Children’s and Women’s Health Centre of BC, Department of Pharmacy - Winter 2020

Updates from C&W Pharmacy, Therapeutics& Nutrition (PTN) Committee

Jennifer Kendrick, BScPharm, PharmDThe C&W PTN Committee serves as the Pediatric Subcommitteeto the Provincial Pharmacy and Therapeutics Committee. We continueto have representation from other Health Authorities, in additionto our membership from C&W.

Backorders and Product Changes:We are currently facing shortages of many essential medications.The Pharmacy Department continues to monitor supplies andusage. We appreciate all of the assistance in reviewing optionsto mitigate these shortages.

The epinephrine backorder is now resolved. The shortage gaveus an opportunity to review stocking of pre-mixed syringes in thehospital and minimize wastage going forward.

Ranitidine oral products were removed from the market per HealthCanada. Famotidine is the alternate H2 receptor antagonist.

Drug Dosage HandbookThe following monographs have been updated. Please considerupdating your hard copy.

Cefepime updated dosingClopidogrel correction to dosingDexrazoxane added dosing for use with other anthracyclinesFamotidine new monographFoscarnet new monographPosaconazole new dose for young children and tablet formulationPrazosin addition of max ‘mg/kg/day’ doseTacrolimus correction of initial dosing to 0.05-0.2 mg/kg/dose POQ12H and change in IV:PO conversion for solid organ transplant

Parenteral Drug ManualThe following monographs have been updated:Alemtuzumab new monographAzacitidine new monographBevacizumab new monographBleomycin changed monitoring requirement for subsequent dosesBrentuximab new monographCarmustine addition of maximum rate of infusionDexmedetomidine change in restriction to allow oncologyphysicians to prescribe dexmedetomidine during dinutuximab forcycles 3 onwardsEtoposide added maximum rate to intermittent infusionGemtuzumab new monographInotuzumab new monographLevofloxacin new monographTreosulfan new monographVancomycin addition of reconstitution instructions for 500 mg vial

Formulary AdditionsInsulin glargine (Basaglar brand) was added to formulary.This is the brand of glargine that is covered by Pharmacare.

Palonosetron was added to formulary for the treatment ofpediatric oncology patients with refractory chemotherapy inducednausea and vomiting despite optimal antiemetic therapy.

Policies & ProceduresThe following new or updated policies & procedures have beenapproved and are posted on the C&W Intranet on ePOPS:

The following PTN Committee Policies have been renewed withminor changes: Medication Order Requirements, PatientSpecific Authorization for Administration and TemporaryLeave of Absence (Pass Medications)

The following medication administration procedures havebeen updated with minor changes: Intranasal MedicationAdministration, Rectal Medication Administration,Intramuscular Medication Administration, SubcutaneousMedication Administration

The Pediatric Asthma Referral Form and Pediatric AsthmaEducation and Discharge Checklist have been updated. TheChild Health BC Provincial Asthma Guideline PediatricAsthma – Initial Management Pathway in an EmergencySetting has been approved for use at BC Children’s Hospital.

The Pharmacological Treatment Algorithm for the Newbornat Risk for Symptoms of Withdrawal Due to AntenatalSubstance Exposure algorithm has been created to assist withmanagement of withdrawal in newborns at Women’s Hospital.

The BCCH Refractory Status Epilepticus Practice Guidelineshave been updated with minor changes.

PediCrisis Guidelines for use in the OR have been updated withadditional guidelines and a separate drug list.

The BCCH Empiric Antimicrobial Guide was updated to alignwith current information about penicillin and beta lactam allergy;new treatment of choice for secondary peritonitis; a new categoryfor health care associate intra-abdominal infections; and newinformation for osteomyelitis.

The BCCH Fever and Neutropenia Clinical Practice Guidelineshave been updated to include cefepime as the treatment ofchoice in stable patients with a penicillin allergy.

The BCCH Handling Medications in Procedures and SurgicalSuites: Authorized Personnel was approved.

