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
(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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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
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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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
* 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
*
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.