Diabetic Ketoacidosis in Children Jim Tsung, MD Bellevue Hospital Center

DKA Is the most common cause of hospitalization of children with diabetes Is the most common cause of death in children with diabetes Is fatal in <1% (from 1-2% of children in the 1970’s) Most DKA deaths are attributable to cerebral edema (62-87%), which occurs in 0.4-1% of kids with DKA Ciordano B, Rosenbloom AL, Heller DR, et al: Regional services for children and youth with diabetes. Pediatrics. 1977;60:492498. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990;13:22-33. Edge J, Ford-Adams M, Dunger D. Causes of death in children with insulin-dependent diabetes 1990-96. Arch Dis Child. 1999;81:318-323.

Background Though it varies depending on the population, 20-40% of newly diagnosed T1DM patients are in DKA. Therefore, a major goal of outpatient diabetes management is to prevent DKA with a high index of suspicion with early DKA symptoms in new or established T1DM patients with close supervision of established patients Pinkney J et al. Presentation and progress of childhood diabetes mellitus: a prospective population-based study. Diabetologia. 1994;37:70-74. G, Fishbein H, Ellis E. The epidemiology of diabetic acidosis: a population-based study. Am J Epidemiol. 1983;117:551

Etiology of DKA--New Onset DM Always due to insulin deficiency--absolute or relative Many previously undiagnosed patients have been seen in pediatric offices or ERs where a detailed history and lab studies could make the diagnosis before DKA ensues A simple urine dip could be life-saving! High index of suspicion is especially important in infants and young children

Etiology of DKA--Established Patients ***Failure to take insulin, especially in adolescents--most common cause of recurrent DKA Acute stress--trauma, febrile illness, psychological turmoil with elevated counterregulatory hormones (glucagon, epi, GH, cortisol)

Etiology of DKA--Established Patients (continued) Poor sick day management not giving insulin because the child is not eating failing to increase insulin for the illness, as dictated by fingerstick blood sugars failure to monitor ketones

Definition Definitions vary, but in general: Hyperglycemia > 200 mg/dl Ketonemia/ketonuria--large serum or urine ketones Acidosis with venous pH <7.3 Serum bicarb <18 Mild 16-22 Moderate 10-15 Severe <10 *Sometimes DKA can occur with normoglycemia when there is continued insulin therapy, vomiting, and/or reduced intake of carbohydrates

Glucagon>Catechols >Cortisol>GH Acetyl-CoA Pyruvate Free Fatty Acids Glycerol Β-hydroxybutyrate Acetoacetate Acetone

Presentation Hyperglycemia insulin deficiency causes decrease glucose uptake with tissue starvation, glycogenolysis, and gluconeogenesis from protein and lipid breakdown. Thirst/Dehydration 20 Osmotic Diuresis/Vomiting dehydration is usually hyperosmolar, so may be underestimated by clinical exam Acidosis from breakdown of lipids to ketone bodies to ketoacids Fruity Odor from Acetone (ketone body, not a ketoacid) from tissue hypoperfusion/dehydration

Presentation (continued) Kussmaul (rapid deep) respiration compensatory response to the metabolic acidosis, contributing to dehydration Coma- due to hyperosmolarity, not acidosis Calculated osm >320 is associated with coma Hyperosmolarity- largely due to glucose, calculated as: 2(Na) + Glucose/18 + BUN/2.8 Other: Na, K, BUN, Cr, WBC

Management--General Resuscitation (ABC’s, O2) if in shock/poor perfusion with NS or albumin 10-20 cc/kg over 10-30 min, may repeat as needed, NGT if vomiting and impaired LOC. The cause of cerebral edema remains unclear. Too rapid reduction of intravascular osmolality thought to aggravate the process. Recommended to rehydrate children with DKA more slowly than in other causes of dehydration. However, newer evidence seems to question this. Start, maintain, and utilize your flowsheet!

Management--Fluids Initial fluid bolus with NS will depend on assessment of severity of dehydration most kids in DKA are  10% dehydrated, unless there is hypotension, poor peripheral perfusion, etc. e.g If 10% dehydrated, should get 10 cc/kg NS over 1 hour

Fluids IVF needed = Maintenance + Deficit + Ongoing Losses Caution: Fluids should not exceed 4 L/m2/day, as this has been associated with cerebral edema and poor outcome (?)

