Diabetes Mellitus Pediatric Critical Care Medicine Emory University Children’s Healthcare of Atlanta.

Diabetes Mellitus

Pediatric Critical Care MedicineEmory University

Children’s Healthcare of Atlanta

2

Goals & Objectives• Understand the action of insulin on the

metabolism of carbohydrates, protein & fat• Understand the pathophysiology of IDDM & DKA• Understand the management approach to the

patient with DKA• Appreciate the complications that occur during

treatment

3

Classification• Type I (insulin-dependent diabetes mellitus, IDDM)

– Severe lacking of insulin, dependent on exogenous insulin– DKA– Onset in childhood– ?genetic disposition & is likely auto-immune-mediated

• Type II (non-insulin-dependent diabetes mellitus, NIDDM)– Not insulin dependent, no ketosis– Older patient (>40), high incidence of obesity– Insulin resistant– No genetic disposition– Increase incidence due to prevalence of childhood obesity

4

IDDM: Epidemiology• 1.9/1000 among school-age children in the US;

12-15 new cases/100,00• Equal male to female • African-Americans: occurrence is 20-30%

compared to Caucasian-Americans• Peaks age 5-7 yrs and adolescence• Newly recognized cases: more in autumn &

winter• Increase incidence in children with congenital

rubella syndrome

5

Type I DM• 15-70% of children with Type I DM present in DKA

at disease onset• 1/350 of type I DM will experience DKA by age 18

yo• Risk of DKA increased by:

– Very young children– Lower socioeconomic background– No family history of Type I DM

• DKA:– Most frequent cause of death in Type I DM– One of the most common reasons for admission to PICU

6

IDDM: Etiology & Pathophysiology

• Diminished insulin secretion by destruction of pancreatic islets cells via autoimmune process

• 80-90% of newly diagnosed cases have anti-islet cell antibodies

• More prevalent in persons with Addison’s disease, Hashimoto’s thyroiditis, pernicious anemia

7

Type I DM: Pathophysiology• Progressive destruction of -cells progressive

deficiency of insulin permanent low-insulin catabolic state

• Phases:– Early: defect in peripheral glucose predominates– Late: insulin deficiency becomes more severe

Decreased renal blood flow and glomerular perfusion

Stimulates counter regulatory hormone release

Dehydration

Increased lactic acidosis

Accelerated production of glucose and ketoacids

10

Type I DM: Pathophysiology• Hyperglycemia glucosuria (renal threshold 180

g/dL) osmotic diruresis: polyuria, urinary losses of electrolytes, dehydration, & compensatory polydipsia

• Hyperglycemia hyperosmolality: cerebral obtundation– {Serum Na+ + K+} x 2 + glucose/18 + BUN/3

• Counter-regulatory hormones (glucagon, catecholamines, cortisol) are released– Increased hepatic glucose production impairing

peripheral uptake of glucose

11

Type I DM: DKA• Lipid metabolism: increase lipolysis

– Increased concentration of total lipids, cholesterone, TG, free FA

– Free FA shunted into ketone body formation; rate of production>peripheral utilization & renal excretion ketoacids

– Ketoacidosis -hydroxybutyrate & acetoacetate metabolic acidosis

– Acetone (not contribute to the acidosis)

12

Type I DM: DKA• Electrolytes loss

– Potassium: 3-5 mEq/kg– Phosphate: 0.5-1.5 mmol/kg

» 2,3-diphosphoglycerate: facilitates O2 release from HgB

» Deficient in DKA, may contribute to formation of lactic acidosis

– Sodium: 5-10 mEq/kg

DKA: Presenting Features• Polyuria• Polydipsia• Polyphagia• Nocturia• Enuresis

• Abdominal pain• Vomiting• Profound weight loss• Altered mental status• weakness

13

14

Type I DM: Clinical Manifestations• Ketoacidosis is responsible for the initial

presentation in up to 25% of children– Early manifestations: vomiting, polyuria, dehydration– More severe: Kussmaul respirations, acetone odor on the

breath– Abdominal pain or rigidity may be present & mimic

acute abdomen– Cerebral obtundation & coma ultimately ensue

• DKA exists when there is hyperglycemia (>300 mg/dL & usually <1,000 mg/dL); ketonemia, acidosis, glucosuria & ketonuria

