Diabetic Ketoacidosis, HONK and

Hypoglycemia
Theo Audi Yanto

Lecturer :

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No part of this work may be reproduced, including photocopied, without written permission of UPH.
 Objectives

• To describe the clinical approach in diagnosing diabetic

ketoacidosis
• To describe the clinical approach in diagnosing
hyperosmolar hyperglycemic state
• To describe the clinical approach in diagnosing
hypoglycemia
• To describe initial treatment of each emergencies of
glucose metabolism disorders
 Diabetic Ketoacidosis (DKA)

• A state of absolute or relative insulin deficiency

aggravated by ensuing hyperglycemia, dehydration, and
acidosis-producing derangements in intermediary
metabolism, including production of serum acetone.
• Can occur in both Type I Diabetes and Type II Diabetes
– In type II diabetics with insulin deficiency/dependence
• The presenting symptom for ~ 25% of Type I Diabetics.
 Hyperosmolar Hyperglycemic State (HHS)

• An acute metabolic complication of diabetes mellitus

characterized by impaired mental status and elevated
plasma osmolality in a patient with hyperglycemia.
• Occurs predominately in Type II Diabetics
– A few reports of cases in type I diabetics.
• The presenting symptom for 30-40% of Type II
diabetics.
 Diagnostic Criteria for DKA and HHS
Mild DKA Moderate DKA Severe DKA HHS

Plasma glucose > 250 > 250 > 250 > 600
(mg/dL)

Arterial pH 7.25-7.30 7.00-7.24 < 7.00 > 7.30

Sodium Bicarbonate 15 – 18 10 - <15 < 10 > 15

(mEq/L)

Urine Ketones Positive Positive Positive Small

Serum Ketones Positive Positive Positive Small

Serum Osmolality Variable Variable Variable > 320

(mOsm/kg)

Anion Gap > 10 > 12 > 12 variable

Mental Status Alert Alert/Drowsy Stupor/Coma Stupor/Coma

 Pathogenesis of DKA

Beta-cell
failure

Insulin
D/C
Insulin Deficiency

Glucotoxicity
 Pathogenesis of DKA

Increased
Insulin glucagon
deficiency GH
cortisol
catecholamines
 Carbohydrate Metabolism in DKA

Relative or absolute insulin deficiency

liver muscle

glucose output glucose uptake

glycogenolysis
 Increased Glucose Production in DKA

Gluconeogenesis Glucose

Activity of gluconeogenic
enzymes
(PEPCK, PC, PFK)

Glycerol Amino acids

Lactate

TG

Lipolysis Protein breakdown

Increased Production of Ketones in DKA

Ketogenesis

B-OH-B
Acetoacetate
FFA Glycerol

TG

Lipolysis
 Pathogenesis of DKA

Liver Peripheral Adipose Liver

tissue tissue

Increased Decreased Increased Increased

glucose glucose release ketogenesis
production uptake FFA

HYPERGLYCEMIA KETOACIDOSIS

Osmotic diuresis Decreased alkali reserve

Volume depletion Metabolic acidosis

 Insulin Deficiency
Glucose uptake Lipolysis
Proteolysis

Glycerol Free Fatty Acids

Amino Acids

Gluconeogenesis
Hyperglycemia Glycogenolysis Ketogenesis

Osmotic diuresis Dehydration Acidosis

 Counterregulatory Hormones - DKA
Increases Activates Activates Inhibits insulin
insulin glycogenolysis lipolysis secretion
resistance and
gluconeogenesis
Epinephrine
X X X X
Glucagon
X
Cortisol
X X
Growth
Hormone X X X
 Causes of DKA/HHS

• Stressful precipitating event that results in increased

catecholamines, cortisol, glucagon.
– Infection (pneumonia, UTI, infected ulcer)
– Alcohol, drugs
– Stroke
– Myocardial Infarction
– Pancreatitis
– Trauma
– Medications (steroids, thiazide diuretics)
– Non-compliance with insulin
 Symptoms of DKA/HHS

• Polyuria
• Polydypsia
• Blurred vision
• Nausea/Vomiting
• Abdominal Pain
• Fatigue
• Confusion
• Obtundation
 Physical Examination in DKA/HHS

• Hypotension, tachycardia
• Kussmaul breathing (deep, labored breaths)
• Fruity odor to breath (due to acetone)
• Dry mucus membranes
• Confusion
• Abdominal tenderness
 Signs and Symptoms of DKA
• Polyuria, polydipsia • Fruity breath
– Enuresis – Acetone
• Dehydration • Kussmaul breathing
– Tachycardia • Mental status changes
– Orthostasis – Combative
• Abdominal pain – Drunk
– Nausea – Coma
– Vomiting
 Serum Sodium

