Xuemei Cai, MD

A 72-year-old woman presents with headache followed by decreased level of consciousness. A non-contrast head CT shows a right parietotemporal intracerebral hemorrhage (ICH) (Figure 1). CT angiography is reveals no underlying vascular lesion or spot sign. She has no underlying coagulopathy and she is not known to be taking anticoagulants. She is taking 81 mg aspirin for primary cardiac prevention. She is admitted to the ICU for close blood pressure monitoring. Her initial BP reading is 176/70 in the emergency department, after a few IV pushes of antihypertensives her SBP is lowered to 130-140 mmHg and maintained. A bedside dysphagia screen is performed and a nasogastric tube for enteral feeding is initiated by day 2 of hospitalization. A repeat non-contrast head CT at 24 hours shows no change in her ICH. No changes to life-sustaining care are made until 48 hrs after admission. MRI of the head shows microhemorrhages suspicious for cerebral amyloid angiopathy (Figure 2). She is ultimately discharged to rehabilitation. Aspirin is not resumed given suspicion for cerebral amyloid angiopathy. Seven months after the initial event she has minor impairments but is able to perform her activities of daily living independently and is ambulatory.

Spontaneous nontraumatic ICH is a significant cause of morbidity and mortality. There are few interventions outside of optimizing critical care that improve outcome. However, an increased number of clinical trials have emerged in recent years that offer improved evidence-based management. This clinical update summarizes current treatment guidelines, application, and areas of emerging development.xx

ICH should be considered in any patient with acute and rapidly developing neurologic deficits. In particular, presence of headache, decreased level of arousal, nausea, and vomiting may suggest hematoma causing elevated intracranial pressure. CT of the head is crucial to early identification and management of ICH. Serial imaging every 6 hours or earlier in the presence of clinical change is crucial to monitoring of hematoma expansion. CT angiography is useful in identifying underlying vascular lesions or spot sign that is an area of contrast extravasation associated with active bleeding (

). MRI with contrast can help determine the etiology of ICH (

). Red flags that indicate need for additional workup include significant subarachnoid hemorrhage, pure intraventricular location, hyperdense vein, irregular shape, early significant edema, or adjacent calcification, dilation, or mass.

 approaching 50%, with a minority of survivors regaining functional independence.

 Advanced age and low baseline Glasgow coma score convey worse outcomes. Further neurologic deterioration is 

 increased mortality. Early deterioration is often driven by large ICH size and presence of intraventricular hemorrhage. Intraventricular blood confers mortality of nearly 50%.

The largest factor driving early deterioration is baseline ICH volume and hematoma expansion. Volume of hematoma is estimated using the ABC/2 method, where A is the greatest hemorrhage diameter (cm), B is the diameter 90 degrees to A (cm), and C is the total slice thickness (cm). Small hematomas are generally 

. Hematoma expansion occurs mostly within the first 3 hours; the hazard ratio of mortality increases by 1% per 1 mL increase in hematoma volume.

 The presence of a spot sign also signals ongoing expansion and is predictive of worse outcome.

Perihematoma edema is closely related to ICH volume and also contributes to mass effect and worsened outcomes. Perihematoma edema is thought to peak between 1 to 2 weeks after ICH, and an increase in absolute volume in the first 3 days is an independent predictor of in-hospital mortality.

Location of the ICH is essential to treatment management. Infratentorial hemorrhages in particular carry risk of brainstem destruction or compression. Other locations associated with worse outcome include the posterior limb of the internal capsule and the thalamus.

Scoring systems as predictors of long-term outcome include the ICH score and the FUNC score, which risk stratify patients for mortality and their return to functional independence.

 Despite these tools, predicting prognosis is difficult. Early withdrawal of care within 24 hours is the most important predictor of survival; it can also contribute to a self-fulfilling prophecy of poor prognosis. When clinical care is optimal in the first 48 hrs, patients with traditionally poor outcomes have had improved survival without worsened neurologic outcomes.

The first steps in management of ICH include airway and circulatory support. The next step is to correct coagulopathy if present. Steps to reversal are listed in 

. Consultation with vascular neurology, neurocritical care, and neurosurgery may be necessary. Indications for neurosurgical intervention are further outlined below. Care should be administered in an intensive care unit or dedicated stroke unit. Further management guidelines are listed in 

Neurosurgery should be consulted early if there is midline shift, evidence of hydrocephalus, or cerebellar bleed. Indications for emergent decompression in cerebellar hemorrhage include: obliteration of the 4th ventricle, a Glasgow coma score of < 14, hematoma diameter > 3-4 cm.

Intracranial pressure monitoring and ventriculostomy placement

. In cases of small hemorrhage with minimal ventricular involvement, intracranial pressure monitoring is not indicated, and ventricular catheters increase risk of infection and hemorrhage. However, intracranial pressure monitoring with ventriculostomy may be considered in patients with a Glasgow coma score of < 8 felt to be related to hematoma mass effect and/or if significant intraventricular hemorrhage and hydrocephalus are present.

