Diabetes Mellitus in Children

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DM can be defined as a chronic metabolic disorder of multiple aetiologies characterized by chronic hyperglycemia with disturbances of CHO, fat, & protein metabolism resulting from defects in insulin secretion, action, or both.

Type 1 - neonatal transient, neonatal permanent, & autoimmune
Type 2 – classically associated with obesity, MODY (genetic, types 1-6)
Secondary Forms (cystic fibrosis, haemochromatosis, Cushing's syndrome, acromegaly, phaeochromatoma, hyperthyroidism)

TDM in the newborn has onset in 1st weeks of life.
Persists several weeks to months.
Occurs most often in SGA.
Low/absent insulin response to glucose.
Characterized by hyperglycemia, glycosuria → severe dehydration ± metabolic acidosis.
Minimal or no ketonemia or ketonuria.
Insulin is mandatory during active phase. (1-2U/kg/day in 2 doses).
Resolves spontaneously.
Improvement, accelerated growth & weight gain.
Prognosis – Excellent.
DD- pancreatic agenesis.

Previously known as Adult-onset, NIDDM, MODY.
Increase incidence because of increase childhood obesity.
Not Insulin-Dependent (except during stress, etc., for symptomatic hyperglycemia).
Not ketosis-prone (severe infections, stress).
Insidious presentation usually - (routine medical exam or for other problems).
Minority of all DM patients in pediatric years (10-20%).
Inherited nature – stronger than T1DM, polygenic but strong family history.
No known HLA or association with autoimmune markers or diagnosis.

Uncommon but distinct entity.
Presentation < 25 years, often teenager.
Probably A-D without skipping.
Associated with mutations of glucokinase gene in chromosome 7.

Epidemiology

Accounts for more than 90% of Childhood & Adolescent DM.
100,000 children < 15 years develop T1DM annually with wide global variations in incidence.
Finland (highest), Korea (low), few data from Africa.
Seasonal onset - winter.
Can manifest at any age (approximately 50% at > 18 years).
Bimodal peak age distribution: 5-7 years & puberty.
No sex predilection.
Autoimmune antibodies in > 90% of patients, associated with thyroiditis.

Risk Factors

Chronic autoimmune disease – vast majority (HLA DR3 & 4, B8, BW15 on chr 6).
T-cell mediated autoimmune destruction of pancreatic β-cells in genetically predisposed individuals. (Islet AB, Insulin AB).
Idiopathic – few.
Seasonal factors - new cases more common in winter/autumn.
No evidence yet with commercial infant formula that contains cow’s milk protein.

Pathophysiology

Insulinopenia → decreased glucose utilization (muscle, fat).
→ postprandial hyperglycemia, at lower insulin levels → increased hepatic glycogenolysis/gluconeogenesis → fasting hyperglycemia → osmotic diuresis.
→ glucosuria → calorie & energy loss → dehydration.

Pathophysiology

Clinical Manifestations

Symptoms develop when about 90% of β cells are destroyed:

Polyuria, nocturia,
Bedwetting,
Excessive thirst,
Weight loss,
Fatigue,
Polyphagia or depressed appetite,
Persistent mycotic infection.

Ketosis ± Acidosis:

Abdominal pain,
Nausea, vomiting,
Tachypnea and deep respiration,
“Ketone smell”,
Lethargy, obtundation, coma.

Asymptomatic:

Fortuitous discovery of glycosuria (beware of renal diabetes).

Diagnosis of Diabetes - ADA Expert Committee

	NORMAL	IMPAIRED	DIABETES
FASTING	< 100 mg% (5.5mmol/L)	100-125	≥ 126 mg% (7mmol/L)
ORAL GTT (2 hours)	< 140 mg% (7.8mmol/L)	140-199	≥ 200 mg% (11.1mmol/L)

Diabetic Ketoacidosis (DKA)

Stage of severe metabolic decompensation as a result of severe deficiency of insulin or its effectiveness.
Most serious metabolic disturbance of T1DM.
DKA & its complications – Most common cause of morbidity and mortality in individuals with T1DM.
Manifestations:

Hyperglycemia – BG > 200mg% (11.1mmol/l).
Metabolic acidosis from overproduction of ketone acids. pH < 7.30, plasma HCO3 < 15mEq/l.

DKA: Lab Features

Ketonuria
Ketoacidosis
Increased anion gap
Decreased Serum HCO3, pH
Increased serum osmolality
Hypertonic dehydration

Risk Factors for DKA

Young age < 5 years, lower socioeconomic status
In established T1D: Higher Hb A1C
Adolescents (especially females)
Infections, longer duration
Psychiatric disorders
Precipitating factors: poor metabolic control & frequently missed insulin injections, infections, trauma, psychological & emotional stress especially in adolescents

DKA: Pathogenesis

Increased counter regulatory hormones → Glycogenolysis & gluconeogenesis BG > 250mg/dl > renal threshold → glycosuria → osmotic diuresis + decreased intake & vomiting → dehydration (decreased GFR) → increased BG → electrolyte disturbance (activation of RAS-aldosterone axis → serum K+ loss → risk of C.Oedema).
Increased catabolism & cellular loss → loss of Na, K, PO4.
Formation of buffers → depletion of buffers → metabolic acidosis.

DKA: Management

Rehydration: Initial fluid is normal saline.

If in shock, give 30ml/kg over 1-2hrs.
Calculate deficit and replace over 48hrs.

Insulin: Regular insulin 0.05units/kg/hr as continuous infusion (infusion pump or soluset).
Potassium: Add to IVF once urine output is adequate.
Determine & treat precipitating factors e.g. fever - blood culture, urine mcs; Avoid urethral catheter - condom drainage of urine.
Rehydration phase: (deficit: Minimal - 30-50mls/kg, Moderate - 50-90mls/kg, Severe - 100mls/kg. Give - 50% in 12hrs, rest in 24hrs, use infusion pump.
Maintenance: 100mls/kg, 1st 10kg, 50ml/kg - 11-20kg, 20ml/kg - >20kg OR 1.5-2 L/m2/day. 10% for fever/hyperventilation.

Electrolytes in DKA

K loss - 6-7 mEq/kg. Urinary loss + increased Aldosterone secondary to dehydration.
Serum K may be normal or increased because of shift to extracellular space, BUT total body K - depleted, serum K - unreliable. Insulin & fluids will also lower K. Give K as long as IVF.
Replace after initial fluid bolus & child making urine.
Options: KCL - hyperchloremic acidosis (worsens acidosis), K acetate - metabolized in liver to HCO3.
KPO4 - if PO4 low (contributes to buffer) but risk of decrease of Ca & Mg; thus use ≤ 1.5mEq/kg/day. Use KPO4 + K acetate.

Others

Monitoring:

Hourly serum glucose
Serum Na, K, PO4, HCO3, Cl, urea, creatinine, calcium, pH, ketones
Urinalysis; ketones, glucose
Neurological signs for cerebral edema

Complications

Mortality in DKA – 0.15-0.31% (UK, North America)
Cerebral edema – 60-90% of deaths - leading cause
Other causes of death - aspiration pneumonia (NGT if vomiting or unconscious), Multi-organ failure
Occasionally cerebral thrombosis, infarct, hemorrhage
Hypoglycemia, congestive heart failure
Renal failure

Cerebral Edema

Complication of DKA & its treatment
Occurs primarily in children
Incidence of clinically significant cerebral edema – low (1-2%)
No single etiology – rapid shift in extracellular fluid (ECF) & intracellular fluid (ICF) osmolality, CNS acidosis, Excess fluid administration, cerebral hypoxia. Final step - through cytokines

Risk factors of cerebral edema

Younger children (below 5 years use 0.05 units/kg/h of insulin)
Children with newly diagnosed T1DM
Failure of Na to rise as predicted
Use of bicarbonate therapy
A greater degree of acidosis and hypovolemia

Signs & Treatment of Cerebral Edema

Usually 4 to 12 hours after initiation of therapy
Headache, decreased consciousness, Hypertension, bradycardia, pupil abnormalities, papilloedema, decorticate posturing
Reduce rate of fluid administration and give mannitol (1 g/kg iv over 20 min)

Outpatient Management

Insulin: T1DM depend on insulin to live.
Nutrition: Require CHO, protein & fat to grow.
Exercise
Psychological support: Child and family.
Blood sugar monitoring & HbA1C

Dreadful disease, requires team support: paediatrician, nurse educator, dietician, mental health professional, social worker, peer discussion group, summer camps, role models, support groups
Aims of therapy:

Provide normal growth, puberty, psychomotor development, & well-being
Exercise is an integral component of growth & dev. No sport is excluded.
Nutrition - one of cornerstone of mx
No sp nutrition required other than for optimal growth & dev. Same food type as for gen populatn
Regular eating pattern for Insulin regimen
Individual nutritional reqment & meal plan based on age, sex, wt, activity, preferences
Meal plan: 50% CHO- 70% as Complex eg starch to prolong digestion & absorption for slow rise of BG
Avoid refined sugars, give high fiber diet eg veg, legumes, whole-meal bread, cereals diet & sugar-free carbonated drinks,
Lipids-30%- limit cholesterol
20% protein (plant)- limit egg-yolk, give fish, poultry, lean-cut meat
Variable daytime fractioning adapted to insulin regimen, age phy activity, life-style etc
3 meals, 2 snacks. Night tx snack essential to avoid nocturnal hypoglycemia
BG target: fasting/preprandial – 70-130mg/dl
After meals < 180mg/dl
Night: not < 60mg/dl (early morning headache- suggestive of hypoglycemia in the night)
Standardized Hb A1c < 7.7%; 6-9-good metab control, 9-12-fair, > 12 poor
Avoid severe or frequent hypoglycemia especially- < 5 years ( HbA1c objectives are higher: > 7.5 & < 8.5%; BG: 100- 200mg/dl)
Hb A1c- glycosylated Hb -A reliable index of long-term glycemic control
Represents fraction of Hb to which glucose has been non-enzymatically & irreversibly bound. Occurs throughout the life-span of RBC (3/12)
Allows estimation & duration of hypoglycemia & initial value to compare treatment
Hb A1c is affected by RBC survival eg haemoglobinopathy
Recurrent hypoglycaemia-depresses overall average
For such cases use fructosamine assay- non-covalent glycation of serum proteins over 2 weeks

Serial Blood Glucose Monitoring

Ideally - 4 times: before breakfast, lunch, supper & bedtime & if symptoms are present.
Many types of glucometer for home use. Some can store data with time & date.
Detect factitious glucose log books.

Treatment: Insulin

Simplest Insulin regimen - split mixed regimen – short + intermediate (regular & NPH). Disadvantage - restriction to specific routine & meals.
Frequent injection of short-acting Insulin - mimics endogenous Insulin secretion. Advantage - more flexibility & improved metabolic control.
Lispro injection – used before each meal + longer-acting Insulin more sophisticated.
Insulin pump (CSII) - increasingly popular – external device - continuous infusion through silicone tubing. Delivers preset amount titrated boluses to meal.
Whichever regimen must match lifestyle of child & family.

Short-acting

Regular/semilente – onset - 30mins, peak - 2-4hrs, duration – 4-6hrs

Intermediate-acting

NPH (pork)
NPH (human) - onset - 2-4hrs, peak - 6-12hrs, duration - 10-20hrs
Lente

Long-acting

Ultralente - onset - 12-18hrs, duration - 18-20hrs

Split-mixed: regular + intermediate 2x/day

2/3 before breakfast
1/3 before supper
1/3 regular + 2/3 NPH
1/2 regular + 1/2 NPH

Metabolic Response

Dawn phenomenon - normal physiology due to overnight GH secretion & increased Insulin clearance.
In T1DM - no compensation with increased insulin output → increased early morning glucose levels. Usually recurrent.
Somogyi - High morning glucose due to a rebound from late night or early morning hypoglycemia → exaggerated counter regulatory response. (hypoglycemia begetting hyperglycemia). But most children remain hypoglycemic. Hence rare in children.
Brittle diabetes - wide fluctuations in BG despite large & frequent adjustment of insulin doses. Recurrent DKA. Usually adolescent female. May be due to psychological problems, eating disorders.
Honeymoon phase - A transient decrease in insulin requirement associated with improved residual β cell function. (Thought to be due to Islet cell regeneration).
Younger children have no or limited H phase. Older children & adolescents - longer.

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