REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
OfficialPublicationoftheBrazilianSocietyofAnesthesiologywww.sba.com.br
SCIENTIFIC
ARTICLE
The
predictive
value
of
plasma
B-type
natriuretic
peptide
levels
on
outcome
in
children
with
pulmonary
hypertension
undergoing
congenital
heart
surgery
Ayse
Baysal
a,∗,
Ahmet
S
¸as
¸mazel
b,
Ayse
Yildirim
c,
Buket
Ozyaprak
d,
Narin
Gundogus
e,
Tuncer
Kocak
aaClinicofAnesthesiologyandReanimation,KartalKos¸uyoluHighSpecialityTrainingandResearchHospital,Istanbul,Turkey
bClinicofCardiovascularSurgery,SiyamiErsekTrainingandResearchHospital,Istanbul,Turkey
cClinicofPediatricCardiology,KartalKos¸uyoluHighSpecialityTrainingandResearchHospital,Istanbul,Turkey
dClinicofAnesthesiologyandReanimation,TrabzonKanuniCardiovascularResearchandTrainingHospital,Trabzon,Turkey
eClinicofAnesthesiologyandReanimation,S¸anlıurfaTrainingandResearchHospital,¸anlıurfa,S Turkey
Received26August2013;accepted17October2013 Availableonline14January2014
KEYWORDS
Pediatrics;
Congenitalheart
defects;
Cardiopulmonary bypass;
B-typenatriuretic
peptide; Outcome; Postoperative
Abstract
Backgroundandobjectives: Inchildrenundergoingcongenitalheartsurgery,plasmabrain natri-ureticpeptidelevelsmayhavearoleindevelopmentoflowcardiacoutputsyndromethatis definedasacombinationofclinicalfindingsandinterventionstoaugmentcardiacoutputin childrenwithpulmonaryhypertension.
Methods:Inaprospectiveobservationalstudy,fifty-onechildrenundergoingcongenitalheart surgery with preoperative echocardiographic study showing pulmonary hypertension were enrolled.The plasma brain natriureticpeptide levelswere collected before operation, 12, 24and48hafteroperation.Thepatientsenrolledintothestudyweredividedintotwogroups dependingon:(1)DevelopmentofLCOSwhichisdefinedasacombinationofclinicalfindings orinterventionstoaugmentcardiacoutputpostoperatively;(2)Determinationofpreoperative brainnatriureticpeptidecut-offvaluebyreceiveroperatingcurveanalysisforlowcardiac out-putsyndrome.Thesecondaryendpointswere:(1)durationofmechanicalventilation≥72h,
(2)intensivecareunitstay>7days,and(3)mortality.
Results:The differences inpreoperative and postoperative brain natriuretic peptidelevels ofpatientswithorwithoutlowcardiacoutputsyndrome(n=35,n=16,respectively)showed significant differences inrepeatedmeasurementtime points(p=0.0001). The preoperative brainnatriureticpeptidecut-offvalueof125.5pgmL−1wasfoundtohavethehighestsensitivity of88.9%andspecificityof96.9%inpredictinglowcardiacoutputsyndromeinpatientswith pulmonary hypertension. A good correlationwas found between preoperative plasma brain natriureticpeptidelevelanddurationofmechanicalventilation(r=0.67,p=0.0001).
∗Correspondingauthor.
E-mails:[email protected],[email protected](A.Baysal).
Conclusions: Inpatientswithpulmonaryhypertensionundergoingcongenitalheartsurgery,91% ofpatientswithpreoperativeplasmabrainnatriureticpeptidelevelsabove125.5pgmL−1areat riskofdevelopinglowcardiacoutputsyndromewhichisanimportantpostoperativeoutcome. © 2013SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights reserved.
PALAVRAS-CHAVE
Pediatria; Cardiopatias congênitas; Circulac¸ão extracorpórea;
Peptídeonatriurético
tipo-B; Desfecho; Pós-operatório
Ovalorpreditivodopeptídeonatriuréticotipo-Bemresultadosdecrianc¸ascom
hipertensãopulmonarsubmetidasàcirurgiacardíacacongênita
Resumo
Justificativaeobjetivo: emcrianc¸assubmetidasàcirurgiacardíacacongênita,osníveis plas-máticosdepeptídeonatriuréticocerebral(PNC)podemterumpapelnodesenvolvimentoda síndromedebaixodébitocardíaco(SBDC),definidacomoumacombinac¸ãodeachadosclínicos eintervenc¸õesparaaumentarodébitocardíacoemcrianc¸ascomhipertensãopulmonar. Métodos: em um estudo prospectivo observacional,foram inscritas 51 crianc¸assubmetidas à cirurgia cardíaca congênita, com avaliac¸ão ecocardiográfica pré-operatória quemostrava hipertensãopulmonar.OsníveisplasmáticosdePNCforamavaliadosantese12,24e48hapós aoperac¸ão.Ospacientesincluídosnoestudoforamdivididosemdoisgruposemfunc¸ãode:(1) desenvolvimentodeSBDC;(2)determinac¸ãodosvaloresdecortedePNCnopré-operatóriopela análisedacurvadefuncionamentodoreceptorparaSBDC.Osdesfechossecundáriosforam:(1) durac¸ãodaventilac¸ãomecânica≥72h,(2)permanênciaemunidadedeterapiaintensiva>7 diase(3)mortalidade.
