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Nejmra 2201449
Nejmra 2201449
Review Article
S
pontaneous intracerebral hemorrhage accounts for approxi- From the Division of Neurocritical Care
mately 10 to 15% of all strokes.1 Other disorders that result in bleeding within and Emergency Neurology, Departments
of Neurology and Neurosurgery, and the
the cranium, such as traumatic hemorrhage, rupture of cerebral aneurysms or Yale Center for Brain and Mind Health,
malformations, and hemorrhagic transformation of ischemic stroke, are not discussed Yale School of Medicine, New Haven, CT.
in this review except as they relate to the differential diagnosis. Dr. Sheth can be contacted at kevin
.sheth@yale.edu or at 15 York St., LLCI
Room 1003C, P.O. Box 208018, New Ha-
ven, CT 06510.
Cl inic a l Pr e sen tat ion a nd E a r ly A sse ssmen t
N Engl J Med 2022;387:1589-96.
Patients with intracerebral hemorrhage present with focal neurologic signs that are DOI: 10.1056/NEJMra2201449
abrupt in onset but not instantaneous, as occurs with embolic ischemic stroke. The Copyright © 2022 Massachusetts Medical Society.
A B C D
E F G H
I J K
points less in the group that received the highest cal outcomes in patients with intracerebral hem-
dose of factor VIIa; however, there was no differ- orrhage. In the Antihypertensive Treatment of
ence between the patient groups in the incidence Acute Cerebral Hemorrhage II (ATACH-2) trial,
of severe disability or death. The recently initiated 1000 patients with supratentorial intracerebral
FASTEST trial (NCT03496883) is testing treatment hemorrhage were randomly assigned to receive
with factor VIIa to limit the expansion of a hema- parenteral nicardipine to maintain a target range
toma when administered within 2 hours after the for systolic blood pressure of 110 to 139 mm Hg
onset of symptoms. (intensive treatment) or to a target range of 140
Patients with intracerebral hemorrhage that to 180 mm Hg (standard treatment) for 24 hours.29
is associated with anticoagulant use are at a risk Clinical outcomes were similar in the two
for hemorrhage expansion, neurologic deteriora- groups at 90 days. In the Intensive Blood Pres-
tion, and poor outcome that is three to six times sure Reduction in Acute Cerebral Hemorrhage
as high as that in patients with intracerebral hem- Trial 2 (INTERACT2),30 2783 patients were ran-
orrhage in the absence of anticoagulation.26 In a domly assigned to the same blood-pressure target
trial of patients with intracerebral hemorrhage ranges as were those patients in the ATACH-2
who had received vitamin K antagonists and who trial, but INTERACT2 investigators extended the
had an international normalized ratio (INR) that intervention for 7 days and left the selection of
was greater than 1.9, four-factor prothrombin antihypertensive medication to the treating cli-
complex concentrate was found to be superior to nicians. The INTERACT2 trial findings were
fresh frozen plasma for normalizing the INR and neutral with regard to the primary end point of
reducing the incidence of hematoma expansion.27 death or severe disability at 90 days. Some pa-
Guidelines recommend intravenous vitamin K and tients in the intensive-treatment group in the
prothrombin complex concentrate over fresh fro- ATACH-2 trial had acute kidney injury. After these
zen plasma if the INR is elevated owing to the use trials, uncertainty remained about the ideal blood-
of vitamin K antagonists.22 The reversal agents pressure target, choice of medication and mode
idarucizumab and andexanet alfa are available of administration, and duration of treatment.
for use in the treatment of patients with intrace- However, it may be reasonable to aim for an inten-
rebral hemorrhage that is associated with direct sive strategy of lowering the patient’s systolic
oral anticoagulants in the form of direct throm- blood pressure to 130 to 150 mm Hg, particu-
bin and factor Xa inhibitors; however, clinical larly if the systolic blood pressure exceeds 220
trials are needed to determine their effect, and mm Hg within 2 hours after intracerebral hem-
it has been suggested that prothrombin complex orrhage. Close monitoring of kidney function
concentrate can be substituted if reversal agents and volume status is advised.
