Diabetic ketoacidosis in children and adolescents with diabetesThe adage A child is not a miniature adult is most appropriate when considering diabetic ketoacidosis.

Diabetic KetoAcidosis (DKA) & Hyperosmolar Hyperglycemic Syndrome (HHS)The two most serious acute metabolic complications of diabetes.

Mortality rate:DKA< 5%HHSabout 15%

Diabetic ketoacidosisDKA results from absolute or relative deciency of circulating insulin and the combined effects of increased levels of the counterregulatory hormones: catecholamines, glucagon, cortisol,growth hormone. FOSTER DW, MCGARRY JD. The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983: 309(3): 15969.KITABCHI AE, UMPIERREZ GE, MURPHY MB, KREISBERG RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006 Dec: 29(12): 273948.

Diabetic ketoacidosisAbsolute insulin deciency occurs in:

previously undiagnosed T1DM when patients on treatment deliberately or inadvertently do not take insulin, especially the long-acting component of a basal-bolus regimen patients who use an insulin pump when insulin delivery fails for any reason

HANAS R, LINDGREN F, LINDBLAD B. A 2-yr national population study of pediatric ketoacidosis in Sweden: predisposing conditions and insulin pump use. Pediatr Diabetes 2009 Feb: 10(1): 337.KITABCHI AE, UMPIERREZ GE, MURPHY MB, KREISBERG RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006 Dec: 29(12): 273948.

Diabetic ketoacidosisRelative insulin deciency occurs when the concentrations of counterregulatory hormones increase in response to stress in conditions such as: sepsis, trauma, gastrointestinal illness with diarrhea and vomitingHANAS R, LINDGREN F, LINDBLAD B. A 2-yr national population study of pediatric ketoacidosis in Sweden: predisposing conditions and insulin pump use. Pediatr Diabetes 2009 Feb: 10(1): 337.KITABCHI AE, UMPIERREZ GE, MURPHY MB, KREISBERG RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006 Dec: 29(12): 273948.

Denition of diabetic ketoacidosis (DKA)The biochemical criteria for the diagnosis of DKA are: Hyperglycemia (blood glucose >11 mmol/L 200mg/dL)

Venous pH

The severity of DKAThe severity of DKA is categorized by the degree ofacidosis:

Mild: pH 7.2 - 7.3 or bicarbonate 10 -15 mmol/L

Moderate: pH 7.1 - 7.2 or bicarbonate 5 - 10 mmol/L

Severe: pH

Frequency of DKAAt disease onset

There is wide geographic variation in the frequency of DKA at onset of diabetes;rates inversely correlate with the regional incidence of T1DM.

Frequencies range from approximately 15% to 70% at diagnosis of T1DM in Europe and North America.

DKA at diagnosis is more common in younger children (

Frequency of DKAIn children with established diabetes (recurrent DKA)

The risk of DKA in established T1DM is 110% per pat. per year.

Risk is increased in: children with poor metabolic control or previous DKA peripubertal and adolescent girls children with psychiatric disorders, including those with eating disorders children with difcult or unstable family circumstances children who omit insulin children with limited access to medical services insulin pump therapy (as only rapid- or short-acting insulin is used in pumps, interruption of insulin delivery for any reason rapidly leads to insulin deciency)HANAS R, LINDGREN F, LINDBLAD B. A 2-yr national population study of pediatric ketoacidosis in Sweden: predisposing conditions and insulin pump use. Pediatr Diabetes 2009 Feb: 10(1): 337.

DKA in children and adolescents with T2DM

T2DM associated with rates of obesity, in some centers now accounts for as much as 1/2 of newly diagnosed DM in children aged 10 to 21 years. Acute decompensation with DKA has been recognized to occur at the time of dg in as many as 25% of children with T2DM.

This is more likely in those of African-American descent, less so in Hispanic, and least in Canadian First Nation teenagers

Overall, approx. 5% of patients with T2DM have DKA at the time of diagnosis.SUGIHARA S, SASAKI N, KOHNO H, et al. Survey of current medical treatments for childhood-onset type 2 diabetes mellitus in Japan Clin Pediatr Endocrinol 2005:14(2):6575.