Resultados: osníveis de PNCnosperíodos pré-epós-operatório dos pacientescomousem SBDC (n=35, n=16,respectivamente) apresentaram diferenc¸as significantes nostemposde mensurac¸ãorepetidos(p=0,0001).OvalordecortedePNCde125,5pgmL−1nopré-operatório obteve a maior sensibilidade de 88,9% e especificidade de 96,9% para prever a SBDC em pacientescomhipertensãopulmonar.Uma boacorrelac¸ãofoidescobertaentreonível plas-máticodePNCnopré-operatórioedurac¸ãoaventilac¸ãomecânica(r=0,67,p=0,0001). Conclusões: empacientescomhipertensãopulmonarsubmetidosàcirurgiacardíacacongênita, 91%comníveisplasmáticosdePNCacimade125,5pgmL−1noperíodopré-operatórioestãoem riscodedesenvolveraSBDC,queéumdesfechoimportantenopós-operatório.
©2013SociedadeBrasileira deAnestesiologia.PublicadoporElsevierEditoraLtda.Todosos direitosreservados.
Introduction
Plasma brainnatriureticpeptide(BNP)is aneurohormone
that is secreted mainly by the ventricles in response to
an increase in right or left ventricular pressures as well
as volume overload. This neurohormone has natriuretic,
diuretic and vasodilatory properties.1,2 Right ventricular
(RV)dysfunctionreferstoabnormalitiesoffillingor contrac-tion without reference to signs or symptoms of heart failure. Pulmonary hypertension (PH) is defined as; an echocardiographicfindingofameanpulmonaryartery pres-sure ≥25mmHg at rest and heart failure (HF) is defined as; left ventricular pump dysfunction causing dilation, thinned walls, and poor contractility of the heart are important causes of RV dysfunction.1,3 The use of brain natriureticpeptide(BNP)asanindicatorofRVdysfunction in children withPH undergoingcongenital heart surgeries remainslargelyunknown.Previousstudiesdemonstratedan increase in BNP levelspreoperatively and postoperatively in patients with ventricular septal defect or ventricular dysfunction.3---6Inrecentstudies,thegoalwastoinvestigate whether BNP levels can be used as a tool in determi-nation of diagnosis and prognosis of children.6---9 It was reported that plasma BNP levels increased immediately
after congenital heart surgeries despite hemodynamic unloading and alsoa correlation between peakBNP level tocardiopulmonarybypass(CPB)timewasdemonstrated.10 The development of low cardiac output state (LCOS) has recentlybeenusedasapostoperativeoutcomemeasurein patientsundergoingcongenitalcardiacsurgery.11,12LCOSis definedas:tachycardia,poorperipheralperfusion,oliguria, cardiacarrest, need for a 100% increase in pharmacolog-ical support or administration of a new inotropic agent, metabolic acidosis with an increase in base deficit.13,14 There are only a few studies providing data that plasma BNP levels may help to identify children with PH caus-ing RV dysfunction. 6,11,12 Also, it was demonstrated that in children with moderately symptomatic HF, BNP level greater than or equal to 140pgmL−1 and age greater than 2 years are independently associated with poorer outcomes.15
Methods
Patients
Fifty-one patients with a diagnosis of PH and congenital heart disease were enrolled in a prospective observa-tionalstudy design. This study was conductedafter local Ethical Committee approval during the period of July 2008---September 2009. We obtained written informed consent from the patients’ parents or guardians before enrollment in the study. In all patients, the presence of PHandRVdysfunctionwasshownbyanechochardiographic studybeforeoperation.PH isdefinedas:systolicsystemic arterial pressures of at least 35mmHg or exceeding 50% of the systemic mean arterial pressure (MAP).12,15,16 The detectionof PHis basedonthe systolicpulmonaryartery pressure (PAp) calculated from velocitiesof the tricuspid orpulmonaryvalveregurgitationsobtainedby echocardio-graphic Dopplerstudies.16,17 During thismeasurement the followingdiagnosticcriteriawereusedinthisstudy;(1) esti-matedratioofpulmonarytosystemicpressure(Pp/Ps)using Dopplerechocardiography>0.5,(2)SystolicPAp was mea-suredbyDoppler analysisof tricuspidregurgitantvelocity Dopplerflowanddependingonpreviousstudiesonchildren arelationshipofsystolicPAptodiastolicandmeanPApwere madeaccordingly,17 (3) significant tricuspid regurgitation, (4)enlargedor hypertrophiedRVwithoutevidenceof pul-monarystenosis,and(5)intraventricularseptalflattening. RVdysfunctionisdiagnosedbasedontheechocardiographic data and the most important parameter in the diagnosis include:tricuspidannularplane systolicexcursion (TAPSE) valuethatisbasedontheageofthepatienttoassessRV sys-tolicfunction.16,17Theechocardiographicstudiesweredone bythesamepediatriccardiologistpreoperativelyand post-operativelyevery12handifthereareclinicalsignsofPH crisis.
