Pediatric Neurology 51 (2014) 624e631

Contents lists available at ScienceDirect

Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Original Article

Use and In-Hospital Outcomes of Recombinant Tissue

Plasminogen Activator in Pediatric Arterial Ischemic Stroke
Patients
Deena M. Nasr DO a, *, Jose Biller MD b, Alejandro A. Rabinstein MD a
a
b

Department of Neurology, Mayo Clinic, Rochester, Minnesota

Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois

BACKGROUND: Outcomes in pediatric stroke are poorly understood. We sought to determine trends in the use of recombinant tissue plasminogen activator (rt-PA), treatment outcomes, and predictors of mortality for pediatric patients
with acute ischemic stroke by using the Nationwide Inpatient Sample. METHODS: Using Nationwide Inpatient Sample
data from 2001 to 2010, we identied pediatric patients (age 30 days to 18 years) with the primary diagnosis of
arterial ischemic stroke. We studied trends of use of intravenous rt-PA and outcomes after thrombolysis. We also
analyzed the associations of demographic factors, comorbidities, and complications of arterial ischemic stroke with
in-hospital mortality. RESULTS: This study included 7044 patients. In-hospital mortality was 4.7%. The comorbidities
associated with the greatest rates of in-hospital mortality were mitochondrial disorders (19.5%, P < 0.0001) and
hypercoagulable states (11.4%, P < 0.0001). The main complications associated with increased mortality were
intracerebral hemorrhage (19.9%, P < 0.0001), sepsis (13.2%, P < 0.0001), and pneumonia (9.3%, P 0.0007). The rate
of rt-PA use was 1.4% (99 patients). rt-PA use increased from 0.9% of patients in 2001-2005 to 2.0% in 2006-2010
(P < 0.0001). Among patients who received rt-PA, the rate of intracerebral hemorrhage was low and without fatalities; however, there was an increased discharge-to-long-term-facilities rate in the rt-PA group (50.8% versus
12.1%, P < 0.0001). CONCLUSION: Arterial ischemic stroke in the pediatric population is associated with a greater rate
of mortality when related to mitochondrial diseases or hypercoagulability. rt-PA use is increasing in pediatric patients with arterial ischemic stroke. Pediatric patients receiving rt-PA have a low risk of fatal hemorrhage. Although
patients receiving rt-PA have a morbidity rate, these individuals may have a worse stroke severity.
Keywords: stroke, epidemiology, thrombolysis, pediatric

Pediatr Neurol 2014; 51: 624-631

2014 Elsevier Inc. All rights reserved.

Introduction

The reported prevalence of pediatric arterial ischemic stroke

is increasing with a reported incidence of 1-3 per 100,000
patients.1,2 Arterial ischemic stroke in this age group is associated with different comorbid conditions and mechanisms of
ischemia compared with adults. The frequency and prognostic
impact of secondary neurological and systemic complications
also differ. Treatment standards are less well dened than in
adults. The use of intravenous recombinant tissue plasminogen
Article History:
Received May 18, 2014; Accepted in nal form July 22, 2014
* Communications should be addressed to: Nasr, DO, Mayo Clinic, 200
SW First Street, Rochester, MN 55905.
E-mail address: nasr.deena@mayo.edu
0887-8994/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.030

activator (IV rt-PA) in the pediatric population is not recommended by multiple societies because of a paucity of data.3-6
Yet, intravenous thrombolysis is used in practice in selected
cases.7 There is very little literature addressing mortality
predictors, use of rt-PA, and overall morbidity among children.
The purpose of this study is to evaluate predictors of mortality
and trends of rt-PA use during a 10-year period in hospitalized
pediatric patients with arterial ischemic stroke.
Materials and Methods
Patient population
Data from the Nationwide Inpatient Sample (NIS) hospital discharge
database concerning the years 2001-2010 were obtained from the
Healthcare Cost and Utilization Project of the Agency for Healthcare

D.M. Nasr et al. / Pediatric Neurology 51 (2014) 624e631

Research and Quality. This database represents 20% of all inpatient discharges from nonfederal hospitals in the United States. Because this
database is publically available, this study was considered exempt from
institutional review board approval by our Institutional Review Board.
Patients included in this study were younger than 18 years and had a
primary diagnosis of arterial ischemic stroke and were identied using
International Classication of Diseases, 9th Revision (ICD-9) codes of 433,
434, 436, 437.0, 437.1, 437.4, 437.5, 437.7, 437.8, and 437.9. No codes for
cerebral venous infarction were included.

