ORIGINAL CONTRIBUTION

Management of Thrombolysis-Associated
Symptomatic Intracerebral Hemorrhage
Joshua N. Goldstein, MD, PhD; Marisela Marrero, MD; Shihab Masrur, MD; Muhammad Pervez, MD;
Alex M. Barrocas, MD; Abdul Abdullah, MD; Alexandra Oleinik, BS; Jonathan Rosand, MD, MS;
Eric E. Smith, MD, MPH; Walter H. Dzik, MD; Lee H. Schwamm, MD

Background: Symptomatic intracerebral hemorrhage agulopathy: 7 received fresh frozen plasma; 5, cryopre-
(sICH) is the most devastating complication of throm- cipitate; 4, phytonadione (vitamin K1); 3, platelets; and
bolytic therapy for acute stroke. It is not clear whether 1, aminocaproic acid. Independent predictors of in-
patients with sICH continue to bleed after diagnosis, nor hospital mortality included sICH (odds ratio, 32.6; 95%
has the most appropriate treatment been determined. confidence interval, 8.8-120.2), increasing National In-
stitutes of Health Stroke Scale score (1.2; 1.1-1.2), older
Methods: We performed a retrospective analysis of our age (1.3; 1.0-1.7), and intra-arterial thrombolysis (2.9;
prospectively collected Get With the Guidelines–Stroke da- 1.4-6.0). Treatment for coagulopathy was not associ-
tabase between April 1, 2003, and December 31, 2007. Ra- ated with outcome. Continued bleeding (⬎33% in-
diologic images and all procoagulant agents used were re- crease in intracerebral hemorrhage volume) occurred in
viewed. Multivariable logistic regression was performed to 4 of 10 patients with follow-up scans available (40.0%).
identify factors associated with in-hospital mortality.
Conclusions: In many patients with sICH after throm-
Results: Of 2362 patients with acute ischemic stroke bolysis, coagulopathy goes untreated. Our finding of con-
during the study period, sICH occurred in 19 of the 311 tinued bleeding after diagnosis in 40.0% of patients
patients (6.1%) who received intravenous tissue plas- suggests a powerful opportunity for intervention. A mul-
minogen activator and 2 of the 72 (2.8%) who received ticenter registry to analyze management of thrombolysis-
intra-arterial thrombolysis. In-hospital mortality was sig- associated intracerebral hemorrhage and outcomes is
nificantly higher in patients with sICH than in those with- warranted.
out (15 of 20 [75.0]% vs 56 of 332 [16.9%], P⬍ .001).
Eleven of 20 patients (55.0%) received therapy for co- Arch Neurol. 2010;67(8):965-969

A
CUTE ISCHEMIC STROKE orrhage (sICH).10 Although the overall ben-
causes substantial morbid- efits of tPA for stroke appear to outweigh
ity and is one of the lead- the risks,4,5,11 up to 7% of patients treated
ing causes of death world- for stroke will develop this complication.
wide.1 The only current The development of sICH is associated with
pharmacotherapy approved by the US worse outcome,12-14 and clinicians caring for
Food and Drug Administration is intra- these patients are faced with the difficult de-
venous recombinant tissue plasminogen cision of how best to treat them.
activator (tPA). Thrombolytic therapies There are no evidence-based guidelines
can also be delivered intra-arterially,2 and that address management of thrombolysis-
this method of therapy is commonly used associated sICH. This is likely because of the
Author Affiliations: off-label.3 Several clinical trials have found lack of published original research exam-
Departments of Emergency that thrombolytic therapy decreases mor- ining management. The American Heart As-
Medicine (Drs Goldstein and bidity and improves long-term out- sociation suggests empirical therapies to re-
Marrero), Neurology come.4-7 The American Heart Association place clotting factors and platelets but
(Drs Masrur, Pervez, Abdullah, has recommended that systems of care be acknowledges the lack of evidence to sup-
Rosand, and Schwamm and established to maximize the ability of all port any specific therapy.15 Even in the ab-
Ms Oleinik), and Hematology patients with stroke to receive the best sence of supporting evidence, some insti-
(Dr Dzik), Massachusetts available therapy, including thrombo- tutions (including ours) have developed care
General Hospital, Boston; lytic agents.8 In fact, it appears that the use pathways for thrombolysis-associated sICH
Department of Radiology,
of thrombolytic agents is increasing9 and for current use.16 At the moment, the most
Mount Sinai Medical Center,
Miami Beach, Florida may continue to increase because recent appropriate management of this complica-
(Dr Barrocas); and Calgary evidence suggests an expanded time win- tion is not clear.
Stroke Program, University dow for intravenous thrombolysis.4 To determine best practice, it is first nec-
of Calgary, Calgary, Alberta, The most feared complication of this essary to examine current practice and to
Canada (Dr Smith). therapy is symptomatic intracerebral hem- ascertain whether any specific factors or

