Diabetic Ketoacidosis

Synonym: DKA

See also: Diabetes and intercurrent illness; hyperosmolar, hyperglycaemic non-ketotic coma (HONK).

This 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, marked glycosuria, significant ketonaemia, ketonuria and acidosis (as shown by a low plasma bicarbonate/arterial pH<7.35).

• 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 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.

History

• The commonest early symptoms of DKA are an insidious onset of increased thirst (polydipsia) and worsening polyuria
• A minority of patients may report increased hunger of late, particularly in children who are presenting with diabetes⁴
• Nausea and vomiting are common and may be associated with non-specific abdominal pain
• Lassitude, weakness and fatiguability often occur
• Global cerebral symptoms such as confusion and disorientation may be noted by the patient or carers
• Progression to an obtunded or comatose state is relatively unusual, but may occur where someone lives alone or is subject to neglect (from others or self)
• Enquire about symptoms of the common precipitants, particularly fever, focal symptoms of infection, dyspnoea, chest pain, palpitations, abdominal pain, recent changes in medication, episodes of overdose/ingestion of poisons, and check recent alcohol intake
• Establish the recent insulin regimen and whether or not it has been adhered to – check that patients on continuous insulin infusion have a functioning pump and patent giving set
• Patients in whom DKA is a presenting feature of their diabetes will invariably have noted recent weight loss, polyuria and polydipsia
• As acidosis progresses patients may notice tachypnoea due to an increase in respiratory rate, attempting to compensate by blowing off CO₂
• Young children may not volunteer any recent symptoms, but their parents are likely to have noted some of the above
• Recent, rapid weight loss is common in children who have DKA as a presenting feature of type 1 diabetes

Examination

• Check temperature, pulse and blood pressure
• There will be signs of gross dehydration such as:
  • Dry mouth
  • Decreased skin turgor/skin wrinkling
  • Sunken eyes
  • Tachycardia with weak pulse
  • Slow capillary refill
  • 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 (may have marginally elevated levels of ketones due to starvation, but should not be grossly elevated)
• Lactic acidosis
• Other causes of metabolic acidosis, particularly overdose of aspirin or ingestion of methanol/ethylene glycol
• Acute pancreatitis
• Septicaemia without ketoacidosis
• Acute abdomen
• Ketoacidosis due to starvation

• Urine dipstick testing should show marked glycosuria and ketonuria
• Assay of blood ketones is more sensitive and specific in detecting ketonaemia but is not always available, although capillary ketone testing kits are becoming increasingly common
• Send urine sample for microscopy and culture
• Plasma glucose will be elevated – where it is extremely high (>30 mmol/l) and there is not significant ketonaemia/ketonuria then consider HONK as a diagnosis
• U&E – 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 depletion of body K⁺ will have occurred; creatinine and urea may be elevated due to pre-renal renal failure or where renal impairment is the primary cause; bicarbonate usually low; obtain specialist medical input to interpret U&Es where glucose is very high.
• Cardiac enzymes should be checked to look for evidence of MI; DKA itself can cause them to be elevated so MI can only be diagnosed in the context of relevant history/examination findings and ECG changes; seek expert advice to interpret the results if abnormal.
• ABGs will show low pH and low HCO₃^–; pCO₂ should be normal but can be depressed by respiratory compensation; low pO₂ may indicate primary respiratory problem as precipitant.
• Plasma osmolarity should be checked, or calculated as below, and will be increased (>290 mOsm/l); if there is impairment of consciousness and osmolarity is <340 mOsm/l then consider another cause for cerebral impairment as it is unusual for it to be caused by DKA itself without a grossly elevated plasma osmolarity.
• Calculate the anion gap as below, which should be elevated (>13 mEq/l)
• If there is abdominal pain check amylase; interpret carefully as DKA itself may raise amylase (thought to be due to parotid irritation).
• FBC often shows raised WCC but this does not necessarily indicate sepsis as it may occur as a primary phenomenon in DKA
• Blood cultures should be taken
• CXR should be arranged to look for evidence of pneumonia or cardiac failure
• ECG is needed to look for evidence of recent MI; potassium abnormalities may cause T- and U-wave changes.
• Where there is impairment of consciousness or focal neurology consider CT/MRI of head to look for stroke/cerebral oedema or other pathology
• If meningitis is a possible precipitant consider LP

• General:
  • ABC – assess airway, breathing and circulation to buy time
  • Alert acute medical/diabetic/paediatric team as appropriate
  • Sit patient upright if they are breathless
  • Commence appropriate therapy on basis of near-patient testing results and clinical scenario if diagnosis is clear; do not wait for lab results.
  • Obtain large-bore peripheral i-v access or insert central venous catheter
  • Place patient in resuscitation area and arrange transfer to high dependency area as soon as feasible
  • Put patient on SaO₂ monitor, continuous ECG monitor and BP monitor
  • If SaO₂ is low give oxygen
  • If consciousness impaired and SaO₂ deteriorating, consider intubation and ventilation after taking senior medical/A&E/anaesthetic advice
  • In unconscious, drowsy or vomiting patients consider passing a nasogastric tube
  • Urinary catheterisation is usually carried out to monitor urine output and allow urinalysis

