ceto acidosis

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Pediatric Diabetes 2009: 10(Suppl. 12): 118–133

doi: 10.1111/j.1399-!!8.2009.00"9.#

♥ 2009 $o%& 'ile So&s */S

*ll ri+%ts reser,ed

Pediatric Diabetes

ISPAD Clinical Practice Consensus Guidelines 2009 Compendium

Diabetic ketoacidosis in children and adolescentswith diabetes

Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, Lee

W, Rosenbloom A, !erling M, and "anas R# Diabetic

ketoacidosis in children and adolescents with diabetes#

Pediatric Diabetes $%%&' (% )u!!l# ($*' ((+(--#

Joseph Wolfsdorf,

Maria E. Craig,Denis Daneman,David Dunger,Julie Edge,Warren Lee,Arlan Rosenbloom,Mark Sperling, andRagnar anas

aDivision of Endocrinology, Children’s Hospital Boston, MA, USA;

bSchool of o!en’s and Children’s Health, University of "e#

So$th ales, Sydney, A$stralia;cUniversity of %oronto, %he

Hospital for Sic& Children, %oronto, Canada;dDepart!ent of

'aediatrics, University of Ca!bridge, Addenbroo&e’s Hospital,

Ca!bridge, U(;eDepart!ent of 'aediatrics, )ohn *adcliffe

Hospital, +ford, U(;f Endocrinology Service Depart!ent of

'aediatric Medicine, (( Children’s Hospital, Singapore;gDivision of Endocrinology, Depart!ent of

'ediatrics, University of -lorida College of Medicine, .ainesville,

-/, USA;hDepart!ent of 'ediatric Endocrinology, Children’s

Hospital, University of 'ittsb$rgh, 'A, USA;iDepart!ent of

'ediatrics, Uddevalla Hospital, Uddevalla, S#eden

Corresponding a$thor0 )oseph olfsdorf, MD

Depart!ent of Endocrinology Children’s Hospital Boston/ong#ood Aven$e 122 Boston, MA 23445 USA6

%el0 224 748 155 3932; fa0 224 748 812 24:9;

e!ail0 <oseph6#olfsdorf=childrens6harvard6ed$

Conflicts of interest0 / has received spea&er’s fees and hasserved on the Advisory Boards of "ovo "ordis&, Eli /illy,SanofiAventis and MSD6 %he re!aining a$thors havedeclared no potential conflicts6

Editors of the >S'AD Clinical 'ractice Consens$s .$idelines

322: Co!pendi$!; *agnar Hanas, (i! Donagh$e,.eorgeanna (lingens!ith, 'eter S#ift6

%his article is a chapter in the ISPAD Clinical PracticeConsensus Guidelines 2009 Compendium6 %he co!plete set ofg$idelines can be fo$nd at ###6ispad6org6 %he evidence gradingsyste! $sed in the >S'AD .$idelines is the sa!e as that $sedby the A!erican Diabetes Association6 See page 3 ?the>ntrod$ction in Pediatric Diabetes 322:; 42 ?S$ppl6 43@0 43@6

Diabetic ketoacidosis )D.A* results from absolute orrelati/e deficienc0 of circulating insulin and the

combined effects of increased le/els of the counterreg1ulator0 hormones' catecholamines, glucagon, cortisol andgrowth hormone )(, $*# Absolute insulin defi1cienc0occurs in !re/iousl0 undiagnosed t0!e ( diabetes

mellitus )2(DM* and when !atients on treatment delib1



eratel0 or inad/ertentl0 do not take insulin, es!eciall0 thelong1acting com!onent of a basal1bolus regimen#

Patients who use an insulin !um! can ra!idl0 de/elo!D.A when insulin deli/er0 fails for an0 reason )-*#Relati/e insulin deficienc0 occurs when the concen1trations of counterregulator0 hormones increase inres!onse to stress in conditions such as se!sis, trauma, or gastrointestinal illness with diarrhea and /omiting#

2he combination of low serum insulin and high

counterregulator0 hormone concentrations results in

an accelerated catabolic state with increased glucose

!roduction b0 the li/er and kidne0 )/ia gl0cogenol0sisand gluconeogenesis*, im!aired !eri!heral glucose

utili3ation resulting in h0!ergl0cemia and h0!erosmo1lalit0, and increased li!ol0sis and ketogenesis, causingketonemia and metabolic acidosis# "0!ergl0cemia thate4ceeds the renal threshold )a!!ro4imatel0 (% mmol5L6(+% mg5dL7* although the range in normal and diabeticindi/iduals is /er0 wide* and h0!erketonemia cause

osmotic diuresis, deh0dration, and obligator0 loss ofelectrol0tes, which often is aggra/ated b0 /omiting#

2hese changes stimulate further stress hormone !ro1duction, which induces more se/ere insulin resistanceand worsening h0!ergl0cemia and h0!erketonemia# 8fthis c0cle is not interru!ted with e4ogenous insulin, fluid

and electrol0te thera!0, fatal deh0dration and metabolicacidosis will ensue# .etoacidosis ma0 be

!!" Update of g$idelines previo$sly p$blished in Pediatric Diabetes 3228; "0 3916



Diabetic ketoacidosis

%able 46 /osses of fl$ids and electrolytes in diabetic &etoacidosis and !aintenance re$ire!ents in nor!al children

Average ?range@ losses per &g39ho$r !aintenance re$ire!ents

ater 82 !/ ?12422@∗42 &g422 !/&g39 hr

4432 &g4222 !/ F 52 !/&g39 hr for each &g fro! 4432

>32 &g4522 !/ F 32 !/&g39 hr for each &g >32Sodi$!7 !!ol ?541@

3 9 !!olG'otassi$!5 !!ol ?17@

3 1 !!olvChloride9 !!ol ?1:@

3 1 !!ol'hosphate?265365@ !!ol

4 3 !!ol

Data are fro! !eas$re!ents in only a fe# children and adolescents ?959:@6 >n any individ$al patient, act$al losses !ay beless or greater than the ranges sho#n in %able 4 ?E@6 %hree !ethods for deter!ining !aintenance #ater re$ire!ents inchildren are co!!only $sed0 the HollidaySegar for!$la ?52@ ?sho#n in %able 4@, a si!plified HollidaySegar for!$la ?see

belo# and Appendi@, and a for!$la based on body s$rface area for children !ore than 42 &g ?4,522 !/!339 hr@ ?54@6