Fluids Maintenance-as per usual, amount based on weight (4/2/1 rule) Deficit replacement usually over 48 hours 5% dehydration = 0.05 L/kg 10% dehydration = 0.1 L/kg Consider deficit replacement over 72 hours if marked hyperosmolality (Gluc >1000 or serum osm >320) or if corrected Na is >150 mEq/L e.g. 30 kg kid with 10% dehydration has a fluid deficit of (30)(0.1)=3 Liters, 300 cc of which have already been replaced with the 10 cc/kg NS bolus, leaving a 2700 cc fluid deficit

Fluids Ongoing losses-usually do not need to replaced If very polyuric or vomiting excessively, can replace urine/vomitus output 0.5 cc/cc Reassessment of I/O’s at least every 4 hrs for first 24 hrs

Sodium Maintenance = 3-5 mEq/kg/day Deficit = 6 mEq/kg Serum Na may be high, normal, or low depending on fluid status Many find calculation cumbersome, so can usually use 1/2 NS as replacement fluid and NS as deficit fluid (running piggyback)

Sodium Use NS if the corrected sodium is <140 and/or if serum osm >310 *To correct Na: Add 1.6 mEq/L to the measured Na for every 100 mg/dl of glucose over 100 mg/dl Monitor electrolytes every 2 hours at first, and then every 4 hours when trend is normalizing

Potassium DKA is associated with total body K depletion, while correction of acidosis causes hypokalemia due to an intracellular K shift, so add K sooner rather than later Add K once the patient has documented urine output and no peaked T’s on ECG or K  6 Hypokalemia on presentation is an ominous sign; beware of arrhythmias

Potassium Usually add 20 mEq KCl and 20 mEq of KPhos per liter to IVFs Some centers prefer Kacetate instead of Kphos for theoretical improvement of acidosis If even mildly hypokalemic, add 40 mEq KCl and 20 mEq of Kphos per liter. Consider K run(s) if hypokalemic. If serum K <3, hold insulin until K has been added to IVFs

Phosphate Body Phosphate is depleted in DKA Need for replacement is controversial Phosphate should be given if there has been prolonged illness or if a prolonged period without food is anticipate Can give half of K requirement as KPhos If Phos <3, give half of K requirement as Kphos If hypocalcemia develops, stop Phos and adjust total K as KCl

Bicarbonate: Don’t Do It! May be given if pH <6.9 - 7.0 considering that severe acidosis can be life-threatening, but… Sudden correction of serum pH can paradoxically lower CSF pH, it should be given by slow IV infusion over several hours Endogenous production of HCO3 occurs as ketones are metabolized The usual calculations for correction of acidosis greatly overestimate bicarbonate needed in DKA May increase the risk of hypokalemia Bicarb use has been associated with increased risk of cerebral edema* *Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344:264-269.

Insulin Goal is to decrease blood sugar by 50-100 mg/dl/hr, after initial drop from rehydration, avoiding rapid drops Usual starting dose is 0.1 u/kg/hr (100 units in 500 cc NS, 0.1 u/kg/hr=0.5ml/kg/hr) Consider starting at 0.05 u/kg/hr if new diabetic, age < 2 yrs, marked hyperglycemia (>1200), or recent large SQ insulin dose in known diabetic

Insulin (continued) If poor response on 0.1 u/kg/hr (e.g. insulin resistance, ongoing infection), may need to increase drip to 0.15-0.2 u/kg/hr, but first make sure IV is infusing properly. Continue insulin infusion until ketonemia is cleared/clearing. Adjust rate of drip to maintain blood glucose 120-200. Do not decrease drip below 0.03 u/kg/hr. If pt is becoming hypoglycemic at this rate, increase dextrose concentration.