All patients had one of the congenital heart diseases thathavehighriskfordevelopingpostoperativepulmonary hypertensionandtheseinclude:(1)isolatedVSD,(2) Ven-tricularseptaldefect(VSD)andtotalanomalouspulmonary venous connection (TAPVR), (3) Ventricular septal defect (VSD) and partial anomalous pulmonary venous connec-tion(PAPVR),(4) VSDwithor without atrial septaldefect (ASD)and/orPAPVR, and(5) atrioventricularcanaldefect (AVSD).18 Patients with single ventricle pathologies were includedintothestudy.Patientshavingcardiomyopathies, transpositionof the greatarteries,truncusarteriosus and hypoplasticleftheartsyndromewerenotincluded. Inthe study group all patients had systolic Pap values between 40and70mmHgwithsystemicMAPvaluesbetween50and 60%.PatientswithsystolicPApvaluesabove70mmHgwith asystemic MAP value above60% were excluded fromthe study.
All of the patients underwent congenital heart repair surgery with CPB. In our study the same surgical team wasinvolvedin allsurgicalprocedures.Thepatientswere dividedintotwogroups dependingon:(1)Developmentof LCOSpostoperativelyand(2)preoperativeBNPcut-offvalue wasdeterminedbyreceiveroperatingcurve(ROC)analysis forLCOS.11,13,14Oliguriaisdefinedasaurineoutputthatis lessthan1mLkg−1h−1 ininfants,less than0.5mLkg−1h−1 inchildren.19 Inchildren,the normalreferencevaluesfor
heart rate(HR) andsystemicmeanarterial pressurewere providedinpreviousguidelines.20,21
Primaryandsecondaryendpoints
TheprimaryendpointwasthedevelopmentofLCOSwithin 30 daysofsurgery whichis an adverse postoperative out-come.Thesecondaryendpointsincludethedevelopmentof otheradverseoutcomeswithin30daysofsurgeryandthese include:(1)Durationofmechanicalventilationlongerthan 72hpostoperatively,(2)Durationofintensivecareunitstay longerthan7days,(3)Mortalityinthe30-daypostoperative period,and(4)Developmentofothercomplicationssuchas neurologicdeficit,pneumonia,renalfailure,ventricularand atrialarrhythmias,completeatrioventricularblock.
Intraoperativeanestheticmanagement
The preoperative anesthesia management, intraoperative surgical strategy, and pediatric intensive care unit man-agement protocols are explained in detail previously.20 Standard anesthetic monitoringinclude: five-lead electro-cardiogram,pulseoximeter,rectaltemperatureprobe,end tidalcarbon dioxide,arterial catheterandcentral venous catheter.Intraoperativetransesophagealechocardiography wasusedonlyoccasionally.At theendof CPB,RVsystolic and diastolic pressures were measured via an appropri-atesized arterialcatheterinserted totheright ventricle. The catheter was pulled out during closure of the ster-num. RVmean pressurewascollected at theend of CPB. Childrenwithhemodynamicinstabilityhadtransthoracicor transesophagealechocardiographicstudiesdoneintheICU; however, echocardiographic evaluation was not available during operation. During surgery, general anesthesia was inducedwiththeuseofmidazolamatadoseof200gkg−1, fentanylsulfate at a doseof 25gkg−1, andpancuronium bromideatadoseof0.1mgkg−1.Patientsreceivedrepeated dosesoffentanylatadoseof5gkg−1andmidazolamata doseof50gkg−1everyhalfanhourthroughoutsurgeryand inhalationalanestheticofsevofluraneatadoseof1.0---2.0 MAC (minimum alveolar concentration) wasalso provided dependingonsystemicMAP.Neonatesandinfantswere intu-batedwithuncuffedendotrachealtubesandintraoperative andpostoperativeventilationwasmaintainedwith volume-or pressure-controlled ventilation. Perioperative antibi-oticprophylaxisincludedcefazolin.Methyprednisolonewas administered to all patients intravenously in two equally divideddosesof10mgkg−1eachbeforethestartofCPB.
Cardiopulmonarybypassprotocol
used.Moderatehypothermiawasperformedat28◦C.After
cross-clampplacement,bloodcardioplegiawithadditionof potassiumchloride,sodiumbicarbonate,magnesiumsulfate wasgivenatthedoseof30mLkg−1.Intermittentantegrade coldbloodcardioplegiaat4◦Cwasusedformyocardial
pro-tection.Heparinwasneutralizedwithprotaminesulfatein a1:1.5ratio.Intravenousadministrationofvasodilatorand inotropic agents were usedif necessary to weanpatients fromCPB. Volumesubstitution wascarried outwithfresh frozenplasmaor5%humanalbumin.