– Hyponatremia is common in patients with DKA

Serum glucose
H2 O H2 O
H2 O H2 O
Na+

Correction of Serum sodium:

Corrected Na+ = [Na+] 1.6 x glucose (mg/dl) – 100
100
Serum Potassium

– Admission serum potassium is frequently elevated (due to a

shift of K- from the intracellular to the extracellular space)

Osmolality
Acidosis Insulin
Na+ regulates
K+ K+
Activity of
K+ K+
K- Na+/K+
K+ pump
 Anion Gap Formula

• Anion gap can be measured as

• AG=[(Na)-(Hco3+CL)]
 Diagnostic Studies in DKA/HHS

• Chemistry • CBC
–  Glucose – Leukocytosis (possible infection)
–  Bicarbonate • Amylase/Lipase
– Anion gap = (Na+) – (Cl- + HCO3-) – To evaluate for pancreatitis
– Frequently seen: – BUT, DKA by itself can also
•  BUN/creatinine (dehydration) increase them!
•  potassium
• EKG
•  sodium
Pseudohyponatremia: to correct, add 1.6 – Evaluate for possible MI
mEq of sodium to every 100mg/dL of
glucose above normal
• Serum acetones
– Positive in DKA; Possibly small in HNS
• Urinalysis
– Ketones (for DKA); leukocyte esterase,
WBC (for UTI)
 TREATMENT OF DKA

Initial hospital management

– Replace fluid and electrolytes

– IV Insulin therapy
– Watch for complications
– Treat causes

Once resolved
– Convert to home insulin regimen
– Prevent recurrence
 Treatment of HHS

• Hydration!!!
– Even more important than in DKA
• Find underlying cause and treat!
• Insulin drip
– Should be started only once aggressive hydration has
taken place.
– Switch to subcutaneous regimen once glucose < 200
and patient eating.
• Serial Electrolytes
– Potassium replacement.
 Fluid Replacement contd…
Hours Volume

 1st half-hour to 1 hour 1L

 2nd hr 1L
 3rd hr 500 mL– 1 L
 4th hr 500 mL– 1 L
 5th hr 500 mL– 1 L
 Total 1st 5 hr 3.5 - 5 L
 6th–12th hr 250– 500 mL/hr

May need to adjust type and rate of fluid administration in the elderly and in
patients with congestive heart failure or renal failure.

14th edition of Joslin's Diabetes Mellitus

POTASSIUM REPLACEMENT CONTD…

Serum K (mEq/L) Additional K required

<3.5 - 4.0 - 40 mEq/L

3.5–4.5 - 20 mEq/L.

4.5–5.5 - 10 mEq/L

>5.5 - Stop K infusion

14th edition of Joslin's Diabetes Mellitus

 BICARBONATE

• Clinical trials donot support the rouine use of

bicarbonate replacement

• HCO3 replacement and rapid reversal of acidosis can

impair cardiac function, reduce tissue oxygenation and
promote hypokalemia and hypocalcemia.

Williams textbook of endocrinology 10th edition p456

 BICARBONATE CONTD…

 However in presence of sevare acidosis ph<6.9,in hemodynamic

instability with ph<7.1 and hyperkaemia with ecg finding
bicarbonate therapy considered .

 In the presence of severe acidosis (arterial pH <6.9), the ADA

advises bicarbonate [50 mmol/L (meq/L) of sodium bicarbonate
in 200 mL of sterile water with 10 meq/L KCl per hour for 2 h
until the pH is >7.0].

Williams textbook of endocrinology 10th edition

 MONITORING

• Flow sheet mantained tabulating mental status,

vital signs,insulin dose,fluid and electrolyte
administered and urine output

• Capillary glucose 1-2hrly,electrolytes especially

K+,bicarbonate and phosphate) and anion gap
every 4 hrly for first 24 hr

• Monitor BP,pulse respiration fluid intake and

output every 1-4 h

Williams textbook of endocrinology 10th edition p 456

 MONITORING

• Flow sheet mantained tabulating mental status,

vital signs,insulin dose,fluid and electrolyte
administered and urine output

• Capillary glucose 1-2hrly,electrolytes especially

K+,bicarbonate and phosphate) and anion gap
every 4 hrly for first 24 hr

• Monitor BP,pulse respiration fluid intake and

output every 1-4 h

Williams textbook of endocrinology 10th edition p 456

 ONCE DKA RESOLVED…

• Most patients require 0.5-0.6 units/kg/day

• highly insulin resistant patients
– 0.8-1.0 units/kg/day

• Give subcutaneous insulin at least 2 hours

prior to weaning insulin infusion.