Glucose Add D5W to IVF when glucose drops below 200-250 mg/dl. If necessary, may further increase dextrose concentration to D7.5 - D10. Consider “2 Bag System” *: One bag NS/0.45NS & 2nd bag D10 NS/0.45NS given simultaneously to vary dextrose concentration while maintaining constant fluid and electrolyte adminstration. More cost-effective than single bag system Monitor glucose hourly either by fingerstick (if within range of the meter) or by grey top glucose. *Grimberg A, Cerri R, Satin-Smith M, et al. The "two bag system" for variable intravenous dextrose and fluid administration: benefits in diabetic ketoacidosis management. J Pediatr. 1999;134:376-3

Other If patient is not improving, reevaluate IVF calculation, insulin delivery system and dose, change insulin bag, consider sepsis and antibiotics.

Initial Labs Fingerstick blood sugar Grey top glucose Urine and/or serum ketones VBG Chem 20 HgA1c Insulin level, C-peptide Antibodies: anti-insulin, anti-islet cell, and anti-GAD (glutamic acid decarboxylase) TFT’s

Risks Factors for Cerebral Edema New Onset DKA (OR-2.9) and Younger Higher blood urea nitrogen concentrations Presenting with greater hypocapnia (↓PCO2) A lesser rise in the measured serum sodium concentration during treatment (as the serum glucose concentration falls) Bicarbonate administration No association found for rate of infusion, volume, rate of change of glucose or sodium concentrations Edge JA, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child. 2001;85:16-22. Glaser N et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med. 2001;344:264-269 Mahoney C, Vlcek B, DelAguila M. Risk factors for developing brain herniation during diabetic ketoacidosis. Pediatr Neurol. 1999;21:721-727.

Signs & Symptoms of Cerebral Edema during DKA Treatment Most commonly occurs in the first 24 hrs (5-15 hrs) after starting rehydration therapy when the child may seem to be improving Does occur prior to treatment in 5% of cerebral edema Headache-most often sudden, severe Altered Mental Status--agitation, combativeness, disorientation, increased drowsiness, incontinence Focal Neurologic Signs-cranial nerve palsies, opthalmoplegia, posturing Papilledema, seizures, resp arrest are late signs with a very poor prognosis

Signs & Symptoms of Cerebral Edema during DKA Treatment pupillary changes (asymmetry, sluggish to fixed) change in VS: hypertension or hypotension, tachycardia, bradycardia, or arrhythmia, apnea, gasping, decr 02 sat falling corrected Na must exclude hypoglycemia as a cause of the symptoms before instituting therapy

Cerebral Edema Treatment Mannitol should be immediately available during DKA treatment Exclude hypoglycemia Mannitol 1 g/kg IV over 20 minutes Cut IVF rate in half until situation improves NGT in vomiting child with impaired LOC Elevate head Consider intubation/hyperventilation But, has been associated with poorer outcome* Consider continuous mannitol infusion Head imaging (CT/Eyeball US) after stabilized as hemorrhage, thrombus, or infarct may also occur *Marcin J, Glaser N, Barnett P, et al. Clinical and therapeutic factors associated with adverse outcomes in children with DKA-related cerebral edema. J Pediatr. 2003;141:793-797

Other Complications to Watch For: Pulmonary Edema CNS hemorrhage or thrombosis Other large vessel thrombosis (femoral catheter) Pancreatitis (salivary amylase elevated; check lipase) Renal Failure Intestinal necrosis Rhinocerebral Mucormycosis

Transport Issues On call for Established T1 Diabetic may consider Sliding Scale: Calculate the present total daily dose (TDD) of insulin (fast plus slow acting). Blood glucose 240-400mg% and urine ketones negative - give 10% TDD Blood glucose 240-400mg% and urine ketones positive - give 20% TDD Blood glucose >400mg% - give 20% TDD Avoid use of sedatives or anti-emetics during transport to avoid masking symptoms associated with cerebral edema Make sure the transport glucometer is working!

Primum Non Nocere Do not give bolus insulin Do not give boluses of sodium bicarbonate Do not start insulin until a fluid bolus has been given and maintenance fluids begun. This may wait until admission to the hospital if this occurs within 2 hours of admission to the ED. Do not give more than 20cc/kg as a single fluid bolus. (?) Do not give more than a total of 30cc/kg of bolus fluids unless the patient is in shock. (?) Do not give more than 3750cc of maintenance fluids in 24 hours (2500cc/m2/24hrs). (?)