ELLIOT MELENDEZ, MD INTERIM CHAIR, DIVISION OF PEDIATRIC CRITICAL CARE JOHNS HOPKINS ALL CHILDREN’S HOSPITAL No conflicts of interest Or financial disclosures Goals & Objectives
Understand the action of insulin on the metabolism of carbohydrates, protein, and fat Understand the pathophysiology of DKA Understand the management approach to the patient with DKA Appreciate the complications that can occur during treatment of DKA Introduction
Diabetes is a syndrome of disturbed energy homeostasis caused by a deficiency of insulin or of its action resulting in abnormal metabolism of carbohydrate, protein, and fat
Diabetes is the most common endocrine-metabolic disorder of childhood and adolescence Introduction
Individuals affected by insulin-dependent diabetes confront serious burdens that include an absolute daily requirement for exogenous insulin, the need to monitor their own metabolic control, and the need to pay constant attention to dietary intake Introduction
Morbidity and mortality stem from metabolic derangements and from long-term complications that affect small and large vessels and result in retinopathy, nephropathy, neuropathy, ischemic heart disease, and arterial obstruction with gangrene of the extremities Introduction
Individuals affected by insulin-dependent diabetes confront serious burdens that include an absolute daily requirement for exogenous insulin, the need to monitor their own metabolic control, and the need to pay constant attention to dietary intake
The most concerning acute complication is cerebral edema in which the risk is present in all patients with DKA Type I Diabetes Mellitus: Epidemiology
The annual incidence in France is 19.1/100,000 in 2015 ¡ This increased from 15.4 in 2010 ¡ The US incidence is about 12 - 15 new cases per 100,000 Type I Diabetes Mellitus: Epidemiology
Peaks of presentation occur at 5 - 7 years of age and at adolescence
Newly recognized cases appear with greater frequency in the autumn and winter Type I Diabetes Mellitus: Etiology and Pathogenesis
Basic cause of clinical findings is sharply diminished secretion of insulin
The mechanism that leads to failure of pancreatic b-cell function is likely autoimmune destruction of pancreatic islets with 80-90% newly diagnosed having islet cell antibodies Pathophysiology: “Am I hypoglycemic?”
Insulin drives glucose intracellularly ¡ The clinical presentation of patients with Type I Diabetes and/or DKA is solely due to absence of insulin ¡ In it’s absence, the cells “think” there is hypoglycemia ¡ Thus, there is unopposed upregulation of hormones which aim are to “increase” serum glucose ÷ Glucagon ÷ Cortisol ÷ Growth hormone ÷ Epinephrine This biochemical response is responsible for all the metabolic derangements that are seen in DKA. Type I Diabetes Mellitus: Pathophysiology
With insulin deficiency, excessive glucose production and impairment of utilization result in hyperglycemia, with glucosuria developing when the renal threshold of ~ 180 mg/dL is exceeded
The resultant osmotic diuresis produces polyuria, urinary losses of electrolytes, dehydration, and compensatory polydipsia DKA Pathophysiology
Hyperosmolality occurs as a result of progressive hyperglycemia
Serum osmolality: ¡ [Na+] x 2 + [glucose] + [BUN] 18 2.8
Hyperosmolality can lead to cerebral edema DKA: Definition
qDKA Definition: q Hyperglycemia (>300 mg/dl) q Ketonemia/ketonuria q Metabolic acidosis (pH<7.30, bicarbonate<15mmol/L) DKA: Epidemiology q30-45% Type I initially present in DKA qHighest rates in teenagers and very young qDKA causes 50% of all deaths in diabetics below 24 years of age Triggers for DKA Onset in Type I DM
Infection Trauma, surgery
Missed insulin (and non-compliant adolescents) Psychological stress Recurrent DKA: eating disorders, sexual/physical abuse, depression DKA Pathophysiology
In the absence of intracellular glucose, counter- regulatory hormones attempt to create energy through breakdown of fat, protein, and glycogen
Glucagon is the major hormone involved ¡ Hyperglycemia results ¡ Secondarily, fat is broken down and ketones are created ÷ This fat breakdown is responsible for the weight loss Clinical Features
Polyuria, polydipsia, polyphagia
Hyperglycemia above 180 (renal threshold) leads to glycosuria and subsequent osmotic diuresis Fluid and Electrolyte Losses
Osmotic Diuresis Hyperventilation GI losses – vomiting from acidosis Shift of water between compartments and hyponatremia qDepletion of total body potassium qDepletion of total body phosphorus Clinical Features
With progressive dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen utilization, consciousness can become impaired, and the patient ultimately will become comatosed if unrecognized early
This occurs due to cerebral edema Treatment of DKA
Make the glucose go intracellularly ¡ This will turn off the counter-regulatory hormones
