28. DKA + HONK

Question 1

What is the mechanism of ketone production in diabetes?

Answer 1

Ketones are produced from acetyl-CoA

in the liver mitochondria and are used as fuel by the brain and muscle.

Acetyl-CoA is the end product of β-oxidation of fatty acids.

If there is excess fatty acid breakdown (as in diabetes and starvation),

then there will not be enough oxaloacetate to join with all the
acetyl-CoA in order for it to enter the citric acid cycle.

In this situation the excess acetyl-CoA is diverted into ketone production.

The accumulation of ketoacids (b-hydroxybutyrate and aceto-acetate)
cause a metabolic acidosis when levels reach about 10 mmol/l.

The rate of production is usually slow, but can be as fast as 1 mmol/min.

Question 2

Conditions required for ketone production

Answer 2

Insulin deficiency. However, only a very low level of insulin is required to
inhibit hepatic ketogenesis.

Counter-regulatory hormone excess (an increase in glucagon,
catecholamines and glucocorticoids)

Question 3

Further pathophysiology . . Renal effects

Answer 3

Insulin lack accelerates glycogenolysis and gluconeogenesis.

An osmotic diuresis results from the high blood glucose
and causes uncontrolled urinary loss of K+, Na+ and water.

This decreased ECF volume leads to pre-renal failure.

Renal excretion of glucose is then inhibited,
which leads to a further increase in plasma glucose level.

Hyperglycaemia moves water out of cells into the ECF.

This can decrease the serum [Na+].

Nausea and vomiting frequently complicate the biochemical picture.

Question 4

What are the actions of insulin?

Answer 4

Insulin prevents

proteolysis, glycogenolysis and lipolysis and promotes uptake and storage of fuel.

It is an anabolic hormone.

Insulin binds to a specific membrane-bound receptor and alters intracellular cAMP levels

Question 5

Insulin action on Carbohydrate

Answer 5

Increases glycogen synthesis
(phosphofructokinase and glycogen synthase).

Inhibits glycogenolysis and gluconeogenesis.

The increased uptake of glucose into cells
(such as adipose tissue and muscles) by increased glucokinase
activity is now considered much less
important.

Question 6

Fat

Answer 6

Decreases triglyceride breakdown in adipocytes (triglyceride–lipase).

Increases fatty acid synthesis in the liver due to activation of acetyl CoA carboxylase.

Activates lipoprotein lipase, which splits triglycerides enabling the fatty
acids to enter adipose tissue for storage.

Increases esterification of fatty acids with glycerol in adipose tissue.

Question 7

Protein

Answer 7

Decreases proteolysis.

Increases uptake of amino acids into cells.

Increases mRNA translation.

Increased K+ and Mg2+ transport into cells

Question 8

How would you manage a diabetic with ketoacidosis?

Answer 8

Fluid deficit/shock
Insulin deficiency
Hypokalaemia
Acidosis
Underlying/precipitating cause

Question 9

History

Answer 9

Examination Sunken eyes

Reduced skin turgor

Acetone smell on breath

Kussmaul’s breathing

Low BP

Decreased conscious level

Question 10

Investigations

Answer 10

Arterial blood gases for acid–base balance

Anion gap

Plasma glucose

Plasma Na+ concentration is usually low as an osmolar compensation for the
high glucose. If the sodium is high, this represents severe water loss.

Plasma K+ concentration may be high on presentation, but the total body
potassium is low due to the absence of insulin allowing it to drift out of the cells.

Urea and creatinine
Pre-renal failure from ECF depletion
Diabetic nephropathy

Osmolality of serum

Question 10

Investigations

Answer 10

Arterial blood gases for acid–base balance

Anion gap

Plasma glucose

Plasma Na+ concentration is usually low as an osmolar compensation for the
high glucose. If the sodium is high, this represents severe water loss.

Plasma K+ concentration may be high on presentation, but the total body
potassium is low due to the absence of insulin allowing it to drift out of the cells.

Urea and creatinine
Pre-renal failure from ECF depletion
Diabetic nephropathy

Osmolality of serum

Serum + Urinary Ketones

PO4 levels tend to follow K+.
CXR, ECG, FBC, blood cultures, urine culture and sputum culture to look for
underlying cause.

Question 11

Serum/urinary ketones (aceto-acetate).

Answer 11

The ratio of B-hydroxybutyrate to aceto-acetate is governed by pH.

As the pH decreases, the ratio increases.

Conventional bedside tests for ketones only react with acetoacetic acid and
therefore it is possible to have a very high B-hydroxybutyrate concentration
and have the test only show a trace of ketones.

Question 12

Monitoring

Answer 12

ECG/heart rate/BP/temp./resp. rate/urine output/NG tube

Regular blood glucose monitoring

HDU/ICU

Question 13

Treatment

Answer 13

ECF volume should be replaced with normal saline (CVP line may be
needed).

Start with 1–2 litres in the first hour. More than 6 litres may be needed.

Insulin (actrapid) at 0.1 unit/kg bolus and then 0.1 unit/kg per hour.

Potassium
replacement should begin when serum [K+] becomes
less than 4.5 mmol/l.
20 mmol/hour if K+ is 4–5 mmol/l,
40 mmol/hour if 3–4
and 40–60 mmol/hour if <3 mmol/l.

