abstract ARTICLE Kent Page, MStat, h J. Michael Dean, MD, h Frank W. Moler, MD, d on behalf of the THAPCA Trial Group

Transcription

1 Neurobehviorl Outcomes in Children After Out-of-Hospitl Crdic Arrest Beth S. Slomine, PhD,, b, c Fye S. Silverstein, MD, d, e Jmes R. Christensen, MD, c, f, g Richrd Holubkov, PhD, h Kent Pge, MStt, h J. Michel Den, MD, h Frnk W. Moler, MD, d on behlf of the THAPCA Tril Group OBJECTIVE: This study exmined 12-month neurobehviorl outcomes in children who survived out-of-hospitl crdic rrest (OH-CA), were comtose fter resuscittion, nd were enrolled in clinicl tril to evlute trgeted temperture mngement to hypothermi (33.0 C) or normothermi (36.8 C) (Therpeutic Hypothermi fter Peditric Crdic Arrest, Out-of-Hopsitl [THAPCA-OH]; NCT ). METHODS: Bseline functioning ws ssessed by cregiver responses on the Vinelnd Adptive Behvior Scles Second Edition (VABS-II) soon fter OH-CA (bsed on functioning before OH-CA); children with brodly norml bseline functioning (VABS-II 70) were included in the THAPCA-OH primry outcome. VABS-II ws completed gin 12 months lter. Then, fce-to-fce cognitive evlutions were completed. Anlyses evluted chnges in VABS-II composite, domin, nd subdomin scores nd cognitive functioning t follow-up. RESULTS: Ninety-six of 295 enrolled children were live t 12 months; 87 of 96 hd brodly norml bseline functioning (VABS-II 70). Follow-up ws obtined on 85/87. Forty-two of 85 hd VABS-II 70 t 12 months. VABS-II composite, domin, nd subdomin scores declined significntly between bseline nd 12-month follow-up (P <.001). Declines were gretest in older children. Most children displyed well below verge cognitive functioning. Older ge t crdic rrest nd higher bseline VABS-II scores were predictive of greter decline in neurobehviorl function. Tretment with hypothermi did not influence neurobehviorl outcomes. CONCLUSIONS: This is the lrgest study exploring long-term neurobehviorl outcomes in children surviving OH-CA who were comtose fter resuscittion. Results reveled significnt neurobehviorl morbidity cross multiple functionl domins, bsed both on cregiver reports nd performnce on objective cognitive mesures, in survivors 1 yer lter. bstrct Deprtments of Neuropsychology nd f Physicl Medicine nd Rehbilittion, Kennedy Krieger Institute, Bltimore, Mrylnd; Deprtments of b Psychitry nd Behviorl Sciences, c Physicl Medicine nd Rehbilittion, nd g Peditrics, John Hopkins University, Bltimore, Mrylnd; Deprtments of d Peditrics nd e Neurology, University of Michign, Ann Arbor, Michign; nd h Deprtment of Peditrics, University of Uth, Slt Lke City, Uth Dr Slomine oversw ll Vinelnd Adptive Behvior Scles-Second Edition dt collection, nd contributed to mnuscript preprtion nd editing; Drs Silverstein nd Christensen contributed to study design nd mnuscript editing; Mr Pge conducted ll sttisticl nlyses; Dr Holubkov oversw ll sttisticl nlyses; Dr Den prticipted in the study design, oversw ll dt collection, nd served s principl investigtor for the Therpeutic Hypothermi fter Peditric Crdic Arrest dt coordinting center; Dr Moler designed the study nd served s principl investigtor for the Therpeutic Hypothermi fter Peditric Crdic Arrest trils; nd ll uthors pproved the finl mnuscript s submitted nd greed to be ccountble for ll spects of the work. This tril hs been registered t www. clinicltrils. gov (identifier NCT ). WHAT S KNOWN ON THIS SUBJECT: Children who survive out-of-hospitl crdic rrest (OH-CA) re t risk for poor neurologic outcome. No prospective study hs exmined long-term neurobehviorl outcome in detil in survivors of OH-CA or exmined vribles ssocited with these outcome mesures. WHAT THIS STUDY ADDS: Among children who survived OH-CA, were comtose fter resuscittion, nd were enrolled in trgeted temperturemngement tril, mny hd significnt neurobehviorl morbidity 1 yer lter. Older ge ws ssocited with worse outcomes, wheres crdic rrest nd fmily vribles were not. To cite: Slomine BS, Silverstein FS, Christensen JR, et l. Neurobehviorl Outcomes in Children After Out-of-Hospitl Crdic Arrest. Peditrics. 2016;137(4):e PEDIATRICS Volume 137, number 4, April 2015 :e ARTICLE

2 Neurobehviorl outcome in peditric survivors of out-ofhospitl crdic rrest (OH-CA) is uncertin. Studies exploring longterm neurobehviorl outcomes in children surviving OH-CA re limited by smll smples, single sites, specific etiologies, nd restricted ges. 1 7 Some studies include children who sustined in-hospitl or unspecified crdic rrest (CA) loction. 1 4, 7 Children who sustin in-hospitl CA undergo more rpid resuscittion nd less incrementl brin injury. 8 Only 2 studies exmined longterm neurobehviorl outcomes in children who were unresponsive in the erly postresuscittion recovery period. 1,9 Multicenter or popultion-bsed studies conducted in peditric OH-CA hve focused on short-term, globl outcome, described s fvorble versus poor t time of hospitl dischrge. 