Rev. paul. pediatr. vol.34 número4

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REVISTA

PAULISTA

DE

PEDIATRIA

www.rpped.com.br

ORIGINAL

ARTICLE

Relation

between

safe

use

of

medicines

and

Clinical

Pharmacy

Services

at

Pediatric

Intensive

Care

Units

Lucas

Miyake

Okumura

a,∗

,

Daniella

Matsubara

da

Silva

b

,

Larissa

Comarella

b

a_Hospital_de_Clínicas_de_Porto_Alegre,_Porto_Alegre,_RS,_Brazil

b_Hospital_Infantil_Waldemar_Monastier,_Campo_Largo,_PR,_Brazil

Received15January2016;accepted17March2016

Availableonline16April2016

KEYWORDS

Criticalcare; Drug-relatedside effectsandadverse reactions;

IntensiveCareUnits, Pediatric;

PharmacyService, Hospital;

Patientsafety; Medicationerrors

Abstract

Objective: ClinicalPharmacyServices(CPS)areconsideredstandardofcareandisendorsed bytheJointCommissionInternational,theAmericanAcademyofPediatrics,andtheAmerican CollegeofClinicalPharmacy.InBrazil,singleexperienceshavebeendiscreetlyarisingandthe importanceoftheseservicestochildrenandadolescentscarehasledtointerestingresults, butcertainlyareunderreported.Thisshortreportaimstodiscusstheeffectofimplementing abedsideCPSataBrazilianPediatricIntensiveCareUnit(PICU).

Methods: Thisisacross-sectionalstudyconductedina12bedPICUcommunityhospital,from CampoLargo/Brazil.Subjectswith<18yearsoldadmittedtoPICUwereincludedfordescriptive analysisifreceivedaCPSintervention.

Results: Of 53 patients accompanied, we detected 141 preventable drug-related problems (DRPs) whichwere solvedwithin clinicians(89%acceptance ofallinterventions). The most commoninterventionsperformedtoimprovedrugtherapyincluded:preventingincompatible intravenous solutions(21%) andacomposite ofinadequatedoses(17%duetolow, highand non-optimizeddoses).AmongthetoptenmedicationsassociatedwithDRPs,fivewere antimi-crobials.ByanalyzingthecorrelationbetweenDRPsandPICUlengthofstay,wefoundthat74% ofallvariationsonlengthofstaywereassociatedwiththenumberofDRPs.

Conclusions: AdversedrugreactionsduetoavoidableDRPscanbepreventedbyCPSina mul-tifacetedcollaborationwithotherhealthcareprofessionals,whoshouldattempttouseactive andevidence-basedstrategiestoreducemorbidityrelatedtomedications.

∗_{Corresponding}_author.

E-mail:lucasokumura@yahoo.com.br(L.M.Okumura).

http://dx.doi.org/10.1016/j.rppede.2016.04.001

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PALAVRAS-CHAVE

Cuidadosintensivos; Efeitoscolaterais relacionadosa medicamentose reac¸õesadversas; UnidadesdeCuidado IntensivoPediátrico; Servic¸odeFarmácia, Hospital;

Seguranc¸ado paciente;

Errosdemedicac¸ão

Relac¸ãoentreousosegurodemedicamentoseServic¸osdeFarmáciaClínicaem UnidadesdeCuidadosIntensivosPediátricos

Resumo

Objetivo: ServiçosdeFarmáciaClínica (SFC)sãoconsiderados umpadrão deatendimentoà saúdeesãoendossadospela JointCommissionInternational,aAmericanAcademy of Pedi-atrics,eaAmericanCollegeofClinicalPharmacy.NoBrasil,experiênciasisoladasvêmsurgindo discretamenteeaimportânciadessesserviçosparaocuidadodecriançaseadolescentestêm levadoaresultadosinteressantes,masquecertamentesãosub-relatados.Esteartigoóriotem comoobjetivodiscutiroefeitodaimplantaçãodeumSFCàbeiradoleitoemumaUnidadede CuidadosIntensivosPediátricos(UCIP)brasileira.

Métodos: Esseéumestudotransversal,realizadoemumaUCIPdehospitaldacomunidadecom 12leitos,emCampoLargo,Brasil.Foramincluídosindivíduoscom<18anosinternadosemUCIP paraanálisedescritiva,quandoreceberamumaintervenc¸ãodoSFC.

