Hemorrhagic Stroke

I. What every physician needs to know.

Hemorrhagic stroke is the second most common cause of stroke. It comprises intracranial hemorrhage (ICH) and subarachnoid hemorrhage (SAH). ICH is most commonly due to rupture of small perforating arteries due to unrecognized or uncontrolled hypertension, but can be due to several other underlying etiologies discussed below. SAH is most commonly due to ruptured intracranial aneurysms. This review will primarily discuss ICH.

II. Diagnostic Confirmation: Are you sure your patient has hemorrhagic stroke?

Intracerebral hemorrhage is diagnosed by the presence of blood in the intraparenchymal space in patients who present with signs and symptoms of stroke. These findings include the sudden and acute onset of hemiparesis, hemisensory loss, aphasia, ataxia, ophthalmoplegia, and/or visual field deficits.

A. History Part I: Pattern Recognition:

Patients usually present with the acute onset of focal neurologic deficits such as loss of sensation of one side of the body (hemisensory loss), paralysis of one half of the body (hemiparesis), impairment of language (aphasia), eye motion abnormalities due to paralysis of one of more of extraocular muscles (ophthalmoplegia), loss of balance or coordination (ataxia), and/or loss of vision (visual field deficits).

When compared to ischemic stroke, patients with ICH are more likely to complain of severe headache, progressive worsening of mental status, neck stiffness, nausea and vomiting. In addition, those with ICH are more likely to prevent with profoundly elevated blood pressure.

These symptoms can vary depending on extent, location, and severity of bleed. Rapid diagnosis is paramount as ICH patients have a high rate of early clinical deterioration from hematoma expansion. This can lead to a herniation syndrome with brain stem compression and exam findings of comatose state, new cranial nerve deficits, and respiratory depression. Acutely worsening patients will require neurosurgical consultation for possible decompression and hematoma evacuation in these cases.

B. History Part 2: Prevalence:

The annual incidence of ICH varies from 15-30 cases per 100,000. Intracerebral hemorrhages comprise 15-20% of all strokes (the rest being ischemic).

Hypertension is well established as the leading risk factor for ICH, accounting for 70-80% of population-attributable risk. Advancing age increases ICH risk amongst all patients. Race also is a significant risk factor that is modified by age. At age 45 blacks will have a 5 fold increased risk of ICH compared to whites. By age 85 that reverses and whites are 3 times more likely to experience ICH. Smoking greater than 20 cigarettes per day, heavy alcohol consumption, low LDL and triglyceride levels all put patients at higher risk of developing intracerebral bleeds.

Hypertension is the most common etiology across the board, especially in patients younger than 55 years old when the ICH is centered in the basal ganglia (putamen and caudate), thalamus, pons, or cerebellum. As patients age lobar hemorrhages become more common. While hypertension is still a frequent cause, cerebral amyloid angiopathy (CAA) becomes of much higher concern. Patients at high risk for CAA include those with known dementia, advanced age, and ApoE ε2 or ε4. Other less common etiologies to consider include vascular malformation (ruptured aneurysm, AVM, or moyamoya disease), cerebral venous sinus thrombosis (patients with risk factors for hypercoagulable states especially women on oral contraception or in peripartum period), septic embolism (usually multiple hemorrhagic foci in the brain), underlying coagulopathy (on therapeutic anticoagulation, recent fibrinolytics, etc), intracerebral tumor, vasculitis and drugs (cocaine, sympathomimetic drugs, etc).

C. History Part 3: Competing diagnoses that can mimic hemorrhagic stroke.

Acute onset of a focal neurologic deficit has a short list of life threatening conditions to be considered immediately: acute stroke (ischemic or hemorrhagic), seizure, or migraine. Recrudescence of symptoms from a prior neurologic injury is also of consideration once a new insult has been ruled out. Therefore evaluation for acute endocrine disorders (hypo or hyperglycemia), electrolyte disturbances (hypo or hypernatremia), and infection should take place. While a seizure with post-ictal paralysis can be a stroke mimic, it is important to remember that a patient with no prior history of seizure could be seizing from a new stroke. Post-ictal paralysis can last anywhere from minutes to days. Finally, psychiatric disorders can also present with signs and symptoms of stroke. All possible medical explanations must be evaluated before settling on a psychiatric etiology.