…update continues on page 2

Get InformedIn this Issue:PTN Committee Updates…Page 1Sepsis - An ED Perspective…Page 2Opioid-induced NAS…Page 3Informer Editorial Board…Page 6Use of Balanced Crystalloids…Page 7

http://policyandorders.cw.bc.ca/

PTN Update continued from Page 1Pre-printed OrdersThe following C&W pre-printed orders have been approved since Mar 2019 and are posted on the C&W Intranet on ePOPs:

Acute Pain Service- P-IVLT Study MorphineBiochemical Diseases- Cerliponase alfa (Brineura) InfusionCardiology- Cardiac Surgery Pre-op AdmissionEmergency Department- Asthma ED Order Set- Heavy Menstrual BleedingEndocrinology- Endocrine Growth Hormone Stimulation- Diabetic KetoacidosisHematology- RBC Administration for Chronically Transfused PatientsNephrology- Kidney Transplant Admission Pre-Op- Kidney Transplant Admission Post-Op (PICU)- Kidney Transplant Admission Post-Op (Inpatient)- Automated Peritoneal Dialysis- Continuous Peritoneal Dialysis- Intermittent Peritoneal DialysisOncology- Chimeric Antigen Receptor (CAR) T cell Infusion Orders – Day 0- Dexmedetomidine Infusion for use during Dinutuximab Administration- Fever and Neutropenia (Stable)Ophthalmology- Ophthalmology Eye Drop AdministrationOrthopedics- Musculoskeletal Tumour Post-Op Admission- Post-op Spinal Surgery InpatientPICU- CRRT- SHIPPS StudyRheumatology- Rheumatology Standard Infliximab Infusion- Rheumatology Rapid Infliximab Infusion- Rheumatology IV Cyclophosphamide Administration (non-Oncology)Other- DNAR- Pediatric Asthma Admission

NICU- Newborn Admission- Phototherapy Initiation

Women’s Hospital- Antepartum Admission- High Acuity Unit (HAU) Admission- IV Iron Infusion- Newborn Admission- Newborn Discharge- Obstructive Sleep Apnea- Penicillin Allergy Skin Test- Perinatal Addiction Service – High dose hydromorphone administration- Postpartum Spinal Epidural Opioid Analgesia- Spinal Epidural- Transfer from High Acuity Unit (HAU) to Inpatient Ward- VTE Thromboprophylaxis

Policy & Procedure updates, continued from page 1The BCCH Palliative and End of Life Symptoms ManagementGuidelines were updated to allow for use outside of PICU.

The Infant and Enteral Nutrit ion Compendiumand the Nutrition Order Requirements policy wereupdated to reflect current evidence and beast practice.

The BCW Procedure for Penicillin Skin Testing was approved,to support the work at the BCW penicillin allergy clinic.

The Mandatory Adverse Drug Reaction Reporting policywas created to support the Health Canada requirement toreport serious adverse drug reactions. This replaces theprevious policy about reporting adverse drug reactions.

All Things Sepsis - from an EmergencyDepartment Perspective

By: Kendra Sih, PharmD and Dr. Vik SabhaneyReviewed by: Dr. Ashley Roberts

Sepsis and septic shock can have devastating outcomes ifnot detected early and treated appropriately.[1-4] TheSurviving Sepsis guidelines represent landmark documentsover the most recent several decades, and pediatricrecommendations were buried amongst adult care therapy.In the last few years, additional neonate and pediatric specificliterature has emerged.[2-3] In collaboration with BCCHInfectious Disease stakeholders, it was decided some changeswere required in the BCCH Emergency Department’s (ED)approach to sepsis and septic shock.

The first stage of the change was to re-invent the scope ofthe previous order set from “Fever in less than 60 days of age”to “Rule out serious bacterial infection in neonates(less than 30 days)”. The rationale for this change is:1) patients less than 30 days of life represent a more vulnerablepopulation with different treatment guidelines, and2) that neonates can often present hypothermic andnot febrile. Diagnostically, the new BCCH algorithmemphasizes the need for a lumbar puncture in this population,unless they are clinically unstable.[4]

In terms of treatment management, it remains that the mostcommon pathogens for neonatal sepsis are group B streptococcus,e. coli, streptococcus viridans and enterococcus while concernfor listeria monocytogenes must be considered in empirictherapy.[4-5] In light of needing antibiotics to cover theseorganisms, it was decided to simplify and standardize theorder set to make them more user friendly for ED cliniciansand align with continued management upon admission.