Maintenance electrolyte re$ire!ents in children are per 422 !/ of !aintenance >I fl$id ?54, 53@6Si!plified !ethod based on HollidaySegar0 <42 &g 9 !/&ghr; 4432 &g 92 F 3 !/&ghr for each &g bet#een 44 and32; >32 &g 72 F 4 !/&gh for each &g >326

aggra/ated b0 lactic acidosis from !oor tissue !erfusionor se!sis#

D.A is characteri3ed b0 se/ere de!letion of water and

electrol0tes from both the intra1 and e4tracellular fluidcom!artments9 the range of losses is shown in 2able (#Des!ite their deh0dration, !atients continue to maintain

normal blood !ressure and ha/e considerable urine

out!ut until e4treme /olume de!letion and shock occurs



leading to a critical decrease in renal blood flow andglomerular filtration# At !resentation, the magnitude ofs!ecific deficits in an indi/idual !atient /aries de!endingu!on the duration and se/erit0 of illness, the e4tent to

which the !atient was able to maintain intake of fluid andelectrol0tes, and the content of food and fluids consumed before coming to medical attention# Consum!tion offluids with a high1carboh0drate content ):uices or sugarcontaining soft drinks* e4acerbate the h0!ergl0cemia );*#

Clinical manifestations of diabetic ketoacidosis

Deh0dration

Ra!id, dee!, sighing ).ussmaul res!iration*

<ausea, /omiting, and abdominal !ain mimic1king anacute abdomen

Progressi/e obtundation and loss of consciousness

8ncreased leukoc0te count with left shift

<on1s!ecific ele/ation of serum am0lase

=e/er onl0 when infection is !resent

Defini#ion of diabe#i$ ke#oa$idosis %D&A'

2he biochemical criteria for the diagnosis of D.A are)>*'

"0!ergl0cemia )blood glucose >(( mmol5L 6J$%%mg5dL7*

?enous !" <@.- or bicarbonate <(> mmol5L

.etonemia and ketonuria#

Partiall0 treated children and children who ha/econsumed little or no carboh0drate ma0 ha/e, on rareoccasion, onl0 modestl0 increased blood glucoseconcentrations )eugl0cemic ketoacidosisBB* ), @*#

20!e $ diabetes mellitus )2$DM*, associated withincreased rates and se/erit0 of obesit0, in some cen1ters

now accounts for as much as one half of newl0 diagnoseddiabetes in children aged (% to $( 0ears, de!ending onthe socioeconomic and ethnic com!o1sition of the !o!ulation )+*# Acute decom!ensation with D.A has been recogni3ed to occur at the time of diagnosis in asman0 as $> of children with 2$DM

)+*# 2his is more likel0 in those of African1Americandescent, less so in "is!anic, and least in Canadian =irst <ation teenagers )&(;*# 2he ma:orit0 of new cases of

diabetes in Ja!anese children and adolescents are

detected in as0m!tomatic indi/iduals b0 routine urinescreening )(>, (*9 howe/er, o/erall, a!!ro4imatel0 >of !atients with t0!e $ diabetes ha/e D.A at the time ofdiagnosis )(@*#

2he severity of DA is categori3ed b0 the degree ofacidosis )(+*'

Mild' /enous !" <@#- or bicarbonate <(> mmol5L

Moderate' !" <@#$, bicarbonate <(% mmol5L

e/ere' !" <@#(, bicarbonate <> mmol5L

!yper"lycemic hyperosmolar state #!!S$% also

referred to as h0!erosmolar nonketotic coma, ma0 occurin 0oung !atients with 2$DM )(&$(*, but rarel0 in

2(DM sub:ects# &he criteria for !!S include )$$*'

!lasma glucose concentration >--#- mmol5L )%%mg5dL*

Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411 !!)'olfsdorf et al(

arterial !" >@#-%

serum bicarbonate >(> mmol5L

small ketonuria, absent to mild ketonemia

effecti/e serum osmolalit0 >-$% msm5kg

stu!or or coma

8t is im!ortant to recogni3e that o/erla! between thecharacteristic features of "" and D.A ma0 occur#

ome !atients with "", es!eciall0 when there is /er0

se/ere deh0dration, ha/e mild or moderate acidosis#Con/ersel0, some children with 2(DM ma0 ha/efeatures of "" )se/ere h0!ergl0cemia* if highcarboh0drate containing be/erages ha/e been used toFuench thirst and re!lace urinar0 losses !rior to diagnosis);*# 2hera!0 must be a!!ro!riatel0 modified to addressthe !atho!h0siolog0 and uniFue biochemical

disturbances of each indi/idual !atient#

*re+uen$ of D&A

At disease onset



2here is wide geogra!hic /ariation in the freFuenc0 ofD.A at onset of diabetes9 rates in/ersel0 correlate withthe regional incidence of 2(DM# =reFuencies range froma!!ro4imatel0 (> to @% in Euro!e and <orth America

)A* )$-$@*# D.A at diagnosis is more com1mon in0ounger children )<> 0ears of age*, and in chil1drenwhose families do not ha/e read0 access to medical carefor social or economic reasons )A* )@* )$@-%*#

>n children #ith established diabetes ?rec$rrentD(A@

2he risk of D.A in established 2(DM is ((% !er !atient !er 0ear )A, C* )-, -(-;*'

Risk is increased in )-;*'

children with !oor metabolic control or !re/ious e!isodesof D.A

!eri!ubertal and adolescent girls

children with !s0chiatric disorders, including those witheating disorders

children with difficult or unstable famil0 circum1stances

children who omit insulin )--* )C*

children with limited access to medical ser/ices

insulin !um! thera!0 )as onl0 ra!id1 or short1actinginsulin is used in !um!s, interru!tion of insulin deli/er0

for an0 reason ra!idl0 leads to insulin deficienc0* )-* )C*

Managemen# of D&A

E!ergency Assess!ent

Perform a clinical e/aluation to confirm the dia"nosis and

determine its cause Carefull0 look for e/idence

of infection# 8n recurrent D.A, insulin omission or

failure to follow sick da0 or !um! failure managementguidelines accounts for almost all e!isodes, e4ce!t forthose caused b0 acute se/ere febrile or gastrointestinal

illness#

'ei"h the !atient# 2his weight should be used for calculations and not the weight from a !re/ious office/isit or hos!ital record#

Assess clinical severity of dehydration.