D. Physical Examination Findings.

Physical signs depend on extent, severity and site of bleed. ICH within the basal ganglia will lead to contralateral hemiparesis, occasionally hemisensory loss, dysarthria, and dysphagia. ICH within the thalamus will lead to severe contralateral hemisensory loss, visual field defect, and vertical gaze difficulty. Pontine ICH will lead to pinpoint pupils, early coma, hemiplegia or quadriplegia depending on size of hemorrhage, and horizontal gaze palsy. Cerebellar ICH will lead to profound ataxia, severe headache, nausea and vomiting. Lobar ICH will cause symptoms based upon the lobe affected (frontal, parietal, temporal, occipital).

All of these patients are at high risk for developing elevated intracranial pressure (ICP). Exam findings concerning for elevated ICP include worsening level of arousal, impaired upward gaze, worsening headache, nausea and vomiting.

E. What diagnostic tests should be performed?

Diagnosis of ICH is based on the combination of clinical exam and imaging studies. Although physical examination can help establish the diagnosis of stroke, there is no single physical exam finding or maneuver that can differentiate hemorrhagic from ischemic stroke. Non-contrast computed tomography (CT) scan of the brain is a quick and reliable test to differentiate between these two diagnoses.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Once diagnosis of stroke is confirmed by history and physical examination, complete blood count (CBC), complete metabolic panel (CMP, including blood glucose level) and coagulation studies (including PT, PTT and INR) should be ordered before moving the patient to the CT scanner.

It includes evaluation of the platelet count, hematocrit and work up of any underlying bleeding disorder. With patients who present with alteration of consciousness, arterial blood gas (ABG) can help to evaluate for underlying hypercapnia or acid base disorder.

Both an EKG and troponin should be obtained. Catecholamines released from brain injury usually cause subendocardial ischemia which appears on EKG as ST segment changes, appearance of U waves or tall T waves and prolonged QT segment. Subendocardial ischemia can also be associated with mild elevation of cardiac biomarkers.

Other studies include a toxicology screen to evaluate for cause of ICH, urinalysis to evaluate for possible stroke mimic, and both hemoglobin A1c and fasting lipid panel to help evaluate underlying comorbidities of the patient.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Non-contrast head CT is the best diagnostic test to diagnose ICH and is equivalent to magnetic resonance imaging (MRI). It can evaluate the size and extent of hematoma (involvement of ventricles) along with the presence or absence of midline shift or herniation of brain parenchyma.

For patients with severe hypertension and an ICH within the basal ganglia, pons or cerebellum, additional imaging may not be necessary. However, in a patient with acute onset (<3 hours) of symptoms, a CT angiogram of the brain can be performed to evaluate for active contrast extension into the hematoma. Evidence of active contrast extravasation (known as a spot sign) can help identify patients at higher risk for hematoma expansion. The CTA will also help rule out aneurysms and AVMs as a cause of the ICH.

Patients with lobar ICH may also require additional imaging with an MRI with and without contrast to evaluate for possible CAA or underlying tumor. Patients who have evidence of multiple microbleeds within the cerebral cortex (on susceptibility weighted imaging or gradient echo imaging) are highly likely to have CAA. If microbleeds are primarily present within the basal ganglia, thalamus, brainstem or cerebellum then hypertension is more likely the cause.