Demographic characteristics
Demographic information analyzed included age, sex, and race
(white versus nonwhite). Each group was stratied by years (2001-2005
and 2006-2010) and rt-PA use to assess for temporal trends. Age was
categorized infant/toddler (30 days-4 years), children (5-9 years), preteen (10-14 years), and teenager (15-17 years). Neonates (<30 days)
were excluded because of the difculty in excluding in utero events as a
cause of stroke among neonates.

Medical comorbidities and complications

Comorbidities and complications included in this study were moyamoya (ICD-9:437.5), sickle cell disease (ICD-9:282.6), patent foramen
ovale (PFO) (ICD-9:7455/7456), congenital heart disease (CCS:213), dissections (ICD-9:44100-44329), hypercoagulable state/thrombophilia
(ICD-9:286.9) intracerebral hemorrhage (ICH; ICD-9:431), pneumonia
(CCS:122), urinary tract infection (CCS:159), sepsis (CCS:2), pulmonary
embolism (ICD-9:41511-41519), deep venous thrombosis (CCS:118),
mitochondrial disease (ICD:277.87), connective tissue disease (CCS: 210),
malignancy (CCS: 11-45), meningitis (CCS: 76) trauma (CCS 2601-2615),
and cerebral vasculitis (ICD-9:4374). The Charlson Comorbidity Index
was calculated for each patient. The Index is a weighted index that takes
into account various comorbid diseases that might alter the risk of
mortality in longitudinal studies and has been found to be associated
with both short- and long-term mortality.8

Interventions and therapies

Using ICD-9 procedure codes, we categorized patients based on the
treatment they received. Data regarding rt-PA therapy administration
were extrapolated with the ICD-9 procedure code 9910. Patients who
underwent cerebral angiography, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) were identied with the ICD-9
procedure codes of CCS:118, CCS:216 and ICD-9 3961/3965/3966,
respectively. Patients undergoing cardiac surgery were identied using
CCS codes 43-44 and 48-50, and patients undergoing cardiac catheterization were identied using CCS code 47.

Outcomes
The primary end points of this study were rt-PA use and in-hospital
mortality rates. Secondary outcomes included rate of ICH and
discharge disposition (discharge to short-term or long-term facility).
Rates of ICH, discharge disposition, and mortality were compared for
patients who received rt-PA versus those who did not. When determining rt-PA use rates, we performed a separate subgroup analysis
excluding patients who would not typically be considered for rt-PA
administration. Thus, patients with sickle cell disease, cancer, trauma,
ECMO, moyamoya, mitochondrial disease, and postsurgical patients
were excluded from this subgroup analysis.

Statistical analysis

c2 tests were used to compare categorical variables, and the Student

t test was used to compare continuous variables assuming statistical
signicance at P < 0.05. P-values for outcomes were obtained using the
no rt-PA as a reference group. Discharge weights were applied.
A multivariate analysis was t to determine comorbidities and

625

demographic characteristics associated with mortality. All comorbidities

and demographic factors were forced into this model. All statistical
analysis was performed by using the SAS-based statistical package JMP
(www.jmp.com; SAS, Cary, NC).

Results
Patient population

A total of 7044 hospitalized patients younger than 18

years of age were assigned a primary diagnosis of arterial
ischemic stroke. Mean age was 8.6  13.2 years. Patients 30
days-4 years old made up the largest age group (2280 patients, 32.2%) and patients 5-9 years old comprised the
smallest age group (1479 patients, 20.9%). 99 patients (1.4%)
received thrombolysis. In-hospital mortality occurred in
329 patients (4.7%). Congenital heart disease, hypercoagulable states, and sickle cell disease were the most common
comorbid conditions associated with ischemic stroke. These
data are summarized in Table 1.
rt-PA use rates and outcomes

The average age among rt-PA patients was 12.4 

9.4 years. rt-PA use was greatest in patients 10-14 years
(N 50, 3.2%) and 15-17 years old (N 31, 1.8%). From 20012005 to 2006-2010, rt-PA use rates increased from 0.9% to
2.0% (P 0.0003). There was an increased rate of dischargedto-long-term facilities during these two time periods from
11.1% to 15.5% (P 0.002) and a decreased mortality from
5.6% to 3.6% (P < 0.0001). Data are summarized in Table 2.
As a whole, rt-PA patients were older than non-rt-PA patients (12.4  9.4 versus 8.5  13.2, P < .0001). The most
common comorbidities in the rt-PA patient group were hypercoagulable state (24.2%) and congenital heart disease
TABLE 1.
Demographics and Outcomes of Pediatric Ischemic Stroke Patients