are not available.22
To inform the treatment of patients with intra- Intraventricular Hemorrhage
cerebral hemorrhage associated with antiplatelet Intraventricular hemorrhage occurs in 30 to 50%
agents, patients in the Platelet Transfusion ver- of patients with intracerebral hemorrhage, and
sus Standard Care after Acute Stroke due to Spon- the resultant hydrocephalus owing to the added
taneous Cerebral Haemorrhage Associated with volume to the ventricular space, obstruction of
Antiplatelet Therapy (PATCH) trial were randomly cerebrospinal fluid (CSF) flow, and inflammation-
assigned to a group that received platelet trans- stimulated secretion of CSF leads to a decreased
fusions or to a control group.28 The group that level of arousal and poor outcome.31 Hydrocepha-
received transfusions had twice the mortality and lus that results in decreased wakefulness usually
higher rates of disability than those in the group is treated by the placement of an external ven-
that did not receive transfusions. As a conse- tricular drain to divert CSF and reduce intracra-
quence, American Heart Association guidelines nial pressure. In the Clot Lysis Evaluation of
suggest that platelet transfusions should be Accelerated Resolution of Intraventricular Hem-
withheld except in patients receiving aspirin orrhage (CLEAR III) trial, which evaluated 500
therapy who have intracerebral hemorrhage and patients with hydrocephalus after intracerebral
undergo neurosurgical procedures.22 hemorrhage, intraventricular administration of
Two trials have tested the hypothesis that alteplase was used to dissolve the ventricular
lowering of blood pressure would improve clini- clot.32 Although the overall comparison between
groups showed no difference in functional out- tensive monitoring improves clinical outcome in
comes, thrombolysis might have been associated intracerebral hemorrhage is not clear, and a trial
with improved survival.33 Patients who survive in- to test this question seems unlikely to be con-
traventricular hemorrhage typically have substan- ducted. Seizures after intracerebral hemorrhage
tial disability at 6 months. can occur, although the role of prophylactic anti-
seizure drugs in patients with intracerebral hem-
Mass Effect orrhage is unclear.37 In patients with a depressed
The most severe consequence of the mass effect level of consciousness after intracerebral hemor-
of an intracerebral clot and surrounding edema rhage, continuous electroencephalography may
is transtentorial herniation. Studies have shown detect inapparent seizures that require the initia-
that surgical removal of the clot, undertaken in tion of antiseizure drugs.38 Routine care in the
an attempt to alleviate transtentorial herniation, intensive care unit includes airway protection and
has had inconsistent or generally negative results. adequate pulmonary gas exchange for mitigation
These findings have led to variations in practice of secondary brain injury from hypoxemia, but
with regard to the performance of craniotomy the effectiveness of these measures is difficult to
for clot removal. The Surgical Trial in Intracere- prove. Assessment of swallowing, maintenance
bral Hemorrhage II (STICH II) trial examined the of normothermia and normal glucose levels, and
role of early clot-removal surgery in 601 patients prophylaxis for deep-vein thrombosis (a therapy
with intracerebral hemorrhage; the results showed that is considered to be safe despite the presence
that the incidence of unfavorable outcome was of intracerebral hemorrhage) reduce additional
similar in operated and conservative-treatment morbidity.
groups but suggested that the removal of lobar Systems for early prognostication may not have
clots located within 1 cm of the cortical surface adequate predictive ability to direct the withdrawal
might have been beneficial.34 of life-sustaining treatments after intracerebral
Randomized trials are not available to gauge hemorrhage.39 Patients who might otherwise have
the effect of surgical treatment for cerebellar survived may succumb if life-sustaining treat-
intracerebral hemorrhage. However, on the basis ments are withdrawn too early.40 Several studies
of large observational studies, the general practice suggest that withholding the determination of
has been to remove the clot if clinical or imaging prognosis in the first few days after hemorrhage
signs of brain-stem compression are present or if is appropriate, and these findings are consistent
the clot volume is greater than 15 ml.35 Cerebellar with American Heart Association guidelines.22,41
hemorrhage commonly causes obstruction of the Shared decision making to gauge the previously
fourth ventricle that leads to hydrocephalus, expressed wishes of the patient and family is a
which requires placement of an external ventricu- fruitful approach.
lar drain.