In other cases, when clinical suspicions arise, magnetic resonance vengoraphy (MRV) can be obtained to evaluate for cerebral venous sinus thrombosis. A repeat MRI with and without contrast (8 to 12 weeks after ICH) can also reveal underlying tumor or vascular malformation.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None

III. Default Management.

Management of ICH depends on the presenting condition. In most of the cases, patients need to be stabilized first. In severe cases, protection of airway may precede diagnostic work-up. Immediate management steps are the same regardless of the etiology of stroke.

These include quick history and physical, airway screen and placing the patient on pulseoxymeter, cardiac monitor and oxygen, obtaining intravenous access and drawing essential blood labs. Once patient is stabilized, etiology of stroke should be established by non-contrast CT scan. After diagnosis is obtained treatment should be initiated right away.

During initial assessment, physicians need to exclude the stroke mimics discussed above as many of these are reversible causes and can treated appropriately.

A. Immediate management.

Once stabilized, a detailed history and physical examination should be performed. The laboratory studies and CT scan results should be reviewed to determine the etiology of stroke. ICH is a medical emergency with a potential for both early and late neurologic deterioration. Early neurologic deterioration occurs primarily due to hematoma expansion and hydrocephalus. Late neurologic deterioration typically occurs due to cerebral edema, fever, infection, or seizures.

Up to one-third of patients will have a greater than 33% expansion in hematoma volume within the first 24 hours. It is recommended to monitor these patients in the intensive care unit initially with close monitoring of the patient’s neurological status. Unfortunately, at this point in time preventing hematoma expansion has proven extremely difficult.

In patients with severe hypertension, blood pressure control via intravenous antihypertensives and continuous blood pressure monitoring is recommended. Much debate has centered on the optimal blood pressure goal after ICH. Two recent trials, INTERACT II and ATACH2, have established that aggressive SBP lowering to less than 140 mmHg does not improve outcome or prevent hematoma expansion. However, a modest reduction in blood pressure is safe. After the results of these trials, many experts recommend a target systolic blood pressure of 160-180 mmHg, Alternatively, mean arterial pressure (MAP) of less than 110mmHg is also an acceptable target blood pressure in patients with ICH. Typical regimens include as needed IV pushes of labetalol or hydralazine initially, and if needed continuous infusions of nicardipine or clevidipine. IV nitrates should be avoided as they can lead to elevation of ICP.

For patients with extensive intraventricular extension of hemorrhage (IVH) or hydrocephalus, placement of an external ventricular drain may be necessary in order to provide CSF diversion. This also adds the capability to monitor ICP.

Early seizures are also common after ICH, occurring in 3-17% of patients. However, the use of prophylactic anticonvulsants is not recommended as observational studies have suggested harm due to worsened cognition. However, in a patient who remains somnolent or has a frequently waxing and waning mental status, there should be a low threshold for EEG or continuous video EEG monitoring. Anti-epileptic medications should be started if seizures are detected during these evaluations. The most commonly used agents are IV fosphenytoin or IV levetiracetam.

For patients on therapeutic anticoagulation, discontinuation of the agent they are using and appropriate reversal are paramount. For patients using warfarin, administration of prothrombin complex concentrate (PCC) provides rapid reversal of the INR while administration of vitamin K provides long term INR correction. Fresh frozen plasma can also be considered for immediate warfarin reversal. However, this process takes longer due to the need to thaw FFP, so when possible PCC should be utilized.

With the rise of direct oral anticoagulant medications, reversal has become an issue. Recently, dabigatran had a reversal agent developed and approved for use: idarucizumab. Meanwhile for the direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) there is a reversal agent in development: andexanat alpha. Until this is approved for use, most experts have been administering PCC in the hopes of partially mitigating the effects of these medications. Standard reversal for heparin infusions and low molecular weight injections with protamine should be pursued. Of note, the use of active Factor VII treatment has not shown any benefit of survival during clinical trials.

The PATCH trial recently demonstrated that administration of platelet transfusions to patients with ICH who took antiplatelet agents at home actually led to increased morbidity. Therefore, the recommendation is to simply stop antiplatelet administration in the setting of ICH. Platelet transfusion can still be considered in cases where the patient needs to go emergently to the operating room for neurosurgical intervention.