8, 10 Recently, prospective, multicenter tril, entitled Therpeutic Hypothermi fter Peditric Crdic Arrest, Out-of-Hospitl (THAPCA-OH) evluted 2 trgeted temperture mngement strtegies, hypothermi or normothermi, in children who were comtose fter OH-CA. One yer lter, only 16% of enrolled children displyed fvorble outcome, defined s survivl nd brodly norml functioning (score 70 on Vinelnd Adptive Behvior Scles, Second Edition [VABS-II], cregiver report mesure of neurobehviorl outcome). Outcomes did not differ between tretment groups. 9 This secondry nlysis of dt, collected for THAPCA-OH, reports detils of neurobehviorl nd cognitive outcomes 1 yer fter OH-CA in children with brodly norml bseline function. METHODS Study Popultion A totl of 295 children, ges 2 dys to 18 yers, were enrolled in THAPCA-OH; children with CA ssocited with trum were excluded. Full inclusion nd exclusion criteri, rndomiztion, nd enrollment detils re described elsewhere. 9 At 12-month follow-up, there were 96 confirmed survivors nd 8 for whom vitl sttus could not be determined. Of the 96 survivors, 87 with pre-ca VABS-II scores 70 were eligible for the THAPCA-OH primry outcome. This report nlyzes 12-month neurobehviorl outcomes in 85 of these 87 survivors; 2 cses were lost to follow-up. Assessment Mesures Fmily Functioning Pre OH-CA fmily functioning ws mesured using the Generl Functioning Scle of the Fmily Assessment Device (FAD), 12-item self-reported mesure, scored 0 to 4; scores 2 indicte bnorml functioning. 11 Globl Functioning Mesures Peditric Cerebrl Performnce Ctegory (PCPC) nd Peditric Overll Performnce Ctegory (POPC) 12,13 : PCPC mesures neurologic functioning, wheres POPC mesures overll helth (including neurologic functioning). These clinicin-rted scles hve been recommended for reporting outcome fter peditric CA 14 ; they provide no detiled mesurements or ge-specific normtive dt. Neurobehviorl Outcome Mesures Vinelnd Adptive Behvior Scles- Second Edition (VABS-II) 15 : VABS-II mesures functionl skills nd provides ge-corrected stndrd scores (men = 100, SD = 15) in 4 domins (communiction, dily living, sociliztion, motor skills) nd n overll dptive behvior composite. Ech domin includes subdomins with developmentlly sequenced items, strting with skills typiclly observed in infncy. Subdomin rw scores re gecorrected nd stndrdized s v-scores. With mens of 15 (SD = 3), v-scores rnge from 4.67 SDs below to 3 SDs bove mens, llowing for more precise mesurement of lowfunctioning individuls. VABS-II includes prent/cregiver rting form nd survey interview (using cregiver s informnt) tht yield comprble scores. 15 Telephone dministrtion of VABS-II is vlidted 16 nd Spnish trnsltion of the interview version is vilble. 15 Wechsler Abbrevited Scle of Intelligence (WASI) 17 : WASI mesures intellectul or generl cognitive functioning. Normtive dt re bsed on stndrdiztion smple highly representtive of the English-speking US popultion ged from 6 to 89. The Vocbulry subtest requires individuls to orlly define words. The Mtrix Resoning subtest, mesure of nonverbl fluid resoning, requires individuls to view incomplete gridded ptterns nd select correct responses. Agecorrected stndrdized t-scores re vilble for both. When combined, these subtests yield ge-corrected stndrd scores (men = 100, SD = 15) for generl intellectul functioning (Full Scle IQ). Mullen Scles of Erly Lerning (Mullen) 18 : The Mullen, mesure of cognitive functioning designed for infnts nd young children, hs 4 scles (visul reception, fine motor, receptive lnguge, nd expressive lnguge). Normtive dt re vilble through ge 5 yers 8 months. Age-corrected stndrdized scores re vilble for ech scle s t-scores nd for overll erly lerning composite s stndrd score. For this report, ll t-scores (Mullen nd WASI) nd v-scores (VABS-II) were trnsformed to stndrd scores. Scores >115 re bove verge, 85 to 115 re verge, 70 to 84 re below verge, nd 50 to 69 re well below verge. The lowest possible Mullen composite score is 49. For Mullen scles, rw scores below the lowest score on the normtive tble for ge 2 SLOMINE et l

3 were referred to s lowest possible scores. Procedures Within 24 hours of enrollment, primry cregiver completed the VABS-II rting form to determine bseline functioning. Site reserch coordintors reviewed instructions for form completion nd responses for ccurcy. In some cses, coordintors red items to cregivers nd recorded responses. Demogrphic vribles (ge, gender, rce, ethnicity, cregiver eduction level, nd fmily functioning) were collected. Bseline neurologic nd overll functioning ws rted by reserch stff by using medicl records or cregiver report. CA-relted vribles (etiology, epinephrine doses, rndomiztion tretment) were collected. Twelve months fter OH-CA, trined reserch ssistnt t 1 site (Kennedy Krieger Institute, Bltimore, MD), unwre of tretment group