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Figure 2 The ED algorithm for early diagnosis and emergent intervention. ICH, intracerebral haemorrhage.
intracranial pressure (ICP). Oral antihypertensive agents 3-factor products currently available in the USA are
need to be started as soon as possible to control resistant Prolnine SD (Grifols Biologicals, Los Angeles,
HTN and facilitate the transition of care from ICU to California, USA) and Bebulin VH (Baxter Healthcare
long-term management. Arterial line placement is Corporation, Westlake Village, California, USA). Kcentra
recommended to optimise blood pressure monitoring (Beriplex outside the USA) is the rst 4-factor PCC indi-
and medication titration. The guidelines for resistant cated for warfarin reversal in adults during acute major
HTN recommend angiotensin converting enzyme inhibi- bleeding or a need for urgent surgery.
tors (ACE-I) or angiotensin receptor blockers (ARB), PCC is preferred over FFP due to more rapid correc-
calcium channel blocker (CCB) and a thiazide-like diur- tion of INR, lower volume and risk of infection, pulmon-
etic at maximal tolerated doses as an optimal triplets ary oedema, Transfusion-Related Acute Lung Injury
formula.32 The CCB and ACE-I or ARB are widely (TRALI) and Transfusion Associated Cardiac Overload
accepted as the rst-line and second-line drugs for resist- (TACO). If repeat INR 1560 min after PCC administra-
ant patients, but the choice of the third-line and fourth- tion shows continued INR elevation above 1.4, consider
line antihypertensive agents varies greatly in real-world further correction with 24 units FFP. Recombinant
practice. Thiazide may cause hyponatraemia and worsen Factor VIIa (rFVIIa) has been associated with relatively
cerebral oedema in patients with large haemorrhage or high thrombosis rates and should only be considered in
mass effect. It should be used with caution. In a recent patients who will not accept blood products (eg,
randomised trial, spironolactone was shown to be very Jehovahs witness).
effective for patients with resistant HTN.33 Direct thrombin inhibitors (DTIs; eg, dabigatran, arga-
Spironolactone and -/-antagonists can be used as the troban and bivalirudin) have signicantly less risk of
third and fourth agents to maintain BP control while ICH than vitamin K antagonists. However, haemorrhages
weaning off intravenous agents. During acute phase, do occur and reversal of coagulopathy is indicated if
patients may have resistant HTN due to sympathetic patient presents within 35 half-lives of drug exposure
surge. A few weeks later, they may require fewer medica- (or beyond in patient with renal insufciency).
tions and be at risk of hypotension unless the doses of Idarucizumab (5 g intravenous divided into two doses),
medications are adjusted promptly.16 a specic neutralising monoclonal antibody fragment
for dabigatran, is recommended in cases of haemor-
rhage associated with dabigatran.36 If idarucizumab is
REVERSAL OF COAGULOPATHIES not available, or if the haemorrhage is associated with a
Coagulopathy, whether medication-induced or due to a DTI other than dabigatran, 4-factor PCC (50 units/kg)
systemic disease process, is associated with haematoma or activated PCC (50 units/kg) is recommended.
expansion, and increased risk of poor outcome and Haemodialysis can also be considered in patients with
death.34 Approximately 1220% of patients presenting dabigatran-associated ICH and renal insufciency, espe-
with ICH are taking oral anticoagulants. Though acute cially if continued haemorrhage despite rst-line
reversal of coagulopathy has not been clearly shown to therapies.
be benecial in large randomised trials, rapid correction For patients taking Factor Xa inhibitors (eg, rivaroxa-
of coagulopathy should be considered in any potentially ban, apixaban and edoxaban), 4-factor PCC (50 units/
salvageable patient. kg) or activated PCC (50 units/kg) is recommended if
In December 2015, the Neurocritical Care Society the haemorrhage occurred within 35 half-lives of drug
together with the Society of Critical Care Medicine pub- exposure (or in context of liver failure). If presenting
lished guidelines for the reversal of antithrombotic within 2 hours of drug exposure, activated charcoal can
agents in patients with ICH.35 Whenever ICH is diag- be administrated to prevent further drug absorption.
nosed, any antithrombotic agent should be immediately Laboratory testing is unlikely to be helpful in guiding
discontinued. The method of reversal will depend on treatment for these patients; therefore, reversal should
the agent used. be guided by bleeding (major or intracranial) instead.
