pediatric diabetes

Pediatric Diabetes 2014: 15: 277–286doi: 10.1111/pedi.12154All rights reserved

2014 John Wiley & Sons A/S.Published by John Wiley & Sons Ltd.

Pediatric Diabetes

Review Article

The International Society of Pediatric andAdolescent Diabetes guidelines formanagement of diabetic ketoacidosis: do theguidelines need to be modified?

Wolfsdorf JI. The International Society of Pediatric and Adolescent Diabetesguidelines for management of diabetic ketoacidosis: do the guidelines need tobe modified?Pediatric Diabetes 2014: 15: 277–286.

The current version of the International Society of Pediatric and AdolescentDiabetes (ISPAD) guidelines for management of diabetic ketoacidosis (DKA)is largely based on the Lawson Wilkins Pediatric Endocrine Society/EuropeanSociety of Pediatric Endocrinology (LWPES/ESPE) consensus statement onDKA in children and adolescents published in 2004. This article criticallyreviews and presents the most pertinent new data published in the past decade,which have implications for diagnosis and management. Four elements of theguidelines warrant modification: (i) The definition of DKA; (ii) insulintherapy; (iii) water and salt replacement; and (iv) blood ß-hydroxybutyratemeasurements for the management of DKA.

Joseph I. Wolfsdorfa,b

aDiabetes Program, Division ofEndocrinology, Boston Children’sHospital, Boston, MA, USA; andbDepartment of Pediatrics, HarvardMedical School, Boston, MA, USA

Key words: diabetes – diabeticketoacidosis – managementguidelines

Corresponding author: Joseph I.Wolfsdorf, MB, BCh,Division of Endocrinology,Boston Children’s Hospital,300 Longwood Avenue,Boston, MA 02115,USA.Tel: (011) 617 355-7477;fax: (011) 617 730-0194;e-mail:[email protected]

Submitted 18 April 2014. Acceptedfor publication 18 April 2014

The current version of the International Society ofPediatric and Adolescent Diabetes (ISPAD) guidelinesfor management of diabetic ketoacidosis (DKA)is largely based on the Lawson Wilkins PediatricEndocrine Society/European Society of PediatricEndocrinology (LWPES/ESPE) consensus statementon DKA in children and adolescents (1, 2). In2003, LWPES/ESPE convened a panel of experts,which included representatives of ISPAD, for aconsensus conference. The literature on each of themajor topics included in the consensus statement wascarefully reviewed, the evidence critically evaluated,and treatment recommendations were formulatedbased on the evidence rating criteria used by theAmerican Diabetes Association at the time. A literature

search in PubMed for publications on DKA in childrenand adolescents since that LWPES/ESPE consensusconference yielded more than 500 articles. The purposeof this article is to critically review and present thenew information that warrants modifying the ISPADguidelines for management of DKA.

Definition of DKA

The current biochemical criteria for the diagnosis ofDKA are: hyperglycemia (blood glucose >11 mmol/Lor 200 mg/dL), venous pH <7.3 or bicarbonate<15 mmol/L, and the presence of ketonemia orketonuria (3). These diagnostic criteria have limitationsbecause serum pH and bicarbonate concentrations

