Diabetic Ketoacidosis

Synonym - DKA

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

Diabetic ketoacidosis (DKA) is a life-threatening acute complication of diabetes mellitus. It occurs when insulin therapy is absent, or becomes inadequate for the current physiological state, usually as a result of intercurrent illness.

• It is normally seen in type 1 diabetics and may be a presenting feature of undiagnosed type 1 diabetes, particularly in children.
• However, it is not unheard of in type 2 diabetics,^1,2 although they are much more likely to suffer from a hyperosmolar, hyperglycaemic, non-ketotic state (HONK) when their diabetic control is deranged.

It manifests clinically as a state of severe uncontrolled diabetes and gross dehydration which will inevitably progress unless it is corrected by rehydration with intravenous fluids and adequate insulin. Its characteristic biochemical features are:

• Severe hyperglycaemia
• Significant ketonaemia
• Severe metabolic acidosis
• Glycosuria and ketonuria

• Progressive hyperglycaemia occurs due to inadequate circulating insulin, preventing cellular uptake of glucose – leading to a state of 'cellular starvation'.
• This induces pancreatic glucagon secretion and release of other stress hormones such as catecholamines, cortisol and GH.
• These humoral factors encourage glycogenolysis and gluconeogenesis, further raising plasma glucose.
• The stress response encourages proteolysis and lipolysis, forming free fatty acids, which are then converted to the ketoacids acetoacetate, beta-hydroxybutyrate and acetone, (due to absence of intracellular glucose required for their metabolic conversion) leading to a metabolic acidosis.
• The very high glucose levels cause a huge osmotic diuresis and gross dehydration.
• Dehydration may reduce tissue perfusion and further derange metabolism by causing lactic acidosis.
• A vicious cycle of progressive metabolic disruption is set in train, continuing until rehydration and insulin therapy are given.

European and American series show an annual incidence of DKA of 1–5% among type 1 diabetics, which has remained constant over the last decade or so. It is much commoner in younger than older type 1 diabetics, and is about twice as common in females compared to 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, derived from series of DKA cases (per cent of total cases in brackets):

• Infection (19-56%, may be overestimated as DKA can cause raised white count and vasodilatation in and of itself)
• Inadequate insulin/non-compliance (15-41%)
• Undiagnosed diabetes (10-22%)
• Other medical illness (10-12%)
• Cardiovascular disease (3-6%)
• Cause unknown (4-33%)

Specifically, conditions such as pneumonia, urinary tract infection, stroke, myocardial infarction, pregnancy, hypothyroidism, pancreatitis, pulmonary embolism, surgery and new medication (notably corticosteroids, sympathomimetics, α- and β-blockers and diuretics) are found as the provoking event for an episode of DKA. Any physiologically stressing illness or event has the potential to cause the condition. Interestingly, some women are more likely to go into DKA at the time of menstruation.⁴

History

• The commonest early symptoms of DKA are
  • An insidious onset of increased thirst (polydipsia)
  • Worsening polyuria
  • Weight loss (especially if first presentation)
  • Nausea and vomiting
  • Non-specific abdominal pain
  • Lassitude, weakness and fatiguability often occur
  • Breathlessness due to an increase in respiratory rate, attempting to compensate by blowing off CO₂
• Global cerebral symptoms e.g. confusion, disorientation. This 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
• Establish recent insulin regimen and dietary patterns

Examination

• Unwell, dehydrated with tendency for rapid deterioration
• Check temperature, pulse and blood pressure
• 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

• Smell the breath for the characteristic fruity/musty odour of ketones – 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

• 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

• 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 as a primary phenomenon in 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 effect of acidosis, normal or occasionally low but overall there is cell depletion of K⁺
  • Urea and creatinine - elevated due to pre-renal renal failure or where renal impairment is the primary cause
  • Arterial blood gas - 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
  • CK - rhabdomyolysis may exist also (also increased in myocardial infarction)
  • Amylase - if suspect pancreatitis
  • Blood cultures
• 12 lead ECG
• CXR
• AXR - if indicated by history and examination
• CT/MRI head - if 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 below). It is increased in both DKA and HONK as both are hyperosmolar states. However, in HONK it is much higher .
• Calculate the anion gap as below, which should be elevated (>13 mmol/L).