ssignment, conducted semistructured telephone interview to ssess neurobehviorl function (including VABS-II). Subsequently, children prticipted in on-site cognitive testing. Children 6 yers who were reported to hve no consistent mens of functionl communiction on the 12-month VABS-II did not undergo dditionl testing nd were ssigned lowest possible scores for outcome nlyses. For Spnish-speking cregivers, telephone VABS-II interviews were completed in Spnish. Spnishspeking children were tested by Spnish-speking exminers nd for those 6 yers, only WASI mtrix resoning ws dministered. Dt Anlysis Chnge in VABS-II scores were clculted for ech child (12-month bseline score). Distributions of continuous vribles were compred between groups by using t-tests or nlysis of vrince. Pired t-tests were used to test differences between 2 continuous vribles (eg, between bseline nd 12-month scores). Ctegoricl vribles were exmined by using Fisher s exct test. Stndrd liner regression models were fit with chnge in VABS-II score s the outcome vrible nd bseline continuous nd ctegoricl fctors s predictors. A multivrible regression model ws fit by using bseline predictors tht showed trend of ssocition (P <.10) in univrite models. Spermn s rnk correltion coefficients were used to mesure reltionships between VABS-II overll nd domin scores nd Mullen overll nd scle scores. All nlyses were performed by using SAS softwre, version 9.4 (SAS Institute, Inc, Cry, NC). RESULTS Demogrphics nd Bseline Functioning There were no differences in demogrphic vribles t ge of follow-up mong infnts/toddlers (<3 yers), preschool-ged children (3 to <6 yers), or older children ( 6 yers) (Tble 1). Most were <6 yers t 12-month follow-up (rnge yers), white, nd not Hispnic. Averge fmily functioning fell within the norml rnge. Men bseline VABS-II scores were verge for ge. Almost ll children obtined norml PCPC rtings; 5 scored in mild nd 3 in moderte disbility ctegories. In ll groups, OH-CA etiology ws primrily respirtory. Neurobehviorl Functioning Tble 2 displys men bseline nd 12-month follow-up scores for VABS-II dptive behvior composite, domin, nd subdomin scores in both tretment groups. Composite, domin, nd subdomin scores declined significntly. Men bseline scores rnged from 95 to 106, men follow-up scores from 68 to 81 nd men chnge from 23 to 35, nd did not differ between hypothermi nd normothermi groups. At 12 months, one-third hd verge functioning nd one-third hd severely deficient functioning (Supplementl Tble 7). At 12-month follow-up, 49% (42/85) hd composite VABS-II scores 70 nd 38% (32/85) hd composite scores within 1 SD (15 points) of their bselines. Similr frctions hd follow-up domin scores within 1 SD of bselines (Communiction, 32/85 [38%]; Dily Living, 28/85 [33%]; Sociliztion, 37/85 [44%]; Motor, 37/80 [46%]). Tble 3 displys men chnge from bseline to follow-up by ge group. For overll dptive behvior composite nd dily living domin, older children hd greter declines in functioning thn infnts/ toddlers nd preschool children. For communiction, sociliztion, nd motor domins, chnge ws significntly greter for older children compred with infnts/ toddlers. For sociliztion, preschool children lso hd greter declines thn infnts/toddlers. To further chrcterize ge-relted differences nd determine whether ny domins were selectively spred or impired, differences in mgnitudes of declines mong domins were compred. For the youngest group, declines were significntly smller for sociliztion compred with other domins (communiction P =.005, dily living P <.001, motor functioning P <.001). For older children, declines were smller in communiction compred with dily living (P =.03). No differences were noted between domins in preschool children. For ll groups, pproximtely hlf hd overll dptive behvior composite scores 70 t follow-up (infnt/toddlers, 15/28 [54%]; preschoolers, 13/24 [54%]; older, 14/33 [42%]). For the younger groups, pproximtely hlf hd PEDIATRICS Volume 137, number 4, April

4 composite scores within 1 SD of their bselines (infnt/toddlers, 14/28 [50%]; preschoolers, 11/24 [46%]), wheres this occurred in pproximtely one-fifth of the oldest group (7/33 [21%]). Similrly, fewer in the older group hd domin scores tht remined within 1 SD of their bselines (for infnts/toddlers, preschoolers, nd older children respectively: communiction [46%, 46%, 24%], dily living [39%, 46%, 18%], sociliztion [61%, 42%, 30%], nd motor [46%, 50%, 43%]). Cognitive test performnce is presented in Tbles 4 nd 5. On Mullen scles, most obtined scores tht were either the lowest possible or were well below verge rnges for overll composite nd individul scles (Tble 4). Becuse the lowest reported Mullen score is 49 nd mny children performed very poorly, developmentl quotients (developmentl ge/chronologic ge 100) were clculted to more fully understnd the rnge of outcomes s devitions from norml