The next immediate consideration is whether the patient would benefit from neurosurgical consultation with possible hematoma evacuation. The primary group that benefits from surgical decompression and evacuation is patients with cerebellar ICH causing symptomatic brainstem compression and hydrocephalus. These patients should proceed to the OR as soon at the earliest manifestation of brainstem compression, before frank herniation occurs. For supratentorial ICH, the ideal patient population has not yet been identified via randomized trials. Currently, patients with large (> 20 mL) lobar hematomas near the surface of the brain within 8 hours of onset can be considered for evacuation. Many will consider surgical intervention for rapid clinical deterioration due to brain compression and herniation as well. Discussion with your neurosurgical colleagues is highly important.

Following these steps, management is largely supportive and geared toward preventing and treating causes of late neurologic deterioration. All patients should have physical therapy, occupational therapy and speech language pathology consultations placed upon admission. They should be kept NPO until they pass a swallow evaluation..

If appropriate, physicians should also consider end of life discussion with the family and next of kin based on the patient’s condition and prognosis. See prognosis after ICH discussion below.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

If coagulation abnormality is the underlying cause, coagulation studies should be followed closely while respective blood products are replaced. For thrombocytopenia induced ICH, many practitioners will transfuse initially to a goal platelet level of greater than 100 x10³/uL and maintain this until the hematoma has stabilized. The transfusion threshold can then be slowly loosened as appropriate.

A CT scan should be repeated 6 hours post initial imaging to assess for expansion of the hematoma. Additional imaging after this repeat scan should be dictated by the clinical exam.

D. Long-term management.

Monitoring for and treating conditions that lead to late neurologic deterioration are the focus of long-term management. Cerebral edema can develop as early as 48 hours post ICH and persist for 1-2 weeks. Untreated edema can lead to brain compression, increased intracranial pressure, herniation, and death. The mainstay of therapy includes osmotic therapy with either mannitol, hypertonic saline, or occasionally both.

Mannitol is the typical first line medication unless the patient has renal failure. While using mannitol in a scheduled fashion every 6 hours, the serum osmolality should be measured along with a BMP prior to every other dose. The osmolality gap (serum osmolality minus calculated osmolality) should then be calculated and mannitol held if the osmolality gap is greater than 14 mOsm/L (the osmolality gap is a measurement of how well the patient is clearing the administered mannitol).

The BMP should also be measured every 6 to 12 hours while on scheduled hypertonic saline. Hypertonic saline is typically held once the serum sodium level is greater than 160 mEq/L, although some institutions will push the sodium higher. Care should be taken to maintain euvolemia during osmotic therapy. Osmotic therapy should be continued until exam stabilizes and then slowly weaned off over a few days. Failure to respond to osmotic therapy should prompt neurosurgical discussion. There is no role for glucocorticoids in cerebral edema in ICH as they have not improved outcomes.

Treatment of fever, hyperglycemia, pain and agitation should be aggressive, as these factors are known to be associated with worse outcomes. Fever should be treated with antipyretics, chilled saline boluses, cooling blankets, or more aggressive means if necessary. Simple measures such as 30 degree elevation of the head of the bed are well known to improve intracranial pressure and decrease complications such as aspiration pneumonia. Headache due to traction of nerves is at times associated with neck stiffness and requires appropriate analgesia. Any neurologic exam change not explained by repeat imaging, fever, or infection should prompt consideration for non-convulsive status epilepticus.

In patients with ICH, deep venous thrombosis (DVT) is very common and can be prevented by placing intermittent pneumatic compression devices upon admission. Pharmacologic DVT prophylaxis with low dose heparin should be started after 48 hours of stable clinical exam and hematoma size.

Initial IV blood pressure control should be transitioned to an oral regimen to provide appropriate long-term control of blood pressure. Oral regimen should be tailored to the patient’s comorbidities.

