Synonym: DKA

See also separate articles: Diabetes and Intercurrent Illness; Hyperosmolar Hyperglycaemic Non-ketotic Coma (HONK); Childhood Ketoacidosis.

Diabetic ketoacidosis (DKA) is a medical emergency with a significant morbidity and mortality. It should be diagnosed promptly and managed intensively. DKA is characterised by hyperglycaemia, acidosis, and ketonaemia:

• Ketonaemia (3 mmol/L and over), or significant ketonuria (more than 2+ on standard urine sticks).
• Blood glucose over 11 mmol/L or known diabetes mellitus (the degree of hyperglycaemia is not a reliable indicator of diabetic ketoacidosis and the blood glucose may rarely be normal or only slightly elevated in DKA).
• Bicarbonate below 15 mmol/L and/or venous pH less than 7.3.

DKA is normally seen in type 1 diabetics and may be a presenting feature of undiagnosed type 1 diabetes, particularly in children. However DKA may rarely occur in type 2 diabetics, although people with type 2 diabetes are much more likely to suffer from a hyperosmolar hyperglycaemic non-ketotic state (HONK) when their diabetic control is deranged.^1,2

Epidemiology

• European and American series show an annual incidence of diabetic ketoacidosis (DKA) of 1-5% among type 1 diabetics, which has remained constant over the last decade or so.³
• DKA is much more common in younger than older type 1 diabetics, and is about twice as common in females compared with males, probably due to the diabetogenic effect of pregnancy.³
• Around 20% or so of cases are thought to occur in undiagnosed type 1 diabetics.

Precipitating conditions³

Listed in approximate order of frequency, precipitating conditions include:

• Infection, e.g. pneumonia, urinary tract infection.
• Inadequate insulin or non-compliance.
• Other medical illnesses, e.g. pancreatitis, pulmonary embolism, hypothyroidism.
• Cardiovascular disease, stroke, myocardial infarction.
• Cause unknown (4-33%).

Any physiological stress (including pregnancy, trauma or surgery) has the potential to initiate DKA. Medication (notably corticosteroids, sympathomimetics, α- and β-blockers and diuretics) may provoke an episode of DKA. Some women are more likely to go into DKA at the time of menstruation.⁴

Presentation

History

• The most common early symptoms of DKA are:
  • An insidious onset of increased thirst (polydipsia).
  • Worsening polyuria.
  • Weight loss (especially if first presentation).
  • Nausea and vomiting.
  • Nonspecific abdominal pain.
  • Lassitude, weakness and fatiguability, which often occur.
  • Breathlessness due to an increase in respiratory rate, attempting to compensate by blowing off CO₂.
• Global cerebral symptoms (e.g. confusion, disorientation), which may progress to an obtunded or comatose state.
• Enquire about:
  • Symptoms of the common precipitants, e.g. fever, dyspnoea, chest pain, palpitations, abdominal pain.
  • Recent changes in medication.
  • Recent alcohol intake.
• Recent insulin regimen and dietary patterns.

Examination

• Unwell, dehydrated with a tendency for rapid deterioration. There will be signs of gross dehydration such as:
  • Dry mucous membranes.
  • Decreased skin turgor/skin wrinkling.
  • Sunken eyes.
  • Slow capillary refill.
  • Tachycardia with weak pulse.
  • Hypotension.

• Check temperature, pulse and blood pressure.
• Smell the breath for the characteristic fruity/musty odour of ketones - the smell is akin to pear drops or nail-polish remover.
• Respiratory compensation of acidosis can lead to tachypnoea or Kussmaul's respiration (very deep, slowly rhythmic breathing).
• Examine the chest for signs of pneumonic consolidation.
• Check cardiovascular system for signs of cardiac failure, pericardial rub and murmurs.
• Examine the abdomen to identify any intra-abdominal precipitant.
• Assess mental status and orientation.
• Perform a screening neurological examination.
• Check the skin surface for evidence of abscesses, boils or other rashes.

