KETOACIDOSIS AND HYPOGLYCAEMIA

Diabetic ketoacidosis

measurement of total ketone bodies is restricted to a few clinical

chemistry laboratories. A working definition (e.g. a medical
emergency requiring hospitalization for rehydration and insulin)
is perhaps more useful. Meters for bedside measurement of
3-hydroxybutyrate are available, but more experience with them
is needed to assess their benefit in the management of DKA.1 It is
important to appreciate that meters measure 3-hydroxybutyrate
in the blood, whereas conventional urine testing for ketones
detects acetoacetate. Total ketone body concentration is the
sum of these.

Malcolm Nattrass

Abstract
Diabetic ketoacidosis is a life-threatening condition requiring immediate
hospitalization and treatment. Pathogenesis is an absolute or relative
insulin deficiency in the presence of elevated catabolic hormone levels.
Patients are dehydrated with Kussmaul respiration and a characteristic
smell of acetone on the breath. Hyperglycaemia is accompanied by
a metabolic acidosis due to excessive circulating ketone bodies. The
aims of treatment are to rehydrate and give insulin. Potassium supplementation is invariably necessary and careful monitoring is necessary.
With a satisfactory response to treatment in glucose and the acidosis infusion fluid is changed and insulin dose is halved as glucose falls below 15
mmol/L. When acidosis persists it is probably best to maintain the same
dose of insulin and prevent hypoglycaemia with 10% glucose infusion.
Complications occur including vomiting with aspiration, thrombotic
events, and cerebral oedema. Marked hyperglycaemia is not accompanied
by acidosis. Treatment is identical to that for ketoacidosis. Lactic acidosis
in a diabetic is likely to be due to hypoxia although occasional cases are
seen with metformin use in a patient with impaired renal function. It may
be necessary to give large amounts of bicarbonate. Mortality rates are
high.

Pathogenesis
Understanding the pathogenesis of DKA is fundamental to
a rational approach to management. The predominant problem is
insulin deficiency. This may be:

a gross lack of insulin, as occurs in patients with newly
diagnosed type 1 diabetes

a relative lack of insulin, as when catabolic hormone
concentrations rise and insulin secretory reserve is limited, as
occurs in patients with type 2 diabetes who become unwell
or, in an analogous situation, in type 1 diabetes patients who
do not increase their insulin at times of intercurrent infection.
The common feature of conditions that precipitate DKA (infection, trauma, insulin errors and myocardial infarction) (Table 1)
is the accompanying 3e7-fold increase in concentrations of
catabolic hormones, such as catecholamines, cortisol, glucagon
and growth hormone.2 The effect of all of these hormones is to
antagonize insulin at the tissue level, thereby accentuating the
effect of insulin deficiency. In addition, catecholamines can
inhibit insulin secretion, exacerbating insulin deficiency.
Insulin deficiency and catabolic hormone excess promote
hepatic glucose output and inhibit peripheral glucose uptake,
leading to hyperglycaemia. Hyperglycaemia results in glycosuria,
increased urinary loss and eventually dehydration, but it is the
effects on the fat cell that is of major importance in producing the
acidosis. Breakdown of triglyceride to glycerol and fatty acids is
extremely sensitive to inhibition by insulin, and is also sensitive
to promotion by catabolic hormones, particularly catecholamines. Fatty acids are transported in the blood to the liver
where they are metabolized to ketone bodies.

Keywords dehydration; diabetic ketoacidosis; fatty acids; hyperglycaemia; hyperglycaemic hyperosmolar non-ketotic coma; insulin; lactic
acidosis

Diabetic ketoacidosis (DKA, Figure 1) is a life-threatening

condition requiring immediate hospitalization and treatment.
Recognition of this condition is of utmost importance, because
even small delays can have an impact on survival. Mortality is
about 5e10% overall, but is higher in the elderly.

Epidemiology
DKA can occur at any age and in any patient who has diabetes
with significant insulin deficiency. Type 2 diabetes is recognized
as a disease of both insulin resistance and reduced insulin
secretion, but the natural history is progressive loss of b-cell
reserve. It is therefore unsurprising that most studies of ketoacidosis find that many patients have type 2 diabetes, though
ketoacidosis is most common in type 1 diabetes.

