Intracranial aneurysms in children are rare and represent. Treatment of cerebral aneurysms in children: analysis of the Kids Inpatient Database

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1 J Neurosurg Pediatrics 14:23 30, 2014 AANS, 2014 Treatment of cerebral aneurysms in children: analysis of the Kids Inpatient Database Clinical article Aws Alawi, M.D., 1 Randall C. Edgell, M.D., 2 Samer K. Elbabaa, M.D., 3 R. Charles Callison, M.D., 4 Yasir Al Khalili, M.D., 1 Hesham Allam, M.D., 1 and Amer Alshekhlee, M.D., M.Sc. 2,4 Departments of 1 Neurology, 2 Neurointerventional Surgery, and 3 Neurosurgery, St. Louis University; and 4 SSM DePaul Health Center, St. Louis, Missouri Object. Endovascular coiling and surgical clipping are viable treatment options of cerebral aneurysms. Outcome data of these treatments in children are limited. The objective of this study was to determine hospital mortality and complication rates associated with surgical clipping and coil embolization of cerebral aneurysms in children, and to evaluate the trend of hospitals use of these treatments. Methods. The authors identified a cohort of children admitted with the diagnoses of cerebral aneurysms and aneurysmal subarachnoid hemorrhage from the Kids Inpatient Database for the years 1998 through Hospitalassociated complications and in-hospital mortality were compared between the treatment groups and stratified by aneurysmal rupture status. A multivariate regression analysis was used to identify independent variables associated with in-hospital mortality. The Cochrane-Armitage test was used to assess the trend of hospital use of these operations. Results. A total of 1120 children were included in this analysis; 200 (18%) underwent aneurysmal clipping and 920 (82%) underwent endovascular coiling. Overall in-hospital mortality was higher in the surgical clipping group compared with the coil embolization group (6.09% vs 1.65%, respectively; adjusted odds ratio [OR] 2.52, 95% CI , p = 0.05). The risk of postoperative stroke or hemorrhage was similar between the two treatment groups (p = 0.86). Pulmonary complications and systemic infection were higher in the surgical clipping population (p < 0.05). The rate of US hospitals use of endovascular coiling has significantly increased over the years included in this study (p < ). Teaching hospitals were associated with a lower risk of death (OR 0.13, 95% CI ; p = 0.001). Conclusions. Although both treatments are valid, endovascular coiling was associated with fewer deaths and shorter hospital stays than clip placement. The trend of hospitals use of coiling operations has increased in recent years. ( Key Words cerebral aneurysm endovascular coiling outcome surgical clipping vascular disorders Kids Inpatient Database Intracranial aneurysms in children are rare and represent 0.6% 4.6% of the total intracranial aneurysms in the general population. 18,19,26 Aneurysms in children are different from those in adults in several aspects; they are more common in males, with a male to female ratio of almost 3:1, and they tend to be larger, with a higher incidence of giant aneurysms in children compared with adults ,25 Because of the latter difference, aneurysms in children may present with nonhemorrhagic symptoms such as mass effect, headaches, focal neurological deficits, and seizures. The risk of rupture of these aneurysms Abbreviations used in this paper: CCI = Charlson Comorbidity Index; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; ISAT = International Subarachnoid Aneurysm Trial; KID = Kids Inpatient Database; OR = odds ratio; ZIP = Zone Improvement Plan. J Neurosurg: Pediatrics / Volume 14 / July 2014 varied in the literature between 22% and 100% depending on the origin, including dissection, trauma, and infection. 12,17,27,29 Overall, children tend to have better clinical Hunt and Hess grades than adults and they are less susceptible to delayed ischemic deficits from vasospasm. 9,30 Although endovascular coiling has emerged in the past two decades as an alternative modality to surgical clipping or wrapping, both treatment options remain available for ruptured and unruptured cerebral aneurysms. There has been a growing interest in endovascular technology as several studies have suggested a lower procedural mortality rate, higher 1-year survival, lower incidence of vasospasm, and a cost benefit with this technology. 3,7,11,23,24,31 The International Subarachnoid Aneurysm Trial (ISAT) evaluated these treatment modalities for ruptured aneurysms in adults. 21 Although ISAT demonstrated superiority of aneurysm coiling over clipping therapy with lower mortality 23

