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Original Contribution

Intraventricular Thrombolysis in Intracerebral


Hemorrhage Requiring Ventriculostomy
A Decade-Long Real-World Experience
Yogesh Moradiya, MD; Santosh B. Murthy, MD, MPH; David E. Newman-Toker, MD, PhD; Daniel
F. Hanley, MD; Wendy C. Ziai, MD, MPH

Background and PurposeIntraventricular thrombolysis (IVT) is a promising treatment in facilitating intraventricular


clot resolution after intraventricular hemorrhage. We examined in-hospital outcomes and resource utilization after
thrombolysis in patients with intraventricular hemorrhage requiring ventriculostomy in a real-world setting.
MethodsWe identified adult patients with primary diagnosis of nontraumatic intracerebral hemorrhage requiring
ventriculostomy from the Nationwide Inpatient Sample from 2002 to 2011. We compared demographic and hospital
characteristics, comorbidities, inpatient outcomes, and resource utilization measures between patients treated with IVT
and those managed with ventriculostomy, but without IVT. Population estimates were extrapolated using standard
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Nationwide Inpatient Sample weighting algorithms.


ResultsWe included 34044 patients in the analysis, of whom 1133 (3.3%) received IVT. The thrombolysis group had
significantly lower inpatient mortality (32.4% versus 41.6%; P=0.001) and it remained lower after controlling for
baseline demographics, hospital characteristics, comorbidity, case severity, and withdrawal of care status (adjusted odds
ratio, 0.670; 95% confidence interval, 0.5200.865; P=0.002). There was a trend toward favorable discharge (home or
rehabilitation) among the thrombolysis cohort (adjusted odds ratio, 1.335; 95% confidence interval, 0.9831.812;
P=0.064). The adjusted rates of bacterial meningitis and ventricular shunt placement were similar between groups. The
thrombolysis group had longer length of stay and higher inflation-adjusted cost of care, but cost of care per day length
of stay was similar to the non-IVT group.
ConclusionsIVT for intracerebral hemorrhage requiring ventriculostomy resulted in lower inpatient mortality and a
trend toward favorable discharge outcome with similar rates of inpatient complications compared with the non-IVT
group. (Stroke. 2014;45:00-00.)
Key Words: cerebral hemorrhage cerebrospinal fluid shunt meningitis mortality thrombolytic therapy
ventriculostomy

ntraventricular extension of intracerebral hemorrhage (ICH) in a large multicenter clinical trial (Clot Lysis Evaluation
Iis common, occurring in 40% cases of nontraumatic ICH, of Accelerated Resolution of Intraventricular Hemorrhage,
and is a strong independent predictor of mortality after ICH. 1,2 CLEAR III).7 Efficacy in clinical trials may not always be
Intraventricular hemorrhage (IVH) is historically treated by reflected at a population level because of limited generalizabil-
insertion of a ventriculostomy catheter to allow for moni- ity of trials using strict study protocols and variations in clini-
toring of intracranial pressure and drainage of hemorrhagic cal practice. Moreover, clinical trials, because of their limited
cerebrospinal fluid. However, ventriculostomy catheter alone sample size, may not have enough power to study differences
does not promote clot resolution and may become obstructed in infrequent treatment-related adverse events. Therefore,
by intraventricular blood. Intraventricular injection of fibrino- large-scale population studies are necessary to substanti-
lytic agents has been shown to facilitate clearing of ventricular ate the results of clinical trials and evaluate the effectiveness
blood clot, decrease the rate of hydrocephalus in animal mod- of the delivery of treatment in clinical practice to a broader
els, and improve mortality in case series and meta-analysis. 36 target. Although not yet approved by the US Food and Drug
Efficacy of intraventricular thrombolysis (IVT) with Administration, intraventricular tissue plasminogen activator
recombinant tissue plasminogen activator is being evaluated is already used off-label for the treatment of IVH-associated

Received May 12, 2014; final revision received June 18, 2014; accepted July 7, 2014.
From the Division of Neurosciences Critical Care (Y.M., S.B.M., W.C.Z.), Department of Neurology (D.E.N.-T.), Division of Brain Injury Outcomes
(D.F.H.), Johns Hopkins University School of Medicine, Baltimore, MD.
Guest Editor for this article was Louis Caplan, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
114.006067/-/DC1.
Correspondence to Yogesh Moradiya, MD, Department of Neurology, Johns Hopkins University, 600 N Wolfe St, Phipps 455, Baltimore, MD 21287-
7840. E-mail yogeshmoradiyamd@gmail.com
2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.006067