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are relatively non-specific and can be affected by thedegree of respiratory compensation or the coexistenceof a separate acid–base disturbance (4). Althoughserum bicarbonate concentration is less susceptiblethan pH to abrupt changes in ventilation, nonetheless,like pH, it is a non-specific measure. Nausea andvomiting, which are common in patients with DKA,can result in metabolic alkalosis secondary to lossof protons (5), and an acute increase in the bloodlactate concentration (from poor tissue perfusion)can lower serum bicarbonate concentrations. Thepresence of ketonemia or ketonuria is qualitative (6),and neither the concentration of blood nor urineketones is specified in the current definition. All ofthe commercially available testing methods rely onthe nitroprusside reaction to produce a purple colorin the presence of ketone bodies; acetone is detectedonly if the reagent contains glycine in addition tosodium nitroprusside, and none of the tests detectß-hydroxybutyrate (BOHB), the predominant ketonebody in DKA. It must also be noted that urine ketonetests using nitroprusside-containing reagents give false-positive results in the presence of several sulfhydryldrugs (e.g., captopril). False negative readings havebeen reported when test strips have been exposed toair for an extended period of time or when urinespecimens are highly acidic, such as after consumptionof a large amount of ascorbic acid (6). The relativeproportions in which the ketone bodies are presentin blood vary according to the redox state of thecell. Normally, BOHB and acetoacetate (AcAc) arepresent in serum in approximately equimolar amounts;however, in DKA the ratio of BOHB:AcAc may varyfrom 1.3:1 to 5.5:1 [‘nitroprusside negative’ patientswith ratios >7:1 have been reported in association withlactic acidosis (4)]. The average ratio is approximately3:1 (standard deviation 0.9 and coefficient of variation30%) (7–10). Reliance on qualitative measurementof plasma or urine AcAc concentration alone, whichtypically represents 15–40% of the total ketone bodyconcentration, therefore, grossly underestimates theseverity of ketonemia. The concentrations of AcAcand BOHB directly reflect the rate of ketone bodyproduction (11), which is accompanied by equimolarproduction of hydrogen ions (12). It would seemlogical, therefore, to include quantitative measurementof BOHB in the diagnostic criteria for DKA.

A retrospective review of records from 129 hospital-ized children <16 yr (mean age 10.8 ± 0.4 yr) admittedfor DKA compared simultaneous measurements ofBOHB performed in the Clinical Chemistry Lab-oratory and serum bicarbonate concentrations (8).The relationship between bicarbonate and BOHB wascurvilinear: the BOHB values that corresponded witha bicarbonate concentration of 18 and 15 mmol/L were3.0 and 4.4 mmol/L, respectively. When these BOHB

levels are used for the diagnosis of DKA, there isdiscordance with at least one of the conventional diag-nostic criteria (bicarbonate, pH, or glucose) in 15%of children. These data suggest that diagnostic confir-mation of ketonuria or ketonemia with a quantitativemeasurement of serum BOHB concentration would bevery useful to evaluate patients presenting with sus-pected DKA. Non-specific tests of acid–base statussuch as pH and bicarbonate concentration have beencentral to the diagnosis of DKA, presumably becauseof their widespread availability in hospital emergencydepartments and, until relatively recently, BOHB wasa research test. However, the widespread use of open-channel automated chemistry analyzers now makes itpossible for virtually any laboratory to rapidly mea-sure serum BOHB levels. Point-of-care (POC), alsoreferred to as near patient BOHB measurement, isnow also readily available, and is increasingly beingused for the evaluation and management of patientswith suspected hyperglycemia emergencies. It must benoted, however, that POC devices have limited pre-cision and accuracy above a BOHB concentration ofapproximately 3 mmol/L (13). Despite this limitation,POC BOHB measurement should, nonetheless, be use-ful for diagnostic purposes as well as for managing theresponse to treatment. The diagnosis of DKA can bemade with confidence in a patient with hyperglycemia(blood glucose >11 mmol/L or 200 mg/dL), a venouspH <7.3, and a serum BOHB value >3 mmol/L.

Insulin therapy

Between the 1950s and early 1970s, insulin doses of25–100 U/h were given to adults with DKA by theintravenous (IV), intramuscular (IM), or subcutaneous(SC) route. Prospective randomized studies, however,subsequently showed no advantage of high-dosecompared with lower doses (see reference 14). In1973, Alberti et al. reported the results of low-doseIM insulin in the management of adult patients withmild to moderate DKA. An initial average bolus doseof 16 U followed by 5–10 U of IM regular insulinper hour was effective in correcting hyperglycemiaand metabolic acidosis (15). Subsequently, a series ofrandomized prospective studies by Kitabchi et al., andothers (10), convincingly demonstrated the efficacy oflow-dose insulin protocols for the treatment of DKA inadults. Even lower doses, referred to as ‘very low dose’insulin therapy [1 U/h (range 0.5–4 U/h)], together withfluid and electrolyte replacement and variable dextroseadministration aiming to decrease blood glucose by≤50 mg/dL/h, has been successfully used to treat severeDKA in adults (16).