expecttions; 31% hd developmentl quotients <25 for ll 4 scles (Supplementl Tble 8, Supplementl Figure 2) Nineteen older children were eligible for cognitive testing, bsed on VABS-II scores, nd 18 of the 19 prticipted; pproximtely hlf performed in the verge rnge nd the others performed below to well below verge (Tble 5). More children displyed verge or bove performnce on nonverbl thn verbl resoning (72% vs 47%). To exmine cognitive functioning cross the ge rnge, performnce bsed on cognitive composite scores (erly lerning composite from Mullen or 2-subtest composite from the WASI) were exmined. Fortyseven percent were either not eligible for testing on the WASI or obtined the lowest possible Mullen score, 17% obtined bove the lowest possible score, but >2 SDs below the mens, 14% obtined scores between >1 nd 2 SDs below mens, 13% within 1 TABLE 1 Chrcteristics of Study Popultion Age t Time of 12-mo Follow-up, y 0 to <3, n = 28 3 to <6, n = 24 6, n = 33 Age t Rndomiztion, y, men (SD) 0.8 (0.6) 3.3 (1.0) 12.8 (3.8) Gender: boys, n (%) 19 (68) 17 (71) 26 (79) Rce, n (%) White 19 (68) 17 (71) 15 (45) Blck or Africn Americn 4 (14) 5 (21) 13 (39) Other/Unknown 5 (18) 2 (8) 5 (15) Ethnicity, n (%) Hispnic or Ltino 5 (18) 5 (21) 8 (24) Not Hispnic or Ltino 21 (75) 19 (79) 24 (73) Stted s Unknown 2 (7) 0 (0) 1 (3) Cregiver s highest level of eduction, n (%) Some high school or less 2 (7) 4 (17) 12 (36) High school grdute or GED 11 (39) 6 (25) 4 (12) Voctionl school or some college 5 (18) 8 (33) 5 (15) College degree 6 (21) 3 (13) 6 (18) Grdute or doctorl degree 4 (14) 3 (13) 6 (18) Averge FAD score, men (SD) b 1.4 (0.4) 1.3 (0.4) 1.6 (0.5) Pre-CA VABS-II Adptive Behvior 96 (14.7) 102 (15.0) 105 (15.8) Composite Score, men (SD) Pre-CA PCPC, n (%) Norml = 1 24 (86) 23 (96) 30 (91) Mild disbility = 2 1 (4) 1 (4) 3 (9) Moderte disbility = 3 3 (11) 0 (0) 0 (0) Pre-CA POPC, n (%) Good = 1 20 (71) 23 (96) 26 (79) Mild disbility = 2 4 (14) 0 (0) 6 (18) Moderte disbility = 3 4 (14) 1 (4) 1 (3) Totl no. of doses of epinephrine 3.0 ( ) 2.0 ( ) 2.0 ( ) dministered by EMS nd t hospitl, medin (interqurtile rnge) c Primry etiology of CA (fewer ctegories), n (%) Crdiovsculr event 3 (11) 4 (17) 7 (21) Respirtory event 21 (75) 19 (79) 19 (58) Other/Unknown 4 (14) 1 (4) 7 (21) Rndomized tretment, n (%) Hypothermi 17 (61) 14 (58) 20 (61) Normothermi 11 (39) 10 (42) 13 (39) EMS, emergency medicl services. P <.05 for comprison between ge groups. P >.05 for ll other comprisons between ge groups. b Missing for 1 subject in the 0 to <3 ge group. A FAD score < 2 is considered norml fmily functioning. c Missing for 1 subject in the 0 to <3 ge group nd 2 subjects in the 6 ge group. SD of mens, nd 9% >1 SD bove mens. Figure 1 depicts percentge of children within ech rnge for the overll cognitive composite. Reltionships Among Outcome Mesures VABS-II overll scores nd domin scores were strongly correlted with erly lerning composites nd ech Mullen scle; correltions rnged from 0.77 to 0.91 (Supplementl Tble 9). In contrst, correltions between VABS-II overll nd domin scores with WASI composite nd subtest scores were moderte t best (VABS-II motor domin versus WASI composite, r = 0.51, P =.04; VABS-II motor domin versus WASI mtrix resoning, r = 0.51, P =.03; no other significnt correltions). Predictors of Neurobehviorl Decline Tble 6 displys results of univrite nd multivrite regression 4 SLOMINE et l

5 TABLE 2 Men VABS-II Scores t Bseline nd 12-mo Follow-Up nd Men Chnge VABS-II Overll, n = 85 Hypothermi Group, n = 51 Normothermi Group, n = 34 n Bseline Follow-up Chnge b Bseline Follow-up Chnge b Bseline Follow-up Chnge b Scores Scores Scores Scores Scores Scores Adptive behvior composite Communiction Receptive Expressive Written Dily living Personl Domestic Community Sociliztion Interpersonl reltionships Ply nd leisure Coping skills Motor functioning Gross Fine c P vlues were >.05 for comprisons of chnge between tretment groups. VABS-II Subdomin scores were trnsformed to correspond to scle with men 100 nd SD 15. The n s vry becuse of ge differences nd missing dt. Domestic, community, nd coping skills subdomins re not dministered to children <1 y of ge. Written subdomin is not dministered to children <3 y of ge. Score for bseline coping nd for bseline personl functioning were ech missing for 1 subject. Scores for bseline gross motor functioning scores were missing for 4 subjects. Scores for bseline fine motors skills were lso missing for 4 subjects. b P <.001 for ll comprisons of bseline nd follow-up scores except where noted. c P =.003 for comprison of bseline nd follow-up scores. nlyses tht exmined predictors of neurobehviorl outcome, defined s bsolute chnge from bseline to follow-up VABS-II scores. Older ge t CA nd higher bseline VABS-II scores influenced mgnitude of VABS-II declines. No other demogrphic vribles predicted outcome. Neither