Therefore, the order set only recommends combination ampicillinand cefotaxime as antibacterial agents, knowing that resistanceto cefotaxime is low in infants and it has the ability to crossthe blood brain barrier in case of meningitis. Another importantshift in this version has been to give all neonates antiviralempiric therapy. A Canadian review found that herpes simplexvirus (HSV) meningitis predominantly affected those less than16 days of life, and had up to 13% mortality rates and severe …article continues on page 7

http://policyandorders.cw.bc.ca/

Opioid-induced Neonatal Abstinence SyndromeJason Tan, BSc(Pharm), PharmD

Reviewed by Vanessa Paquette, BSc(Pharm), PharmD and Dr. Robert Everett, MD, FRCP(C)Opioid-induced neonatal abstinence syndrome (NAS) is a withdrawal syndrome in the neonate secondary to maternal opioid use during pregnancy.[1] Incidence of NAS is growing, and estimated at 0.51% of all infants born in Canada.[1] Presentation of NAS varies, with the central nervous system (e.g. irritability, high-pitched crying, tremors, seizures), metabolic (e.g. febrile), respiratory (e.g. tachypnea), and gastrointestinal (e.g. poor feeding, poor weight gain, diarrhea, emesis) systems affected.[2] BC Women’s Hospital is introducing the “Eat, Sleep, Console” model, a new standardized treatment protocol using morphine (when pharmacotherapy indicated; first-line treatment is non-pharmacological) as a first-line option for opioid-induced NAS.[3] The Canadian Pediatric Society (CPS) does not provide specific recommendations for NAS management but notes morphine is the most common first-line treatment option.[1] A review of NAS drug therapy alternatives is presented in Table 1. This review excludes articles published before 2000 and articles using paregoric or diluted tincture of opium (DTO), as these do not reflect current practice. Table 2 summarizes included head-to-head comparisons.Network Meta-AnalysisThe different pharmacological treatments for NAS were compared in a network meta-analysis.[4] Only randomizedcontrolled trials (RCTs) were analyzed, and older trials using DTO were also included.[4] Of the different pharmacologicalagents available, buprenorphine had the greatest median rank for the outcomes of length of stay and treatment.[4]Several issues hamper interpretation of these results, including imprecision with large credible intervals, inter-trialheterogeneity with treatment protocols and patient populations, and an incomplete network for meta-analysis.Table 1: Pharmacological agents for the treatment of NASMedication Mechanism of action Pharmacokinetics CommentsMorphine [23] µ-opioid receptor agonist Bioavailability: 20-40%

Half-life: 2-9 hCurrent 1st-line treatmentalternative at BCWH

Methadone [1,24,25] Long-acting synthetic opioid,µ-opioid receptor agonist,and NMDA receptorantagonist

Bioavailability: 50%Half-life: 16-25 hhigh interpatient variabilityin pharmacokinetics

Prescribers requireauthorization from theMethadone MaintenanceProgram, (including NAS)

Buprenorphine [1,26] Partial µ-opioid receptoragonist, and κopioidreceptor antagonist

Bioavailability: 7%Half-life: 11 h

Formulations for the treatment of NAS are not available in Canada

Clonidine [27,28] Centrally-acting alpha-2-adrenergic agonist

Bioavailability: 50%Half-life: 44-72 h

Primarily used as adjunctivetreatment at BCWH

Phenobarbital [1,29] GABA receptor agonist Bioavailability: >90%Half-life: 74 – 150 h

Primarily used as adjunctivetreatment at BCWH

Methadone vs MorphineTwo RCTs and 3 retrospective cohort trials assessed the differences between morphine and methadone for NAS.[5,6]The RCTs examine similar maternal and infant patient populations, and use a modified Finnegan score to determinetreatment initiation, titration, and weaning.[5,6] Both RCTs found methadone superior to morphine in reducing length ofhospital stay (LOH) and length of drug treatment (LOD).[5,6]There were no differences in adjunctive treatments.[5,6]

The 3 retrospective cohort trials had variable results: one showing statistical superiority, one showing no difference, andone showing inferiority of methadone to morphine.[7-9] Interpretation of these results are limited due to the lack of astandardized treatment protocol between sites, and significant differences in inter- and intra-trial baseline characteristics.

Clonidine vs MorphineIn 1 RCT, clonidine was superior to morphine in reducing LOD, outpatient treatment duration, and LOH.[10] The trialalso assessed patients using the NICU Network Neurobehavioral Scale (NNNS) at 5 to 7 days after the start of treatmentand again at 40 to 44 weeks postmenstrual age.[10] No clinically significant differences were seen between groups.[10]One retrospective trial comparing continuous infusions of morphine and clonidine found similar results in LOH and LOD.[11]

Clonidine as adjunct (Morphine vs Morphine and Clonidine)One retrospective cohort trial found no differences between morphine monotherapy and concomitant morphine andclonidine therapy for LOH.[12] However, morphine monotherapy was statistically superior for length of morphinetreatment and total LOD.[12] Significant differences in baseline characteristics confound interpretation of these results.