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 Table 1. Characteristics of 352 Patients Who Received Table 2. Frequency of sICH Stratified by Therapy Received
a Thrombolytic Intervention
No. (%)
No sICH sICH
Characteristic (n=332) (n=20) P Value No. of Patients Frequency of sICH
Therapy (N = 352) (n = 20/352 [5.7%]) a
Age, median (IQR), y 74 (62-82) 80 (71-88) .06
Female sex, No. (%) 176 (53.0) 9 (45.0) .50 Any use of IV tPA 311 (88.4) 19/311 (6.1)
White race, No. (%) 306 (92.2) 18 (90.0) .67 Any use of IAT 70 (19.9) 2/70 (2.9)
Medical history, No. (%) Any mechanical device 76 (21.6) 4/76 (5.3)
Atrial fibrillation 92 (27.7) 7 (35.0) .45 IV tPA given 177 (50.3) 11/177 (6.2)
Diabetes mellitus 65 (19.6) 4 (20.0) ⬎.99 at outside hospital
Hypertension 221 (66.6) 14 (70.0) ⬎.99 IV but no IAT 282 (80.1) 18/282 (6.4)
Coronary artery disease 80 (24.1) 8 (40.0) .12 IAT but no IV 41 (11.6) 1/41 (2.4)
Smoker 58 (17.5) 1 (5.0) .22 Combined IV and IAT 29 (8.2) 1/29 (3.4)
Initial NIHSS score, median (IQR) 14 (9-20) 16 (9-20) .41
In-hospital mortality, No. (%) 55 (16.6) 15 (75.0) ⬍.001 Abbreviations: IAT, intra-arterial thrombolysis; IV, intravenous;
sICH, symptomatic intracerebral hemorrhage; tPA, tissue plasminogen
activator.
Abbreviations: IQR, interquartile range; NIHSS, National Institutes of a The frequency of sICH is shown as a proportion of patients receiving
Health Stroke Scale; sICH, symptomatic intracerebral hemorrhage. each therapy.

