DIABETICKETOACIDOSIS (DKA)

&HYPEROSMOLAR HYPERGLYCEMIC

SYNDROME (HHS)

DR. JAYESH VAGHELA

KETONE BODIESSYNTHESIS

2

SPECTRUM OFDKA AND HYPEROSMOLAR COMA

Pure Ketoacidosis

Ketoacidosis-Hyperosmolar

Coma

PureHyperosmolar

Coma

Rapid OnsetMarked Insulin

Lack

Intermediate Slow OnsetMild Insulin Lack

DIABETICKETOACIDOSIS

INTRODUCTION

•Diabetic : Glucose >250 mg/dL

•Keto – :ketones produced

Blood concentration: 90mg/100ml

Urinary excretion: 5000mg/24 hr

•Acidosis :

Anion gap metabolic acidosis;

HCO3- : <15mEq/L,

pH : <7.30

[N: 70-110mg/dL]

[N : < 3mg/100 ml]

[N : 125mg/24 hr]

[N: 5-16 mEq/L]

[N: 22-26 mEq/L]

[N: 7.35-7.45]

• DKA - potentially life-threatening complication

• Medical emergency,

• Predominantly in those with type 1 diabetes ,It may be the first symptom of previously undiagnosed diabetes.

• can occur in patients with type 2 diabetes .

HISTORY

• The first full description of DKA : Julius Dreschfeld

• In 1886,described the main ketones, acetoacetate and -hydroxybutyrate, and βtheir chemical determination.

• DKA remained almost universally fatal until the discovery of insulin in the 1920s;

• 1930s, mortality had fallen to 29%

• 1950s : less than 10%

HISTORY CONTD.

• The entity of “ketosis-prone type 2 diabetes” was first fully described in 1987.

• It was initially thought to be a form of maturity onset diabetes of the young

• Then went through several other names, such as,

• "idiopathic type 1 diabetes",

• "Flatbush diabetes",

• "atypical diabetes“

• "type 1.5 diabetes"

CLASSIFICATION2006, American Diabetes Association (for adults)

Grade Blood pH S. Bicarbonate Status of patient

Mild 7.25 - 7.3015–18 mEq/L

( N: > 20) Patient is alert

Moderate 7.00–7.25 10–15 mEq/L Mild drowsiness may

be present

Severe < 7.00 < 10 mEq/L Stupor or coma may

occur

2004, European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society (for children)

Grade Blood pH S. Bicarbonate

Mild 7.20 - 7.30 10–15 mEq/L

Moderate 7.1 – 7.2 5-10 mEq/L

Severe < 7.1 < 5 mEq/L

PRECIPITATING FACTORS

1. Inadequate insulin administration

2. Infections (Pneumonia, UTI, Gastroenteritis, Sepsis)

3. Infarction (Cerebral, myocardial, coronary, mesenteric, etc.)

4. Pregnancy

5. Use of medications: steroids (glucocorticoids), thiazide diuretics, calcium-channel blockers, propranolol, Cocaine

PATHOPHYSIOLOGY

↑ Glycogenolysis↑ Gluconeogenesis,

↑ Protein catabolism

↑ Hyperglycemia

Glucosuria

Osmotic diuresis

Dehydration

↓

↓

↓

↓

Diabetic ketoacidosis

Insulin deficiency

↑ Lipolysis

↑ Free fatty acids

↓

↓

↑ Ketone bodies

Hyperketonemia

↓

↓

Acidosis

CLINICAL

PRESENTATION

SYMPTOMS

• Nausea & vomiting

• Polyuria / ↑ Thirst

• Abdominal pain

• Shortness of breath

SIGNS

Dehydration

• Mild: Dry mouth

• Severe: Tachycardia, Low BP ( d/t ↓ circulatory volume)

Abdominal tenderness (may resemble acute pancreatitis / Acute Appendicitis)

• Tachypnoea, Kussmaul’s respiration, “Fruity” smell of breath, Respiratory distress

• Lethargy, cerebral edema & coma

DIAGNOSIS1. History and physical examination:

2. Laboratory investigations:

PARAMETER NORMAL VALUE VALUE in DKA

1. B. Glucose 70-110 mg/dL 250 -600 mg/dL

2. S. Bicarbonate 22-26 mEq/ L < 15 mEq/ L

3. Ketone bodies

• Plasma concentration < 3 mg/ 100 ml 90 mg/ 100 ml (++++)

• Urine excretion 125 mg/ 24 hr 5000 mg/ 24 hr(++++)

4. S. Osmolality 275-295 mosm/L 300-320 mosmol/L

5. Art. pH 7.35-7.45 6.8 - 7.3

6. Art. pCo2 35-45 mmHg 20-30 mmHg

PARAMETER NORMAL VALUE VALUE in DKA

7. S. Electrolytes

• K + 3.5 – 6.5mEq/ L N to ↑

• Na + 135 – 148 mEq/ L125-135 mEq /L

(100mg ↑ in glucose asso. with 1.6 mEq reduction in S. Na )

• Mg +2 1.5 -2.5 mg/dL N

• Phosphate 2.2 -4.8 mg/dL ↓

• Chloride 46-112 mEq/ L N

• Anion gap [ Na – (Cl + Hco3) ]

5-16 mEq/ L ↑

TREATMENT

1. Initial evaluation & admission to hospital

2. Dehydration (fluid therapy)

3. Hyperglycemia (insulin)

4. Electrolyte deficits (potassium , sodium, phosphate therapy)

5. Ketoacidosis ( insulin as well as bicarbonate therapy)

6. Other measures.

1.Initial evaluation

&Admission to

hospital

If vomiting Or altered mental status : insert nasogastric tube.

Intensive care is necessary for frequent monitoring, If pH is < 7.0 or pt is unconscious.

Assess patient:

History & Physical examination

Blood sugar.

S. Electrolytes

Acid base status

Renal function

CBC with differential count, ECG

TREATMENT Contd…

• Start I.V. Fluids 1 L, 0.9 % Normal saline / Hr (15-20ml/kg/hr)

• Confirm the Diagnosis :

• Blood Glucose : > 250 mg/dl

• Arterial pH : < 7.3

• S. Bicarbonate < 15 mEq/L

• ketonuria & ketonemia

2.Fluid Therapy

(Dehydration)THESE IS THE MAINSTAY OF THERAPY…

• Deficit : 3-5 L

• 2-3 L → Isotonic Saline ( 0.9 % NaCl) → over 1-3 hrs (Bolus) ( 10-15ml/ kg/ hr)

↓ followed by

• 150 – 300 ml/ hr → Hypotonic Saline ( O.45 % NaCl)

• Only when Haemodynamic stability & adequate Urine output are achieved

↓

• When Blood Glucose comes to 250-300 mg/dL

• 100-200 ml/ hr → ½ NS ( O.45 % NaCl) + 5 % Glucose

• Amount of i. v. fluids to be used: ~ 3L /m2/24 hr

Advantages of early rehydration:1. Dehydration :Restores circulatory volume

2. Hyperglycemia is treated

3. Hyperkalemia is reversed

Complications of fluid therapy:1. Excessive therapy may result in ARDS

2. Cerebral edema

3. Hyperchloremic acidosis

3.Insulin therapy

(Hyperglycaemia)

INSULIN TREATMENT 1. Type of insulin: Plain / Regular insulin

2. Route : Bolus I.V. → CLDII (Continuous low dose i.v. infusion)

3. Dose : 0.1 U /kg → I. V. Bolus immediately

↓

0.1U/kg/hr → CLDII (Conti. low dose i.v. inf.)

Mix to run @ 10ml/hr

(regular insulin equal to wt. in kg x 2.5, mixed in 250ml bag of saline)

Example: weight = 50kg

[50 x 2.5 = 125 units in 250ml = 5u/hr (i.e. 0.1 U/kg/hr)

INSULIN TREATMENT CONTD.