Clinical assessment of deh0dration is im!recise,

inaccurate and generall0 shows onl0 fair to moderateagreement among e4aminers# 8t should be based on acombination of !h0sical signs# 2he three most usefulindi/idual signs for assessing deh0dration in 0oungchildren and !redicting at least > deh0dration andacidosis are'

o !rolonged ca!illar0 refill time )normal ca!illar0 refill is(.>1$ seconds*

o abnormal skin turgor )BtentingB or inelastic skin* oh0!er!nea )->*#

ther useful signs in assessing degree of deh0drationinclude' dr0 mucus membranes, sunken e0es, absenttears, weak !ulses, cool e4tremities# More signs ofdeh0dration tend to be associated with more se/eredeh0dration )->*#

o K(% deh0dration is suggested b0 the !resence ofweak or im!al!able !eri!heral !ulses, h0!oten1sion, andoliguria#

Assess level of consciousness )Glasgow coma scale

6GC7 1 see 2able $* )-*#

-io$hemi$al assessmen#

btain a blood sample for laboratory measurement ofserum or !lasma glucose, electrol0tes )including bicarbonate or total carbon dio4ide*, blood urea nitrogen,creatinine, osmolalit0, /enous )or arterial in criticall0 ill

!atient* !", !C$, calcium, !hos1!horus, and

magnesium concentrations )if !ossible*, "bA(c,hemoglobin and hematocrit or com!lete blood count# <ote, howe/er, that an ele/ated white blood cell count inres!onse to stress is characteristic of D.A and is notnecessaril0 indicati/e of infec1tion )-%*#

Perform a urinalysis for ketones#

Measurement of blood H1h0dro40but0rate concen1tration,

if a/ailable, is useful to confirm ketoacidosis and ma0 beused to monitor the res!onse to treatment )-@-&*#

btain a!!ro!riate specimens for culture )blood, urine,throat*, if there is e/idence of infection#

8f laborator0 measurement of serum !otassium isdela0ed, !erform an electrocardio"ram )ECG* for baseline e/aluation of !otassium status );%, ;(*#

!( Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411




%able 36 .lasgo# co!a scale or score ?.CS@6 %he .CS consists of three para!eters and is scored bet#een 1 and 45; 1 beingthe #orst and 45 the best ?17@6 +ne of the co!ponents of the .CS is the best verbal response, #hich cannot be assessed innonverbal yo$ng children6 A !odification of the .CS #as created for children too yo$ng to tal&6

Best verbal response

Best eye responseBest verbal response?nonverbal children@Best !otor response

46"o eye opening46"o verbal response46"o response46"o !otor response36Eyes open to pain36"o #ords, only36>nconsolable, irritable,36Etension to pain

inco!prehensible so$nds;

restless, cries

?decerebrate post$re@

!oaning



16Eyes open to verbal16ords, b$t incoherent16>nconsistently consolable16-le,ion to pain ?decorticate

co!!and

and !oans; !a&es vocal

post$re@

So$nds

96Eyes open96Conf$sed, disoriented96Consolable #hen crying and96ithdra#al fro! pain

spontaneo$sly

conversationG

interacts inappropriately

56

+rientated, nor!al56S!iles, oriented to so$nd,56/ocaliLes pain

conversation

follo#s ob<ects and interacts76+beys co!!ands



∗ >nappropriate #ords, rando! or ecla!atory artic$lated speech, b$t no s$stained conversational echange6

G Attention can be held; patient responds to $estions coherently, b$t there is so!e disorientation and conf$sion6

S$pportive !eas$res

Secure the air)ay and if there is deterioration in

conscious le/el, em!t0 the stomach b0 continuousnasogastric suction to !re/ent !ulmonar0 as!iration#

A peripheral intravenous #I*$ catheter should be !laced for con/enient and !ainless re!etiti/e bloodsam!ling# An arterial catheter ma0 be necessar0 insome criticall0 ill !atients managed in an intensi/e careunit#

A cardiac monitor should be used for continuouselectrocardiogra!hic monitoring to assess 21wa/es fore/idence of h0!er1 or h0!okalemia );%, ;(*#

Gi/e o+y"en to !atients with se/ere circulator0im!airment or shock#

Give antibiotics to febrile patients after obtaining a!!ro!riate cultures of bod0 fluids#Catheteri3ation of the bladder usuall0 is not necessar0,

but if the child is unconscious or unable to /oid ondemand )e#g#, infants and /er0 ill 0oung children* the bladder should be catheteri3ed#

here sho$ld the child be !anaged

2he child should recei/e care in a unit that has'

E4!erienced nursing staff trained in monitoring andmanagemento Written guidelines for D.A management in children

Access to laboratories that can !ro/ide freFuent andtimel0 measurements of biochemical /ariableso Effecti/e osmolalit0 )msm5kg* N $4

A s!ecialist5consultant !ediatrician with training ande4!ertise in the management of D.A should directin!atient management#

Children with se/ere D.A )long duration of s0m!1toms,

com!romised circulation, or de!ressed le/el of

consciousness* or those who are at increased risk forcerebral edema )e#g#, <> 0ears of age, se/ere acidosis,

low !C$, high blood urea nitrogen* should be consid1

ered for immediate treatment in an intensi/e care unit)!ediatric, if a/ailable* or in a unit that has eFui/alentresources and su!er/ision, such as a childrenBs wards!eciali3ing in diabetes care )C,E* )>, ;$*#