Variable
Total N
Age distribution
Age, mean (SD)
30 days-4 years, n (%)
5-9 years, n (%)
10-14 years, n (%)
15-17 years, n (%)
Sex
Male, n (%)
Race
White, n (%)
CCI, mean (SD)
Outcomes, n (%)
rt-PA use
ICH
Discharge to home
Discharge to short-term facility
Discharge to long-term facility
Mortality
LOS, mean (SD)
Abbreviations:
CCI
Charlson Comorbidity Index
ICH Intracerebral hemorrhage
LOS Length of stay
rt-PA Recombinant tissue plasminogen activator
SD
Standard deviation

7044
8.6
2280
1479
1570
1716

(13.2)
(32.2)
(20.9)
(22.3)
(24.4)

3970 (56.6)
2607 (48.2)
1.2 (1.4)
99
110
4821
524
921
329
8.6

(1.4)
(1.6)
(68.4)
(7.4)
(13.1)
(4.7)
(27.0)

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D.M. Nasr et al. / Pediatric Neurology 51 (2014) 624e631

TABLE 2.
Trends in Outcomes of Pediatric Ischemic Stroke Patients

Time period
2001-2005

TABLE 3.
Demographics, Outcomes, and Procedures of rt-PA Versus Non-rt-PA Patients

P value
2006-2010

Total N
3796 (53.9) 3247 (46.1) e
rt-PA
35 (0.9)
64 (2.0)
0.0003
Discharge to home
2645 (69.8) 2176 (67.0)
0.01
Discharge to short-term facility 248 (6.5)
276 (8.5)
0.002
Discharge to long-term facility
421 (11.1) 502 (15.5)
0.002
Mortality
214 (5.6)
116 (3.6) <0.0001
LOS
9.1 (27.2)
7.9 (25.6)
0.06
ICH
59 (1.6)
59 (1.6)
0.99
Abbreviations:
ICH Intracerebral hemorrhage
LOS Length of stay
rt-PA Recombinant tissue plasminogen activator

(25.1%). Only 4.2% of rt-PA patients had sickle cell disease

compared with 11.0% of the nonert-PA population (P 0.02).
rt-PA patients had greater rates of mechanical ventilation
(29.5% versus 13.6%, P < 0.0001) and cerebral angiography
(44.1% versus 25.9%, P < 0.0001). When considering only patients who did not receive cerebral angiography, we found that
patients undergoing rt-PA had a similar rate of mechanical
ventilation compared with non-rt-PA patients (9.2% versus
14.4%, P 0.27). No patients undergoing rt-PA received ECMO.
Patients undergoing rt-PA had greater ICH rates compared
with patients not undergoing rt-PA (4.9% versus 1.6%, P 0.01).
No ICH cases in the rt-PA group were fatal. There were no inhospital deaths among rt-PAetreated patients (0.0% versus
4.5%, P 0.01). There was an increased rate of dischargeto-long-term-facilities in the rt-PA group (50.8% versus
12.5%, P < 0.0001). These data are summarized in Table 3.
rt-PA use, excluding ineligible patients

When excluding patients who would be ineligible for rtPA administration given their comorbidities, we calculated a
total of 5645 patients; 1398 patients were excluded based on
comorbidities. Among patients who had no comorbid contraindications to rt-PA use, rt-PA use was 1.7% and increased
from 1.1% in 2001-2005 to 2.4% in 2006-2010 (P 0.0002).
Only 0.3% of patients with contraindications to rt-PA received
rt-PA therapy. Among patients without comorbid contraindications, mortality for rt-PA recipients was 0% and mortality
for non-rt-PA recipients was 4.8% (P 0.03).
Factors associated with mortality

On univariate analyses, female sex was associated with

greater in-hospital mortality (5.8% versus 3.7%; P < 0.0001).
Patients who were 30 days to 4 years old and 10-14 years
old had the greatest rates of mortality (6.1% and 5.3%,
respectively). The comorbidities associated with the greatest rates of in-hospital mortality were mitochondrial disorders (19.5%, P < 0.0001) and hypercoagulable state (11.4%,
P < 0.0001). The main complications associated with
increased mortality were ICH (19.9%, P < 0.0001), sepsis
(13.2%, P < 0.0001), and pneumonia (9.3%, P 0.0007).
Mortality was also much greater in patients who required
ECMO or mechanical ventilation. The results are summarized in Table 4.

rt-PA
Total patients
Demographics
Age, mean (SD)
Age group, n (%)
30 days-4 years
5-9 years
10-14 years
15-17 years
Female, n (%)
Nonwhite, n (%)
CCI, mean (SD)
Complications
Pneumonia
UTI
Sepsis
PE
DVT
Comorbidities
Moyamoya
Sickle cell disease
Cardiac valvular disease
Hypercoagulable state
Congenital heart disease
PFO
Dissection
Mitochondrial Disorder
Cerebral vasculitis
Malignancy
Connective tissue
disease
Trauma
Meningitis
Procedures, n (%)
Mechanical ventilation
Cerebral angiography
Extracorporeal
membranous
oxygenation
Heart surgery
Coronary angiography
Outcomes, n (%)
Discharge to home
Discharge to short-term
facility
Discharge to long-term
facility
Mortality
LOS, mean (SD)
ICH

no rt-PA

P value

99 (1.4)