↓

Double the dose : if B. Glucose does not fall in 2 hrs

When decrease in B. Glucose level = 10% /hr : Adequate response

Hyperglycemia improves at a rate of 75-100 mg/dl/hr

DURATION OF INSULIN THERAPY

Until acidosis recovers&

Metabolism is normal

↓

Dose: 0.05-0.1U/Kg/hr

Intermediate or Long actingInsulin

+Short acting s.c. insulin

↓

As patient resumes eating

It is crucial to continueInsulin infusion

Until adequate insulin levelsAre achieved by s.c. injection

↓Even brief episode of

Insulin lack↓

DKA relapse

With insulin regimen, patient recovers within 36 – 48 hoursInitial S. K+ : < 3mEq/L, Don’t administer insulin until it is corrected to > 3mEq/L

• Role of insulin

Hyperglycemia: Insulin mediated glucose disposal

↓ Hepatic glucose release

Ketoacidosis: ↓ lipolysis

↓ hepatic Ketone Body formation

↑ Peripheral Ketone Body use

Hyperkalemia: Transport of K+ In to cell

4.Electrolyte deficit

(Na+, K+, PO4-)

POTASSIUM TREATMENT :

Deficit : 3-5 mEq / kg

During treatment with insulin & I.V. fluids, dangerous hypokalemia can occur

So K+ repletion is commenced as soon as,

• Adequate Urine output : >1ml /min

• Normal Serum Creatinine

• Normal ECG

• Normal Serum K+ level is achieved

B. SODIUM TREATMENT :

Initial s. sodium may be ‘low’ : Depletion secondary to urinary losses / vomiting

“Pseudohyponatremia” is often present

Corrected Na= Measured Na + 0.016(measured glucose - 100)If Na+ does not rise, true hyponatremia may be present (possibly increasing

cerebral edema risk) and should be treated

C. PHOSPHATE TREATMENT :

Any patient with phosphate concentration

< 1mg/ dL → should receive phosphate Therapy.

↓

5-10 mmol / hr Na+ Or K+ phosphate .

5.Bicarbonate

therapy

(Acidosis)

Bicarbonate therapy:

When SEVERE acidosis ( pH < 7 after initial hydration) : l/t cardio-respiratory compromise

pH : 6.9-7.0 → 50 mEq /L NaHCo3 in 200 ml sterile water with 10 mEq/L KCl over 1 hr.

pH : < 6.9 → 100mEq /L NaHCo3 in 400 ml sterile water with 20 mEq/L KCl over 2 hr

Until pH > 7.0.

OTHER MEASURES

Assess patient for Precipitating factors:

• Non compliance, Infection, Trauma, Infarction, Drugs history

• Initiate appropriate workup for that event like history, Culture, ECG etc

• Based on that treat the patient with antibiotics & supportive measures.

• Appropriate treatment ↓es the mortality of DKA to < 5%, That is mainly related to precipitating factors

Measurements:

• Capillary B. Glucose → every 1-2 hrly

• S. Electrolytes → every 4 hrly for first 24 hrs

• Monitor BP /Pulse / Respi./Mental status /Fluid intake & output → every 1-4 hrly

• Nursing care of patient about skin, mouth, position & bladder.

Remember, The Ideal Treatment For DKA Is Prevention

Educate the patient about,

• Symptoms of DKA,

• Its precipitating factors

• Management of diabetes during concurrent illness

• Frequent measurement of blood glucose.

• Measure Urinary Ketones when S. Glucose > 300mg/dl

• Drink fluids

• Continuous/Increase insulin

• Seek medical attention, If persistent Vomiting, uncontrolled hyperglycemia & dehydration

COMPLICATIONS

OF

DKA TREATMENT

1) Dehydration / shock

2) Hypokalemia (Cardiac arrhythmia) / hyperkalemia (Cardiac arrest)

3) Hypoglycemia

4) Aspiration pneumonia

5) Sepsis

6) ATN/ MI/ stroke

7) Insulin resistance (unremitting acidosis after 4-6hrs of treatment)

8) Cerebral edema

CEREBRAL OEDEMA

• Almost exclusively a condition of childhood.

• The pathophysiology is not completely understood

• Usually occurs between 4-12 hours from the start of treatment,

• but may be present at onset of DKA and can occur up to 24 hours later.