8n a child with established diabetes, whose !arents ha/e been trained in sick da0 management, h0!er1gl0cemiaand ketosis without /omiting or se/ere deh01dration can be managed at home or in an out!atient health carefacilit0 )e#g#, emergenc0 ward*, !ro/ided an e4!erienced

diabetes team su!er/ises the care )C,E* )(+, ;-, ;;*#

*ur#her $lini$al and bio$hemi$al moni#oring

uccessful management of D.A and "" reFuiresmeticulous monitorin" of the !atientBs clinical and

biochemical res!onse to treatment so that timel0ad:ustments in treatment can be made when indicated b0the !atientBs clinical or laborator0 data )E*#

2here should be documentation on a flo) chart of hour1 b01hour clinical obser/ations, 8? and oral medications,

fluids, and laborator0 results# Monitoring should includethe following'

"ourl0 )or more freFuentl0 as indicated* vital si"ns

)heart rate, res!irator0 rate, blood !ressure*

"ourl0 )or more freFuentl0 as indicated* neurolo"ical

observations )Glasgow coma score* for warning signs

and s0m!toms of cerebral edema )see below*

o headache

o ina!!ro!riate slowing of heart rate o recurrence of/omiting

o change in neurological status )restlessness, irri1tabilit0,

increased drowsiness, incontinence* or

Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411 !!'olfsdorf et al(

s!ecific neurologic signs )e#g#, cranial ner/e !alsies,abnormal !u!illar0 res!onses*

o rising blood !ressure

o decreased o40gen saturation

Amount of administered insulin

"ourl0 )or more freFuentl0 as indicated* accurate fluid

input )including all oral fluid* and output.

Capillary blood "lucose should be measured hourl0 )butmust be cross1checked against laborator0 /enous glucose,as ca!illar0 methods ma0 be inac1curate in the !resenceof !oor !eri!heral circulation and acidosis*#

,aboratory tests' serum electrol0tes, glucose, blood urea

nitrogen, calcium, magnesium, !hos!horus, hematocrit,



and blood gases should be re!eated $1hourl0 for the first($ hours, or more freFuentl0, as clinicall0 indicated, inmore se/ere cases#Irine ketones until cleared or blood H1h0dro40but01

rate )"* concentrations, if a/ailable, e/er0 $ hours)-+, -&*#

8f the laborator0 cannot !ro/ide timel0 results, a !ortable

biochemical anal03er that measures !lasma glucose,serum electrol0tes and blood ketones on fingerstick blood

sam!les at the bedside is a useful ad:unct to laborator01 based determinations#Additional calculations that may be informative-

Anion ga! N <a O )Cl F "C-*' normal is ($ P $)mmol5L*

8n D.A the anion ga! is t0!icall0 $%-% mmol5L9 an

anion ga! >-> mmol5L suggests concomitant lacticacidosis )E*

Corrected sodium N measured <a F $)6!lasma glucose

O>.75>#* )mmol5L*

Effecti/e osmolalit0 N )msm5kg* $4)<a F .* F glucose)mmol5L*

Goals of therapy

Correct deh0dration

Correct acidosis and re/erse ketosis

Restore blood glucose to near normal

A/oid com!lications of thera!0

8dentif0 and treat an0 !reci!itating e/ent

-l$ids and salt

Patients with D.A ha/e a deficit in e4tracellular fluid

)EC=* /olume that usuall0 is in the range >(% #C$ );>,;*# hock with hemod0namic com!romise is rare in !ediatric D.A# Clinical estimates of the /olume deficitare sub:ecti/e and inaccurate )>-, >;*9 therefore, inmoderate D.A use >@ and in se/ere D.A @(%

deh0dration#

2he effecti/e osmolalit0 )formula abo/e* is fre1Fuentl0 inthe range of -%%->% mmol5.g# 8ncreased serum ureanitrogen and hematocrit ma0 be useful markers of these/erit0 of EC= contraction );;, >>*# 2he serum sodium

concentration is an unreliable mea1sure of the degree ofEC= contraction for two reasons'

)(* glucose, largel0 restricted to the e4tracellular s!ace,causes osmotic mo/ement of water into the e4tra1cellulars!ace thereb0 causing dilutional h0!onatremia )>, >@*and, )$* the low sodium content of the ele/ated li!idfraction of the serum in D.A# 2he latter is not a concern

with most modern methods for measuring sodium#

2herefore, it is im!ortant to calculate the cor1rectedsodium )using the abo/e formula* and monitor itschanges throughout the course of thera!0# As the !lasmaglucose concentration decreases after adminis1tering fluidand insulin, the measured serum sodium concentration

should increase, but it is im!ortant to a!!reciate that thisdoes not indicate a worsening of the h0!ertonic state# Afailure of measured serum sodium le/els to rise or afurther decline in serum sodium le/els with thera!0 isthought to be a !otentiall0 ominous sign of im!ending

cerebral edema )>+%*#

2he ob:ecti/es of fluid and electrol0te re!lacement

thera!0 are'

Restoration of circulating /olume

Re!lacement of sodium and the EC= and intracellu1larfluid deficit of water

8m!ro/ed glomerular filtration with enhanced clear1anceof glucose and ketones from the blood

Reduction of risk of cerebral edema

'rinciples of ater and Salt *eplace!ent

Des!ite much effort to identif0 the cause of cerebraledema its !athogenesis is incom!letel0 understood# 2hereis no con/incing e/idence of an association between therate of fluid or sodium administration used in thetreatment of D.A and the de/elo!ment of cerebral edema

)(*# <o treatment strateg0 can be definiti/el0recommended as being su!erior to another based one/idence# 2he !rinci!les described below were de/elo!edafter a com!rehensi/e re/iew of the literature and wereacce!ted and endorsed b0 a !anel of e4!ert !h0siciansre!resenting the Lawson Wilkins Pediatric Endocrine

ociet0 )LWPE*, the Euro!ean ociet0 for PaediatricEndocrinolog0 )EPE*, and the 8nternational ociet0 forPediatric and Adolescent Diabetes )8PAD* )>, $*#