Williams textbook of endocrinology 10th edition p455

 COMPLICATIONS OF DKA

•Shock
– If not improving with fluids r/o •Cerebral Edema
MI – First 24 hours
– Mental status changes
•Vascular thrombosis – May require intubation
– Severe dehydration with hyperventilation
– Cerebral vessels
– Occurs hours to days after DKA

•Pulmonary Edema
– Result of aggressive fluid
resuscitation

14th edition of Joslin's Diabetes Mellitus

Hypoglycemia
 DEFINITION
“Glucose levels <55mg/dl (<3.0mmol/l) with symptoms
that are relieved promptly after the glucose level is
raised document hypoglycemia.”
• Hypoglycemia is most convincingly documented by,
Whipple’s triad, i.e:
– Symptoms consistent with hypoglycemia
– Low plasma glucose concentration (measured with a
precise method)
– Relief of symptoms when plasma glucose concentration is
increased.
 GLUCOSE HOMEOSTASIS – Key roles

RESPONSE GLYCEMIC PHYSIOLOGIC EFFECTS ROLE IN GLUCOSE

THRESHOLD REGULATION
(mg/dl)
↓ Insulin 80-85 ↑ Ra (↓ Rd) 1st line of defense (Primary
glucose regulatory factor)
↑ Glucagon 65-70 ↑ Ra 2nd line of defense (Primary
glucose counterreg. factor)
↑ Epinephrine 65-70 ↑ Ra ↓ Rc 3rd line of defense (critical
when glucagon ↓)
↑ Cortisol & GH 65-70 ↑ Ra ↓ Rc Defense against prolonged
hypoglycemia, not critical
Symptoms 50-55 Recognition of Prompt behavioral
hypoglycemia defense(food ingestion)
↓ Cognition < 50 ----- Compromises behavioral
defense against hypoglycemia
↓ ARTERIAL GLUCOSE
↓ INSULIN LIVER
PANCREAS ↑ GLUCAGON ↑ GLUCOSE
PRODUCTION
KIDNEY
BRAIN
↑ GLUCONEOGENIC
PRECURSORS
↑ SYM ADR OUTFLOW
PITUITARY MUSCLE FAT

↑GH ↑ ARTERIAL
GLUCOSE
ACTH ↑E
ADR MEDULLA
↓ GLU CLEARANCE INGESTION
ADR CORTEX
↑ NE
↑ CORTISOL Post Gn SymN
SYMPTOMS
↑ Ach
 CLINICAL FEATURES - Symptoms
• Neurogenic symptoms:
– Sweaty
– Hungry
– Tingly
– Shaky (Tremulous)
– Poundy (Palpitations)
– Nervy (Anxious/Nervous)
• These symptoms are the result of the perception of
physiologic changes caused by the ANS discharge (Adr & Chol)
triggered by hypoglycemia.
 CLINICAL FEATURES - Symptoms
• Neuroglycopenic symptoms:
– Warm
– Weak
– Confused/Difficulty thinking
– Tired/Drowsy
– Faint
– Dizzy
– Difficulty speaking
– Blurred vision
• These symptoms are the result of direct CNS glucose
deprivation.
 CLINICAL FEATURES - Signs
• Pallor
• Diaphoresis
• ↑ RR
• ↑ BP
• TIA occasionally (Permanent damage is rare)

“The magnitude of the responses to hypoglycemia is an inverse

function of the nadir plasma glucose concentration rather
than the rate of decrease in plasma glucose.”
(Ref: William’s T. of Endo 10/e)
 MECHANISMS OF HYPOGLYCEMIA
• Hypoglycemia implies that the rate of glucose efflux from
circulation > rate of glucose influx into circulation.

↑ Efflux ↓ Influx

↑ Utilisation ↑ Losses ↓ Endogenous glucose

production in the
• Exercise • Pregnancy absence of exogenous
• Pregnancy • Renal Glycosuria glucose delivery
• Sepsis – Most Common cause
 MECHANISMS OF HYPOGLYCEMIA

Defects causing Hypoglycemia

REGULATORY ENZYMATIC SUBSTRATE

↑ Secretion of Insulin Primary Failure to

OR OR mobilize or
↓ Secretion of glucose May result from utilize
counter regulatory hepatic disease gluconeogenic
hormones substrates
 DIAGNOSIS
1. Whipple’s triad
2. Venous plasma glucose after an overnight fast:
• > 70mg/dl (>3.9 mmol/) : Normal
• 50 - 70 mg/dl (2.8-3.9 mmol/l) : s/o Hypoglycemia
• < 50 mg/dl (<2.8 mmol/l) : => Postabsorptive hypoglycemia
3. Postprandial (=Reactive) hypoglycemia:
– Diagnosis requires documentation of Whipple’s triad
after a mixed meal (low venous plasma concentration
post oral glucose load is not sufficient for diagnosis).