For all patients taking vitamin K antagonists (eg, war- Andexanet alfa is a recombinant modied factor Xa that
farin), vitamin K 10 mg and 3-factor or 4-factor pro- can bind and reverse oral and parenteral factor Xa inhi-
thrombin complex concentrates (PCCs) should be bitors, including rivaroxaban, apixaban and edoxaban,
administered intravenously for patients with INR 1.4. and low-molecular-weight heparin.37 It has not been
PCC is an inactivated concentrate of factors II, IX and approved by the FDA for clinical use.
X, with variable amounts of factor VII. Variation in The guidelines for reversing warfarin and novel oral
factor VII concentrations in PCC has led to their classi- anticoagulants (NOAC) coagulopathies in patients with
cation as either 3- or 4-factor. Unlike serum-containing symptomatic ICH are shown in gure 3.
products such as fresh frozen plasma (FFP), PCCs are Reversal of unfractionated heparin is recommended
lyophilised and can be reconstituted quickly for timely for patients who develop ICH while on heparin infusion.
administration. In addition, the concentration of vitamin Reversal of prophylactic subcutaneous heparin should
K-dependent clotting factors is 25 times higher than only be considered if activated partial thormboplastin
plasma and can reverse coagulopathy quickly. The two time (aPTT) is signicantly prolonged in setting of new
Figure 3 The guidelines for reversing warfarin and NOAC coagulopathies in patients with symptomatic ICH. ICH, intracerebral
haemorrhage.
haemorrhage. Intravenous protamine (1 mg per every platelet function testing, haemorrhage volume or neuro-
100 units of heparin given in past 23 hours, maximum logical examination. In a multicentre, open-label rando-
50 mg) should be utilised and repeated at half of the mised trial at 60 hospitals in the Netherlands, UK and
initial dose if repeat aPTT remains elevated. France, 190 patients with ICH on antiplatelet therapy
Reversal of low-molecular-weight heparin (low molecular for at least 7 days prior to ICH were randomly assigned
weight heparin (LMWH); eg, enoxaparin, dalteparin, to platelet transfusion and standard care. Platelet trans-
nadroparin and tinzaparin) is also recommended only if fusion seems inferior to standard care for patients taking
receiving therapeutic doses, rather than prophylactic doses. antiplatelet therapy before ICH.38
For enoxaparin administered within past 8 hours, 1 mg of Platelet transfusion should be considered for patients
protamine per every 1 mg of enoxaparin should be admi- with aspirin- or adenosine diphosphate receptor (ADP)
nistered. If enoxaparin given 812 hours, 0.5 mg of protam- inhibitor-associated ICH who will undergo a neurosurgi-
ine per every 1 mg of enoxaparin should be administered. cal procedure. Platelet function testing prior to platelet
For the reversal of dalteparin, nadroparin and tinzaparin, transfusion should be performed if possible and timely
dose 1 mg per every 100 anti-Xa units of LMWH, up to results available. If platelet function is within normal
maximum 50 mg. This can be repeated at half of the initial limits or patient has documented antiplatelet resistance,
dose if continued bleeding or patient has renal insuf- platelet transfusion should be avoided. Platelet transfu-
ciency. rFVIIa is generally not recommended, but can be sion is not recommended for non-steroidal anti-inam-
considered if protamine contraindicated. matory drugs (NSAIDs) or glycoprotein (GP) IIb/IIA