Question 14

Rx

Answer 14

5% or 10% Dextrose should be started when the plasma glucose falls below
14 mmol/l.

Bicarbonate therapy is controversial.
Several centres use it if pH<7.0 or if
the [HCO3 −] is <5.0 mmol/l.

The problems with it are:
Large Na+ load
Increased CO2 production (may easily enter cells
and cause a paradoxical intracellular acidosis)

Hypokalaemia

Metabolic alkalosis as ketoacids disappear

Left-shift of oxyhaemoglobin dissociation curve

The underlying cause must be treated (myocardial infarction, infection,
etc.).

Question 15

Anion gap

Answer 15

= (Na+ + K+) – (HCO3 − + Cl−)

Normal value = 10 – 18 mmol/l.

Represents unmeasured anions, e.g. albumin, sulphate and phosphate.

An increase is due to an unmeasured anion that is
balanced by H+ causing an acidosis, e.g. lactate or ketoacids.

Question 16

Complications

Answer 16

Shock and lactic acidosis

Coma

Cerebral oedema

Hypothermia

DVT

Iatrogenic electrolyte imbalance

Question 17

Definition

Answer 17

DKA is a serious complication of diabetes mellitus. It can occur both in
type 1 insulin-dependent, and type 2 non-insulin-dependent disease, although it is
more common in the former. It is characterized by the biochemical triad of hyperglycaemia,
metabolic acidosis and ketonaemia and is a manifestation of an extreme
disorder of carbohydrate metabolism.

Question 18

Hyperosmolar Non-Ketotic Acidosis (HONK)

Answer 18

is a pH that is close to normal (>7.30).

less common than DKA and typically presents in patients with
type 2 diabetes and in an older age group,

usually in their sixties
(reported average age is 57–69 years)

rather than in their thirties as is the case with DKA

It is usually precipitated by a dehydrating illness, most commonly by
infection, but a large number of physiological and pharmacological stressors can
provoke the same effect.

40% of cases HONK is the first presentation of diabetes.

Patients may present with altered cerebration

(although coma is a feature of fewer than 20% of cases)

clinical signs of severe dehydration and with deranged
biochemistry: glucose >33 mmol l–1, serum osmolality 320 mOsm kg–1 or greater,
pH >7.30, HCO3 >15 mmol l–1, but with no ketonaemia. Quoted mortality is high
at 10–20%.

Question 19

Management

Answer 19

Precipitants: there is always a precipitating cause of DKA and HONK. Disparate
factors can be involved, some of which are amenable to treatment. Onset can be
provoked by infection, inadequate insulin treatment, alcohol abuse, trauma, myocardial
infarction and the use of certain drugs, amongst them β-adrenoceptor blockers,
corticosteroids and thiazide diuretics.

Question 20

Treatment aims:

Answer 20

the goals are to restore normovolaemia and adequate tissue perfusion,
to reduce plasma glucose and osmolality towards normal, to clear ketones at a
steady rate (in DKA) and to correct the deranged acid–base and electrolyte status.

Question 21

HONK management

Answer 21

correction of dehydration is the first priority,

initially with NaCl 0.9% 1.0–2.0 litres over 1–2 hours.

Insulin should not be given until the volaemic status has improved,

otherwise the cellular uptake of K+, glucose and water will further
deplete the intravascular compartment. T

hereafter, glucose 5% should be given to further replete
intracellular dehydration, at which point insulin (with K+)
can be given at a starting rate of 0.1 units kg–1 h–1

and aiming initially for a blood glucose concentration
of around 15 mmol l–1, and keeping it at between 10–15 mmol

Too rapid a correction can be associated with the development of
cerebral oedema, particularly in the rare cases of HONK in children.

Question 22

Phosphate

Answer 22

: phosphate, like potassium, shifts from the intracellular to the extracellular
compartment, while the osmotic diuresis contributes to urinary losses. During
treatment of DKA the phosphate re-enters cells to unmask the total body depletion.
There are theoretical problems associated with hypophosphataemia which include
muscle weakness, haemolytic anaemia, cardiac depression and depleted 2,3-DPG, but
there is no evidence that supplemental phosphate improves outcome in these cases.
The mean phosphate deficit is around 1 mmol kg1.

Question 23

Bicarbonate

Answer 23

: the administration of HCO3 - remains contentious.

Bicarbonate does not cross the blood–brain barrier,

and so, if given, it will worsen intracellular cerebral acidosis.

It can also reduce extracellular potassium and may provoke cardiac arrhythmias.

If the patient’s pH is >6.8, there is no evidence of any outcome benefit.

Question 24

‘Euglycaemic ketoacidosis’:

Answer 24

This is a described entity whose name is misleading. By
‘euglycaemic’ is meant a blood glucose concentration of less than 16.7 mmol l1, and
so in some patients the sugar will still be relatively high. The key factor in its
pathogenesis appears to be the patient’s recent oral intake. If the patient is well fed,
then liver glycogen stores are high and ketogenesis is suppressed. If the patient has
been unable to eat, for example because of intractable vomiting, then glycogen stores
are depleted and the liver is primed for ketogenesi