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Diabetic Ketoacidosis in Infants, Children,and AdolescentsA consensus statement from the American Diabetes Association

JOSEPHWOLFSDORF, MB, BCH1,2NICOLEGLASER, MD3

MARKA. SPERLING, MD4,5

The adage A child is not a miniatureadult is most appropriate whenconsidering diabetic ketoacidosis

(DKA). The fundamental pathophysiol-ogy of this potentially life-threateningcomplication is the same as in adults.However, the child differs from the adultin a number of characteristics.

1) The younger the child, the moredifficult it is to obtain the classical historyof polyuria, polydipsia, and weight loss.Infants and toddlers in DKA may be mis-diagnosed as having pneumonia, reactiveairways disease (asthma), or bronchiolitisand therefore treated with glucocorti-coids and/or sympathomimetic agentsthat only compound and exacerbate themetabolic derangements. Because the di-agnosis of diabetes is not suspected as itevolves, theduration of symptoms maybelonger, leading to more severe dehydra-tion and acidosis and ultimately to obtun-dation and coma. Even in developedcountries, some 1570% of all newly di-agnosed infants and children with diabe-tes present with DKA (18). Generally,the rates of DKA are inversely propor-tional to rates of diabetes in that commu-nity, but throughout the U.S., the overallrates of DKA at diagnosis have remainedfairly constant at 25% (6). DKA, de-fined by blood bicarbonate 15 mmol/land/or pH7.25 (7.3 if arterial or cap-illary), was present in 23.3% of a carefully

analyzed cohort. However, the preva-lence of DKA decreased significantly withage from 36% in children5 years of ageto 16% in those 14 years but did notdiffer significantly by sex or ethnicity (6).

2) The higher basal metabolic rateand large surface area relative to totalbody mass in children requires greater

precision in delivering fluids and electro-lytes. The degree of dehydration is ex-pressed as a function of body weight, i.e.,10% dehydration implies 10% loss of to-tal body weight as water. However, thecalculation of basal requirements, al-though a constant per unit of surface area,must be carefully adjusted when calculat-ing per unit mass because the amount offluid perkilogramdeclines as theinfant orchild grows.

3) Cerebral and other autoregulatorymechanisms may not be as well devel-oped in younger children. Hence, greaterseverity at presentation in younger chil-dren together with less maturity of auto-regulatory systems combine to predisposechildren to cerebral edema, which occursin 0.51% of all episodes of DKA inchildren and is the most common cause ofmortality in children with DKA (912).Only a minority of deaths in DKA are at-tributable to other causes, such as sepsis,other infections (including mucormyco-sis), aspiration pneumonia, pulmonaryedema, acute respiratory distress syn-

drome, pneumomediastinum, hypo- orhyperkalemia, cardiac arrhythmias, cen-tral nervous system (CNS) hematoma orthrombosis, and rhabdomyolysis. Cur-rently, the etiology, pathophysiology, andideal treatment are poorly understood,but these are areas of intense investiga-tion. Because cerebral edema occurs inthe context of DKA, reduction of the inci-dence of DKA should be a major goal oftreating children with diabetes. The re-ported mortality rates in children withDKA are constant in national population-

based studies varying from 0.15 to0.3%. Once cerebral edema develops,death occurs in some 2025%, and sig-nificant morbidity, including pituitary in-s u f fi c i e n c y , o c c u r s i n 1 0 2 5 % o f survivors. Where medical services are lesswell developed, the risk of dying fromDKA is greater, and children may die be-fore receiving treatment. Overall, cerebraledema accounts for 6090% of allDKA-related deaths in children.

4) Whereas delay in diagnosis is themajor cause of DKA in previously unrec-ognized disease in younger children,omission of insulin is the leading cause ofrecurrent DKA, most prevalent amongadolescents. In this group, some 5% ofpatients account for 25% of all admis-sion for DKA (11).

These important differences betweenchildren and adults require careful atten-tion to issues of management. Here, webriefly review the pathophysiology ofDKA in childhood and discuss recom-mended treatment protocols. Currentconcepts of cerebral edema are presented.

We conclude with recommendations andstrategies for the prediction and preven-tion of DKA and, hence, its complicationsin infants, children, and adolescents.

These considerations and recommen-dations are in agreement with those re-cently endorsed by the Lawson WilkinsPediatric Endocrine Society (LWPES),European Society for Pediatric Endocri-nology (ESPE), and the International So-ciety for Pediatric and AdolescentDiabetes (ISPAD).

From the1Division of Endocrinology, Childrens Hospital Boston, Boston, Massachusetts; 2Harvard MedicalSchool, Boston, Massachusetts; the 3Department of Pediatrics, University of California Davis School ofMedicine, Sacramento, California; the 4Department of Pediatrics, Universiy of Pittsburgh School of Medi-cine, Pittsburgh, Pennsylvania; and the 5Division of Endocrinology, Metabolism and Diabetes, ChildrensHospital of Pittsburgh, Pittsburgh, Pennsylvania.