Water and salt deficits must be re!laced )A*#

8? or oral fluids that ma0 ha/e been gi/en in another

facilit0 before assessment should be factored intocalculation of deficit and re!air )E*#

=or !atients who are se/erel0 /olume de!leted but not inshock, /olume e4!ansion )resuscitation*



! Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411

should begin immediatel0 with %#& saline to restore the !eri!heral circulation )E*#

8n the rare !atient with D.A who !resents in shock,ra!idl0 restore circulator0 /olume with isotonic saline )or RingerBs lactate* in $% mL5kg boluses infused as Fuickl0

as !ossible through a large bore cannula withreassessment after each bolus#

o 2he /olume and rate of administration de!ends oncirculator0 status and, where it is clinicall0 indicated, the/olume administered t0!icall0 is (% mL5kg5h o/er ($hours, and ma0 be re!eated if necessar0 )E*#

o Ise cr0stalloid not colloid )E*# 2here are no data tosu!!ort the use of colloid in !reference to cr0stalloid inthe treatment of D.A#

Subseue&t fluid management )deficit re!lacement* should be with %#& saline or RingerBs acetate for at least; hours )C,E* )>>, >+, ->*#

o 2hereafter, deficit re!lacement should be with asolution that has a tonicit0 eFual to or greater than %#;>saline with added !otassium chloride, !otassium

!hos!hate or !otassium acetate )see below under !otassium re!lacement* )C,E* )>>, >+, -, , @*#

o 2he rate of fluid )8? and oral* should be calculated toreh0drate e/enl0 o/er ;+ hours )C, E* )>, >>*#

o As the se/erit0 of deh0dration ma0 be difficult to

determine and freFuentl0 is under1 or o/eres1timated )C*)>;*, infuse fluid each da0 at a rate rarel0 in e4cess of(#>$ times the usual dail0 maintenance reFuirement based on age, weight, or bod0 surface area )E* )>*# ee2ables ( and - for e4am!les of calculations#

8n addition to clinical assessment of deh0dration,calculation of effecti/e osmolalit0 ma0 be /aluable toguide fluid and electrol0te thera!0 )E*#

Irinar0 losses should not routinel0 be added to the

calculation of re!lacement fluid, but ma0 be necessar0 inrare circumstances )E*#

2he sodium content of the fluid ma0 need to be increasedif measured serum sodium is low and does not rise

a!!ro!riatel0 as the !lasma glucose concentration falls)C* )>+, +*#

2he use of large amounts of %#& saline has beenassociated with the de/elo!ment of h0!erchloremicmetabolic acidosis )&, @%*#

/nsulin #herap

D.A is caused b0 a decrease in effecti/e circulatinginsulin associated with increases in counter1regulator0hormones )glucagon, catecholamines, G", cortisol*#Although reh0dration alone causes some decrease in blood glucose concentration )@(, @$*, insulin thera!0




is essential to normali3e blood glucose and su!!ressli!ol0sis and ketogenesis )A* )@-*#

E4tensi/e e/idence indicates that .lo) dose/ 8? insulinadministration should be the standard of care )A* )@;*#

tart insulin infusion ($ hours after starting fluid

re!lacement thera!09 i#e# after the !atient has recei/edinitial /olume e4!ansion )E,C* )@>*#

%able 16 %his table sho#s an alternative ea!ple of fl$idvol$!es for the s$bse$ent phase of rehydration

D(A0 .ive !aintenance F

Body

Maintenance5Q of body #eight39h

#eight &g!/39 h!/E39 h!/h

913551233

5

925752

38

7958:211

8582:321

792429291

:

84244729

428243251

4492

41:25

43:249:273

41:9245:2

77

49::247:282

45421248289



4742824828

4844324:82

3

4445232525

4:44:23492:

3243123312:1

3341223922422

3941723572428

3749123812449

349:23:2432

124572127243

13

47321332419

194721172492

1748121972499

148:215249:

924521822459

954:21:72475

5234229322485

553342993249

72

313297924:1

753942932324

823522522232



8535:2542347

2

37:2512339

∗ After initial res$scitation, and ass$!ing 42Q dehydration,

the total a!o$nt of fl$id sho$ld be given over 9 ho$rs6 %able1 gives vol$!es for !aintenance and rehydration per 39ho$rs and per ho$r6 >f fl$id has been given for res$scitation,the vol$!e sho$ld not be s$btracted fro! the a!o$nt sho#nin the table6 -l$ids given orally ?#hen patient has i!proved@should be s$btracted fro! the a!o$nt in the table6 %able 1 is

based on !aintenance vol$!es according to Darrro# ?453@6-or body #eights >13 &g, the vol$!es have been ad<$sted soas not to eceed t#ice the !aintenance rate of fl$idad!inistration6

Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411 !0'olfsdorf et al(

Correction of insulin deficienc0

o Dose' %#( unit5kg5hour )for e4am!le, one method is todilute >% units regular 6soluble7 insulin in >% mL normalsaline, ( unit N ( mL* )@;, @*

o Route of administration 8? )A*

o An 8? bolus is unnecessar0 )@@*, ma0 increase the riskof cerebral edema )@>*, and should &ot be used at the startof thera!0 )C*

2he dose of insulin should usuall0 remain at %#(

unit5kg5hour at least until resolution of D.A )!" >@#-%, bicarbonate >(> mmol5L and5or closure of the anionga!*, which in/ariabl0 takes longer than normali3ation of blood glucose concentrations )* )@+*#

8f the !atient demonstrates marked sensiti/it0 to insulin)e#g#, some 0oung children with D.A, !atients with

"", and some older children with established diabetes*,the dose ma0 be decreased to %#%> unit5kg5hour, or less, !ro/ided that metabolic acidosis continues to resol/e#

