Detailed information on DKA and HONK

1. ACUTE
COMPLICATIONS OF
DIABETES MELLITUS
MEDICAL UNIT II
Dr. VISHNU V B

2. DIABETIC KETOACIDOSIS
● Described by Dr. Julius Dreschfeld in 1886.
● Diabetic Ketoacidosis is an acute, major, life-threatening
complication of Diabetes mellitus.
● It mainly occurs in patients with Type 1 Diabetes but it is not
uncommon in some patients with Type 2 diabetes.

3. DEFINITION
• DKA is defined as an complex acute metabolic state
characterized by hyperglycemia, ketoacidosis and ketonuria.
• It is associated with absolute or relative insulin deficiency,
volume depletion and acid base abnormalities that results in
potentially serious complication if not promptly treated.

4. EPIDEMIOLOGY
• The incidence of DKA in developing countries is higher.
• It is far more common in young patients.
• DKA is frequently observed in diagnosis of type 1 diabetes and often
indicates this diagnosis (3%).
• DKA accounts for 14% of all hospital admissions of patients with
diabetes and 16% of all diabetes-related fatalities.
• The overall mortality rate for DKA is 0.2-2%, being at the highest in
developing countries.

5. DIAGNOSIS
• Triad of hyperglycemia, high anion gap metabolic acidosis
and ketonemia.
• Glucose >13.9 mmol/L (250 mg/dl).
• Bicarbonate <15 mmol/L; pH< 7.3.
• Ketonemia (>3mmol/L) and ketonuria.

6. ETIOLOGY
● Inadequate insulin treatment or noncompliance.
● New onset diabetes (20-25%)
● Acute illness
○ Infection (30 to 40%)
○ Infarction (cerebral, coronary, mesentric,
peripheral)
● Drugs
○ Cocaine
● Pregnancy

7. PATHOPHYSIOLOGY
● It usually occurs as a consequence of absolute or relative
insulin deficiency that is accompanied by an increase in
counter-regulatory hormones (i.e, glucagon, cortisol, growth
hormone, epinephrine)
● Both insulin deficiency and glucagon excess are necessary
for DKA to develop.

8. ● Decreased ratio of insulin to glucagon promotes gluconeogenesis,
glycogenolysis and ketone body formation in liver, as well as
increase in substrate delivery from fat and muscle (free fatty
acids, amino acids) to the liver.
● Insulin deficiency also reduces the levels of GLUT4 glucose
transporter, which impairs glucose uptake into skeletal muscle
and fat and reduces intracellular glucose metabolism.

9. ● Insulin deficiency and hyperglycemia reduces the activity of F2,6BP
increase the activity of PEPCK. Glucagon excess decrease the
activity of pyruvate kinase.
● This changes shift the handling of pyruvate toward glucose
synthesis and away from glycolysis
● Increased levels of glucagon and catecholamines promote
glycogenolysis and proteolysis.
● Increased levels of catecholamines and growth hormones activate
hormone sensitive lipase that leads to lipolysis.
Increased FFA and decreased activity of insulin sensitive
lipoprotein lipase increases VLDL-triglyceride production and
decreases VLDL removal.

10. ● Glucagon activate CPT I - Beta oxidation of fatty acid to acetyl CoA
and later to ketone body formation.
At physiological pH, ketone bodies exist as ketoacids, which are
neutralized by bicarbonate. As bicarbonate stores are depleted,
metabolic acidosis ensues.
● Marked hyperglycemia causes osmotic diuresis with loss of water
and electrolytes. Increased extracellular osmolarity shifts water
from cells resulting in cellular dehydration.

13. CLINICAL PRESENTATION:
SYMPTOMS
• DKA usually evolves rapidly, over a 24 hour period.
• Earliest symptoms are polyuria, polydipsia, weight loss.
• Nausea, vomiting and abdominal pain are usually present.
• Malaise, generalized weakness, fatigability and shortness of
breath.
• As the duration of hyperglycemia progresses, neurologic
symptoms, including lethargy, focal signs, and obtundation
can develop. Frank coma is uncommon in DKA.