Several reports also attest to the successful useof low-dose insulin in the treatment of DKA inchildren; however, most of these reports included

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DKA: do the guidelines need to be modified?

small numbers of patients, and failed to compare onetreatment against the other (17–19). Two prospectivestudies involving small numbers of children with DKAcompared low-dose with high-dose insulin treatment(20, 21). For example, Burghen et al. compared twodoses of regular insulin: 0.1 and 1 U/kg/h of regularinsulin in 32 children (6.2–15.8 yr), 16 in each group. Asin adults, low-dose insulin treatment was as effective ashigh-dose treatment; however, plasma glucose reached250 mg/dL in the high-dose group in 3.4 ± 0.4 h ascompared with 5.4 ± 0.5 h in the low-dose group. It wasalso observed that a priming dose of insulin was notnecessary when the IV route of insulin administrationwas used. Despite a slower rate of decline of plasmaglucose concentrations, the authors concluded that thelow-dose insulin protocol was as effective as the high-dose for the treatment of DKA in children and hada lower potential for hypoglycemia and less frequenthypokalemia (22).

On the basis of the best data available at the time,consensus guidelines for the management of childrenwith DKA recommended the use of a continuousIV insulin infusion at a dose of 0.1 U/kg/h (1, 3).The studies on which the consensus guidelines werebased do not, however, provide evidence that a dose of0.1 U/kg/h is superior to lower doses of insulin for thetreatment of DKA in children. Although 0.1 U/kg/his widely used for treatment of DKA in children andadolescents, a recent report has convincingly shownthat lower initial insulin doses (for example, between0.03 and 0.05 U/kg/h) can adequately normalize BOHBlevels associated with DKA (23). However, clinicaljudgment must guide the required dose in individualpatients who may not respond to the lower doses forvarious reasons.

Although the cause of cerebral edema is unknown, itis by far the greatest risk for morbidity and mortality.The role of therapeutic interventions in its pathogenesiscontinues to be controversial. Described associationsinclude: insulin administered within 1 h of starting fluidreplacement (24), a greater insulin dose within 2 h ofcommencing fluid therapy (24), and rapid decline inblood glucose levels after starting insulin treatment(25). The latter observation has not been substantiatedin other studies (24, 26, 27).

Most children presenting with DKA have adequatetissue perfusion and investigators have argued thatit is prudent to correct hyperglycemia, acidosis, anddehydration slowly over 48 h (28–30). Despite theongoing controversy regarding the role of the rateof change in plasma effective osmolality on risk ofdevelopment of cerebral edema, it has been suggestedthat assuming a rapid decrease in the effective plasmaosmolality (equal to the plasma glucose concentrationin mmol/L plus twice the plasma sodium concentrationin mmol/L) increases the risk of cerebral edema, it

would be desirable to gradually reduce the serumeffective osmolality. To insure a slow fall in effectiveosmolality, the plasma sodium concentration has to riseby nearly 1 mmol/L for every 2 mmol/L decrease in theplasma glucose concentration (30). However, the doseof insulin is only one of several factors that influencethe rate of fall of plasma glucose concentration.Other factors include the initial degree of compromiseof renal function caused by dehydration, rate ofinfusion of IV fluid, and the timing and amount ofdextrose administration. Given the proven risk forhypoglycemia and unproven but possible associationbetween insulin treatment and cerebral edema, ithas been proposed that lower insulin doses, i.e.,0.05 U/kg/h, rather than the current standard of0.1 U/kg/h, may be safer while still effectively correctingthe abnormalities associated with DKA (31).

