Risk factors and the relation of lactic acid to neonatal mortality in the first week of life

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www.elsevier.es/rmuanl

ORIGINAL

ARTICLE

Risk

factors

and

the

relation

of

lactic

acid

to

neonatal

mortality

in

the

first

week

of

life

I. Rodríguez-Balderrama

∗

_,

_P.J.

_Ostia-Garza,

_R.D.

_{Villarreal-Parra,}

_M.

_{Tijerina-Guajardo}

NeonatologyServiceatthe‘‘Dr.JoséEleuterioGonzález’’UniversityHospitaloftheAutonomousUniversityofNuevoLeónin Monterrey,NuevoLeón,Mexico

Received19August2015;accepted17December2015 Availableonline8May2016

KEYWORDS Lacticacid; Neonatalmortality; Preterm;

Mechanical ventilation; Mexico

Abstract

Objective: Todeterminetherelationshipbetweenlacticacidlevelsandneonatalmortalityin thefirstweekoflife,inpatientsadmittedtotheNeonatalIntensiveCareUnit(NICU)ofthe ‘‘Dr.JoséE.González’’UniversityHospital.

Materialandmethods: Prospective,observationalanddiagnostictestperformedinthe neona-talwardofthe‘‘Dr.JoséEleuterioGonzález’’UniversityHospital.Weincludedalllivepreterm infantsonmechanicalventilationwhowereadmittedtotheNICUfromNovember1,2011to October31,2012.

Results:Onehundredandfiftyfourpatientsmettheinclusioncriteria.At72h,wefoundthat thebestsensitivity(95%)waswhenlactatewaslessthan1.5mmol/landthebestspecificity (89%)waspresentwhenlactatelevelsweregreaterthan2.5mmol/l.ThepH<7.25hada sen-sitivityof76%andspecificityof96%.At168h(7days)wefoundthatthebestsensitivity(91%) waswhenlactatelevelswerelessthan1.5mmol/l,andthatthebestspecificity(96%)waswhen lactatelevelsweregreaterthan2.5mmol/l.WefoundthatthepH<7.25hadasensitivityof 36%andspecificityof91%.

Conclusion: Thelactateserum,at1.5mmol/l,hasasensitivity(tobekilled)of95%onthethird dayand91%ontheseventhday.WhenthepHisgreaterthan7.25thereisaspecificity(tobe alive)of96%onthethirddayand91%ontheseventhday.67%ofthedeadwereunder1500g, andwere61%under28gestationalweeks.

∗_{Corresponding}_author_at:_Servicio_de_{Neonatología}_del_Hospital_{Universitario}_‘‘Dr._José_Eleuterio_{González’’}_de_la_UANL,_Avenida_Francisco

IMaderoyGonzalitos,s/n,Col.MitrasCentro,códigopostal64460Monterrey,N.L.,Mexico.

E-mailaddress:[email protected](I.Rodríguez-Balderrama).

http://dx.doi.org/10.1016/j.rmu.2015.12.001

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Introduction

Lactic acid is a terminal product of the anaerobic metabolismofglucose,anditisobtainedbyareductionof pyruvicacidinareactioncatalyzedbythelactic dehydro-genaseenzyme,whereadinucleotideadeninenicotinamide (NAD)coenzymegoesfromitsreducedformtoitsoxidized form.1---3

Undernormalconditions,serumlevelsareat2mEq/Lor lower.However,exercisecanelevateitupto4mEq/L.Most lactateisefficientlyeliminatedbytheliverandisutilizedin gluconeogenesisorintheproductionofenergy.When con-siderableincreasesinlactateserumnumbersareproduced, withareductioninlactatetopyruvatemetabolism conver-sion,metabolicacidosisoccurs,whichisusuallysevereand mayleadtopatientdeath.4

Lactic acid is increased in situations of tissue hypoxia---ischemia.Different studies conductedin adults,5 aswellasinchildren6,7_and_newborns,8_have_shown_that_in criticalsituations,lacticacidlevelsatthemomentofthe patient’s admittance tothe ICU and its evolution have a positivecorrelationwiththeriskofdeath.9

Lactic acid can increase for several causes other than tissuehypoxia.Within thecontext ofthe ICU, inorderof frequency,amongstthemost probablearethoseof hemo-dynamiccauses,10 _which_determine _tissue_hypoxia,11 _as_in the case of sepsis, heart failure, shock (cardiogenic and septic)andmultipleorgandysfunction.11_Amongst_the non-hemodynamic causes thereare12,13_: _the _use_of _biguanides in diabetic patients, the use of pharmaceuticals such as adrenalin and nitroprusside, seizures, intestinal infarc-tion, or in general, patients with intestinal hypomotility, shortbowels,thiaminedeficiency,liverdiseasesingeneral, ethanoloverdoses,methanol,salicylatesandethylene gly-col.

