRAM (DIagnostic Angiography to Find Vascular Malformations) study, the median interval between NCCT and CTA was 1 day. In patients with lobar ICH and age <70 years, or deep/posterior fossa ICH and age <45 years, or deep/posterior fossa and age 45 to 70 years without hypertension, the diagnostic yield for diagnosis of a macrovascular cause was 17%. Hypertension was defined as history of hypertension, use of antihypertensive drugs before ICH, or evidence of left ventricular hypertrophy on admission ECG. None of the 291 patients had complications with CTA.¹¹⁸ In multivariable analysis, younger age, location of ICH, absence of signs of small vessel disease (defined as presence of white matter lesions or a lacunar infarct in basal ganglia, thalamus, or posterior fossa, regardless of whether symptomatic or asymptomatic), and a positive or inconclusive CTA were independent predictors for the presence of an underlying macrovascular cause.¹¹⁸ Estimated risks to identify a macrovascular cause varied from 1% in patients 51 to 70 years of age with deep ICH and signs of small vessel disease to >50% in patients 18 to 50 years of age with lobar or posterior fossa ICH and no signs of small vessel disease.¹¹⁷
2. Isolated IVH is a rare condition. In a single-center case series, 39 patients with isolated IVH were included during a 10-year period. In 30 patients, ≥1 angiographic examinations had been performed; 23% had an underlying macrovascular cause (arteriovenous malformation and dural arteriovenous fistula).¹¹⁹ In a systematic review of the literature by the same authors, 16 studies reported 209 patients with isolated IVH. The yield of DSA was 58% (95% CI, 48%–68%) with large variations according to the design of the studies. Younger patients were more likely to have a macrovascular cause, but there was no influence of history of hypertension, small vessel disease, or anticoagulation use. There are currently insufficient data on the diagnostic yield of CTA or MRA for this purpose to know whether they provide equivalent diagnostic sensitivity.¹¹⁹
3. Identification of patients with underlying macrovascular lesions is important because lesions such as arteriovenous malformations and aneurysms are associated with potential rebleeding that should be prevented.^129,132 In addition to the characteristic appearances of macrovascular lesions on CTA and MRA, suggestive imaging findings can include CT demonstration of enlarged vessels or calcifications along the hematoma margins or hyperdensity within a dural venous sinus or cortical vein along the presumed venous drainage pathway of the hematoma.^120,129
4. In the DIAGRAM study, DSA was assessed in 103 of 232 patients with negative or inconclusive CTA test results, of whom 97 also had negative or inconclusive MRI/MRA test results. The result of DSA was positive in 13%. The diagnostic yield for a macrovascular cause of combined CTA, MRI/MRA, and DSA was 23%. Complications with DSA resulting in permanent sequelae occurred in 0.6%.¹¹⁸ In addition to the DIAGRAM score,¹¹⁷ the simple ICH score¹²¹ and secondary ICH score^120,129 have been developed to predict the probability of a macrovascular cause of ICH. The models incorporate a similar group of factors favoring further testing (CTA, MRI/MRA, or DSA): young age, lobar (or cerebellar) location, and absence of hypertension. The presence of small vessel disease on brain imaging also may be a useful variable associated with a lower likelihood of an underlying macrovascular cause.¹²² Female sex was identified as a predictor of higher likelihood of a macrovascular lesion in the secondary ICH derivation study¹²⁰ but not in validation studies.^129,133
5. MRI and MRA may provide valuable information on DSA-negative ICH causes (such as CAA, deep perforating vasculopathy, cavernous malformation, or malignancy).^123,124 Blood-sensitive T2*-weighted sequences should be included to detect brain microbleeds or cortical superficial siderosis that may contribute to discussions of the nature of the underlying vessel disease and of the prognostication of future ICH risk (Section 9.1.1, Prognostication of Future ICH Risk). Some 3-dimensional susceptibility-weighted sequences (eg, susceptibility-weighted imaging and susceptibility-weighted angiography) are particularly sensitive to these chronic hemorrhagic lesions. Contrast-enhanced T1-weighted MRI should be included to exclude neoplasm or other underlying mass lesion and is often repeated after 3 to 6 months for this purpose. In the DIAGRAM study, the median interval between CTA and MRI/MRA was 46 days. The diagnostic yield of combined CTA and MRI/MRA was 18%.¹¹⁸ Both CTA and MRA appear to have good sensitivity and specificity after ICH for the detection of intracranial vascular malformations.¹²⁸ However, there is no head-to-head comparison to guide clinicians in their choice of imaging modality. The MRI approach will have the advantage of exploring both the detection of vascular malformations and giving clues on possible nonmacrovascular causes. Nonenhanced CT also can be used to detect ICH features suggestive of CAA such as subarachnoid extension or finger-like projects¹³⁴ or features of all small vessel diseases such as white matter hypodensity.
6. The rapid identification of any underlying intracranial vascular malformation (arteriovenous malformations, dural arteriovenous fistulae, and aneurysms) and of cerebral venous thrombosis is important and will influence treatment strategies and outcome.^118,135 The likelihood of identifying an underlying structural lesion appears to be somewhat lower in unselected patients with ICH than in those in one of the higher-risk categories listed in Recommendation 1 (lobar spontaneous ICH and age <70 years, deep/posterior fossa spontaneous ICH and age <45 years, or deep/posterior fossa and age of 45–70 years without a history of hypertension).
7. The concept of “primary” ICH or IVH is misleading. A thorough search for a cause should be performed and repeated if no definite microvascular or other structural cause is initially identified. This evaluation might include a second catheter intra-arterial DSA in patients with a low risk of complication. In a study of patients <65 years of age with subcortical ICH, 4 of the 22 who had a second catheter angiogram after an initial negative angiogram were found to have an arteriovenous malformation.¹²⁵

Knowledge Gaps and Future Research

• Diagnostic performance of noninvasive neuroimaging to disclose the underlying cause of the bleeding has been explored only in selected cohorts. For example, no data are available in people >70 years of age.
• Criteria to select people for further investigations would ideally not be based solely on the presence or absence of vascular risk factors such as hypertension or diabetes, which can be difficult to ascertain with certainty. In future studies, markers of small vessel disease (such as white matter hyperintensities, lacunes, microbleeds, or superficial siderosis) can increasingly be incorporated to classify people in high- or low-risk categories of underlying macrovascular lesions.
• Diagnostic criteria should be developed and validated to help clinicians and researchers to categorize people with ICH according to the cause of the bleeding. The presence or absence of risk factors does not definitively establish or preclude a specific ICH cause. Future diagnostic criteria might incorporate molecular fluid-based or imaging-based biomarkers such as β-amyloid.^136,137
• Well-designed studies in nonselected populations should explore further whether DSA remains the gold standard to detect vascular malformations in patients with ICH at admission. Noninvasive imaging (including sequences such as arterial spin labeling or vessel wall imaging) could be useful in the future.
• Future clinical trials could be used to establish whether particular diagnostic strategies improve ICH outcome or recurrence risk.

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