Ketoacidosis is a high anion gap metabolic acidosis due to an excessive blood concentration of ketone bodies (keto-anions). Ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) are released into the blood from the liver when hepatic lipid metabolism has changed to a state of increased ketogenesis. A relative or absolute insulin deficiency is present in all cases.

 

The three major types of ketosis are:
    * Starvation ketosis
    * Alcoholic ketoacidosis
    * Diabetic ketoacidosis

 

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When hepatic glycogen stores are exhausted (eg after 12-24 hours of total fasting), the liver produces ketones to provide an energy substrate for peripheral tissues. Ketoacidosis can appear after an overnight fast but it typically requires 3 to 14 days of starvation to reach maximal severity. Typical ketoanion levels are only 1 to 2 mmol/l and this will not much alter the anion gap. The acidosis even with quite prolonged fasting is only ever of mild to moderate severity with ketoanion levels up to a maximum of 3 to 5 mmol/l and plasma pH down to 7.3. This is probably due to the insulin level, which though lower, is still enough to keep the FFA levels less than 1mM. This limits substrate delivery to the liver restraining hepatic ketogenesis. Ketone bodies also stimulate some insulin release from the islets. The anion gap will usually not be much elevated.

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Alcoholic ketoacidosis

Typical Presentation
This typical situation leading to alcoholic ketoacidosis is a chronic alcoholic who has a binge, then stops drinking and has little or no oral food intake. Food intake may be limited because of vomiting. The two key factors are the combination of ethanol and fasting. Presentation is typically a couple of days after the drinking binge has ceased.
Pathophysiology
The poor oral intake results in decreased glycogen stores, a decrease in insulin levels and an increase in glucagon levels. Hepatic metabolism of ethanol to acetaldehyde and then to acetate both involve NAD+ as a cofactor. The NADH/NAD+ ratio rises and this:
    * inhibits gluconeogenesis
    * favours the production of beta-hydroxybutyrate over acetoacetate
The insulin deficiency results in increased mobilisation of free fatty acids from adipose tissue. The decreased insulin/glucagon ration results in a switch in hepatic metabolism favouring increased beta-oxidation of fatty acids. This results in an increased production of acetylCoA which forms acetoacetate (a keto-acid). (The pathophysiology of the insulin deficiency and the switch in hepatic metabolism is discussed in more detail in DKA section below.)
Other points to note:
    * Volume depletion is common and this can result in increased levels of counter-regulatory hormones (eg glucagon)
    * Levels of FFA can be high (eg up to 3.5mM) providing plenty of substrate for the altered hepatic lipid metabolism to produce plenty of ketoanions
    * GIT symptoms are common (eg nausea, vomiting, abdominal pain, haematemesis, melaena)
    * Acidaemia may be severe (eg pH down to 7.0)
    * Plasma glucose may be depressed or normal or even elevated
    * Magnesium deficiency is not uncommon
    * Patients are usually not diabetic

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An absolute or relative lack of insulin leads to diabetic metabolic decompensation with hyperglycaemia and ketoacidosis. A precipitating factor (eg infection, stress) which causes an excess of stress hormones (which antagonise the actions of insulin) may be present.
Situations leading to DKA
The most common situations in patients presenting with DKA are:
    * Infection as precipitant (30% of cases)
    * Treatment non-compliance (20%)
    * New diagnosis of diabetes (25%)
    * No known precipitating event (25%)

 

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Hyperglycaemia & Ketoacidosis cause most symptoms
Two basic mechanisms underlie the pathophysiology of DKA: hyperglycaemia and ketoacidosis. The above discussion shows how both these problems follow from relative insulin deficiency coupled with stress hormone excess. The problem however is not just of hepatic over-production of glucose and ketones but also of peripheral underutilisation of both glucose and ketones.
Acetoacetic acid (pKa 3.58) and beta-hydroxybutyric acid (pKa 4.70) dissociate producing H+ which is buffered by HCO3- in the blood. For each anion produced there is a loss of one bicarbonate. The increase in the anion gap (representing the increase in the unmeasured acid anions) should approximately equal the decrease in the [HCO3-]. A ‘pure’ high anion gap metabolic acidosis results.

 

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Development of hyperchloraemic acidosis
In some cases, a hyperchloraemic metabolic acidosis develops: this is most common during the treatment phase. Why does this occur? Acetoacetate and beta-hydroxybutyrate are moderately strong acids and even at the lowest urinary pH are significantly ionised. They are excreted with a cation (usually Na+ or K+) to maintain electroneutrality. The net effect is the loss of ‘potential bicarbonate’ equal to the level of urinary ketone body loss. The HCO3- is replaced in the blood by Cl- derived from renal reabsorption, gut absorption or (particularly) IV saline administered during treatment. The effect is to cause a rise in plasma [Cl-] and the anion gap returns towards normal despite the persistence of the metabolic acidosis.

 

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A predominant hyperchloraemic acidosis (defined as a DKA patient with a delta ratio < 0.4) is present in about 10% of patients on arrival at hospital and in about 70% after 8 hours of treatment. Patients who are more severely dehydrated retain more keto-anions and have a lower incidence of hyperchloraemic acidosis.

 

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Administration of large volumes of normal saline in resuscitation of patients with acute DKA promotes continued diuresis (and continued loss of ketone bodies with Na+ as the cation) and provides plenty of chloride to replace the lost ketoanions. This hyperchloraemic acidosis is slower to resolve because the keto-anions needed for regeneration of bicarbonate have been lost. Patients who have been able to maintain fluid intake during development of their illness are more likely to have a hyperchloraemic acidosis component present on admission.