Perioperativeandpostoperativecare
The parametersthatwerecollectedduringsurgeryandin the 24h postoperative period include:demographic data, CPB,aortic cross-clamp time,HR,systemic MAP,mean RV pressure,centralvenouspressure(CVP),arterialoxygen sat-uration, urine output, fluid balance, inotrope agents and doses.Parameterswererecordedevery30minthroughout theoperative procedureandevery30min intheintensive care unit afteroperation. Postoperative adverse outcome relatedparameters includingdurationof mechanical ven-tilation, intensive care unit (ICU) stay, hospital stay and 30-daymortalitywerecollected.Prolongedmechanical ven-tilation is described asmechanical ventilation (MV) ≥72h followingoperation.22 ProlongedICUstay>7daysis consid-ered as an adverse event.23 The patients were evaluated forpostoperativeadverseeventsevery12hbytheresearch teamincludingaphysicianandresident.
Postoperative PH crisis was defined as an increase in systolic PAp tothe level of systemic MAP or greater and is accompanied by a fall in systemic MAP, a fall in arte-rialorvenousoxygensaturation,orboth.Thedefinitionis alsoassociatedwithhypoxemia,developmentofmetabolic acidosis and/or hypovolemia. In all of our children PAps (systolicandcorrelateddiastolicandmeanPAps)17were cal-culatedbyechocardiographicDopplerstudiesintheICUas describedinpatientssection.The detectionof postopera-tivePH wasbasedonclinical signsandechocardiographic studiesintheICU.16,17Theimportanttreatmentmeasuresto avoidanincreaseofPApsintraoperativelyandinthe post-operativeperiodinICUinclude:(1)Tosupportoxygenation withinspiratoryFiO2 at alevel of 0.6---1.0;(2) Toprovide moderatehyperventilation(tokeepPaCO2levelbetween30 and35mmHg);(3)Toavoiddevelopmentofmetabolic acid-osis(to keep pH above7.4);(4)To provide arecruitment maneuver toavoid ventilation/perfusionmismatch; (5)To provide a low-tidal-volume ventilation to avoid overinfla-tionofaveoli(tokeeptidalvolumebetween6and8mLkg−1 idealbodyweight); (6)Toprovideatemperature manage-menttomaintainbodytemperatureof36---37◦Cattheend
ofCPBand(7)Toprovidea‘‘goal-directed’’fluidandvolume therapytheeffectivenessofhemodinamicalmonitoringwas followedbymeasurementsofnecessary parameterswhich include;HR,systemicMAP,meanRVpressure,centralvenous pressure(CVP),arterialoxygensaturation,urineoutputand fluidbalance.24,25
Children at risk for or with signs of postoperative PH were sedated, received mechanical ventilatory sup-port, and usually received inotropic support (dobutamine and/ordopamine,additionalinotropesofadrenalineand/or noradrenaline). Intravenous nitroglycerin at a dose of
0.5---3gkg−1min−1wasprovidedtopatientsbyappropriate follow-upofthehemodynamicalparameters.Theseagents are administered through a right central venous line in an attempt to keep PAps less than 40% of systemic MAP. The administration of nitroglycerin is recommended for intravenousvasodilation. As the effectof this medication is notlimited to thepulmonary circulation and therefore alsoinducessystemicvasodilation,itsadministrationoften causesaconsiderabledecreaseinsystemicMAPandinvolves theriskofright-ventricularperfusionpressurefallingbelow a critical limit.16,24,25 In the acutely decompensated PH, inhaled nitricoxide, intravenousor inhaled epoprostenol, iloprost,andinotropicsupportarethemostusefulagents.18 However,inourstudyroutineuseoftheseagentswasnot available.
PHrelatedeventsweretreatedwithmanual hyperven-tilation with100% oxygen and intravenous use of opiate; fentanylat a dose of 5---10gkg−1. For patients withPH, mechanical ventilation was continued until the echocar-diographicstudiesshowedwell-controlledmeasurementsof PApsaswellasanimprovementinclinicalstatusindicating thatmyocardial function had recovered. Afterextubation andwhentherewasnolongeranyneedforinvasive moni-toringorvasoactivedrugs,thechildwastransferredtothe ward.16,24,25
Perioperativemeasurements
Plasma levels of BNP and arterial blood gases were col-lectedpreoperatively,12,24and48hpostoperativelyfrom blood samples of an arterial catheter that was inserted at thebeginning of the surgery beforeinduction of anes-thesia. The surgical and medical teams that are involved inthemanagement ofthe studypatients wereblinded to plasmaBNPvalues.TheplasmalevelsofBNPweremeasured usinga commercially available fluorescence immunoassay (Triage,BeckmanCoulter,Inc.SanDiego,California,USA). Themeasurable rangeofBNPonthis deviceis between5 and5000pgmL−1.
Statisticalanalysis
Results
Patientdata
Fifty-onepatientswereincludedintothestudygroup.Age, weight,gender,andthetypeofcardiaclesionsareshownin Table1.Themedian ageofthestudygroupof51patients was1.10years (range0.3---3.0 years).The median weight was7.00kg(range4.00---26.00).Inthisgroup,therewere23 (45.1%)maleand28(54.9%)femalepatients.Inthewhole group, therewere 5 patients (9.8%) with isolated VSD,2 (3.9%)patients with VSDwith TAPVR,13 (25.5%) patients withVSDandPAPVR (w/wo ASD),15(29.4%) patientshad VSDwithASDand16(31.4%)patientshadAVSD.Sixpatients hadtrisomy21.Inthewholegroupofpatients,thirty-seven patients(72.5%)showedoneormoreofthesignsofHFand theseinclude:failuretothrive,respiratorydistress,or hepa-tomegalyandallofthemhadoneormoreofthefollowing medications:digitalis, diureticandangiotensin converting enzymeinhibitor.