1
2 Stroke September 2014

hydrocephalus in the United States. 8 Frequency of utilization database is discharge after hospitalization rather than an individual
and outcomes of such treatment outside the context of clini- patient, cases transferred to another hospital were excluded to
prevent double counting of the same patient. Patients enrolled in a
cal trials are largely unknown. Therefore, we aimed to study
clinical trial (ICD-9-CM code V70.7) were also excluded (Figure 1).
in-hospital outcomes and resource utilization after IVT for
patients with ICH requiring ventriculostomy in a population-
based, retrospective cohort study from a large national health Comorbidity and Severity Adjustment
We calculated the modified Charlson comorbidity index, 13 a weighted
database.
score of 17 different comorbidities validated for outcome adjustment for
analyses of administrative data sets using ICD-9-CM codes.14 Case
Methods severity was determined using the all patient refined diagnosis-related
groups (APR-DRGs) to assess risk of mortality using an algo-rithm
Data Source developed by 3M Health Information Systems. This proprietary 4-point
We analyzed data from the Nationwide Inpatient Sample (NIS) of the ordinal scale (minor, moderate, major, and extreme risk of mortality) is
Healthcare Cost and Utilization Project from January 1, 2002, to derived from age, primary and secondary diagnoses, and procedures. 15,16
December 31, 2011. NIS is a 20% stratified random sample of all The APR-DRG methodology has been validated to predict mortality
admissions to nonfederal hospitals in the United States. It contains in- more reliably than other severity measures using administrative data sets
formation regarding demographics, hospital characteristics, primary and
and has been used as a severity indicator in prior studies, including those
secondary diagnoses, inpatient procedures, comorbidities, and case
relating to hemorrhagic stroke.1719
severity measures. All diagnoses and procedures are recorded using
International Classification of Diseases version 9 Clinical Modification
(ICD-9-CM) codes. Discharge weights are provided to permit Outcomes Measures
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extrapolation of population estimates from the sampled cases. Detailed The primary outcome of interest was inpatient mortality. Secondary
information regarding the design and the contents of NIS is available at outcomes studied were a composite favorable outcome of discharge to
the Healthcare Cost and Utilization Project web site. 9 home/self-care or rehabilitation and a composite unfavorable outcome of
discharge to skilled nursing facility, hospice, or death. Discharge
Case Selection disposition has been shown to correlate with 90-day and 1-year modified
We first identified cases with primary diagnosis of nontraumatic ICH Rankin Scale with discharge to home or rehabilita-tion indicating higher
with or without IVH by using ICD-9-CM code 431. 10,11 Only patients functional potential than discharge to skilled nursing facility. 20 Other
with IVH requiring ventriculostomy were selected, using proce-dure safety outcomes studied were rates of bacteri-al meningitis, permanent
code 02.2 (before October 1, 2011) and 02.21 (from October 1, 2011). 12 ventricular shunting, gastrointestinal bleed-ing, gastrostomy, and
We excluded cases of age <18 years, traumatic brain in-jury, brain tracheostomy. Resource utilization measures used in the study were
malignancy, cerebral vascular malformations, and those undergoing length of stay (LOS), overall cost of care, and cost of care per day LOS.
aneurysm clipping or coiling to restrict our population to those with Cost of care was obtained by using hospital charges and Healthcare Cost
primary ICH. Thrombolytic treatment was ascertained by procedure and Utilization Project cost-to-charge ratios and was adjusted for
code 99.10. As the ICD-9-CM code does not distinguish the indication inflation to obtain 2013 US dollar values by using yearly inflation rates
and route of thrombolytic treatment delivery, cases with acute stroke, published by the US Department of Labor/Bureau of Labor Statistics. 21
myocardial infarction, pulmonary embolism, and end-stage renal disease
requiring dialysis with possibility of access catheter thrombosis were We also compared the outcomes between the IVT group and the
excluded to minimize the uncertainty of indication for thrombolytic non-IVT group among the following subcohorts to assess robust-
treatment. Because the unit of the NIS ness of the primary results: (1) cases excluding withdrawal of care

Figure 1. Case selection. *Not mutually exclusive.


Moradiya et al Intraventricular Thrombolysis in ICH 3

(ICD-9-CM code V66.7),22 (2) survival >48 hours from admission, components transfusion, performance of cerebral angiography, cra-
(3) high ICH case-volume hospitals (>47 cases per year comprising niectomy and craniotomy, prolonged mechanical ventilation, and
top 2 quartiles), (4) coding for obstructive hydrocephalus, (5) pro- withdrawal of care status. We studied 10-year temporal trends of
longed mechanical ventilation (>96 hours), (6) transferred in from utilization of ventriculostomy in ICH and of IVT among the cases
another hospital. included in the analysis using 2 test for linear association. As rec-
ommended by Healthcare Cost and Utilization Project, population
estimates were obtained by complex sample analyses that consider
Statistical Analysis weights, clustering, and stratification used for NIS sampling. 23 All
Comparisons were made using 2 and Wilcoxon rank-sum tests for analyses were performed by using IBM SPSS version 20 (IBM
categorical and continuous variables, respectively. Multivariate Corporation, NY) with statistical significance set at P<0.05. No ad-
logistic regression was used to adjust for available potential con- justment was made for multiple comparisons because of the explor-
founders in assessing the effect of IVT on outcomes. The following atory nature of the analysis.
covariates were included in all regression models: age, sex, race/eth-
nicity, interinstitutional transfer, hospital characteristics (location, Results
teaching status, geographic region, bedsize, and ICH case-volume
quartile), modified Charlson comorbidity index, 3M APR-DRG risk
Of the 655078 cases with primary diagnosis of ICH, 42422
of mortality subclass, coronary artery disease, diabetes mellitus, hy- (6.5%) underwent ventriculostomy. Among 34044 patients
pertension, atrial fibrillation, dyslipidemia, anemia, valvular disease, meeting eligibility criteria, 1133 (3.3%) patients received
anticoagulation-associated hemorrhage, thrombocytopenia, blood IVT. Patients receiving IVT were slightly younger (median
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Table 1. Baseline Patient and Hospital Characteristics