Resultados: De 53 pacientesacompanhados, foram detectados 141Problemas Relacionados aMedicamentos(PRM)evitáveisqueforamresolvidos emconjunto comosmédicos(89%de aceitaçãode todasas intervenções).Asintervençõesmais comunspara melhoraraterapia medicamentosaforam:prevençãodesoluçõesintravenosasincompatíveis(21%)edoses inade-quadas(17%devidoadosesbaixa,altaenãootimizadas).Entreosdezprincipaismedicamentos associadosàPRM,cincoeramantimicrobianos.AoanalisaracorrelaçãoentreoPRMetempo depermanêncianaUCIP,verificamosque74%detodasasvariaçõesnotempodepermanência eramassociadascomonúmerodePRM.

Conclusões: Reac¸õesadversasamedicamentosdevidoaPRMevitáveispodemserprevenidas porSFCemumacolaborac¸ãomultifacetadacomoutrosprofissionaisdesaúde.Taisproblemas podemser evitadospormeiodeestratégias ativasebaseadasem evidênciaspara reduzira morbidaderelacionadaamedicamentos.

Introduction

The increasing number of medications being approved to adultswithpotentialuseonPediatrics,1_the_need _to_treat clinicallychallenging diseases, andthe ethical issues sur-roundingpediatricsresearchput childrenand adolescents atmorerisksassociatedtomedicationadverseevents.2,3_To illustratethisscenario,anested-cohortstudyconductedby Bellisandcolleagues2 _demonstrated_that_unapproved pre-scriptions were associated with an augmented hazard of havinganadverseevent(hazardratio1.30,95%CI1.20---1.30, p<0.001).

Todetectmedicationadversereactionsandtoavoid pre-ventable drug-related problems (DRPs), many accredited hospitals4---7 _have _been _putting _efforts_to _implement Clin-ical Pharmacy Services (CPS). Since the last decade, the multifacetedcollaborationbetween Pediatricians, Critical CarePhysicians and Clinical Pharmacists wasendorsed by theAmericanAcademyofPediatrics,5 _American_College_of ClinicalPharmacyandmanystudiesinthefield.5---9

Despitethewell-stablishedimportance5---9_of_CPS_to chil-drenandadolescents,in thelastyears,Brazilhasstarted theimplementationofsingleexperiencesaroundthe coun-try,especiallyforPICUpatients,whichhasledtointeresting butunderreportedresults.

This study is endorsed by the evolving role of CPS in Brazil, which has been due to the recent approval of a legislation about clinical activities developed by

pharmacists10_; _and _the _increasing _interest _of _Latin Amer-ican health institutions to get accredited.11 _Noteworthy, AccreditationOrganizations,suchastheJointCommission International, advocates that strategies to prevent medi-cationerrors,likewisepharmacists-drivenclinicalservices, should be implemented to reduce the number of drug-relatedundesiredevents.12

Theaimofthisshortreportistodescribethe implemen-tationandresultsofaCPSdirectedtoPICUinpatientsina Braziliansetting.

Method

This study complies with Helsinki’s Declaration and was approvedbytheLocalEthicsCommittee.

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responsibletoprovideCPS toinpatients (PICUand30bed generalpediatricwards).

The CPS consisted in a systematic service dedicated to: participating in clinical rounds, elaborating institu-tionalprotocols,antiepilepticTherapeuticDrugMonitoring (TDM), reviewingeach ofprescribeddrugdosages, indica-tions, duration of treatments, drug interactions, relative andabsolutecontraindicationsandintravenousdrug incom-patibilities.

We soughttoretrospectivelyanalyzethedemographics (age and sex) and clinical variables (cause of admission, comorbidities,use of vasoactivedrugs, use ofmechanical ventilation,useof artificialnutrition,useof antimicrobial therapyandPICUlengthofstay).Theprevalenceandtypes ofDRPsfoundinsuchvulnerablepopulationattendedbythe CPSduringtheimplementationphase(May,October2012) werealsoreported.

DRPs are defined as all situations that predisposed patients of not having optimized drug therapy, such as: intravenoussolutionsinstabilityandincompatibility,wrong infusiontime,highorlowdosesaccordingtoliterature,need toadjustadoseaccordingtorenalclearanceorTDM(serum concentrations of selecteddrugs), presence of duplicated drugtherapy and wrongpharmaceuticalform.Finally, we assessedthe acceptanceofourservice byquantifying the acceptabilityofCPSinterventionsbyphysiciansandnursing team.