This can ONLY be done by giving insulin Important Principals of Treatment
1. Fluid resuscitation and gradual rehydration – there is no rush
2. Initiation of insulin therapy to correct fat breakdown in order to stop acidosis
3. Avoid too rapid correction of hyperglycemia – treat the acidosis NOT the glucose
4. Treat any underlying trigger Management: Fluids
Rapid IV bolus not needed unless cardiovascularly unstable – for example, signs of shock ¡ Start with NS 10cc/kg given over 1 hour ¡ Give further boluses if signs of shock ¡ Rarely is more than 20 mL/kg fluid required to restore hemodynamics
Replace fluid deficits gradually over next 48 hrs ¡ Start maintenance fluids at 1.5x maintenance ¡ This alone will often slightly lower the blood glucose Management-Fluids
Initial maintenance IV fluids should be 0.9 NS ¡ Hydration alone will often slightly lower the blood glucose
Add 5% Dextrose to NS if blood glucose is ~ 300 mg/dL
Add 10% Dextrose is added when blood glucose is ~ 200 mg/dL. Management-Insulin
Insulin is needed to turn off ketone production ¡ Start continuous IV infusion of insulin (0.1 units/kg/hr) ¡ Bolus of insulin IS NOT needed nor recommended ¡ Goal is to allow a slow decrease serum glucose of no more rapid than 100 mg/dL/hr) ÷ Check glucose levels every hour ¡ Check electrolytes and pH or tCO2/HCO3 every two hours Management-Insulin
Insulin in DKA is used to treat acidosis, not hyperglycemia
Insulin should never be stopped or decreased if ongoing acidosis persists ¡ Add dextrose if glucose decreasing Management: Electrolytes
Sodium ¡ usually low due to hyperglycemia (pseudohyponatremia) and increases as glucose corrects ¡ Calculating corrected sodium
Corrected Na = Serum Na + [1.6 x (measured glucose -100)/100] ¡ If corrects in hyponatremic range, this suggests SIADH or excessive free water, and increases risk of cerebral edema ¡ Corrected Na in hypernatremic range indicates severe dehydration Example of Na Correction Calculation
Corrected Na = Serum Na + [0.16 (measured glucose -100)]
Glucose 765, Na 126 ¡ Corrected Na = 126 + [1.6 x (765-100)/100] ¡ Corrected Na = 136.6 à appropriate
Glucose 822, Na 120 ¡ Corrected Na = 120 + [1.6 x (822-100)/100] ¡ Corrected Na = 131.6 à hyponatremia ÷ Likely SIADH and risk of cerebral edema Management-Electrolytes
Potassium ¡ Initially appears adequate, but truly total body K deplete ¡ As acidosis corrects and due to insulin, potassium moves intracellularly ¡ Once pt urinates and K<4.5, add K to IVF ÷ Usually add 40meq/L in form of Kphos and KCl
H+ improving
Potassium Management-Electrolytes
Phosphate ¡ Body stores of phosphate are also depleted ¡ As acidosis corrects, phosphate moves intracellularly
H+ improving
Phosphate Management-Electrolytes
NaHCO3 should ALMOST NEVER be administered
Bicarbonate administration has been associated with increased incidence of cerebral edema HCO3 and Cerebral Edema
Bicarbonate administration leads to increased cerebral acidosis - + ¡ HCO3 combines with H and dissociates to CO2 and H2O ¡ Whereas bicarbonate passes the blood-brain barrier slowly, CO2 diffuses freely, converting back to H+ ¡ Exacerbating cerebral acidosis and cerebral depression
H+ + HCO3- à CO2
H+ + HCO3- ß CO2 CO2 Management-Electrolytes
Bicarbonate-studies show no beneficial value in pts with pH >7.1 and even marginal improvement in pts with pH 6.9-7.14; some studies showed bicarb actually counterproductive
Indications for bicarbonate administration include severe acidosis (pH < 7.0) IF associated with cardiac compromise/arrest Complications during Treatment
Hypoglycemia Electrolyte abnormalities Cerebral edema Cerebral Edema
Cerebral edema is the major life-threatening complication seen during treatment ¡ Clinically apparent cerebral edema occurs in ~1% of episodes of DKA ¡ Mortality is 40 - 90% ¡ Cerebral edema is responsible for 50 - 60% of diabetes deaths in children Cerebral Edema
Usually develops several hours after the institution of therapy
Manifestations: ¡ Headache ¡ Alteration in level of consciousness ¡ Diminished responsiveness to painful stimuli ¡ Bradycardia ¡ Unequal, fixed, or dilated pupils Cerebral Edema Associations
Excessive use of fluids, large doses of insulin, and especially the use of bicarbonate
Children who present with elevated BUN, PaCO2 < 15, or who demonstrate a lack of an increase in serum Na+ during therapy
Therapy of cerebral edema may include treatment with mannitol, hypertonic saline and hyperventilation Cerebral Edema - Treatment
If clinical concern, treat 1st rather than getting CT
3% NS – 4-6 mL/kg over 30 minutes
Or
Mannitol 0.5 -1 gram/kg Summary
DKA is characterized by: ¡ Hyperglycemia ¡ Acidosis due to ketones ¡ Dehydration ¡ Associated with life threatening cerebral edema Therapy is to give insulin to reverse acidosis Monitor electrolytes and labs to prevent complications of treatment Monitor neurologic exam to monitor for signs of cerebral edema