2 A. Alawi et al. and epilepsy rates at 1 year, results remain controversial in children. There has been no similar clinical trial to compare these treatment options in children. Although there are observational studies addressing the efficacy and safety of endovascular coiling and clipping in children, 1,14,16,27 the largest study included only 33 patients with 37 aneurysms, which showed better clinical outcomes associated with coiling compared with clipping. 1 Because of the lack of evidence in children with intracranial aneurysms, and because of the small sample size in most published series, we sought to evaluate these treatment options in a large sample abstracted from a national database. The main objective of this study was to determine the hospital mortality and complication rates associated with surgical clipping and endovascular coiling of cerebral aneurysms in children. In addition, we evaluated the use of these treatment options in US hospitals in recent years. Methods Study Sample, Data Cleaning, and Comorbidity Index We identified our cohort from the Kids Inpatient Database (KID) for the years 1998 through 2009, by searching for the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for unruptured cerebral aneurysm (437.3), congenital aneurysm and arteriovenous malformation (747.81), and subarachnoid hemorrhage (430). The ICD-9-CM code includes aneurysms of the intracranial portion of the internal carotid artery. We excluded children with secondary diagnoses of traumatic aneurysms ( ), acquired arteriovenous fistulas (447.0), extracranial internal carotid aneurysms (442.81), and traumatic subarachnoid hemorrhages ( , 852.9, , ). To avoid double representation of the same child in the database, the KID data set provides a unique identifier that was used for each admission to prevent counting multiple admissions of the same child. Additionally, we excluded transfers to another short-term hospital if discharge type indicated such a transfer, to avoid double representation of similar patients. Three major ethnic categories were kept, including White, Black, and Hispanic race, and the rest of the ethnic groups along with those missing information on their ethnicity were aggregated into an others category. The Charlson Comorbidity Index (CCI) was used to classify the comorbidity status of each child, but this index did not replace cerebral hemorrhage scales. The CCI is a weighted composite score of 19 different chronic conditions; the index is scored mild if the child has only chronic medical conditions without cancer, moderate if the chronic conditions include cancer without metastasis, and severe if metastatic cancer and AIDS are present. 5 Operations for Cerebral Aneurysms and Outcomes Cerebral aneurysms are treated by either surgical clipping or endovascular coiling; these operations were identified by the procedure codes for aneurysmal clipping (39.51) and endovascular coil embolization and occlusion (39.79 and 39.72). The latter procedure codes (to deploy the coil to treat an intracranial aneurysm) were established in 2001; hence, we included data from the years , which pre-date the establishment of these procedure codes and were used as a baseline for trend analyses. The primary outcome variable was in-hospital mortality rate, which was a separately reported variable in the database. From 14 secondary diagnoses, 3 major neurological and 4 other medical or systemic complications were identified separately in this cohort, including: 1) iatrogenic (or postoperative) cerebrovascular infarction or hemorrhage (ICD- 9-CM code ); 2) obstructive hydrocephalus (331.4); 3) generalized grand mal status epilepticus and epilepsia partialis continua (345.3, 345.7); 4) cardiac complications, including cardiac arrhythmia, acute myocardial infarction, congestive heart failure, and cardiac arrest (997.1, 427.8, 427.9, 428.0, 428.9, 410); 5) pulmonary complications, including acute respiratory distress, respiratory failure, and acute respiratory arrest (518.81, , 799.1); 6) systemic infection, including bacteremia, septicemia, and systemic inflammatory response syndrome (790.7, 038, , ); and 7) acute renal failure, including nontraumatic acute tubular, cortical, and medullary necrosis, and nephropathy otherwise nonspecified (584, 584.5, 584.6, 584.7, 584.8, 584.9, 583). Statistical Analysis