Clinical features
Increased production and reduced use of glucose lead to hyperglycaemia exceeding the renal threshold. Loss of glucose in the
urine is accompanied by water and electrolytes, and despite the
thirst generated, it becomes impossible for the patient to maintain hydration by drinking. Dehydration ensues and this cardinal
feature should alert the clinician to the need for hospitalization.
Some spontaneous decarboxylation of acetoacetate allows
excretion of acetone through the lungs, giving a characteristic
odour on the breath that is variously described as pear drops,
nail varnish or musty apples. This odour may be overpowering, but cannot be detected by everyone. Ketone bodies are
weak acids and the hydrogen ions produced must be buffered.
Bicarbonate ions are used, but as the buffering capacity is
overwhelmed, plasma pH and bicarbonate decline and respiration is stimulated. The typical respiration of metabolic acidosis is
rapid, deep breathing termed Kussmaul respiration or air

Definition
DKA is defined as metabolic acidosis with plasma bicarbonate
less than 15 mmol/L and total ketone body concentration more
than 5 mmol/L. This definition is largely theoretical, because

Malcolm Nattrass PhD FRCP FRCPath was Consultant Diabetologist at the

University Hospital Birmingham NHS Trust and Senior Lecturer at the
University of Birmingham, UK from 1979 to 2008. Competing interests:
none declared.

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KETOACIDOSIS AND HYPOGLYCAEMIA

Development of diabetic ketoacidosis

Pathogenesis

Clinical presentation

Hyperglycaemia

Thirst
Polyuria
Dehydration
Drowsiness
Confusion
Coma

Plasma glucose
Glycosuria

Hyperketonaemia

Abdominal pain
Vomiting
Kussmaul respiration

Total ketone bodies

Heavy ketonuria
Metabolic acidosis
Acetone on breath

Insulin
Hepatic glucose output
Peripheral glucose use

Catecholamines
Glucagon
Cortisol
Growth hormone

Triglyceride breakdown
Ketogenesis

Biochemical investigations

Figure 1

Management

hunger. Abdominal pain and vomiting are common presenting

features that may result from the acidosis. Coma is uncommon;
most patients are lucid or exhibit mild-to-moderate disturbance
of consciousness.

The main aims of treatment in DKA are to rehydrate the patient,

and to give insulin in a sufficient amount and for as long as
necessary. In doing so, blood glucose concentration will fall but it
may be necessary to continue to give significant amounts of
insulin even after blood glucose concentration has normalized.
Attention to the serum potassium is also important. One of the
most important tasks is ensuring quality of management,
particularly accurate record-keeping. Many units have developed
protocols and record charts.

Investigations
Hyperglycaemia should always be confirmed with a laboratory
estimation of plasma glucose. In many hospitals, detection of
ketone bodies continues to rely on heavy ketonuria.
Blood gas analysis reveals the typical features of metabolic
acidosis e low pH, pCO2 and bicarbonate.
There may be confusion over the lactate result. Most blood
gas analysers now also supply a measurement of serum
lactate. Commonly, there is a small increase in lactate
concentration in DKA, and this usually rises as treatment is
begun. Initial concentrations seldom exceed 5 mmol/L, the
level at which lactic acidosis is diagnosed, and lower
concentrations should not lead to any hesitation in treating
for ketoacidosis.
Measurement of electrolytes is important, because concentrations can seldom be predicted. Although there is a total body
deficit of sodium and potassium, circulating concentrations
may be low, normal or high. Pseudohyponatraemia is
uncommon, following the introduction of ion-specific electrodes for electrolyte measurement, but the initial plasma ion
concentration also reflects the effect of hyperglycaemia in
drawing water into the circulating volume and diluting the ion
concentration.

Insulin
Short-acting insulin should always be given. If the intramuscular
route is used,3 a dose of 20 units is given immediately the
diagnosis of DKA is confirmed, followed by 6 units given hourly.
The intravenous route4 is preferred, with an infusion rate of 6
units/h. When there is a satisfactory clinical and biochemical
response and plasma glucose declines to less than 15 mmol/L,
the infusion rate is changed to 3 units/h. This is continued until
the patient can safely be transferred to the normal insulin
regimen.
It cannot be overemphasized that the aim is to give insulin to
correct the metabolic abnormalities. That is, not just to lower
glucose but, particularly, to inhibit the generation of ketone
bodies.5 For this reason, regimens in which insulin infusion is
titrated against blood glucose (sliding scales) are usually inadequate for the management of DKA. If the giving of insulin is
thwarted by a rapid decline in glucose, the correct response is to
increase glucose infusion. Elaborate sliding scales of insulin
administration should not be used in DKA, because they almost
always result in administration of insufficient insulin. Hypoglycaemia should be prevented by infusion of glucose and not by
reduction of insulin.