Address correspondence and reprint requests to Dr. Mark A. Sperling, Professor, Division of Endocrinol-ogy, Metabolism and Diabetes, Childrens Hospital of Pittsburgh, 3705 Fifth Ave., DeSoto 4A-400, Pitts-burgh, PA 15213. E-mail: [email protected].

Ad di ti on al in fo rm at io n fo r th is ar ti cl e ca n be fo un d in an on li ne ap pe nd ix at ht tp :/ /care.diabetesjournals.org.

Abbreviations: -OHB, -hydroxybutyrate; CNS, central nervous system; DKA, diabetic ketoacidosis;ECF, extracellular fluid.

A table elsewhere in this issue shows conventional and Systme International (SI) units and conversionfactors for many substances.

DOI: 10.2337/dc06-9909 2006 by the American Diabetes Association.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s

C O N S E N S U S S T A T E M E N T

1150 DIABETESCARE, VOLUME29, NUMBER5, MAY2006


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PATHOPHYSIOLOGY OF

DKA The pathophysiology of DKAin children is summarized in Fig. 1. The

interacting factors are insulin deficiencyas the initial primary event in progres-sive -cell failure, its omission in a pa-tient with established disease, or itsrelative ineffectiveness when insulin ac-tion is antagonized by physiological stresssuch as sepsis and in the context of coun-terregulatory hormone excess. Together,these hormonal changes augment glucoseproduction from glycogenolysis and glu-coneogenesis while limiting glucose utili-zation, resulting in hyperglycemia (11mmol/l [200 mg/dl]), osmotic diuresis,

electrolyte loss, dehydration, decreasedglomerular filtration (further compound-ing hyperglycemia), and hyperosmolar-ity. Simultaneously, lipolysis providesincreased free fatty acids, the oxidation ofwhich facilitates gluconeogenesis andgenerates acetoacetic and -hydroxybu-tyric acids (ketones) that overwhelm buff-ering capacity, resulting in metabolicacidosis (pH 7.3), which is com-pounded by lactic acidosis from poor tis-sue perfusion. Progressive dehydration,hyperosmolarity, acidosis, and electrolytedisturbances exaggerate stress hormone

secretion and establisha self-perpetuatingcycle of progressive metabolic decompen-sation. The clinical manifestations are

polyuria, polydipsia, signs of dehydra-tion, deep sighing respirations to reducepCO

2and buffer acidosis, and progres-

sive obtundation leading to coma.The severity of DKA is defined by the

degree of acidosis: mild, venous pH 7.27.3; moderate, pH 7.17.2; and severe,pH 7.1.

Frequency of DKA and precipitatingfactorsThere is wide geographic variation in thefrequency of DKA at onset of diabetes;

rates inversely correlate with the regionalincidence of type 1 diabetes. Frequenciesrange from 15 to 70% in Europe, Aus-tralia, and North America (18). DKA atdiagnosis is more common in youngerchildren (5 years of age) and in childrenwhose families do not have ready accessto medical care for social or economic rea-sons (5,1315). A recent survey through-out the U.S. showed that the rate of DKAis 25% at the time of diagnosis (6).Lower income and lower parental educa-tional achievement were associated withhigher risk of DKA. Lack of health insur-

ance also is associated with higher rates(and greater severity) of DKA at diagnosis,presumably because uninsured subjects

delay seeking timely medical care (15).Thus, younger and poorer children aredisproportionately affected (6).

The risk of DKA in children and ado-lescents with established type 1 diabetesis 110 per 100 person-years (5,1619).Insulin omission, either inadvertently ordeliberately, is the cause in most cases.There usually is an important psychoso-cial reason for omitting insulin. Risk isincreased in children with poor metaboliccontrol or previous episodes of DKA,peripubertal and adolescent girls, chil-

dren with clinical depression or otherpsychiatric disorders (including thosewith eating disorders), children with dif-ficult or unstable family circumstances(e.g., parental abuse), children with lim-ited access to medical services, and thoseon insulin pump therapy (as only rapid-or short-acting insulin is used in pumps,interruption of insulin delivery for anyreason rapidly leads to insulin deficiency)(5,19). An intercurrent infection is sel-dom the cause when the patient/family isproperly educated in diabetes manage-ment and is receiving appropriate fol-

Figure 1Pathophysiology of DKA. FFA, free fatty acid.

Wolfsdorg, Glaser, and Sperling

DIABETESCARE, VOLUME 29, NUMBER5, MAY 2006 1151


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low-up care by a diabetes team with a24-h telephone helpline (2023).

MANAGEMENT OF DKA

Emergency assessment Perform a clinical evaluation to confirm

the diagnosis and determine its cause.(Carefully look for evidence of infec-tion; in recurrent DKA, insulin omis-sion or failure to follow sick day orpump failure management guidelinesaccounts for almost all episodes.)