The distributionof baselinecharacteristics of patients afterdetermination of preoperative BNPcut-off value by receiver operating curve (ROC) analysis for LCOS is pre-sented in Table 1. The preoperative BNPcut-off value of 125.5pgmL−1 wasfound tohave thehighest sensitivityof 88.9%andspecificityof96.9%inpredictingLCOSinpatients withPH and the area under curve (AUC) is 91% (Fig. 1). Thisfindingshowsthat91%ofpatientswithapreoperative plasmaBNPlevelabove125.5pgmL−1valueisatveryhigh risk of developing LCOS. Perioperative BNPlevels in both groupsareshowninTable2.Thereweresignificant differ-encesin the comparisonof plasma BNPlevelsof patients in repeated measure time points with or without LCOS (p=0.0001).
1.0
0.8
6
4
0.2
0.0
0.0 0.2 0.4
1- Specificity
Sensitivity
0.6 0.8 1.0
For preoperative plasma BNP =125.5 pg/dL, sensitivity=0.87, specificity=0.80,Area under ROC curve=0.91
Figure 1 ROC (receiver operating curve) for preoperative plasmaBNPvalues.Acut-offvalueof125.5pgmL−1hasa
sen-sitivityof88.9%,aspecificityof96.9% andareaunder curve (AUC)of91%forpredictinglowcardiacoutputstate(LCOS).
FiveinfantswithPHdiedwithin30daysafteroperation (n=5/51,9.8%).Twoofthedeathsoccurredwithintwodays aftercorrection.Thetwoinfants,a30-month-old,11-kggirl withhistoryofDownsyndromeandAVSDanda 14-month-old,9-kgboywithVSDandTAPVRweredetected toshow increasedmeanRVpressureandsevererighttoleftshunting withatranscutaneous oxygensaturationof45---84% during surgery.Attheendofthecorrection,bothinfantsrequired inotropicsupportofdopamine,dobutamine,adrenalineand noradrenalineinadditiontovasodilatortherapyofiloprost
Table1 The distributionofbaseline characteristicsofpatients after determination ofpreoperative BNP cut-offvalue by receiveroperatingcurve(ROC)analysisforLCOS.
Patients LCOS(−) LCOS(+) pa preBNP≤125 preBNP>125 pa
n=35 n=16 n=30 n=21
Age(year) 2.00 0.95 0.072 2.00 0.80 0.009
(median,range)a (0.3---3.0) (0.4---3.0) (0.3---3.0) (0.4---3.0)
Weight(kg) 10.0 5.25 0.017 10.3 5.5 0.024
(median,range)a (4.0---26.0) (4.0---26.0) (4.0---26.0) (4.0---26.0)
Male/female,n(%)a 18(35.3)/17(33.3) 5(9.8)/11(21.6) 0.179 15(50)/15(50) 13(61.9)/8(38.1) 0.290 ap<0.05statisticallysignificant,median(range;minimumandmaximum)valueswereprovidedfornotnormallydistributeddata. n(%),number(percentage);LCOS,lowcardiacoutputsyndrome;preBNP,preoperativeplasmabrainnatriureticpeptide(pgmL−1).
Table2 ThecomparisonofchangesinplasmaBNPlevelsovertimebeforeandaftersurgery.
Preoperative BNP
Postoperative 12-hBNP
Postoperative 24-hBNP
Postoperative 48-hBNP
pa
Allpatients(n=51) 138.6± 109.6 482.9± 501.8 850.2± 1186.9 914.6± 1199.3 0.0001 LCOS(−)(n=35) 88.9±60.9 264.2±184.5 337.1±232.5 289.3±222.7 0.0001 LCOS(+)(n=16) 247.1± 115.5 961.3± 637.8 1972.4± 1617.5 1331.9± 2222.5 0.0001
pa 0.0001 0.0001 0.0001 0.0001
Table3 Theparameterssignificantforoutcomeinthe30-dayearlypostoperativeperiod.
Patients LCOS(−)(n=35) LCOS(+)(n=16) pa preBNP≤ 125(n=30) preBNP>125(n=21) pa
CPBatime,(min)b 92.0(30.0---120.0) 102.0(65.0---217.0) 0.003 41.5(10.0---93.0) 56.0(15.0---217.0) 0.128
Aorticcrossclamp time,(min)b
41.0(10.0---77.0) 48.0(20.0---126.0) 0.431 91.0(40.0---120.0) 97.0(30.0---126.0) 0.066
Durationof mechanical ventilation, (day)b
2.0(1.0---5.0) 5.0(2.0---32.0) 0.0001 2.0(1.0---4.0) 4.0(1.0---32.0) 0.0001
Intensivecareunit stay,(day)b
4.0(2.0---10.0) 9.0(2.0---32.0) 0.008 4.0(2.0---15.0) 8.0(2.0---32.0) 0.026
Developmentof LCOS,n(%)
0(0) 16(100) 0.0001 2(6.7) 14(66.7) 0.0001
30-daymortality,
n(%)
0(0) 5(31.3) 0.0001 0(0) 5(23.8) 0.0001
a p<0.05statisticallysignificant;dataarepresentedasmean±standarddeviationorn:number,percentage.