Precipitating causes of diabetic ketoacidosis

C
C
C
C
C

Infection e 30%
Errors in management e 15%
Newly diagnosed diabetes e 10%
Other identifiable medical disease e 5%
No cause found e 40%

Rehydration
At presentation, the cumulative fluid deficit is 5e12 L, and fluid
loss continues with persisting glycosuria. The initial choice of
fluid is sodium chloride 0.9% at a rate exceeding continuing
losses; e.g. 1 L/h for 1 h, 1 L/2 h for 2 h and 1 L/4 h for 4 h, and

Table 1

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KETOACIDOSIS AND HYPOGLYCAEMIA

then 1 L 6-hourly until the deficit is corrected. Once plasma

glucose declines below 15 mmol/L, the fluid given is changed to
glucose 5%, at a rate that allows continued insulin delivery and
avoids hypoglycaemia. Fluid replacement rates should always
take account of continuing losses as well as co-existing conditions, such as ischaemic heart disease and renal impairment.

Follow-up

Potassium
Both hypokalaemia and hyperkalaemia must be avoided by
regular measurement of serum potassium and adjustment of
infusion rates of potassium chloride. Infusion rates of 40 mmol/L
may be required if hypokalaemia threatens. It must be remembered that serum potassium decreases with rehydration, with
insulin and with bicarbonate.

Other types of hyperglycaemia10

On recovery, all patients should be seen by a diabetes nurse

specialist for reinforcement of sick-day rules; that is, the
importance of blood glucose and urinary ketone testing during
illness. This should also address other aspects of management,
such as insulin injection technique and sites.

Hyperosmolar hyperglycaemic state (formerly known as

hyperosmolar non-ketotic diabetic coma) is less common than
DKA and predominantly affects the elderly and those of AfroCaribbean origin. Severe hyperglycaemia (up to, and occasionally exceeding 100 mmol/L) is not accompanied by metabolic
acidosis. Ketones may be detected, but these seldom exceed 1
of ketonuria. Treatment is identical to that of DKA, though the
argument has been made that the absence of ketone bodies and
acidosis may allow greater sensitivity to insulin. With low-dose
insulin regimens this is rarely obvious or a problem, and similar
infusion regimens to those used in the treatment of DKA can be
safely used. It may also be necessary to modify fluid replacement
protocols, giving less to the elderly patient. Mortality is high
(about 33%), usually from underlying disease, but survivors may
have diabetes that can subsequently be controlled by diet or diet
plus oral agents.

Bicarbonate
Use of bicarbonate is contentious; there is little evidence of
benefit and considerable evidence of risk.6 On somewhat flimsy
grounds some advocate its use when the pH is less than 7.0,
claiming that a transient increase in pH makes the patient feel
better. Bicarbonate is probably best reserved for those with
marked hyperkalaemia at presentation (as a rapid means of
increasing potassium excretion) or impending cardiovascular
collapse.

Complications

Lactic acidosis occurs in patients with diabetes as in those

without. The most common precipitating cause is hypoxia from
circulatory collapse. In addition, diabetes per se may lead to
lactic acidosis without any other precipitating cause and metformin therapy can occasionally result in lactic acidosis particularly if renal function deteriorates either acutely or chronically
in a patient on metformin. Treatment of the acidosis is difficult;
the prime aim should be to correct the cause. When the acidosis
requires urgent treatment, sodium bicarbonate should be used.
Unlike ketoacidosis, large volumes of bicarbonate may be
necessary. Specialist advice is required. Mortality is high (about
50%); death is usually from the precipitating disease.
Hyperlactataemia in the course of treating ketoacidosis should
not be confused with lactic acidosis, in which the acidosis is from
lactate rather than ketones.
A

Complications occur in about 6% of episodes of DKA in centres

with an interest in the management of the condition; this figure is
probably higher in other centres. Most deaths occur in the
elderly,7 who are less able to cope with the fluid shifts.
Occasionally, death occurs from vomiting and aspiration
pneumonia. At presentation, the stomach is dilated and contains
significant amounts of fluid. An argument could be made for
routine use of a nasogastric tube, but insertion is fraught with
danger in patients with disturbed consciousness and it is unclear
whether the risk of precipitating vomiting outweighs the potential benefits.
The rare death of a young patient in DKA usually results from
cerebral oedema.8 Numerous possible explanations for the
development of cerebral oedema have been advanced, but none is
convincing. Typically, the patient appears to make good initial
progress, but a catastrophic collapse ensues. There is little
evidence that mannitol and dexamethasone improve outcome, but
there is little else to offer; the condition is serious, leading to death
or physical impairment with or without mental impairment.
The lungs rather than the brain may be affected, leading to
adult respiratory distress syndrome.
Acidosis that does not respond to treatment is a significant
finding and may herald serious underlying problems, such as
undetected sepsis. The first step is to check that insulin is being
delivered. Bicarbonate infusion is not the answer in this situation, though infusion produces a transient increase in plasma
bicarbonate concentration. The correct approach is to try to
increase peripheral ketone body uptake and metabolism. Intracellular metabolism of ketone bodies generates intracellular
alkali and corrects the acidosis. There is some evidence that
doubling the dose of insulin and giving glucose 10% help to
promote this.9

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