6944 (98.6)

12.4 (9.4)

8.5 (13.2)

<10
<10
50
31
33
24
1.2

(0.4)*
(0.7)*
(3.2)
(1.8)
(35.4)
(32.6)
(1.4)

2271
1469
1520
1684
3183
2777
1.1

14
0
11
0
<10

(14.5)
(0.0)
(9.7)
(0.0)
(4.9)*

0
<10
<10
24
25
15
<10
0
0
0
<10

(0.0)
(4.2)*
(5.2)
(24.2)*
(25.1)
(15.5)
(9.7)*
(0.0)
(0.0)
(0.0)
(5.7)*

<0.0001

(99.6)
(99.3)
(96.9)
(98.2)
(43.7)
(52.1)
(1.1)

<0.0001
0.005
0.01
Ref
0.11
0.0008
0.63

202
214
90
24
132

(2.9)
(3.1)
(1.4)
(0.4)
(1.9)

<.0001
0.08
<0.0001
0.55
0.12

350
766
260
640
899
477
251
84
127
438
62

(5.0)
(11.0)
(3.8)
(9.2)
(12.9)
(6.9)
(3.6)
(1.2)
(1.8)
(6.3)
(0.9)

0.02
0.02
0.46
<0.0001
0.002
0.004
0.004
0.27
0.42
0.002
0.002

0 (0.0)
0 (0.0)

211 (3.0)
46 (0.7)

0.12
1.00

29 (29.5)
44 (44.1)
0 (0.0)

943 (13.6)
1801 (25.9)
31 (100.0)

<0.0001
<0.0001
0.52

0 (0.0)
0 (0.0)

51 (0.7)
43 (0.6)

0.39
0.43

33 (33.6)
15 (15.6)

4787 (68.9)
508 (7.3)

<0.0001
0.002

51 (50.8)

870 (12.5)

<0.0001

0 (0.0)
10.1 (19.4)
<10 (4.9)*

329 (4.8)
8.5 (26.6)
105 (1.5)

0.02
0.42
0.01

Abbreviations:
CCI
Charlson Comorbidity Index
DVT Deep-vein thrombosis
ICH Intracerebral hemorrhage
LOS Length of stay
PE
Pulmonary embolism
PFO Patent foramen ovale
rt-PA Recombinant tissue plasminogen activator
SD
Standard deviation
UTI
Urinary tract infection
* Per Healthcare Cost and Utilization Project guidelines, number of patients is not
to be published if <10.

Outcomes and comorbidities by age group

Outcomes and comorbidities by age group are summarized in Table 5. Congenital heart disease was the most

D.M. Nasr et al. / Pediatric Neurology 51 (2014) 624e631

common comorbidity among patients 30 days-4 years and

10-14 years old (17.4% and 11.7% of patients, respectively).
Sickle cell disease was the most common comorbidity
among patients 5-9 years old (18.7%) and second mostcommon comorbidity among patients 10-14 years old
(11.1%). Hypercoagulable state and congenital heart disease
were the two most common comorbidities among patients
15-17 years old (14.0% and 13.5% respectively). Patients

627

10-14 years and 15-17 years old had the lowest rates of
discharge to home (66.4% and 66.5%, respectively).
Multivariate analysis

Age 5-9 years was associated with signicantly lesser

mortality rates compared with patients 15-17 years.
(P < 0.0001 and P 0.004, respectively). ICH and MI

TABLE 4.
Univariate Analysis Mortality Predictors

Total patients
Age group
30 days-4 years
5-9 years
10-14 years
15-17 years
Sex
Female
Male
Race
Nonwhite, n (%)
White, n (%)
Complications
ICH
MI
Pneumonia
UTI
Sepsis
PE
DVT
Comorbidities
Moyamoya
Sickle cell disease
Cardiac valvular disease
Hypercoagulable state
Congenital heart disease
PFO
Dissection
Mitochondrial disorder
Cerebral vasculitis
Malignancy
Connective tissue disease
Trauma
Meningitis
Procedures
Mechanical ventilation
Cerebral angiography
ECMO
rt-PA
Cardiac catheterization
Cardiac Surgery

Total patients, n (%)

Mortality, n (%)

Mortality, OR (95% CI)

P value

7044 (100.0)

