Diabetic ketoacidosis (DKA)

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Definition
Pathophysiology
Precipitating conditions
Investigations
Key initial investigations
Management
Monitoring;
Discontinuation:
Fluid therapy in children
Insulin infusion in children

Definition

DKA is an acute metabolic complication of diabetes resulting from insulin deficiency. DKA is characterised by the triad of:

Hyperglycaemia
Acidosis
Ketonaemia

Diagnostic criteria

Ketonaemia (≥3 mmol/L) OR ketonuria (> 2+ on urine dipstick)
Blood glucose > 11 mmol/L OR known diabetes mellitus
Blood pH <7.3 OR bicarbonate < 15 mmol/L

Note the blood glucose value may rarely be normal or only slightly elevated in DKA

Background
DKA is the most common acute hyperglycaemic complication of type 1 diabetes mellitus. DKA is potentially fatal and requires prompt medical intervention.

Pathophysiology

DKA arises due to a lack of insulin in the body. Insulin has a number of functions including:

Inducing cellular uptake of glucose from plasma
Inhibiting gluconeogenesis and glycogenolysis (decreasing glucose production)
Inducing glycogen synthesis from glucose

All of the above actions result in a decrease in plasma glucose. Note that one of the ways insulin achieves the above is by inhibition of glucagon and other hormones (catecholamines, cortisol and growth hormone) that would normally stimulate a rise in blood glucose. Thus when insulin is deficient levels of these antagonist hormones rise compounding the hyperglycaemic effect.

Hyperglycaemia via its osmotic effects leads to water and solute (sodium and potassium) loss. This manifests as polyuria, polydipsia and dehydration. In some cases the fluid shifts can lead to cerebral oedema.

Another function of insulin is inhibition of lipolysis. Insulin deficiency therefore results in increased lipolysis and high levels of free fatty acids in the blood. These free fatty acids are ultimately metabolised into ketone bodies through a process called ketogenesis. Ketone bodies are acidic. The body will attempt to buffer the pH change by metabolic (bicarbonate buffering system) and ventilatory means. The result is typically metabolic acidosis (low bicarbonate) with respiratory compensation (high respiratory rate and low pCO2).

Precipitating conditions

Insulin requirements increase during times of stress therefore conditions that increase physiological stress increase the bodies insulin requirement. In diabetic patients this increased demand may not be met and DKA can result.

Precipitating factors include:

Infection
Physiological stress e.g. pregnancy, trauma or surgery
Non-compliance with insulin therapy (unintentional or deliberate).
Acute medical conditions e.g. stroke, myocardial infarction, pancreatitis
Drugs eg, steroids, thiazides, SGLT2 inhibitors.

Clinical features

Polydipsia and polyuria
Signs of dehydration (dry mucous membranes. decreased skin turgor, slow capillary refill, tachycardia and hypotension)
Ketotic breath smell (described as smelling like pear and nail-polish remover)
Tachypnoea or Kussmaul respiration
Confusion, reduced GCS or even coma
Headache
Nausea and vomiting
Lethargy
Abdominal pain

DKA is normally seen in people with type 1 diabetes but can occur in type 2 diabetes mellitus. It should be suspected in all known diabetics who are unwell.

Note DKA is a relatively common first presentation of type 1 diabetes. Remember the average age of diagnosis of type 1 DM is 13 years old so DKA should be considered in unwell children.

In the UK nearly 4% of people with type 1 diabetes experience DKA each year

Investigations

Key initial investigations

Venous blood gas to determine pH (many blood gas analysers will also give U&E and glucose results though these should be checked with a formal serum sample)
Calculate the plasma osmolality: high (>320 osmol/kg) in DKA
Urine dipstick for glucose and ketones
Blood glucose (capillary blood glucose may be checked prior to formal plasma sample)
U&E's (hyponatraemia & hyperkalaemia are most common but these abnormalities often reverse in severe DKA due to diuresis i.e. hypernatraemia & hypokalaemia)
FBC

Investigations to consider
A number of investigations may be appropriate to assess for a precipitating cause and complications. Note a septic screen is often performed. Further investigations include:

ECG & cardiac monitoring
Cardiac enzymes
Chest X-ray
MSU for culture and sensitivities
Blood cultures
LFT's and amylase
Pregnancy test
Creatinine kinase (rhabdomyolysis is a rare complication of DKA. The mechanism is not fully understood)

pH <7.1 indicates severe DKA

Consider involving intensive care

Management

Fluid replacement, electrolyte correction, insulin therapy and treatment of any underlying cause are the key components of management.

Fluid replacement: most patients with DKA are deplete around 5-8 litres. Isotonic saline is used initially. Please see an example fluid regime below.
Insulin therapy: an intravenous infusion should be started at 0.1 unit/kg/hour. Once blood glucose is < 15 mmol/l an infusion of 5% dextrose should be started
Electrolyte correction: Additional potassium may be required to treat hypokalaemia.

Example fluid therapy regime in adults

In adults who present with a systolic BP (SBP) < 90mmHg 500ml of 0.9% sodium chloride solution should be given over 10-15 minutes. If SBP remains below 90mmHg give further 500ml over 10-15 minutes whilst requesting senior input. Most patients require between 500 to 1000ml be given rapidly.