Meanwhile, in the decade since publication of theconsensus statement, treatment outcomes using lowerdoses of IV insulin have been published (23, 31–33).These data must be cautiously interpreted owing tothe limitations of retrospective observational studies.Nonetheless, in the absence of Randomized controlledtrials (RCTs), these studies show that lower doses ofIV insulin can be successfully used to treat DKA.Key features of these studies are summarized belowand in Table 1. In a retrospective observational studyinvolving pediatric centers in the Greater ManchesterRegion in the UK, Puttha et al. compared outcomesfrom five pediatric centers that treated 41 episodes ofDKA with IV insulin at a dose of 0.05 U/kg/h (low dose)with 52 episodes treated with 0.1 U/kg/h (standarddose) (31). Comparable data were only available at 6 hfollowing admission. The decline in blood glucose levels11.3 mmol/L (95% confidence intervals, 8.6–13.9) vs.11.8 mmol/L (95% confidence intervals, 8.4–15.2) andincrease in pH [0.13 (0.09–0.18) vs. 0.11 (0.07–0.15)]were similar at 6 h. These changes were comparablebetween doses in relation to: severity of initial acidosis,children with newly diagnosed diabetes, or age lessthan 5 yr. After adjustment for other clinical andbiochemical covariates, insulin dose was unrelated tothe change in pH and blood glucose concentrationsat 6 h after admission. Glasgow Coma Scores (GCS)≤13 were more frequent in the standard dose group.The authors concluded that low dose (0.05 U/kg/h)insulin was as effective as 0.1 U/kg/h in correcting themain biochemical abnormalities in the initial (<6 h)treatment of DKA in children with type 1 diabetes.

In a retrospective non-randomized study thatincluded all children with DKA admitted to thepediatric intensive care unit (ICU) at the RoyalChildren’s Hospital, Melbourne during the period2000–2005, Al Hanshi and Shann compared theeffects of infusing insulin at 0.05 U/kg/h (n = 33) ascompared with 0.1 U/kg/h (n = 34) (32). Compared

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Table 1. Studies comparing insulin infusion doses ≤0.05 U/kg/h with 0.1 U/kg/h

Study Aim Design Endpoint Results and conclusions

Puttha et al. (31) To compare0.05 U/kg/h IVinsulin infusion forinitial treatment ofDKA with0.01 U/kg/h.

Retrospectiveobservational;data from fivecenters: 41 vs.52 episodes.

At 6 h, fall in BG and risein pH similar: 11.3 vs.11.8 mM and 0.13 vs.0.11.

Changes comparable betweendoses in relation to: severity ofinitial acidosis, newlydiagnosed or aged <5 yr. Afteradjustment for other clinicaland biochemical covariates,insulin dose was unrelated tochange in pH and BG levels at6 h after admission. Safetycomparisons (especiallyabnormal Glasgow ComaScore) inconclusive.

Al Hanshi et al. (32) To compare insulininfusion at 0.05 vs.0.1 U/kg/h inchildren admittedin ICU.

Retrospectiveobservational;34 childrenreceived 0.1 vs.0.05 U/kg/h in33 children;0.05 U/kg/hchildrenyounger (25 vs.62 months).

Assessed parameters12 h aftercommencing insulininfusion.

More gradual reduction ineffective plasma osmolalityover first 12 h because PGdecreased more slowly andplasma sodium concentrationincreased faster. Both groupshad satisfactory improvementsin acidosis and ketosis, andhad similar length of stay inICU. Smaller dose may make iteasier to gradually lowereffective plasma osmolality.

Kapellen et al. (33) To compare insulininfusion at0.025 U/kg/h vs.standard0.1 U/kg/h(0.05 U/kg/h<5 yr).

Retrospective,observational;23 treated inICU of center A,mean age 8.9 yr(low dose) vs.41 in ICU ofcenter B, meanage 13.5 yr,(standard dose).

Follow-up to 48 h. Timeto normalize pH (≥7.3)and BG; occurrenceof hypoglycemia(<56 mg/dL, 3.1 mM)or hypokalemia<3.2 mmol/L.

Standard dose resulted in slightlyshorter duration of acidosis (8vs. 6.5 h) and fasternormalization of BG,<11 mmol/L (18 vs. 10.5 h).Similar low rates ofhypoglycemia during first day.Center B, one case of cerebraledema with cerebral infarction.In first 12 h, patients in centerB received twice as much fluidas in center A; 70% of patientsin center A and 17% in centerB received HCO3. Cumulativeinsulin dose until pHnormalized 0.21 vs. 0.48 U/kg,center A vs. B, respectively.