329 (4.7)

2280
1479
1570
1716

138
34
82
74

(6.1)
(2.3)
(5.3)
(4.3)

1.42 (1.07-1.90)
0.52 (0.34-0.79)
1.22 (0.88-1.68)
Ref

0.02
0.002
0.23
Ref

3040 (43.4)
3970 (56.6)

177 (5.8)
152 (3.78

1.55 (1.24-1.93)

<0.0001

2802 (51.8)
2602 (48.2)

147 (5.3)
147 (5.6)

0.93 (0.73-1.17)

0.53

110 (1.6)
<10 (0.1)*
217 (3.1)
214 (3.0)
110 (1.6)
24 (0.4)
137 (1.9)

24
<10
20
15
14
0
<10

(19.9)
(100.0)
(9.3)
(7.0)
(13.2)
(0.0)
(5.7)

5.90
NA
2.16
1.55
3.18
0.0
1.24

(1.34-3.46)
(0.90-2.65)
(1.81-5.59)
(NA)
(0.59-2.52)

<0.0001
<0.0001
0.003
0.11
<0.0001
0.62
0.55

(30.8)
(20.0)
(21.2)
(23.2)

(3.69-9.43)

350
770
265
664
924
492
256
84
127
438
68
206
46

(5.0)
(10.9)
(3.8)
(9.4)
(13.1)
(7.0)
(3.6)
(1.2)
(1.8)
(6.2)
(1.0)
(2.9)
(0.7)

<10
11
15
75
21
<10
<10
16
<10
19
0
12
<10

(1.3)
(1.3)
(5.5)
(11.4)
(2.3)
(1.0)
(2.0)
(19.5)
(6.8)
(4.3)
(0.0)
(5.9)
(10.7)

0.27
0.25
1.24
3.10
0.44
0.20
0.40
5.42
1.57
0.92
0.0
1.29
2.45

(0.10-0.69)
(0.13-0.48)
(0.73-2.13)
(2.37-4.06)
(0.28-0.69)
(0.08-0.48)
(0.16-0.98)
(3.12-9.41)
(0.78-3.17)
(0.57-1.48)
(NA)
(0.71-2.32)
(0.95-6.31)

0.002
<0.0001
0.37
<0.0001
0.0001
<0.0001
0.04
<0.0001
0.19
0.82
0.07
0.40
0.06

968
1840
31
99
43
51

(13.8)
(26.1)
(0.4)
(1.3)
(0.6)
(0.7)

261
42
16
0
<10
16

(27.0)
(2.3)
(50.3)
(0.0)
(11.8)
(30.5)

32.7
0.40
22.8
0.0
2.74
9.34

(24.8-43.2)
(0.29-0.55)
(11.2-46.4)
(NA)
(1.08-6.98)
(5.09-17.11)

<0.0001
<0.0001
<0.0001
0.03
0.05
<0.0001

Abbreviations:
CCI
Charlson Comorbidity Index
CI
Condence interval
DVT
Deep-vein thrombosis
ECMO Extracorporeal membrane oxygenation
ICH
Intracerebral hemorrhage
LOS
Length of stay
MI
Myocardial infarction
OR
Odds ratio
PE
Pulmonary embolism
PFO
Patent foramen ovale
rt-PA Recombinant tissue plasminogen activator
SD
Standard deviation
UTI
Urinary tract infection
* Per Healthcare Cost and Utilization Project guidelines, number of patients is not to be published if <10.

628

D.M. Nasr et al. / Pediatric Neurology 51 (2014) 624e631

TABLE 5.
Outcomes and Complications by Age Group

Number of patients
Demographics
Female, n (%)
Nonwhite, n (%)
Comorbidities
Moyamoya
Sickle cell disease
Cardiac valvular disease
Hypercoagulable state
Congenital heart disease
PFO
Dissection
Mitochondrial disorder
Cerebral vasculitis
Malignancy
Connective tissue disease
Trauma
Meningitis
CCI, mean (SD)
Outcomes, n (%)
Discharge to home
Discharge to short-term
facility
Discharge to long-term
facility
Mortality
LOS, mean (SD)
Complications
ICH
MI
Pneumonia
UTI
Sepsis
PE
DVT
Procedures
Mechanical ventilation
Cerebral angiography
ECMO
rt-PA
Cardiac catheterization
Cardiac surgery

30 days-4 years

5-9 years

10-14 years

15-17 years

2280 (32.4)

1479 (21.0)

1570 (22.3)

1716 (24.4)

1010 (44.4)
1020 (56.9)

556 (38.0)
603 (53.1)

744 (47.4)
605 (49.6)

735 (43.1)
574 (45.5)

