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  • Pediatric Diabetes 2013: 14: 435446doi: 10.1111/pedi.12027All rights reserved

    2013 John Wiley & Sons A/S

    Pediatric Diabetes

    Original Article

    Pediatric diabetic ketoacidosis, fluid therapy,and cerebral injury: the design of a factorialrandomized controlled trial

    Glaser NS, Ghetti S, Casper TC, Dean JM, Kuppermann N, for the PediatricEmergency Care Applied Research Network (PECARN) DKA FLUID StudyGroup. Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: thedesign of a factorial randomized controlled trial.Pediatric Diabetes 2013: 14: 435446.

    Treatment protocols for pediatric diabetic ketoacidosis (DKA) varyconsiderably among centers in the USA and worldwide. The optimal protocolfor intravenous (IV) fluid administration is an area of particular controversy,mainly in regard to possible associations between rates of IV fluid infusionand the development of cerebral edema (CE), the most common and the mostfeared complication of DKA in children. Theoretical concerns aboutassociations between osmotic fluid shifts and CE have promptedrecommendations for conservative fluid infusion during DKA. However,recent data suggest that cerebral hypoperfusion may play a role in cerebralinjury associated with DKA. Currently, there are no existing data fromprospective clinical trials to determine the optimal fluid treatment protocol forpediatric DKA. The Pediatric Emergency Care Applied Research NetworkFLUID (FLuid therapies Under Investigation in DKA) study is the firstprospective randomized trial to evaluate fluid regimens for pediatric DKA.This 13-center nationwide factorial design study will evaluate the effects ofrehydration rate and fluid sodium content on neurological status during DKAtreatment, the frequency of clinically overt CE and long-term neurocognitiveoutcomes following DKA.

    Nicole S Glasera, SimonaGhettib, T Charles Casperc,J Michael Deanc, NathanKuppermanna,d and for thePediatric Emergency CareApplied Research Network(PECARN) DKA FLUID StudyGroup

    aDepartment of Pediatrics, Universityof California Davis, School of Medicine,Davis, CA, USA; bDepartment ofPsychology, University of CaliforniaDavis, Davis, CA, USA; cDepartment ofPediatrics, University of Utah School ofMedicine, Salt Lake City, UT, USA; anddDepartment of Emergency Medicine,University of California Davis, School ofMedicine, Davis, CA, USASee Appendix for the members of thePECARN DKA FLUID Study Group.

    Key words: brain injury CerebralEdema DKA

    Corresponding author: NathanKuppermann, MD, MPH,Department of Emergency Medicine,University of California Davis,School of Medicine,2315 Stockton Blvd.,Davis, CA 95817,USA.Tel: (916) 734-1535;fax: (916) 734-7950;e-mail: [email protected]

    Submitted 23 November 2012.Accepted for publication 29 January2013

    The optimal treatment for pediatric diabetic ketoacido-sis (DKA) has been a topic of debate for decades. Mul-tiple working groups and consensus conferences havebeen convened to develop guidelines for pediatric DKA

    treatment. These efforts, however, have been hamperedby a lack of high-quality data from randomized con-trolled trials to guide therapeutic recommendations(13). Intravenous (IV) fluid regimens for rehydration

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    of children with DKA have been the main topic of con-troversy. Consensus statements concerning IV fluidregimens for rehydration of children with DKA haveprovided broad, general guidelines because data areunavailable to support more precise recommendations.A recent informal poll of 20 hospitals participating inthe Pediatric Emergency Care Applied Research Net-work (PECARN) suggests that substantial variabilityin DKA management continues to exist (unpublisheddata), similar to that documented in older publishedliterature (4). According to currently used protocols inthe pediatric referral centers participating in PECARN,a 40-kg child with DKA could receive IV fluid at ratesas high as 215 mL/h or as low as 114 mL/h. Similarly,there is a disagreement about the optimal sodium con-tent of rehydration fluid with some using 0.45% saline,others 0.9% saline, and others using a combination.This substantial treatment variation reflects the lackof evidence to guide management and underscores theneed for a definitive randomized controlled trial.