DKA at Diagnosis of DM in YouthThe SEARCH for Diabetes in Youth Study Incidence of DKA at the time of Dg SEARCH is multicenter study In 2002 began population-based ascertainment of incident cases of DM in youth younger than 20 years Incidence:Overall: 25.5% (CI 23.9-27.1)Type 1: 29.4% (CI 27.5-31.3%)Type 2: 9.7% (CI 7.1-12.2)

Rewers A et al., Pediatrics, May 2008

Mortality in Children with DKA0.15% USA0.18% Canada0.31% UK80% of deaths occurs in association with signs of CEOther causes: hypokalemia / hyperkalemiathrombosisintracranial bleeding, infarction sepsis and other infections, e.g., mucormycosis aspiration pneumoniapulmonary oedema, ARDS

Hyperglycemic hyperosmolar state (HHS)The criteria for HHS includeplasma glucose concentration >33.3 mmol/L (>600 mg/dL)arterial pH >7.30serum bicarbonate >15 mmol/Lsmall ketonuria, absent to mild ketonemiaeffective serum osmolality >320 mOsm/kgstupor or comaKITABCHI AE, NYENWE EA. Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am 2006 Dec: 35(4): 72551.HHS, also referred to as hyperosmolar nonketotic coma, may occur in young patients withT2DM, but rarely in T1DMsubjects.

Diabetic KetoacidosisPathophysiology

PathophysiologyInsulin

GlucagonEpinephrineCortisolGrowth Hormone

Pathophysiology Glucose Utilization LipolysisInsulinGlucagonEpinephrineCortisolGrowth Hormone

DKA - EarlyRelative Insulin Deficiency Decreased Utilization: Post-prandialandStress-Induced Hyperglycemia Peripheral glucose uptake

Elevates blood glucose Glycogenolysis & gluconeogenesis restrained

PathophysiologyGluconeogenesisGlycogenolysisLipolysisKetogenesisInsulinGlucagonEpinephrineCortisolGrowth Hormone

DKA PathophysiologyThe combination of low serum insulin and high counterregulatory hormone concentrations results in an accelerated catabolic state with: - glucose production by the liver and kidney (via glycogenolysis and gluconeogenesis), - peripheral glucose utilization resulting in hyperglycemia and hyperosmolality, - lipolysis and ketogenesis, causing ketonemia and metabolic acidosis. Hyperglycemia, that exceeds the renal threshold, and hyperketonemia cause:- osmotic diuresis, - dehydration, - loss of electrolytes, which often is aggravated by vomiting.

DKA PathophysiologyThese changes stimulate further stress hormone production, which induces:- more severe insulin resistance- worsening hyperglycemia and hyperketonemia.

If this cycle is not interrupted with exogenous insulin, uid and electrolyte therapy, fatal dehydration and metabolic acidosis may be aggravated by lactic acidosis from poor tissue perfusion or sepsis.

Diabetic ketoacidosis in children and adolescents with diabetes. Pediatric Diabetes 2009:10 (12): 118133

DKA - LateInsulin Deficiency GlycogenolysisGluconeogenesisHepatic glucose outputPeripheral gluc. uptakeElevates blood glucoseLipolysisRelease FFA -> liverVLDL & ketones Ketonemia and HTG Acidosis & DiuresisIncreased Production &Decreased Utilization Fasting hyperglycemia + acidosis

DKA Pathophysiology

Losses of uids and electrolytes in diabetic ketoacidosis and maintenance requirements in normal childrenThree methods for determining maintenance water requirements in children are used: - the Holliday-Segar formula (shown in Table)- a simplied Holliday-Segar formula: 20 kg: 60 + 1 mL/kg/h for each kg >20- a formula based on body surface area for children more than 10 kg (1,500 mL/m2/24 hr)*Maintenance electrolyte requirements in children are per 100 mL of maintenance IV uidFRIEDMAN AL. Pediatric hydration therapy: historical review and a new approach. Kidney Int 2005:67(1):3808.HENDRICKS K, DUGGAN C, editors. Manual of Pediatric Nutrition. 4th ed. Hamilton, Ontario: BC Decker; 2005.*

DKA Pathophysiology

DKA - Diagnosis

What are the presenting complaints?Gastro-enteritis Vomiting - but no diarrhea Dehydration - but excessive urine output !