CA etiology nor tretment group ws ssocited VABS-II chnge. In multivrite model, when controlling for bseline VABS-II, older ge t OH-CA remined ssocited with greter decline in functioning. DISCUSSION This is the first detiled, prospective study of long-term neurobehviorl outcomes in peditric OH-CA survivors who were comtose fter resuscittion. Results reveled significnt declines in ll domins of cregiver-reported neurobehviorl functioning, including communiction, dily living, sociliztion, nd motor skills. TABLE 3 Age Group Comprison of Men Chnge in VABS-II Composite nd Domin Scores from Bseline to 12-mo Follow-up VABS-II Older children sustined gretest declines from bseline functioning. Most children displyed significnt deficits on performnce-bsed Age, y t Time of 12-mo Follow-up 0 to <3, n = 28 3 to <6, n = 24 6, n = 33 P Adptive behvior composite b,c Communiction b Receptive b Expressive b Written d c Dily living b,c Personl b,c Domestic d b,c Community d b Sociliztion <.001 b,e Interpersonl reltionships b Ply nd leisure b,c Coping skills d b,e Motor functioning b Gross Fine P vlues re from n nlysis of vrince test. b P <.05 from t-test compring the 0 to <3 nd 6 ge groups. c P <.05 from t-test compring the 3 to <6 nd 6 ge groups. d Missing for more thn hlf of subjects in youngest ge group becuse domestic, community, nd coping skills subdomins re not dministered to children <1 y of ge nd written subdomin is not dministered to children <3 y of ge. e P <.05 from t-test compring the 0 to <3 nd 3 to <6 ge groups. cognitive testing. Older ge t OH-CA nd higher bseline VABS-II were predictive of decline in neurobehviorl functioning. Other PEDIATRICS Volume 137, number 4, April

6 demogrphic nd CA chrcteristics, including trgeted temperture tretment group, were not predictive of outcomes. Strengths of this study re the prospective design, reltively lrge smple size compred with previous reports, brod ge rnge, high follow-up rte, nd detiled outcome mesures tht ssess multiple domins of functioning, including cregiver report nd objective performnce. Our smple ws restricted to well-chrcterized nd rrely studied group of children who were comtose within the first severl hours fter resuscittion (pin locliztion or responsiveness to commnds were THAPCA-OH exclusion criteri). Although our results cn help clinicins tsked with erly prognostiction to better understnd the rnge of neurobehviorl outcomes in children t highest risk for neurobehviorl morbidity fter OH-CA, results cnnot be generlized to ll OH-CA survivors. Our results revel considerble neurobehviorl morbidity, including significnt declines in ll domins of neurobehviorl functioning. Although mny children displyed severe to profound impirment, we found rnge of outcomes with hlf functioning brodly within norml limits (within 2 SDs of the men) bsed on the VABS-II nd third functioning similrly well on cognitive testing. To our knowledge, with the exception of the THAPCA-OH tril outcome report, 9 only 1 other study hs exmined long-term outcome in children who re comtose fter resuscittion fter CA. In tht study of 25 children who remined comtose for t lest 24 hours fter CA, 23 hd profound cognitive nd motor impirment t lest 1 yer lter. 1 In the THAPCA-OH popultion, mximum durtion of com could not be evluted, becuse children received sedtive nd prlytic gents during the study TABLE 4 Mullen Scles of Erly Lerning Composite nd Scle Scores for Children <6 y Old t Followup (n = 42) Score Rnge Erly Lerning Composite intervention period for temperture mngement. A mjor strength of VABS-II is tht it ssesses multiple domins. We speculted tht domins could be Visul Fine Motor Receptive Reception Lnguge Expressive Lnguge n (%) n (%) n (%) n (%) n (%) Lowest possible score 18 (43) 15 (36) 19 (45) 15 (36) 20 (48) (well below verge) 9 (21) 7 (17) 6 (14) 9 (21) 9 (21) (below verge) 7 (17) 7 (17) 5 (12) 6 (14) 4 (10) (verge) 1 (2) 7 (17) 8 (19) 9 (21) 6 (14) >115 (bove verge) 7 (17) 6 (14) 4 (10) 3 (7) 3 (7) Scores were trnsformed to correspond to scle with men 100 nd SD 15. TABLE 5 WASI Full-Scle IQ Composite nd Subtest Scores for Children 6 y t Follow-Up Score Rnge Full Scle IQ Composite, n = 17 Vocbulry, n = 17 Mtrix Resoning, n = 18 n (%) n (%) n (%) (well below verge) 4 (24) 5 (29) 3 (17) (below verge) 4 (24) 4 (24) 2 (11) (verge) 9 (53) 7 (41) 13 (72) >115 (bove verge) 0 (0) 1 (6) 0 (0) Eighteen dditionl subjects were not eligible for testing becuse they were reported to hve no mens of functionl communiction. One child ws Spnish speking nd therefore ws dministered only Mtrix Resoning. Scores were trnsformed to correspond to scle with men 100 nd SD 15. FIGURE 1 Cognitive composite stndrd scores. selectively ffected or spred t different ges or possibly in different tretment groups. Our results indicte functioning ws dversely ffected with significnt declines 6 SLOMINE et l