The Student t-test and Wilcoxon rank-sum test were used to compare normally distributed and skewed continuous variables. Chi-square or Fisher exact tests used to compare proportions. For stratified analyses to measure the covariate confounding effect, we used the Cochran- Mantel-Haenszel test. Age was stratified into 3 groups: patients less than 1 year old, 2 12 years old, and older than 12 years. Because of the missing observation and collinearities among independent variables, stepwise multivariate logistic regression models were fitted to determine the independent association of significant variables for the outcome variable of in-hospital mortality. The model included the basic demographics (age, sex, and ethnicity), hospital complications, CCI, hospital characteristics, and the type of procedure used to treat cerebral aneurysms. The Hosmer-Lemeshow test was used to evaluate the goodness of fit (the predictive ability of the model). The Cochran-Armitage test was used to assess the trend of hospital use of the treatment modalities per year group ( , , , and ) over the years included in this study. The trend was determined among patients who had documented aneurysm therapy during their hospital course. In addition, we evaluated the trend of hospital mortality stratified by the type of aneurysm treatment and the year group. Statistical significance was determined at p < All statistical tests were performed using SAS 9.2 (SAS Institute). Results From the initial sample of 4401 children with cerebral aneurysms, 770 patients (17.5%) were excluded for transfers between short-term hospitals as well as associated diagnoses of nonaneurysmal subarachnoid hemorrhage or traumatic aneurysms (Fig. 1). From the remain- 24 J Neurosurg: Pediatrics / Volume 14 / July 2014

3 Cerebral aneurysms in children from the KID data set Fig. 1. Flow chart for cohort selection. ing 3631 eligible children, only 1125 (30.98%) had a documented history of treatment with surgical clipping or endovascular coiling of cerebral aneurysms during the same hospital stay; 5 children underwent both treatments and were eliminated from the analysis. In the treated cohort of 1120 patients, 200 children (17.9%) underwent surgical clipping and 920 (82.1%) underwent endovascular coiling (Table 1). The mean age of the treated cohort was years, with patients older on average in the surgical clipping population (14.5 ± 4.9 years vs 11.3 ± 6.6 years, respectively; p < ). During infancy (< 1 year of age), 14.3% of infants underwent coiling whereas 3.5% underwent clipping. A slight preponderance of female sex (50% vs 42.7%, respectively) and Whites (55.8% vs 47%, respectively) were noted in the coil embolization group compared with the surgical clipping group. The rest of the basic demographic information, including family income approximated by ZIP code (Zone Improvement Plan), insurance carrier, and CCI were similar between the two groups. In the treated cohort, 848 patients (75.7%) had unruptured aneurysms and 272 (24.3%) presented with J Neurosurg: Pediatrics / Volume 14 / July 2014 subarachnoid hemorrhage due to ruptured aneurysms (Table 2). Twenty-seven patients died in this cohort, with an overall mortality rate of 2.41%, which was higher in the ruptured aneurysm group (6.99%) than in the unruptured aneurysm group (0.94%, p < ). Among all patients who were treated, the mortality rate was lower in the coil embolization group compared with the surgical clipping group (1.65% vs 6.09%, respectively; p < ). The mortality rate was highest among infants (5.26%) compared with children between 2 and 12 years of age (1.33%) and children older than 12 years (2.45%; p = 0.04). There was no difference in mortality rates among different sexes and races. The overall risk of any hospital-associated neurological or medical complications was higher in the surgical clipping population (30.4% vs 15.7%, respectively). However, the risk of postoperative stroke or hemorrhage was similar between the two treatment groups (3.38% vs 3.20%; p = 0.86). Children in the surgical clipping group had higher risks of hydrocephalus and pulmonary complications (Table 2). Other medical 25

