Diabetic ketoacidosis
Pathophysiology
- Insulin deficiency leads to fasting hyperglycaemia, counter-regulatory response (despite raised blood glucose levels) and subsequent ketosis
- Beta-hydroxybutyrate and acetic acid are responsible largely for the ketoacidosis seen in DKA and are in equlibrium
- Acetic acid + NADH = beta-HB + NAD
- Acetic acid is metabolised to acetone (another major ketone body)
- Low insulin levels decrease ability of tissues to use ketones as fuel source, further increasing ketonaemia
- Persistently elevated serum glucose leads to glucosuria and osmotic diuresis
- Resulting volume depletion worsens hyperglycaemia and ketonaemia
- RAS system, upregulated by volume depletion, exacerbates renal potassium losses already occuring through osmotic diuresis leading to profound whole body potassium depletion
- Chloride is retained in exchange for ketoanions lost in urine adding a hyperchloraemic metabolic acidosis to ketoacidosis
- Paradoxical vasodilatation occurs due to adipose tissue breakdown and prostaglandin release
Causes of DKA
- Omission of insulin
- Pump failure
- Infection
- Pregnancy
- Hyperthyroidism
- Sympathomimetic abuse
- Steroids, thiazides, antipsychotics, sympathomimetics
- Heat-related illness
Clinical presentations
- Osmotic diuresis leads to renal loss of sodium, potassium, chloride, phosphorous, magnesium and calcium
- Prostaglandin release may also play a role in abdominal pain, nausea, vomiting frequently seen
- As volume depletion progresses, SC insulin is poorly absorbed into systemic circulation
- ALOC likely multifactorial due to metabolic acidosis, hyperosmolarity, low extracellular fluid volume and haemodynamic collapse
- Alteration of conscious state correlates more closely to serum osmolality > 320mOsm/L than with severity of metabolic acidosis
- Absence of fever DOES NOT rule out infection as underlying cause
- Hypothermia may occur due to inappropriate vasodilation
- Serum lipase can be elevated in DKA but is more specific for pancreatitis
Diagnosis
- Definition
- Metabolic acidosis pH <7.3 or serum bicarb <15
- Ketonaemia >3 mmol/L or 2+ on urine (may miss beta-hydroxybutyrate early)
- BSL >11
- Severe
- pH <7.1, bicarb <,5, K <3.5 on admission, GCS <12, SBP <90 or SpO2 <92%
- Caveats
- Patients with liver failure may have impaired gluconeogenesis and lower glucose levels
- Patients who abuse alcohol also may have impaired gluconeogenesis
- SGLT-2 inhibitors can induce euglycaemic DKA in T2DM
- Nitroprusside reagent used in serum and urine dipstick ketone tests are only sensitive to acetic acid (and acetone marginally; Beta-HB not at all)
- As patient improves, ketone levels will rise as body converts more acidic beta-hydroxybutyrate to acetic acid
- If severe vomiting, metabolic alkalosis can mask acidosis. In this situation elevated anion gap may be the only clue
- If PaCO2 is lower than expected, suggests primary respiratory alkalosis and may be early clue to pulmonary disease as underlying cause
- Leukocytosis is common due to stress/haemoconcentration
- Absolute band count >10000microlitres suggests underlying infection
- Check ECG for electrolyte changes + underlying MI
Differential diagnosis
- HAGMA
- Alcoholic ketoacidosis (glucose usually low or normal)
- Beta-hydroxybutyrate predominates so dipsticks can be negative
- Starvation ketoacidosis (glucose usually low or normal)
- Renal failure
- Lactic acidosis
- Ingestions – Salicylates, ethylene glycol, methanol, paracetamol
- Check serum salicylates and osmolar gap is suspicion exists
- Paracetamol toxicity can cause renal failure, HAGMA and liver damage
- Alcoholic ketoacidosis (glucose usually low or normal)
- HHS
- More profound hypovolaemia, electrolyte disturbances, osmolality rise and hyperglycaemia
- Far greater risk of VTE
Treatment
- Priorities – Volume, potassium, insulin + Treat underlying cause
- Fluid bolus 10-20mL/kg N/S if shocked initially
- Fluids
- Improves response to insulin therapy
- Average free water deficit of 100mL/kg (5-10L)
- Average sodium deficit of 7-10mmol/kg
- Average potassium deficit 3-5mmol/kg
- Aim to replace deficit over 24 hours (48 hours if comorbidities or young adults/children)
- Fluid regimes
- Cameron
- First litre at 1000mL/hr
- 2nd litre at 500mL/hr + K
- 3rd litre at 500mL/hr + K
- 4th litre at 500mL/hr + K
- 5th litre at 250mL/hr + K
- Tintinalli
- First litre within 30 minutes of arrival
- First 2 litres over 0-2 hours
- Next 2 L over 2-6 hours
- Next 2 litres over 6-12 hours
- Cameron
- Fluids
- Add 10% dextrose at 125mL/hr if BSL <15mmol/L
- Potassium
- Only add once making urine
- If serum K <5, add 10mmol/100mL over each hour
- If serum K <3.5 add 2x 10mmol/100mL over each hour
- Development of severe hypokalaemia is likely the most dangerous and life-threatening electrolyte derangement during treatment of DKA
- Insulin (Cameron)
- Should be started within first 60 minutes
- 50IU soluble insulin in 50mL N/S = 1U/mL