No IVT (n=32911) IVT (n=1133)


n % n % P Value
Age, y
1864 19325 58.7 751 66.3 0.013
6579 10169 30.9 271 23.9
80 3417 10.4 111 9.8
Female sex 14365 43.7 502 44.3 0.806
Race/ethnicity
White 13970 42.4 434 38.3 0.102
Black 6712 20.4 235 20.7
Hispanic 2638 8.0 131 11.6
Asian or Pacific Islander 1469 4.5 85 7.5
Other 1160 3.5 48 4.2
Missing information 6961 21.2 200 17.6
Transferred in from another hospital 5763 17.5 311 27.4 <0.001
Hospital geographic region
Northeast 5690 17.3 182 16.0 0.020
Midwest 5760 17.5 180 15.9
South 14282 43.4 383 33.8
West 7179 21.8 388 34.2
Hospital location
Rural 584 1.8 10* 0.0 0.133
Urban 32006 98.2 1122 100.0
Teaching hospital 24266 74.5 995 88.7 <0.001
Hospital bed size
Small 1031 3.2 28 2.5 0.428
Medium 5829 17.9 160 14.2
Large 25730 79.0 935 83.3
Hospital ICH case volume quartile (cases/y)
1st (123) 2754 8.4 46 4.1 <0.001
2nd (2447) 7558 23.0 170 15.0
3rd (4884) 9869 30.0 305 26.9
4th (85) 12730 38.7 612 54.0
ICH indicates intracerebral hemorrhage; and IVT, intraventricular thrombolysis.
*Nationwide Inpatient Sample data use agreement prohibits reporting of cells with n10.
4 Stroke September 2014

Table 2. Comorbidities, Inpatient Procedures, and Case Severity

No IVT (n=32911) IVT (n=1133)


n % n % P Value
Modified Charlson comorbidity index
0 16742 51.3 539 47.5 0.038
1 8699 26.7 286 25.2
2 4155 12.7 207 18.2
3 3042 9.3 102 9.0
Hypertension 24669 75.6 925 81.6 0.030
Diabetes mellitus 6749 20.7 280 24.7 0.071
Dyslipidemia 4724 14.4 186 16.4 0.303
Coronary artery disease 3798 11.5 135 11.9 0.829
Congestive heart failure 2609 8.0 101 8.9 0.579
Atrial fibrillation 4309 13.1 142 12.6 0.774
Valvular disease 1154 3.5 55 4.8 0.291
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Anemia 5311 16.1 286 25.2 <0.001


Thrombocytopenia 1610 4.9 55 4.8 0.961
Alcohol abuse 2873 8.8 97 8.6 0.902
Drug abuse 1923 5.9 85 7.5 0.288
Chronic kidney disease 1852 5.6 83 7.3 0.185
Transfusion of packed red blood cells 2812 8.5 122 10.7 0.315
Transfusion of platelets 1758 5.3 58 5.1 0.884
Transfusion of fresh frozen plasma 2837 8.6 124 10.9 0.199
Cerebral angiogram 3498 10.6 217 19.2 <0.001
Craniotomy 1113 3.4 10* 0.4 0.003
Craniectomy 515 1.6 10* 0.5 0.164
Mechanical ventilation >96 h 14773 44.9 662 58.4 <0.001
Obstructive hydrocephalus 20189 61.3 801 70.7 0.003
3M APR-DRG risk of mortality
Minor likelihood of dying 399 1.2 10* 0.9 <0.001
Moderate 1235 3.8 45 3.9
Major 17449 53.5 437 38.6
Extreme 13555 41.5 641 56.6
APR-DRG indicates all patient refined diagnosis-related group; and IVT, intraventricular thrombolysis.
*Nationwide Inpatient Sample data use agreement prohibits reporting of cells with n10.

age [interquartile range]: 58 [5170] versus 61 [5172] were also higher in thrombolysis group (P<0.001 and 0.003,
years; P<0.001). Sex and racial distributions were similar respectively; Table 2).
between the IVT and non-IVT groups. The IVT group had The rate of ventriculostomy utilization in ICH increased
proportionately higher rates of interinstitutional transfer, and from 5.7% in 2002 to 2003 to 7.0% in 2010 to 2011 (trend
patients were more likely to be treated in a teaching hospital P<0.001), and the rate of IVT among the cases included in
and in the western United States. Annual hospi-tal ICH case this analysis also showed an upward trend from 0.6% to
volume was also higher among the treatment group (Table 5.6% across the same interval (trend P<0.001; Figure 2).
1). The thrombolysis group had lower unadjusted inpatient
Patients receiving IVT were more likely to have history of mortality compared with the non-IVT group (32.4% versus
hypertension (P=0.030) and anemia (P<0.001). IVT group also 41.6%; odds ratio [OR], 0.671; 95% confidence interval [CI],
had a higher modified Charlson comorbidity index (P=0.038), a 0.5280.854; P=0.001). Adjusted inpatient mortal-ity
higher rate of undergoing cerebral angiography (P<0.001), and a (adjusted OR, 0.670; 95% CI, 0.5200.865; P=0.002) and the
lower rate of craniotomy (P=0.003). Overall case severity as rate of composite unfavorable discharge were lower
assessed by 3M APR-DRGs risk of mortal-ity was higher in the (adjusted OR, 0.670; 95% CI, 0.5020.894; P=0.007) in the
thrombolysis group (extreme likelihood of dying: 56.6% versus IVT group after controlling for available potential con-
41.5%; P<0.001). The rates of pro-longed mechanical founders. There was a trend toward higher rate of favorable
ventilation and obstructive hydrocephalus discharge in the treatment group (adjusted OR, 1.335; 95%
Moradiya et al Intraventricular Thrombolysis in ICH 5