Transthoracic echocardiography should be considered in most patients. It can help establish evidence to support long standing undiagnosed hypertension, evaluate left ventricular systolic and diastolic function, and in some cases diagnose takasubo cardiomyopathy (which can happen not infrequently in ICH and SAH). It is also beneficial in patients where septic emboli are high on the differential diagnosis.

Early physical, occupational, and speech therapy are highly important. These consultants will aide decision making regarding discharge destination: inpatient rehab, skilled nursing facility, or home with outpatient therapy. Early mobilization and ambulation, if possible, should be initiated in all ICH patients.

In cases with severe deficits, where patients cannot be extubated and are unable to feed themselves, the long-term plan should be discussed with the family including need for tracheostomy and feeding tube (PEG) tube placement.

Other interventions include maintenance of good oral hygiene and evaluation for early removal of urinary catheter during hospital stay. Pneumonia and influenza vaccinations should be given before discharge from the hospital.

E. Common Pitfalls and Side-Effects of Management

Osmotic therapy with mannitol can lead to acute kidney injury if euvolemia is not maintained. Mannitol should not be used in the setting of acute or chronic kidney disease. Glucocorticoids are not effective in managing cerebral edema associated with ICH.

Overaggressive blood pressure lowering to SBP < 120 mmHg has been shown to lead to acute kidney injury. Intravenous nitrates should be avoided as it can cause cerebral vasodilation and thereby increase intracranial pressure.

Patients with extensive intraventricular hemorrhage who require external ventricular drain (EVD) placement will often develop EVD occlusion from blood clotting within the tubing. In these cases, tPA can be administered into the EVD system only (without flushing into the ventricles) in order to unclot the drain. Use of intrathecal tPA (flushing tPA through the EVD into the ventricles) has been shown to lead to earlier resolution of IVH. However, it has not yet shown a mortality benefit.

Fever control can be quite difficult, especially in patients with IVH. Be cognizant of how much acetaminophen and NSAIDs are being administered on a daily basis to control fever to avoid toxicity from these medications.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Mannitol should not be used in these patients, utilize hypertonic saline instead. Also, based on the cause of renal insufficiency, angiotensin converting enzyme inhibitors (ACEI) and diuretics may need to be avoided.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

D. Coronary Artery Disease or Peripheral Vascular Disease

Use of antihypertensives such as ACE-I and beta-blockers are preferred.

E. Diabetes or other Endocrine issues

Use of antihypertensives such as ACE-I is preferred. Aggressive control of blood sugar is recommended in diabetic patients with acute stroke.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

Beta-blockers should be avoided in patients as such medications can worsen bronchospasm.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

Transfusion thresholds for INR and platelets will need frequent re-evaluation once the ICH size stabilizes as patients with thrombocytopenia or coagulation difficulty from underlying malignancy, cirrhosis, or infection may never reach normal levels.

K. Dementia or Psychiatric Illness/Treatment

In cases of severe dementia, concern for CAA is higher. Patients with CAA will likely continue to experience additional episodes of spontaneous ICH with increasing disability each time. This prognosis and treatment plan should be discussed in detail with the family.

No change in standard management in patients with psychiatric illness.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

The on-call team should be signed out to obtain stat imaging study along with neurosurgery consult with any changes in the mental status of the patient. Detailed sign-out should be given regarding patients’ current mental and neurological status. Care should be taken to identify the patient’s pupil size and reactivity. Team also should be given details about blood pressure control and overnight treatment strategy.

B. Anticipated Length of Stay.

Anticipated length of stay depends on case to case basis, generally patients with ICH without any superimposed complications will stay in the hospital between 5-10 days.

C. When is the Patient Ready for Discharge.

Discharge should be planned in association with the recommendations from speech therapy, physical and occupational therapy. Patient’s home condition, place of discharge and availability of family support also effect the decision of their discharge.

