2014 Low-dose vs Standard-dose Insulin in Pediatric Diabetic Ketoacidosis, A Randomized Clinical Trial

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    Copyright 2014 American Medical Association. All rig hts reserved.

    Low-Dose vs Standard-Dose Insulin inPediatric

    Diabetic Ketoacidosis

    A Randomized Clinical Trial

    Karthi Nallasamy, MD,DM; Muralidharan Jayashree, MD; SunitSinghi, MD; ArunBansal, MD

    IMPORTANCE  The standard recommended dose (0.1 U/kg per hour) of insulin in diabetic

    ketoacidosis (DKA)guidelinesis not backed by strong clinical evidence. Physiologic

    dose-effect studies have found that even lower doses could adequately normalize ketonemia

    and acidosis.Lowering theinsulin dose maybe advantageous in theinitial hours of therapy

    when a gradual decrease in glucose, electrolytes, and resultant osmolality is desired.

    OBJECTIVE To compare theefficacy and safetyof low-doseinsulin against thestandard dose

    in children with DKA.

    DESIGN, SETTING, AND PARTICIPANTS   This was a prospective, open-labelrandomized clinical

    trial conducted in thepediatric emergencydepartment andintensive care unit of a tertiary care teaching hospital in northern India from November 1, 2011, through December 31,2012.

    A total of 50 consecutive children 12 years or younger with a diagnosisof DKA were

    randomized to low-dose (n = 25) and standard-dose (n = 25) groups.

    INTERVENTIONS Low-dose(0.05 U/kg per hour) vs standard-dose (0.1 U/kg per hour) insulin

    infusion.

    MAINOUTCOMES AND MEASURES  The primary outcome was therate of decrease in blood

    glucose until a level of 250mg/dLor less is reached (toconvert to millimoles per liter,

    multiply by 0.0555). The secondary outcomes included time to resolution of acidosis,

    episodes of treatment failures, and incidences of hypokalemia and hypoglycemia.

    RESULTS The mean(SD)rate ofbloodglucose decrease until a level of250 mg/dLor lessis reached (45.1 [17.6] vs 52.2 [23.4] mg/dL/h) andthe mean (SD) time taken to achieve this

    target (6.0 [3.3] vs 6.2 [2.2] hours) were similar in thelow- andstandard-dosegroups,

    respectively. Mean (SD) lengthof time to achieve resolution of acidosis (low vs standard dose:

    16.5 [7.2] vs 17.2 [7.7] hours; P  = .73)and rate of resolution of acidosis were also similar in the

    groups. Hypokalemia was seen in 12 children (48%) receivingthe standarddose vs 5 (20%)of 

    thosereceivingthe lowdose (P  = .07); the tendency was more pronounced in malnourished

    children (7 [88%] vs 2 [28%]). Five children (20%) and1 child (4%) receivingstandard- and

    low-dose infusion (P  = .17), respectively, developed hypoglycemia. Treatment failure was rare

    and comparable. Onechild in thestandard-dosegroup developed cerebral edema,and no

    deaths occurred during the study period.

    CONCLUSIONS AND RELEVANCE  Low dose is noninferior to standarddose with respect to rate

    of blood glucose decrease and resolution of acidosis.We advocate a superiority trial with a

    largersample size before0.05 U/kg per hour replaces 0.1 U/kg per hour in thepractice

    recommendations.

    TRIAL REGISTRATION   ctri.nic.in Identifier: CTRI/2012/04/002548

     JAMA Pediatr . 2014;168(11):999-1005. doi:10.1001/jamapediatrics.2014.1211

    Published onlineSeptember 29,2014.

    Editorialpage990

    JournalClubSlides and

    Supplementalcontent at

     jamapediatrics.com

    CMEQuizat

     jamanetworkcme.com and

    CMEQuestionspage1083

    Author Affiliations: Departmentof 

    Pediatrics, Postgraduate Instituteof 

    Medical Education and Research,

    Chandigarh,India.

    Corresponding Author:

    MuralidharanJayashree, MD,

    Departmentof Pediatrics,

    Postgraduate Instituteof Medical

    Education and Research,Sector 12,

    Chandigarh,India 160012

    (mjshree@hotmail.com).

    Research

    Original Investigation

    999

    Copyright 2014 American Medical Association. All rig hts reserved.

    wnloaded From: http://archpedi.jamanetwork.com/ by Prateek Lala on 04/06/2016

    To convert blood glucose values from milligrams per deciliter to millimoles per liter, multiply by 0.0555.