b Median(minimumand maximum)valueswereprovidedfor notnormallydistributeddata.BNP, plasmabrainnatriureticpeptide (pgmL−1);CPB,cardiopulmonarybypass;LCOS,lowcardiacoutputstate.
and nitroglycerine; however, cardiac arrest was unpre-ventable within 36---48h after surgery. In both cases, PH andtricuspidinsufficiency wereobserved by the echocar-diographicDopplerstudiesthatwereperformedwithin12h after surgery. The third patient was a boy at age of 12 monthsandweightof8kg. Hehadadiagnosis ofVSDand PAPVRandthispatientsurvivedfivedaysintheICUbefore cardiac arrest secondary to a PH crisis which was diag-nosed with clinical findings. The two other patients had both ASD and VSD as well as severe PH before surgery. One of them wasa 4-month-old, 5-kgboy and the other wasa3-month-old,4-kggirlwithadiagnosisofDown syn-drome. The male patient survived for only three daysin ICU beforecardiacarrestsecondaryPH crisis whereasthe female patient had symptoms of LCOS within 12h after surgeryrequiringperitonealdialysisandinotropicsupport. Despiteadequatetherapy,shesurvived13daysintheICU beforecardiacarrestsecondarytoLCOS.Inhalationofnitric oxidewasprovidedtoonlysixpatientswithsignsofsevere PHinICU.
Outcomemeasures
TheLCOS (−)grouphadnodeathsandbetter outcomein the 30-day postoperative periodafter surgery whereas in LCOS (+) group 5 of the 16 patients (31.25%) died in the earlypostoperativeperiod.Fourpatientsdiedwithin7days periodwhereasonepatientsurvivedfor12days postopera-tively.Thedataonpostoperativeoutcomesaswellas30-day mortalityareprovidedinTable3.
The differences between systemic MAPs, mean RV pressures and CVPs during surgery and on postoperative 12hareshown inTable 4.SystemicMAPs werenot signif-icantlydifferentbetweenLCOS(−)andLCOS(+)groupsat theendof CPB.However,at thistimepoint, thepatients withLCOSshowedhigherRVpressuresof43.50±5.96mmHg
in comparison to the other patients showing a value of 38.89±5.03mmHg(p=0.005). The comparisonofarterial oxygensaturationandCVPshowednosignificantdifferences betweengroups (98.04±2.56%vs.96.01±9.24%,p=0.191 and 10.26±2.15mmHgvs. 10.19±2.29mmHg, p=0.385,
Table4 Divisionofintraoperativeandpostoperativecharacteristicsofpatientsdependingonlowcardiacoutputstate.
Parameters GroupLCOS(−)(n=35) GroupLCOS(+)(n=16) pa
Intraoperativehemodynamicaldata(attheendofCPB)
Heartrate(/min) 159.42± 9.25 156.30± 8.82 0.213 Meansystemicarterialpressure(mmHg) 81.91±14.08 77.44±11.44 0.359 Meanrightventricularpressure(mmHg) 39.89± 5.63 43.50± 5.96 0.005 Arterialoxygensaturation(%) 98.04±2.56 96.01±9.24 0.191 Centralvenouspressure(mmHg) 10.26± 2.15 10.19± 2.29 0.385
Postoperative12hhemodynamicdata
Heartrate(min) 165.42± 7.81 166.42± 8.43 0.581 Meansystemicarterialpressure(mmHg) 79.94±13.16 81.44±10.98 0.329 Arterialoxygensaturation(%) 95.75± 3.80 86.06± 7.57 0.0001 Centralvenouspressure(mmHg) 10.14±2.43 16.19±3.26 0.0001
respectively). On postoperative 12h, while there was no differencein comparisonof systemicMAPs between LCOS (−)andLCOS(+)groups,patientswithLCOSshowedhigher
CVpsandlowerarterialoxygensaturationsincomparisonto thepatientswithoutLCOS(95.75±3.80%vs.86.06±7.57%,
p=0.0001 and 10.14±2.43mmHg vs. 16.19±3.26mmHg p=0.0001,respectively)(Table4).
A good correlation was found between preoperative plasma BNP level and duration of mechanical ventila-tion(r=0.67,p=0.0001);however,weakcorrelationswere presentbetweenpreoperativeplasmaBNPlevelandaortic crossclamptime(rho=0.431,p=0.002),intensivecareunit stay(r=0.42,p=0.002)andmortality(r=0.47,p=0.001).
