dka review

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THERAPY I NPRACT ICE Pe dia if Drugs 2008; 10 4): 209-21174-5878/08/0004-0209/S48.00O 2008 Adte Dato Informot ion BV.All rights reserve

Management of Diabetic Ketoacidosis inChildrenand dolescentsNicoleA Sherry and ynne L evitskyPdiatrie Endocrine Unit, Massachusetts General Hospitalfor Children, Harvard University, Boston, Massachusetts, USA

ContentsAbstract 2091. Diagnosis of Diabetic Ketoacidosis DKA) 2102. Compiicatians 2102.1 Cerebral Edema 210

2.2 Otiier Camplicatians 2113. iVianagement of DKA 211

3.1 Fiuid Therapy 2113.2 Electroiyte Tiierapy 2123.3 Insuiin Therapy 2123.4 Bicarbonate Therapy 2133.5 Management af Cerebrai Edema 213

3.5.1 Mannitol 2133.5.2 Hypertonie Saiine 213

Future Passibiiities for Medicai iVianagement 2134.1 Subcutaneous insuiin: Treatment of DKA 2134.2 Bumetanide 214

5. Conciusion 214

bstract Diabetic ketoacidosis DKA ) is a life-threatening complicationofdiabetes me llitus. Wh ileitcan occur inalltypes of diabetes mellitus, it is seen most often in patients with type 1 diabetes, either at presentation orasa resultof non-compliance with medical therapy. DKA ischaracterizedbyhyperglycemia, acidosis, dehydration,andelectrolyte abnormalities, which result from a deficiency of insulin and an excess of counter-regulatoryhormones.

Therapy is aimed at repleting fluids, and correcting acidosis and electrolyte disturbances by adm inistration ofintravenous fluidand intravenous insulin. Rapid correction shouldbeavoided as it mayresult inuntowardeffects, including cerebral edema. Frequent monitoringof neurologic statusandmetabolic parameters aidsinavoidance or early detection of complications. While much is still not understood about the most seriouscomplication, cerebral edema, recent studies suggest that itsdevelopment may be tied to a lossof cerebralautoregulation and avasogenic mechanismof edema formation. Treatmentof cerebral edema includes fluidrestriction and administrationofmannitol. Once DKA has resolved, subcutaneous insulin is initiated with carefulconsideration ofits pharmacokineticstoavoidaperiodofinsulin deficiency andmetabolic decompensation.

Diabetic ketoacidosis DKA) is the result of a relative orofinsulin, and increased levelsofthe c ounter-

Glu-cagon seemsto be particularly important in thepathogenesisoketoacidosis. Individuals with glucagon and insulin deficienci.e. patients post pancreatectomy or with cystic fibrosis-relate


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210 Sherry Le

diabetes mellitus) rarely develop DKA,and DKA takes longertodevelop when insuliniswithdrawn.''-^'

Blood glucose levels rise because thereisincreased productionof new glucose (gluconeogenesis) and failure to store glucose thatis absorbed through the gut. In addition, glycogenolysis, as a resultof both insulin deficiency andelevations of counter-regulatoryhormones, contributestohyperglycemia. W ith insulin deficiency,there areminimal glycogen storesin theliver or other tissues.Hyperglycemia inducesanosmotic diuresisandobligate lossofsalt as wellaswater. Lossofsodium and potassiuminadults mayamountto up to20 of total body stores;'^' therearesparse dataquantitating these lossesin children. Without insulin, thereis abreakdown of fat withthereleaseof free fatty acids. Free fattyacids are converted to ketones through glucago n-dependent hepat-ic pathways. The released ketoacids are excreted by the kidneyaslongas thereis sufficient hydrogen exchange. With decreasingfluid volume as a result of osmotic diuresis and loss of saltnecessaryfor hydrogen exchange, blood levelsofketoacids riseand acidosis develops. Pulmonary compensation for the metabolicacidosisis notsufficient, leadingtoincreasingly severe acidosis.

DKA is the presenting manifestation of type diabetes m ellitus(TIDM)inabout 25 ofchildren andoftype2diabetes m ellitusin 5-25 .[''l DKA inchildren with established T ID M canbe theresultof non-compliance with insulin therapy, insulin pump fail-ure,or intercurrent illness. DKAin thesettingof an intercurrentillness can often be avoided with close home mo nitoringofbloodglucose andurineor blood ketone levelsandadministrationofsupplemental insulinasneeded.In one study, home-meter moni-toringofblood 3-hydroxybu tyrate levels significantly decreasedhospital visits compared with urine ketone monitoring.'^'

This article reviews the management of diabetic ketoacidosisinchildrenandadolescents. Referenceto adult datais made wheredatainchildrenarelimited.