Buprenorphine vs MethadoneTwo retrospective cohort trials compared buprenorphine and methadone.[13,14] In both trials, buprenorphine was superiorfor reducing LOH and length of treatment.[13,14] Several limitations impact interpretation of the results, includingconfounding of the methadone arm by allowing patients to be on morphine instead, exclusion of patients from the buprenorphinetreatment arm based on maternal methadone exposure, and potential treatment site differences. …article continues on page 4

Phenobarbital vs MorphineTwo RCTs comparing phenobarbital and morphine monotherapy found differing results. One RCT found that the morphinemonotherapy group had a statistically significant lower LOD, and lower admission to the Special Care Baby Unit.[15]One prospective pre-post cohort trial found similar results for LOD with similar limitations.[16] The other RCT demonstrateda nearly identical LOH and LOD.[17] These results may be accounted for by several significant differences, includingprevalence of maternal methadone use, phenobarbital and morphine dosing, and maternal exposure to alternativedrugs, such as benzodiazepines.

Buprenorphine vs MorphineThree sequentially published RCTs, culminating in the BBORN trial, compared the use of buprenorphine to morphine,and all found that the LOD and LOH were reduced in the buprenorphine group.[18-20] One of the RCTs did not findstatistical significance, but the trial was underpowered. Results appear clinically significant and consistent with other RCTs.[18]

Morphine and Phenobarbital vs Morphine and ClonidineOne RCT compared the adjunctive use of phenobarbital and clonidine with morphine. The RCT initiated eitherphenobarbital or clonidine at the same time as morphine, and not sequentially after trialing morphine as istypically done at BCWH.[21] In this context, phenobarbital was superior to clonidine in the average time taken towean off morphine and the total morphine dose given.[21] Unfortunately, these positive findings in the phenobarbitalgroup are limited due to the much extended duration of outpatient phenobarbital use, 3.8 months (range 1-8 months),compared to clonidine which was, according to protocol, weaned off completely within 48 hours of morphinediscontinuation. One retrospective pre-post cohort trial found conflicting results, in that the total length of treatmentand length of hospitalization was reduced in the adjunctive clonidine group.[22] In this retrospective trial, phenobarbitaland clonidine were sequentially added to morphine therapy, and morphine was up-titrated more rapidly than thephenobarbital group, potentially confounding the results in favour of the clonidine group.[22]

ConclusionsCurrent literature does not state a superior pharmacological option for treatment of NAS. No significant adverse eventswere observed in any of the included trials. A recent network meta-analysis found buprenorphine is likely superior toother options, but limitations impact indirect comparisons. Logistical issues prevent use of buprenorphine and methadoneat BCWH. While phenobarbital remains a viable treatment option for NAS, morphine and clonidine appear superior.

Table 2: Evidence summary of NAS head-to-head comparison trials

First Author(Publication year)

Study design(Total N)

Patientpopulation

LOH (d) LOD (d) Use of anyadjunct/rescue

Methadone vs MorphineDavis (2018) [5] R, DB, AC

(N = 116)Term infants,maternal treatmentwith methadoneor buprenorphine

Mean: 21.8±15vs 23.2±8.8,adjusted p=0.046

Mean: 14.7±8.0vs 16.6±6.9;adjusted p=0.02

17.2% vs 29.3%;adjusted p=0.07

Brown (2015) [6] R, DB, AC(N = 31)

Term infants,maternal treatmentwith methadoneor buprenorphine,no maternalbenzodiazepineexposure

Mean: 14 vs 21;p=0.008

Mean: 14.5 vs25; p=0.004

40% vs 56%;p=0.64

Lainwala (2005) [7] Retrospectivecohort(N = 46)

Term infants,maternal exposureto any opioid

Median: 40 (IQR30–51) vs 36(IQR 33-39);p=0.142

Not assessed Not assessed

Tolia (2018) [8] Retrospectivecohort(N = 7667)

Term infants,diagnosed with NAS,received morphineor methadonefirst prior to anyother drugtherapy for NAS

Median: 18 (IQR11–30) vs 23(IQR 16-33);p

First Author(Publication year)

Study design(Total N)

Patientpopulation

LOH (d) LOD (d) Use of anyadjunct/rescue

Clonidine vs MorphineBada (2015) [10] R, DB, AC

(N = 31)Term infants,maternal exposureto any opioid

Mean: 14.9±6 vs21±12.3; p>0.05

Mean: 32±20.4vs 42.9±17.8;p=0.02

Not assessed

Esmaeili (2009) [11] Retrospectivecohort(N = 93)

Term infants,maternal exposureto any opioid, thoughiatrogenic opioidwithdrawal included

Median: 32(range 14-56) vs44 (range 16-100)