Our conventional sample was calculated based on a 5% alfa, 80% power and r=0.50 as statistically significant correlation for this exploratory analysis, which led to 29 patients.13 _An_exploratory_univariable_analysis_(two-tailed, Spearman rho) was performed to assess the association between DRPs and PICU length of stay. All tests were two-sided and p<0.05 was set as null hypothesis rejec-tion.DescriptivestatisticsappliedtoallpatientswithDRPs. The aforementioned covariates were reported as median andinterquartileintervals,anddichotomousvariableswere reportedasabsoluteandrelativenumbers(%)(Table1).

Results

In 5 consecutive months of implementation, 53 patients were accompanied by two part-time clinical pharmacists (5h/daily dedication, except on weekends). 18 patients did not present a DRP, so they were not included in the descriptive analysis. We found 141 DRPs in 35 patients (Tables 1 and 2), who were likely to be male (63%) and were 1.50-years-old in average. Most of them were admitted due to respiratory disorders, such as acute asthma,bronchospasmandbronchiolitis-associated respira-tory insufficiency. One third (31.40%) needed mechanical ventilation during PICU stay, and 34.30% used vasoactive drugstotreathemodynamicinstability.

Out of the 141 DRPs detected by CPS, the most common interventions performed to improve drug ther-apy were: preventing incompatible intravenous solutions (21%) and a composite of inadequate doses (17% due to low, high and non-optimized doses) (Fig. 1). Among the top ten medications associated with DRPs, five were antimicrobials: meropenem, vancomycin, piperacillin and tazobactan,cefepimeandoseltamyvir(Table2).

Table1 Patients’characteristics.

Characteristics n(%)

Numberofincludedpatients 35

Ageinyears 1.50(0.35---3.25)

Male 22(63)

Diagnosticatadmission(ICD-10)

Infectiousdiseases 4(11) Neurologicsystemdisorders 4(11) Respiratorysystemdisorders 20(57) Digestivesystemdisorders 4(11)

Co-morbiditiesduringhospitalstay

(InternationalClassificationofDiseases-10) Endocrineormetabolicdisorders 4 Neurologicsystemdisorders 6 Circulatorysystemdisorders 4 Respiratorysystemdisorders 10

Numberofdrug-relatedproblems 141

Mechanicalventilation 11(31)

Useofartificialnutrition 28(80)

Useofvasoactivedrugs 12(34)

Useofformularyrestricted antimicrobialtherapy

15(43)

Intensivecarelenghtofstayindays 18(8.50---38.25)

Unlessotherwisestated,allvariablesareexpressedasabsolute

and/or relative (%) values. Artificial nutrition includes

par-enteralandenteralnutrition.

All continuousvariablesweredescribedas medianand

inter-quartilerange.

ICD-10,InternationalClassificationofDiseasesEditionn.10.

ByanalyzingtheSpearman-rhocorrelationbetweenDRPs andPICUlengthofstay,wefoundthat74%ofallvariations onPICU lengthof staywere associatedwiththedetected DRPs.

Discussion

Inoursample,theimplementationofaCPSdirectedatPICU inpatientshasshownthevalueofsuchservicesondetecting andsolvingDRPs,whichwereatmostpreventablesituations thatcouldleadtounnecessarymorbidity.

Through an average 33 days of PICU stay (95%CI 20.22---46.38),wefoundthateachpatientcouldbeexposed to as much as 2.6 DRPs, and interventions toward solv-ing them were highly accepted by medical and nursing team (89% acceptability rate). Such acceptance of inter-ventions by PICU team was consistently high, as already demonstratedbefore.8,11,12_The_message_behind_these find-ingsstandsfor agoodCPSimplementationprocess,which had asdeterminants of success: the institutional support andcommunicationbetweenhospital’spharmacymanager, clinicaldirector,PICUnursesandinfectiousdiseaseteam.

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Table2 Commondrug-relatedproblemsinpediatricintensivecare.

Typeofdrug-relatedproblems Number(%)ofdrug-relatedproblemsinvolvedwitheachmedication

Meropenem Vancomycin Piperacillin/tazobactam Fentanyl Cefepime Omeprazole

Incompatibility 6(4) 4(2.70) 9(6) 2(1.30) 6(4) 2(1.30)

Highdose 1(0.60) 3(2) --- --- --- 3(2)

Renaldoseadjustment 1(0.60) 1(0.60) --- 1(0.60) 1(0.60) ---Wronginfusiontime --- 1(0.60) --- 3(2) ---

