British Medical Journal

1. JOURNAL CLUB
BRITISH MEDICAL JOURNAL:
DIABETIC KETOACIDOSIS
Dr. Sujay Iyer

2. TABLE OF CONTENT
 Introduction
 Definition
 Diagnosis
 Epidemiology
 Pathophysiology
 Etiology
 Clinical Presentation
 Laboratory Evaluation
 Management
 Complications
 Topics of discussion
 References

3. INTRODUCTION
 Diabetic Ketoacidosis is an acute, major, life-
threatening complication of Diabetes.
 It mainly occurs in patients with Type 1 Diabetes
but it is not uncommon in some patients with type 2
diabetes.
 The overall mortality rate for DKA is 0.2-2%, being
at the highest in developing countries.

4. DEFINITION
 DKA is an extreme metabolic state caused by
insulin deficiency. It is defined as an acute state of
severe uncontrolled diabetes associated with
ketoacidosis that requires emergency treatment.
 It is a state of absolute or relative insulin deficiency
aggravated by ensuing hyperglycemia, dehydration
and acidosis-producing derangements in
intermediary metabolism.

5. DIAGNOSIS
 Triad of hyperglycemia, anion gap metabolic
acidosis and ketonemia.
ADA (2009)
 Glucose> 13.9 mmol/L (250 mg/dl).
 Bicarbonate< 18mmol/L; pH< 7.3.
 Ketones positive result for urine or serum ketones
by nitroprusside reaction.
JBDS (2013)
 Glucose> 11 mmol/L (200 mg/dl) or known
Diabestes.
 Bicarbonate< 15mmol/L or pH< 7.3 or both.
 Ketones> 3mmol/L or (++) in urine dipstick.

6. EPIDEMIOLOGY
 DKA accounts for 14% of all hospital admissions of
patients with diabetes and 16% of all diabeties-
related fatalities.
 DKA is frequently observed in diagnosis of type 1
diabetes and often indicates this diagnosis (3%).
 It occurs primarily in patients with type 1 diabetes,
but can also occur in type 2 patients.
 The incidence of DKA in developing countries is
higher.
 It is far more common in young patients.

7. PATHOPHYSIOLOGY
 DKA is a complex disordered metabolic state
characterized by hyperglycemia, ketoacidosis and
ketonuria.
 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).
 This imbalance enhances hepatic gluconeogenesis,
glycogenolysis, lipolysis and ketogenesis.

8. PATHOGENESIS ALGORITHM

9. ETIOLOGY
 Inadequate insulin treatment or noncompliance.
 New onset diabetes (20-25%)
 Acute illness
- Infection (30 to 40%)
- CVA
- Acute MI
- Acute pancreatitis
 Drugs
- Clozapine or olanzapine
- Cocaine
- Lithium
- SGLT2 inhibitors
- Terbutaline

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

11. CLINICAL PRESENTATION: SIGNS
 Ill appearance.
 Labored respiration (Kussumaul).
 Dry mucous membranes, dry skin and decreased skin
turgor.
 Decreased reflexes.
 Characterstic ketotic breath odor.
 Tachycardia
 Hypotension
 Tachypnea
 Hypothermia/ Fever (if infection is present)
 Confusion
 Coma
 Abdominal tenderness.

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

14. MANAGEMENT
 Correction of fluid loss with intravenous fluids.
 Correction of hyperglycemia with insulin.
 Correction of electrolyte disturbances, particularly
potassium loss.
 Correction of acid-base balance.
 Treatment of concurrent infection, if present.

15. MANAGEMENT ALGORITHM

16. CORRECTION OF FLUID LOSS
 It is a critical part of treating patients with DKA.
 Use of isotonic saline.
 15-20mL/kg/hour for the first few hours.
 Recommended schedule:
- Administer 1-3 L during first hour.
- Administer 1 L during second hour.
- Administer 1 L during the following 2 hours.
- Administer 1 L every 4 hours, depending on the
degree of dehydration and CVP.
 When patient becomes euvolemic, switch to 0.45%
saline is recommended, particularly if
hypernatremia exists.

18. INSULIN THERAPY
 Insulin therapy to be initiated only if potassium levels are
above 3.3 mEq/L.
 Intravenous regular insulin preferred.
 Initiated with IV blous 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).
 When serum glucose reaches 200 mg/dl, reduce insulin
infusion to 0.02-0.03 U/kg/hour and switch the IV saline
solution to dextrose in saline.
 Revert to SC insulin, after patient begins to eat
(continue IV infusion simultaneously for 1 to 2 hours).