therapies are associated with outcome. We performed a ret-

tal uses a computerized order entry and laboratory reporting
rospective review of current sICH management to deter- system, and all computer and laboratory orders were retrieved
mine the frequency of ongoing bleeding and patterns of electronically and reviewed; nursing notes in the medical rec-
emergency therapy. ords were then reviewed to confirm interventions that the pa-
tients received. Radiology images were electronically trans-
METHODS ferred in Digital Imaging and Communications in Medicine
(DICOM) standard format to a dedicated workstation for analy-
sis with the use of commercial image-analysis software (Alice;
PATIENT SELECTION AND DATA COLLECTION PAREXEL International, Waltham, Massachusetts) and re-
viewed by study staff blinded to the patient’s clinical out-
We performed a retrospective analysis of a prospectively col- comes.19 For the purposes of this analysis, intracerebral hem-
lected cohort of consecutive patients with acute ischemic stroke orrhage volumes were measured as the sum total of all
presenting to a single urban tertiary care hospital between April intracranial blood, irrespective of type or location, by means
1, 2003, and December 31, 2007. Data from all patients at our of computerized planimetry.
institution who are diagnosed as having ischemic stroke are en-
tered into our local Get With the Guidelines—Stroke data-
base. The details of this database have been described in pre- DATA ANALYSIS
vious publications.17,18
Demographic data including medical history of atrial fibril- Continuous variables were analyzed with the Kruskal-Wallis
lation, diabetes mellitus, hypertension, and coronary artery dis- test because none demonstrated a normal distribution as de-
ease; laboratory values; initial National Institutes of Health Stroke termined by the Shapiro-Wilk test. Dichotomous variables were
Scale score (NIHSS); whether the patient presented primarily analyzed with the Fisher exact test. Multivariable analysis for
or was transferred in; any therapy (including intravenous tPA, the outcomes of sICH and in-hospital mortality was per-
intra-arterial thrombolysis [IAT], and mechanical thrombec- formed with a backward-selection logistic regression model, in-
tomy); any development of intracerebral hemorrhage (ICH); cluding variables associated (P⬍.20) in univariate analysis and
and in-hospital mortality were prospectively ascertained. Pa- then removing variables in a stepwise fashion for P⬎.10. Given
tients receiving thrombolytic therapy were treated in our neu- the small number of outcomes, no interaction terms were in-
rosciences intensive care unit for the first 24 hours. (Our stan- cluded. All analyses were performed in Stata software, version
dard protocols are available at http://www.stopstroke.org.) 10 (StataCorp, College Station, Texas).
Platelet function tests were not routinely performed. Clinical
course and radiographic images for all patients were reviewed RESULTS
by our hospital’s Acute Stroke Quality Task Force as part of a
required ongoing quality-assurance review (members of the task
force included J.N.G., S.M., M.P., A.A., E.E.S., and L.H.S.). Symp- During the study period, 2362 patients presented with
tomatic ICH was defined using National Institute of Neuro- acute ischemic stroke, of whom 352 (14.9%) received a
logical Disorders and Stroke (NINDS) criteria as the presence thrombolytic agent: intravenous tPA only (n=282), IAT
of intracranial blood in association with neurologic deteriora- only (n=41), or both (n=29). Of the 352 patients, sICH
tion5; although this definition may include patients for whom developed in 20 (5.7%). Their demographic and clinical
deterioration was not due to hemorrhage, it has a high inter- features are shown in Table 1.
rater reliability and is the most inclusive. The presence or ab- The risk of developing sICH in this cohort was strati-
sence of ICH and the clinical assessment of symptomatic wors-
fied by the intervention received, and the results are shown
ening by NINDS criteria were determined through consensus
review by this group of local experts. in Table 2. None of the interventions tested were signifi-
A separate retrospective review of electronic and hospital cantly associated with sICH in univariate analysis. Multi-
records was performed for all patients with sICH. Serial labo- variable analysis did not identify any independent predic-
ratory values, including coagulation measures, fibrinogen lev- tors of sICH. Multivariable analysis of in-hospital mortality
els, and all procoagulant therapies, were recorded. Our hospi- is shown in Table 3. The use of do-not-resuscitate or-