Heparinoids (eg, danaparoid) are not available in the inhibitor-related ICH. Desmopressin (ddAVP) (0.4 g/
USA, but are used in other countries. In ex vivo studies, kg intravenous once) can be considered in ICH asso-
danaparoid was not reversed with protamine, PCC, ciated with cyclooxygenase (COX) inhibitors or ADP
aPCC or FFP; therefore, these agents are not recom- receptor inhibitors.35
mended for reversal in patients with ICH. rFVIIa
(90 g/kg intravenous once) has shown some efcacy Management of intraventricular haemorrhage and
and therefore is recommended instead. hydrocephalus
For thrombolytic (eg, recombinant tissue plasminogen Intraventricular haemorrhage (IVH) occurs in up to
activator (rtPA)) reversal, 10 units of cryoprecipitate may 45% of patients with ICH. It is associated with lower
be considered. If the level of brinogen is <150 mg/dL GCS and an independent predictor of poor outcome.39
post cryoprecipitate use, consider additional cryoprecipi- External ventricular drain (EVD) placement should be
tate administration. If cryoprecipitate is contraindicated considered in any patient with GCS 8, signicant IVH,
or unavailable, an antibrinolytic agent (tranexamic hydrocephalus or evidence of transtentorial hernia-
acid 1015 mg/kg intravenous or -aminocaproic acid tion.20 Elevated ICP (>20 mm Hg) should be treated
45 g intravenous) can be considered. with hyperosmolar therapy (HTS and/or mannitol),
For patients taking antiplatelet agents (eg, aspirin, clo- cerebrospinal uid drainage or sedation, though none
pidogrel and abciximab), platelet transfusion is not of these therapies has been shown to improve
recommended routinely, regardless of antiplatelet agent, outcomes.12
Apart from clotting the cerebral aqueduct leading to treatment and may lead to upward herniation and
obstructive hydrocephalus, intraventricular blood and its further neurological decline.12 27 Select patients with
breakdown products cause inammation of the epen- large lobar ICH or temporal lobe haemorrhage may also
dymal layer and subependymal brain tissue. In addition, benet from emergent haematoma evacuation.
the clot also causes inammation and brosis of the
arachnoid granulations, leading to delayed communicat-
MANAGEMENT OF PERIHAEMATOMA OEDEMA
ing hydrocephalus. Intraventricular brinolysis with rtPA
Perihaematomal oedema (PHE) develops within the
was an emerging therapy for clearing IVH as soon as
rst few days after ICH and may cause elevated ICP,
possible. It was shown to clear IVH without increasing
mass effect, midline shift and brain herniation.48 49 50
perihaemorrhagic oedema.40 Recently, a large, phase III,
The degree and growth of PHE are strongly related to
multicentre, randomised, placebo controlled clinical
the size of haematoma.48 Data from several clinical trials
trial evaluating the use of intraventricular tPA adminis-
indicate that the absolute increase in PHE during the
tration in patients with IVH has completed enrolment.
rst 2472 hours was associated with worse functional
The preliminary results of the Clot Lysis: Evaluating
outcomes at 90 days after ICH.49 50
Accelerated Resolution of Intraventricular Hemorrhage
Patients with asymptomatic PHE require no specic treat-
III (CLEAR III) trial showed no outcome benet.
ment except maintaining a normal sodium goal. There is
Subgroup analysis showed reduced mortality in patients
no indication for routine use of osmotic agents, such as
with large IVH (2016 International Stroke Conference
mannitol or HTS, in most patients with small ICH.
Press Release18 February 2016).