Lactate has proven to be a good prognostic indica-tor in hospitalized adults and children14,15 _and _different typesofpatients,includingcritical,16---18_and_surgical,19_with sepsis20,21 _and _trauma.22,23 _Its_main _advantage_is _how_fast andeasyitsdeterminationis,anditsevolutionaryprognosis capability.24,25

Theobjectiveofthisstudyistodeterminethe relation-ship of lacticacid levelswith neonatalmortality rates in thefirstweekoflife,inpatientsadmittedtotheNeonatal IntensiveCareUnitatthe‘‘Dr. JoseE. Gonzalez’’ Univer-sityHospital,aswellastoquantifyneonatalmortalityrate prevalenceinthefirstweekoflifeinrelationtolacticacid levels,toknownon-pathologicalandpathologicalmaternal backgrounds,learnthenewborn’scharacteristics, to iden-tifythe main in-hospital morbidities, document the main causesofassociateddeath,andidentifylactatelevels asso-ciatedandahighermortalityrate.

Materials

and

methods

Aprospective, observational and diagnostic test was per-formed in the neonatal ward of the ‘‘Dr. José Eleuterio González’’University Hospital of the Autonomous Univer-sity of Nuevo León. We included all live preterm infants onmechanicalventilation whowereadmittedtotheNICU withintheperiodofNovember1,2011toOctober31,2012.

ThestudywasapprovedbytheUniversity’sEthics Commit-teewiththefoliono.NE12-003.

Exclusioncriteriaincluded alllivepreterm infantswho didnotrequiremechanicalventilationadmittedtotheNICU betweenNovember1,2011andOctober31,2012,patients transferredfromotherhospitalunits,andthosewhodidnot meettherequirementsofthefile.

Variableswere the following: theevaluatednewborns’ characteristicswereweightatbirth,andwereclassifiedinto <1000g, 1001---1500g, 1501---2500g and 2501---4000g cate-gories. Also,gestational age wasevaluated and classified accordingtothenumberofweeksofgestationas<28weeks, 28---33weeks,and34---36weeksofgestation.Trophismwas evaluatedandclassifiedasadequateweightforgestational ageandlowweightforgestationalage.26_They_were_divided bymaleandfemale,accordingtogender,andwere evalu-atedandclassifiedaccordingtotheirAPGARscoreat5min in0---3,4---6and7---10points.

Withinthesevariables,the studyincluded pathological andnon-pathologicalmaternalfamilyhistory:nofamily his-tory,smoking,alcoholism,drugaddictionandtattoosonthe mothers of the newborns, the number of sexual partners wasstudied,dividedintoone,two,threeormore. Accord-ing to the mother’s health during pregnancy, they were dividedintohealthy, or whetherthemotherpresentedan ailment,suchashighbloodpressure,infections, preeclamp-sia,eclampsiaorgestationaldiabetes,amongothers.Also, itwasdeterminedwhetherornotthepatientscarriedout properprenatalcare.

Additionally,themothers’agewasevaluatedanddivided asfollows:under18yearsold,from19to30yearsold,and over 30 yearsold.Theywere dividedintosingle,married and the consensual union, according to theirmarital sta-tus.Regardingschooling,theclassificationswereilliterate, elementary,juniorhighschool,highschool,andbachelor’s degree. Also, a classification according to their occupa-tionwasmade,dividingthemasfollows:housewife,worker and student. Among the evaluatedvariables were causes ofin-hospitalmorbidityandmortality,fromwhichthe fol-lowingpathologieswerestudied:hyalinemembranedisease grades 1 through 4, pulmonary edema, meconium aspira-tion syndrome,septic shock, sepsis, extreme prematurity andperinatalasphyxia.

LactateandpHwerestudiedat72h (3days),assessing sensitivity, specificity, positive predictive value and nega-tivepredictivevalueoflactatelevels>1.5mmol/l,2mmol/l and lactate at 2.5mmol/l, as well as pH <7.25 and <7.30.

Similarly,lactateandpHwerestudiedat168h(7days), assessing sensitivity, specificity, positive predictive value andnegativepredictivevalueoflactatelevels>1.5mmol/l and2mmol/landlactateat2.5mmol/l,aswellaspH<7.25 and<7.30.