Discussion
Themajorfindingsofthisstudyinclude:(1)Incomparisonto preoperativeplasmaBNPlevels,postoperativevaluesshow significant increase in repeatedmeasurement time points of 12,24 and 48h after surgery inpatients with or with-outdevelopmentofLCOS in thepostoperativeperiod.(2) In patients with PH undergoing congenital heart surgery, 91%ofpatientswithpreoperativeplasmaBNPlevelsabove 125.5pgmL−1areathighriskofdevelopingLCOSwhichisan importantriskfactorfordeterminationofearly30-day post-operativeoutcome.(3)ThepreoperativeplasmaBNPlevel accuratelypredictspostoperativeLCOSinchildrenwithPH andthesefindingshavenotbeenreportedpreviouslyin stud-iesinvestigatingpulmonaryhypertensioninchildren.16,24---27 (4)Secondaryoutcomemeasuresintheearlypostoperative periodsuchasdurationofmechanicalventilationand inten-sivecareunitstaywereprolongedinpatientswithLCOSin comparisontopatientswithoutLCOS(p=0.0001,p=0.008, respectively).
InthestudybyHoffmannetal.,238patientsweredivided intothreegroupsas:placebo,low-dosemilrinone,and high-dose milrinonegroups and LCOSrates were 25.9%,17.5%, and11.7%respectivelyinthefirst36haftercongenitalheart surgery. LCOS patients had a significantly longerduration ofmechanical ventilation(3.1 vs.1.4days,p=0.001)and hospitalstay(11.3vs.8.9days,p=0.016)incomparisonto patientswithoutLCOS.13
In children with congenital heart disease who present withsignificantPH and predominantleft-to-rightshunt,a ratioofpulmonary tosystemicresistance≤2/3is usedas
athresholdassociatedwithbettersurgicaloutcomes.18The causesofsignsofdevelopmentofRVfailureatthe opera-tionmayberelatedto:(1)differentinitialvolumestatus, (2) varying baseline end-diastolic volumes, or (3) varying degreesof ischemic burden and injury and for treatment ofthis pathophysiologicalfindingan initialfluid challenge ofnormalsalinefollowedbydiuresisisrequired.17,24Inthe studybyBandoetal.childrenwithAVcanal,truncus arterio-sus,TAPVR,transpositionofthegreatarteries,hypoplastic left heart syndrome, and VSD were determined to be at highrisk for thedevelopmentof postoperativepulmonary hypertensiveevents.25Inthisstudy880patientsathighrisk of developing postoperative pulmonary events were eval-uatedand the number of pulmonary hypertensive events wererecordedin138(16%)ofthepatientsandthe mortal-ityinthispatientpopulationwas75(8.5%).Thedatashow
thatthemortalityrates inchildrenwithadiagnosisof PH undergoing congenitalheart repair surgery is significantly higherthanpatientswithoutPH.Furthermore,thenumber ofearlydeathsassociatedwithPHeventwas31(22.5%)in 138patients.RegardingpatientswithseverePHcrisis,the studybyBandoetal.foundamortalityof35.5%(n=11/31) in 1990 through1994 whereas in recent studies it is also notedthatonecomplicationinadditiontosimplecorrection of congenital heart diseaseis associated witha mortality rateupto9.0%.26 Lindbergetal.reportedamortalityrate of 7.4%(n=2/27).24 The mortalityrateinourstudy group is9.8%andthisprimaryoutcomeresultiscompatiblewith previousreports.24---27
Ourpatientspresentedlatertotheclinicatsickerhealth statusincomparisontothereportedcaseseriesinthe liter-ature.Inourstudygroupthemedianageof12monthswas higherthanthemedianage(4.2---8.6months)ofthereported studiesshowingthatearlydiagnosesandtreatmentwasnot always possible inour groupof patients.24,27 In ourstudy, thepatients withLCOShadlowermean bodyweightsand theincidenceof pretermbirth historyinthis groupwas9 outof 16 patients(56.3%) whereaspatients withoutLCOS hadhighermeanbodyweightwithanincidenceofpreterm birth history was 4 out of 35 (11.4%) (Table 2). Our find-ingssupportthedataprovidedbytheliteraturethatfailure tothriveisasignificantfindingincongenitalheartdiseases withPH.3Remarkably,outcomeofpreterminfantswithCHD wassignificantlyworsethanthatforfull-terminfants.27
An increased PVR and PAP and RV failure may have played an important role in the cause of deaths of our patients. In prevention of PH crisis in the early postop-erativeperiodinhalednitric oxide,intravenousorinhaled epoprostenol, iloprost, and inotropic support are the most useful agents andnewer emergingmethods include: extracorporealmembraneoxygenationandcontinuous mon-itoringofmixedvenoussaturation(SvO2)throughpulmonary artery catheter.16,18,24 We were not able to perform pul-monary artery catheterization in all of our patients and inclusionof thedataofthesemeasurementswasnot pos-sible in our study although our observations support that pulmonary artery catheterization is beneficial in detec-ting pulmonaryhypertensive eventsinthe earlyperiod.It has been reportedthat PAps and CVPs gradually increase andSvO2 decreasesbeforeseverepulmonary hypertensive crisesoccur.24,25,28Hypoxemia,hypercapnia,metabolic acid-osis, restlessness, and tracheal suctioning may increase pulmonaryvasoreactivityandthustriggerpostoperative pul-monaryhypertensiveevents.Forpreventionoftheseevents, moderatehyperventilationwithahighinspiredoxygen frac-tion,sedation,and paralysishave been usedinourstudy. Inhaled nitricoxidewasavailable inonly sixpatientswho hadseverePHcrisisintheICUinourstudygroup.