Noyes et al. (23) To assess clinicalapplication of nearpatient testingdevice for capillaryBOHBmeasurement inevaluating a newendpoint for IVinsulin. Startinginsulin dose0.03–0.05 U/kg/h(median 0.045,range 0.02–0.1).

Prospective studyof 40 DKAepisodes in 25subjects1–14 yr.Evaluated twotreatmentendpoints insame subjects:(i) pH>7.3 + urineketone free; (ii)pH >7.3 + twosuccessivehourly BOHBvalues<1 mmol/L.

35 of 40 episodes, ICPcompleted withoutsignificant variation;28 episodes followedto negative urineketones. Endpoint Areached after 17 h(4–39); endpoint Bwas reached after 28(14–64) h. Median lagwas 11(1–36) h. For59 paired venoussamples (excludingsamples with labBOHB >6 mM) POCand laboratory BOHBy = 0.92x − 0.05,r2 = 0.94, mean bias−0.25 mmol/L).

Serial measurements of BOHBallow a new simple earlierendpoint for IV insulin therapy.

BG, blood glucose; BOHB, ß-hydroxybutyrate; DKA, diabetic ketoacidosis; ICU, intensive care unit; IV, intravenous; ICP,integrated care pathway; PG, plasma glucose.



with the 34 children who received 0.1 U/kg/h, thosewho received 0.05 U/kg/h were younger (median age25 vs. 62 months) and had a more gradual reductionin the effective plasma osmolality over the first 12 hof treatment. The more gradual decline in plasmaosmolality was attributed to a slower decrease inplasma glucose concentration and a faster increasein plasma sodium concentration. Acidosis and ketosisimproved satisfactorily in both treatment groups, andlength of stay in the ICU was similar. An accompanyingeditorial pointed out that the authors used analysisof covariance methods to compare the two groupson laboratory values obtained approximately 12 hafter initiation of treatment, controlling for age andlaboratory values at presentation (34). This analyticalmethod, according to the editorialists, is not optimalfor between-group comparisons of repeated laboratoryvalues when treatment group is not independent ofpretreatment laboratory values, and advised cautiousinterpretation of the results (34).

Another recent retrospective, observational studycompared treatment of DKA with a regimen oflow dose (0.025 U/kg/h) vs. a standard insulin dose(0.1 U/kg/h; 0.05 in children <5 yr) (33). A chartreview was performed of the first 48 h after onsetof DKA in all cases of children and adolescents,n = 64, (0–18 yr) with type 1 diabetes and DKAtreated in the intensive care unit at two pediatriccenters (Children’s Hospitals of Chemnitz and Leipzig,Germany) from 1998 to 2005 (Table 1). Patients’ ages,initial blood glucose concentrations, venous pH andbicarbonate concentrations were similar at the twocenters. Treatment with 0.1 U/kg/h resulted in a shorterduration of acidosis (6.5 vs. 8 h) and significantly fasternormalization of blood glucose concentration (10.5vs. 18 h). Similar low rates of hypoglycemia (bloodglucose <3.1 mmol/L) were observed on the first dayof treatment. Interpretation of the results of this studyis further confounded because treatment strategiesbetween the two centers did not only differ with respectto the amount of insulin administered but also in thefrequency of sodium bicarbonate administration andin the amount of fluid administered in the first 4 h oftreatment

A study performed at Royal Hospital for SickChildren, Edinburgh, analyzed 35 episodes of DKAin 25 subjects (aged 1–14 yr). Although the purpose ofthis study was to examine the advantages of monitoringblood BOHB levels (as compared with urine ketones)during DKA therapy and to evaluate a new end-point(venous pH >7.3 and two successive hourly BOHBmeasurements <1 mmol/L) for IV insulin therapy inDKA management, it is notable that the startingdose of IV insulin in this prospective study was0.03–0.05 U/kg/h (23) and the median IV insulininfusion rate was 0.045 U/kg/h (range 0.02–0.1). In

the 28 patient episodes followed to negative ketonuria,venous pH >7.3 and two successive hourly BOHBmeasurements <1 mmol/L, was reached after 17 h(median, range 4–39 h), whereas the end-point pH>7.3 and urine ketone free was not reached until 28 h(14–64 h) after starting treatment.