14. CLINICAL PRESENTATION:
SIGNS
● Dehydration - Dry mucous membranes, dry skin and decreased
skin turgor
● Tachycardia/Hypotension
● Tachypnea
● Kussmauls respiration/ ketotic odor of breath- characteristic
● Abdominal tenderness
● Hypothermia/ Fever (if infection is present)
● Decreased reflexes
● Confusion
● Coma

16. LABORATORY EVALUATION
• Blood test for glucose every 1-2 hour.
• ABG/ VBG.
• Serum electrolytes (includes phosphate and
magnesium)
• Renal function test.
• Urine dipstick test (acetoacetate).
• Serum ketones (3-hydroxybetabutyrate).
• CBC.
• Anion gap.
• Osmolarity.
• Cultures.
• Amylase.
Repeat lab investigations are key!

19. MANAGEMENT
• Correction of fluid loss with intravenous fluids.
• Correction of hyperglycemia with insulin.
• Correction of electrolyte disturbances, particularly
potassium.
• Correction of acidosis.
• Treatment of concurrent infection, if present.

20. CORRECTION OF FLUID LOSS
• It is a critical part of treating patients with DKA.
• Recommended fluid - isotonic saline. 0.45% saline once euvolumic
or serum Na+ >150 mEq/l to prevent overhydration and
hyperchloremia acidosis.
• Replete circulating volume - 2- 3 L of isotonic saline over first
• 1 - 3 hrs (10-20mL/kg/hour)
• After initial bolus of normal saline, replacement of the sodium and
free water deficit is carried out over the next 12 - 24 h
• Total water deficit - 10% of body weight
• Replenish total body water deficit - 0.45% saline over 150-500ml/hr

21. INSULIN THERAPY
• Insulin therapy to be initiated only if potassium levels are above
3.3 mEq/L.
• Intravenous regular insulin preferred.
• Initiated with IV bolus of regular insulin (0.1 units/kg) followed by
continuous infusion of regular insulin of 0.1 units/kg/hour.
• SC route may be taken in uncomplicated DKA (0.3 U/kg then 0.2 U/kg
one hour later)
• Target decrease in blood glucose - 50 -100mg/dL
• Most rapid correction of serum glucose can precipitate cerebral edema

22. ● When serum glucose reaches 200 mg/dl, reduce insulin infusion
to 0.02-0.05U/kg/hour and switch the IV saline solution to
dextrose in 0.45% saline.
● Acidosis and ketosis resolves slowly than hyperglycemia. So
insulin infusion should be maintained at lower rate to inhibit
ketogenesis.
● Revert to SC insulin, after patient begins to eat (continue IV
infusion simultaneously for 1 to 2 hours).

23. POTASSIUM REPLACEMENT
• If the initial serum potassium is below 3.3 mEq/L, IV potassium
chloride is started with saline (20 to 40 mEq/hour).
• If the initial serum potassium is between 3.3 and 5.3 mEq/L, IV
KCl (20 to 40 mEq) is added to each liter of IV replacement fluid
and continued to maintain serum potassium between 4.0 to 5.0
mEq/L range.
• If the serum potassium is initially greater than 5.3 mEq/L, then
potassium replacement should be delayed.

24. CORRECTION OF ACIDOSIS
• Bicarbonate therapy still remains a controversial subject, as clear
evidence of benefit is lacking.
• Indications
○ pH < 6.9
○ Bicarbonate < 5mEq/L
○ Shock/coma
○ Severe hyperkalemia
• 50 mEq of sodium bicarbonate in 200 mL sterile water is
administered over 2 hours with potassium supplements. Repeat
doses until pH rises above 7.0.