thrombolysis. This finding is consistent with randomized stud-


ies showing decreased mortality in patients treated with IVT
compared with those with standard treatment. 4,24,25 The 33%
mortality seen in the treatment group in this study is higher than
that reported in the thrombolytic trials, 4,25 but the throm-bolysis
trials excluded patients with predicted poor prognosis such as
hematoma volume >30 cc, age >80 years, and midbrain
compression; the mortality rates in prior observational studies
from clinical chart abstraction are similar to those found in the
current study.26,27 The effect size of survival benefit with throm-
bolytic treatment (33% lower odds of mortality) is also close to
that found in a previous meta-analysis of observational stud-ies
showing decrease in odds by 56% (95% CI, 2175%) with IVT
versus ventriculostomy alone.3 We also found a higher rate of
Figure 2. Temporal trends. Error bar indicates standard error of favorable discharge among the thrombolysis group, which
the population estimate.
reached statistical significance in the subgroups of high ICH
case-volume hospitals and transfer-in from another hospital.
CI, 0.9831.812; P=0.064). The adjusted rates of bacterial
This finding may indicate a potential benefit of the treatment on
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meningitis, permanent ventricular shunting, gastrostomy, and


functional outcome in addition to improved survival, espe-cially
tracheostomy were similar between the 2 groups. The
in hospitals with experience in this procedure. It is well known,
outcome comparisons between the IVT and non-IVT groups
however, that functional recovery continues for months after
after excluding withdrawal of care were comparable to the
hemorrhagic stroke,28 and a well-validated follow-up functional
primary results as shown in Table 3. The outcomes of the
assessment such as 180-day modified Rankin Scale (not
other subcohorts were also largely consistent with the pri-
mary results that included all cases and are shown in Table I available in NIS database) is needed to confirm or refute the
in the online-only Data Supplement. It is noteworthy that the treatment effect on functional outcome.
proportions of patients with favorable outcome was higher The adjusted rates of permanent ventricular shunt place-ment
for IVT versus non-IVT patients for patients treated in high were similar between the 2 comparison groups (adjusted OR,
ICH case-volume hospitals (adjusted OR, 1.497; 95% CI, 1.358; 95% CI, 0.9291.984; P=0.114). This result may indicate
1.0752.086; P=0.017) and for patients transferred from that thrombolytics do not prevent communicating hydrocephalus
another hospital (adjusted OR, 2.159; 95% CI, 1.190 3.918; despite faster clearance of intraventricular blood. Alternatively,
P=0.011). Overall inpatient mortality improved from 43.3% this finding may be driven by a higher survival rate of patients
during 2002 to 2007 to 38.7% during 2008 to 2011 with more severe disease in IVT com-pared with non-IVT
(P<0.001). IVT cohort had lower mortality during 2002 to patients. Of note, consistent with the cur-rent study, a prior
2007 (31.9% versus 43.5%; OR, 0.606; 95% CI, 0.398 meta-analysis found no evidence that IVT reduces the need for
0.924; P=0.019) and a trend toward lower mortality during ventricular shunting procedures.3 Prior studies have shown no
2008 to 2011 (32.6% versus 39.0%; OR, 0.757; 95% CI, increase in infectious complications with IVT. 3 This was also
0.5551.031; P=0.076). found in our study showing similar rates of bacterial meningitis
Patients receiving IVT had longer LOS (median [interquar- in both groups.
tile range]: 18 [1026] versus 14 [625] days; P<0.001]. The This is also the first large study analyzing the hospital char-
IVT group also incurred higher inflation-adjusted cost of care acteristics and resource utilization measures associated with
(58770 [3337988434] versus 42052 [2175771481] US$; IVT. Teaching hospitals and hospitals with larger annual ICH
P<0.001). These rates remained higher in the IVT group after case volume were more likely to use IVT, possibly because of
excluding cases with withdrawal of care. The cost of care per greater availability of resources and technical expertise, more
day LOS was similar between the 2 groups (P=0.285 for all full-time in-hospital staffing, and higher experience with
cases and P=0.270 after excluding withdrawal of care; Table resultant higher comfort level of treating physicians for using
II in the online-only Data Supplement). LOS was similar this infrequent treatment. Higher overall cost associated with
between the 2 groups among the survivors (21 [1529] ver- IVT is largely explained by longer LOS in the thrombolysis
sus 21 [1431] days; P=0.931). Resource utilization group, because the cost of care per day of hospitalization was
measures stratified by risk of mortality subclass revealed not higher. We speculate that preferential improvement in
higher cost of care and LOS in IVT cohort only among cases survival of the most severe cases may have contributed to
with major or extreme likelihood of dying (Table III in the comparative higher cost of care and longer LOS in the IVT
online-only Data Supplement). group. Patients in the nontreatment group had higher rates of
craniotomy. This may reflect differences in the population
considered for surgery and thrombolysis with larger ICH more
Discussion
likely to receive surgical treatment and larger IVH more likely to
This study exploring the outcomes of IVT for IVH requiring
receive thrombolysis.
ventriculostomy at the population level showed that patients
treated with intraventricular thrombolytics had lower inpatient The results of this study should be interpreted with caution
mortality compared with those given standard care without because of inherent limitations of administrative databases, the
6 Stroke September 2014

