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
• 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
    • 2^nd litre at 500mL/hr + K
    • 3^rd litre at 500mL/hr + K
    • 4^th litre at 500mL/hr + K
    • 5^th 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

• 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

• 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