Notwithstanding the important limitations ofretrospective, non-randomized observational studies,in aggregate the above studies suggest that it may besafe and effective to treat most children with DKA withan insulin infusion of 0.05 U/kg/h. There remains someconcern, however, about whether patients with severeDKA (pH <7.1 or HCO3 < 5 mmol/L) will respondequally well to the lower dose regimen. A prospectiverandomized controlled trial with different insulin doseswill be required to show whether there are realand clinically significant differences between insulindose regimens with respect to metabolic outcomes,occurrence of cerebral edema, duration of hospitalstay, and costs.

Water and salt replacement

There has been a longstanding controversy concerningthe optimal fluid treatment regimen for pediatricDKA. Much of this debate has centered on how toprevent cerebral edema, the most feared complicationof DKA in children (35, 36). At the center of thecontroversy is the potential role of fluid therapy in thepathogenesis of cerebral edema. Clinically overt, life-threatening cerebral edema is infrequent, occurring in0.5–1% of episodes of DKA, which makes it a difficultdisorder to study (37, 26). Cerebral edema that is eitherasymptomatic or only mildly symptomatic has nowbeen documented to occur during treatment in mostchildren with DKA (38–41).

Some investigators have suggested that cerebraledema is the result of osmotic shifts causedby rapid IV rehydration (42–45, 28) and haverecommended conservative (slower) fluid therapy.However, properly controlled retrospective studieshave not detected associations between osmoticchanges during treatment and risk of cerebral edema(26, 27, 46), leading to the conclusion that there islittle or no convincing evidence of an associationbetween the rate of fluid or sodium administrationused in the treatment of DKA and the development ofcerebral edema (47). Indeed, recent data suggest thatcerebral hypoperfusion and the effects of reperfusionduring DKA treatment may play a role in thedevelopment of cerebral injury and edema (26, 48–50).Conservative rates of rehydration, therefore, coulddelay restoration of normal cerebral perfusion and beharmful, and use of fluids with low sodium contentmay exacerbate this problem by decreasing the volumeof fluid retained in the vascular compartment, whereas


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Table 2. Overview of fluid regimens used in the FLUID Trial (adapted from reference 51)

Protocol A1 Protocol A2 Protocol B1 Protocol B1

Assumed fluiddeficit

10% of body weight 10% of body weight 5% of body weight 5% of body weight

Initial fluid bolus 10 cc/kg of 0.9% saline 10 cc/kg of 0.9% saline 10 cc/kg of 0.9% saline 10 cc/kg of 0.9% salineAdditional fluid

bolus10 cc/kg of 0.9% saline 10 cc/kg of 0.9% saline No additional bolus No additional bolus

Deficitreplacement

1/2 deficit + maintenancefluids over initial 12 h;remainingdeficit + maintenancefluids over next 24 h

1/2 deficit + maintenancefluids over initial 12 h;remainingdeficit + maintenancefluids over next 24 h

Deficit + maintenancefluids evenly over 48 h

Deficit + maintenancefluids evenly over 48 h

Fluid used fordeficitreplacement

0.45% saline 0.9% saline 0.45% saline 0.9% saline

FLUID, Fluid Therapies Under Investigation in DKA.Protocol A1 more rapid rehydration with 0.45% saline; protocol A2 more rapid rehydration with 0.9% saline; Protocol B1slower rehydration with 0.45% saline; and protocol B2 slower rehydration with 0.9% saline.

isotonic saline may slow the repair of intracellulardehydration. Conversely, more rapid rates of fluidinfusion might increase vasogenic edema associatedwith cerebral reperfusion, especially if prior ischemiaaffected integrity of the blood–brain barrier (51). Arecent pilot randomized study compared two rates ofdeficit replacement in children with DKA: protocolA replaced two-thirds of an assumed 10% fluiddeficit over the first 24 h and the remaining one-third over the next 24 h (in addition, half the urinevolume was replaced while the serum glucose remained>250 mg/dL); protocol B assumed a 7% fluid deficitand replaced the deficit evenly over 48 h (36). Inthis comparison, the rate of fluid infusion did notsubstantially affect magnetic resonance imaging (MRI)measures of cerebral edema.