86
276
<10
63
112
48
60
11
23
93
<10
58
<10
1.2

77
174
69
136
184
107
68
36
39
171
24
34
<10
1.3

14
96
114
241
231
167
103
15
29
102
38
54
15
1.2

173
225
78
224
397
170
30
22
36
73
0
64
16
<10

(7.6)
(9.9)
(3.4)
(9.8)
(17.4)
(7.5)
(1.3)
(1.0)
(1.6)
(3.2)
(0.0)
(2.8)
(0.7)
(1.0)*

(5.8)
(18.7)
(0.3)
(4.2)
(7.6)
(3.2)
(4.0)
(0.7)
(1.6)
(6.3)
(0.4)
(4.0)
(0.4)
(1.2)

(4.9)
(11.1)
(4.4)
(8.7)
(11.7)
(6.8)
(4.3)
(2.3)
(2.5)
(10.9)
(1.5)
(2.2)
(0.6)
(1.8)

(0.8)
(5.6)
(6.6)
(14.0)
(13.5)
(9.7)
(6.0)
(0.9)
(1.7)
(5.9)
(2.2)
(3.2)
(0.9)
(1.6)

1585 (69.5)
98 (4.3)

1055 (71.4)
101 (6.8)

1042 (66.4)
141 (9.0)

1138 (66.5)
183 (10.7)

269 (11.8)

180 (12.2)

246 (15.7)

226 (13.2)

138 (6.1)
<10(22.9)*

34 (2.3)
8.8 (31.8)

82 (5.3)
9.0 (34.9)

74 (4.3)
7.1 (17.8)

39
<10
108
76
54
16
51

(1.7)
(0.2)*
(4.7)
(3.3)
(2.4)
(0.7)
(2.3)

25
0
29
20
16
0
15

24
0
34
60
30
0
36

405
483
<10
<10
15
11

(17.8)
(21.2)
(0.2)*
(0.4)*
(0.7)
(0.5)

165
449
<10
<10
13
10

(1.7)
(0.0)
(2.0)
(1.4)
(1.1)
(0.0)
(1.0)
(11.2)
(30.4)
(0.7)
(0.7)
(0.9)
(0.7)

239
448
<10
50
15
16

(1.5)
(0.0)
(2.2)
(3.8)
(1.9)
(0.0)
(2.3)

22
0
45
58
<10
<10
34

(1.3)
(0.0)
(2.7)
(3.4)
(0.6)
(0.5)
(2.0)

(15.2)
(28.6)
(0.4)
(3.2)
(0.9)
(1.0)

163
465
<10
31
0
15

(9.5)
(27.1)
(0.6)
(1.8)
(0.0)
(0.9)

Abbreviations:
CCI
Charlson Comorbidity Index
DVT
Deep-vein thrombosis
ECMO Extracorporeal membrane oxygenation
ICH
Intracerebral hemorrhage
LOS
Length of stay
MI
Myocardial infarction
PE
Pulmonary embolism
PFO
patent foramen ovale
rt-PA Recombinant tissue plasminogen activator
SD
Standard deviation
UTI
Urinary tract infection
* Per Healthcare Cost and Utilization Project guidelines, number of patients is not to be published if <10.

were associated with a greater odds of mortality

(P < 0.0001 for both). Hypercoagulable state (P 0.001),
mitochondrial disorder (P < 0.0001), and cerebral
vasculitis (P 0.02) were associated with greater odds of
mortality. Mechanical ventilation and ECMO were associated with greater odds of mortality (P < 0.0001).
Conversely, rt-PA was associated with a lesser odds of
mortality (P 0.0005). These data are summarized in
Table 6.

Discussion

The size of the population allowed us to provide some

insight into the frequency of the main causes, short-term
outcomes, and factors associated with in-hospital mortality among pediatric patients with arterial ischemic stroke.
We were able to determine that the rate of rt-PA use, albeit
still low, is growing over time. Among patients without
comorbidities precluding rt-PA administrations, rt-PA use

D.M. Nasr et al. / Pediatric Neurology 51 (2014) 624e631

TABLE 6.
Multivariate Analysis Mortality Predictors

Age group
30 days-4 years
5-9 years
10-14 years
15-17 years
Sex
Female versus male
Race
White versus nonwhite
Complications
ICH
Pneumonia
UTI
Sepsis
PE
DVT
Comorbidities
Moyamoya
Sickle cell disease
Cardiac valvular
disease
Hypercoagulable state
Congenital heart
disease
PFO
Dissection
Mitochondrial disorder
Cerebral vasculitis
Malignancy
Connective tissue
disease
Trauma
Meningitis
Procedures
Mechanical ventilation
Cerebral angiography
ECMO
Cardiac catheterization
Cardiac surgery
rt-PA