19. 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 30 mEq) is added to each
liter of IV replacement fluid and continued until the
serum potassium concentration has increased to
the 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.

20. CORRECTION OF ACIDOSIS
 Bicarbonate therapy is a bone of contention among
physicians and still remains a controversial subject,
as clear evidence of benefit is lacking.
 Bicarbonate therapy is only administered if the
arterial pH is less than 6.9.
 100 mEq of sodium bicarbonate in 400 mL sterile
water is administered over two hours. Repeat
doses until pH rises above 7.0.
 Bicarbonate therapy has several potential harmful
effects.

21. COMPLICATIONS
 CVT
 Myocardial Infarction
 DVT
 Acute gastric dilatation
 Erosive gastritis
 Late hypoglycemia
 Respiratory distress
 Infection (UTI)
 Hypophosphatemia
 Mucormycosis
 CVA
 Cerebral edema (rare in adults)

22. TOPICS OF DISCUSSION
 ABG or VBG (Kelly Am et al. & Ma OJ et al.)
 Insulin when? (S Arora et al.)
 Bicarbonate therapy: to use or not to use? (Chua et
al. & Duhon et al.)
 Utility of insulin bolus (Goyal et al.)
 Euglycemic DKA: It’s not a myth (Peters et al.)
 Which fluid? (3 Studies)
 Insulin How? (4 Studies)
 Transition from IV to SC insulin (O’ Malley et al. &
Avanzini et al.).

23. ABG OR VBG?
Study #1: Kelly AM et al. Review Article – Can Venous Blood
Gas Analysis Replace Arterial in Emergency Medical Care
(2010)
 For pH, mean difference was found to be 0.02.
 For bicarbonate, mean difference was found to be -1.41
mmol/L.
Study #2: Ma OJ et al. - Arterial Blood Gas Results Rarely
Influence Emergency Physician Management of Patients
with Suspected Diabetic Ketoacidosis
 ABG analysis changed ED physicians diagnosis in 1% of
patients.
 ABG analysis changed ED physicians treatment in 3.5% of
patients (Change from SQ to IV insulin or vice versa).
 ABG analysis changed patient disposition in 2.5% of patients.
 Venous pH correlated well with arterial pH with difference of -
0.015 +/- 0.006 pH units.

24. ABG OR VBG
Other Reasons
 ABGs can cause radial artery spasm, infarct, and/or
aneurysms
 ABGs are painful to patients, even more so than IV
access
 By the way, when is the last time you checked
a Modified Allen’s Test before doing a radial ABG?
The VBG-electrolytes were 97.8% sensitive and
100% specific for the diagnosis of DKA in
hyperglycemic patients (Menchine M et al., 2011).

25. INSULIN WHEN?
Study: S. Arora et al - Prevalence of hypokalemia
in ED patients with diabetic ketoacidosis (2012)
 Hypokalemia was observed in 5.6% of patients with
DKA.
 These findings support the ADA recommendation to
obtain a serum potassium before initiating
intravenous insulin therapy in a patient with DKA.

26. BICARBONATE THERAPY
Study #1: Chua et al. - Bicarbonate in Diabetic
Ketoacidosis – A Systematic Review (2011).
 Transient improvement in metabolic acidosis.
 No improved glycemic control.
 Risk of cerebral edema in pediatric patients.
 No studies with pH <6.85.
Study #2: Duhon et al. - Intravenous Sodium
Bicarbonate Therapy in Severely Acidotic Diabetic
Ketoacidosis (2013).
 No difference in: Time to resolution of acidemia, time to
hospital discharge, time on IV insulin, potassium
requirement in first 24hrs.
 Subgroup Analysis of pH < 6.9 showed no statistical
difference in time to resolution of acidemia.

27. BICARBONATE THERAPY
Clinical Bottom Line
 Intravenous bicarbonate therapy may transiently
make acidemia better, but there is no improvement
of glycemic control, time on insulin, time to hospital
discharge, and in kids can worsen cerebral edema.

28. UTILITY OF INSULIN BOLUS
Study: Goyal et al. - Utility of Initial Bolus Insulin
in the Treatment of Diabetic Ketoacidosis
(2010).
 Insulin bolus at the start of an insulin infusion IS
EQUIVALENT to no insulin bolus at the start of an
insulin infusion in several endpoints including:
 Decrease normalization of glucose
 Affect the rate of change of anion gap
 Reduce ED or hospital length of stay
 Insulin bolus at the start of an insulin infusion
DOES:
 Increase hypoglycemic events by 6 fold (6% vs 1%).