Resuscitation

• Always begin with resuscitation of the patient.
• So begin by assessing airway, breathing and circulation.
• Remember the airway may be compromised if the patient is drowsy or obtunded.

Initial monitoring and management

• Put patient on SaO₂ monitor, continuous ECG monitor and BP/HR monitor.
• Obtain large-bore peripheral i-v access or insert central venous catheter.
• Urinary catheterisation is usually carried out to monitor urine output and will also allow urinalysis.

1. Correct dehydration – this will improve the acidosis (along with insulin and thus bicarbonate not required)
2. Insulin – this will reduce the glucose level and improve the acidosis (aim for a steady fall in glucose of approximately 4 mmol/L/hr)
3. Potassium supplementation
4. Treatment of any precipitating illness

Correct dehydration

• Assess severity of dehydration e.g. capillary refill time, dry mucous membranes, tachycardia, hypotension, oliguria.
• If severely dehydrated or shocked - administer a colloid infusion.
• Otherwise begin with N. saline 0.9% (with or with out potassium – see below).
• One example of a regimen is as follows - 1 litre of normal saline over the first 30 mins, followed by 1litre per hour over the next two hours and then 1litre over 2 hours.
• At this point the patient and their blood results and observations should be reviewed and then further intravenous fluids prescribed.
• Repeat U & E’s should also be sent at this time.

Replace potassium

• There is always depletion in total body potassium, however the initial serum K+ values may not be low, instead they can be normal to high reflecting the transcellular shift caused by the ketoacidosis.
• This masks the deficit which is uncovered once insulin has commenced.
• Potassium should be checked immediately – the arterial blood gas will provide a quick result.
• Potassium replacement therapy should be started immediately if the patient is hypokalaemic – but only if potassium level is<5.0-5.5 mmol/L and the patient is passing urine.
• Very rarely potassium replacement therapy may need to be given before insulin if the patient is profoundly hypokalaemic to begin with e.g. K+ <3.5 mmol/L.
• If the patient is hyperkalaemic do not give potassium therapy – recheck after 30 minutes.

Replace insulin

• Treatment with insulin will not only return the blood sugar level to normal but also prevent further lipolysis and ketogenesis.
• Start intravenous insulin sliding scale - see local guidelines for regimen.
• If there is any delay in starting IV insulin and K⁺ is >3.3 mmol/L then a bolus of 10U may be given by SC or IM routes (bear in mind that absorption may be variable due to poor perfusion).
• After an initial, often sizeable, drop in blood glucose from rehydration the aim is to reduce the blood glucose by <= 4 mmol/L/hr.
• When the blood glucose falls to <12 mmol/L change fluids to 5% dextrose.
• If the blood glucose rises reduce the amount of glucose infused and if necessary increase the insulin infusion.

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.

• Low molecular weight heparin and 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.

• Patients should ideally be managed in a HDU type 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 2-4 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/hr.
• Plasma glucose should also be checked regularly as capillary blood glucose may be inaccurate in 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.

• Cerebral oedema - commoner in children/adolescents where it affects around 1% of cases of DKA. Mortality is significant and estimated at 20–90%. Presents in first 24 hours with headache, behavioural changes and urinary incontinence progressing to abrupt neurological deterioration and coma.
• Pulmonary oedema due to overzealous fluid replacement or as a spontaneous phenomenon
• Iatrogenic hypoglycaemia or 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 of, or complication of DKA)
• Diabetic retinopathic changes may be seen prior to or after therapy for DKA
• Hypophosphataemia - rarely has significant clinical effects
• Adult respiratory distress syndrome
• Death still occurs

• Prognosis is excellent in cases that are appropriately managed and which present before progression to coma.
• Prognosis worsens with age and the severity of the underlying precipitating pathology (particularly MI, sepsis and pneumonia).
• The presence of coma at presentation, hypothermia or persistent oliguria are poor prognostic indicators.
• Overall mortality rates vary from 1–10% depending on case mix and expertise of management.
• There has been a marked reduction of mortality in expert centres over the last 20 years; some units now have mortality rates of <1%.

• Education programs for diabetic patients, particularly concerning what to do in cases of illness ('sick day rules'); see separate article on Diabetes and Intercurrent Illness.
• 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.