. Hematoma evacuation through early craniotomy did not demonstrate survival or disability benefit.

 Minimally invasive hematoma removal shows promise, with several phase 3 trials. One trial is using alteplase infusion delivered via catheter into the hematoma. Previously in phase 2, CT guided endoscopic surgery without thrombolysis also resulted in reduction of hemorrhagic volume. Perihematomal edema was also reduced, but no mortality benefit was seen.

Recently the results of CLEAR III were published on ventriculostomy for ICH with intraventricular hemorrhage with alteplase administered via an extraventricular catheter.

 While the study did not show functional outcome improvement, subgroup analysis of the patients who had larger volume of intraventricular hemorrhage and those with most percentage removal of intraventricular hemorrhage showed a trend towards improved outcomes and improved survival.

Resuming anticoagulation and timing of resumption are still debated. Hemorrhage secondary to cerebral amyloid angiopathy is more likely to re-bleed than hypertensive hemorrhage; therefore resuming anticoagulation after lobar hemorrhage is generally not recommended. However, a recent meta-analysis of observational studies in vitamin K antagonist associated ICH found that resuming anticoagulation in the setting of atrial fibrillation in ICH survivors protects against future ischemic events better than antiplatelet agents without increase risk of ICH recurrence.

 A randomized controlled trial including newer oral anticoagulants is essential in guiding decision making for resumption of anticoagulant therapy after ICH.

Numerous anticoagulant reversal agents aimed at achieving hemostasis are in development for early prevention of hemostasis (

). Perihematoma edema expansion has also emerged as a 

 with increasing clinical relevance. Larger edema volumes are associated with clinical deterioration and poor outcomes.

 A number of neuroprotective therapies aimed at reducing perihematoma edema, such as such as deferoxamine, pioglitazone, albumin, statins, and G-CSF, are now in clinical trials. Hypothermia especially shows promise, as targeting 35 degrees centigrade for several days has decreased mortality at 3 months and 1 year.

, hypertonic saline infusion targeting 145-155mEq/L serum sodium also reduced absolute and relative perihematoma edema, along with in-hospital mortality.

Dr Alice Cai reports no conflicts of interest concerning the subject matter of this article. Dr Xuemei Cai is employed by Pfizer Inc.

. Long-term prognosis after recovery from primary intracerebral hemorrhage

2. Lord AS, Gilmore E, Choi HA, Mayer SA. 

Time course and predictors of neurological deterioration after intracerebral hemorrhage

3. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. 

4. Hemphill JC, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. 

5. Rost NS, Smith EE, Chang Y, et al. Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score. 

6. Morgenstern LB, Zahuranec DB, SÃ¡nchez BN, et al. 

Full medical support for intracerebral hemorrhage

7. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. 

8. Mould WA, Carhuapoma JR, Muschelli J, et al. Minimally invasive surgery plus rt-PA for intracerebral hemorrhage evacuation (MISTIE) decreases perihematomal edema. 

9. Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. 

10. Biffi A, Kuramatsu J, Leasure A, et al. Resumption of oral anticoagulation after intracerebral hemorrhage is associated with decreased mortality and favorable functional outcome. 

Prognostic significance of perihematomal edema in acute intracerebral hemorrhage: pooled analysis from the intensive blood pressure reduction in acute cerebral hemorrhage trial studies

12. Staykov D, Wagner I, Volbers B, et al. Mild prolonged hypothermia for large intracerebral hemorrhage. 

13. Wagner I, Hauer E-M, Staykov D, et al. 

Effects of continuous hypertonic saline infusion on perihemorrhagic edema evolution

14. Pollack CVJ, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal: full cohort analysis. 

15. Connolly SJ, Milling TJJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. 

16. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. 

17. Penn Neurology: Division of Stroke Anticoagulation reversal for ICH. June 2016. 

https://pennstroke.org/protocols-and-schedules/anticoagulation-reversal-for-ich

18. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. 

19. Qureshi AI, Palesch YY, Barsan et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. 

20. Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. 2015. http://stroke.ahajournals.org/content/early/2015/05/28/STR.0000000000000069. Accessed November 29, 2017.

21. Adult Intracerebral Hemorrhage (MGH Stroke Service). http://stopstroke.massgeneral.org/protocolAdultHemorrhage.aspx. Accessed November 29, 2017.

22. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebralh. 

23. Arkin S, Hua F, Kantaridis C, Li G, et al. Escalating single doses of PF-05230907 are safe and demonstrate hemostatic pharmacology in healthy volunteers. 

24. Naidech AM, Maas MB, Levasseur-Franklin KE, et al. Desmopressin improves platelet activity in acute intracerebral hemorrhage. 

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A summary of current treatment guidelines, application, and emerging developments in the area of spontaneous nontraumatic ICH.

Xuemei Cai, MD

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