7 TABLE 6 Predictors of VABS-II Overll Behvior Composite Chnge from Bseline to 12-mo Follow-up Univrite Multivrible, R 2 = 0.24 Prmeter Estimte (95% CI) R 2 P Prmeter Estimte (95% CI) P Child/Fmily vribles Age, y (continuous) 1.84 ( 2.92 to 0.75) ( 2.36 to 0.25).02 Boys 2.19 ( to 17.49) Cregiver s highest level of eduction Some high school or less [reference] High school grdute or GED 2.13 ( to 22.29) Voctionl school or some college ( 7.48 to 34.37) College degree ( 8.19 to 35.70) Grdute or doctorl degree 6.86 ( to 29.71) Fmily functioning 6.75 ( 9.46 to 22.96) Bseline VABS-II 0.85 ( 1.25 to 0.46) 0.18 < ( 1.12 to 0.31) <.001 CA chrcteristics No. of epinephrine doses b 1.02 ( 3.83 to 1.79) CA etiology (respirtory, crdic, or other) Respirtory [reference] Crdic (0.91 to 37.45) Other/Unknown 2.75 ( to 22.22) Hypothermi 1.81 ( to 15.69) CI, confidence intervl. Missing for 1 subject. b Missing for 3 subjects. cross ll domin nd ll subdomin scores (men declines of 23 to 35 stndrd score points representing men chnge of 22% to 33%). Qulittively, performnce ws most impired for motor nd dily-living skills. This pttern is consistent with recent study of school-ged children who were ssessed by using the originl VABS fter very severe trumtic brin injury (ll requiring rehbilittion nd mny unble to prticipte in performnce-bsed cognitive testing). In tht study, children unble to prticipte in stndrdized testing were impired in ll domins. Similr to our findings, gretest impirment ws noted on motor nd dily living skills domins nd lest in sociliztion. 19 Older children hd gretest declines in VABS-II functioning. Literture exploring the reltionship between ge t brin injury nd neurobehviorl outcome hs yielded inconsistent findings; however, older ge t the time of CA nd follow-up were lso ssocited with worse outcomes in recent study tht exmined long-term neuropsychologicl outcomes in peditric CA. 3 Although there is evidence to suggest tht children who sustin erly diffuse brin injuries re more vulnerble to ongoing impirment thn those injured lter, there my be >1 criticl developmentl period ssocited with heightened risk for poor outcome. 23 Thus, older children my be more vulnerble to the impct of brin injury ssocited with OH-CA thn younger children. However, the testing mesures my hve been more sensitive to detection of chnge in older children (ie, the VABS-II my hve floor effect for very young children), s fewer items re required to obtin score within ech subdomin in the youngest compred with older children. Moreover, mny functionl skills mesured by the VABS-II re not expected to be present in young children nd therefore ge-corrected VABS-II scores my pper less impired in younger reltive to older children with the sme severity of neurobehviorl impirments. For exmple, the youngest children hd significntly smller decline on the sociliztion domin compred with the other 3 domins. Sociliztion items designed for the youngest children focus on simple interctions (eg, shows interest in surroundings by looking round, smiles when pproched) nd few functionl skills need be present to obtin gepproprite scores in this domin. Young children with severe brin injury who re cpble of interction with the environment my obtin VABS-II sociliztion scores tht reflect smller declines from bseline compred with chnges in other domins of functioning or compred with declines in older children in whom more complex sociliztion skills cn be mesured. Longer, prospective studies would be necessry to dequtely ssess the impct of OH-CA on sociliztion skills. Higher bseline VABS-II scores were ssocited with greter decline. We speculte tht new deficits were more redily discerned in children who were functioning the best before OH-CA. No fmily or CA chrcteristics influenced decline in functioning. Contrry to studies of outcome fter other types of PEDIATRICS Volume 137, number 4, April

8 peditric brin injury, fmily fctors commonly ssocited with better outcome, including higher prentl eduction/socioeconomic sttus nd stronger fmily functioning 25, 28 were not protective; however, neurobehviorl impirments were less severe. In our study popultion, fmily fctors likely did not modify outcome due to the severity of neurobehviorl morbidity. Performnce on composite mesure of cognitive functioning for ll survivors enrolled in the THAPCA-OH tril ws previously reported. 9 In this nlysis focusing only on survivors who displyed brodly norml bseline functioning, 36% hd cognitive composite scores within 2 SDs of norml mens, wheres 47% were either not eligible for WASI testing or obtined lowest possible Mullen scores. A recent study exmining cognitive outcome fter peditric CA found much better outcomes with group men IQ score of 87, nd only 6% too low functioning for testing. 