Qualitativevariableswereusedinthestatisticalanalysis. Thechisquare(non-parametric)testswereutilizedtotest thehypothesis.Analphavalueof0.05wasusedandthenull hypothesiswasrejectedwhenthecriticalvaluewasunder 0.05.

Sensitivity, specificity, and both positive and negative predictionvaluesweredeterminedwitha2×2contingency

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Table1 Newborncharacteristics.

Total Alive(n=118) Dead(n=36) Valueofp Weightatbirth(g)

<1000 30 10(8.4%) 20(55.5%) <0.001 1001---1500 43 39(33%) 4(11.1%) <0.05 1501---2500 53 46(38.9%) 7(19.5) <0.05 2501---4000 28 23(19.7%) 5(13.9%) 0.44

Gestationalage(weeks)×DS

<28sdg 29 7(6%) 22(61%) <0.001

28---33 68 59(50%) 9(25%) <0.001

34---36 57 52(44%) 5(14%) <0.05

Trophism

PAEG 76 59(50%) 17(47%)

PBEG 78 59(50%) 19(53%) 0.77

Gender

Male 93 69(58%) 24(66%) 0.37

Female 61 49(42%) 12(34%)

APGARat5mins

0---3 4 0 4(11%)

4---6 15 12(11%) 3(9%) <0.01

7---10 135 106(89%) 29(80%)

were lactate levels >1.5mmol/l, 2mmol/land lactate at 2.5mmol/l,aswellaspH<7.25and<7.30.

Results

Withintheperiodoftimeoutlinedinthisstudy,therewere 2657births.363(13.6%)ofthesewereadmittedtotheNICU. Outofthe363admittedtotheNICU,226(67.2%)were pre-mature.Outoftheprematureones,154mettheinclusion criteria,fromwhich36diedand118survived.

When comparingtheir weight at birth, we areable to findthatthereweremorechildrenunder1000ginthedead group (p<0.001) and there were more children between 1000and2500ginthealivegroup(p<0.05).Regarding ges-tational age, there were more children under 28 weeks of gestation in the dead group with (p<0.001) and more children with a gestationalage of 28---33 weeks of gesta-tion(p<0.001)and34---36weeksofgestation(<0.05)inthe alivegroup.Concerning trophismand gender,both groups were similar (NS). When comparing APGAR scores, there weremoredeadchildrenwithalowAPGAR(p<0.001)(see Table1).

When comparing non-pathological and pathological maternalhistory,weareabletofindthatthereweremore mothers without anyhistory in thealive group (p<0.001) and there was a greater link of alcoholism (<0.05), drug addiction(<0.05)andtattoos(<0.001)inmothersofthose patientswhodied.Regardingthenumberofsexualpartners, thosewith3ormoresexpartnerswerehigherinthedead group(<0.05).

When comparingthemothers’healthduringpregnancy, resultsshowthatinthedeadgroupthereweremoremothers withhighbloodpressure(<0.001)andgestationaldiabetes (p<0.05) and the presence of infections, preeclampsia,

eclampsiaandotherdiseaseswasnotsignificant(NS). Pre-natalcarewassimilarinbothgroups(NS)(seeTable2A).

When comparingassociatedmaternal age, weareable toobservemore mothers<18 yearsoldinthedead group (p<0.01) andmore mothersbetween 19and 30yearsold (p<0.01) in the alive group. Maritalstatus was similarin both groups (NS). Regarding schooling, there were more childrenin the dead groupwhose mothers hascompleted highschool(p<0.001),whereasinthealivegroup elemen-taryschoolwaspredominant(p<0.001).Thereweremore workingmothersinthedeadgroup(p<0.05)(seeTable2B). When comparing in-hospital morbidity and mortality causes,weareabletoobservethatthereweremoredead childrenwithgrade3and4hyalinemembranedisease diag-nosis (p<0.001), septic shock (p<0.01) and prematurity (p<0.001). On the other hand, sepsis was higher in the alivegroup(p<0.05).Thepresenceofgrade1and2HMD, pulmonaryedema,meconiumaspirationsyndromeand peri-natalasphyxiawerenotsignificant(NS)(seeTable3).

At72h,findingsshowthebestsensitivity(95%)waswhen lactatewaslowerthan1.5mmol/landthebestspecificity (89%) waswith lactatelevels higher than 2.5mmol/l; pH <7.25hadasensibilityof76%andaspecificityof96%(see Table4).

At 168h (7 days), findings show the best sensitivity (91%)waswhenlactatewaslowerthan1.5mmol/landthe bestspecificity (96%) was with lactatelevels higher than 2.5mmol/l;pH <7.25hadasensibilityof36% anda speci-ficityof91%(seeTable5).