Respiratory distressBut no lung findings

Simptoms and signs of DKADKA is characterized by severe depletion of water and electrolytes from intra- and extracellular uid compartments.Despite their dehydration, patients continue to maintain normal BP and have urine output until extreme volume depletion and shock occurs leading to a critical decrease in renal blood ow and glomerular ltration.

At presentation, the magnitude of specic decits varies:upon the duration and severity of illness, the extent to which the patient was able to maintain intake of uid and electrolytes,the content of food and uids consumed before coming to medical attention. Consumption of uids with a high-carbohydrate content exacerbate the hyperglycemia.MCDONNELL CM, PEDREIRA CC, VADAMALAYAN B, et al. Diabetic ketoacidosis, hyperosmolarity and hypernatremia: are highcarbohydrate drinks worsening initial presentation? Pediatr Diabetes 2005:6(2): 904.

History

When DKA occurs as a first presentation of DMsymptoms are likely to develop over several days, with progressive dehydration and ketosisin a small child wearing diapers and with naturally high fluid intake, polyuria and polydipsia are easily missed when DM is developing, the stress and symptoms of another illness may precipitate DKA, as well as mask the underlying problem.

DKA can develop very rapidly in a patient with established DM, particularly when insulin therapy has been forgotten, deliberately omitted, or disrupted, as with children on continuous subcutaneous insulin infusions or using the newer analogue insulins. Under these circumstances, diabetic ketoacidosis may present with relatively normal blood glucose levels (ie, 250 mg/dL, 15 mmol/L) or less.

Hyperglycemia

Polyuria - Increased volume and frequency of urinationPolydipsia - Thirst is often extreme, with children waking at night to consume large quantities of any available drinkNocturia and secondary enuresis in a previously continent childWeight loss - May be dramatic due to breakdown of protein and fat storesMuscle pains and cramp

Acidosis and dehydration

Abdominal pain that may be severe enough to present as a surgical emergency; for children with a failure of continuous subcutaneous insulin infusion, this may be the first presenting sign, along with vomitingShortness of breath that may be mistaken for primary respiratory distressConfusion and coma in the absence of recognized head injury

Signs of DKAVomiting Increased urinationAbdominal painFruity odor to breathDry mouth and tongueDrowsinessDeep breathingComaDeath

Physical ExamPerfusionVital Signs - including weightHydrationMental StatusEvidence for insulin resistance

Physical ExamWeigh the patient - should be used for calculations and not the weight from a previous ofce visitr hospital record.

Assess clinical severity of dehydration. Clinical assessment of dehydration is imprecise, inaccurate. It should be based on a combination of physical signs. The three most useful individual signs for assessing dehydration in young children and predicting at least 5% dehydration and acidosis are:- prolonged capillary rell time (normal capillary rell is

Physical ExamOther useful signs in assessing degree of dehydration include:dry mucus membranes, sunken eyes, absent tears, weak pulses, cool extremities. More signs of dehydration tend to be associated with more severe dehydration (10%) is suggested by:the presence of weak or impalpable peripheral pulseshypotensionoliguria.

Assess level of consciousness (Glasgow coma scale).

Dehydration

Clinical Assessment of Dehydration

Other symptoms BP - Usually normal until terminal stages of illnessTachycardia - May be presentCapillary refill - Initially maintained, but a combination of increasing acidosis and dehydration cause poor tissue perfusionKussmaul breathing or deep sighing respiration - A mark of acidosis; these symptoms may be mistaken for status asthmaticus, pneumonia, and even hysterical hyperventilationKetone odor - Patient may have a smell of ketones on the breath, although many people cannot detect this smellImpaired consciousness - Occurs in approx 20% of patientsComa - May be present in 10% of patientsAbdominal tenderness - May occur; tenderness is usually nonspecific or epigastric in location; bowel sounds may be reduced or absent in severe cases

Consciousness

Check the patients consciousnesslevel hourly for up to 12 hours, especially in a young child with a first presentation of diabetes. The Glasgow coma scale is recommended for this purpose.The normal maximum score on the Glasgow coma scale is 15. A score of 12 or less implies significant impairment of consciousness. A falling score may signify the development of cerebral edema. Glasgow Coma Scale, modified for age of verbal response

Initial Laboratory EvaluationpHBlood gasesBUN, urea and creatinineSerum osmolarityPhosphateCalcium, magnesiumAnion gapFull blood countAmylase Glucose* Ketones* Sodium Potassium Chloride HCO3*Always perform in an ill child

CalculationsSerum Osmolality:2[Na+K] + (glucose/18) + BUN/2.8 (ureea/6)

Serum Na:Corrected Na = measured Na + (1.6)(glucose - 100)/100Anion Gap:[Na] ([Cl]+[HCO3])Normally 12+/-2 mmol/L

Blood glucoseCapillary blood samples analyzed on any modern blood glucose meter are acceptable for monitoring, but measure at least 1 whole blood glucose at presentation.Check blood glucose at least hourly during the initial stages of treatment.