Differential diagnosis

• Alcoholic ketoacidosis.
• Hyperosmolar hyperglycaemic non-ketotic state.
• Lactic acidosis.
• Other causes of metabolic acidosis, e.g. aspirin overdose or ingestion of methanol/ethylene glycol.
• Acute pancreatitis.
• Septicaemia without ketoacidosis.
• Acute abdomen.
• Ketoacidosis due to starvation.

Investigations

• Capillary blood glucose (remember to send a plasma glucose also).
• Urine dipstick testing shows marked glycosuria and ketonuria (also send urine for microscopy and culture).
• Assay of blood ketones is more sensitive and specific in detecting ketonaemia but is not always available.
• Blood tests:
  • Plasma glucose will be elevated.
  • FBC - raised WCC is often seen but this does not necessarily indicate sepsis as it may occur in diabetic ketoacidosis (DKA).
  • Electrolytes - Na⁺ may be high due to dehydration, low due to interference of glucose/ketones with assay, or normal; K⁺ may be high due to the effect of acidosis, normal or occasionally low but overall there is cell depletion of K⁺.
  • Urea and creatinine - elevated due to prerenal renal failure or where renal impairment is the primary cause.
  • Arterial blood gases - metabolic acidosis with low pH and low HCO₃; pCO₂ should be normal but can be depressed by respiratory compensation; low pO₂ may indicate primary respiratory problem as a precipitant.
  • Cardiac enzymes - if myocardial ischaemia/infarction suspected, e.g. troponin.
  • Creatine kinase - rhabdomyolysis may also exist (also increased in myocardial infarction).
  • Amylase - if pancreatitis is suspected.
  • Blood cultures.
• 12 lead ECG.
• CXR.
• Abdominal X-ray - if indicated by history and examination.
• CT/MRI scan of the head - if there is impairment of consciousness or focal neurology.
• Lumbar puncture - may be indicated if meningitis is a possible precipitant.

Plasma osmolality and anion gap

• Plasma osmolality - should be checked, or calculated (see box, below). It is increased in both DKA and hyperosmolar hyperglycaemic non-ketotic coma (HONK), as both are hyperosmolar states. However, in HONK it is much higher .
• Calculate the anion gap (as detailed in box, below), which should be elevated (>13 mmol/L).

Management

Assessment of severity⁵

The presence of one or more of the following may indicate severe DKA and admission to a high dependency unit (HDU), with insertion of a central line and immediate senior review:

• Blood ketones above 6 mmol/L.
• Bicarbonate level below 5 mmol/L.
• Venous/arterial pH below 7.1.
• Hypokalaemia on admission (below 3.5 mmol/L).
• Glasgow coma scale (GCS) less than 12.
• Oxygen saturation below 92% on air (assuming normal baseline respiratory function).
• Systolic blood pressure below 90 mm Hg.
• Pulse rate over 100 or below 60 beats per minute.
• Anion gap above16.

Initial management and monitoring

• Immediate resuscitation as required.
• Put the patient on SaO₂ monitor, continuous ECG monitor and blood pressure/heart rate monitor.
• Obtain large-bore peripheral intravenous (IV) access or insert central venous catheter.
• Urinary catheterisation is usually carried out to monitor urine output and will also allow urinalysis.
• Low molecular weight heparin and thromboembolic deterrent (TED) stockings are given prophylactically (but see local guidelines). It should be considered for those who are obtunded or comatose, or have other risk factors for venous thromboembolism, although as yet there are no concrete trial data to support this approach.
• In unconscious, drowsy or vomiting patients, consider passing a nasogastric tube.

Correct dehydration⁵

• The main aims for fluid replacement are to restore circulatory volume, clearance of ketones and correction of electrolyte imbalance.
• The fluid deficit should be replaced as crystalloid (0.9% sodium chloride solution is the recommended fluid of choice). In patients with kidney failure or heart failure, as well as the elderly and adolescents, the rate and volume of fluid replacement may need to be modified.