Table 3. Discharge Outcomes and Inpatient Complications


No IVT IVT Unadjusted OR (95% CI) P Value Adjusted OR (95% CI) P Value
All cases n=32991 n=1133
Inpatient mortality, % 41.6 32.4 0.671 (0.5280.854) 0.001 0.670 (0.5200.865) 0.002
Favorable discharge,* % 23.2 28.1 1.292 (0.9691.724) 0.080 1.335 (0.9831.812) 0.064
Unfavorable discharge, % 61.3 54.1 0.745 (0.5750.965) 0.026 0.670 (0.5020.894) 0.007
Bacterial meningitis, % 3.0 2.0 0.674 (0.2661.708) 0.402 0.525 (0.2021.362) 0.185
Ventricular shunting, % 7.8 11.1 1.470 (1.0272.103) 0.034 1.358 (0.9291.984) 0.114
Gastrointestinal bleeding, % 1.7 1.3 0.731 (0.2622.037) 0.547 0.591 (0.2041.719) 0.334
Tracheostomy, % 2.3 2.9 1.230 (0.5372.817) 0.624 1.401 (0.5923.317) 0.442
Gastrostomy, % 26.0 33.3 1.422 (1.0691.893) 0.015 1.250 (0.9471.650) 0.116
Withdrawal of care excluded n=30581 n=1020
Inpatient mortality, % 38.7 26.9 0.583 (0.4450.764) <0.001 0.614 (0.4600.821) 0.001
Favorable discharge,* % 24.6 30.9 1.365 (1.0221.825) 0.035 1.333 (0.9831.807) 0.064
Unfavorable discharge, % 58.8 49.7 0.693 (0.5280.909) 0.008 0.677 (0.5050.906) 0.009
Bacterial meningitis, % 3.1 2.2 0.720 (0.2851.823) 0.487 0.560 (0.2171.449) 0.232
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Ventricular shunting, % 8.3 11.1 1.388 (0.9482.033) 0.091 1.248 (0.8471.841) 0.263
Gastrointestinal bleeding, % 1.8 1.4 0.774 (0.2762.169) 0.625 0.610 (0.2091.784) 0.367
Tracheostomy, % 2.5 2.6 1.041 (0.4902.213) 0.917 1.142 (0.5222.497) 0.739
Gastrostomy, % 27.3 34.5 1.404 (1.0541.871) 0.020 1.183 (0.9021.552) 0.224
Sum of favorable and unfavorable discharge rates is not 100% as other less common specified (such as home health care, law enforcement, intermediate care
center) and unspecified discharge dispositions were not included in the definitions. CI indicates confidence interval; IVT, intraventricular
thrombolysis; and OR, odds ratio.
*Discharge to home/self-care or rehabilitation.
Discharge to skilled nursing facility, hospice, or death.

retrospective and exploratory nature of the analysis, and a lack To increase the accuracy of case ascertainment, we excluded the
of well-validated ICH severity measures and follow-up data. For cases with confounding diagnoses for thrombolysis indica-tion
.org/ by guest on December 3, 2017