1 . Diagnosiso Diabe tic Ketoacidosis DKA)The diagnosisofDKA canbemissedas itcan resemble other,

more common, pdiatrie illnesses suchassevere dehydrationdueto gastroenteritis. DKA should be considered in any child or youngadult with mental status changes.ThepresenceofDKAis sup-ported by a history of polyuria, polydipsia, weight loss, rapidbreathing with fruity-smelling breath,andvomiting.

The diagnosis ofDKA is based on biochemical evidenceofhyperglycemia (serum glucose levels >200-250 mg/dL), acidosisand ketosis (venous pH 80 mg/dL. DKA may be characterized as mild (venouspH

7.2-7.3, serum bicarbonate level 10-15 mEq/L), moderatnous pH 7.1-7.2, serum bicarbonate level 5-10 mEq/L),ors(venouspH90 mmHg,


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Management of Diabetic Ketoacidosis 21

intravenous bicarbonate) may cause cerebral edema, but cerebraledema is evident in many patients before treatment is initiated.'^' Acompilation of risk factors associated with cerebral edema inchildren, including prolonged illness, greater initial dehydrationand hypocapnia, and persistent hyponatremia,'^' does not clearlydelineate a causal mechanism. Recent studies using radiologietechniques to study the brain in children during treatment of DKAsuggest that the development of cerebral edema may be linked to aloss of cerebral autoregulation and a vasogenic mechanism ofedema formation.'' l These findings suggest the need for closemonitoring of blood pressure and fluid status in the treatment ofDKA in order to prevent the development of cerebral edema.

2.2 Other ComplicationsOther complications of DKA are rare. Although cerebral edema

accounts for 90% of neurologic complications, other possibleetiologies should be considered in a patient with an encephalo-pathy without cerebral edema (i.e. no evidence on CT scan and noresponse to osmotherapy). These include subarachnoid hemor-rhage, basilar artery stenosis, durai sinus thrombosis, cerebralvenous thrombosis, meningo-encephalitis, infarction, and thia-mine deficiency.''-^1

Abdominal pain and vomiting are common complaints amongpatients w ith DKA . While elevations of amylase and lipase levels(up to 3 times the upper limit of normal) are common, pancreatitisis rare in children, suggesting that pancreatic enzymes should only

be checked in patients with persistent abdominal pain after correction of acidosis. ^' Diabetes is associated with a prothrombotistate in adults and children.I''*' There have been reports of deevein thrombosis in children with DKA and femoral intravenoulines. ^'^' Cases of rhabdomyolysis, ^' pulmonary edema, anrhinocerebral mucormycosis have been reported in children witDKA.

3 Management of DKAFigure 1 provides an overview of the management of D KA

Because common management practices may be linked to thdevelopment of cerebral edema, the use of these interventionmust be employed judiciously. Th ere are often com peting factorin an individual patient. For example, the administration of bicarbonate may be important for quickly correcting peripheral acidosiin the setting of cardiac impairment but may paradoxically worseintracranial acidosis and lead to CNS hypoxia. High initial fluivolumes may increase intracranial pressure in the setting of impaired cerebral autoregulation, but too little fluid may result ishock and cerebral hypoperfusion. In such circumstances, clinicajudgment must be employed and, thus, strict guidelines cannot bcreated.

3.1 Fluid TherapyAssessment of the fluid deflcit in children with DKA is diffi

cult. In a prospective study of 7children, no clinical sign reliablDiagnose DKA:1.serum glucose level >200-250 mg/dL2.venous pH


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correlated with the degree of dehydration as measured by com par-ing admission and discharge bodyweights. The average fluid defi-cit was 8.7%. It was suggested that an initial estimate of 7-9%dehydration for all patients was appropriate.''^^ The InternationalSociety of Pdiatrie and A dolescent Diabetes (ISPAD) has recent-ly recommended using an estimate of 5-7% dehydration in pa-tients with moderate DKA and 7-10% in patients with severe

Fluid therapy should be administered as an initial 0.9% salinebolus of 10-20 mL/kg, followed by deficit replacement with0.45-0.9% saline administered evenly over the next 48 hours.Again, given the difficulties in assessing the fiuid deficit, replace-ment at a rate of 1.5-2 times the daily maintenance rate has beensuggested as a rough guideline.' "' Generally, urinary losses are notreplaced. The 2004 position statement by the American DiabetesAssociation recommends that if the corrected serum sodium" ishigh or normal, 0.45% saline should be used and if it is low 0.9%saline should be administered.'-^'l Rapid fiuid resuscitation and arapid decrease in osmolality have been associated with the devel-opment of cerebral edema (see also section 3 introduction).'^^-^^JWe suggest frequent monitoring of serum sodium levels with thegoal of correcting the sodium at a rate no greater than 1-2 mEq/Lper hour.

