JOURNAL CLUB

BRITISH MEDICAL JOURNAL:

DIABETIC KETOACIDOSIS

Dr. Sujay Iyer

TABLE OF CONTENT

Introduction

Definition

Diagnosis

Epidemiology

Pathophysiology

Etiology

Clinical Presentation

Laboratory Evaluation

Management

Complications

Topics of discussion

References

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.

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.

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.

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.

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.

PATHOGENESIS ALGORITHM

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

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.

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.

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!

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.

MANAGEMENT ALGORITHM

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.

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).

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.

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.

COMPLICATIONS

CVT

Myocardial Infarction

DVT

Acute gastric dilatation

Erosive gastritis

Late hypoglycemia

Respiratory distress

Infection (UTI)

Hypophosphatemia

Mucormycosis

CVA

Cerebral edema (rare in adults)

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.).

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.

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).

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.

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.

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.

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%).

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.

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.

EUGLYCEMIC DKA

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.

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 hyperchloremicmetabolic 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.

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.

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.

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).

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

THANK YOU