During initial /olume e4!ansion the !lasma glu1coseconcentration falls stee!l0 )@(* )C*# 2hereafter, and aftercommencing insulin thera!0, the !lasma glucoseconcentration t0!icall0 decreases at a rate of $>mmol5L5hour, de!ending on the timing and amount of

glucose administration )C* )@&+>*#

2o !re/ent an undul0 ra!id decrease in !lasma glu1coseconcentration and h0!ogl0cemia, > glucose should be

added to the 8? fluid )e#g#, > glucose in %#;> saline*when the !lasma glucose falls to a!!ro4imatel0 (;(@mmol5L )$>%-%% mg5dL*, or sooner if the rate of fall is !reci!itous )*#

o 8t ma0 be necessar0 to use (% or e/en ($#> de41trose to !re/ent h0!ogl0cemia while continuing to infuseinsulin to correct the metabolic acidosis#

8f G falls /er0 ra!idl0 )>> mmol5L5h* after initial fluid

e4!ansion, consider adding glucose e/en before !lasma

glucose has decreased to (@ mmol5L )E*#

8f biochemical !arameters of D.A )!", anion ga!* do not

im!ro/e, reassess the !atient, re/iew insulin thera!0, andconsider other !ossible causes of im!aired res!onse toinsulin9 e#g#, infection, errors in insulin !re!aration )E*#

8n circumstances where continuous 8? administra1tion isnot !ossible, hourl0 or $1hourl0 C or 8M administrationof a short1 or ra!id1acting insulin analog )insulin lis!ro or insulin as!art* is safe and ma0 be as effecti/e as 8?regular insulin infusion

)C* )+%, ++&*, but should not be used in sub:ects whose !eri!heral circulation is im!aired )E*#

o 8nitial dose C' %#- unit5kg, followed ( hour later b0 Cinsulin lis!ro or as!art at %#( unit5kg e/er0 hour, or %#(>

%#$% units5kg e/er0 two hours#

8f blood glucose falls to <(; mmol5L )$>% mg5dL* before

D.A has resol/ed, )!" still <@#-%*, add > glucose andcontinue with insulin as abo/e#

Aim to kee! blood glucose at about (( mmol5L )$%%mg5dL* until resolution of D.A#

1o#assium repla$emen#

Children with D.A suffer total bod0 !otassium deficitsof the order of - to mmol5kg );>;&*# 2he ma:or loss of !otassium is from the intracellular !ool# 8ntracellular !otassium is de!leted because of transcellular shifts of

this ion caused b0 h0!ertonicit0 )increased !lasmaosmolalit0 causes sol/ent drag in which water and !otassium are drawn out of cells* and gl0cogenol0sis and !roteol0sis secondar0 to insulin deficienc0 cause !otassium efflu4 from cells# Potassium is lost from the bod0 from /omiting and as a conseFuence of osmotic

diuresis# ?olume de!letion causes secondar0h0!eraldosteronism, which !romotes urinar0 !otassiume4cretion# 2hus, total bod0 de!letion of !otassium occurs,

but at !resentation serum !otassium le/els ma0 be



normal, increased or decreased )&%*# Renal d0sfunction, b0 enhancing h0!ergl0cemia and reducing !otassiume4cretion, contributes to h0!erkalemia )&%*#Administration of insulin and the correction of acidosis

will dri/e !otassium back into the cells, decreasing serumle/els )&(*# 2he serum !otassium concentration ma0decrease abru!tl0, !redis!osing the !atient to cardiacarrh0thmias#

Re!lacement thera!0 is reFuired regardless of the serum !otassium concentration )A* )&$, &-*#

8f the !atient is h0!okalemic, start !otassium re!lacementat t%e tie o initial /olume e4!ansion and before startinginsulin thera!0# therwise, start re!lacing !otassiumater initial /olume e4!ansion and concurrent withstarting insulin thera!0# 8f the !atient is h0!erkalemic,

deer !otassium re!lacement thera!0 until urine out!ut is

documented )E*#

8f immediate serum !otassium measurements areuna/ailable, an ECG ma0 hel! to determine whether thechild has h0!er1 or h0!okalemia )C* );%, ;(*# =latteningof the 2 wa/e, widening of the K2 inter/al, and thea!!earance of I wa/es indicate h0!okalemia# 2all, !eaked, s0mmetrical, 2 wa/es and shortening of the K2

inter/al are signs of h0!er1kalemia#

2he starting !otassium concentration in the infusate

should be ;% mmol5L# ubseFuent !otas1siumre!lacement thera!0 should be based on serum !otassiummeasurements )E*#

o 8f !otassium is gi/en with the initial ra!id /olumee4!ansion, a concentration of $% mmol5L should be used#

!2 Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411

Potassium !hos!hate ma0 be used together with !otassium chloride or acetate9 e#g#, $% mmol5L !otas1siumchloride and $% mmol5L !otassium !hos!hate or $%

mmol5L !otassium !hos!hate and $% mmol5L !otassiumacetate )C,E*#

Potassium re!lacement should continue throughout 8?fluid thera!0 )E*#

2he ma4imum recommended rate of intra/enous

!otassium re!lacement is usuall0 %#> mmol5kg5hr )E*#

8f h0!okalemia !ersists des!ite a ma4imum rate of

!otassium re!lacement, then the rate of insulin infu1sioncan be reduced#

1hospha#e

De!letion of intracellular !hos!hate occurs in D.A and !hos!hate is lost as a result of osmotic diuresis );>;@*#Plasma !hos!hate le/els fall after starting treatment andthis is e4acerbated b0 insulin, which !romotes entr0 of

!hos!hate into cells )&;&*# 2otal bod0 !hos!hatede!letion has been associated with a /ariet0 of metabolicdisturbances )&@&&*# Clinicall0 significant

h0!o!hos!hatemia ma0 occur if intra/enous thera!0without food intake is !rolonged be0ond $; hours );> ;@*#

Pros!ecti/e studies ha/e not shown clinical benefit from !hos!hate re!lacement )A* )(%%(%>*#

e/ere h0!o!hos!hatemia in con:unction withune4!lained weakness should be treated )E* )(%*#

Administration of !hos!hate ma0 induce h0!ocal1cemia)C* )(%@, (%+*#

Potassium !hos!hate salts ma0 be safel0 used as analternati/e to or combined with !otassium chloride oracetate, !ro/ided that careful monitoring of serum

calcium is !erformed to a/oid h0!ocalcemia )C* )(%@,(%+*#

A$idosis

e/ere acidosis is re/ersible b0 fluid and insulinre!lacement9 insulin sto!s further ketoacid !roductionand allows ketoacids to be metaboli3ed, which generates bicarbonate )A*# 2reatment of h0!o/olemia im!ro/estissue !erfusion and renal function, thereb0 increasing thee4cretion of organic acids#