However, mannitol and HTS are the rst-line medical
therapies for patients with symptomatic cerebral oedema
and elevated ICP. Mannitol is an osmotic diuretic. It
SURGICAL INTERVENTION
increases water excretion by the kidneys and reduces
The International Surgical Trial in Intracerebral
cerebral oedema and ICP. HTS increases plasma osmo-
Hemorrhage (ISTICH) and the subsequent STICH II
larity and the ow of excess water from cerebral tissue to
demonstrated no benet for early haematoma evacu-
the blood via the osmotic gradient.
ation in patients with supratentorial ICH.41 42 Subgroup
In a small retrospective study, treatment with 23.4% of
analysis shows a small survival benet in patients with
HTS was associated with rapid reversal of transtentorial
supercial lobar haemorrhages without signicant
herniation and reduced ICP.51 Early continuous infusion
improvement in functional outcomes.
of 3% of HTS for sodium goal of 145155 mmol/L was
Utilisation of minimally invasive techniques for clot
associated with less cerebral oedema and ICP crisis
evacuation, however, may be promising.43 In a clinical
(>20 mm Hg for > 20 min or new anisocoria) than his-
trial performed in China a decade ago, 377 patients
torical control (n=64).52 A meta-analysis performed in
with basal ganglia ICH were randomised to treatment
2011 showed that HTS is slightly more effective than
with minimally invasive craniopuncture and needle
mannitol for the treatment of elevated ICP.53 A recent
aspiration versus conservative treatment.44 The study
analysis of the INTERACT2 data showed that mannitol
showed a signicant improvement in neurological func-
seems safe, but might not improve outcome in patients
tion at 2 weeks and 3 months without mortality benet.
with acute ICH.54
The Minimally-Invasive Surgery plus rtPA for
In real-world practice, the patients medical history
Intracerebral Hemorrhage Evacuation (MISTIE) phase
and the side effect proles of mannitol and HTS may be
II trial evaluated the utilisation of stereotactic clot cath-
the major factors for choosing an osmotic agent for an
eterisation and intermittent dosing of rtPA to facilitate
individual patient. For example, patients with congestive
clot breakdown and aspiration.45 It showed a trend
heart failure should receive a bolus of mannitol or
towards improved outcomes in the surgical patients com-
23.4% of HTS, whereas continuous infusion of 3% of
pared with the medically managed patients. The
HTS can be used for patients with dehydration or
ongoing MISTIE III trial has added a Stereotactic
decreased urine output.
CT-guided Endoscopic Surgery arm. Preliminary data
Of note, Minimally Invasive Surgery Plus tPA for ICH
showed that the newer trans-sylvian, transinsular
Evacuation (MISTIE) II study revealed signicant associ-
minimal invasive approaches may yield better results due
ation of haematoma removal and oedema reduction in
to relative sparing of cortical function.46 47 Randomised
the surgical group.45 Additional study is warranted to
controlled studies are required to evaluate their clinical
show the effect on outcomes.
benet.
Unlike supratentorial ICH, cerebellar ICH is consid-
ered a neurosurgical emergency and evacuation is SEIZURE PROPHYLAXIS AND TREATMENT
recommended per current guidelines given the high Patient with ICH have up to 16% risk of clinical seizures
morbidity from rapid development of brainstem com- within 1 week, with majority occurring at or near
pression.20 Surgical indications include haematoma size onset.55 56 Lobar ICH with cortical involvement is the
>3 cm in diameter, brainstem compression or hydro- most important risk factor.57 Prospective and population-
cephalus. EVD placement alone is not sufcient based studies have shown no association between clinical
seizures and neurological outcome or mortality.58 59 Patients with DVT or PE should be considered for sys-
Between 28% and 31% of patients will have electro- temic anticoagulation depending on stability of the haema-
graphic seizures on continuous electroencephalographic toma, cause of haemorrhage and time since presentation.