Discussion

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Table2A Pathologicalandnon-pathologicalmaternalantecedents.

Total Alive(n=118) Dead(n=36) Valueofp Non-pathologicalantecedents

None 119 104(88%) 15(42%) <0.001

Smoking 13 7(6%) 5(14%) 0.10

Alcoholism 5 2(2%) 3(8%) <0.05

Drugaddiction 11 5(4%) 6(16%) <0.05

Tattoos 7 0 7(20%) <0.001

Numberofsexualpartners

One 148 115(97%) 33(92%)

Two 4 3(3%) 1(2%) <0.05

Threeormore 2 0 2(6%)

Maternalhealthduringpregnancy

Healthy 115 92(77%) 23(64%) 0.089

Art.hypertension 8 2(2%) 6(17%) <0.001

Infections 2 2(2%) 0 0.88

Preeclampsia 12 9(8%) 3(9%) 0.43

Eclampsia 2 2(2%) 0 0.88

Gestationaldiabetes 5 2(2%) 3(9%) <0.05

Other 10 9(8%) 1(4%) 0.30

Prenatalcontrol

Yes 135 102(85%) 33(92%) 0.40

No 19 16(14%) 3(8%)

levels are at 2mEq/L or lower.4 _Lactic _acid _is _increased in situations of tissue hypoxia---ischemia,5---8 _and _its _levels haveahighcorrelationwithmortality.9---11_The_causes_which provokean increaseoflacticacidcanbehemodynamicor non-hemodynamic.12---25

Thenumberofprematurebirthscontinuestoincreasein developedcountries,aswellastherelatedlowweight,with anincreasedmortalityrateforpatientsthatweighlessthan

1500g.27,28_Within_the_findings_of_our_study,_when_comparing weightatbirth,wefoundthatthereweremorechildrenthat weighedlessthan1000ginthedeadgroup.

A very important relation between a high number of deaths and a gestational age of 28---31 weeks has been reported in various studies, showing that they present a higherriskofcomplicationsandmortalityduringtheirtime in the NICU.28,29 _Within _our _findings, _upon _comparison _of

Table2B Pathologicalandnon-pathologicalmaternalantecedents.

Total Alive(n=118) Dead(n=36) Valueofp Maternalage

<18years 22 12(10%) 10(28%) <0.01 19---30years 112 92(78%) 20(55%) <0.01

Over30years 20 14(11%) 6(17%) 0.45

Maritalstatus

Single 77 58(49%) 19(53%) 0.70

Married 68 54(45%) 14(39%) 0.46

FreeUnion 9 6(5%) 3(8%) 0.46

Schooling

Illiterate 2 2(5%) 0 0.43

Elementary 35 26(13%) 9(25%) 0.71

Juniorhigh 103 87(74%) 16(44%) <0.001

Highschool 13 3(7%) 10(27%) <0.001

Bachelor’s 1 0 1(4%) 0.069

Occupation

Housewife 126 99(84%) 27(75%) 0.22

Worker 19 11(9%) 8(22%) <0.05

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Table3 Causesofintrahospitalmorbidity.

Total Alive(n=118) Dead(n=36) Valueofp HMD

Degree1and2 8 8(7%) 0 0.10

Degree3and4 89 76(64%) 13(36%) <0.01

PE 8 8(7%) 0 0.10

MAS 1 1(0.9%) 0 0.57

Septicshock 2 0 2(5.5%) <0.01

Sepsis 12 12(10%) 0 <0.05

Extremeprematurity 29 9(7.5) 20(56%) <0.001

Perinatalasphyxia 5 4(3.5%) 1(2.5%) 0.85

Table4 LactateandpHofthepatientsat72h(3days).

Sensibility Specificity VPP VPN

Lactate>1.5mmol/l 95% 60% 35% 98%

Lactate>2mmol/l 83% 76% 45% 95%

Lactate>2.5mmol/l 75% 89% 62% 94%

pH>7.25 76% 96% 82% 94%

pH>7.30 29% 80% 24% 83%

Table5 Lactateandphofthepatientsat168h(7days).

Sensibility Specificity VPP VPN

Lactate>1.5mmol/l 91% 70% 35% 98%

Lactate>2mmol/l 75% 85% 68% 89%

Lactate>2.5mmol/l 52% 96% 86% 83%

pH>7.25 36% 91% 62% 78%

pH>7.30 22% 75% 93% 71%

gestationalages,we foundthat thereweremorechildren at less than 28 weeks (p<0.001) in the dead group, and morechildrenat28---33weeksand34---36weeksinthealive group(p<0.001).