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 ders was not included in the model because it was so highly
covariate with death; all deaths but 1 were preceded by a Table 3. Multivariable Analysis of Predictors
do-not-resuscitate order, and only 1 patient had such an of In-Hospital Mortality
order but did not die in the hospital. (That patient was dis-
Variable OR (95% CI) P Value
charged to hospice care at home.)
We next examined how patients with sICH were sICH 32.6 (8.8-120.2) ⬍.001
treated. Table 4 shows the 20 patients with sICH and Any IAT 2.9 (1.4-6.0) .004
Age, per 10-y increase 1.3 (1.0-1.7) .02
their treatment. A fibrinogen level was measured in 14 NIHSS score, per unit increase 1.2 (1.1-1.2) ⬍.001
patients (mean [SD] level, 264 [86] mg/dL) (to convert
fibrinogen to micromoles per liter, multiply by 0.0294), Abbreviations: CI, confidence interval; IAT, intra-arterial thrombolysis;
and no patients had a level less than 100 mg/dL. D- NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio;
dimer was measured in 12 patients (mean level, 5.1 [2.7] sICH, symptomatic intracerebral hemorrhage.
µg/mL) (to convert to nanomoles per liter, multiply by
5.476). Eleven patients (55.0%) received some type of The choice of hemostatic therapy remains controver-
procoagulant therapy: 7 (35.0%) received fresh frozen sial. Thrombolytic agents convert plasminogen to plas-
plasma, 5 (25.0%) received cryoprecipitate, 4 (20.0%) re- min, which degrades fibrin at the site of thrombus forma-
ceived phytonadione (vitamin K1), 3 (15.0%) received tion.23 Antifibrinolytics such as aminocaproic acid (Amicar)
platelets, and 1 (5.0%) received aminocaproic acid. Five seem to be a logical antidote to fibrinolytic therapy and have
patients received more than 1 type of procoagulant been proposed as an aggressive measure for limiting intra-
therapy. No patient received recombinant factor VIIa. The cranial bleeding.24-27 Only 1 of our patients received this;
use of procoagulant therapy was not significantly asso- it is not specifically recommended in the American Heart
ciated with any patient characteristic or outcome. Association guidelines or our own internal guidelines be-
To evaluate the frequency of hematoma expansion or cause of the risk of inadvertent prothrombotic activity.15
further intracranial bleeding after diagnosis of sICH, se- In addition, if tPA induces systemic fibrinogenolysis,28 fi-
rial computed tomographic (CT) scans were evaluated brinogen replacement in the form of fresh frozen plasma
for total ICH volume (Figure). The initial ICH volume or cryoprecipitate would be a logical choice for patients with
was a mean (SD) of 65.3 (56.2) mL. Of 10 patients with low fibrinogen levels.29 However, we found no cases in
follow-up scans available for analysis (performed a me- which patients developed fibrinogen levels of less than 100
dian of 8.8 [IQR, 7-14] hours after the initial scan), 4 pa- mg/dL, suggesting that currently used tPA dosing regi-
tients (40.0%) had an increase in ICH volume of greater mens are unlikely to induce hypofibrinogenemia, and any
than 33% (Table 4). Of these patients, the mean (SD) per- benefit of such therapy may be limited. Because clot lysis
centage of change in ICH volume was 47% (12%). There releases D-dimers, which can exert an antiplatelet effect by
were too few events to statistically analyze any effect of binding to the platelet fibrinogen receptor, there is a theo-
hemostatic therapy on ICH expansion. retical basis for infusion of platelets as a rescue therapy.29
To our knowledge, this hypothesis has not yet been tested.
Finally, thrombolytic agents may affect a number of pro-
COMMENT
cesses independent of their effects on clot disruption,
including extracellular matrix degradation and cell signal-
To our knowledge, this is the first published analysis of ing.23 Interventions aimed at reversing these noncoagulo-
current therapies used for thrombolytic agent reversal fol- pathic effects may offer promising avenues of research.
lowing sICH. Overall, we found that different strategies It is also possible that no currently available interven-
were used in clinical practice to treat thrombolysis- tion provides benefit. Many of the therapies used in prac-
associated sICH. For many patients, no procoagulant tice or that are recommended by guidelines are not clearly
therapy was provided, whereas others received a single specific for reversal of fibrinolytic activity. Given the short
therapy or a combination of multiple therapies. Very few half-life of thrombolytic agents, by the time the diagno-
patients were treated the same way. This heterogeneity sis is made the biological effect of the drug may have
likely reflects the absence of evidence supporting any spe- abated. In addition, not all intracranial bleeding after
cific intervention. The low frequency of sICH probably stroke can be ascribed to tPA, and it may be that only a
contributes to this dearth of data. subset of those with sICH will benefit from procoagu-
Our finding that 40.0% of patients with follow-up CT lant therapy. Nevertheless, our finding that ongoing bleed-
scans showed evidence of ICH expansion and ongoing ing is common suggests that a therapeutic opportunity
bleeding suggests a potential window of opportunity for exists. Given the low frequency of sICH after thromboly-
therapy. Reducing early hematoma expansion after sICH sis, large multicenter prospective trials will be required
might improve clinical outcomes. A similar frequency of to determine which therapy can best arrest or prevent
hematoma expansion has been noted following sponta- ongoing bleeding.
neous, nonthrombolysis-associated ICH,20 and clinical Our analysis has several limitations. First, only a small
trials for this entity have demonstrated that hemostatic number of individuals developed sICH after thrombo-
therapy reduces the risk of hematoma expansion.21,22 Of lytic therapy. Second, the wide variation in therapy made
note, patients with any coagulopathy were excluded from it impossible to perform robust statistical analysis exam-
these trials. Patients who are coagulopathic because of ining the effect of any specific therapy. Similarly, the wide
receipt of a thrombolytic agent may be more likely to re- variation in workup performed limited our ability to ex-
ceive clinical benefit from hemostatic therapy. amine whether laboratory values such as D-dimer or fi-

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 Table 4. Clinical Management of sICH