Lack of high quality data from randomized con-trolled trials has hampered the formulation of evidence-based definitive therapeutic recommendations (51),and there continues to be substantial variability inDKA management (51, 52) as evident from a recentpoll of 20 hospitals participating in the Pediatric Emer-gency Care Applied Research Network (PECARN),cited by Glaser et al. (51). According to currently usedprotocols at the pediatric referral centers participatingin PECARN, a 40-kg child with DKA could receiveIV fluid at rates as low as 114 mL/h or as high as215 mL/h. There is also disagreement about the opti-mal sodium content of rehydration fluid. Some centersuse 0.45% saline, others use 0.9% saline, and yet othersa combination.

It is important to note that a single major pediatricreferral center in the USA recently reported theoutcomes of 3712 episodes of DKA in children andadolescents during the period 1999–2011. Cerebraledema occurred in 0.5% of cases and the overallrate of death or disability was 0.08% (53). This vast

experience and good outcomes comparable to thosereported in other large studies, using the so-called‘Dallas protocol’, warrants serious consideration as analternative, simplified fluid therapy strategy. Briefly,in the ‘Dallas protocol’, after an initial fluid bolus of20 mL/kg of normal saline, 0.675% saline (3/4 normalsaline, 115.5 mmoL sodium) is infused at 2–2.5 timesthe calculated maintenance rate of fluid administration,regardless of the degree of dehydration, and decreasedto 1–1.5 times the maintenance rate after 24 h, or earlierif acidosis resolved, until urine ketones are negative (54,53).

The PECARN sponsored ‘Fluid Therapies UnderInvestigation in DKA’ (FLUID) study in theUSA, currently in progress, is a randomizedcontrolled clinical trial to investigate the impactof fluid rehydration regimens on neurological andneurocognitive outcomes in children with DKA(Table 2). The study will determine the effectsof rehydration rate and fluid sodium content onneurological status during DKA treatment, thefrequency of clinically overt cerebral edema and long-term neurocognitive outcomes (51). It is anticipatedthat the results of this study will provide definitivetherapeutic recommendations concerning the optimalfluid treatment regimen for pediatric DKA. The2009 version of the ISPAD guidelines state that ‘notreatment strategy can be definitively recommended asbeing superior to another based on evidence’ (3), andthis view is reiterated in the current revision of theISPAD guidelines to be published in September 2014.

Blood BOHB for the managementof ketoacidosis

POC, also referred to as near patient, capillaryblood measurement of BOHB using a meter hasbeen available for more than a decade (55), and



Fig. 1. Hourly near patient β-hydroxybutyrate (HOB) (circles, medians; bars, interquartile intervals) compared with 4-hourly laboratory HOB(squares, medians; bars, interquartile intervals) during the first 24 h of treatment in the 31 diabetic ketoacidosis (DKA) patients in whomtreatment started in the tertiary pediatric referral hospital. Reproduced from reference (23) with permission of the author and publisher.

several studies have examined the utility of POCBOHB measurements for the prevention, diagnosis,and management of DKA. The package insert states‘the test strips are not intended for use in the diagnosisor screening of diabetes mellitus, but are to be usedas an aid in monitoring the effectiveness of diabetescontrol programs’. BOHB measurements at home andin the clinic are now widely used (and frequentlypreferred by patients to urine AcAc testing) to guide themanagement of marked hyperglycemia and sick days,especially in patients who use insulin pumps when thereis a concern about failure of insulin delivery (56) (seereference 57).