Blood gasesTraditionally, arterial blood samples are used.Mild DKA - pH level of less than 7.3, bicarbonate level of less than 15 mmol/LModerate DKA - pH level of less than 7.2, bicarbonate level of less than 10 mmol/LSevere DKA - pH level of less than 7.1, bicarbonate level of less than 5 mmol/L

SodiumMeasured Na+ values are likely to be low because of the dilutional effect of hyperglycemia. True Na + levels can be calculated by adding 1.6 mEq/L sodium for every 100 mg/dL glucose.Na+ levels should rise with treatment. Failure of Na + levels to rise is associated with an increased risk of cerebral edema.

Blood urea and creatinineSome creatinine assays can be affected by the presence of ketones, thus giving falsely elevated results. Under these circumstances, blood urea may give a better measure of dehydration.

Capillary blood ketoneThis can be measured using a handheld meter; the level is always elevated at presentation of diabetic ketoacidosis (>2 mmol/L).

InsulinThis test is especially indicated in children with recurrent DKA, as an absence of measurable insulin can confirm omission. Caution is needed because not all assays measure the newer analogue insulins; insulin antibody levels can also affect the result.

Other lab studies Bicarbonate - This reflects the degree of acidosisHigh HbA1c - High results are expected in a patient with newly dg diabetes and in patients with an established dg who have poor compliance with treatmentUrine - Check all urine for glucose and ketones for at least 24 hours, particularly if capillary blood ketones are not availableFull blood count - WBC count is usually elevated, even in the absence of infectionCulture - Perform blood culture and other cultures as clinically indicated (eg, urine, throat swab)Amylase - levels often are elevated in DKA and can be misleading in the presence of abdominal painSerum osmolarity - This is usually elevatedPhosphate, Ca, and Mg - These levels are invariably reducedLipids - High TG levels are sometimes present; this causes an artificial lowering of other blood values, such as those for glucose, Na, and K

Electrocardiography ECG is a useful adjunct to monitor potassium status.

Apparent prolongation of QT intervalST segment depressionFlat or diphasic T wavesProminent U wavesProlongation of PR intervalSinoatrial block

Broadening of the QRSPeaked T wavesProlonged PR intervalDisappearance of P waveDiphasic QRS complexAsystole

Imaging studies

Perform head CT scanning if coma is present or develops. Concurrently, initiate appropriate measures to manage cerebral edema. Perform chest radiography if clinically indicated.

DKADifferential Diagnoses Respiratory acidosisIn considering a dg of DKA, the following indications should be taken into account: - uremia, - acute hypoglycemia coma, - catheter-related venous thrombosis (femoral central venous catheters in children).

Diabetic KetoacidosisDifferential Diagnoses Alcoholic KetoacidosisAppendicitis, AcuteHyperosmolar ComaHypophosphatemiaHypothermiaLactic AcidosisMetabolic AcidosisMyocardial InfarctionPancreatitis, AcuteHypoglycemia ComaShock, SepticToxicity, Salicylate

Respiratory Acidosis Asthma Hypokalemia Pneumonia Respiratory distress syndrome Acute abdomen Gastroenteritis Urinary Tract Infection

DKADifferential Diagnoses

Causes of hyperglycaemic emergencies and their differentiation

Cerebral EdemaMajor cause of death in childhood DKA 20% with cerebral edema die20% with mild to severe neurologic outcomes

At risk:Initial pH < 7.1Baseline mental status abnormalNewly diagnosed, < 5 years oldRapid rehydration (> 50cc/ kg in first 4 hrs)Hypernatremia/ persistent hyponatremia