Controlled trials ha/e shown no clinical benefit from bicarbonate administration ),C* )(%&(($*# icarbonate

thera!0 ma0 cause !arado4ical C< acidosis )((-, ((;*9ra!id correction of acidosis with bicarbonate causesh0!okalemia )((-, ((>, ((*, and failure to account forthe sodium being administered and a!!ro!riatel0reducing the <aCl concentration of the fluids can result inincreasing osmolalit0 )((-*# <e/ertheless, there ma0 be

selected !atients who ma0 benefit from cautious alkalithera!0# 2hese include' !atients with se/ere acidemia)arterial !" <#&* in




whom decreased cardiac contractilit0 and !eri!heral/asodilatation can further im!air tissue !erfusion, and !atients with life1threatening h0!erkalemia )E* )((@*#

icarbonate administration is not recommended unlessthe acidosis is !rofound and likel0 to affect ad/ersel0 the

action of adrenaline5e!ine!hrine during resuscitation )A*#

8f bicarbonate is considered necessar0, cautiousl0 gi/e ( $ mmol5kg o/er % minutes )E*#

Complications of therapy

8nadeFuate reh0dration

"0!ogl0cemia

"0!okalemia

"0!erchloremic acidosis

Cerebral edema

/n#rodu$#ion of oral fluids and #ransi#ion #o SCinsulin in3e$#ions

ral fluids should be introduced onl0 when substantialclinical im!ro/ement has occurred )mild acidosis5ketosis

ma0 still be !resent* )E*#

When oral fluid is tolerated, 8? fluid should be reduced)E*#

When ketoacidosis has resol/ed, oral intake is tolerated,and the change to C insulin is !lanned, the mostcon/enient time to change to C insulin is :ust before amealtime )E*#

2o !re/ent rebound h0!ergl0cemia the first C in:ectionshould be gi/en (>-% minutes )with ra!id1acting insulin*or ($ hours )with regular insulin* before sto!!ing theinsulin infusion to allow suf1ficient time for the insulin to

be absorbed )E*# With intermediate1 or long1actinginsulin, the o/er1la! should be longer and the 8? insulingraduall0 lowered# =or e4am!le, for !atients on a basal1 bolus insulin regimen, the first dose of basal insulin ma0 be administered in the e/ening and the insulin infusion issto!!ed the ne4t morning )E*#

2he dose and t0!e of C insulin should be according to

local !references and circumstances#

After transitioning to C insulin, freFuent blood glucosemonitoring is reFuired to a/oid marked h0!ergl0cemiaand h0!ogl0cemia )E*#

Morbidi# and mor#ali#

8n national !o!ulation studies, the mortalit0 rate fromD.A in children is %#(> to %#-% )C,* )((+, ((&*#Cerebral edema accounts for % to &% of all D.A

deaths )C,* )%, ($%*# =rom (% to $> of sur/i/ors

Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411 !4'olfsdorf et al(

of cerebral edema ha/e significant residual morbidit0)C,* )%, ($%, ($(*#

ther rare causes of morbidit0 and mortalit0 include'

"0!okalemia

"0!erkalemia

e/ere h0!o!hos!hatemia

"0!ogl0cemia

ther central ner/ous s0stem com!lications )dis1seminated intra/ascular coagulation, dural sinusthrombosis, basilar arter0 thrombosis*

Peri!heral /enous thrombosis

e!sis

Rhinocerebral or !ulmonar0 mucorm0cosis

As!iration !neumonia

Pulmonar0 edema

Adult res!irator0 distress s0ndrome )ARD*

Pneumothora4, !neumomediastinum and subcuta1neous

em!h0sema

Rhabdom0ol0sis

Acute renal failure

Acute !ancreatitis )($$*

Cerebral edema



2he incidence of cerebral edema in national !o!u1lation

studies is %#>%#& and the mortalit0 rate is $($; )%,($%, ($(*# 2he !athogenesis of both its initiation and !rogression is unclear and incom1!letel0 understood#Demogra!hic factors that ha/e been associated with anincreased risk of cerebral edema include'

ounger age )C* )($-*

<ew onset diabetes )* )((&* )C* )($-*

Longer duration of s0m!toms )C* )($;*

2hese risk associations ma0 reflect the greater likelihoodof se/ere D.A#

E!idemiological studies ha/e identified se/eral !otentialrisk factors at diagnosis or during treatment of D.A#2hese include'

Greater h0!oca!nia at !resentation after ad:usting fordegree of acidosis )C* )%, ($>, ($*

8ncreased serum urea nitrogen at !resentation )C* )%,($*

More se/ere acidosis at !resentation )C* )@>, ($@*

icarbonate treatment for correction of acidosis )C* )%,($+*

An attenuated rise in measured serum sodiumconcentrations during thera!0 )C* )>+%*

Greater /olumes of fluid gi/en in the first ; hours )@>*

Administration of insulin in the first hour of fluid

treatment )@>*

E/idence for disru!tion of the bloodbrain barrier has been found in cases of fatal cerebral edema asso1ciatedwith D.A )($&*# 8n recent studies, the degree of edema

formation during D.A in children correlates with thedegree of deh0dration and h0!er/entilation at !resentation, but not with factors related to ini1tialosmolalit0 or osmotic changes during treatment# 2hesedata ha/e been inter!reted as su!!orting the h0!othesisthat cerebral edema is related to cerebral h0!o!erfusionduring D.A, and that osmotic fluctu1ations during D.A

treatment do not !la0 a !rimar0 causal role )($*#

'arnin" si"ns and symptoms of cerebral edema

include-

"eadache slowing of heart rate

Change in neurological status )restlessness, irritabilit0,increased drowsiness, incontinence*