Ham et al. measured the precision and bias ofbedside BOHB measurement in the acute caresetting (58). As compared with a hospital laboratorymeasurement, a Bland–Altman analysis (a methodused to analyze the agreement between two differentassays) showed that meter values >4 mmol/L are lessaccurate when compared with a reference method (58).Similarly, in a study in which a laboratory technologistsimultaneously measured BOHB in venous wholeblood samples by a reference method and with a ketonemeter good correlation was found up to 3 mmol/L;however, at higher BOHB concentrations, accuracydeteriorated (high AcAc concentrations affect the assayresulting in lower BOHB measurement compared witha reference method) (59). Because any meter value>1.5 mmol/L indicates significant ketosis and potentialfor DKA, lack of accuracy >4 mmol/L should notprevent the meter from being used to detect DKA.

Furthermore, meter BOHB values steadily decreasedduring treatment of DKA as pH and bicarbonateconcentration increased and acidosis resolved, leadingthe investigators to conclude that the meter may beuseful in monitoring therapy of DKA (58). Likewise,near patient BOHB levels were significantly lower thanlaboratory BOHB levels at presentation of DKA;however, from approximately 12 h onward the twomethods gave similar results leading to the conclusionthat IV insulin therapy can be stopped and SC insulincommenced when the venous pH is ≥7.3 and twosuccessive BOHB values are ≤1 mmol/L (Fig. 1) (23).Three studies have shown that when blood BOHBvalues (as compared with urine ketone measurement)are used as an endpoint to define resolution of DKA,time to recovery is significantly reduced, with meandifferences reported of 17.4 (60), 4.6 (61) and 11 h(23). An earlier treatment endpoint would be expectedto decrease time spent in the ICU and cost of care.One study showed that the time spent in the ICU wasreduced by a mean of 6.5 h and estimated substantialtotal cost savings per subject (61).

The evidence indicates that the currently availableBOHB meter is accurate up to 3–4 mmol/L. Therefore,a value >3 mmol/L in the patient whose venous pH is<7.3 and plasma glucose is >200 mg/dL confirms thediagnosis of DKA. During treatment, when the venouspH is ≥7.3 and a meter BOHB is <1 mmol/L (within themeter’s accurate range), one can confidently concludethat DKA has resolved. It has been suggested thatinitial measurement of pH, pCO2, and bicarbonate are


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necessary to confirm the diagnosis of DKA and assessits severity, but real-time POC measurements of BOHBmay be able to replace repeated measurements of theseparameters in the management of DKA (13).

Conclusions

Controversy persists concerning the appropriatestarting dose of insulin for the treatment of DKA.Notwithstanding the important limitations of smallretrospective, non-randomized observational studies,the available data suggest that it may be safe andeffective to treat most children with DKA with aninsulin infusion of 0.05 U/kg/h. The longstandingcontroversy continues concerning the optimal fluidtreatment regimen for pediatric DKA, and a lack ofhigh quality data from randomized controlled trials hashampered the formulation of definitive evidence-basedtherapeutic recommendations. The 2009 version of theISPAD guidelines stated that ‘no treatment strategycan be definitively recommended as being superior toanother, based on evidence’ (3). This view is reiteratedin the current revision of the ISPAD guidelines tobe published in September 2014. The guidelines, onceagain, indicate that there is no strong evidence fora more protracted replacement regimen being saferor more efficacious. Data suggest that diagnosticconfirmation of qualitative measurements of ketonuriaor ketonemia with a quantitative measurement ofserum BOHB concentration may be useful in theevaluation of patients whose clinical presentationis indicative of DKA. Also, quantitative serialmeasurements of serum BOHB concentrations at thebedside are useful to monitor the response to treatmentand as a criterion for resolution of DKA. In additionto the topics discussed in this article, hyperglycemichyperosmolar state (HHS) and a mixed picture ofDKA and HHS are now occurring with increasedfrequency in the pediatric age group. Accordingly, therevised version of the ISPAD guidelines will includea discussion about the recognition and managementof these hyperglycemic crises, the use of standardor lower doses of insulin and the value of bedsidemonitoring of BOHB for management of establishedand impending DKA.

References

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