    At the center of the controversy surrounding DKAtreatment in children are physicians concerns aboutpossibly causing or exacerbating DKA-related cerebraledema (CE) or cerebral injury with inappropriateIV rehydration. Clinically overt and potentially life-threatening CE occurs in only 0.51% of DKAepisodes, making this entity difficult to study. (5,6) However, CE that is asymptomatic or associatedwith only minor mental status disturbances hasbeen documented to occur in most children withDKA (710). In addition, while it was previouslyassumed that children who did not develop clinicallyovert CE recovered fully, without lasting neurologicalinjury, recent data suggest that this is not the case.DKA episodes without clinically overt CE have beenassociated with permanent deficits in memory function(11). Evidence to guide clinical care of children withDKA is therefore essential not only for the goal ofdecreasing the rate of clinically overt, life-threateningCE, but also to reduce the incidence of subclinical CEresulting in neurocognitive dysfunction.

    Some investigators hypothesized that CE may resultfrom osmotic shifts caused by rapid IV rehydration(1214). As a consequence, many protocols manageDKA in children with conservative fluid therapy.Although this hypothesis is intuitively appealing,data showing clear associations between aggressivefluid therapy and CE are lacking. Instead, recentdata suggest that cerebral hypoperfusion and theeffects of reperfusion during DKA treatment mayplay a prominent role in the development of cerebralinjury and CE (6, 1517). Conservative rehydrationprotocols could delay reestablishment of normalcerebral perfusion, and could be detrimental, ratherthan protective. Use of low sodium content fluidsmay exacerbate this problem by decreasing the volume

    of fluid retained in the vascular space, while useof isotonic saline may slow repair of intracellulardehydration. Conversely, more rapid infusion offluids might increase vasogenic edema associated withcerebral reperfusion, particularly if breakdown of thebloodbrain barrier has occurred from ischemia.

    The PECARN Fluid Therapies Under Investigationin DKA (FLUID) study is the first prospectiverandomized controlled clinical trial to investigate theimpact of fluid rehydration regimens on neurologicaland neurocognitive outcomes in children with DKA.The study will determine the effects of rehydration rateand fluid sodium content on neurological status duringDKA treatment, the frequency of clinically overt CE,and long-term neurocognitive outcomes.

    Methods

    Overview

    The PECARN FLUID study is a factorial designrandomized controlled trial comparing four fluidtreatment protocols for children with DKA. Tworates of rehydration will be compared; a more rapidrate, designed to promote faster reperfusion of braintissue and a slower rate, geared toward more gradualreperfusion. Within each of these two rehydration rateschemes, we will compare two sodium concentrations(0.9% saline or 0.45% saline), although all initialfluid boluses will be with 0.9% saline. The studytreatment arms were based on the high and low endsof the range of treatment protocols in current usein PECARN hospitals. We will compare treatmentarms using comprehensive assessments for neurologicalinjury including measurements of subtle neurologicaldysfunction during DKA treatment (in addition torecording the frequency of acute, clinically overt CE)and measures of long-term neurocognitive functionseveral months after hospital discharge.

    Inclusion/exclusion criteria

    Children meeting the following criteria will beconsidered for enrollment:

    (i) age 300 mg/dL, and venouspH < 7.25 or serum bicarbonate concentration

  • Pediatric DKA fluid therapy randomized trial

    during DKA treatment or neurocognitive testingafter recovery;

    (ii) Patients who present with DKA concomitantwith alcohol or drug use, head trauma,meningitis, or other conditions that affectneurological function;

    (iii) Patients with DKA transferred to one of the studysites after receiving an IV fluid bolus of more than10 mL/kg;

    (iv) Patients who have begun DKA treatment priorto being approached for enrollment and havereceived (a) more than 2 h of IV fluid infusion atmaintenance rates or higher, OR (b) more than4 h of DKA treatment with insulin and/or fluidsregardless of rate of infusion;

    (v) Patients who are pregnant;(vi) Patients for whom the treating physicians feel a

    specific fluid or electrolyte regimen is necessarysuch that patient safety or well-being could becompromised by enrollment into the study.

    Enrollment and DKA treatment protocols

    Upon arrival, patients will begin standard fluid therapyusing an initial IV fluid bolus of 10 cc/kg of 0.9% saline.During this initial therapy, study personnel will obtaininformed consent. Randomization will ideally occurprior to initial bolus completion. If consent cannot beobtained within this time frame, patients will be treatedwith the usual DKA protocol for the study site untilconsent is completed, but not beyond the time frameoutlined in the exclusion criteria.

    Children will be randomized to one of four treatmentprotocols (Table 1). In all protocols, initial bolusvolumes will be subtracted from the fluid deficit used tocalculate the rate of fluid replacement. Because studiesshow that clinical estimates of percent dehydrationin children with DKA are inaccurate (18, 19), weassigned an assumed fluid deficit to each protocol(Table 1) based on the upper or lower end of the rangedocumented in rec

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