severity measures, the NIS database does not have critically such as ischemic stroke, myocardial infarction, pulmonary
important prognostic elements such as Glasgow Coma Scale and embolism, and those on hemodialysis with possibility of clotted
ICH/IVH volume and location. We have used a previously access lines requiring thrombolytic agents. The temporal trend in
validated DRG-based risk of mortality algorithm to partially the fraction of treated cases is coincident with development and
overcome this limitation and found APR-DRG risk of mor-tality publication of research data supporting the use of throm-bolysis
to be a strong predictor of mortality in a doseresponse fashion in IVH, lending some credibility to our case selection method.
(Table IV in the online-only Data Supplement). The primary Nevertheless, it remains possible that our cases were not all
limitation in assessing any treatment effect from a cases of IVH and that some treated cases were given
nonrandomized study is the risk of confounding by indication thrombolytic agents via some other route than intraventricular.
(ie, the choice to treat with thrombolysis was tied to the final Although diagnosis coding is imperfect, random ICD-9 coding
outcomes in a noncausal way) and survivor bias (ie, patients errors would bias the results toward the null, so are unlikely to
surviving initial days after ICH had more time to be selected for account for the measured differences in mortality rates found in
IVT, thus causing spurious association of IVT with sur-vival). 29 this study. Despite these limitations, we think that large-scale
In this case, however, patients given thrombolysis had higher studies to analyze the effects of infrequently used treatments
APR-DRG severity scores, arguing against our findings being such as IVT by chart abstraction are not feasible and national
solely because of confounding. Additionally, more than two administrative databases such as the NIS provide a more read-ily
third of patients in the IVT group received thrombolysis <2 days accessible tool to validate the effectiveness of this treatment at
after ventriculostomy. Therefore, survivor bias in this study, the population level in routine clinical practice.
although possible, is less likely to impact the mortal-ity In conclusion, using population-based data, we have shown
significantly as suggested by lower mortality in IVT group that IVT in patients with primary ICH requiring ventriculos-
among patients surviving 2 days from admission. Our method tomy may be associated with higher survival to discharge and
of case selection is also an important limitation. ICD-9-CM code perhaps even improved favorable discharge disposition. We
431 is validated to have high positive predictive value for found no evidence that IVT increased the rate of bacte-rial
diagnosing primary ICH from administrative data sets, but its meningitis. This finding is consistent with the results from prior
accuracy in identifying IVH has not previously been studied. 10,11 randomized pilot trials and small observational studies. A more
Similarly, procedure code 99.10 has high specific-ity for definitive conclusion regarding the effect of the treat-ment on
intravenous thrombolysis in stroke. 30 However, no prior study outcomes requires confirmation by large randomized studies,
has validated the use of the code for ascertaining IVT. such as the ongoing CLEAR III trial.7
Moradiya et al Intraventricular Thrombolysis in ICH 7

Sources of Funding 14. Bar B, Hemphill JC III. Charlson comorbidity index adjustment in
intra-cerebral hemorrhage. Stroke. 2011;42:29442946.
National Institute of Health/National Institute of Neurological 15. Averill RF, Goldfield N, Hughes JS, Bonazelli J, McCullough EC, Steinbeck
Disorders and Stroke supported this research with grant number BA, et al. All Patient Refined Diagnosis Related Groups (APR-DRGs),
5U01NS062851. version 20.0. Methodology Overview. 3M Health Information Systems.
http://www.hcup-us.ahrq.gov/db/nation/nis/APR-DRGsV20M
ethodologyOverviewandBibliography.pdf. Accessed December 1, 2012.
Disclosures 16. Edwards N, Honemann D, Burley D, Navarro M. Refinement of the
Dr Hanley was awarded significant research support through grant Medicare diagnosis-related groups to incorporate a measure of severity.
numbers 5U01NS062851 for Clot Lysis Evaluation of Accelerated Health Care Financ Rev. 1994;16:4564.
Resolution of Intraventricular Hemorrhage III and for Minimally 17. Baram D, Daroowalla F, Garcia R, Zhang G, Chen JJ, Healy E, et al.
Invasive Surgery Plus r-tPA for Intracerebral Hemorrhage Evacuation Use of the All Patient Refined-Diagnosis Related Group (APR-DRG)
(MISTIE) III 1U01NS08082. The other authors report no conflicts. risk of mortality score as a severity adjustor in the medical ICU. Clin
Med Circ Respirat Pulm Med. 2008;2:1925.
18. Shen Y. Applying the 3M All Patient Refined Diagnosis Related Groups
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Intraventricular Thrombolysis in Intracerebral Hemorrhage Requiring Ventriculostomy:
A Decade-Long Real-World Experience
Yogesh Moradiya, Santosh B. Murthy, David E. Newman-Toker, Daniel F. Hanley and Wendy
C. Ziai
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Stroke. published online July 24, 2014;


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SUPPLEMENTAL MATERIAL

Intraventricular thrombolysis in intracerebral hemorrhage requiring


ventriculostomy: a decade-long real-world experience

Authors:
1
Yogesh Moradiya, MD
1
Santosh B. Murthy, MD, MPH
2
David E. Newman-Toker, MD, PhD
3
Daniel F. Hanley, MD
1
Wendy C. Ziai, MD, MPH

Author Affiliations:
1 2 3
Division of Neurosciences Critical Care, Department of Neurology, Division of Brain Injury Outcomes,
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
TABLE I. Discharge outcomes and inpatient complications among specified sub-groups