Weigh the patient. (If body surface areais used for fluid therapy calculations,measure height or length to determinesurface area.) This weight should beused for calculations and not theweightfrom a previous office visit or hospitalrecord.

Look for acanthosis nigricans suggest-ing insulin resistance and type 2 diabetes. Assess clinical severity of dehydration.

Accurate clinical assessment of dehy-dration may be difficult in DKA, at leastin part due to the hyperosmolar stateand polyuria caused by osmotic diure-sis. Some findings that may be helpfulinclude: 5%: reduced skin turgor, dry mucous

membranes, tachycardia 10%: capillary refill 3 s, sunken

eyes 10%: weak or impalpable periph-

eral pulses, hypotension, shock, oli-guria

Assess level of consciousness (Glasgowcoma scale; see online appendix for de-tails [available at http://care.diabetes

journals.org]) (24,25). Obtain a blood sample for laboratory

measurement of serum or plasma glu-cose; electrolytes (including bicarbon-ate or total carbon dioxide [TCO

2]);

urea nitrogen; creatinine; osmolality;venous (arterial only in critically ill pa-tient) pH; pCO

2; pO

2; hemoglobin and

hematocrit or complete blood count*;calcium, phosphorus, and magnesiumconcentrations; HbA

1c; and blood

-hydroxybutyrate (-OHB) concen-tration (26). (*An increased whiteblood cell count in response to stress ischaracteristic of DKA and is not indic-ative of infection.)

Perform a urinalysis for ketones. If there is evidence of infection, obtain

appropriate specimens for culture(blood, urine, and throat).

If laboratory measurement of serumpotassium is delayed, perform an elec-

trocardiogram for baseline evaluationof potassium status (27,28).

Supportive measures In the unconscious or severely ob-

tunded patient, secure the airway andempty the stomach by continuous na-sogastric suction to prevent pulmonary

aspiration. A peripheral intravenous catheter

should be placed for convenient andpainless repetitive blood sampling.

A cardiac monitor should be used forcontinuous electrocardiographic moni-toring to assess T waves for evidence ofhyper- or hypokalemia and monitor forarrhythmias (27,28).

Give oxygen to patients with severe cir-culatory impairment or shock.

Give antibiotics to febrile patients afterobtaining appropriate cultures of body

fluids. Catheterization of the bladder is usuallynot necessary, but if the child is uncon-scious or unable to void on demand(e.g., infants and very illyoung children),the bladder should be catheterized.

Central venous pressure monitoringrarely may be required to guide fluidmanagement in the critically ill, ob-tunded, or neurologically compromisedpatient. (Central lines in children withDKA are frequently associated withthrombosis and should be resorted toonly when absolutely necessary.)

Where should the child be managed? The child should receive care in a unit

that has: Experienced nursing staff trained in

monitoring and management Written guidelines for DKA manage-

ment in children Access to laboratories for frequent

and timely evaluation of biochemicalvariables

A specialist with training and expertisein the management of DKA should di-

rect inpatient management. Children with severe DKA (longduration of symptoms, compromisedcirculation, or depressed level of con-sciousness) or those who are at in-creased risk for cerebral edema (e.g.,5 years of age, low pCO

2, high urea

nitrogen) should be considered for im-mediate treatment in an intensive careunit (pediatric if available) or in a unitthat has equivalent resources and su-pervision, such as a childrens wardspecializing in diabetes care (29,30).

In a child with established diabetes,

whose parents have been trained in sickday management, hyperglycemia andketosis without vomiting or severe de-hydration can be managed at home orin an outpatient health care facility(e.g., emergency ward), provided an

experienced diabetes team supervisesthe care (3133).

Clinical and biochemical monitoringSuccessful management of DKA and hy-perglycemic hyperosmolar syndrome re-quires meticulous monitoring of thepatients clinical and biochemical re-sponse to treatment so that timely adjust-ments in treatment can be made whenindicated by the patients clinical or labo-ratory data.

There should be documentation on aflow chart of hour-by-hour clinical obser-

vations, intravenous and oral medica-tions, fluids, and laboratory results.Monitoring should include: Hourly (or more frequently as indi-

cated) vital signs (heart rate, respiratoryrate, and blood pressure).

Hourly (or more frequently as indi-cated) neurological observations forwarning signs and symptoms of cere-bral edema (Table 1).

Amount of administered insulin. Hourly (or more frequently as indi-

cated) accurate fluid input (including

all oral fluid) and output. Capillary blood glucose should be mea-sured hourly (but must be crosschecked against laboratory venous glu-cose because capillary methods may beinaccurate in the presence of poor pe-ripheral circulation and acidosis).