15

DKA: Physical Exam• Tachycardia• Dry mucous membrane• Delayed capillary refill• Poor skin turgor• Hypotension• Kussmaul breathing

16

DKA: Physical Exam• Dehydration

– Hyperosmolar: translocation of intracellular water to extracellualr comparment

– A rough estimation of how dehydrated the patient is to facilitate proper rehydration

– Studies have shown that clinical approximations often are poor

17

DKA: Laboratory• Blood glucose• Urinary/plasma ketones• Serum electrolytes• BUN/Cr• Osmolarity• CBC, blood cx (if infection is suspected)• Blood gas

18

DKA: Laboratory Findings• Elevated blood glucose (usually <1,000)• Low bicarbonate level• Anion gap metabolic acidosis

– Unmeasured ketoacids– Urine dipsticks measure acetoacetate: in DKA B-

hydroxybutyrate to acetoacetate is 10:1– Helpful in determining if there is ketoacids in urine but

not sererity of DKA or response to treatment

19

DKA: Laboratory Findings• Sodium: low

– Osmotic flux of water into extracellular space reduces serum sodium concentration

– Actual sodium: 1.6mEq/L per 100mg/dL rise in glucose over 100

– Hypertriglyceridemia low sodium pseudohyponatremia

• Potassium: – Level varies depending on urinary loss and severity of

acidosis– Potassium moves extracellularly in exchange for

hydrogen ions typical hyperkalemia on presentaion– Total body stores are depleted due to urinary loss

20

DKA: Laboratory Findings• Phosphate

– Depleted in the setting of DKA– Serum level may not accurately represent total body

stores

21

DKA: Management• Goals: correction of

– Dehydration– Acidosis– Electrolytes deficits– Hyperglycemia

22

DKA: Management• Fluids:

– Avoid impending shock» Fluid replacement >4L/m2/24 hrs has been associate with

cerebral edema

– Usually necessary to help expand vascular compartment» Fluid deficit should gradually be corrected over 36-48 hrs

– Rehydration fluids should contain at least 115-135 mEq/L of NaCl

» Start with NS and switch to ½ NS if neccessary

23

DKA: Management• Postassium:

– Total body depletion will become more prominent with correction of acidosis

– Continuous EKG monitoring is standard of care– 30-40 mEq/L: in either KCl or KPhos

24

DKA: Management• Phosphate:

– Total body depletion will become more prominent with correction of acidosis

– Hypophosphatemia may cause rhabdomyolysis, hemolysis, impaired oxygen delivery

– Calcium should be monitored during replacement

25

DKA: Management• Insulin should be initiated immediately

– Insulin drips 0.1 U/kg/hr (NO BOLUS)– Gradual correction reducing serum glucose by 50-100

mg/dL/hr– Serum glucose often falls after fluid bolus: increase in

glomerular filtration with increased renal perfusion

26

DKA: Management• Dextrose should be added to IVF when serum

glucose <300– Blood glucose levels often correct prior to ketoacidosis– Should not lower insulin infusion unless: rapid correction

of serum glucose or profound hypoglycemia

27

DKA: Management• Bicarbonate is almost never administered

– Bicarb administration leads to increased cerebral acidosis:

– HCO3- + H+ dissociated to CO2 and H2O

– Bicarbonate passes the BBB slowly

– CO2 diffuses freely exacerbating cerebral acidosis & depression

• Indications for bicarbonate use: only in severe acidosis leading to cardiorespiratory compromise

28

DKA: Complication, Cerebral Edema• Cerebral edema: 0.5-1% of pediatric DKA

– Mortality rate of 20%– Responsible for 50-60% of diabetes deaths in children– Permanent neurologic disability rate of 25%

• Typically develops within the first 24 hrs of treatment

• Etiology is still unclear• Signs & symptoms:

– Headache – Confusion– Slurred speech– Bradycardia– Hypertension

29

DKA: Complication, Cerebral Edema• Theories of cerebral edema

– Rapid decline in serum osmolality» This leads to the recommendation of limiting the rate of

fluid administration

– Edema due to cerebral hypoperfusion or hypoxia– Activation of ion transporters in the brain– Direct effects of ketoacidosis and/or cytokines on

endothelial function

DKA: Cerebral Edema, risk factors

• Younger age• New onset• Longer duration of

symptoms

• Lower PCO2

• Severe acidosis

• Increase in BUN• Use of bicarbonate• Large volumes of

rehydration fluids• Failure of correction of

Na with treatment

30

31

DKA: Cerebral Edema, treatment• Lower intracranial pressure

– Mannitol or 3% saline

• Imaging to rule out other pathologies• Hyperventilation & surgical decompression are

less successful at preventing neurologic morbidity & mortality

DKA: Complications• Thrombosis (esp with

CVL)• Cardiac arrhythmias• Pulmonary edema• Renal failure• Pancreatitis

• Rhabdomyolysis• Infection

– Aspiration pneumonia– Sepsis– Mucormycosis

32

Hyperglycemia Hyperosmolar Syndrome

33

34

Pathophysiology• Insulin levels are sufficient to suppress lipolysis

and ketogenesis• Insulin levels are inadequate to promote normal

anabolic function & inhibit gluconeogeneis & glycogenolysis

• Cell deprivation triggers counter-regulatory surge, increasing glucose via enhanced hepatic glucose generation & insulin resistance

35

Pathophysiology• Hyperglycemia heightened inflammatory state

exacerbating glucose dysregulation

• Osmotic diuresis dehydration decreased GFR further glucose elevation

36

Pathophysiology• Morbidity & mortality associated with acute

hyperglycemia– Vascular injury– Thrombus formation– Disrupts the phagocytotic & oxidative burst functions of

the immune systemt– Disrupts BBB– Disrupts metabolism of the CNS worsens the effects of

ischemia on brain tissue

37

Pathophysiology• Dehydration is a major component• 15-20% volume depleted

– 5-10% in DKA

• Greater electrolyte loss due to massive osmotic diuresis

38

Clinical Presentation• Similar to DKA

– Polyuria– Polydipsia– Weight loss– Neurologic impairment

• Different from DKA– Kussmaul breathing– Acetone breath– Abdominal discomfort, nausea & vomiting are less

severe

39

Laboratory Findings• Glucose: >600 mg/dL• HCO3>15• Serum osmolarity >320 mOsml/L• pH>7.3 without evidence of significant ketosis

– Level of acidemia is influenced by severity of shock & starvation

• Lab values consistent with acute renal failure, rhabodmyolysis & pancreatitis

40

Treatment• Insulin plays a secondary role

– Hyperglycemia can often be corrected via volume resuscitation

– Renal perfusion is improved, GF is enhanced– Insulin gtt 0.1 U/kg/hr

Complications• Cardiac arrest• Refractory

arrhythmias• Pulmonary

thromboemboli• Circulatory collapse• Refractory shock

• Acute renal failure• Rhabdomyolysis• Neurologic deficits• Electrolyte

disturbances• Multisystem organ

failure

41

42

Treatment• Adult mortality: 15%• Pediatric prevalence of HHS is unknown

43

DKA DKA DKA HHS

Mild Moderate Severe

Plasma glucose mg/dL

>250 >250 >250 >600

Arteial pH 7.25-7.3 7.0-7.24 <7.0 >7.3

Serum bicarb mEq/L

15-18 10 to <15 <10 >18

Urine ketones Positive Positive Positive Small

Serum ketones Positive Positive Positive Small

Effective sOsmomOsm/kg

variable variable Variable >320

Anion gap >10 >12 >12 Variable

AMS Alerg Alert/drowsy Stupor/coma Stupor/coma

44

DKA HHS

Total water(L) 6 9

Water (ml/kg) 100 100-200

Na+ (mEq/kg) 7-10 5-13

CL- (mEq/kg) 3-5 5-15

K+ (mEq/kg) 3-5 4-6

PO42- (mmol/kg) 5-7 3-7

Mg2+ (mEq/kg) 1-2 1-2

Ca2+(mEq/kg) 1-2 1-2

45