- 0.1IU/kg/hr (maximum 6 units/hr) adjusting rate to achieve drop in glucose of 3mmol/L/hr with a rise in bicarb of at least 3mmol/L/hr
- Once BSL <15, halve insulin infusion rate and adjust to maintain BSL 9-14mmol/L
- Withold until K >3.5 if initially hypokalaemic
- Calculating free water deficit
- = 0.6 x BW x (Current Na/140 -1)
- E.g. If current Na 160 then FWD = 0.6 x 70 x (160/140 – 1) = 6
- Failure to respond to insulin
- If glucose level does not fall with insulin therapy can double rate to 0.2IU/kg/hr
- Continue insulin until ketonaemia resolved and anion gap normalised
- Phosphate
- Crucial for ATP and oxygen delivery at tissue level through 2,3-DPG
- Intra- to extracellular shift in DKA with subsequent whole body depletion due to osmotic diuresis
- Re-enters cells with insulin therapy and serum levels can fall precipitously
- Usually most severe 24-48 hours down the line
- If critically low, can replace IV
- Magnesium
- Whole body Mg depletion
- HypoMg impairs PTH release causing hypocalcaemia and hyperphosphataemia
- Replace
- Bicarbonate
- Disadvantages
- Severe and worsening hypokalaemia
- Paradoxical CNS acidosis
- Worsening intracellular acidosis
- Impaired (left shift) O2 delivery to tissues
- Hypertonicity
- Sodium overload
- Delayed recovery from ketosis
- Elevation in lactate
- Precipitation of cerebral oedema
- Possible advantage in critical acidaemia impairing myocardial contractility, vascular tone or critical hyperkalaemia
- Some studies have shown increased mortality with bicarbonate use in DKA
- Disadvantages
- Mildly unwell ketotic hyperglycaemic non-acidaemic insulin-dependent diabetics
- 10% of total daily dose of insulin as SC of rapid-acting insulin (in addition to usual regime)
- Monitor hourly BSL and ketones
- Can repeat stat dose SC insulin q2-4h until ketones <1.0mmol/L
Prognosis
- Prognostic factors
- Higher serum osmolality, BUN, glucose and lower bicarb = higher mortality
- Precipitants: Infection and MI are main contributors to high mortality
- Old age
- Hypotension
- Coma
- Underlying renal or cardiovascular disease
- Severe volume depletion increases risk of DVT precipitously (especially in the elderly)
Prognosis
- Overall mortality of DKA and HHS 6.2%
- HHS has 2-3x mortality however DKA is 6x more common
- Most common causes of death
- Pneumonia (37%)
- MI (21%)
- Mesenteric/iliac thrombosis (16%)
Complications
- Hypoglycaemia
- Hypokalaemia
- Hypophosphataemia
- ARDS
- Typically seen with overzealous fluid administration with decrease in plasma oncotic pressure and fluid leak
- VTE very common in HHS and DKA
- Cerebral oedema (0.5-1%)
- Mostly in children (<12yo) between 4-12 hours after initiation of therapy
- Risk factors: Degree of hypocapnoea and dehydration, failure of serum sodium to rise with Rx and use of bicarb
- Can occur up to 48 hours from presentation
- Often seen when patient improving clinically and biochemically with precipitous decline and high mortality
- No evidence of any association between volume or content of IV fluids or rate of change in glucose
- Gradual replacement of water and sodium deficits and slow correction of glucose may lessen the risk
- Young age and new-onset diabetes are the only known risk factors
- Warning signs include: Severe headache, incontinence, change in arousal or behaviour, pupillary changes, BP changes, seizures, bradycardia or altered temperature regulation
- IV mannitol 1-2g/kg stat or 3% saline 5-10mL/kg and straight to CT
Late complications
- Metabolic acidosis refractory to usual therapy may be secondary to unrecognised infection, insulin antibodies (rarely) or iatrogenic mistake in insulin delivery
- Shock unresponsive to fluid boluses suggests Gram-negative sepsis or silent MI
- Must monitor anion gap during therapy not serum bicarb as patient retains Cl- in exchange for ketoanions (bicarb equivalents) during therapy
- Late vascular thrombosis can occur in any vessel although cerebral vessels most at risk
- No study has shown prophylactic anticoagulant use to be of benefit however
Insulin pumps
- Turn off and treat as like anyone else
DKA in pregnancy
- Leading cause of fetal loss (fetal mortality 30%)
- Physiological changes
- Maternal fasting glucose levels are lower, leading to relative insulin deficiency and increase in baseline free fatty acid concentrations
- Increased levels of counter-regulatory hormones
- Chronic respiratory alkalosis leads to decreased bicarb levels (compensatory renal response) with decrease in buffering capacity when metabolic acidosis does occur
- Increased incidence of vomiting and UTI which can precipitate DKA
- Maternal hyperglycaemia causes fetal hyperglycaemia and osmotic diuresis
- Maternal acidosis causes fetal acidosis, decreased uterine blood flow and fetal oxygenation AND shifts Hb-O2 dissociation curve to right (reduced Hb affinity)
- Maternal hypokalaemia can lead to fetal dysrhythmias
- Treat the same however
Last Updated on October 6, 2021 by Andrew Crofton
Andrew Crofton
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