Laboratory tests: serum electrolytes,glucose, calcium, magnesium, phos-phorus, and blood gases should berepeated every 24 h (or more fre-quently, as clinically indicated) inmore severe cases. Blood urea nitro-ge n, c re a t inine , a nd he ma t oc ri t

Table 1Symptoms and signs of cerebral

edema

Headache

Recurrence of vomitingInappropriate slowing of heart rate

Rising blood pressureDecreased oxygen saturation

Change in neurological status:Restlessness, irritability, increased

drowsiness, incontinenceSpecific neurologic signs, e.g., cranial nerve

palsies, abnormal pupillary responses,posturing

DKA in infants, children, and adolescents



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should be repeated at 6- to 8-h inter-vals until they are normal.

Urine ketones until cleared. If the laboratory cannot provide timely

results, a portable biochemical analyzerthat measures plasma glucose, serumelectrolytes, and blood ketones on fin-gerstick blood samples at the bedsideis a useful adjunct to laboratory-based

determinations. Calculations: Anion gap Na (Cl HCO

3);

normal is 12 2 mmol/l Corrected sodiummeasured Na

2 [(glucose mmol/l 5.6) 5.6]or Na 2 [(glucose mg/dl 100) 100]

Effective osmolality 2 (Na K) glucose mmol/l (mg/dl 18)

Fluid and electrolyte therapyDKA is characterized by severe depletionof water and electrolytes from both the

intracellular fluid and extracellular fluid(ECF) compartments; the range of lossesis shown in Table 2. Despite their dehy-dration, patients continue to have consid-erable urine output until extreme volumedepletion leads to a critical decrease inrenal blood flow and glomerular filtra-tion. At presentation, the magnitude ofspecific deficits in an individual patientvaries depending upon the duration andseverity of illness, the extent to which thepatient was able to maintain intake offluid and electrolytes, and the content of

food and fluids consumed before comingto medical attention (34).Children with DKA have a deficit in

ECF volume that is usually in the range of510% (35,36). Shock is rare in pediatricDKA. Clinical estimates of the volumedeficit are subjective and inaccurate; fre-quently, they either under- or overesti-mate the deficit (37,38). Therefore, use57% dehydration in moderate DKA and10% dehydration in severe DKA. The ef-fective osmolality (formula above) is fre-quently in the 300- to 350-mosm/l range.Increased serum urea nitrogen and he-

matocrit may be useful markers of the se-verity of ECF contraction (33,39). Theserum sodium concentration is an unreli-able measure of the degree of ECF con-traction for two reasons: 1) glucose,largely restricted to the extracellularspace, causes osmotic movement of waterinto the extracellular space, thereby in-ducing dilutional hyponatremia (40,41);

and 2) the elevated lipid fraction of theserum in DKA has a low sodium content.Therefore, it is important to calculate thecorrected sodium (using the above for-mula) and monitor its changes through-out the course of therapy. As the plasmaglucose concentration decreases after ad-ministering fluid and insulin, the measuredand corrected serum sodium concentrationshould increase appropriately.

The objectives of fluid and electrolytereplacement therapy are restoration ofcirculating volume, replacement of so-dium and the ECF and intracellular fluid

deficit of water, restoration of glomerularfiltration with enhanced clearance of glu-cose and ketones from the blood, andavoidance of excessive rates of fluid ad-ministration so as not to exacerbate therisk of cerebral edema (Table 3).

If needed, volume expansion to re-store peripheral circulation (resuscita-tion) should begin immediately with anisotonic solution (0.9% saline or balancedsolution such as Ringers lactate). The vol-ume and rate of administration depends

on circulatory status, and, where it is clin-ically indicated, the volume is typically1020 ml/kg over 12 h and may be re-peated if necessary. Subsequent fluidmanagement (deficit replacement)should be with 0.9% saline or a balancedsalt solution such as Ringers lactate (oracetate) for at least 4 6 h. Thereafter, def-

icit replacement should be with a solutionthat has a tonicity 0.45% saline withadded potassium chloride, phosphate, oracetate (see below under potassium re-placement). The rate of intravenous fluidshould be calculated to rehydrate evenlyover at least 48 h (42,43).

In addition to clinical assessment ofdehydration, calculation of effective os-molality may be valuable to guide fluidand electrolyte therapy. As the severity ofdehydration may be difficult to determineand frequently is either under- or overes-

timated (38), infuse fluid each day at arate rarely in excess of 1.52 times theusual daily maintenance requirementbased on age and weight or body surfacearea. Urinary losses should not be addedto the calculation of replacement fluid.The sodium content of the fluid may needto be increased if serum corrected sodiumis low and/or the measured serum sodiumdoes not rise appropriately as the plasmaglucose concentration falls (44,45). Theuse of large amounts of 0.9% saline hasbeen associated with the development ofhyperchloremic metabolic acidosis. A re-

placement procedure in a patient weigh-ing 30 kg who is 1 m2 is illustrated inTable 4.