!ecific neurological signs )e#g#, cranial ner/e !alsies*

Rising blood !ressure

Decreased $ saturation

Clinicall0 significant cerebral edema usuall0 de/elo!s ; ($ hours after treatment has started, but can occur beforetreatment has begun )%, ($(, (-%(--* or, rarel0, ma0de/elo! as late as $;;+ hours after the start of treatment

)C,* )%, ($-, (-;*# 0m!toms and signs are /ariable# A

method of clinical diagnosis based on bedside e/aluationof neurological state is shown below )C* )(->*'

Diagnostic criteria

Abnormal motor or /erbal res!onse to !ain

Decorticate or decerebrate !osture

Cranial ner/e !als0 )es!eciall0 888, 8?, and ?8*

Abnormal neurogenic res!irator0 !attern )e#g#, grunting,tach0!nea, Che0ne1tokes res!iration, a!neusis*

Ma<or criteria

Altered mentation5fluctuating le/el of consciousness

ustained heart rate deceleration )decrease more than $% beats !er minute* not attributable to im!ro/edintra/ascular /olume or slee! state

Age1ina!!ro!riate incontinence

Minor criteria

?omiting

"eadache

Letharg0 or not easil0 arousable

!5 Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411



Diastolic blood !ressure >&% mm "g

Age <> 0ears

ne diagnostic criterion, two ma:or criteria, or one ma:or and two minor criteria ha/e a sensiti/it0 of &$ and a

false !ositi/e rate of onl0 ;#

A chart with the reference ranges for blood !ressure and

heart rate, which /ar0 de!ending on height, weight, andgender, should be readil0 a/ailable, either in the !atientBschart or at the bedside#

6rea#men# of $erebral edema

8nitiate treatment as soon as the condition is sus!ected#

Reduce the rate of fluid administration b0 one1third#

Gi/e mannitol %#>( g5kg 8? o/er $% minutes and re!eat

if there is no initial res!onse in -% minutes to $ hours

)C,E* )(-(-+*#

"0!ertonic saline )-*, >(% mL5kg o/er -% minutes,ma0 be an alternati/e to mannitol or a second line ofthera!0 if there is no initial res!onse to mannitol )C*)(-&, (;%*#

o Mannitol or h0!ertonic saline should be a/ailable at the bedside

Ele/ate the head of the bed

• 8ntubation ma0 be necessar0 for the !atient withim!ending res!irator0 failure, but aggressi/e

h0!er/entilation )to a !C$ <$#& kPa 6$$ mm "g7* has

been associated with !oor outcome and is notrecommended )C* )(;(*#

*ter treatment for cerebral edema has been started, acranial C2 scan should be obtained to rule out other !ossible intracerebral causes of neurologic deterioration )

J(% of cases*, es!eciall0 throm1bosis )(;$(;>* orhemorrhage, which ma0 benefit from s!ecific thera!0#

1reven#ion of re$urren# D&A

Management of an e!isode of D.A is not com!lete untilits cause has been identified and an attem!t made to treatit#

8nsulin omission, either inad/ertentl0 or deliberatel0, isthe cause in most cases )C,A* )--,-;*#

2he most common cause of D.A in insulin !um! users isfailure to take e4tra insulin with a !en or s0ringe whenh0!ergl0cemia and h0!erketonemia or ketonuria occur

)E*#

"ome measurement of blood " concentrations,

when com!ared to urine ketone testing, decreasesdiabetes1related hos!ital /isits )both emergenc0de!artment /isits and hos!itali3ations* b0 the earl0identification and treatment of ketosis )(;*# lood" measurements ma0 be es!eciall0 /aluable to !re/ent D.A in !atients who use a !um! because

interru!ted insulin deli/er0 ra!idl0 leads to ketosis#




2here ma0 be dissociation between urine ketone )sodiumnitro!russide onl0 measures acetoacetate and acetone*and serum " concentrations, which ma0 be

increased to le/els consistent with D.A when a urineketone test is negati/e or shows onl0 trace or smallketonuria )(;@*#

2here usuall0 is an im!ortant !s0chosocial reason forinsulin omission#

an attem!t to lose weight in an adolescent girl with aneating disorder,

o a means of esca!ing an intolerable or abusi/e homesituation,

clinical de!ression or other reason for inabilit0 of the !atient to manage the diabetes unassisted#

An infection that is not associated with /omiting anddiarrhea is seldom the cause when the !atient5famil0 is !ro!erl0 educated in diabetes management and isrecei/ing a!!ro!riate follow1u! care b0 a dia1betes teamwith a $;1hour tele!hone hel!line )* )(;+(>%*#

A !s0chiatric social worker or clinical !s0cholo1gistshould be consulted to identif0 the !s0chosocial reason)s*contributing to de/elo!ment of D.A )E*#

8nsulin omission can be !re/ented b0 schemes that !ro/ide education, !s0chosocial e/aluation and treatmentcombined with adult su!er/ision of insulin administration

)* )(>(*#

Parents and !atients should learn how to recogni3e

and treat im!ending D.A with additional ra!id1or short1acting insulin and oral fluids )E*

o Patients should ha/e access to a $;1hour tele!honehel!line for emergenc0 ad/ice and treatment )* )(;+*

o When a reliable adult administers insulin there ma0 be

as much as a tenfold reduction in freFuenc0 of recurrentD.A )* )(>(*#

Re$ommenda#ions7ke poin#s

D.A is caused b0 either relati/e or absolute insulindeficienc0#

Children and adolescents with D.A should be managedin centers e4!erienced in its treatment and where /italsigns, neurological status and laborator0 results can bemonitored freFuentl0

egin with fluid re!lacement before starting insulinthera!0#

?olume e4!ansion )resuscitation* is reFuired onl0 ifneeded to restore !eri!heral circulation#

ubseFuent fluid administration )including oral fluids*should reh0drate e/enl0 o/er ;+ hours at a rate rarel0 ine4cess of (#>$ times the usual dail0 maintenance

reFuirement#

egin with %#( I5kg5h# ($ hours A=2ER starting fluidre!lacement thera!0#

Pediatric Diabetes 322:0 !( ?S$ppl6 43@0 44411 !8



'olfsdorf et al(



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