Insulin therapy⁵

• Insulin is required for suppression of ketogenesis, reduction of blood glucose and correction of electrolyte imbalance.
• It is now recommended that 'sliding scale' insulin be replaced with weight-based fixed rate IV insulin infusion (IVII). A fixed-rate IVII calculated on 0.1 units/ per kilogram infusion is recommended.
• Aim to reduce capillary blood glucose by 3 mmol/L/hour (rapid reduction of glucose causes rapid changes in serum osmolality and may precipitate cerebral oedema).
• A priming dose (bolus) of insulin should not be used.
• Long-acting insulin analogues should be continued as normal.
• Introduction of 10% glucose is recommended when the blood glucose falls below 14 mmol/L. It is important to continue 0.9% sodium chloride solution to correct circulatory volume. Glucose should not be discontinued until the patient is eating and drinking normally.
• Convert back to an appropriate subcutaneous regime when biochemically stable (blood ketones less than 0.3, pH over 7.3) and the patient is ready and able to eat.

Metabolic treatment⁵

• The recommended targets are (if these rates are not achieved then the fixed-rate IVII rate should be increased):
  • Reduction of the blood ketone concentration by 0.5 mmol/L/hour.
  • Increasing the venous bicarbonate by 3 mmol/L/hour.
  • Potassium being maintained between 4.0 and 5.0 mmol/L:
    • Hypokalaemia and hyperkalaemia are potentially life-threatening conditions during the management of diabetic ketoacidosis (DKA).
    • Because of the risk of prerenal acute kidney injury associated with severe dehydration, it is recommended that no potassium be prescribed with the initial fluid resuscitation or if the serum potassium level remains above 5.5 mmol/L.
    • Potassium will almost always fall as the DKA is treated with insulin, and so 0.9% sodium chloride solution with potassium 40 mmol/L should be used as long as the serum potassium level is below 5.5 mmol/L and the patient is passing urine.
    • If the serum potassium level falls below 3.5 mmol/L, the potassium regimen needs review. An increase in rate of 0.9% sodium chloride solution with potassium 40 mmol/L infusion may be possible. Otherwise, a more concentrated potassium infusion will be needed.
• Bicarbonate administration is not routinely recommended.
• Phosphate should not be supplemented routinely.

Treat any precipitating illness

• Measures to actively detect a precipitating cause should be pursued.
• One clue to the possibility of an unrecognised underlying cause is if the pH and anion gap fail to improve despite the aforementioned measures. In this case, review insulin therapy and consider other further investigations, e.g. serial ECGs in silent cardiac ischaemia.
• If an underlying cause is identified then it should also be treated, as appropriate.
• If there are reasonable clinical grounds to suspect infection as the precipitant then appropriate antibiotic therapy should be given (usually broad-spectrum blind treatment); routine antibiotics are not advised.

Monitoring

• Patients should ideally be managed in an HDU type of setting, or even ITU if they are severely unwell.
• Electrolytes and venous bicarbonate must be checked at least every 1-2 hours for the first 2-4 hours and then 2- to 4-hourly thereafter (frequency will depend upon the individual clinical scenario).
• Monitor hourly fluid balance.
• Monitor capillary blood glucose every hour with an aim to reduce plasma glucose by 3-5 mmol/hour.
• Plasma glucose should also be checked regularly, as capillary blood glucose may be inaccurate in diabetic ketoacidosis (DKA).
• If capillary/plasma glucose has not fallen by at least 4 mmol/L in the first hour, then check adequacy of rehydration and patency of infusion lines; if these are not at fault then double the dose of insulin for the next hour.
• When plasma glucose is <12 mmol/L then replace normal saline with 5% dextrose to prevent over-rapid correction of blood glucose and hypoglycaemia.

Recent guidance has recommended:⁵

• Venous and not arterial blood should be used to monitor pH and bicarbonate.
• Blood ketone and glucose meters should be used for near patient testing when available.
• Electrolyte measurements can be obtained from most modern blood gas analysers and should be used to monitor sodium, potassium and bicarbonate levels - with intermittent laboratory confirmation.