InsulinDKA is caused by a decrease in effectivecirculating insulin associated with in-creases in counterregulatory hormones(glucagon, catecholamines, growth hor-mone, cortisol). Although rehydrationalone causes some decrease in blood glu-cose concentration (46,47), insulin ther-

Table 2Usual lossesof fluids andelectrolytesin DKA andnormal maintenance requirements

Average losses per kg (range) Maintenance requirements

Water 70 (30100) ml 1,500 ml/m2

Sodium 6 (513) mmol 45 mmol/m2

Potassium 5 (36) mmol 35 mmol/m2

Chloride 4 (39) mmol 30 mmol/m2

Phosphate 0.52.5 mmol 0.51.5 mmol/kg*Data are from measurements in only a few children and adolescents (ref. 30). *See ref. 114.

Table 3Fluid and electrolyte losses based on assumed 10% dehydration in a child (weight 30kg, surface area 1 m2) with DKA

Fluid and electrolyte

Approximate

accumulatedlosses with

10% dehydration

Approximate

requirementsfor maintenance

(48 h)

Working total

(48 h)

Water (ml) 3,000 3,000 6,000Sodium (mEq) 180 90 270

Potassium (mEq) 150 70 220Chloride (mEq) 120 60 180

Phosphate (mmol) 75 20 95




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apy is essential to normalize bloodglucose and suppress lipolysis and keto-genesis (48).

Extensive evidence indicates thatlow-dose intravenous insulin adminis-tration should be the standard of care(49). Start insulin infusion after the pa-tient has received initial volume expan-

sion; i.e., 12 h after starting fluidreplacement therapy (50). The dose is 0.1unit kg1 h1 (50 units regular insulindiluted in 50 ml normal saline; 1 unit 1ml) (51). An intravenous insulin bolus(0.1 unit/kg) is unnecessary (52), may in-crease therisk of cerebraledema(50), andshould not be used at the start of therapy.The dose of insulin should remain at 0.1unit kg1 h1 at least until resolution ofDKA (pH 7.30, bicarbonate 15mmol/l, and/or closure of the anion gap),which invariably takes longer than nor-

malization of blood glucose concentra-tions (53).During initial volume expansion, the

plasma glucose concentration may fallsteeply (46). Thereafter, the plasma glu-cose concentration typically decreases at arate of35 mmol l1 h1 (5490 mgdl1 h1) (54). To prevent an undulyrapid decrease in plasma glucose concen-tration and hypoglycemia, 5% glucoseshould be added to the intravenous fluidwhen the plasma glucose falls to 17mmol/l (300 mg/dl). If blood glucose fallsvery rapidly (5 mmol l1 h1) (after

the initial period of volume expansion),consider adding glucose even beforeplasma glucose has decreased to 17mmol/l. It may be necessary to use 10% oreven 12.5% dextrose to prevent hypogly-cemia while continuing to infuse insulinto correct the metabolic acidosis. If thepatient demonstrates marked sensitivityto insulin (e.g., some young children withDKA and patients with hyperglycemic hy-perosmolar syndrome), the dose may bedecreased to 0.05 units kg1 h1, orless, provided that metabolic acidosis

continues to resolve. If biochemical pa-rameters of DKA (pH, anion gap) do notimprove, reassess the patient, review in-sulin therapy, and consider other possiblecauses of impaired response to insulin(e.g., infection, errors in insulin prepara-tion). If no obvious cause is found, in-crease the insulin infusion rate and adjustthe rate of glucose infusion as needed tomaintain a glucose concentration of17mmol/l (300 mg/dl).

In circumstances where continuousintravenous administration is not possi-ble and in patients with uncomplicated

DKA, hourly or 2-hourly subcutaneous orintramuscular administration of a short-or rapid-acting insulin analog (insulin lis-pro or insulin aspart) is a safe and effectivealternative to intravenous regular insulininfusion (5458).

Potassium

Children with DKA suffer total-body po-tassium deficits of the order of 36mmol/kg (35,36,59 61). The major lossof potassium is from the intracellularpool. Intracellular potassium is depletedbecause of transcellular shifts of this ioncaused by hypertonicity. Increasedplasma osmolality results in osmotic wa-ter transport from cells to the ECF,thereby concentrating cellular potassium.

As a result of the increased potassium gra-dient, potassium is drawn out of cells.Glycogenolysis and proteolysis secondary

to insulin deficiency also cause potassiumefflux from cells. Acidosis may play a mi-nor role in the distribution of potassiumto the ECF.