29. 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 can possibly
occur in type 2 diabetes as well., but has been
associated with partial treatment of diabetes,
carbohydrate food restriction, alcohol intake, and
inhibition of gluconeogenesis. euDKA, can also be
associated with sodium-glucose cotransporter 2
(SGLT-2) inhibitor medications.
 The exact mechanism of euDKA is not entirely
known.

30. EUGLYCEMIC DKA
 Study: Munro JF et al. – Euglycemic DKA exists in
patients who are not on SGLT-2 Inhibitors.
- Vomiting was the most common symptom.
- Most of the cases were Type 1 DM.
- Management was same as DKA.
 Study: Peters AL et al. - SGLT-2 Inhibitors cause
DKA.

31. EUGLYCEMIC DKA

32. WHICH FLUID TO USE?
Study #1: Van Zyl et al - Fluid management in diabetic-
acidosis--Ringer's lactate versus normal saline
(2012).
 This study failed to indicate benefit from using Ringer's
lactate solution compared to 0.9% sodium chloride
solution regarding time to normalization of pH in patients
with DKA. (Although, RL showed faster trend in
normalization of pH in a few patients)
 This study found that patients in the NS group
experienced a decrease in average serum bicarbonate
during the first hour of treatment, whereas patients in
the LR group experienced an increase in average serum
bicarbonate during the first hour of treatment.
 The time to reach a blood glucose level of 14 mmol/l
took significantly longer with the Ringer's lactate
solution.

33. WHICH FLUID TO USE?
Study #2: Chua et al. - Plasma-Lyte 148 vs 0.9% saline
for fluid resuscitation in diabetic ketoacidosis (2012)
 Patients with DKA resuscitated with PL instead of NS
had faster initial resolution of metabolic acidosis and
less hyperchloremia, with a transiently improved blood
pressure profile and urine output.
Study #3: Mahler et al. - Resuscitation with balanced
electrolyte solution prevents hyperchloremic
metabolic acidosis in patients with diabetic
ketoacidosis (2011)
 Resuscitation of DKA patients with BES results in lower
serum chloride and higher bicarbonate levels than
patients receiving NS, consistent with prevention of
hyperchloremic metabolic acidosis.

34. INSULIN HOW?
Study #1: Fisher JN et al. - Diabetic ketoacidosis:
low-dose insulin therapy by various routes
(1977).
 Intravenous infusion of insulin is superior to
subcutaneous route.
Study #2: Umpierrez et al. - Treatment of diabetic
ketoacidosis with subcutaneous insulin aspart
(2004).
 The use of subcutaneous insulin aspart every 1 or 2
h represents a safe and effective alternative to the
use of intravenous regular insulin in the
management of patients with uncomplicated DKA.

35. INSULIN HOW?
Study #3: Umipierrez et al. - Efficacy of subcutaneous
insulin lispro versus continuous intravenous regular
insulin for the treatment of patients with diabetic
ketoacidosis (2004).
 Treatment of adult patients who have uncomplicated diabetic
ketoacidosis with subcutaneous lispro every hour in a non-
intensive care setting may be safe and more cost-effective
than treatment with intravenous regular insulin in the intensive
care unit.
Study #4: Ersoz et al. - Subcutaneous lispro and
intravenous regular insulin treatments are equally
effective and safe for the treatment of mild and moderate
diabetic ketoacidosis in adult patients (2006).
 Treatment of mild and moderate DKA with SC insulin lispro is
equally effective and safe in comparison with IV regular
insulin.

36. TRANSITION FROM IV TO SC
Study #1: O’Malley et al. - Bridge over troubled waters: safe
and effective transitions of the inpatient with
hyperglycemia (2008).
 First dose of SC insulin to be given atleast 1 hour prior to
discontinuation of IV insulin infusion, failing which allows
development of rapid rebound hyperglycemia.
Study #2: Avanzini et al. - Transition from intravenous to
subcutaneous insulin: effectiveness and safety of a
standardized protocol (2011).
 Stable blood glucoses which are less than 180 mg/dL for at
least 4–6 h consecutively (Some studies suggest 24 hours)
 Normal anion gap and resolution of acidosis in DKA
 Stable clinical status; hemodynamic stability
 Not on vasopressors.
 Stable nutrition plan or patient is eating.
 Stable IV drip rates (low variability).

37. REFERENCES
 Harrison’s Principles of Internal Medicine
 British Medical Journal
 www.diabetes.org
 www.uptodate.com
 www.medscape.com
 www.rebelem.com
 www.ncbi.nlm.nih.gov

38. THANK YOU 