Median: 14(range 6-40) vs35 (range 6-92)

Not assessed

Morphine vs Morphine plus Clonidine

Gullickson (2018) [12] Retrospectivecohort(N = 122)

Late pretermand term infants,diagnosed with NAS

Median: 22.5(IQR 14-33) vs21 (IQR 15-33);p=0.6

All treatment,mean: 11.3±7.6vs 19.7±12.9;p

Pharmacy Informer Editorial Board

Dean Elbe, BScPharm, PharmD, BCPP (Editor)delbe@cw.bc.caVanessa Paquette, BScPharm, PharmD (Editor)vpaquette@phsa.caJason Tan, BScPharm, PharmD (Editor)Jason.Tan@cw.bc.caJennifer Kendrick, BScPharm, PharmD (PT&N Liaison)Roxane Carr, BScPharm, PharmD, BCPS, FCSHP(Clinical Coordinator)

References - Opioid-induced Neonatal Abstinence Syndrome

1. Lacaze-Masmonteil T, O’Flaherty P. Managing infants born to mothers who have used opioids during pregnancy. 2018 May [revised 2018 Jun, cited 2019 Sep]. In: Canadian Pediatric SocietyON (CAN): Canadian Pediatric Society. 2019. Full Text2. Kocherlakota, P. Neonatal abstinence syndrome. Pediatrics 2014 134:e547-61. Abstract3. Grossman MR, Lipshaw MJ, Osborn RR, et al. A novel approach to assessing infants with neonatal abstinence syndrome. Hosp Pediatr 2018;8:1-6. Abstract4. Disher T, Gullickson C, Singh B, et al. Pharmacological treatments for neonatal abstinence syndrome: a systematic review and network meta-analysis. JAMA Pediatr 2019;173:234-43. Abstract5. Davis JM, Shenberger J, Terrin N, et al. Comparison of safety and efficacy of methadone vs morphine for treatment of neonatal abstinence syndrome: a randomized clinical trial.JAMA Pediatr 2018;172:741-8. Full Text6. Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol 2015;35:278-83. Abstract7. Lainwala S, Brown ER, Weinschenk NP, et al. A retrospective study of length of hospital stay in infants treated for neonatal abstinence syndrome with methadone versus oral morphinepreparations. Adv Neonatal Care 2005;5:265-72. Abstract8. Tolia VN, Murthy K, Bennett MM, et al. Morphine vs methadone treatment for infants with neonatal abstinence syndrome. J Pediatr 2018;203:185-9. Abstract9. Young ME, Hager SJ, Spurlock D. Retrospective chart review comparing morphine and methadone in neonates treated for neonatal abstinence syndrome. Am J Health-Syst Pharm 2015;72:S162-7. Abstract10. Bada HS, Sithisarn T, Gibson J, et al. Morphine vs clonidine for neonatal abstinence syndrome. Pediatrics 2015;135:e383-91. Full Text11. Esmaeili A, Keinhorst AK, Schuster T, et al. Treatment of neonatal abstinence syndrome with clonidine and chloral hydrate. Acta Paediatrica 2010;99:209-14. Abstract12. Gullickson C, Kuhle S, Campbell-Yeo M. Comparison of outcomes between morphine and concomitant morphine and clonidine treatments for neonatal abstinence syndrome.Acta Paediatrica 2019;108:271-4. Abstract13. Hall ES, Isemann BT, Wexelblatt SL, et al. A cohort comparison of buprenorphine versus methadone treatment for neonatal abstinence syndrome. J Pediatr 2016;170:39-44. Abstract14. Hall ES, Rice WR, Folger AT, et al. Comparison of neonatal abstinence syndrome treatment with sublingual buprenorphine versus conventional opioids. Am J Perinatol 2018;35:405-12. Abstract15. Jackson L, Ting A, Mckay S, et al. A randomised controlled trial of morphine versus phenobarbitone for neonatal abstinence syndrome. Arch Dis Child Fetal Neonatal Ed 2004;89:F300-4. Full Text16. Ebner N, Rohrmeister K, Winklbaur B, et al. Management of neonatal abstinence syndrome in neonates born to opioid maintained women. Drug Alcohol Depen 2007;87:131-8. Abstract17. Nayeri F, Sheikh M, Kalani M, et al. Phenobarbital versus morphine in the management of neonatal abstinence syndrome, a randomized control trial. BMC Pediatrics 2015;15:1-7. Full Text18. Kraft WK, Gibson E, Dysart K, et al. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics 2008;122:e601-7. Full Text19. Kraft WK, Dysart K, Greenspan JS, et al. Revised dose schema of sublingual buprenorphine in the treatment of neonatal opioid abstinence syndrome. Addiction 2011;106:574-80. Full Text20. Kraft WK, Adeniyi-Jones SC, Chervoneva I, et al. Buprenorphine for the treatment of the neonatal abstinence syndrome. N Engl J Med 2017;376:2341-8. Full Text21. Surran B, Visintainer P, Chamberlain S, et al. Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomizedclinical trial. J Perinatol 2013;33:954-9. Abstract