Laboratory Values
Patient ICH Volume, Change
Age, y/Sex Intervention D-Dimer, µg/mL Fibrinogen, mg/dL Therapy mL in Volume, % Outcome
89/M IV 8.6 417 Phytonadione a 31.3 36.9 Death
88/M IV NM NM None 153.8 ND Death
80/F IV NM NM None 105.8 ND Death
56/M IV 6.6 288 None 15.7 64.1 Death
78/M IAT NM 286 FFP b 140.3 1.4 Death
91/M IV 2.8 132 None 103.6 ND Death
77/M IV NM 377 Cryo 81.1 ND Rehab
53/M IV 3.0 249 FFP, cryo, and platelets 9.0 −1.0 Rehab
71/M IV 7.3 291 FFP, cryo, and platelets 53.7 39.7 Death
92/F IV NM NM Phytonadione a 9.3 6.3 Death
72/M IV 4.5 284 FFP and phytonadione a,b 43.7 ND Death
86/M IV NM 194 None 8.8 ND Death
89/F IV 2.8 301 Cryo 9.8 45.7 Death
75/F IV 8.2 282 FFP, cryo, aminocaproic 131.6 ND Death
acid, and platelets
81/F IV 8.6 315 None 169.0 6.8 Death
79/F IV NM NM None b 9.5 ND Rehab
84/F IV 5.2 164 None 41.1 −2.4 Home
89/F IV ⫹IAT NM NM FFP and phytonadione a 132.4 ND Death
24/F IV 1.7 None 8.8 −1.1 Death
58/M IV 1.7 115 FFP b 49.3 ND Rehab

Abbreviations: cryo, cryoprecipitate; FFP, fresh frozen plasma; IAT, intra-arterial thrombolysis; ICH, intracerebral hemorrhage; IV, intravenous thrombolysis;
ND, follow-up computed tomography not done; NM, not measured; Rehab, rehabilitation; sICH, symptomatic ICH.
SI conversion factors: To convert D-dimer to nanomoles per liter, multiply by 5.476; fibrinogen to micromoles per liter, multiply by 0.0294.
a Vitamin K .
1
b These patients were receiving warfarin sodium before their stroke but were still considered candidates for thrombolysis depending on the initial international
normalized ratio as per institutional protocol.

A B C

Figure. Ongoing bleeding after diagnosis in a patient with thrombolysis-associated symptomatic intracerebral hemorrhage. A, A 56-year-old man with acute
left-sided weakness and dysarthria underwent computed tomography (CT) 1.5 hours after symptom onset and received intravenous tissue plasminogen activator
35 minutes later. B, Follow-up CT 11 hours later showed hemorrhagic conversion of a large right frontoparietal ischemic infarct, along with small foci of
subarachnoid hemorrhage along the right cerebral convexity. C, Follow-up CT 8 hours later showed increased hemorrhage with increasing edema and mass effect.

brinogen level could predict development of sICH or hem- low-up studies were not obtained. As a result, our esti-
orrhage expansion following sICH. Third, our single- mates of the frequency of hematoma expansion were based
center experience may not reflect practice at other on a small sample and may be biased. Future studies in
institutions nationwide. Fourth, measurement of hema- which follow-up CT is systematically performed would
toma volume was difficult owing to the variation in types provide more accurate estimates. Finally, we were not
of hemorrhage and the frequent use of contrast me- able to systematically obtain long-term outcome infor-
dium, which can mimic blood, for CT-angiography and mation on patients in this cohort, limiting our outcome
interventional procedures. Fifth, not all patients re- evaluation to the time of hospital discharge.
ceived follow-up CT, and the timing of follow-up CT was In conclusion, we found that for many patients with
not standardized; this could reflect withdrawal of care sICH after thrombolysis, no acute reversal of coagulop-
or patients whose clinical course was so benign that fol- athy is attempted. Even among those treated, no particu-

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 lar therapy is associated with improved survival. The find- mittee. Guidelines for management of ischaemic stroke and transient ischaemic
attack 2008. Cerebrovasc Dis. 2008;25(5):457-507.
ing that continued bleeding occurs after diagnosis suggests
8. Schwamm LH, Pancioli A, Acker JE III, et al; American Stroke Association’s Task
an opportunity for intervention; it remains to be deter- Force on the Development of Stroke Systems. Recommendations for the estab-
mined whether any currently available therapy can meet lishment of stroke systems of care: recommendations from the American Stroke
this need or whether novel treatments should be devel- Association’s Task Force on the Development of Stroke Systems. Stroke. 2005;
oped. As a next step, a multicenter registry of current man- 36(3):690-703.
9. Kleindorfer D, Lindsell CJ, Brass L, Koroshetz W, Broderick JP. National US es-
agement of thrombolysis-associated ICH and outcomes
timates of recombinant tissue plasminogen activator use: ICD-9 codes substan-
appears warranted. tially underestimate. Stroke. 2008;39(3):924-928.
10. Brown DL, Barsan WG, Lisabeth LD, Gallery ME, Morgenstern LB. Survey of emer-
Accepted for Publication: December 21, 2009. gency physicians about recombinant tissue plasminogen activator for acute is-
Correspondence: Joshua N. Goldstein, MD, PhD, De- chemic stroke. Ann Emerg Med. 2005;46(1):56-60.
partment of Emergency Medicine, Massachusetts Gen- 11. Wahlgren N, Ahmed N, Davalos A, et al; SITS investigators. Thrombolysis with
alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study.
eral Hospital, Zero Emerson Place, Ste 3B, Boston, MA Lancet. 2008;372(9646):1303-1309.
02114 ([email protected]). 12. Berger C, Fiorelli M, Steiner T, et al. Hemorrhagic transformation of ischemic
Author Contributions: Study concept and design: Gold- brain tissue: asymptomatic or symptomatic? Stroke. 2001;32(6):1330-1335.
stein, Marrero, Rosand, and Schwamm. Acquisition of data: 13. Libman R, Kwiakowski T, Lyden P, et al; NINDS rt-PA Stroke Study Group.
Goldstein, Marrero, Masrur, Pervez, Barrocas, Abdul- Asymptomatic hemorrhagic transformation of cerebral infarction does not worsen
long-term outcome. J Stroke Cerebrovasc Dis. 2005;14(2):50-54.
lah, Rosand, Smith, and Schwamm. Analysis and inter- 14. Sloan MA, Sila CA, Mahaffey KW, et al. Prediction of 30-day mortality among
pretation of data: Goldstein, Oleinik, Barrocas, Smith, Dzik, patients with thrombolysis-related intracranial hemorrhage. Circulation. 1998;
and Schwamm. Drafting of the manuscript: Goldstein, Mar- 98(14):1376-1382.
rero, Barrocas, Rosand, and Dzik. Critical revision of the 15. Broderick J, Connolly S, Feldmann E, et al; American Heart Association; Ameri-
manuscript for important intellectual content: Goldstein, can Stroke Association Stroke Council; High Blood Pressure Research Council;
Quality of Care and Outcomes in Research Interdisciplinary Working Group.
Marrero, Masrur, Pervez, Barrocas, Abdullah, Oleinik, Guidelines for the management of spontaneous intracerebral hemorrhage in adults:
Smith, and Schwamm. Statistical analysis: Goldstein and 2007 update: a guideline from the American Heart Association/American Stroke
Barrocas, . Obtained funding: Rosand. Administrative, tech- Association Stroke Council, High Blood Pressure Research Council, and the Qual-
nical, and material support: Marrero, Masrur, Pervez, and ity of Care and Outcomes in Research Interdisciplinary Working Group. Stroke.
Oleinik. Study supervision: Goldstein, Pervez, Barrocas, 2007;38(6):2001-2023.
16. Rasler F. Emergency treatment of hemorrhagic complications of thrombolysis
Rosand, Dzik, and Schwamm. [letter]. Ann Emerg Med. 2007;50(4):485.
Financial Disclosure: Dr Goldstein reported receiving 17. Reeves MJ, Smith E, Fonarow G, Hernandez A, Pan W, Schwamm LH; GWTG-
consulting fees from CSL Behring and Genentech Inc. Stroke Steering Committee & Investigators. Off-hour admission and in-hospital
Funding/Support: This study was funded in part by K23 stroke case fatality in the Get With the Guidelines—Stroke program. Stroke. 2009;
career development award NS059774 from the NINDS 40(2):569-576.
18. Schwamm LH, Fonarow GC, Reeves MJ, et al. Get With the Guidelines-Stroke is
(Dr Goldstein). associated with sustained improvement in care for patients hospitalized with acute
stroke or transient ischemic attack. Circulation. 2009;119(1):107-115.
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