Osmotherapy is typically used to treat acute Sec onda r y Pr e v en t ion a nd
neurologic deterioration that is secondary to the R e sump t ion of A n t ic oagul a n t s
mass effect or edema associated with intracere-
bral hemorrhage, but the results have been un- Fewer than half the patients who survive intra-
certain. Raised intracranial pressure is usually cerebral hemorrhage have adequate blood pres-
treated with mannitol or a bolus of hypertonic sure control after discharge. Poorly controlled
saline.36 Data are lacking to support prophylacticblood pressure is associated with adverse events
infusion of hypertonic saline or administration such as recurrent stroke and death and is more
of glucocorticoids for conditions caused by the common among Black persons than among non-
mass effect of an intracerebral hemorrhage. Black persons.42 In addition to recurrent intrace-
rebral hemorrhage, survivors are at risk for
In tensi v e C a r e a nd W i thdr awa l thrombotic events both43in the brain and in the
of L ife-Sus ta ining T r e atmen t cardiovascular system. The Restart or Stop
Antithrombotics Randomised Trial (RESTART)
Despite the inherent appeal of admitting patients showed that resumption of antiplatelet agents that
with cerebral hemorrhage to an ICU, whether in- are considered necessary (e.g., in patients with
coronary stents) after intracerebral hemorrhage between low levels of low-density lipoprotein
led to a modest increase in the rate of recurrent cholesterol and the risk of intracerebral hemor-
intracerebral hemorrhage.44 rhage.47 The Statins in Intracerebral Hemorrhage
Among patients with intracerebral hemor- trial (SATURN, NCT03936361) is evaluating the
rhage and atrial fibrillation, the safety of either resumption of statin medications in patients with
starting or resuming anticoagulation remains lobar intracerebral hemorrhage who are at risk for
unclear. In the phase 2 Apixaban after Anticoag- recurrence and vascular thrombotic events.
ulation-associated Intracerebral Hemorrhage in
Patients with Atrial Fibrillation (APACHE-AF) tri- F u t ur e Dir ec t ions
al, a slightly higher percentage of patients as-
signed to receive apixaban had nonfatal stroke In addition to the ongoing trials mentioned, trials
or vascular death than patients assigned to avoid of minimally invasive surgical evacuation of clots
anticoagulation (26% vs. 24%).45 The Start or (e.g., aspiration, stereotactic removal, and intra-
Stop Anticoagulants Randomised Trial (SoSTART) ventricular thrombolysis) could determine wheth-
showed that 8% of the patients assigned to start er these procedures are effective and whether
anticoagulation therapy had recurrence of intra- outcomes can be improved according to the type
cerebral hemorrhage, as compared with 4% of and location of the clot. Strategies are needed
the patients who did not start anticoagulation to test antiinflammatory and neuroprotective
therapy, but the trial was underpowered for stroke therapies.
events and the criteria for showing the inferiority Organized systems of care for stroke and clini-
of avoiding medication during the first 2 years cal trials may offer an improved outlook for pa-
after intracerebral hemorrhage were not met.46 tients. Recent small trials tentatively suggest that
The above-mentioned phase 3 trials (ASPIRE and mobile stroke units that are designed for the
ENRICH-AF) to assess the effects of factor Xa treatment of ischemic stroke could also facilitate
inhibitors (e.g., apixaban) as compared with as- prehospital detection, triage, and management
pirin in patients with atrial fibrillation and in- of intracerebral hemorrhage, but further studies
tracerebral hemorrhage are currently enrolling are needed.48
participants. Observational and mendelian ran- Disclosure forms provided by the author are available with the
domization studies have shown a relationship full text of this article at NEJM.org.
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