Mortality, OR (95%CI)

P value

0.89 (0.59-1.34)
0.47 (0.28-0.79)
0.86 (0.55-1.36)
Ref

0.56
0.004
0.52
Ref

1.34 (0.98-1.82)

0.06

0.79 (0.57-1.08)

0.14

17.0
0.69
0.74
0.16
0.00
1.38

(7.67-36.54)
(0.35-1.32)
(0.37-1.42)
(0.06-0.41)
(0.00-0.05)
(0.52-3.26)

<0.0001
0.27
0.38
<0.0001
<0.0001
0.49

0.69 (0.21-1.78)
0.54 (0.25-1.08)
0.44 (0.13-1.20)

0.47
0.08
0.12

1.97 (1.30-2.96)
0.47 (0.24-0.87)

0.001
0.02

0.00
0.21
6.11
4.20
0.67
0.00

(0.00-0.50)
(0.07-0.50)
(2.64-13.60)
(1.30-10.84)
(0.35-1.22)
(0.00-0.16)

1.19 (0.54-2.52)
0.00 (0.00-0.07)
55.67
0.59
77.53
41.92
0.00
0.00

(38.90-81.51)
(0.38-0.89)
(22.29-297.48)
(12.00-30.31)
(0.00-174.16)
(0.00-0.24)

<0.0001
0.0002
<0.0001
0.02
0.20
0.20
0.66
0.02
<0.0001
0.01
<0.0001
<0.0001
0.86
0.0005

Abbreviations:
CI
Condence interval
DVT
Deep-vein thrombosis
ECMO Extracorporeal membrane oxygenation
ICH
Intracerebral hemorrhage
LOS
Length of stay
MI
Myocardial infarction
OR
Odds ratio
PE
Pulmonary embolism
PFO
patent foramen ovale
rt-PA Recombinant tissue plasminogen activator
SD
Standard deviation
UTI
Urinary tract infection

increased from 1.1% in 2001-2005 to 2.4% in 2006-2010. Our

analysis shows a low rate of ICH and a remarkable absence
of fatal cases among patients treated with thrombolysis.
Approximately two-thirds of patients who underwent rt-PA
were discharged to locations other than home compared
with approximately 30% of non-rt-PA patients; however,
only 5% of rt-PA patients suffered ICH. This nding suggests
that the greater rates of poor outcomes (i.e., discharge to
short- and long-term facilities), may be related to greater
rates of pretreatment morbidity rather than complications

629

associated with rt-PA. Nonetheless, the possibility that rtPA worsened clinical outcome leading to increased rehabilitation requirements cannot be excluded.
The three most common risk factors conditions associated with acute ischemic stroke in this study were
congenital heart disease, sickle cell disease, and hypercoagulable state. Mackay et al9 reported that up to one third of
childhood arterial ischemic stroke obtained through the
International Pediatric Stroke study were associated with
cardiac disease, with 18% being congenital heart disease.
Nonatherosclerotic arteriopathies were found in 53% of
cases. They also reported that prothrombotic states and
sickle cell disease were present in 13% and 6% of their patient population, respectively. Ganesan et al10 also reported
that one third of their 212 children had structural cardiac
abnormalities and 16% had sickle cell disease. Williams
et al11 reported a series of 92 patients among whom the
most common identiable factor was prothrombotic diseases (25%), including sickle cell disease, followed by cardioembolism (15%), which included PFO, valvular heart
disease, cyanotic heart diseases, myocarditis, and endocarditis. In an epidemiologic study of 26 patients with acute
ischemic stroke from Sweden, investigators found that
cardiac disease (7.7%), mitochondrial disease (7.7%), moyamoya (11.5%), and trauma (11.5%) were the most common
risk factors for acute ischemic stroke.1 A single center study
from China found the most common comorbidities associated with acute ischemic stroke were infections (38%) and
moyamoya (12%).12 Although some risk factors are consistent across studies, it is clear that the proportion of patients
with certain genetic diseases (i.e., moyamoya, mitochondrial diseases, and sickle cell) differs based on the population being studied.
Our study also demonstrated a slight male predominance. This predominance has been demonstrated in
many previously published studies.13-15 A subgroup
analysis of the International Pediatric Stroke Study found
a slight male predominance for acute ischemic stroke
among neonates (61% of patients) and for later childhood
(59%) but no sex differences in mortality. On univariate
analysis, our study found that male sex was associated
with a greater mortality rate; however, this difference
did not persist on multivariate analysis.
In-hospital mortality rates in pediatric arterial ischemic
stroke ranges from 3% to 28%.1,2,16-20 The mortality rate of
4.7% in this study reects of the overall outcome of pediatric
patients hospitalized for acute ischemic stroke in the United
States. Because of smaller sample sizes, few previous
studies have reported etiologic predictors of mortality.
Because of the larger sample size and the time span of our
analysis, we were able to dene mortality rates for multiple
demographic factors and comorbidities. The conditions
associated with the greatest in-hospital mortality in our
study were mitochondrial diseases and hypercoagulable
states. ICH, sepsis, and pneumonia also increased the risk of
early death, and such risk also was greater in those patients
who required ECMO and mechanical ventilation. Goldenberg et al19 noted an 8% mortality rate in cardiac disease, 2%
in dissection, and 0% in sickle cell disease. Rodan et al21
found a 10-year mortality rate of 26% among pediatric
stroke patients with underlying congenital heart disease.