(Ref: William’s T. of Endo 10/e, Harrison’s Principles of Int Med 17/e, 339:2308)
 CLINICAL CLASSIFICATION
1. Postabsorptive (=Fasting) Hypoglycemia
2. Postprandial (=Reactive) Hypoglycemia
Significance:
– Reproducible hypoglycemia in the postabsorptive state,
implies the presence of disease and requires diagnostic
explanation and treatment.
– It may become apparent during the latter part of any
interdigestive period (NOT necessarily in the fasting state) esp.
post-exercise.
– Postprandial (=reactive) hypoglycemia does not usually imply a
serious underlying disorder.
 CLINICAL CLASSIFICATION
I) POSTABSORPTIVE (=FASTING) HYPOGLYCEMIA:
1. DRUGS:
– Esp. Insulin, SU, alcohol
– Pentamidine, quinine
– Rarely salicylates, sulphonamides
– Others
2. CRITICAL ILLNESSES:
– Hepatic failure
– Cardiac failure
– Renal failure
– Sepsis
– Inanition contd…
 CLINICAL CLASSIFICATION
I) POSTABSORPTIVE (=FASTING) HYPOGLYCEMIA:
3. HORMONAL DEFICIENCIES:
– Cortisol or GH or both
– Glucagon or Epinephrine
4. NON β CELL TUMORS
5. ENDOGENOUS HYPERINSULINISM
– Pancreatic β cell disorders
– β cell secretagogue (eg: SU)
– Autoimmune hypoglycemia (IA, IRA, ? βcell Ab)
– ? Ectopic insulin secretion
6. HYPOGLYCEMIA OF INFANCY & CHILDHOOD
 CLINICAL CLASSIFICATION
II) POSTPRANDIAL (=REACTIVE) HYPOGLYCEMIA:
1. Congenital deficiencies of enzymes of carbohydrate
metabolism:
– Heriditary Fructose intolerance
– Galactosemia
2. Alimentary Glycosuria:
– Post gastrectomy
3. Idiopathic (=Functional) postprandial hypoglycemia
 HYPOGLYCEMIA IN DM – The Burden
• T1DM-
– Fact of life
– Average of 2 episodes of symptomatic hypoglycemia per week and at
least one episode of sever, at least temporarily disabling
hypoglycemia each year.
– Estimated 2-4% of people with T1DM die due to hypoglycemia.
• T2DM-
– Less frequent than T1DM.
– Metformin, TZDs, AGIs, GLP-1 analogues, DDP-4 inhibitors should not
cause hypoglycemia, however the risk increases when combined with
insulin/SU.
– As insulin resistance increases and patients require insulin the risk of
hypoglycemia in T2DM approaches that in T1DM.
HYPOGLYCEMIA ASSOCIATED AUTONOMIC FAILURE
Insulin deficient diabetes
(Imperfect insulin replacement)
(No ↓insulin, No ↑ Glucagon)

Antecedent hypoglycemia
Antecedent
Reduced sympathoadrenal exercise
Sleep
responses to hypoglycemia

Reduced sympathetic Reduced epinephrine

neural responses responses

Hypoglycemia Defective glucose

unawareness counterregulation

Recurrent hypoglycemia
 HYPOGLYCEMIA IN T2DM

THERAPY N HBA1C % ANY % MAJOR

HYPO HYPO
Diet 379 8.0 3.0 0.2
Sulphonyl urea 922 7.1 45.0 3.3
Insulin 689 7.1 76.0 11.2

Diet 297 8.2 2.8 0.4

Metformin 251 7.4 17.6 2.4

Ref: UKPDS, Diabetes 1995-44-1249-1258

 DRUGS CAUSING HYPOGLYCEMIA
ESTABLISHED DRUGS:

DISORDER DRUG

DM Insulin, SU, other secretogogues, metformin,

alcohol
Infection Pentamidine, Quinine, Sulphonamides

Arrhythmias Quinidine, dispyramide, cibenzoline

Pain Acetylsalicylic acid

 DRUGS CAUSING HYPOGLYCEMIA
PUTATIVE DRUGS:

• Fluroquinolones esp. Gatifloxacin

• Acetaminophen

• ACEI, BB (nonsel>sel), Furosemide

• MAOI, Haloperidol, CPZ, Fluoxetine

• Diphenhydramine, Clofibrate, Phenytoin, Pencillamine

• Enflurane, Halothane, Ranitidine, Colchicine

 HYPERINSULINEMIC HYPOGLYCEMIA – D/D

INSULIN C-PEPTIDE PROINSULIN SU INSULIN DIAGNOSIS

ANTIBODY
↑ ↓ ↓ - - Exogenous insulin
↑ ↑ ↑ - - Insulinoma,
Congenital
hyperinsulinism
↑ ↑ ↑ + - Suphonylurea
↑ ↑ (Free ↓) ↑ (Free ↓) - + Insulin
autoimmune
↑ +/- ↓ ↓ - - Insulin Receptor
autoimmune
(Insulin receptor
Antibody +)
 ENDOGENOUS HYPERINSULINEMIA
• Hypoglycemia related to endogenous hyperinsulinemia can
be caused by-
– A primary pancreatic islet (β) cell disorder, typically a β cell tumour
(insulinoma), sometimes multiple insulinomas, or, esp. in
infants/young children, a functional β cell disorder with β cell
hyperplasia or without an anatomic correlate.

– A β cell secretogogue, often a SU, theoritically a β cell stimulating

antibody.

– An antibody to insulin

– Ectopic insulin secretion (rare).

 ENDOGENOUS HYPERINSULINEMIA
• Fundamental pathophysiologic feature of endogenous
hyperinsulinemia caused due to a primary β cell disorder or
an insulin secretogogue is failure of insulin secretion to fall to
very low levels during hypoglycemia.

• Critical diagnostic findings:

– Plasma insulin ≥3 uU/ml

– Plasma C-Peptide concentration ≥ 0.6 ng/ml

– Plasma proinsulin concentration ≥ 5.0 pmol/l, when the plasma

glucose concentration is < 55 mg/dl with symptoms of hypoglycemia.
 INSULINOMA
• Uncommon, 1/250,000; > 90% benign, treatable cause of
potentially fatal hypoglycemia.

• Median age of presentation – 50 yrs (sporadic cases), third

decade in MEN 1.

• Symptoms:
– Various combinations of diplopia, blurred vision, sweating,
palpitations or weakness: 85%

– Confusion or abnormal behaviour: 80%

– Unconsciousness or amnesia: 53%

– Grand mal seizures: 12%

DIAGNOSTIC APPROACH
 DIAGNOSTIC APPROACH - ALGORITHM

Suspected/Documented Hypoglycemia

Diabetes No diabetes

Treated with: Clinical clues

• Drugs Apparently
• Insulin healthy
• Organ failure
• Sulphonylurea • Sepsis
• Other secretogogue • Hormone deficiencies
• Non-β-cell tumor
Adjust regimen • Previous gastric Sx

Document improvement Provide adequate glucose,

and monitor treat underlying cause
 Suspected/Documented
No diabetes Apparently healthy
Hypoglycemia

< 55 mg/dl Fasting glucose

History ≥ 55 mg/dl

Strong Weak

Extended fast
↑ Insulin,
Whipple’s < 55 mg/dl Glucose ≥ 55 mg/dl
triad

↑ C-peptide Mixed meal

↓ C-peptide
Exogenous
insulin
Whipple’s triad
Insulinoma Autoimmune SU + --

Likely Factitious Reactive Hypoglycemia

hypoglycemia excluded
 TREATMENT
• Oral treatment with glucose tablets or glucose containing fluids,
candy or food is appropriate if the patient is able & willing to
take these.

• Initial dose = 20 g of glucose

• Unable to take oral foods  parenteral therapy

• IV glucose 25 g bolus followed by infusion guided by serial

plasma glucose measurements.

• Inj.Glucagon 0.1 mg sc/im can be used esp in T1DM. (it has no

role in alcohol induced hypoglycemia)

• Eat ASAP  restore glycogen stores.

 Treatment Hypoglycemia

• Mild Hypoglycemia:
– Give oral glucose (sweet tea, sugar drink)
– Eat adequate calorie
• Severe Hypoglycemia
– Administer 40% 25 ml IV until the patient awake
– Administer D 10% 500 ml per 6-8 hour
– Measure blood glucose per hour
 PREVENTION

• Identifying & addressing the cause

• Encouraging SMBG by patient

• Education & empowerment of patient

• Flexible insulin or OAD regimens

• Rational, individual glycemic goals

• Ongoing professional guidance & support

 Reference

• Harrison 18th Edition

• ADA Practice Guidelines
• Williams textbook of endocrinology 10th edition
• Joslin’s Diabetes Melitus 14th edition
Thank You