Potassium is lost from the body as aconsequence of vomiting, urinary ketoan-ion excretion (which requires excretion ofcations, particularly sodium and potas-sium), and osmotic diuresis. Volumedepletion causes secondary hyperaldoste-ronism, which promotes urinary potas-sium e xc re t ion. Thus, t ot a l-bodydepletion of potassium occurs, but at pre-sentation serum potassium levels may be

normal, increased, or decreased (62). Re-nal dysfunction, by enhancing hypergly-cemia and reducing potassium excretion,contributes to hyperkalemia (62). Ad-ministration of insulin and the correctionof acidosis drives potassium back into thecells, decreasing serum levels (63). Theserum potassium concentration may de-crease abruptly, predisposing the patientto cardiac arrhythmias.

Potassium replacement therapy is re-quired regardless of the serum potassiumconcentration; start replacing potassium

after initial volume expansion and con-current with starting insulin therapy.However, if the patient is hypokalemic,start potassium replacement immediatelyafter initial volume expansion and beforestarting insulin therapy. If the patient ishyperkalemic, defer potassium replace-ment therapy until urine output is docu-mented. If immediate serum potassiummeasurements are unavailable, an electro-cardiogram may help to determinewhether the child has hyper- or hypoka-lemia (27,28). Flattening of the T wave,widening of the QT interval, and the ap- T

able4Replacementprocedurefora

child(weight30kg,surfacearea1m

2)withDKAestimatedtobe10%dehydrated

Approximatedurationandrate

Fluidcompositionandvolume

Sodium(mEq)

Potassium(mEq)

Chloride(mEq)

Phosphate(mmol)

Hour1(300ml/h)

300ml0.9

%NaCl(normalsaline)

46

46

Hours24(125ml/h);startregularinsu

lin

at0.1unit

kg

1

h1

375ml(normalsaline)

20mEq

potassiumacetate/

l

20mEqpotassiumphosphate/l

58

15

58

5.1

Hours548(125ml/h);continueregular

insulin(0.1unit

kg

1

h1

untilpH

7.3orHCO3

18mEq/l)

5,5

00ml(one-halfnormalsaline

dextrose)

20

mEqpotassiumacetate/l

20m

Eqpotassium

phosphate/l

424

220

424

75

Totalin48h

6,1

75mlfluid

528

235

528

80

Normalsaline(10ml/kg)isgivenover1hforinitialvolumeexpansion;thereafter,t

hechild

isrehydratedover48hatanevenrateattwotimesthemaintenancerateoffluidrequiremen

t.Potassiumphosphate:4.4

mEqpotassiumand3mmolphosphate(1mEqpotassiumand0.6

8mmolphosphate).




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pearance of U waves indicate hypokale-mia. Tall, peaked, symmetrical T wavesand shortening of the QT interval aresigns of hyperkalemia. The starting potas-sium concentration in the infusate shouldbe 40 mmol/l; subsequent potassium re-placement therapy should be based on se-rum potassium measurements. Potassiumadministration should continue through-out the period of intravenous fluid ther-apy. Potassium phosphate may be usedtogether with potassium chloride or ace-tate (e.g., 20 mmol/l potassium chloride

and 20 mmol/l potassium phosphate or20 mmol/l potassium phosphate and 20mmol/l potassium acetate). The maxi-mum recommended rate of intravenouspotassium replacement is usually 0.5mmol kg1 h1.

PhosphateDepletion of intracellular phosphate oc-curs in DKA, and phosphate is lost as aresult of osmotic diuresis (35,36,60).Plasma phosphate levels fall after startingtreatment, and this is exacerbated by in-

sulin, which promotes entry of phosphateinto cells (64 66). Total-body phosphatedepletion has been associated with a vari-ety of metabolic disturbances (6769).Clinically significant hypophosphatemiamay occur if intravenous therapy withoutfood intake is prolonged beyond 24 h(35,36,60). Prospective studies have notshown clinical benefit from phosphate re-placement (7075); however, severe hy-pophosphatemia (1 mg/dl), which maymanifest as muscle weakness, should betreated even in the absence of symptoms(76). Administration of phosphate may

induce hypocalcemia (77,78), and if hy-pocalcemia develops, administration ofphosphate should be stopped. Potassiumphosphate salts may be safely used as analternative to or combined with potas-sium chloride or acetate provided thatcareful monitoring is performed to avoidhypocalcemia (77,78).

AcidosisSevere acidosis is reversible by fluid andinsulin replacement. Insulin stops furtherketoacid production and allows ketoacids

to be metabolized, which generates bicar-bonate. Treatment of hypovolemia im-prove s t issue pe rfusion a nd re na lfunction, increasing the excretion of or-ganic acids. Controlled trials have shownno clinical benefit from bicarbonate ad-ministration (7982), and there are well-recognized adverse effects of bicarbonatetherapy, including paradoxical CNS aci-dosis (83,84) and hypokalemia fromrapid correction of acidosis (83,85,86).Failure to account for the sodium beingadministered and appropriately reducing

the NaCl concentration of the fluids canresult in increasing osmolality (83). Nev-ertheless, there may be selected patientswho may benefit from cautious alkalitherapy. These include patients with se-vere acidemia (arterial pH 6.9), inwhom decreased cardiac contractility andperipheral vasodilatation can further im-pair tissue perfusion, and patients withlife-threatening hyperkalemia (87). Bicar-bonate administration is not recom-mended for resuscitation unless theacidosis is profound and likely to ad-versely affect the action of epinephrine

during resuscitation. If bicarbonate isconsidered necessary, cautiously admin-ister 12 mmol/kg over 60 min.