Clinical Factors Associated with Cerebral EdemaProlonged IllnessSevere acidosis - low PA CO2Severe dehydrationBicarbonate therapyPersistent hyponatremiaExcessive fluid admistration

Etiology of CEVasogenic - excessive accumulation of water and solutes in the interstitial space, due to dysfunction of the blood-brain barrier Cytotoxic - excessive accumulation of water and solutes in the intracellular space, due to dysfunction of cell-volume regulatory mechanisms Both forms may co-exist

Diagnostic criteria Abnormal motor or verbal response to pain

Decorticate or decerebrate posture

Cranial nerve palsy (especially III, IV, and VI)

Abnormal neurogenic respiratory pattern (e.g.,grunting, tachypnea, Cheyne-Stokes respiration,apneusis)Pediatric Diabetes 2009: 10 (Suppl. 12): 118133

Major criteria Altered mentation / uctuating level of consciousness Sustained heart rate deceleration (decrease more than 20 beats per minute) not attributable to improved intravascular volume or sleep state

Age-inappropriate incontinencePediatric Diabetes 2009: 10 (Suppl. 12): 118133

Minor criteria Vomiting Headache Lethargy or not easily arousable Diastolic blood pressure >90 mm Hg Age

Practice Essentials

DKA, in pediatric and adult cases, is a metabolic derangement caused by the absolute or relative deficiency of the anabolic hormone insulin. Together with the major complication of cerebral edema, it is the most important cause of mortality and severe morbidity in children with diabetes.

Signs and symptoms

Symptoms of acidosis and dehydration include the following:

abdominal pain - May be severe enough to present as a surgical emergency

shortness of breath - May be mistaken for primary respiratory distress

confusion and coma in the absence of recognized head injury

Symptoms of hyperglycemia, a consequence of insulin deficiency, include the following:

Polyuria - Increased volume and frequency of urination

Polydipsia - Thirst is often extreme

Nocturia and secondary enuresis in a previously continent child

Weight loss - May be dramatic due to breakdown of protein and fat stores

Muscle pains and cramps

Patients may also have the following signs and symptoms:

VomitingDehydrationSigns of intercurrent infectionWeakness and nonspecific malaise that may precede other symptoms of hyperglycemiaTachycardiaReduced capillary refillKussmaul breathing or deep sighing respirationKetone odor Impaired consciousness - Occurs in approx 20% of patientsComa - May be present in 10% of patientsAbdominal tenderness - Usually nonspecific or epigastric in location

Cerebral edema Most cases of cerebral edema occur 4-12 hours after initiation of treatment.

Diagnostic criteria of cerebral edema include the followingAbnormal motor or verbal response to painDecorticate or decerebrate postureCranial nerve palsy - Especially III, IV, and VIAbnormal neurogenic breathing pattern (eg, Cheyne-Stokes), apneusis

Major criteria include the followingAltered mentation, fluctuating level of consciousnessSustained and inappropriate bradycardiaAge-inappropriate incontinence

Minor criteria include the followingVomitingHeadacheAbnormal drowsinessDiastolic hypertension (>90 mm Hg)

Laboratory studies

Blood glucoseBlood gasesPotassiumSodiumBlood urea and creatinineBicarbonate - Usually available from blood gas analysisCapillary blood ketoneHigh glycosylated hemoglobin (HbA1c)Full blood countUrineInsulinCultureAmylaseSerum osmolarityPhosphate, calcium, and magnesiumLipids

Management

Replacement of the following is essential in the treatment:

Fluid - the best outcomes have been achieved by using isotonic NaCl sol or half-strength NaCl sol for first resuscitation and replacement

Insulin - continuous, low-dose, IV insulin infusion is generally considered the safest and most effective insulin delivery method

Potassium - after initial resuscitation and if serum/plasma levels are below 5 mEq/L or a good renal output has been maintained, add potassium to all replacement fluids

Bicarbonate - used only in select cases; the only justification for using IV bicarbonate is acidosis sufficiently severe to compromise cardiac contractility

Cerebral edema If cerebral edema is suspected and hypoglycemia is excluded, prompt treatment with an osmotic diuretic is indicated, followed by a CT scan and referral to a neurosurgeon. Intubation, hyperventilation, and intracranial pressure monitoring reportedly improve outcomes.

Dicton, zicalaTemperate, inabusiteIn ciuda