In mild cases, once patients are able to take care of themselves, discharge planning should be initiated. In moderate and severe cases, patients may be discharged to an inpatient rehabilitation unit, skilled nursing facility, or nursing homes once long term plan is discussed with the family.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Patients should follow-up with the primary care doctor after discharge. Follow-ups should also be arranged with a neurologist. Outpatient’s physical/occupational therapy and speech therapy should also be arranged based on the patient’s residual deficits.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

Placement decision is usually based on recommendations from physical therapy, occupational therapy, and speech language pathology evaluation. Family preference and patient’s home support should also be honoured.

F. Prognosis and Patient Counseling.

Prognosis of ICH depends on extent and location of ICH. The Joint Commission has adopted the ICH score as a standard severity of illness scoring system. It takes into account the volume of hemorrhage (1 point for 30 mL or greater), the patient’s age (1 point for 80 years old or greater), location of hemorrhage (1 point for infratentorial origin), GCS upon arrival (2 points for GCS 3 or 4, 1 point for GCS 5-12), and presence of IVH (1 point). The score should be calculated for all patients upon arrival to the ICU, and subsequent 30 day mortality can be estimated from it.

High scores have much higher mortality. It is important to note that the high mortality with high ICH scores may have been confounded by decisions to withdraw life supporting measures in these patients with severe ICH when the scoring system was validated. American Heart Association and American Stroke Association currently recommend against clinicians making a new “do not resuscitate” order on a patient within the first 24 hours of ICH. Patients with pre-existing DNR/DNI orders in place should clearly have their wishes fulfilled. With continued supportive care, noting further hematoma expansion and early neurologic deterioration is important as both are additional poor prognostic factors.

ICH is the type of stroke with highest mortality. Literature review showed 35% of patients who present with hemorrhagic stroke die within 30 days, and 25% die within the first 2 days following stroke. Not only does it have high mortality, one of the research studies showed that only 20% of the patients who experience hemorrhagic stroke are independent at 6 months.

Patients should be counseled to know about early signs of stroke. These include presence of facial droop, strange speech, and asymmetrical weakness in one of the extremities and should be told to call 911 right away without any delay.

Patients should be counseled to stop smoking, stop use of illegal drugs and asked to control blood pressure aggressively.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

All patients with new diagnosis of stroke should undergo a speech/swallow evaluation (dysphasia screen), along with physical/occupational therapy evaluation.

The ICH score is required to be documented upon arrival to the intensive care unit.

During the hospital stay, patients should have appropriate DVT prophylaxis and smoking cessation counseling. Patients should be assessed for rehabilitation and should have a rehabilitation plan discussed with the patient or/and care taker. Also, the patient and/or family/care taker should be extensively educated about hemorrhagic stroke and its outcome.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

In general, about 50% of the patients who survive stroke (including ICH and ischemic stroke) are permanently disabled at the time of discharge and need long term rehabilitation and closer follow-up. Literature review showed 30% of the patients with stroke are known to be readmitted to the hospital within the first year after discharge, mostly due to infectious causes. Other causes include another stroke and cardiovascular events.

The three most common infections are pneumonia, urinary tract infection and infections of the bed sores, and are usually related to residual neurological deficits. Closer monitoring, either at skilled nursing facility or by trained nurses at home, can help avoid these infections.

One published study showed a significant decrease in hospital admissions (from complications of stroke) with closer outpatient follow-ups. Aggressive pulmonary toilet, straight urinary catheterization and frequent change in positions are some maneuvers which can help with avoiding these infections, in turn avoiding frequent admissions to the hospital.

Appropriate control of blood pressure by medications and/or life style modifications such as diet (salt restriction, low fat diet) and exercise (weight loss) can help avoid re-bleeds. Attention should also be given to quit smoking, alcohol and drug abuse and also on control of blood sugar in patients with previous hemorrhagic strokes.

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