Introduction of oral fluids andtransition to subcutaneous insulininjections

Oral fluids should be introduced onlywhen substantial clinical improvementhas occurred (mild acidosis/ketosis maystill be present) and the patient indicates adesire to eat. When oral fluid is tolerated,intravenous fluid should be reduced. Thechange to subcutaneous insulin shouldoccur when ketoacidosis has resolved (se-rum bicarbonate 18 mEq/l and venouspH7.3), plasma glucose is200 mg/dl,and oral intakeis tolerated. Themost con-venient time to change to subcutaneousinsulin is just before a meal. To preventrebound hyperglycemia, the first subcu-

taneous injection should be given 1560min (with rapid-acting insulin) or 12 h(with regular insulin) before stopping theinsulin infusion, depending on theplasma glucose concentration, to allowsufficient time for the injected insulin tobe absorbed. The dose and type of subcu-taneous insulin should be according tolocal preferences and circumstances.

In patients with established diabetes,the patients usual insulin regimen may beresumed. Two methods of starting subcu-taneous insulin after resolution of DKA in

newly diagnosed patients are presented inTable 5. After transitioning to subcutane-ous insulin, frequent blood glucose mon-itoring is required to avoid markedhyperglycemia and hypoglycemia. Sup-plemental rapid-acting insulin is given at4-h intervals to correct blood glucoselevels that exceed 200 mg/dl.

Cerebral edemaSymptomatic cerebral edema occurs in0.51% of pediatric DKA episodes (912). This complication has a high mortal-

ity rate (2124%), and a substantialpercentage of survivors (1526%) are leftwith permanent neurological injury(9,11,12). The pathophysiology of thiscomplication is not well understood, butsome have hypothesized that various as-pects of DKA treatment may cause or ac-celerate the development of cerebraledema (88). Concerns about the avoid-ance of cerebral edema have exerted astrong influence on treatment recommen-dations for pediatric DKA, underscoringthe need for better understanding of thiscondition.

Table 5Insulin regimens for newly diagnosed diabetes after resolution of DKA

Prepubertal TDD 0.751.0 unit/kgPubertal TDD 1.01.2 unit/kg

Before breakfast Two-thirds of TDDOne-third rapid-acting insulin*

Two-thirds intermediate-acting insulinBefore dinner One-third to one-half of the remainder of the TDD

as rapid-acting insulin*Before bedtime One-half to two-thirds of the remainder of the

TDD as intermediate-acting insulinAn alternative, basal-bolus method,

consists of administering One-half of the TDD as basal insulin (using insulinglargine)

AND

One-half of the TDD as rapid-acting insulin;

the dose before each meal comprises

1520% of the TDD

*In infants, toddlers, and preschool-age children, some clinicians use relatively smaller proportions ofrapid-acting insulin before breakfast and dinner (e.g., one-quarter to one-third rather than one-third toone-half) and relatively larger amounts of intermediate-acting insulin. TDD, total daily dose.




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Clinical manifestationsThe signs and symptoms of cerebraledema are shown in Table 1. Typically,symptomatic cerebral edema occurs 4 12h after the initiation of treatment for DKA,but cases have also occurred before initi-ation of therapy (9,12,8993) and as lateas 2428 h after the initiation of therapy

(9,88,94). Cerebral imaging studies mayshow focal or diffuse cerebral edema, butup to 40% of initial computed tomogra-phy scans on children with DKA and clin-ically diagnosed cerebral edema arenormal (95). Subsequent imaging studieson these patients often demonstrateedema, hemorrhage, or infarction.

Pathophysiological mechanismsSeveral hypotheses have been proposedto account for the occurrence of cerebraledema during DKA, but the cause re-

mains poorly understood. Fluid influxinto the brain caused by rapid declines inserum osmolality and/or overly vigorousfluid resuscitation has often been cited asa potential cause of DKA-related cerebraledema (9699). Evidence from clinicalstudies, however, suggests that this mech-anism may not play a central role. Casereports have documented the occurrenceof symptomatic and even fatal cerebraledema before initiation of DKA treatment(9,12,8993). In addition, studies em-ploying sequential cerebral imaging inchildren with uncomplicated DKA have

shown that mild, asymptomatic cerebraledema is likely present in most childrenwith DKA, both at the time of presenta-tion and during therapy (100102). Fi-nally, studies investigating associationsbetween treatment variations and risk forcerebral edema have yielded mixed re-sults. Only a few studies have employedmultivariate statistical techniques to ad-