3 This study lso found visul to be more impired thn verbl resoning; in contrst, in our study, more children 6 yers performed in the verge rnge on the visul thn the verbl resoning WASI subtest. Severl key differences preclude direct comprison between these studies. vn Zellem et l 3 included both OH-CA nd in-hospitl CA cses, time of follow-up ws much longer (medin 5.6 yers), nd only subset of children were comtose fter resuscittion. Our results need to be considered in the context of severl limittions. Accurcy of bseline functioning my hve been limited, becuse fmilies were sked to complete the VABS-II questionnire during time of crisis within 24 hours of their child s OH-CA. It ws prticulrly chllenging to ccurtely ssess bseline functioning in young infnts. Dt collection in the THAPCA-OH protocol did not include some sources of vrition in ptient chrcteristics nd tretment tht could influence outcome (eg, neuroimging bnormlities, seizure burden, durtion of com, medicl comorbidities, medictions, rehbilittion services received). Moreover, given the limited number of older children eligible for testing, we could not exmine functioning in specific neuropsychologicl domins (eg, executive functions, memory). CONCLUSIONS In this popultion of children who incurred OH-CA nd were comtose fter resuscittion, there ws substntil neurobehviorl morbidity 1 yer lter. Older ge ws ssocited with worse outcomes, wheres CA nd fmily vribles were not. ACKNOWLEDGMENTS We cknowledge the contributions of THAPCA-OH Tril Group collbortors (see Supplementl Informtion Appendix for THAPCA Tril Group Collbortors) nd the fmilies who prticipted in the THAPCA-OH tril. ABBREVIATIONS CA: crdic rrest FAD: Fmily Assessment Device Mullen: Mullen Scles of Erly Lerning OH-CA: out-of-hospitl crdic rrest PCPC: Peditric Cerebrl Performnce Ctegory POPC: Peditric Overll Performnce Ctegory THAPCA-OH: Therpeutic Hypothermi fter Peditric Crdic Arrest, Out-of-Hospitl VABS-II: Vinelnd Adptive Behvior Scles-Second Edition WASI: Wechsler Abbrevited Scle of Intelligence FUNDING: Primry support for the conduct of the Therpeutic Hypothermi fter Peditric Crdic Arrest, Out-of-Hospitl Tril ws funding from Ntionl Institutes of Helth U01HL (Dr Moler) nd U01HL (Dr Den). Additionl support from the following federl grnts contributed to the plnning of the Therpeutic Hypothermi fter Peditric Crdic Arrest Trils: Eunice Kennedy Shriver Ntionl Institute of Child Helth nd Development, Bethesd, MD, HD (Dr Moler) nd HD (Dr Moler). In prt, support ws from the prticiption of the following reserch networks: Peditric Emergency Cre Applied Reserch Network from coopertive greements U03MC00001, U03MC00003, U03MC00006, U03MC00007, nd U03MC00008; nd the Collbortive Peditric Criticl Cre Reserch Network from coopertive greements U10HD500009, U10HD050096, U10HD049981, U10HD049945, U10HD049983, U10HD050012, nd U01HD At severl centers, clinicl reserch support ws supplemented by the following grnts or coopertive greements: UL1TR000003, P30HD040677, P30HD062171, U07MC09174, UL1 RR , nd UL1 TR Funded by the Ntionl Institutes of Helth (NIH). DOI: /peds Accepted for publiction Dec 22, 2015 Address correspondence to Beth Slomine, PhD, Deprtment of Neuropsychology, Kennedy Krieger Institute, 707 N. Brodwy, Bltimore, MD E-mil: slomine@kennedykrieger.org PEDIATRICS (ISSN Numbers: Print, ; Online, ). Copyright 2016 by the Americn Acdemy of Peditrics FINANCIAL DISCLOSURE: The uthors hve indicted they hve no finncil reltionships relevnt to this rticle to disclose. POTENTIAL CONFLICT OF INTEREST: The uthors hve indicted they hve no potentil conflicts of interest to disclose. 8 SLOMINE et l

9 REFERENCES 1. Kriel RL, Krch LE, Luxenberg MG, Jones-Sete C, Snchez J. Outcome of severe noxic/ischemic brin injury in children. Peditr Neurol. 1994;10(3): Mrynik A, Bielwsk A, Wlczk F, et l. Long-term cognitive outcome in teenge survivors of rrhythmic crdic rrest. Resuscittion. 2008;77(1): vn Zellem L, Buysse C, Mdderom M, et l. Long-term neuropsychologicl outcomes in children nd dolescents fter crdic rrest. Intensive Cre Med. 2015;41(6): vn Zellem L, Utens EM, Legerstee JS, et l. Crdic rrest in children: Longterm helth sttus nd helth-relted qulity of life. Peditr Crit Cre Med. 2015;16(8): Li G, Tng N, DiScl C, Meisel Z, Levick N, Kelen GD. Crdiopulmonry resuscittion in peditric trum ptients: survivl nd functionl outcome. J Trum. 1999;47(1): Suominen PK, Sutinen N, Vlle S, Olkkol KT, Lönnqvist T. Neurocognitive long term follow-up study on drowned children. Resuscittion. 2014;85(8): Horisberger T, Fischer E, Fnconi S. One-yer survivl nd neurologicl outcome fter peditric crdiopulmonry resuscittion. Intensive Cre Med. 2002;28(3): Moler FW, Meert K, Donldson AE, et l; Peditric Emergency Cre Applied Reserch Network. In-hospitl versus out-of-hospitl peditric crdic rrest: multicenter cohort study. Crit Cre Med. 2009;37(7): Moler FW, Silverstein FS, Holubkov R, et l; THAPCA Tril Investigtors. Therpeutic hypothermi fter out-ofhospitl crdic rrest in children. N Engl J Med. 2015;372(20): Young KD, Gusche-Hill M, McClung CD, Lewis RJ. A prospective, popultionbsed study of the epidemiology nd outcome of out-of-hospitl peditric crdiopulmonry rrest. Peditrics. 