No IVT IVT IVT vs No IVT IVT vs No IVT


Unadjusted OR Adjusted OR
% % P value P value
(95% CI) (95% CI)
Survival beyond 48 hrs [Total N=31,573, no IVT=30,455 (96.5%), IVT=1,118 (3.5%)]
Inpatient mortality 36.9 31.4 0.784 (0.615-0.999) 0.049 0.743 (0.577-0.957) 0.021
Favorable discharge* 25.0 28.5 1.193 (0.895-1.592) 0.228 1.259 (0.932-1.701) 0.133
Unfavorable discharge 58.2 53.4 0.823 (0.633-1.070) 0.144 0.711 (0.535-0.944) 0.018
Bacterial meningitis 3.2 2.1 0.631 (0.249-1.599) 0.327 0.505 (0.194-1.311) 0.160
Ventricular shunting 8.5 11.2 1.372 (0.959-1.963) 0.082 1.304 (0.890-1.911) 0.173
Gastrointestinal bleeding 1.8 1.3 0.709 (0.255-1.975) 0.508 0.595 (0.204-1.740) 0.343
Tracheostomy 2.5 2.9 1.160 (0.504-2.668) 0.726 1.382 (0.585-3.263) 0.460
Gastrostomy 28.1 33.8 1.306 (0.981-1.738) 0.067 1.203 (0.910-1.590) 0.194
High ICH case volume hospitals [Total N=23,516, no IVT=22,599 (96.1%), IVT=917 (3.9%)]
Inpatient mortality 41.2 32.2 0.676 (0.521-0.878) 0.003 0.670 (0.505-0.889) 0.006
Favorable discharge* 23.7 30.2 1.390 (1.019-1.896) 0.037 1.497 (1.075-2.086) 0.017
Unfavorable discharge 60.7 52.8 0.725 (0.544-0.967) 0.028 0.610 (0.446-0.835) 0.002
Bacterial meningitis 3.1 2.5 0.810 (0.317-2.066) 0.657 0.701 (0.264-1.864) 0.476
Ventricular shunting 8.4 10.8 1.328 (0.888-1.985) 0.165 1.254 (0.823-1.912) 0.293
Gastrointestinal bleeding 1.7 1.6 0.926 (0.326-2.631) 0.885 0.815 (0.264-2.513) 0.721
Tracheostomy 2.0 3.5 1.798 (0.757-4.271) 0.177 1.755 (0.743-4.150) 0.200
Gastrostomy 26.1 34.5 1.491 (1.081-2.058) 0.015 1.336 (0.974-1.831) 0.072
Obstructive hydrocephalus [Total N=20,990, no IVT=20,189 (96.2%), IVT=801 (3.8%)]
Inpatient mortality 39.4 27.5 0.581 (0.433-0.780) <0.001 0.587 (0.429-0.803) 0.001
Favorable discharge* 24.5 27.1 1.145 (0.815-1.610) 0.435 1.113 (0.771-1.607) 0.568
Unfavorable discharge 59.5 54.3 0.809 (0.605-1.082) 0.152 0.735 (0.521-1.039) 0.081
Bacterial meningitis 3.3 2.9 0.859 (0.338-2.183) 0.749 0.698 (0.261-1.867) 0.474
Ventricular shunting 11.2 13.2 1.203 (0.791-1.830) 0.386 1.124 (0.716-1.766) 0.611
Gastrointestinal bleeding 1.7 1.2 0.720 (0.208-2.493) 0.602 0.544 (0.146-2.022) 0.363
Tracheostomy 2.2 3.4 1.548 (0.603-3.971) 0.359 1.794 (0.664-4.847) 0.249
Gastrostomy 26.0 37.4 1.697 (1.211-2.379) 0.002 1.681 (1.179-2.396) 0.004
Mechanical ventilation >96hrs [Total N=15,435, no IVT=14,773 (95.7%), IVT=662 (4.3%)]
Inpatient mortality 38.7 33.8 0.809 (0.576-1.136) 0.219 0.753 (0.523-1.084) 0.127
Favorable discharge* 19.0 20.6 1.108 (0.717-1.712) 0.643 1.131 (0.699-1.832) 0.616
Unfavorable discharge 61.7 60.6 0.955 (0.691-1.320) 0.781 0.842 (0.588-1.204) 0.345
Bacterial meningitis 3.6 2.0 0.535 (0.137-2.097) 0.362 0.480 (0.116-1.992) 0.312
Ventricular shunting 8.7 14.4 1.764 (1.149-2.709) 0.009 1.630 (1.031-2.578) 0.037
Gastrointestinal bleeding 2.3 2.2 0.964 (0.343-2.706) 0.944 0.850 (0.279-2.586) 0.774
Tracheostomy 4.3 4.9 1.159 (0.493-2.726) 0.735 1.556 (0.642-3.775) 0.328
Gastrostomy 41.5 52.9 1.584 (1.149-2.185) 0.005 1.684 (1.188-2.386) 0.003
Transferred in from another hospital [Total N=6,074, no IVT=5,763 (94.9%), IVT=311 (5.1%)]
Inpatient mortality 39.1 30.2 0.675 (0.417-1.094) 0.108 0.727 (0.439-1.204) 0.215
Favorable discharge* 26.5 40.0 1.850 (1.080-3.170) 0.023 2.159 (1.190-3.918) 0.011
Unfavorable discharge 58.1 45.8 0.611 (0.368-1.014) 0.055 0.493 (0.270-0.901) 0.022
Bacterial meningitis 3.4 0.0 N/A 0.174 N/A 0.143
Ventricular shunting 9.1 11.9 1.345 (0.717-2.521) 0.353 1.146 (0.558-2.353) 0.711
Gastrointestinal bleeding 1.6 1.6 1.002 (0.173-5.811) 0.998 0.661 (0.116-3.765) 0.641
Tracheostomy 2.1 6.9 3.493 (1.047-11.650) 0.030 2.055 (0.456-9.258) 0.348
Gastrostomy 25.7 32.1 1.368 (0.794-2.355) 0.256 0.958 (0.596-1.542) 0.861
*Favorable discharge is defined as discharge to home/self-care or rehabilitation
Unfavorable discharge is defined as discharge to skilled nursing facility, hospice or inpatient death
Unable to calculate odds ratio due to low number of cases in IVT group
High case volume hospital defined as case volume quartile 3 or 4 (>47 ICH cases/year)
ICH = intracerebral hemorrhage, IVT = Intraventricular thrombolysis
TABLE II. Resource utilization measures