just for differences in DKA severity amongpatients, thereby attempting to addressbias attributable to variation in treatmentof DKA among patients with varying dis-

ease severity (9,12,50,103). In these stud-ies, associations between the rate of fluidadministration and risk for cerebraledema were found in some (50,103), butnot others (9,12), and none of these stud-ies found an association between the rateof change in serum glucose concentrationor change in osmolality and risk for cere-bral edema. All of these studies gatheredclinical and treatment data retrospec-tively, however, making it difficult to fullyadjust for illness severity and othersources of bias. Treatment factors unre-lated to osmotic changes (bicarbonate

treatment, insulin administration withinthe first hour of fluid therapy) have alsobeen implicated in some studies (9,50),but the mechanism by which these treat-ment variations might influence risk ofcerebral edema is unclear.

In contrast to previous hypothesesproposing osmotically mediated fluid

shifts as a cause for DKA-related cerebraledema, recent data suggest that vaso-genic, rather than cytotoxic, cerebraledema may be the predominant finding inDKA (101,104). Animal studies have sug-gested that activation of ion transportersin the blood-brain barrier may be respon-sible for fluid influx into the brain (104).

Activation of these ion transporters mayresult from cerebral hypoperfusionand/or from direct effects of ketosis or in-flammatory cytokines on blood-brainbarrier endothelial cells (104,105).

Risk factorsChildren at greatest risk for symptomaticcerebral edema are those who presentwith high blood urea nitrogen concentra-tions and those with more profound aci-dosis and hypocapnia (9,12,50,103). Alesser rise in the measured serum sodiumconcentration during treatment (as the se-rum glucose concentration falls) has alsobeen associated with cerebral edema(9,45). Children with these characteris-tics as well as very young children inwhom assessment of mentalstatus may be

more difficult should be more intensivelymonitored.

Treatment of cerebral edemaBecause cerebral edema occurs infre-quently, data are limited regarding theeffectiveness of pharmacological inter-ventions for treatment of cerebral edema.Case reports and small case series suggestthat prompt treatment with mannitol(0.251.0 g/kg) may be beneficial(106,107). Recent case reports also pro-pose the use of hypertonic saline (3%),

510 ml/kg over 30 min, as an alternativeto mannitol (108,109). Intubation may benecessary to protect the airway and insureadequate ventilation; however, hyperven-tilation (pCO

222 mmHg) in intubated

patients with DKA-related cerebral edemahas been correlated with poorer neuro-logical outcomes (110). In intubated pa-tients, therefore, hyperventilation beyondthat which would normally occur in re-sponse to metabolic acidosis should likelybe avoided unless absolutely necessary totreat elevated intracranial pressure. In pa-tients suspected to have cerebral edema,

CNSimaging studies arerecommendedtorule out other causes of neurological deteri-oration, but treatment generally should notbe delayed while awaiting results.

Prevention of DKAManagement of an episode of DKA in apatient with known diabetes is not com-

plete until its cause has been identifiedand an attempt made to treat it. Delayeddiagnosis is the cause in new-onset diabe-tes, whereas insulin omission, either in-advertently or deliberately, is the cause inmost cases of established diabetes. Themost common cause of DKA in insulinpump users is failure to take extra insulinwith a pen or syringe when hyperglyce-mia and hyperketonemia or ketonuria oc-c ur. Home me a sure me nt of blood-OHB, when compared with urine ke-tone testing, decreases diabetes-related

hospital visits (both emergency depart-ment visits and hospitalizations) by theearly identification and treatment of keto-sis (111). Blood -OHB measurementsmay be especially valuable to preventDKA in patients who use a pump becauseinterrupted insulin delivery rapidly leadsto ketosis. There may be dissociation be-tween urine ketone (acetoacetate) and se-rum -OHB concentrations, which maybe increased to levels consistent withDKA when a urine ketone test is negativeor shows only trace or small ketonuria(112).

An intercurrent infection is seldomthe cause when the patient/family is prop-erly educated in diabetes managementand is receiving appropriate follow-upcare by a diabetes team with a 24-h tele-phone helpline (2123). There usually isan important psychosocial reason for in-sulin omission (see FREQUENCY OF DKA ANDPRECIPITATING FACTORS above), and a psychi-atric social worker or clinical psychologistshould be consulted to identify the psy-chosocial reason(s) contributing to devel-opment of DKA. Insulin omission can be

prevented by schemes that provide edu-cation, psychosocial evaluation, andtreatment combined with adult supervi-sion of insulin administration (113).

Parents and patients should learnhow to recognize and treat impendingDKA with additional rapid- or short-acting insulin and oral fluids. Patientsshould have access to a 24-h telephonehelpline for emergency advice and treat-ment (21). When a responsible adult ad-ministers insulin, there may be as much asa 10-fold reduction in frequency of recur-rent DKA (113).




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