Complications

• Cerebral oedema:⁵
  • Cerebral oedema causing symptoms is relatively uncommon in adults during diabetic ketoacidosis (DKA), although asymptomatic cerebral oedema may be common.
  • Cerebral oedema usually occurs within a few hours of the initiation of treatment. It presents in the first 24 hours with headache, behavioural changes and urinary incontinence, progressing to abrupt neurological deterioration and coma.
  • Cerebral oedema associated with DKA is more common in children than in adults. In the UK around 70-80% of diabetes-related deaths in children under 12 years of age are caused as a result of cerebral oedema.
• Pulmonary oedema:⁵
  • Pulmonary oedema has only been rarely reported in DKA. Pulmonary oedema usually occurs within a few hours of the initiation of treatment.
  • Elderly patients and those with impaired cardiac function are at particular risk, and monitoring of central venous pressure should be considered.
• Iatrogenic hypoglycaemia: severe hypoglycaemia is also associated with cardiac arrhythmias, acute brain injury and death.⁵
• Iatrogenic hypokalaemia.
• Cardiac dysrhythmia due to electrolyte disturbance (particularly K⁺) or metabolic acidosis.
• Myocardial suppression due to metabolic acidosis.
• Venous thromboembolism.
• Myocardial infarction (may be a cause or a complication of DKA).
• Diabetic retinopathic changes may be seen prior to or after therapy for DKA.
• Hypophosphataemia - rarely has significant clinical effects. Although there is a large loss of total body phosphate in DKA, there is no evidence of benefit of phosphate replacement but phosphate measurement and replacement should be considered in the presence of respiratory and skeletal muscle weakness.⁶
• Adult respiratory distress syndrome.

Prognosis

• Mortality rates have fallen significantly in the last 20 years from 7.96% to 0.67%. The mortality rate is still high in developing countries and among non-hospitalised patients.⁵
• Prognosis worsens with age and the nature and severity of the underlying precipitating pathology (particularly myocardial infarction, sepsis and pneumonia).
• The presence of coma at presentation, hypothermia or persistent oliguria are poor prognostic indicators.
• Cerebral oedema remains the most common cause of mortality, particularly in young children and adolescents.⁵
• The main causes of mortality in the adult population include severe hypokalaemia, adult respiratory distress syndrome, and comorbid states such as pneumonia, acute myocardial infarction and sepsis.⁵

Prevention

• Education programmes for diabetic patients, particularly concerning what to do in cases of illness ('sick day rules'); see separate Diabetes and Intercurrent Illness article.
• Provision of handheld ketone meters and education on management of ketonaemia.⁵
• Patients with diabetes who are admitted with diabetic ketoacidosis (DKA) should be counselled about the precipitating cause and early warning symptoms of DKA.
• Similar education for carers of those who do not manage their own diabetes.
• Improved awareness of the management of diabetes and intercurrent illness, and the presentation and early management of DKA, in the medical/allied healthcare professions.

Document references

1. Valabhji J, Watson M, Cox J, et al; Type 2 diabetes presenting as diabetic ketoacidosis in adolescence. Diabet Med. 2003 May;20(5):416-7. [abstract]
2. Umpierrez GE, Smiley D, Kitabchi AE; Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med. 2006 Mar 7;144(5):350-7. [abstract]
3. English P, Williams G; Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J. 2004 May;80(943):253-61. [abstract]
4. Ovalle F, Vaughan TB 3rd, Sohn JE, et al; Catamenial diabetic ketoacidosis and catamenial hyperglycemia: case report and review of the literature. Am J Med Sci. 2008 Apr;335(4):298-303. [abstract]
5. Clinical practice consensus guidelines 2009, International Society for Pediatric and Adolescent Diabetes (ISPAD) (September 2009)
6. Joint British Diabetes Societies Inpatient Care Group, The Management of Diabetic Ketoacidosis in Adults, March 2010

Internet and further reading

• Diagnosis and management of type 1 diabetes in children, young people and adults, NICE Clinical Guideline (July 2004)
• Guidelines for the management of diabetic ketoacidosis, British Society of Paediatric Endocrinology and Diabetes (2009)

Acknowledgements