25. Harmful effects
Hypokalemia
Reduce tissue oxygenation
Imapirs cardiac function

26. MANAGEMENT
ALGORITHM

27. COMPLICATIONS
● Lactic acidosis
● Arterial thrombosis - stroke, MI, peripheral limb ischemia
● Venous thrombosis - DVT, CVT
● Cerebral edema (rare in adults)
● Rebound ketoacidosis
● Late hypoglycemia
● Gastric dilatation (vomiting of bloody and dark material)
● Respiratory distress syndrome
● Infections (pneumonia, cystitis)

28. EUGLYCEMIC DKA: IT’S NOT A
MYTH!
• It is essentially DKA without hyperglycemia (Glucose< 200).
• Euglycemic DKA is a rare entity that mostly occurs in patients
with Type 1 Diabetes, but also in Type 2 Diabetes.
• It has been associated with fasting or starvation, alcohol
ingestion, pregnancy and with Sodium-Glucose Cotransporter 2
(SGLT-2) inhibitor medications [Glifozins].
• The exact mechanism of euDKA is not entirely known.

30. ● HHS is an subacute metabolic complication with high morbidity
and mortality occurring in middle aged and elderly diabetics.
● Precipitating factors
● Infection - sepsis, pnemonia, UTI, MI, prior stroke
● Drugs - Diazoxide, Diuretics, phenytoin,Chlorpromazine
HYPERGLYCEMIC HYPEROSMOLAR STATE

31. PATHOPHYSIOLOGY
● Relative insulin deficiency and inadequate fluid intake are the
underlying causes of HHS
● Insulin deficiency - increase glycogenolysis, gluconeogenesis
and impairs peripheral glucose utilization.
● Less severe insulin deficiency and lower level of counter
regulatory hormones and FFA compared to DKA are
responsible for absence of ketosis in HHS

32. CLINICAL MANIFESTATIONS: SYMPTOMS &
SIGNS
● Earliest symptoms are polyuria, polydipsia, weight loss.
● Malaise, generalized weakness, fatigability.
● Dehydration, Hypotension, tachycardia and shock
● As the duration of hyperglycemia progresses, neurologic
symptoms including lethargy, focal signs, seizures,
obtundation and frank coma can develop.
● Nausea, vomiting and abdominal pain are usually absent.
● Kussmaul respiration and fruity odor of breath are absent.

33. DIAGNOSIS
● Marked Hyperglycemia >600mg/dl
● Hyperosmolality >330 mosm/L
● Absence of acidosis and ketonemia
(Small anion gap metabolic acidosis and moderate ketonuria
may be present secondary to lactic acidosis and starvation
respectively)

34. MANAGEMENT
• Correction of fluid loss with intravenous fluids.
• Correction of hyperglycemia with insulin.
• Correction of electrolyte disturbances, particularly potassium.
• Correction of precipitating causes.

35. CORRECTION OF FLUID LOSS
● Fluid loss and dehydration are more pronounced in HHS.
● Recommended fluid - isotonic saline. 0.45% saline once
euvolumic or serum Na+ >150 mEq/l
● Replete circulating volume - 1- 3 L of isotonic saline over first
2 - 3 hrs.
● After initial bolus of normal saline, replacement of the sodium
and free water deficit is carried out over the next 1 - 2days
● Total water deficit - 25% of body weight
● Replenish total body water deficit - 0.45% saline over 200-
300ml/hr

36. ● Insulin therapy to be initiated only if potassium levels are above
3.3 mEq/L.
● Intravenous regular insulin preferred.
● Initiated with IV bolus of regular insulin (0.1 units/kg) followed by
continuous infusion of regular insulin of 0.1 units/kg/hour.
● Target decrease in blood glucose - 50-100mg/dL
● Most rapid correction of serum glucose can precipitate cerebral
edema
INSULIN THERAPY

37. ● A low dose heparin may be advantageous to prevent vascular
thrombosis and intramuscular coagulation.
● Seizure in HHS should not be treated with phenytoin as it
worsens hyperglycemia by impairing insulin release.