2004;114(1): Epstein B, Bldwin L, Bishop D. The McMster fmily ssessment device. J Mritl Fm Ther. 1983;9(2): Fiser DH. Assessing the outcome of peditric intensive cre. J Peditr. 1992;121(1): Fiser DH, Long N, Roberson PK, Hefley G, Zolten K, Brodie-Fowler M. Reltionship of peditric overll performnce ctegory nd peditric cerebrl performnce ctegory scores t peditric intensive cre unit dischrge with outcome mesures collected t hospitl dischrge nd 1- nd 6-month follow-up ssessments. Crit Cre Med. 2000;28(7): Zritsky A, Ndkrni V, Hzinski MF, et l. Recommended guidelines for uniform reporting of peditric dvnced life support: the Peditric Utstein Style. A sttement for helthcre professionls from tsk force of the Americn Acdemy of Peditrics, the Americn Hert Assocition, nd the Europen Resuscittion Council. Resuscittion. 1995;30(2): Sprrow S, Cicchetti D, Bll D. Vinelnd Adptive Behvior Scles: Survey Forms Mnul. 2nd ed. Minnepolis, MN: NCS Person; Lux AL, Edwrds SW, Hncock E, et l; United Kingdom Infntile Spsms Study. The United Kingdom Infntile Spsms Study (UKISS) compring hormone tretment with vigbtrin on developmentl nd epilepsy outcomes to ge 14 months: multicentre rndomised tril. Lncet Neurol. 2005;4(11): Wechsler D. Wechsler Abbrevited Scle of Intelligence. New York, NY: Psychologicl Corportion; Mullen EM. Mullen Scles of Erly Lerning. Circle Pine, MN: Americn Guidnce Service; Recl M, Brdoni A, Glbiti S, et l. Cognitive nd dptive functioning fter severe TBI in school-ged children. Brin Inj. 2013;27(7-8): Anderson V, Ctropp C, Morse S, Hritou F, Rosenfeld J. Functionl plsticity or vulnerbility fter erly brin injury? Peditrics. 2005;116(6): Anderson V, Ctropp C, Morse S, Hritou F, Rosenfeld JV. Intellectul outcome from preschool trumtic brin injury: 5-yer prospective, longitudinl study. Peditrics. 2009;124(6). Avilble t: www. peditrics. org/ cgi/ content/ full/ 124/ 6/ e Krver CL, Wde SL, Cssedy A, et l. Age t injury nd long-term behvior problems fter trumtic brin injury in young children. Rehbil Psychol. 2012;57(3): Anderson V, Spencer-Smith M, Wood A. Do children relly recover better? Neurobehviourl plsticity fter erly brin insult. Brin. 2011;134(pt 8): Tylor HG, Yetes KO, Wde SL, Drotr D, Stncin T, Minich N. A prospective study of short- nd long-term outcomes fter trumtic brin injury in children: behvior nd chievement. Neuropsychology. 2002;16(1): Yetes KO, Swift E, Tylor HG, et l. Short- nd long-term socil outcomes following peditric trumtic brin injury. J Int Neuropsychol Soc. 2004;10(3): Yetes KO, Tylor HG, Wde SL, Drotr D, Stncin T, Minich N. A prospective study of short- nd long-term neuropsychologicl outcomes fter trumtic brin injury in children. Neuropsychology. 2002;16(4): Ment LR, Vohr B, Alln W, et l. Chnge in cognitive function over time in very low-birth-weight infnts. JAMA. 2003;289(6): McCrthy ML, McKenzie EJ, Durbin DR, et l; Children s Helth After Trum Study Group. Helth-relted qulity of life during the first yer fter trumtic brin injury. Arch Peditr Adolesc Med. 2006;160(3): PEDIATRICS Volume 137, number 4, April

10 Neurobehviorl Outcomes in Children After Out-of-Hospitl Crdic Arrest Beth S. Slomine, Fye S. Silverstein, Jmes R. Christensen, Richrd Holubkov, Kent Pge, J. Michel Den, Frnk W. Moler nd on behlf of the THAPCA Tril Group Peditrics originlly published online Mrch 3, 2016; Updted Informtion & Services References Subspecilty Collections Permissions & Licensing Reprints including high resolution figures, cn be found t: This rticle cites 25 rticles, 3 of which you cn ccess for free t: #BIBL This rticle, long with others on similr topics, ppers in the following collection(s): Neurology Neurologic Disorders sub Crdiology Crdiovsculr Disorders ers_sub Informtion bout reproducing this rticle in prts (figures, tbles) or in its entirety cn be found online t: Informtion bout ordering reprints cn be found online:

11 Neurobehviorl Outcomes in Children After Out-of-Hospitl Crdic Arrest Beth S. Slomine, Fye S. Silverstein, Jmes R. Christensen, Richrd Holubkov, Kent Pge, J. Michel Den, Frnk W. Moler nd on behlf of the THAPCA Tril Group Peditrics originlly published online Mrch 3, 2016; The online version of this rticle, long with updted informtion nd services, is locted on the World Wide Web t: Dt Supplement t: Peditrics is the officil journl of the Americn Acdemy of Peditrics. A monthly publiction, it hs been published continuously since Peditrics is owned, published, nd trdemrked by the Americn Acdemy of Peditrics, 141 Northwest Point Boulevrd, Elk Grove Villge, Illinois, Copyright 2016 by the Americn Acdemy of Peditrics. All rights reserved. Print ISSN: