Diabetic Ketoacidosis

EPU Team (Dr. Uko P., Dr. Eke E.P., Dr. Jemide O., Dr. Osang S.)

FMC Keffi

28th of May, 2014

Outline

Overview of Diabetic Mellitus Diabetic Ketoacidosis: Introduction Epidemiology Physiology Pathophysiology Clinical Presentation Diagnosis Complications Treatment/Monitoring Prevention Conclusion References 2

Overview of Diabetes Mellitus

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycaemia resulting from defects in insulin secretion, insulin action or both.

Criteria for diagnosis

Symptoms of DM and casual plasma glucose conc. > 11.1mmol/L(200mg/dl) (10 for venous)

Fasting Plasma Glucose > 7.0mmol/L (126mg/dl) (6.3 for venous and capillary)

2hr post load of glucose >11.1mmol/L during an OGTT

Types of DM

1. Type 1 Diabetes Mellitus (T1DM):- β cell destruction leading to absolute insulin deficiency. Immune mediated, idiopathic

2. Type 2 Diabetes Mellitus (T2DM):- insulin resistance with relative insulin deficiency

3. Other types Gestational DM

Genetic defects of ◦β cell function◦Insulin action

Diseases of the pancreasEndocrinopathiesInfectionsDrug or chemical inducedGenetic syndromesUncommon forms of immune related

TYPE 1 DM

Type 1 DM is the most common endocrine metabolic disorder of childhood and adolescence.

Autoimmune mechanisms are factors in the genesis of T1DM.

• Most cases are primarily due to T-cell mediated pancreatic islet β-cell destruction.

Serological markers of an autoimmune pathologic process, including islet cell, glutamic acid decarboxylase (GAD), islet antigen (IA)-2, IA-2b, or insulin autoantibodies (IAAs), are present in 85–90% of individuals when fasting hyperglycaemia is detected

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Etiology of T1Diabetes

EnvironmentalFactors

•Cow’s milk?•Viruses ?•Nitrates?

Genetic Susceptibility•DM1: HLADR3,DR4↑•Protective DRB1,DQB1↓•DM2

Autoimmunity & Insulitis

Destruction of pancreatic β cells

EPIDEMIOLOGY

T1DM accounts for about 10% of all diabetes,

affecting 1.4million in the USA and over 15million

in the world.

While it accounts for most cases of diabetes in

childhood, it is not limited to this age group; new

cases continue to occur in adult life and

approximately 50% of individuals with T1DM

present as adults.

The incidence of type 1 DM is highly variable among different ethnic groups.

Girls and boys are almost equally affected but there is a modest female preponderance in some low risk populations (e.g the Japanese).

There is no apparent correlation with socioeconomic status.

Peaks of presentation occur in 2 age groups: at 5-7 years of age and at the time of puberty.

The first peak may correspond to the time of increased exposure to the infectious agents coincident with the beginning of school;

The 2nd peak may correspond to the pubertal growth spurt induced by gonadal steroids and the increased pubertal growth hormone secretion( which antagonizes insulin).

These possible cause-and-effect relationships remain to be proved.

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Morbidity and mortality stem from acute metabolic derangement and long-term complications (usually in adulthood) that affect small and large vessels resulting in retinopathy, nephropathy, neuropathy, ischaemic heart disease and arterial obstruction with gangrene of the extremities.

The acute clinical manifestations are due to hypoinsulinaemic hyperglycaemic ketoacidosis.

Individuals with TIDM confront serious lifestyle alteration that include an absolute daily requirement for exogenous insulin, the need to monitor their own glucose level, and the need to pay attention to dietary intake.

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Predisposing Factors for T1DM

The major histo-compatibility complex on chromosome 6 – greatest contribution

Viral infections: Congenital rubella syndrome, Enteroviruses, Mumps virus.

Diet: Breast-feeding may lower the risk of T1DM either directly or by delaying exposure to cow’s milk protein.

Hygiene Hypothesis: Possible protective role of infections. Lack of exposure to childhood infections may somehow increase an individual’s chances of developing autoimmune diseases including T1DM.

Psychologic stress

T2DM

Heterogenous disorder characterized by peripheral resistance and failure of the β-cell to keep up with increasing insulin demand.

These patients have relative rather than absolute insulin deficiency.

Generally they are not ketosis prone, but ketoacidosis may develop in some circumstances.

Aetiology is not known, but these patients do not have autoimmune destruction of β-Cell nor do they have any of the known causes of secondary diabetes mellitus.

DKA: INTRODUCTION

Diabetic ketoacidosis (DKA) is a metabolic derangement caused by the absolute or relative deficiency of insulin

It is one of the most important causes of mortality and severe morbidity in children with diabetes, particularly at the time of first diagnosis.

Early recognition and careful management are essential if death and disability are to be avoided

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HISTORY

The first full description of diabetic ketoacidosis is attributed to Julius Dreschfeld, a German pathologist working in Manchester, United Kingdom in 1886

The condition remained almost universally fatal until the discovery of insulin in the 1920s;

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Insulin was first isolated from the pancreas in 1922 by Banting and Best.

The entity of cerebral oedema due to DKA was described in 1936 by a team of doctors from Philadelphia.

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EPIDEMIOLOGY

Few data are availableIn the United Kingdom national study,

60% of all cases occurred in patients with known diabetes

In the USA, 25% of new cases of Type 1 DM present with ketoacidosis, approximate incidence of 4 per 100,000 children annually.

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88% of patients first present in the children's emergency room with Diabetic ketoacidosis (DKA) (Ugochi Ibekwe et al, Federal Teaching Hospital Abakaliki)

DKA has been found in the range of 7-80% in newly diagnosed patients and 25-90% in children who have already been diagnosed with diabetes.

This high prevalence of DKA is attributed to the lack of awareness among health workers and the community at large (Adesiyan et al) 23

In FMC Keffi:From January 2013 to May 2014, a total of 6 patients were admitted for DKA5 females and 1 maleAge range: 8-11years (except the male, 3years 9months)2 cases were admitted in May 2014

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Sex: Although no difference in DKA rates exists between the sexes at diagnosis and during early childhood, adolescent girls with diabetes are twice as likely to develop DKA as adolescent boys.

Age: – Preschool aged children are at greatest risk of

presenting with DKA because the diagnosis of diabetes in children is often missed.

– Adolescents are more likely to develop DKA after diagnosis of diabetes 25

PHYSIOLOGY

Insulin is a polypeptide containing two chains of amino acids linked by disulfide bridges

The net effect of the hormone is storage of carbohydrate, protein, and fat. Therefore, insulin is appropriately called the “hormone of abundance”

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Rapid (seconds)   Increased transport of glucose, amino acids, and K+ into insulin-sensitive cells Intermediate (minutes)   Stimulation of protein synthesis  Inhibition of protein degradation  Activation of glycolytic enzymes and glycogen synthase  Inhibition of phosphorylase and gluconeogenic enzymes

Delayed (hours)   Increase in mRNAs for lipogenic and other enzymes

Principal Actions of Insulin

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Insulin inactivates liver phosphorylaseIncreases the activity of the enzyme

glucokinase which causes the initial phosphorylation of glucose after it diffuses into the liver cells.

Increases the activity of glycogen synthase

Insulin inhibits the action of hormone-sensitive lipoprotein lipase 28

Adipose tissue   Increased glucose entry  Increased fatty acid synthesis  Increased glycerol phosphate synthesis  Increased triglyceride deposition  Inactivation of lipoprotein lipase  Inhibition of hormone-sensitive lipase  Increased K+ uptake

Effects of Insulin on Various Tissues

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  Increased glucose entry  Increased glycogen synthesis  Increased amino acid uptake  Increased protein synthesis in ribosomes  Decreased protein catabolism  Decreased release of gluconeogenic

amino acids  Increased ketone uptake  Increased K+ uptake

Muscle 

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  Decreased ketogenesis   Increased protein synthesis   Increased lipid synthesis   Decreased glucose output due to decreased

gluconeogenesis, increased glycogen synthesis, and increased glycolysis

General    Increased cell growth

Liver 

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INFLUENCE OF FEEDING (HIGH INSULIN) OR OF FASTING (LOW INSULIN) ON SOME METABOLIC PROCESSES IN LIVER, MUSCLE AND ADIPOSE TISSUE

HIGH PLASMA INSULIN (POSTPRANDIAL STATE)

LOW PLASMA INSULIN (FASTED STATE)

Liver Glucose uptake Glucose production

Glycogen syntheses Glycogenolysis

Absence of gluconeogenesis Gluconeogenesis

Lipogenesis Absence of lipogenesis

Absence of ketogenesis Ketogenesis

Muscle Glucose uptake Absence of glucose uptake

Glucose oxidation Fatty acid and ketone oxidation

Glycogen synthesis Glycogenolysis

Protein synthesis Proteolysis and amino acid release

Adipose Tissue Glucose uptake Absence of glucose uptake

Lipid synthesis Lipolysis and fatty acid release

Triglyceride uptake Absence of triglyceride uptake 32

PATHOPHYSIOLOGY

Insulin deficiency exaggerates the normal response to fasting: gluconeogenesis and glycogenolysis.

Peripheral glucose uptake is impaired and levels of the main counter-regulatory hormones increase (glucagon, cortisol, catecholamines, growth hormone).

A variety of metabolic consequences follow. 33

Secondary to insulin deficiency and the action of counter-regulatory hormones (glucagon), blood glucose increases due to glycogenolysis and gluconeogenesis, leading to hyperglycemia and glucosuria.

Blood glucose levels rise above the renal threshold for glucose reabsorption, causing an osmotic diuresis, leading to waterwater & electrolyte loss.

In the absence of insulin activity the body fails to utilize glucose as fuel and uses fats instead. This leads to ketosis.

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The excess of ketone bodies will cause metabolic acidosis, the latter is also aggravated by lactic acidosis caused by dehydration & poor tissue perfusion.

Vomiting due to an ileus, plus increased insensible water losses due to tachypnea will worsen the state of dehydration.

Electrolyte abnormalities are secondary to their loss in urine & trans-membrane alterations following acidosis & osmotic diuresis.

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Because of acidosis, K+ ions enter the circulation leading to hyperkalemia, this is aggravated by dehydration and renal failure.

Depending on the duration of DKA, serum K+ at diagnosis may be high, normal or low, but the intracellular K+ stores are always depleted.

Phosphate depletion will also take place due to metabolic acidosis.

Na+ loss occurs secondary to the hyperosmotic state & the osmotic diuresis. 36

The dehydration can lead to decreased kidney perfusion and acute renal failure.

Accumulation of ketone bodies contributes to the abdominal pain and vomiting.

The increasing acidosis leads to acidotic breathing and acetone smell in the breath and eventually causes impaired consciousness and coma.

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Fluid and electrolytes

Fluid losses are considerable, typically 3-10% of body weight.

Most water is lost by osmotic diuresis, with important contributions from hyperventilation and vomiting.

The diuresis also leads to considerable urinary losses of potassium, sodium, phosphate, and magnesium ions

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Ketoacidosis

Insulin inhibits the lipolytic action of cortisol and growth hormone, so insulin deficiency increases circulating levels of fatty acids.

These are oxidized in the liver, producing the acidic ketone bodies: beta-hydroxybutyrate and acetoacetate, from which acetone spontaneously forms.

The resulting acidosis primarily is due to circulating ketone bodies, with a smaller contribution from excess fatty acids and lactic acidosis, as a consequence of poor tissue perfusion. 39

Absolute insulin deficiency ORStress, infection or insufficient insulin intake

Counter-regulatory hormones: Glucagon, Cortisol,Catecholamines, GH

Lipolysis

FFA to liver

Ketogenesis

Alkali reserve

Acidosis

Lactate

Glucose utilization

Proteolysis Protein synthesis

Glycogenolysis

Gluconeogenic substrates

Gluconeogenesis

Hyperglycemia

Glucosuria (osmotic diuresis)

Loss of water and electrolytes

Dehydration

Impaired renal function

Hyperosmolarity

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Clinical Presentation

Features of DKA are progressive. Symptoms are aggravated by presence of some

precipitating factors. Inter current infections Drugs e.g steroids, thiazides, terbutaline, dobutamine Psychological stress Trauma Alcohol and drug abuse Insulin omission in already diagnosed diabetics

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Features include:

Polyuria- nocturiaNocturnal enuresisPolydipsiaHyperphagiaWeight lossVaginitisMuscle cramps and pains

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Abdominal discomfort or painNausea, vomitingDehydration- moderate to severeDeep, heavy and rapid breathing- Kussmaul’ s

breathingFruity acetone breathLethargyAltered mental state from disorientation to coma

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Diagnosis – Cardinal Features

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DKA can present;ShockDehydration with no shockPresence of complicationsPresence of cardinal features otherwise stable

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Classification of DKAMild Moderate Severe

HCO3 (mmol/L)

10-15 5-10 <5

CO2 (mEq/L)

16 - 20 10 - 15 < 10

pH 7.25 – 7.35 7.15 – 7.25 < 7.15

Clinical state Oriented, alert but fatigued

Oriented but sleepy; arousable; Kussmaul respiration

Kussmaul or depressed respiration; sleepy to depressed sensorium to coma

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Work up

Plasma glucose – hyperglycemia HbA1c Serum ketone assay Urinalysis – glucosuria, ketonuria, evidence of

infection E, U, Cr – K+, Na+, HCO3, PO4, elevated BUN Arterial Blood gases – acidosis FBC – infection Malaria parasite, Cultures – infection ECG

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Insulin / Islet cell AntibodiesThyroid function tests/ thyroid auto

antibodiesBrain CTAbdominal X rays/ Abdominal USS

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Differential Diagnosis

1. Non-ketotic Hyperosmolar Coma/ HHS2. Urinary tract infection3. Acute gastroenteritis with dehydration4. Acute pancreatitis5. Acute abdomen6. Meningitis7. ARI – pneumonia, bronchiolitis8. Status asthmaticus9. Hysterical hyperventilation

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Complications

1. Cerebral edema

2. Intracranial infarction

3. Cerebral venous thrombosis

4. Acute Tubular Necrosis

5. Deep Venous Thrombosis

6. Pulmonary edema

7. Electrolyte derangement(s)

8. Cardiac dysrhythmias51

Cerebral Edema

Occurs in 0.5 – 1% of children.Accounts for 90% of neurological complications of

DKACarries a high mortality risk – 70%. Only about 15% recover without sequelae.Typically occurs 6 – 10 hours after initiation of

treatment. It often follows a period of clinical improvement.Can occur prior to therapy.

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Mechanism not fully understood but few theories-Loss of cerebral autoregulationVasogenic mechanism of edema formation.Cerebral ischemia

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Risk factors

Younger age - < 5 yearsRapid rehydrationProlonged duration of symptoms prior to

therapyAdministration of IV bicarbonateHigh initial glucose concentrationHypernatremia or persistent hyponatremia.

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Clinical features

Headache, lethargy, confusionPupillary changesIncontinenceDeteriorating consciousnessSeizuresCushings triad – hypertension,

bradycardia, irregular respiration

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Diagnosis

Based on a single criterion:Decorticate or decerebrate postureCranial nerve palsy – iii, iv, viAbnormal respirationAbnormal verbal or motor response to pain

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Major CriteriaAltered mental stateBradycardiaIncontinence

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Minor Criteria:VomitingHeadacheLethargyHypertension DBP> 90mmHgAge < 5

2 major, or 1 major + 2 minor58

Treatment of DKA

DKA is an emergency; but, it is managed with cautious urgency

Treatment of DKA requires frequent eyes-on, hands-on and brain-on reassessment

It should never be “auto-pilot” or managed from the call room

Team consultant must be informed

Emergency assessment + Resuscitation

Quick history

Weigh the child/ estimate

Assess consciousness (Glasgow Coma Scale)

Bedside tests ( RBS, Urinalysis, PO2)

Examination

General state/level of consciousness

Level of hydration (usually overestimated)3% -just detectable5% -dry mucus membranes/reduced skin

tugor8%-slow cap. Refill(>3sec)/sunken eyes>10%-shock, weak pulses, ↓BP

Respiration HyperventilationIrregular in cerebral edemaCongestion/consolidationCardiovascular Low volume/thready pulseTachycardiaBradycardia in ↓ ICP

EyesPapilloedema

Abdomen TendernessReduced bowel sounds (ileus)

Resuscitation

Airway SuctionOropharyngeal airwayNG tube for gastric emptyingBreathing 100% O2 by face mask

CirculationInsert iv canula; collect all blood samples

Modalities

Fluid replacement

Electrolyte replacement

Insulin infusion

Treatment of infections

Correct complications

Monitoring

Fluid replacement

Deficit + maintenance

Correction of deficit: 10-20ml/kg in 1st hr IVF N/S OR Ringer’s bolus (max 3 doses

in shock)

Maintenance + remainder of deficit over 48hrs

IVF N/S Change to 0.45% saline + 5% DW (when

RBS ≤ 15 mmol/L)

Age (yrs) Weight (kg)

Maintenance fluid/24hr

< 1 3-9 80

1-5 10-19 70

6-9 20-29 60

10-14 30-50 50

> 15 > 50 35

Fluid calculation

Deficit= estimated% dehydration x wt x 10 (mls)

Maintenance= wt x 100ml/kg (1st 10kg)+50ml/kg (2nd 10kg)+20ml/kg (subsequent kg)

Example; 20kg child, 10% dehydratedDeficit= 10x 20 x10 = 2000 mlMaintenance= 20 x 60= 1200 x2=2400/48hrsTotal fluids over 48hr= 4800ml @ 33dpm

Electrolyte replacement

Electrolyte depleted in DKA include; K+,Na+ PO4, and Mg2+

Total body K+ always depleted in DKA (≈4-6mmol/kg)

initial level of K+ may be low, normal or high

K ⁺ Should not be started until shock is corrected

Requires ECG monitoring

Rate of infusion is usually 3mmol/kg/24hr (max dose 0.5mmol/kg/hr)

Hypokalemia; give after initial fluid resuscitation

20mmol/L

Eukalemia; at the time of insulin introduction

40mmol/L (20 as KCl, 20 as KPO4)

Hyperkalemia; when patient makes urine

Insulin

Insulin is required to reverse the metabolic abnormalities by further decreasing blood glucose and inhibiting ketone body formation.

Only give when shock has been reversed

Usually started in the 2nd hr of management

Optimal method is by continuous low dose intravenous infusion (via pump)

Recommended initial dose is 0.1U/kg/hr of soluble insulin

Subcutaneous insulin 0.3U/kg stat, then 0.1U/kg/hr if iv access not possible: provided good peripheral circulation

Insulin can be reduced to 0.05U/kg/hr (if pH > 7.3, HCO3

-1, rate of fall of glucose > 5mmo/L/hr)

If RBS falls to < 4mmol/L (give 2ml/kg of 10% DW bolus)

Insulin Therapy

10 units of short-acting Insulin with 0.9%saline into a soluset/syringe pump to make up 100ml, producing a concentration of 1U/10mlE.g. a seven year old weighing 30kg requiring 0.1U/kg/hour of insulin0.1 x 30 = 3U/hourSince 10ml=1U, then 3U/hour = 30ml/hour60drops = 1mlHence 30 x 60 = 1800drops/hour (60mins =1hour)30 drops/minute

Correction of acidosis

Usually autocorrected by IVF and insulin administration ( improved GFR)

NaHCO3 is given cautiously if there is;

pH< 6.9HCO3

-1 < 5mmol/L

Given empirically at dose of 1-2mmol/kg over 1hr as infusion

Treat infections

Commonest precipitant of DKA

Usually started empirically until blood culture is available

May include treatment for malaria, pneumonia, meningitis etc as appropriate

Monitoring treatment complicationsCerebral edemaMajor cause of mortalityComplicated by early commencement of

insulinOverzealous rehydration also a culpritAlso implicated is correction of acidosis

with NaHCO₃Severe hyperglycemia with high

osmolality (Sosm >350 mOsm /L)

Treatment includes;

Reduction of IVF to ½ or 2/3rd of maintenance

Elevate head 30 to the horizontal⁰

IV mannitol 0.5-1g/kg/dose 6-8hrly (iv furosemide as adjunct)

IV 3% (hypertonic) saline 2-4ml/kg alternative

Hyperventilation

Dialysis

Hypoglycemia

Usually caused by high insulin doses/bolus injections

Prevented by regular blood sugar monitoring while patient is on insulin infusion

Corrected by giving 2-4ml/kg of iv 10% DW bolus, continuing ivf 0.45% saline + 5% DW (which may be increased to 10% DW)

Dose of insulin infusion may be reduced by 0.025U up to 0.5U/kg/hr

Cardiac dysrhythmia

Usually secondary to hypokalemia /acidosis

Need for cardiac monitoring

Usually corrected when cause is treated

Monitoring

Neurological assessment: ½ -1hourly

Vital signs: Pulse rate, respiratory rate BP - hourly

Strict intake / output chart

Random blood sugar & urine/blood ketones hourly

Electrolytes: initially 2hourly. When K and Na are normal and HCO₃ > 15mmol/L 4-6 hourly ⁻

Transition to subcutaneous insulin

When dehydration, acidosis and hyperglycemia are corrected

Blood ketone levels are low (<1mmol/L)

Patient is tolerating orally, no longer vomiting

Target blood sugar before commencement 8.3-13.8 mmol/L

Dose; 0.5-0.7U/kg/dose of soluble insulin 8 hourly

Dose up to 1.0U/kg/day of mixtard on discharge

< 30kg: 0.3U/kg/day; 2/3rd AM,1/3rd PM > 30kg: 0.6U/kg/day; 2/3rd AM, 1/3rd PMStop insulin infusion ½ to 1hour after

commencement of subcutaneous injection

Counseling for discharge

Treatment is lifelong Educating patient and family members on:Basic pathophysiology of DMImportance of adequate control to avoid

complicationsSurvival skills:How to check/monitor blood glucoseMonitor urine glucose and ketonesPreparation and injection of insulinHow to recognize hypoglycemia and hyperglycemiaHow to plan meals

Long term monitoring

HbAIC; Normal < 6%:In diabetics;6-7.9: good control8.0-9.9: fair control>10: poor control

Early treatment of infections/injuriesGrowth monitoring

Regular eye check

Renal status check

Regular neurological checks

Cardiovascular assessment: BP, arterial wall thickness

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Prevention

General Health Promotion: enlightenmentSpecific preventionEarly diagnosis and treatmentLimitation of disabilityRehabilitation

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Conclusion

DKA is a common complication of paediatric diabetes melitus

It carries significant risk of death and/or morbidity especially with delayed treatment

High index of suspicion is required for early detection and treatment

Treatment is done with cautious urgency in order to forestall complications of treatment

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References

Nelson Textbook of Paediatrics, 19th EditionMedscape: Paediatric Diabetes MellitusPaediatric Management of Paediatric DKA;

Guidline No. 13; 3rd Edition by Dr. Carrihill and Greening

BSPED Recommended DKA Guidelines 2013Endocrinology update 2012/2013

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Thank You!

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