630

D.M. Nasr et al. / Pediatric Neurology 51 (2014) 624e631

Knowledge of these associations is important to guide

further clinical research in management and prognostication.
Similar to previous studies, we demonstrated no increase
in mortality among patients receiving rt-PA.17,22 The lack of
reported fatalities associated with rt-PA is interesting given
that thrombolysis in pediatric patients is more often
considered for the most severe strokes, as suggested by the
greater rate of mechanical ventilation and cerebral angiography among thrombolized patients in our study population. Amlie-Lefond et al22 reported an ICH rate of 27% (4 of
15) among rt-PA patients compared with a substantially
lower rate of 4.9% in our study. The authors did note,
however, that all ICH cases identied in their study were
asymptomatic, which may explain the low reported rates in
the NIS. Regardless, ICH did not inuence mortality in patients who received rt-PA in our analysis.
.Our data also show that those who received rt-PA were
more likely to be discharged to short-term and long-term
facilities, which contrasts with the previous NIS study by
Janjua et al17 that showed a greater incidence of discharge
to short-term facilities and to long-term facilities in the
nonert-PA arterial ischemic stroke group. This difference
is likely attributable to an updated assessment of the
population and the larger sample size in our study,
because Janjua et al included patients admitted from 2000
to 2003 whereas we report ndings from 2001 to 2010.
Despite the American College of Chest Physicians and
American Heart Association discouraging the use of rt-PA
in childhood arterial ischemic stroke, its use continues.
Amlie-Lefond et al22 reported that 2% of the patients in this
prospective study between 1999 and 2007 received rt-PA.
The overall use of rt-PA in this study was calculated to be
1.3% and increased signicantly during the course of the
study.
Our study has limitations. The NIS is an administrative
database and is susceptible to coding errors.6,23 Golomb
et al24 found that the accuracy of ICD-9 codes in identifying
pediatric patients with acute ischemic stroke ranged from
37% to 88%. Qureshi et al25 found that the sensitivity for the
ICD-9 code 99.10 for rt-PA use in ischemic stroke was 55%
and the specicity was 98% in an adult population. This
nding suggests that, using ICD-9 codes alone, we may
have missed a substantial number of pediatric patients
receiving rt-PA. The high specicity, however, suggests a
low rate of contamination from rt-PA use in conditions
such as peripheral blood clots or using lytic therapy to
clear central lines. Furthermore, the accuracy of ICD-9
codes for the treatments and comorbidities examined in
our study has not been established. This database provides
no information regarding screening for cardiac disease,
PFO, hypercoagulability, and other comorbidities. Thus, it
is possible that we may have underestimated the prevalence of these risk factors in this patient population. This
database lacks variables of interest, such as initial stroke
severity, functional outcomes, and cause of death. This is
relevant because a difference in stroke severity might
explain the greater rate of discharge to long-term facilities
among patients treated with thrombolysis. We did not
have information on the dosage and route of the thrombolytic therapy administered. Improvement after hospitalization could not be assessed.

Conclusion

Pediatric arterial ischemic is an uncommon disease with

devastating consequences. The use rate of thrombolytics in
the pediatric acute ischemic stroke population is low but has
increased over the past decade. Patients receiving rt-PA have
greater rates of ICH and discharge to long-term facilities but a
remarkably low mortality. Further clinical trials and large
clinical registries are needed to better characterize the safety
and efcacy of rt-PA use in the pediatric stroke population.
Financial disclosures: J.B.: Editor, Journal of Stroke and Cerebrovascular Diseases; Chief
Editor, Frontiers in Neurology, royalties from up-to-date (Stroke - Section Editor).

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Perhaps its what they call compassion fatigue, the idea that we get so much human suffering thrust in our faces every
day from the media that weve become sort of numbed, weve used up all our reserves of pity, anger, outrage, and can only
think of the pain in our own knee.
David Lodge, 1995