No IVT IVT P value*


Median (IQR) Median (IQR)
All cases
Cost of care, USD** 42,052 (21,757-71,481) 58,770 (33,379-88,434) <0.001
LOS, days 14 (6-25) 18 (10-26) <0.001
Cost of care per day LOS, USD 3,198 (2,380-4,580) 3,309 (2,591-4,238) 0.285
Withdrawal of care excluded
Cost of care, USD** 43,474 (22,757-73,266) 59,556 (34,469-88,434) <0.001
LOS, days 15 (6-25) 18 (11-27) <0.001
Cost of care per day LOS, USD 3,148 (2,344-4,464) 3,266 (2,520-4,230) 0.270

* Mann-Whitney rank sum test, **inflation-adjusted 2013


value IVT=Intraventricular thrombolysis; LOS=length of stay
TABLE III. Resource utilization stratified by severity indicator (risk of mortality)

No IVT IVT P value*


3M APR-DRG risk of mortality subclass Median (IQR) Median (IQR)
All Cases
Cost of care, USD**
Minor likelihood of dying 79,303 (53,526-10,4873) 108,210 (99,286-117,134) 0.162
Moderate 80,683 (58,666-113,907) 71,752 (55,944-102,359) 0.562
Major 38,335 (20,570-65,664) 53,540 (32,085-79,789) <0.001
Extreme 43,342 (22,518-73,400) 58,910 (34,469-88,762) <0.001
LOS, days
Minor likelihood of dying 28 (18-36) 41 (37-45) 0.116
Moderate 28 (20-38) 25 (21-34) 0.468
Major 14 (6-23) 18 (11-26) 0.005
Extreme 13 (5-24) 17 (8-26) 0.002
Cost of care per day LOS, USD
Minor likelihood of dying 2,734 (2,231-3,758) 2,686 (2,206-3,166) 0.689
Moderate 2,996 (2,320-3,694) 3,198 (2,237-3,755) 0.959
Major 2,993 (2,262-4,265) 3,048 (2,332-4,238) 0.928
Extreme 3,507 (2,559-5,070) 3,667 (3,014-4,448) 0.629
Withdrawal of care excluded
Cost of care, USD**
Minor likelihood of dying 81,822 (53,869-106,004) 108,210 (99,286-117,134) 0.166
Moderate 82,443 (58,633-115,089) 90,836 (67,156-110,528) 0.859
Major 39,681 (21,584-66,998) 53,991 (32,424-79,792) 0.001
Extreme 45,280 (23,845-75,420) 59,244 (34,561-88,682) <0.001
LOS, days
Minor likelihood of dying 29 (18-36) 41 (37-45) 0.119
Moderate 28 (20-39) 25 (21-41) 0.517
Major 15 (7-24) 19 (11-26) 0.005
Extreme 15 (6-25) 17 (9-26) 0.017
Cost of care per day LOS, USD
Minor likelihood of dying 2,752 (2,269-3,758) 2,686 (2,206-3,166) 0.660
Moderate 2,996 (2,309-3,719) 3,264 (2,299-3,859) 0.647
Major 2,978 (2,242-4,246) 3,048 (2,336-4,230) 0.925
Extreme 3,428 (2,495-4,969) 3,649 (2,889-4,338) 0.504

* Mann-Whitney rank sum test, **inflation-adjusted 2013 value APR-DRG=all patient refined diagnosis-
related group; IVT=Intraventricular thrombolysis; LOS=length of stay
TABLE IV. 3M APR-DRG as a valid predictor of inpatient mortality in primary intracerebral hemorrhage
requiring ventriculostomy, NIS 2002-2011

Outcome: Inpatient mortality


*
Predictor variable Unadjusted OR P value Adjusted OR P value
(95% CI) (95% CI)
3M APR-DRG risk of
mortality subclass
Minor vs. extreme 0.143 (0.076-0.270) <0.0001 0.116 (0.064-0.210) <0.0001
Moderate vs. extreme 0.168 (0.117-0.241) <0.0001 0.146 (0.103-0.207) <0.0001
Major vs. extreme 0.561 (0.506-0.622) <0.0001 0.560 (0.508-0.617) <0.0001

*
Unadjusted logistic regression


Logistic regression controlling for age, sex, race/ethnicity, inter-institutional transfer, hospital characteristics
(location, teaching status, geographic region, bedsize and ICH case volume quartile), modified Charlson
comorbidity index, coronary artery disease, diabetes mellitus, hypertension, atrial fibrillation, dyslipidemia,
anemia, valvular disease, anticoagulation associated hemorrhage, thrombocytopenia, blood components
transfusion, performance of cerebral angiography, craniectomy and craniotomy, prolonged mechanical
ventilation, withdrawal of care status and intraventricular thrombolysis.

APR-DRG=all patient refined diagnosis-related group