study,postoperativeBNPlevelsweresignificantlyhigherin patientswithuniventricularhearts(median1300pgmL−1).10 Oosterhofandhiscoworkersshowedthatinuniventricular heart morphologies with systemic right ventricular dys-functions,preoperativeBNPlevelsgreaterthan45pgmL−1 detectrightventricularinsufficiencieswithasensitivityof 78% and a specificity of 84%.29 Mainly, these two studies provide data for need of further investigation of pre-operative plasma BNP levels in children with pulmonary hypertensionundergoing congenitalheart surgeryand our studyprovidesvaluabledatathatapreoperativeplasmaBNP levelgreater than125.5pgmL−1 detectsLCOSwhich isan importantprognosticriskfactorintheearly30-day postop-erativeperiodwithasensitivityof88.9andaspecificityof 96.9%.LCOShasbeenusedasatooltodetermineoutcome after congenital heart surgeries.11,29 An important finding is thatthe patientswithLCOS showedsignificantly higher preoperativeBNPvaluesinpatientsundergoingcongenital heartsurgerywithCPB.Ourobservationissimilartoarecent study by Hsuand hiscolleagues that: (1) LCOS is associ-ated with poor postoperative outcome, (2) LCOS actually developsbefore48hafteroperation,(3)PostoperativeBNP levelsdonotpredictLCOS;however,thesevaluesare associ-atedwithLCOS.11ApreoperativeBNPvalueorpostoperative 2,4,12 or24hBNPvalueswerereportedasindependent biomarkers of postoperative outcome related risk factors suchasICUstayorprolongedmechanicalventilation.24,27---30 A correlation between plasma BNP levelsand duration of mechanical ventilation was shown in previous studies by Hsu and Shih et al.12,31 The study by Hsu and his co-workers was mainly on neonates undergoing Norwood or two-ventriclecorrectiverepairanditsupportsthevaluable roleofBNPinpredictingpoorpostoperativeoutcomeafter congenital surgery with CPB especially in the 24h period afteroperation.31 InarecentstudyShihandhiscolleagues showed that 12-h B-type natriuretic peptide levels were associatedwiththedurationofmechanicalventilationand thepresenceofaLCOSaftersurgicalintervention.Intheir study,thecut-off value of 12h B-typenatriureticpeptide levelgreaterthan540pgmL−1predictedmechanical venti-lationbeyond48hwithasensitivityof88.9%andaspecificity of82.5%.12Inourpatientpopulation,agoodcorrelationwas foundbetweenpreoperativeplasmaBNPlevelandduration ofmechanicalventilation(r=0.67,p=0.0001)whichis sim-ilartothefindingsofShihetal.Wethinkthestudyneedsto beperformedonlargergroupofpatientstodemonstratethe importanceofplasmaBNPvaluesinpatientswithadiagnosis ofPHundergoingcongenitalheartsurgeries.
There areseverallimitations ofthe presentstudy.One important limitation is the selection of patients into the study group. We used general echocardiographic diagnos-tic criteria for measurement of PAps instead of cardiac catheterization. However, we think the whole group of patientsrepresentsasinglegroupasweevaluatedsystolic PApswithsystemicMAPs.Ourpatientspresentedatanolder ageafteraperiodofinadequatemedicaltreatmentcausing deteriorationofclinical status.Inourstudygroupwe had elevenpatients (11/51, 21.6%) withpreterm birth history andithasbeenreportedthatpretermbabiesshowpoorer postoperative outcomes.3,27 We did not have a transtho-racic echocardiographyinourclinic andpulmonary artery catheterizationwasnotperformedinthesesickerchildren.
Duringcompletionofthisstudyinhalednitricoxidewasnot available to all patients and other newer agents such as intravenousorinhaledepoprostenol,iloprostwerenotused topreventPHcrisisduringoraftersurgery.
Inconclusion,thepreoperative plasmaBNPlevel accu-ratelypredicts postoperative LCOS which is an important prognosticriskfactorfordeterminationofearly30-day post-operative outcomeand 91% of patients withpreoperative plasmaBNPlevelsabove 125.5pgmL−1are athigh risk of developing LCOS in children undergoing congenital heart surgerywithCPB.
Funding
ThisstudywassupportedsolelybytheDr.Kartal Kosuyolu TrainingandResearchHospital,Kartal,Istanbul,Turkey.
Authorship
AyseBaysalcontributedtowardthecollectionofdata,study design,statisticsandpreparationofmanuscripttext.Ahmet S¸as¸mazelcontributedtowardsthecollectionofdata,study designandstatistics.AyseYildirimcontributedtowardsthe collectionofechocardiographicdata.Buket Ozyaprak con-tributedtowardsthecollectionofdataduringsurgery;Narin Gundogus contributed towards the collection of data in intensivecare unit andTuncer Kocakcontributedtowards thestudydesign.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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