Thrombolysis for Ischemic Stroke in Children

Data From the Nationwide Inpatient Sample

Nazli Janjua, MD; Abu Nasar, MS; John K. Lynch, DO, MPH; Adnan I. Qureshi, MD

Background and Purpose—Few pediatric reports of thrombolysis exist. We sought to determine national rates of
thrombolysis among pediatric ischemic stroke patients using a national database.
Methods—Patients between the ages of 1 and 17 years, entered in the Nationwide Inpatient Sample between 2000 and
2003, with International Classification of Diseases codes for ischemic stroke were included in the study. Differences in
mean age, gender distribution, ethnicity, secondary diagnoses, medical complications, associated procedure rates, modes
of discharge, and hospital costs between pediatric stroke patients receiving and not receiving thrombolysis were
estimated.
Results—In the United States, between 2000 and 2003 an estimated 2904 children were admitted with ischemic stroke, of
which 46 children (1.6%) received thrombolytic therapy. Children who received thrombolysis were on the average older
(11 versus 9 years), more likely to be male (100% versus 53.8%), with significantly higher hospital costs ($81 800
versus $38 700). These children were also less likely to be discharged home with higher rates of death and dependency,
although differences in clinical severity between the 2 groups was not known.
Conclusion—Thrombolysis, though not indicated for patients ⬍18 years of age, is currently being administered to children,
with unclear benefit. Larger studies are needed to evaluate the safety and efficacy of this treatment for children. (Stroke.
2007;38:1850-1854.)
Key Words: ischemic 䡲 pediatric 䡲 stroke 䡲 thrombolysis

I schemic stroke in children between the ages of 30 days and

18 years occurs at a rate of 2 to 3/100 000.1,2 Though this
(HCUP), a Federal-State-Industry partnership sponsored by the
Agency for Healthcare Research and Quality (AHRQ), which ob-
Downloaded from http://ahajournals.org by on August 8, 2022

rate is much lower than that seen in the adult population, the
sequelae are significant.2 At present, there is minimal epide-
miological evidence to guide the treatment of ischemic stroke
in the pediatric population. Most acute intervention studies of
stroke have excluded children, and treatment decisions are
typically based on adult studies, animal studies, or nonran-
domized trials. Thrombolytic therapies have been shown to
be safe and effective in adults, but there is no data in the
population below 18 years of age. There are several reports of
intravenous and intra-arterial thrombolysis among chil-
dren,3–11 but national estimates are unknown. We sought to
determine rates of thrombolysis for pediatric ischemic stroke
as well as associated demographic and clinical data, and
compare these between children who did and did not receive
thrombolysis in a national government sponsored database.
Materials and Methods
Nationwide Inpatient Sample
Data were obtained from the Nationwide Inpatient Sample (NIS),
developed as part of the Healthcare Cost and Utilization Project
tains information from 995 hospitals (7 to 8 million admissions)
annually from the HCUP State Inpatient Database (SID), providing
a 20% stratified sample of acute care community hospitals.12 Because
of hospital reporting differences across geographical regions in the
United States, the NIS sampling frame contains 97.6% of the population
in the Northeast, 89.6% in the Midwest, 83.7% in the West, and 81.2%
in the South. Overall, the NIS sampling frame comprises 73.8% of all
United States hospitals and covers 86.8% of the United States popula-
tion. Inpatient records in the NIS include clinical and resource use
information available from discharge abstracts. To allow extrapolation
for national estimates, both hospital and discharge weights are provided.
Detailed information on the design of the NIS is available at http://
www.hcup-us.ahrq.gov. The NIS includes ⬎100 clinical and nonclini-
cal variables for each hospital stay. These include primary and second-
ary diagnoses, primary and secondary procedures, admission and
discharge status, patient demographics (eg, gender, age, and race), total
charges, and lengths of stay.
Patient Selection and Variables Collected
Patients between the ages of 1 and 17 years, registered in the NIS from
the years 2000 to 2003, were included in the analysis. Those with
ischemic stroke were identified using the first listed International
Classification of Disease, 9th Revision clinical modifier (ICD-9 CM)
codes 433, 434, 436, 437.0, 437.1, 437.4, 437.5, 437.7, 437.8, and

Received September 29, 2006; final revision received November 14, 2006; accepted November 17, 2006.
From the Long Island College Hospital, Department of Neurology, and State University of New York Health Sciences Center, Downstate Campus,
Brooklyn, NY (N.J.); the Zeenat Qureshi Stroke Research Center (A.I.Q.), University of Minnesota, Minneapolis, Minn; Columbia University Medical
Center (A.N.), Department of Surgery, New York, NY; and the National Institutes of Neurological Disorders and Stroke, Office of Minority Health and
Research, National Institutes of Health, Bethesda, Md (J.K.L.)
Correspondence to Dr Nazli Janjua, Long Island College Hospital, Department of Neurology, 339 Hicks St, Brooklyn, NY 11201. E-mail
NJanjua@chpnet.org
© 2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/STROKEAHA.106.473983

1850
 Janjua et al Thrombolysis for Stroke in Children 1851

TABLE 1. Demographic and Clinical Characteristics

Patients Who Did Not
Total Pediatric Stroke Patients Who Received Receive Thrombolysis
Patients (n⫽2904) Thrombolysis (n⫽46) (n⫽2858) P Value
Demographics
Age (years⫾SD) 9.4⫾5.2 11.1⫾4.1 9.4⫾5.2 P⫽0.22
Gender
Male 1584 (54.5%) 46 (100.0%) 1538 (53.8%) Pⴝ0.00
Female 1320 (45.5%) 0 (0.0%) 1320 (46.2%)
Race/ethnicity
White 1136 (39.2%) 26 (56.5%) 1110 (39.0%) P⫽0.32
Black 524 (18.0%) ⬍10 (10.9%) 519 (18.2%) P⫽0.46
Other/not stated 1244 (42.8%) 15 (32.6%) 1229 (43.0%) P⫽0.54
Medical comorbidities/complications
Moyamoya disease 97 (3.3%) 0 (0.0%) 97 (3.4%) Pⴝ0.01
Sickle cell disease 182 (6.3%) 0 (0.0%) 182 (6.4%) Pⴝ0.01
Cardiac valvular disease ⱕ10 (0.3%) 0 (0.0%) ⬍10 (0.3%) P⫽0.20
Mechanical valves 0 (0.0%) 0 (0.0%) 0 (0.0%) P⫽1.00
Procoaguable conditions ⬍10 (0.1%) 0 (0.0%) ⬍10 (0.1%) P⫽0.34
Intracranial hemorrhage 23 (0.8%) 0 (0.0%) 23(0.8%) P⫽0.07
Myocardial infarction ⬍10 (0.2%) 0 (0.0%) ⬍10 (0.2%) P⫽0.34
Pneumonia 50 (1.7%) ⬍10 (10.9%) 45 (1.6%) P⫽0.39
Urinary tract infection 89 (3.1%) 0 (0.0%) 89 (3.1%) Pⴝ0.01
Sepsis 0 (0.0%) 0 (0.0%) 0 (0.0%) P⫽1.00
Pulmonary embolism 0 (0.0%) 0 (0.0%) 0 (0.0%) P⫽1.00
Deep venous thrombosis ⬍10 (0.7%) ⬍10 (10.9%) 15 (0.5%) P⫽0.34
Procedures
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Mechanical ventilation 210 (7.2%) 20 (43.5%) 190 (6.6%) P⫽0.08

Cerebral angiography 817 (28.1%) 24 (52.2%) 793 (27.7%) P⫽0.15
Mode of thrombolysis
IV 22 (⬍1%) 24 (52.2%) N/A
IA 19 (⬍1%) 19 (41.3%) N/A
IV indicates intravenous; IA, intraarterial.
Bold indicates statistically significant comparison.

437.9. The ICD-9 CM procedure code 99.10 was then applied to
identify the subpopulation receiving thrombolysis. Age, gender, race,
ethnicity, and associated diagnoses (including cardiac, arteriopathic, and
hematological), complications, procedures, discharge status, and hospi-
talization costs were determined for all cases. No variables for stroke
severity at baseline were available in the NIS dataset.
Statistical Analysis
Comparisons were made between children who received
thrombolytic therapy and those who did not. ␹2 tests and Student t
tests were performed to compare differences in the weighted vari-
ables between these 2 groups of children, assuming statistical signif-
icance at P⬍0.05. For calculation of average hospital costs, the mean
yearly charges for each group were adjusted for the inflation rate in 2005
using an internet tool available at http://www.westegg.com/inflation/
and then averaged for a single average hospital cost for each group.
The software program SUDAAN (Research Triangle Inst) was used
to convert raw counts generated from the NIS database into weighted
counts, representing national estimates. Weighted data were used for
all statistical analysis. The study was exempted from formal review
by the Institutional Review Board.
Results
Demographic and clinical results are tabulated in Table 1 and
are summarized below. From 2000 to 2003 there were an
estimated 2904 pediatric ischemic stroke admissions, 46
(1.6%) of whom received thrombolytic therapy. Among these
patients, the mean age was 11.1⫾4.1 years versus 9.4⫾5.2
years among children who did not receive thrombolysis
(P⫽0.22). All 46 children in the NIS receiving thrombolysis
were male, compared with 1538 (53.8%) of the other group
(P⬍0.05). Children who received thrombolysis were most
often white (56.5%) as compared with other children (39.0%,
P⫽0.32).
None of the children receiving thrombolysis had an asso-
ciated medical condition commonly reported in children with
stroke, whereas among other children, there was a 3.4% rate
of moyamoya disease (n⫽97), a 6.4% rate of sickle cell
disease (n⫽182), a 0.3% rate of cardiac valvulopathy (nⱕ10),
and a 0.1% rate of procoaguable conditions (nⱕ10). There
were few reported complications including deep venous
thrombosis and pneumonia (nⱕ10, 10.9%) and no cases of
myocardial infarction, pulmonary embolism, intracranial
hemorrhage, urinary tract infection, and sepsis among chil-
dren receiving thrombolysis, compared with 23 (0.8%) cases
of intracranial hemorrhage, ⬍10 (0.2%) myocardial infarc-
 1852 Stroke June 2007
TABLE 2. Hospital Type and Discharge Outcomes
Total Pediatric Stroke Patients Who Received
Discharge Status Patients (n⫽2904)
Hospital type
Rural 117 (4.0%)
Urban nonteaching 349 (12.0%)
Urban teaching 2438 (84.0%)
Length of stay (days⫾SD) 7.6⫾12.1
Discharge mode
Routine 2317 (79.8%)
Short-term facility 185 (6.4%)
Long-term facility 293 (10.1%)
In-hospital mortality 99 (3.4%)
Not stated/missing ⬍10 (0.3%)
Cost of hospitalization $39 400
Bold indicates statistically significant comparison.
tions, 45 (1.6%) cases of pneumonia, 89 (3.1%) urinary tract
infections, and 15 (0.05%) deep venous thrombosis in the
other group.
Twenty patients (43.5%) receiving thrombolytics were also
maintained on mechanical ventilation at some point during
their hospital course compared with 190 (6.6%) of patients
who did not receive thrombolysis. Over half of the children
receiving thrombolysis also underwent cerebral angiography
(n⫽24, 52.2%), 19 of which were on the incident stroke day.
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Cerebral angiography was reported among 793 patients
(27.7%) in the conventionally managed cohort.
The median length of stay was nearly twice as long for
children who received thrombolysis (15.3⫾12.4 days) com-
pared with those who did not (7.4⫾12.1 days, P⬍0.05).
Patients receiving thrombolysis were less likely to be dis-
charged to home (n⫽20, 43.5% versus n⫽2297, 80.4%;
P⫽0.07) or a short-term rehabilitation center (n⫽0 versus
n⫽185, 6.5%; P⬍0.05), and at discharge had higher rates of
in-hospital mortality (n⬍10, 19.6% versus n⫽90, 3.1%;
P⫽0.22) and dependency at discharge (n⫽17, 37.0% versus
n⫽276, 9.7%; P⫽0.16). The overall estimated cost of hospi-
talization among children who received thrombolysis was
nearly twice that for children who did not receive
thrombolysis ($81 800 versus $38 700, P⬍0.05). Outcomes
results are tabulated in Table 2.
Discussion
We report the first study to estimate the national rate of
thrombolytic therapy for ischemic stroke in children in the
United States. Based on data from the NIS, from 2000 to
2003, ⬍2% of children with ischemic stroke received
thrombolytic therapy. Children who received thrombolytic
therapy were more likely to be male, white, ⬎11 years, and
had higher rates of dependency and mortality than children
who did not receive thrombolytic therapy.
The data in our study must be considered in the context of
certain limitations of the analysis. We used data from the
NIS, a large size data set with standardized methodology
representative of the United States, eliminating the bias
Patients Who Did Not
Receive Thrombolysis
Thrombolysis (n⫽46) (n⫽2858) P Value
⬍10 (10.9%) 112 (3.9%) P⫽0.50
⬍10 (10.9%) 344 (12.0%) P⫽0.93
36 (78.2%) 2402 (84.1%) P⫽0.66
15.3⫾12.4 7.4⫾12.1 Pⴝ0.00
20 (43.5%) 2297 (80.4%) P⫽0.07
0 (0.0%) 185 (6.5%) Pⴝ0.01
17 (37.0%) 276 (9.7%) P⫽0.16
⬍10 (19.6%) 90 (3.1%) P⫽0.22
⬍10 (2.2%) ⬍10 (0.3%) P⫽0.20
$81 800 $38 700 Pⴝ0.03
observed in local and community based studies. However, the
weighted estimates have more variability than expected from
the magnitude of the numbers presented. The relatively
infrequent occurrence of pediatric patients receiving
thrombolysis for stroke led to final estimates based on small
numbers of inpatient records with possible under-repre-
sentation of certain demographic groups such as females.
This low female sample size does not affect our conclusion
because the occurrence of stoke in pediatric patients is not
correlated with their gender. Adult men are associated with a
higher incidence of strokes only because they typically
engage in more high-risk behaviors (ie, drinking, smoking).
These behaviors are not part of the lifestyle of the normal
child, making gender an irrelevant factor in statistical evalu-
ation. Therefore, we can only conclude from the total number
of pediatric stroke patients those who receive thrombolysis or
not receive thrombolysis.
The overall rate of 1.6% of thrombolysis among all
pediatric ischemic stroke patients is much lower than the
highly variable rates of 3% to 20% reported for adult stroke
patients,13,14 though it is higher than generally accepted rates
among children. Alternate indications for thrombolysis such
as venous thromboembolism may have adulterated our re-
sults, though we excluded patients with a primary diagnosis
of deep venous thrombosis and pulmonary embolism from
the analysis.
Risk factors for pediatric stroke, as identified by associated
medical conditions, were not reported for most of the children
in this study, and only pneumonia and deep venous throm-
bosis were reported as complicating illnesses for children
with thrombolysis. The most frequently reported risk factors
for ischemic stroke in children are cardiac disorders, hema-
tological disorders, metabolic disorders, arteriopathies, and
infection.15–18 Risk factors identified in previous reports of
children receiving thrombolytic therapy include steno-
occlusive disease, arterial dissection, or other thrombotic
conditions,3,4,6,8 though in most series, the extent of the
evaluation was limited, and no risk factors are identified in
over 20% of cases.18 It is unclear why the rates of stroke risk
 Janjua et al
factors were so low among the patients receiving
thrombolysis in this study, but may be attributable to limited
investigations or reporting errors, further amplified by the
overall lower numbers of patients receiving thrombolytics.
Additionally, reluctance of physicians to offer thrombolytics
to children with underlying diseases such as sickle cell
disease or moyamoya disease, for fear of the potential for
hemorrhagic complications, may have also impacted these
results.
We were not able to assess stroke severity at baseline, time
to treatment, dosage, and long-term outcome with the vari-
ables collected in the NIS. Thus, though a greater percentage
of patients receiving thrombolysis required mechanical ven-
tilation during their hospitalization compared with other
children with stroke, it is not clear whether the former group
required assisted ventilation before treatment. There have
been several small reports and series of children receiving
thrombolytic therapy.3–11 Most involved cases of intra-arterial
delivery of thrombolytic (urokinase, tissue plasminogen ac-
tivator) with varying stroke etiologies, treatment windows,
dosages and outcome measures, though largely the immediate
results were favorable. Mode of delivery could also not be
ascertained, though it is possible that the patients who
underwent cerebral angiography on the incident stroke day
did so for the purposes of intra-arterial delivery of thrombo-
tics. Further prospective studies would be needed to identify
treatment patterns and benefits and risks associated with dose
ranges and modes of delivery.
Though it is widely believed that children have a greater
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capacity than adults for recovery after neurological in-
sults,19,20 the majority of children with ischemic stroke will
develop some motor or cognitive abnormality. A study of
pediatric stroke from the Toronto Hospital for Sick Children
revealed that after a mean of 2.1 years of follow-up only 31%
were neurologically normal.19 Fatality rates for pediatric
stroke have ranged from 0% to 21%.21 Though in the NIS
dataset there were no reports of intracranial hemorrhage
among the group receiving thrombolysis, children receiving
thrombolysis had higher mortality rates, and discharge to a
skilled nursing facility, with lower rates of routine or short-
term rehabilitation center discharges. It is unclear whether
these results were attributable to selection bias or adverse
effects of thrombolytic therapy in children with stroke. A
larger prospective clinical trial would more suitably address
the issue of efficacy and safety of thrombolysis among
children with ischemic stroke.
Despite lower rates of pediatric stroke compared with
adults the financial burden of pediatric stroke is substantial,
attributable to extended hospital stays, loss of decades of
productive years of life and extended periods of supportive
care in skilled nursing facilities.22–24 We found that the length
of hospitalization and median costs for children with stroke
were significantly higher among children receiving
thrombolysis ($81 800 versus $38 700).
Our study represents 20% of all community hospital
admissions in the United States, and thus far establishes the
largest series of pediatric stroke thrombolysis, and the first
study to report mean costs for stroke hospitalizations in
children. However, patient selection based on ICD-9 coding
Thrombolysis for Stroke in Children 1853
may have biased the total number of stroke patients and those
receiving thrombolysis in our study. The sensitivity and
specificity of ICD-9 coding for arterial ischemic stroke in
children has not been determined. Adult stroke studies using
ICD-9 coding have varied in accuracy.25,26 The use of all
discharge diagnostic codes classifying adult ischemic stroke
has a sensitivity of 86%, specificity of 95%, and positive
predictive value of 90%,27 and the sensitivity for the 99.10
code for thrombolysis has been reported as low as 55%,
though the specificity may be as high as 98%.28 Furthermore,
during the time period of this study, no specific code for
intra-arterial modes of thrombolysis existed, and is therefore
undifferentiated in the NIS database.
Conclusions
Arterial ischemic stroke is a well-recognized cause of mor-
bidity and mortality in children. The acute treatment and
prevention of pediatric stroke is based on limited studies in
children. Although the use of thrombolytic therapy is being
used in children with stroke, the safety and efficacy has not
been established. Further studies are needed to evaluate the
proper dosage, safety, and efficacy of thrombolytic agents in
children with stroke.
Disclosures
None.
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