Potassium should not usually be given with these initial fluid boluses. Add potassium to the second litre of intravenous fluids, if required, which is given over 1 hour

Consider possibility of underlying pathology such as sepsis and involving the ITU/critical care team. Once SBP above 90mmHg give 1000ml 0.9% sodium chloride over next 60 minutes as per the fluid therapy table below.

In adults who present with a systolic BP >90mmHg the following fluid replacement regimen is advised.

Fluid	Volume
0.9% sodium chloride 1L	1000ml over 1st hour
0.9% sodium chloride 1L with potassium chloride	1000ml over next 2 hours
0.9% sodium chloride 1L with potassium chloride	1000ml over next 2 hours
0.9% sodium chloride 1L with potassium chloride	1000ml over next 4 hours
0.9% sodium chloride 1L with potassium chloride	1000ml over next 4 hours
0.9% sodium chloride 1L with potassium chloride	1000ml over next 6 hours

Add 10% glucose 125ml/hr if blood glucose falls below 14 momol/l

More cautious fluid replacement in young people aged 18-25 years, elderly,
pregnant, heart or renal failure. (Consider HDU and/or central line)

Potassium should be added to fluid depending on the serum potassium level as per the table below:

Potassium level in first 24 hours (mmol/L)	Potassium replacement in mmol/L of infusion solution
Over 5.5	Nil
3.5-5.5	40
Below 3.5	Senior review as additional potassium needs to be given

Example insulin regime in adults
Insulin infusion should be commenced after fluid replacement is underway. Commence a fixed rate intravenous insulin infusion (0.1unit/kg/hr) based on estimate of weight).

Infusion solution is made up of 50 units human soluble insulin (Actrapid or Humulin S) made up to 50ml with 0.9% sodium chloride solution.

If patient normally takes long acting insulin analogue (Lantus, Levemir) continue at usual dose and time.

Monitoring, targets & discontinuation
Monitoring; Hourly capillary blood glucose Hourly capillary ketone measurement if available Venous bicarbonate and potassium at 60 minutes, 2 hours and 2 hourly thereafter 4 hourly plasma electrolytes Continuous cardiac monitoring if required Continuous pulse oximetry if required
Targets: review insulin infusion rate if: Capillary ketones not falling by at least 0.5 mmol/L/hr Venous bicarbonate not rising by at least 3 mmol/L/hr Plasma glucose not falling by at least 3 mmol/L/hr
Discontinuation: Continue fixed rate IVII until ketones less than 0.3 mmol/L, venous pH over 7.3 and/or venous bicarbonate over 18 mmol/L Do not discontinue intravenous insulin infusion until 30 minutes after subcutaneous short acting insulin has been given

Fluid therapy in children

Shocked children should be given a fluid bolus of 10ml/kg. Repeated 10ml/kg boluses should be given if patient remains shocked until they are adequately resuscitated (up to a total of 40 ml/kg at which stage inotropes should be considered).

All children and young people who are not shocked with mild, moderate or severe DKA and are felt to require IV fluids should receive a 10 ml/kg 0.9% sodium chloride bolus over 30 minutes.

Once initial fluid therapy has been given, the circulating blood volume should have been restored. Further fluid requirements are calculated as follows:

Further fluid requirement = Deficit + Maintenance

Deficit is calculated based on pH as follows:

Assume a 5% fluid deficit in children and young people in mild or moderate DKA (indicated by a blood pH 7.1-7.29 &/or bicarbonate 5-15)
Assume a 10% fluid deficit in children and young people in severe DKA (indicated by a blood pH <7.1 &/or bicarbonate <5)

Notes on deficit:

The volume of any fluid boluses given for resuscitation in children with shock SHOULD NOT be subtracted from the estimated fluid deficit.
The initial 10ml/kg bolus given to all non-shocked patients requiring IV fluids SHOULD BE subtracted from total calculated fluid deficit.
The deficit volume should be given over 48 hours in addition to appropriate maintenance fluids

Maintenance fluid is given according to the Holliday - Segar formula:

100 ml/kg/day for the first 10 kg of body weight
50 ml/kg/day for the next 10 to 20 kg
20 ml/kg/day for each additional kilogram above 20 kg

Type of fluid
Except for initial fluid boluses the fluid used should be: 0.9% sodium chloride with 20 mmol potassium chloride in 500 ml (40 mmol per litre) until blood glucose levels are less than 14 mmol/l

Insulin infusion in children

In children start insulin infusion 1-2 hours after beginning intravenous fluid therapy due to cerebral oedema risk
Use 50 units of soluble insulin in 50 ml 0.9% sodium chloride if possible
Use a soluble insulin infusion at a dosage between 0.05 and 0.1 units/kg/hour.
Insulin infusion may need halting if child develops hypokalaemia (K+ <3.0 mmol/l)

Complications of DKA and its treatment

Gastric stasis
Thromboembolism
Arrhythmias secondary to electrolyte disturbance
Iatrogenic complications of fluid therapy: cerebral oedema, hypokalaemia, hypoglycaemia
Acute respiratory distress syndrome (pulmonary oedema)
Acute kidney injury