4 TABLE 1: Cohort demographics comparing patients treated with clipping and coiling of unruptured intracranial aneurysms* Demographics All Children Clipped Aneurysm Coiled Aneurysm p Value no. of patients age (yrs) mean ± SD ± ± ± 6.57 < median (IQR) 14 (7 17) 16 (12 18) 13 (5.5 17) groups (%) < > sex (%) female male race (%) White Black Hispanic others income by ZIP code (%) <$25, $26,000 $35, $36,000 $45, >$45, pay (%) Medicare Medicaid commercial other CCI (%) mild moderate severe * IQR = interquartile range. Represents the p value for the differences between coiled and clipped aneurysms. Missing or suppressed information in 21.3%. A. Alawi et al. complications, including cardiac, systemic infection, and acute renal failure, were similar between the treatment groups. The length of hospital stay was longer in the surgical clipping group (median 11 versus 3 days, respectively; p < ), and more expensive hospital charges were found in this group as well (median $100,000 vs $65,000, respectively; p < ). More children were discharged home in the coil embolization group than in the surgical clipping group (90.4% vs 80.3%, respectively; p < ). Stratified analysis according to aneurysmal rupture status showed a higher mortality rate in the surgical clipping population in both groups, but this difference failed to reach statistical significance. The length of hospital stay was shorter in the coil embolization groups in both strata (Table 2). The multivariate logistic regression analysis (Table 3) showed a 3-fold increase in the risk of death in the surgical clipping group compared with the coil embolization group (odds ratio [OR] 2.52, 95% CI ; p = 0.05). Covariates associated with higher mortality included infants compared with older children (OR 6.71, 95% CI ; p < ), the presence of postoperative stroke or hemorrhage (OR 3.35, 95% CI ; p = 0.09), pulmonary complications, and systemic infection. A covariate associated with a lower mortality rate was teaching hospitals compared with non teaching hospitals (OR 0.13, 95% CI ; p = 0.001). Trend analyses for hospital use of these treatment modalities over the years included in the study ( ) favored endovascular coiling. Less than 10 coiling operations were performed during the first period ( ), which increased to 395 during the last period ( ) of the study sample (Fig. 2A). The number of surgical clipping procedures was essentially unchanged; there were 49 and 48 operations in the first 26 J Neurosurg: Pediatrics / Volume 14 / July 2014

5 Cerebral aneurysms in children from the KID data set TABLE 2: Outcomes associated with aneurysmal clipping and coiling in children Outcomes Clipping (n = 200) Total Aneurysms (n = 1120) Unruptured Aneurysms (n = 848) Ruptured Aneurysms (n = 272) Coiling (n = 920) Relative Risk (95% CI) Clipping (n = 70) Coiling (n = 778) Relative Risk (95% CI) Clipping (n = 130) Coiling (n = 142) Relative Risk (95% CI) overall mortality (%) ( )* ( ) ( ) any complication (%) ( )* ( ) ( ) postop stroke ( ) ( ) ( ) hydrocephalus ( )* ( ) ( ) status epilepticus ( ) ( ) pulmonary ( )* ( ) ( )* cardiac ( ) systemic infection ( ) ( ) acute renal failure ( ) ( ) length of stay (days) median (IQR) 11 (6 18) 3 (1 7) 1.43 ( )* 5 (4 8) 2 (1 5) 1.15 ( )* 14 (10 20) 13 (8 21) 1.35 ( )* median (%) hospital charge ($) median (IQR) ( ) 65 ( ) 1.16 ( )* 66.6 ( ) 55.5 ( )** 1.03 ( )* ( ) 157 ( ) 0.86 ( ) median (%) discharge destination (%) home ( )* ( ) ( ) rehabilitation * Statistically significant. Relative risks calculated for clipping relative to coiling in all categories. Hospital charges given in thousands; for example indicates $100,200 and 65 indicates $65,000. Significant difference in medians between the 2 groups (p < ). Nonsignificant difference in medians between the 2 groups (p = 0.36). ** Nonsignificant difference in medians between the 2 groups (p = 0.45). J Neurosurg: Pediatrics / Volume 14 / July

6 A. Alawi et al. Fig. 2. Trend analysis showing the declining rates of surgical clipping and the increasing rates of endovascular coiling in different hospital types: all hospitals (A), non children s hospitals (B), general hospitals with children s units (C), and children s general hospitals (D). In addition, the mortality rates for each type of hospital are listed under each graph. and last periods, respectively. The trend in mortality rates among the surgical clipping population remained higher (5.4% 6.2%) compared with the endovascular coiling group (1% 2.4%) over the years (Fig. 2A). A stratified analysis according to the type of hospital in which the operations were performed showed similar patterns of declining use of surgical clipping compared with endovascular coiling (Fig. 2B D). Most operations were performed in general hospitals with children s units (Fig. 2C; n = 522) followed by non children s