Itisworthconsideringthatsomestudieshavefoundan association between the masculine gender and a risk of death.2,14,16,23---25,27,28 _The _studies _say_that _when_comparing genders in relation to mortality, it is commonly observed thatthedeathrateofmalesishigherthanthatoffemalesat allages.Inourstudy,whencomparinggenders,bothgroups weresimilar(NS).

TheAPGARscorehasbeenconsideredanimportant pre-dictivevariableofneonatalmortality.Thisvariableismore directly relatedto thequality ofattention at delivery,in spite of the influence of previous conditionsof the new-born during theintrauterineperiod, which determinesits vitalityatbirth.Thisscorehasbeenmentionedbyvarious authors23---25,27,28 _as _an _important _variable _which _is _closely relatedtotheriskofdeathwhenscores oflessthan7are obtainedatthefirstandfifthminutes.Withinourfindings, weobservedthatthereweremoredeadinthelowAPGAR category(p<0.001).

The important increaseof neonataldeathrates dueto thehighprevalenceofprematurebirthsandlowweightat birthhasbeenmentionedinvariousstudies.27,28_These_are

closelyrelatedtootherindicators inthemothers,suchas theintakeofalcohol,tobaccoandillicit drugs.Withinour pathologicalandnon-pathologicalfindingsonthemothers, wefoundthatthemothersofdeceasedpatientspresented a greater relation to alcoholism (<0.05), drug addiction (<0.05)andtattoos(<0.001).

Regarding prematurity, various studies have reported thatitis afactor inrisksassociatedwithneonataldeath, malnutrition,infections, iatrogenicprematurity, hyperten-sionandtheprematureruptureofmembranes,amongother things.17,27---29_In_our_study,_we_observed_that_there_were_more motherswitharterialhypertension(<0.001)andgestational (p<0.05)diabetesinthedeadgroup.Thepresenceof infec-tions,preeclampsia,eclampsiaandotherdiseaseswerenot significant(NS).

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themotherswithlessthan5consultationshavea2.5times higherriskthantheothers.Inthefindingsofourgroup,upon comparisonof prenatal control, both groups were similar (NS).

deFátimaAlmeidaetal.,28 _in_their_study_performed_at theFederal University of Espíritu Santo in Brazil, studied neonataldeathsaswellastheriskfactorsassociatedwith them,findingariskofdeath3timeshigherinmothersthat wereless than15yearsold(OR=2.97;IC95%).This bears acloseresemblance toour study,whichfound that there weremoremotherthatwerelessthan18yearsoldinthe deadgroup(p<0.01).

Maternaleducationis considered an indicatorof social status.Themother’slevelofeducationcanbeconsidereda factorrelatedtoherculturalprofileandconductofhealth care, which has an important effect on the determina-tionofmortality.23,27,28_This_{investigation}_has_{demonstrated,} through an analysis of the correlation between maternal educationandobstetricalindicators,thatthereisa statisti-callysignificantassociationbetweenalowlevelofeducation andlowweightatbirth,anelevatednumberofpremature birthsandalessernumberofprenatalconsultations. Mater-nal educationcan beconsidered to bean obstetrical risk factorforpregnantwomenandnewborns.Theanalysisalso signifiedthatthesignificant associationbetween neonatal mortalityandaninferioreducationwiththesewomenmay beduetolowersocialconditionsandlimitedaccesshealth services.28

Withinthefindingsofourstudy,uponcomparisonof edu-cationallevels,wefoundthattherewereagreaternumber ofchildreninthedeadgroupofmotherswithahighschool education(p<0.001) andthereweremore childreninthe alivegroup of mothers withan elementary school educa-tion(p<0.001).Withinthefindingsofourstudy,wefound that,at 72h, the bestsensitivity (95%)was when lactate waslower than 1.5mmol/land the best specificity (89%) waswithlactatelevelshigherthan2.5mmol/l, whichisin accordancewithmedicalliterature.

Conclusion

Accordingtoourfindings, we canconclude thefollowing: thestudyofriskfactorsinmothersisimportantinorderto preventprematurebirthsas well asitsstrong connection withlowweightatbirthandalowergestationalage,since resultsshowthat67%ofdeathswereunder1500gandthat 61%wereunder28weeksofgestation.

Lactateover1.5mmol/lhasasensitivity(tobedead)of 95%atday3and91%atday7.

WhenpHishigherthan7.25thereisaspecificity(tobe alive)of96%atday3and91%atday7.

Conflict

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

Funding

Nofinancialsupportwasprovided.

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