First Author(Publication year)

Study design(Total N)

Patientpopulation

LOH (d) LOD (d) Use of anyadjunct/rescue

Buprenorphine vs MorphineKraft (2008) [18] R, OL, AC

(N = 26)Term infants,maternal exposureto any opioid,no benzodiazepineexposure

Mean:27±11 vs 38±16;p = 0.068

Mean:22±11 vs 32±16;p = 0.077

23.1% vs 7.7%;p > 0.05

Kraft (2011) [19] R, OL, AC(N = 24)

Term infants,maternal exposureto any opioid,no benzodiazepineexposure

Mean:32±24 vs 42±13;p = 0.05

Mean:23±12 vs 38±14;p = 0.01

25% vs 8.3%;p > 0.05

Kraft (2017) [20] R, DB, AC(N = 63)

Term infants,maternal exposureto any opioid,no benzodiazepineexposure

Median: 21(range 7-71) vs33 (18-70);p < 0.001

Median: 15(range 3-67) vs28 (range 13-67);p < 0.001

15% vs 23%;p = 0.36

Morphine and Phenobarbital vs Morphine and ClonidineSurran (2013) [21] R, OL, AC

(N = 68)Term infants,maternal exposureto any opioid,no benzodiazepineexposure

Not assessed Mean morphinetreatment time:12.4 (95% CI10.1-14.7) vs19.5 (95% CI15.7-23.2);p = 0.001

Not assessed

Devlin (2017) [22] Retrospective,pre-post cohort

Term infants,diagnosed withNAS

Mean: 42 vs 33;p < 0.001

Mean: 35 vs26.5; p < 0.001

63% vs 39%;p = 0.004

22. Devlin LA, Lau T, Radmacher PG. Decreasing total medication exposure and length of stay whilecompleting withdrawal for neonatal abstinence syndrome during the neonatal hospital stay.Front Pediatr 2017;5:216. Full Text23. Pediatrics and NeoFax. Micromedex Solutions. Ann Arbor, MI: Truven Health Analytics, Inc;2019. Morphine [revised 2019 July; cited 2019 Sep].24. Pediatrics and NeoFax. Micromedex Solutions. Ann Arbor, MI: Truven Health Analytics, Inc;2019.Methadone [revised 2019 July; cited 2019 Sep].25. College of Physicians and Surgeons of British Columbia. Methadone Maintenance program:Clinical practice guideline. BC (CAN): College of Physicians and Surgeons of British Columbia;2014 Feb [updated 2015 Sep; cited 2019 Sep]. 49 p. Full Text26. Pediatrics and NeoFax. Micromedex Solutions. Ann Arbor, MI: Truven Health Analytics, Inc;2019. Buprenorphine [revised 2019 July; cited 2019 Sep].27. Pediatrics and NeoFax. Micromedex Solutions. Ann Arbor, MI: Truven Health Analytics, Inc;2019. Clonidine [revised 2019 July; cited 2019 Sep].28. Larsson P, Nordlinder A, Bergendahl HT, et al. Oral bioavailability of clonidine in children.Paediatr Anaesth 2011;21:335-40. Abstract29. Pediatrics and NeoFax. Micromedex Solutions. Ann Arbor, MI: Truven Health Analytics, Inc;2019. Clonidine [revised 2019 July; cited 2019 Sep].

AC = active-comparator; DB = double-blind; IQR = interquartile range; NSS = not statistically significant;OL = open-label; R = randomized