monitoring.58 The clinical impact of subclinical seizures If systemic anticoagulation is contraindicated, inferior vena
is unclear. Prophylactic phenytoin usage has been asso- cava lter placement should be considered.20 71
ciated with worse outcomes in several studies.59 60
Continuous EEG monitoring should be considered for
PROGNOSIS
patients with ICH with depressed mental status out of
ICH is the most debilitating and deadly type of stroke. A
proportion to the degree of brain injury. Clinical sei-
number of factors may affect outcome after ICH, includ-
zures should be treated with antiepileptic medications,
ing haematoma volume and location, haematoma
as should electrographic seizures accompanied by
expansion, age, GCS score on presentation, intraventri-
changes in mental status.20
cular extension and anticoagulant use. The ICH score
was developed to predict 30-day mortality rate and func-
GLUCOSE MANAGEMENT tional outcomes at 1 year.72 73 Most patients die from
Hyperglycaemia on admission is associated with worse ICH within the initial hospitalisation due to presumed
morbidity and mortality independent of the presence of poor outcome leading to withdrawal of care.74 None of
diabetes.61 However, tight glucose control with target the existing prediction models, including the ICH score,
glucose 80110 mg/dL increases hypoglycaemia and the is proven reliable. Several studies have shown that with-
risk of morbidity and mortality.62 Care should be taken drawal of support and early care limitations, such as do-
to avoid hyperglycaemia and hypoglycaemia.20 It is rea- not-resuscitate (DNR) orders, within the rst day of hos-
sonable to target glucose level at 100150 mg/dL for pitalisation are an independent predictor of poor
patients with ICH. outcome.7376 This raises concerns for self-fullling
prophecies. Of note, ICH mortality rate in China was
much lower than that in the USA,77 likely due to fewer
FEVER CONTROL withdrawal of life support.
Fever is common after ICH, particularly in patients with The current AHA/ASA guidelines recommend early
intraventricular extension. Sustained fever after ICH is and aggressive care after ICH and postponement of any
an independent prognostic factor for worse outcome.63 new DNR orders until at least the second full day of
However, neither therapeutic hypothermia nor nor- treatment. Patients with pre-existing DNR orders are
mothermia was shown to improve outcome.64 65 In a excluded from this recommendation. However, DNR
retrospective casecontrol study of patients with spontan- status should not limit appropriate medical and surgical
eous ICH having two consecutive fevers 38.3C despite interventions, unless explicitly indicated.20
acetaminophen administration, therapeutic normother-
mia was shown to be associated with increased duration
of sedation, mechanical ventilation and Neuro-ICU CONCLUSIONS
length of stay without discharge outcome benet.65 ICH is a medical emergency with high risk of morbidity
Normothermia or hypothermia should not be used after and mortality. Recent advances in early diagnosis and
ICH except in the setting of clinical trials. neurocritical care have contributed to improved survival.
Continued research into prevention and effective
therapy is pivotal in reducing disease burden and
DEEP VEIN THROMBOSIS PROPHYLAXIS AND TREATMENT improving functional recovery.
There is a signicant risk of venous thromboembolism
Contributors CKD is involved in drafting the work. WY is responsible revising
(VTE) in patients with ICH, with the rate of symptom-
the manuscript critically for important intellectual content.
atic deep vein thrombosis (DVT) at 15%.6670 The inci-
dence of symptomatic pulmonary embolism (PE) is Competing interests None declared.
0.52%.6870 Up to half of the PE are fatal. It is there- Provenance and peer review Commissioned; internally peer reviewed.
fore essential to prevent VTE. Data sharing statement No additional data are available.
Guidelines published by the Neurocritical Care
Open Access This is an Open Access article distributed in accordance with
Society in December 2015 recommend the initiation of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
mechanical VTE prophylaxis, preferably with intermit- which permits others to distribute, remix, adapt, build upon this work non-
tent pneumatic compression (IPC) devices at the time commercially, and license their derivative works on different terms, provided
of admission.20 71 If IPC devices are unavailable, gradu- the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/4.0/
ated compression stockings (GCS) can be utilised.
Prophylactic doses of subcutaneous unfractionated
heparin or LMWH should be started in patients with REFERENCES
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