hospitals (Fig. 2B; n = 380), and children s general hospitals (Fig. 2D; n = 157). Sixty-one operations were missing the hospital type in the records. The mortality rate was highest (15.8%) in the children who underwent surgical clip placement treated in non children s hospitals and children s general hospitals. Mortality rates with endovascular coiling rose to the highest rate of 5.5% in children s general hospitals. Discussion The results of this study show higher hospital mortality and complication rates associated with surgical clipping of cerebral aneurysms compared with endovascular coiling. Additionally, we found a robust increase in US hospital use of aneurysm coiling compared with essentially unchanged rates of surgical clipping operations. These patterns were consistent among various hospital types. It is important to highlight that these observations are uncontrolled and a clinical trial comparing these treatment options in children is lacking. The ISAT is the largest randomized clinical trial to compare these treatments in an adult population with ruptured aneurysms. 21 The mortality rates in the ISAT ranged between 7.5% in the coil embolization group to 8.3% in the clip placement group, which further increased to 14% in the surgical clipping population and 11% in the coil embolization group at 5 years. 21,22 These rates might not be similar in children and young adolescents because cerebral aneurysms in children are heterogeneous and they vary in origin, morphology, and clinical presentation; 28 therefore outcomes may differ. Observational studies have demonstrated the superiority of the endovascular coiling approach in treating aneurysms in children, but most of these studies are small and uncontrolled. Agid et al. reported that 77% of children treated by endovascular coiling achieved good recovery, compared with 44% in the surgical clipping population. 1 In a case series of 8 patients treated using the endovascular approach, 7 of these patients were successfully treated with complete regression of symptoms. 15 None of the above studies addressed hospital mortality in relation to a given treatment. In this cohort, we found 28 J Neurosurg: Pediatrics / Volume 14 / July 2014

7 Cerebral aneurysms in children from the KID data set TABLE 3: Multivariate logistic regression analysis of independent variables associated with the outcome variable of in-hospital mortality* Comparison OR (95% CI) p Value clipping vs coiling treatment (reference) 2.52 ( ) 0.05 age >12 yrs (reference) <1 vs >12 yrs 6.71 ( ) < vs >12 yrs 0.47 ( ) 0.08 any associated complication (reference) postop stroke or hemorrhage 3.35 ( ) 0.09 respiratory failure 8.67 ( ) < systemic infection 6.22 ( ) 0.01 hospital characteristics teaching vs non teaching 0.13 ( ) large vs small bed size 0.35 ( ) 0.01 large vs medium bed size 1.53 ( ) 0.10 * Hosmer-Lemeshow goodness-of-fit test for the model shows a p value of 0.88, C-statistic of 91%, and model maximum inflation of higher mortality rates among children treated with surgical clipping compared with endovascular coiling (6.09% vs 1.65%, respectively). This trend was present even when the sample was stratified according to the aneurysm rupture status. We also observed that infants had the highest mortality rate compared with children between 2 and 12 years of age and children older than 12 years. This predilection of high mortality in infants might be attributed to a greater tendency to hemorrhage and a higher prevalence of giant aneurysms in the posterior circulation. A systematic review of the literature by Buis et al. identified 131 cases of intracranial aneurysms in infants; 73% presented with initial hemorrhage, and 31% had giant aneurysms more often located in the posterior circulation. 4 It is worth mentioning that the risk of postoperative stroke and cerebral hemorrhage was similar between the two treatment groups in the univariate analysis, even when the sample was stratified according to rupture status. However, postoperative stroke and cerebral hemorrhage predicted a higher mortality rate in the adjusted analysis. There were higher rates of pulmonary complications and systemic infection in the surgical clipping group, both of which predicted a higher mortality rate in the total sample. Interestingly, we found no difference in the rates of acute renal failure between the two treatment populations, suggesting a lack of association between contrast administration during endovascular therapy and contrast-induced nephropathy. A similar observation was made in a large adult patient series. 