Opioid-induced Neonatal Abstinence Syndrome - continued from page 5

mailto:delbe@cw.bc.camailto:vpaquette@phsa.camailto:Jason.Tan@cw.bc.cahttps://www.cps.ca/en/documents/position/opioids-during-pregnancyhttps://www.ncbi.nlm.nih.gov/pubmed/?term=25070299https://www.ncbi.nlm.nih.gov/pubmed/?term=29263121https://www.ncbi.nlm.nih.gov/pubmed/?term=30667476https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142918/https://www.ncbi.nlm.nih.gov/pubmed/?term=25357093https://www.ncbi.nlm.nih.gov/pubmed/?term=16202968https://www.ncbi.nlm.nih.gov/pubmed/?term=30220442https://www.ncbi.nlm.nih.gov/pubmed/?term=26582303https://www.ncbi.nlm.nih.gov/pubmed/?term=26582303https://pediatrics.aappublications.org/content/pediatrics/135/2/e383.full.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/?term=19839963https://www.ncbi.nlm.nih.gov/pubmed/?term=29972601https://www.ncbi.nlm.nih.gov/pubmed/?term=26703873https://www.ncbi.nlm.nih.gov/pubmed/?term=29112997https://fn.bmj.com/content/fetalneonatal/89/4/F300.full.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/?term=17000060https://bmcpediatr.biomedcentral.com/track/pdf/10.1186/s12887-015-0377-9https://bmcpediatr.biomedcentral.com/track/pdf/10.1186/s12887-015-0377-9https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574639/pdf/nihms66569.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022999/pdf/nihms-231900.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662132/pdf/nihms889790.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/?term=23949834https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641300/pdf/fped-05-00216.pdfhttp://www.bccdc.ca/resource-gallery/Documents/Statistics%20and%20Research/Publications/Epid/Other/02_CPSBC-Methadone_Maintenance_Program_Clinical%20_Practice_Guideline.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/?term=20735802

The use of balanced crystalloids is becoming increasingly popularin both critical care and other settings.[1] The rationale for theiruse is that their composition more closely resembles the compositionof plasma when compared to normal saline.[1] (Table 1).

Specifically, balanced crystalloids contain less chloride as well asadditional anions such as lactate, or gluconate and acetate thatare metabolized by the liver to carbon dioxide and water whichconsumes hydrogen cations and produces a metabolic alkalinizingeffect. [2,3] This could possibly reduce the development of ahyperchloremic metabolic acidosis, especially in patients requiringlarge volumes of intravenous fluid.[1] The balanced crystalloidsmost commonly used at BCCH are Plasma-Lyte and Ringer’s Lactate.

The development of a metabolic acidosis can be undesirable incritically ill patients, as is the development of hyperchloremiaitself.[1] Hyperchloremia has been associated with developmentof acute kidney injury (AKI); while the exact mechanism ofhyperchloremia associated AKI is unclear, it is thought to berelated to renal vasoconstriction mediated by tubuloglomerularfeedback.[4] Whether the use of balanced crystalloids reduces AKIor other morbidities compared to normal saline has been debatedin the literature. The SPLIT trial, a large randomized controlledtrial (RCT) that included ICU patients receiving saline or a balancedcrystalloid found no difference in mortality, development of AKI,or need for renal replacement therapy (RRT).[5] A more recentmeta-analysis found decreased mortality at 28 or 30 days in groupsthat received balanced crystalloids compared to normal saline(RR: 0.86, 95% CI: 0.75-0.99), however this was powered byobservational studies and the effect was not significant among thesubgroup of RCTs.[6] Additionally, there was a significant reductionin the incidence of AKI (RR: 0.91, 95% CI: 0.85-0.98), howeverthe difference in progression to RRT was not statistically significant(RR: 0.91, 95% CI: 0.79-1.04).[6] Two large recently publishedRCTs comparing the use of saline to balanced crystalloids, theSALT-ED study, conducted in critically ill patients, and the SMARTstudy conducted in non-critically ill patients, both found significantreductions in major adverse kidney events, but did not findsignificant reductions in mortality or other morbidities.[7,8]

Despite the theoretical advantages to balanced crystalloids and possible benefits in reducing adverse outcomes, there are potential limitations to their widespread use. Ringer’s lactate has a sodium concentration of 130 mmol/L, and could increase the risk of hyponatremia.[1] The incidence of hyponatremia was higher in ICUs that used more Ringer’s lactate compared to saline.[8] This is not normally an issue for Plasma-Lyte, unless dextrose is added, which is commonly done in an attempt to reduce the risk of hypoglycemia. As dextrose is added to a bag of Plasma-Lyte, its contents become more dilute, making it a more hypotonic solution (Table 1). Additionally, there is less data regarding intravenous compatibility of medications with balanced crystalloids, particularly Plasma-Lyte.[1,9] Of note, Plasma-Lyte has been reported to be incompatible with propofol and with certain concentrations of midazolam.[1,9] Lastly, balanced crystalloids tend to be more expensive; while the cost of obtaining a 1 liter bag of Ringer’s Lactate is only 20% higher than saline, a 1 liter bag of Plasma-Lyte is 2.5 times the cost of saline.