3.2 E lectrolyte TherapyAlthough the serum potassium level at presentation in patientswith DKA is often normal or elevated, the total body potassium

level is low and should be replaced. Initial increased serum potas-sium levels reflect an extracellular shift of potassium due in part tothe concurrent acidosis and extracellular hypertonicity secondaryto hyperglycemia. Total body depletion results mainly from urin-ary loss of this extracellular potassium due to osmotic diuresis.Adm inistration of potassium at 40 mEq/L is generally sufficient.However, replacement should be performed carefully with avoid-ance of hyperkalemia (serum potassium level >5.5 mEq/L) andhypokalemia (serum potassium level


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ybutyrate are metabolized and acidosis is corrected by the genera-tion of bases; ho wever, during the correction p hase, appearance ofacetoacetate generated from betahydroxybutyrate may maintainappare nt ketonuria.' ^"" Acid osis often does not correct untilseveral hours after the serum glucose level is in the normal rangeand, thus, dextrose (5% increasing to 12.5% as necessary) shouldbe added to the intravenous solutions when the serum glucoselevel is


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214 Sherry Le

insulin injections given at 4-6 hourly intervals demonstrated thatcontinuous intravenous insulin therapy was equivalent in outcomeand easier to manage. Given the rapid onset of action of the new erinsulin analogs (aspart and lispro), several recent studies havesuccessfully substituted insulin delivered subcutaneously for intra-venous insulin infusion in the treatment of DKA.

In a study of 60 children and adolescents with DKA random-ized to receive either 0.1 U/kg/h of intravenous regular insulin or0.15 U/kg of subcutaneous insulin lispro every 2 hours, DeliaManna et alS *^^ found that the correction of glucose levels wasidentical. While correction of acidosis was faster in patients re-ceiving intravenous insulin, correction in both groups occurredless than 12 hours after normalization of glucose levels.

Several small, prospective, randomized clinical trials in adultswith DKA have shown no differences in the rate of resolution ofhyperglycemia and acidosis between subcutaneous and intrave-nous insulin regimens.f'' '' ' Insulin delivery via subcutaneousinsulin pumps, although reported only anecdotally, theoreticallywould have a similar effect. These therapeutic options offer thelargely economic advantage of enabling management of DKAoutside of the intensive care unit. However, the risk of cerebraledema or other complications remains a concern and resources forrapid intervention must be available.

4.2 BumetanideWh ile the mechanism of cerebral edema in DKA is still largely

unknown, stimulation of the sodium-potassium-chloride cotrans-porter on the cells of the BBB has been found to be important incerebral edema associated with ischmie stroke. A recent study byLam et al.,' ' ' ' using the streptozotocin rat model of diabetes,suggests that this cotransporter is also important in the develop-ment of cerebral edema in DKA. In this study, the cotransporterwas found to be stimulated by ketoacids. Treatment of rats withDKA and evidence of cerebral edema with bumetanide, an inhibi-tor of the sodium-potassium-chloride cotransporter, reversed theexperimental cerebral edema.

5 ConclusionDKA is the major cause of severe morbidity and mortality in

children with TIDM. Careful fluid, electrolyte, and insulin man-agement as well as close monitoring may prevent the most com-mon and serious complication - cerebral edema. If cerebral edemais suspected, prompt intervention is necessary to prevent irreversi-ble neurologic damage. Newer techniques for the prevention ofcerebral edema are currently theoretical but could potentiallyreduce this complication in the future.

AcknowledgmentsNo sources of funding were used to assist in the preparation of this re

Lynne L. Levitsky has received consulting fees and honoraria from saaventis. Nicole A. Sherry has no conflicts of interest that are directly relto the content of this review.

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Correspondence: Dr icoleA .Sherry Pdiatrie Endocrine Unit, Massacsetts General Hospital for Children, Harvard University, 175 CambridgStreet, 5th Floor/R oom 537, Boston, MA 02114, USA.E-mail; [email protected]

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