 

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It should not just be assumed that the patient only has a diabetic ketoacidosis. Possible complicating acid-base disorders are:
    * Lactic acidosis due to hypoperfusion and anaerobic muscle metabolism
    * Metabolic alkalosis secondary to excessive vomiting
    * Respiratory acidosis due to pneumonia or mental obtundation
    * Respiratory alkalosis with sepsis
    * Renal tubular acidosis (type 4)

 

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DKA management

Cerebral oedema is a dangerous complication that occurs in about 1% of children and adolescents with DKA.
Onset of headache and deteriorating level of consciousness typically occurs between 2 and 24 hours after onset of treatment. Onset of symptoms is often sudden. Mortality is about 70% in this group.
Recommended treatment is immediate IV mannitol in a dose of 0.5 to 2.0 g/kg body weight. Dexamethasone or hyperventilation have no proven benefit. (Lebovitz, 1995)

 

DKA : Routine Management
1. General
    * Oxygen by mask
    * Urinary catheter
    * Consider low dose calcium heparin to decrease risk of arterial thrombosis
    * Investigate for underlying illness (history, examination, cultures of blood, urine or sputum, chest xray, ECG etc)
2. Fluids
Immediate aim is to restore intravascular volume to improve tissue perfusion.
Replacement solutions (eg Normal saline or Hartmann’s solution) are appropriate for initial management. Subsequently fluids need to be adjusted to provide ‘free water’ to replenish intracellular fluid and to provide glucose. Maintenance fluids such as dextrose-saline or oral fluid intake are appropriate at this later stage depending on the individual circumstances but such solutions should not be used initially.
Colloids are necessary only in shocked patients. Colloids are expensive and have a low but significant risk of reactions. Albumin solutions are not required.
3. Potassium
Serum level is commonly normal or high (due to the acidosis) at presentation despite the presence of a large total body potassium deficit (due to renal losses). The best approach is to commence therapy with fluid and insulin and monitor the serum [K+].
Potassium replacement can be commenced when the [K+] falls below 5 mmols/l. Infuse at 10 to 30 mmol/hr dependent on [K+]. Rates greater than 20 mmols/hr are reserved for severe hypokalaemia and require at least hourly [K+] monitoring. Never commence a potassium infusion without checking the level.
4. Insulin
Fluid resuscitation is necessary to deliver insulin to its sites of action in liver, muscle and adipose tissue. Rehydration itself will cause a fall in blood glucose level.
A typical regime would be to give a stat dose initially (say 10-20U IV) and commence the patient on a continuous insulin infusion at 5 to 10 U/hr decreasing to 1-3 U/hr to maintain blood glucose at 5 to 10 mmols/l. A paediatric regime would be: insulin at 0.1U/kg IV loading dose then infusion at 0.1U/kg/hr.
The blood glucose always falls on this regime and control of blood glucose is almost never a problem. Insulin reverses the peripheral mobilisation of FFA and alters hepatic metabolism to switch off ketone body production. These effects are maximal at insulin levels of 100 micromoles/l and this level is achieved with the low dose regime. The average rate of fall of plasma glucose at this insulin level is about 4.5 mmol/l/hr. There is no advantage in giving more insulin once the ceiling level is reached. This absence of additional effectiveness with very high insulin levels has been referred to in the past as insulin resistance
5. Phosphate
Though a total body deficiency is always present, it has not been possible to show that acute phosphate administration makes any difference to outcome. However the occasional patient develops extremely low phosphate levels and phosphate administration is undoubtably necessary in these patients and must be given. Phosphate level on presentation is typically high so phosphate administration should be delayed.
By twelve hours after commencement of treatment, the majority (90%) of patients are hypophosphataemic. Ampoules of phosphate available in my hospital contain about 15 mmoles of phosphate and 20 mmoles of potassium and one ampoule can be diluted in the IV fluids and infused over an hour.
6. Bicarbonate
Sodium bicarbonate in DKA has arguably a minor role is in urgent management of serious arrhythmias due to hyperkalaemia in DKA. However, glucose-insulin is the preferred treatment in this patient group.
None of the studies done in DKA have shown any benefit of bicarbonate treatment. Potential problems are sodium overload, CSF acidosis, intracellular acidosis, exacerbation of hypokalaemia, rebound alkalosis and impaired tissue oxygen delivery (shift of oxyhaemoglobin dissociation curve). After treatment of DKA starts, the slowest biochemical parameter to recover is usually the serum bicarbonate - this is especially so when substantial amounts of ketones have been lost in the urine. New bicarbonate is generated when the condition is reversed and the ketones are metabolised. Bicarbonate administration is not necessary.
7. Monitoring
Management in an Intensive Care Unit is recommended.
Monitoring should include observations of airway, breathing, circulation and level of consciousness, serial blood gases and electrolytes, urinary ketones and urine output. Serum lactate is occasionally useful. A Biochemistry Flowchart of results is strongly recommended.
Cerebral oedema presents 2 to 12 hours after start of treatment
Cerebral oedema is the commonest single cause of mortality, particularly in children. It typically develops after treatment has commenced. A headache or decreasing level of consciousness are the usual initial sign. Onset may be sudden. Treat urgently with IV mannitol. Intubation for airway protection may be required. Maintain hyperventilation in ventilated patients.
8. Treat the Underlying Cause
The commonest precipitants in young diabetics are inadequate insulin (eg first presentation of diabetes, omission of doses) and infection. Often no specific cause can be found. In older diabetics, DKA may be precipitated by a major medical illness (esp infection). Antibiotics or surgical management are necessary in some cases. Patient education to prevent further episodes is very important.