Recent studies have served to spur further debate regarding theuse of balanced crystalloids.[1,6–8,10] Pharmacists play a role inthe management of intravenous fluids and determination ofcompatibilities with other medications and therefore should befamiliar with the literature pertaining to balanced crystalloids aswell as the practicalities regarding their use.

BCCH Drug Information Rounds:Use of Balanced Crystalloids

Kyle Collins, BSc(Pharm), PharmDNa* K* Cl* Mg* Ca* Dextrose (%)

Ringers Lactate** 130 4 109 0 1.4 0Plasma-Lyte*** 140 5 98 1.5 0 0D5-Plasma-Lyte 127 4.5 89 1.36 0 4.5D10-Plasma-Lyte 115 4.1 81 1.23 0 9.1

Table 1. Balanced Crystalloid Solutions

*mmol/L**Ringer’s lactate also contains 28 mmol/L of lactate***Plasma-Lyte also contains 27 mmol/L of acetate and 23 mmol/L of gluconate

AcknowledgementTable 1 was created by Nicole Primus, BSc(Pharm), PharmDReferences

1. Weinberg L, Collins N, Mourik VK, et al. Plasma-Lyte 148: A clinical review. World J Crit Care Med2016;5:235. Full Text2. Product information. Lactated Ringer’s Injection. [accessed 2019 Sept 5]. Available from:https://www.baxter.ca/sites/g/files/ebysai1431/files/2018-11/Lactated_Ringers_Inj_EN.pdf3. Product information. PLASMA-LYTE 148 (An Electrolyte Solution) Injection. [accessed 2019 Sept 5].Available from: https://www.baxter.ca/sites/g/files/ebysai1431/files/2018-11/Plasma-Lyte_EN.pdf4. Rein JL, Coca SG. “I don’t get no respect”: The role of chloride in acute kidney injury.Am J Physiol - Ren Physiol 2019;316:F587–605. Abstract5. Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acutekidney injury among patients in the intensive care unit: The SPLIT randomized clinical trial.JAMA 2015;314:1701–10. Abstract6. Hammond DA, Lam SW, Rech MA, et al. Balanced Crystalloids Versus Saline in Critically Ill Adults:A Systematic Review and Meta-analysis. Ann Pharmacother 2019;106002801986642. Abstract7. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in Noncritically Illadults. N Engl J Med 2018;378:819–28. Full Text8. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in Critically Illadults. N Engl J Med 2018;378:829–39. Full Text9. Dawson R, Wignell A, Cooling P, et al. Physico-chemical stability of Plasma-Lyte 148® andPlasma-Lyte 148® + 5% Glucose with eight common intravenous medications. Paediatr Anaesth2019;29:186–92. Abstract10. Various authors [letters]. Balanced Crystalloids versus Saline in Critically Ill Adults.N Engl J Med 2018;378:1949–51. Full Text

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neurodevelopmental morbidity.[6] With this in mind, the new algorithmrecommends all neonates receive acyclovir until lumbar puncturesrules out the possibility of neonatal HSV.

These changes prompted the creation of an additional order setthat addressed ED management of sepsis and septic shock inpediatric patients greater than 30 days of life to adolescence.The need for this order set was to create concise information thataligns with early goal-directed therapy from landmark guidelinessuch as the Surviving Sepsis Campaign as well as antibiotictherapy guided by the BCCH Empiric Guide.[1,2,5] The order setprovides conservative guidelines in which antibiotics, fluids andif needed, vasopressors, should be initiated in a timely manner.

Both “ED Rule Out Serious Infections in Neonates less than 30Days of Age” and “ED Suspected Sepsis and Septic Shock (greaterthan 30 days of age)” can be found on ePOPs.References1. Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for

Management of Sepsis and Septic Shock. Intensive Care Med 2017;43:304–77. Full Text2. Kawasaki T. Update on pediatric sepsis: a review. J Intensive Care 2017;5:47. Full Text3. Davis AL, Carcillo JA, Aneja RK et al. American College of Critical Care Medicine Clinical

Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. CritCare Med 2017;45:1061–93. Abstract

4. Puopolo KM, Benitz WE, Zaoutis TE, AAP COMMITTEE ON FETUS AND NEWBORN, AAPCOMMITTEE ON INFECTIOUS DISEASES. Management of Neonates Born at ≥35 0/7 Weeks’Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics 2018;142:e20182894. Full Text

5. BC Children’s Hospital Empiric Antimicrobial Guide, 6th edition.6. PICNIC CNS infections study. Manuscript submitted for publication.

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