• Intravenous fluid and electrolyte replacement:
  • Give 1 litre of normal saline over first 30 mins in adults; be cautious if there is evidence of cardiac failure or the patient is very elderly – seek senior advice.
  • If there is significant hypotension consider colloid infusion
  • Fluid replacement in children should be given according to local guidelines and based on child's weight (usually initial infusion of 20 mL/kg over an hour or less)⁴
  • In adults continue rehydration at around 1l/hr over next two hours
  • Total fluid deficit usually around 6l and this should be given over first 24 hrs, depending on subsequent electrolyte results
  • Do not give potassium replacement until lab K⁺ result is available
  • There is total body K⁺ depletion; K⁺ will need to be added to subsequent infusions as insulin causes an intracellular shift of K⁺.
  • Electrolytes must be checked at least every 2 hours for the first 2–4 hours and then 4 hourly thereafter
  • When plasma glucose is <10–15 mmol/l then replace normal saline with 5% glucose or dextrose-saline infusion to prevent over-rapid correction of blood glucose and hypoglycaemia
  • Infusion of bicarbonate remains controversial as it causes the generation of CO₂ which can worsen acidosis if there is insufficient respiratory drive; it may also increase the risk of cerebral oedema; it can be given to severely acidotic patients with pH≤6.9 in specialist hands.
  • DKA leads to phosphate depletion but this rarely causes significant clinical problems; there is no evidence that its routine administration improves outcome; where there may be clinical effects due to its deficiency its replacement should be considered on a case-by-case basis by a specialist physician.³

• Insulin therapy:³
  • Initially give infusion of 6 U/hr as fast-acting soluble insulin
  • If there is delay in instituting infusions and K⁺ is >3.3 mmol/l then a bolus of 10U may be given by IV or IM routes
  • Aim is to reduce plasma glucose by 3–5 mmol/hr
  • If capillary/plasma glucose has not fallen by at least 3 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.
  • Use a sliding scale (adult example given below) to determine hourly insulin dose based on capillary/plasma glucose
  • Children's insulin dose should be based on weight and local/national guidelines

• Further measures:
  • Ongoing care and monitoring of the effects of treatment should be carried out by the acute medical/diabetic/paediatric team as appropriate, in a setting that allows careful analysis of clinical and biochemical response to therapy, according to latest guidelines
  • Any precipitating illness should be managed optimally as per current guidance
  • Heparinisation 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
  • 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.

• Cerebral oedema is 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
• Iatrogenic hypokalaemia
• Cardiac dysrhythmia due to electrolyte disturbance (particularly K⁺) or acidosis
• Myocardial suppression due to 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
• Adult respiratory distress syndrome
• Death

• 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 casemix 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

• Failing to detect the early symptoms and signs of DKA in diabetic patients with intercurrent illness
• Avoidable delays in assessment and diagnosis in primary care or emergency departments
• Incorrect interpretation of electrolyte values in the presence of severe hyperglycaemia
• False readings for creatinine due to interference of ketones with assay
• Always interpreting raised WCC as indicative of infection, without realising that it can be elevated by DKA itself (the same is thought to be true of a raised temperature)
• Misinterpretation of elevated amylase (may be due to pancreatitis but salivary glands can be the source – consider checking pancreatic isozyme level if this is available)
• Over-interpretation of triglyceride levels found to be elevated in the acute phase; although hypertriglyceridaemia may cause pancreatitis and then DKA, the metabolic derangement of DKA itself will inevitably increase free fatty acid and triglyceride levels.
• Reliance on urinary ketone levels alone (3-hydroxybutyrate concentrations in plasma are 2–3 times those of acetoacetate, but in acidotic states this ratio is increased further); as therapy corrects the acidosis, levels of acetoacetate may rise and thus methods that measure only acetoacetate concentration in urine could suggest that ketonaemia is worsening;³ if direct assay of blood ketones is available to monitor the effect of therapy then it should be used.
• Failure to diagnose DKA when urinary ketones are negative (blood assay should be performed where all other indicators suggest DKA)
• Failing to look for or detect a treatable underlying cause for DKA such as MI, UTI, occult sepsis, perinephric abscess or a cause of an acute abdomen
• Failure to recognise early symptoms and signs of cerebral oedema, particularly in children
• Over-rapid correction of hyperglycaemia in the initial phase
• Failure to adequately rehydrate before commencing insulin therapy or using anti-acidosis treatments such as bicarbonate
• Discontinuing monitoring of plasma potassium once it is back in the normal range; it is subject to marked variability in the early phase of the illness and its treatment.
• Infusing potassium without monitoring its level, or continuous ECG monitoring
• Failing to consider alternative causes of metabolic acidosis in a diabetic patient, particularly salicylate overdose, methanol ingestion, ethylene glycol toxicity and alcohol excess
• Failing to consider hyperosmolar, hyperglycaemic non-ketotic state in those presenting with very high glucose and possibility of type 2 diabetes (particularly if undiagnosed)