---Lowdose 1(0.60) 1(0.60) --- 2(1.30) ---

---Therapeuticdrugmonitoring doseadjustment

--- --- --- --- ---

---Duplicateddrugs --- --- --- --- --- 1(0.60)

Wrongpharmaceuticalform 1(0.60) --- --- --- --- 1(0.60) Total(%) 10(6.80) 10(6.80) 9(6) 8(5.30) 7(4.70) 7(4.70)

Typeofdrug-relatedproblems Number(%)ofdrug-relatedproblemsinvolvedwitheachmedication Other

Oseltamyvir Captopril Methyprednisolone Phenobarbital

Incompatibility --- --- 1(0.60) --- 24(17)

Highdose --- 1(0.60) 3(2) 1(0.60) 10(8)

Renaldoseadjustment --- 2(1.30) --- --- 10(8)

Wronginfusiontime --- --- --- --- 4(3)

Lowdose --- 1(0.60) --- --- 7(5)

Therapeuticdrugmonitoring doseadjustment

--- --- --- 2(1.30) 7(5)

Duplicateddrugs --- --- --- --- 4(3)

Wrongpharmaceuticalform 5(3.30) --- --- --- 4(3)

Total(%) 5(3.30) 4(2.70) 4(2.70) 3(2) 74(53)

Selecteddrugsaccountsfor67(47%)from141drug-relatedproblems(DRP)foundbypharmacists.Stability,compatibilityanddosewere

commonproblemsidentifiedbyclinicalpharmacists.‘‘Others’’columnreferstodrugsthatwerelesscommon.Onlydrugswithmore

than4DRPswerereported.

(intravenous and oral routes prescribed). Sub-therapeutic doses of phenobarbital were corrected by pharmacists, eitherbyliterature-basedinformationorbyTDM.

Few studies8,14---17 _were _already_published _in _PICU sett-ings,butnonecomesfromLatinAmericancountries.Asingle randomizedcontrolledtrial8 _assessed_the _{effectiveness}_of CPSin reducinginpatient lengthof stay.An observational studyconductedinFrench-speakingcountriesdescribed966 interventionsdone to solve DRPin 270 patients, through 6 months of CPS implementation.14 _Other _researches _had alsoshowedpositive results. Acohort study conductedin United States included 1120 patients andfound that half ofpatientswereexposedtomedicationerrors.Theyfound that 28% of all problems detected were related to dose, and other 18% with wrong route of administration.15 _In United Kingdom, antibiotics and inotropes were reported tobethe top drugs associated withmedicationserrors.16 Our study showed similar results by having meropenen, piperacillin and tazobactam, vancomycin, cefepime and oseltamyviraspartthe toptenmedicationsassociated to DRP.

Unfortunately,somestudies16_did_not_specify_the_details ofthemedicationerrorsdetected,whichareindispensable for PICU pharmacists. To overcome such lack of descrip-tiveinformation,ourstudyidentifiedthatweightvariation, acute kidney injury and TDM led to dose adjustment

interventions, namely: vancomycin, captopril and pheno-barbital.

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Figure1 IncompatibilityproblemsavoidedbyClinical Phar-macyServices.

pharmacistsinthisactivity,whoconsultedeachotherwhen discrepancies/inconsistencieswerefound.

Every ten patients admitted to PICU, six had a DRPs detectedbyCPSandfivereceivedan interventionto opti-mize drugtherapy. PICU setting has a high prevalence of compatibilityandstabilityDRPs(Table2),anddose adjust-mentsshouldbepromptlyassessedespeciallyoninadequate therapeuticdrugserumconcentrations,weightchangesand other risk factors that may change drug distribution and excretion,suchasacutekidneyinjury.Basedonour imple-mentationexperience,CPSmightbeafeasibletechnology thatimproveinfants,childrenandadolescentscare. Pedia-tricians’andstakeholdersshouldattempttopreventDRPsby usingactiveandevidence-basedstrategiestoreduce avoid-ablemorbidity-relatedtomedications.4---6,8,9

Funding

LMOreceivesamonthlyscholarshipfromtheBrazilian Min-istryofEducation. BythetimeofCPSimplementation,he wasasixthyearpharmacystudent.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

We would like to thank Dr. Leonardo Cavadas Soares (FormerClinicalDirector),whoprovidedanoutstanding pre-ceptorship, scientific and clinical support among Clinical PharmacyServicesimplementation.Theservicereportedin thismanuscriptwassupportedbyallhealthcare profession-alsfromWaldemarMonastierChildren’sHospital,especially thosededicatedtocriticallyillchildren.

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