38. HYPOGLYCEMIA IN DM
● Hypoglycemia is a reversible condition associated with severe
morbidity and if severe can be fatal.
● It is a limiting factor in the glycemic management of diabetes
mellitus and requires more complex treatment.
● The incidence of hypoglycemia is higher in T1DM but the
prevalence of hypoglycemia is higher in T2DM.
● A person with T1DM suffer an average of 2 episodes per
week of symptomatic hypoglycemia and atleast 1 episode per
year of severe disabling hypoglycemia

39. DEFINITION
WHIPPLE’S TRIAD
●Symptoms consistent with hypoglycemia
●Low plasma glucose concentration < 70mg/dl
●Relief of symptoms after plasma glucose level is raised
●It should be considered in any patient with episodes of confusion,
an altered level of consciousness, or a seizure.

40. GLUCOSE HOMEOSTASIS
● Plasma glucose concentrations are normally maintained within a
relatively narrow range roughly 70 - 110 mg/dl in the fasting state
● Between meals and during fasting, plasma glucose levels are
maintained by endogenous glucose production, hepatic
glycogenolysis and hepatic gluconeogenesis.
● Hepatic glycogen stores are usually sufficient to maintain plasma
glucose levels for ~ 8h period
● Systemic glucose balance is accomplished by a network of
hormones, neural signals, and substrate effects that regulate
endogenous glucose production and glucose utilization by tissues.

43. ● The glucose thresholds in DM is Dynamic.
● In poorly controlled diabetes, they shift to higher than normal
glucose levels and so the patient experience symptoms when
their glucose levels decline towards normal range
● In intensively treated diabetes, they shift to lower than normal
glucose levels and so the patients experience symptoms
when their glucose levels lower than those that cause
symptoms in healthy individuals.

44. ● Increased insulin (or secretagogue) intake - High dose, wrong
type, ill timed
● Increased insulin sensitivity - late after exercise, weight loss,
glycemic control
● Decreased insulin clearance - renal failure
● Decreased glucose intake - fasting or missed meals
● Decreased glucose production - Alcohol
● Increased glucose utilisation - during exercise
CONVENTIONAL RISK FACTORS

45. RISK FACTORS IN DM
● Absolute insulin deficiency
● History of severe hypoglycemia or hypoglycemia
Unawareness
● Impaired renal function
● Classical diabetic autonomic neuropathy
● Lower HBA1c

46. ● Autonomic symptoms
○ Adrenergic symptoms - palpitation, tremor, anxiety
○ Cholinergic symptoms - sweating, hunger, paresthesis
● Neuroglycopenic symptoms
○ Behavioral changes
○ Confusion
○ Fatigue
○ Seizure
○ Loss of consciousness
○ Cardiac arrhythmia
○ Coma
CLINICAL MANIFESTATIONS - SYMPTOMS

49. CLINICAL MANIFESTATIONS - SIGNS
● Pallor
● Diaphoresis
● Tachycardia
● Elevated SBP
● Focal neurological deficit

50. Hypoglycemia Associated Autonomic Failure (HAAF)
● HAAF occurs as a result of interplay between relative or
absolute therapeutic excess and and compromised
physiologic and behavioral defenses against falling plasma
glucose concentrations.
● Defective glucose counter regulation - loss of physiologic
defense
● Hypoglycemia Unawareness - loss of behavioral defense
● It causes a vicious cycle of recurrent iatrogenic hypoglycemia.

52. TREATMENT
● Concious - Oral Glucose tablets or glucose containing food
● Unconscious - IV Glucose (25 g) or Glucagon 1mg IM/SC
(Glucagon is ineffective in alcohol induced hypoglycemia and
T2DM)
● Sulfonylurea induced hypoglycemia - somatostatin analogies
(Octreotide)

53. REFERENCES
• Harrison’s Principles of Internal Medicine 20E
• A Handbook on Diabetes Mellitus - V. Seshiah
• The Washington Manual of Medical therapeutics

54. THANK YOU ☺