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    eter range were counterchecked by serum BG measurement

    using the hexokinase method. Serum electrolytes, urea, cre-

    atinine, urine ketones, and venous blood gas were measured

    every 4 hours. Fluid intake, urine output, and electrocardio-

    gram changes were monitored continuously, whereas neuro-

    logic assessment was performed every 2 hours. Malnutrition

    was defined based on weight for age matched for Indian

    standards.16

    TreatmentFailure

    Thedatawerereviewed every 4 hours in both groups. Failure

    to achievea BG reductionof 18 mg/dL perhour for2 consecu-

    tivehours and/or a decrease or failure to increasein bicarbon-

    ate with persistent high anion gap acidosis was considered a

    nonresponse. A careful review of insulin therapy was per-

    formedfor errorsin dose, preparation, or infusion rate before

    labelingthe nonresponse as treatment failure.The existing in-

    fusion rate was thereafter increased by 0.02 U/kg per hour.

    OutcomeMeasures

    Theprimary outcome wasthe rate of decrease in BG untilthe

    level reached 250 mg/dL or less. Time to resolution of acido-

    sis,episodes of treatment failures, and incidencesof hypoka-

    lemia and hypoglycemia were secondary outcomes.Hypoka-

    lemia was defined as a serum potassium level less than 3.5

    mEq/L and/or suggestive electrocardiographic changes.6

    Hypoglycemia was defined as a BG level of 60 mg/dL or less.

    StatisticalAnalysis

    We estimated sample size to detect noninferiority; low dose

    wasconsiderednoninferior if thedifference betweenthe stan-

    dard and low dose for mean BG decrease did not exceed 18

    mg/dL per hour. Previous data suggest that the SD of BG de-

    crease withstandard-doseinsulinwas 24 mg/dL perhour.17Cal-

    culated sample size with a power of 80%using a significance level of .05(α = .05) was44. Assuming an attrition rate of 10%,

    we enrolled 50 participantsin total.

    Intergroup comparisons were performed using the  t  test

    and χ 2 test with the Fisher exact test. For assessment of non-

    inferiority, we calculated the differences in BG decrease be-

    tween the2 groupswith 95%CIs andcomparedthe upper limit

    of the CI to the preset noninferiority margin. To mitigate the

    problem of multiple testing for serially measured quantita-

    tive outcomes, we used repeated-measures analysis of vari-

    ance and a summary measure of areasunder thecurve. Toes-

    timate theareaunderthe curve from baseline until6 hoursof 

    insulin therapy, we imputed missing values (few participants

    in whom target BG valueswere attained before 6 hours)withmultivariate imputation by chained equations.

    Hazardratios (HRs)were estimatedfor outcomes of BG de-

    creaseand resolutionof acidosis usingCox proportional model

    adjusted a priori for age, weight, andacidosis severity. For all

    secondary outcomes, the Monte Carlo permutation test was

    performed to adjust for multiple outcomes. For primary out-

    come, P < .05was considered statistically significant. Data en-

    try and analysis were performed using IBM-SPSS, version 22

    (SPSS Inc), MedCalc,version13.2(MedCalc Software), andStata/

    IC, version 12 (Stata Corp).

    Results

    Baseline Characteristics Figure 1 showsthetrialprofile. Ofthe 57childrenscreened for

    eligibility, 50were enrolledand randomlyassignedto thelow-

    dose(n = 25)or standard-dose(n = 25) group. Baseline demo-

    graphic and biochemical characteristics in both groups were

    well matched (Table 1). A total of 13 children (26%) were

    younger than 5 years.New-onset diabetes presenting as DKA

    wasseenin 29children(58%). A totalof 34children (68%)had

    severe DKA(pH

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    Copyright 2014 American Medical Association. All rig hts reserved.

    area underthe curve valueswerealsosimilar(AUC,2201;95%

    CI, 2014-2388; vs AUC, 2263; 95% CI, 2093-2434; for low dose

    vs standard dose; t  = 0.49;  P  = .62).

    Theserial (hourly)changes in rate of decrease andpercent-

    agedecrease in BG between thegroupsrevealed no significant

    difference( F = 0.47; P = .71). However, themeandecreasein BG

    atthe endof first hour of insulin infusion washigher withstan-

    dard- compared withlow-doseinsulin(61vs 39mg/dL)(Table 2).

    Episodesof BG decreasegreater thanthedesiredrange(>90mg/

    dL)were alsomore frequentwith theformercomparedwith the

    latter (12 [10%] of 124 vs 4 [4%] of 113; relative risk, 0.51; 95%

    CI, 0.21-1.20; P = .05).In fact, noout-of-range decrease wasnoted

    with low-dose insulin during the first hour of infusion.

    No difference was found in the mean (SD) length of time

    to achieve a BG