• Responsible for 50-60% of all diabetes-related deaths in children

Causes:

Excessive use of fluids

Large doses of insulin

Use of bicarbonate

Manifestations:

Headache - Alteration in level of consciousness

Bradycardia - Emesis

Diminished responsiveness to painful stimuli

Unequal or fixed, dilated pupils

TREATMENT:

• Mannitol 0.5-1 gm/kg IV over 15 minutes

• Reduce IV fluid rate to 70% maintenance

• Hypertonic saline ( 3% N.S.)

• Elevate Head end to 45o

• Consider intubation

• hyperventilation

• keep pCO2 > 22mmHg

HYPOGLYCEMIC REACTIONS(INSULIN SHOCK)

• Is a life threatening complication: blood Glucose < 50 mg/dl

Symptoms and signs : pallor, sweating, apprehension, trembling, tachycardia, hunger, drowsiness, mental confusion, seizures and coma

Management :

• If conscious: - Carbohydrate - containing snack or drink

• If patient is unconscious: - Glucagon 0.5 mg (S.C. or I.M.) or

Glucose solution 20-50 ml I.V. infusion

HYPEROSMOLAR HYPERGLYCEMIC

SYNDROME(HHS)

Synonym:

• Hyperosmolar hyperglycemic non-ketotic coma (HHNKC)

• Mainly seen in elder individuals with Type 2 DM.

• Is characterized by profound hyperglycemia & dehydration.

• Mortality

• Variable 10-50%

• Most often due to the precipitating illness

Difference Between DKA & HHS

Parameters DKA HHS

Type of DM Mc in Type 1 DM Mc in Type 2 DM

Precipitating factor

Mc : Inadequate or omitted insulinMC :Serious concurrent illness + debilitating condition that compromises water intake

Symptoms Abdominal pain, Kussmaul’s respi. Absent

Signs

Dry mouth,hypotension, tachycardiaAbdominal tenderness,Fruity smell of breath

Profound dehydration ↓Tachycardia, hypotension & altered mental status

Dehydration(loss of water)

3 - 5 L 8 - 10 L

Parameters Normal value DKA HHS

Blood Glucose 70-110 mg/dL 250 - 600 mg/dL 600 - 1200 mg/dL

S. Bicarbonate 22-26 mEq/ L < 15 mEq/ LN to slight ↓Mild or no acidosis

Ketone bodies

ABSENT / Mild ketosis

• Plasma conc. < 3 mg/ 100 ml 90 mg/ 100 ml (++++)

• Urine excretion

125 mg/ 24 hr 5000 mg/ 24 hr (++++)

S. Osmolality 275-295 mosmol/L 300-320 mosmol/L 330– 380 mosmol/L

Arterial pH 7.35-7.45 < 7.3 > 7.3

Arterial pCo2 35-45 mmHg 20-30 mmHg N

BUN 2.8 -7.9mmol/L 11.4 (mean) 21.8 (mean)

Parameter Normal Value Value In DKA HHS

K + 3.5 – 6.5 mEq/ L N to ↑ (4.5) N (3.9)

Na + 135 – 148 mEq/ L 125-135 mEq /L

(100mg ↑ in glucose asso. with 1.6 mEq ↓ in S. Na+ )

135-145 mEq /L

Mg +2 1.5 -2.5 mg/dL N N

Phosphate 2.2 -4.8 mg/dL ↓ N

Chloride 46-112 mEq/ L N N

Anion gap 5-16 mEq/ L ↑ N to ↑

TREATMENT

Initial Evaluation: ABCs; Exam; Labs; Causes

Close Monitoring

Fluid Replacement : vigorous

Insulin Therapy

Electrolyte Replacement

Patients are prone to develop thrombosis : prophylactic heparin

REFERENCES

• Standaert DG & Roberson E. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia.In : Bruton LL, editor. Goodman & Gilman’s – The Pharmacological basis of therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011. p. 609- 28.

• Tripathi KD. Essentials of Medical Pharmacology. 6th ed. Jaypee brothers medical publishers; New Delhi 2009. p. 425-34.

• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. Paras publication; New Delhi 2012. p. 532-42.

• Olanow CW, Schapira AH. Diabetes Mellitus. In: LongoDL, editor :Harrisons’s principles of internal medicine.18th edition. New york:Mc Grew hill;2012. P.3317-35.