2 Lastly, a shorter hospital stay was found in the coil embolization group (median 3 vs 11 days, respectively; p < ); a similar observation was noted in the unruptured aneurysm group (median 2 vs 5 days, respectively; p < ). The total hospital charge reflects the length of hospital stay, and as expected, it was much lower in the coil embolization group (median $65,000 vs $100,000, respectively; p < ). The length of hospital stay and the hospital charge was comparable between the two treatments in J Neurosurg: Pediatrics / Volume 14 / July 2014 the ruptured aneurysm group. A similar finding was identified in a previous study assessing the effectiveness of endovascular and neurosurgical treatment for unruptured intracranial aneurysms at hospital discharge in an adult population. 10 Higashida et al. evaluated 2535 treated unruptured cerebral aneurysms in adults, and similar to the results in our study, endovascular coiling was associated with shorter lengths of stay (4.5 vs 7.4 days, respectively) and lower hospital charges ($42,044 vs $47,567, respectively) compared with surgical clipping. 10 The trend of hospital use of endovascular coiling has increased significantly during the years included in this study. Figure 2A demonstrates the number of coiling operations over this period, which has increased from less than 10 during the first period ( ) to 395 during the last period ( ) in the study; the steepest increase was observed from 2001 to On the other hand, the number of surgical clipping operations essentially remained unchanged (49 and 48 operations in the first and last periods, respectively). Therefore, the proportion of aneurysm clipping compared to coiling declined sharply from 98% in the first period to 10.8% in the last period. This increase in coil embolization compared with surgical clipping operations may be due to the observed good outcome rates associated with coil embolization in previous studies. 1,6,8,15,16,20 This study has several limitations. First and foremost, we were unable to address information about aneurysm morphology, anatomical location, and other clinical characteristics such as the clinical grade that might affect decision making in selecting the type of treatment. Also, there is a lack of information on 30-day mortality, rebleeding rates, incidence of vasospasm, experience of surgical/endovascular physicians, and long-term functional outcomes. Coding inaccuracies are a potential concern for any study based on the ICD-9-CM identifiers. Finally, our study is retrospective and susceptible to selection bias. Nevertheless, this study provides important information on the trend of surgical and endovascular operations used to treat cerebral aneurysms in children as well as the determinants of mortality and complications associated with these treatment strategies. Conclusions Although both surgical clipping and endovascular coiling are valid treatment options for cerebral aneurysms in children, the results of this analysis favor endovascular therapy. The trend of hospitals use of coil embolization procedures has increased in recent years. Many unanswered questions in this study can be potentially addressed by a randomized controlled trial in children. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Alshekhlee, Alawi, Edgell, Elbabaa, Callison. Acquisition of data: Alshekhlee. Analysis and interpretation of data: Alshekhlee, Alawi, Khalili. 29

8 A. Alawi et al. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Alshekhlee. Statistical analysis: Alshekhlee. Administrative/technical/material support: Alshekhlee, Alawi, Allam. Study supervision: Alshekhlee, Elbabaa. References 1. Agid R, Souza MP, Reintamm G, Armstrong D, Dirks P, Ter- Brugge KG: The role of endovascular treatment for pediatric aneurysms. Childs Nerv Syst 21: , Alshekhlee A, Mehta S, Edgell RC, Vora N, Feen E, Mohammadi A, et al: Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm. 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AJNR Am J Neuroradiol 27: , 2006 Manuscript submitted September 11, Accepted April 8, Please include this information when citing this paper: published online May 16, 2014; DOI: / PEDS Address correspondence to: Amer Alshekhlee, M.D., M.Sc., Vascular and Neurointervention, SSM Neuroscience Institute, St. Louis University, 1255 DePaul Dr., Ste. 200, St. Louis, MO aalshekh@slu.edu. 30 J Neurosurg: Pediatrics / Volume 14 / July 2014