Thiopentone

CLASS

• a thiobarbiturate

INDICATIONS

1. Induction of anaesthesia
2. Treatment of status epilepticus
3. Neuroprotection

ADMINISTRATION / DOSING

• IV or PR
• RSI: 3-7 mg/kg IV can give in divided doses and lasts 5-15 min
• PR: 1 g per 22 kg of bodyweight –> acts within 15 min
• Elevated ICP 1-2 mg/kg IV as required
• For thiopentone coma dosing, please see below
• Ensure to give a good flush pre and post-thiopentone, don’t lose that important cannula or lumen.

MECHANISM OF ACTION

• Is a hypnotic and anticonvulsant
• Barbiturates work predominantly at the GABA_A receptors at the alpha and beta sites (as opposed to the alpha and gamma sites like benzodiazepines)
• Prolong GABA receptor opening duration (benzodiazepines increase the frequency), and cause direct activation of the channel at higher doses
• Primarily act at synapses by depressing post-synaptic sensitivity to neurotransmitters and impairs pre-synaptic neurotransmitter release.
  • Multisynaptic pathways are depressed preferentially, such as the RAS
• Membrane stabilising effects thought to be similar to local anaesthetics – enter the cell unionised, then become ionised and decrease Na+ and K+ conductance
• In high concentrations – depresses enzymes responsible for glucose oxidation which form ATP and depress Ca²⁺ dependent channels
• Also inhibits Ca²⁺ dependent neurotransmitter release and enhances Cl^– conductance in the absence of GABA

PHARMACEUTICS

• hygroscopic yellow powder
• thiopentone sodium (weak acid)
• stored under an atmosphere of nitrogen and contains 6% sodium carbonate
  • This is to improve the solubility of thiopentone where:
    • Sodium carbonate creates a strongly alkaline solution when combined with water and,
    • If the vial was stored in air, CO₂ would form a less alkaline solution
• reconstituted with sterile water
• produces a 2.5% solution
• Of note, barbiturates are not readily soluble in water at neutral pH, their solubility depends on transformation from the keto to the enol form which occurs more readily in an alkaline solution –> Tautomerism
• Is a racemic mixture
• Not removed by dialysis

PHARMACOKINETICS

• Absorption
  • Acts in one arm-brain circulation time and lasts 5-15 mins after bolus – accumulates with repeated administration
  • Rectal administration: 1 g/22 kg of bodyweight acts in 15mins
• Distribution
  • Vd ~2 L/kg
  • ~80% protein bound in the plasma, predominantly albumin
  • pK_a of 7.6 with 60% unionised at pH 7.4 –> where only 12% free drug is immediately available
  • Distribution half-life: T_1/2 (alpha) fast: 8 min // T_1/2 (alpha) slow: 60 min
  • Rapid onset due to:
    • High blood flow to the brain
    • Lipophilicity
    • Low % ionised
• Metabolism
  • Hepatic
  • Saturable pathway –> first order –> Zero order kinetics
  • Liver oxidation (CYP450) –> pentobarbital (active metabolite)
• Elimination
  • Predominantly in the urine, 0.5% unchanged
  • Clearance is 2.7-4.1 mL/kg/min
  • Elimination half-life:
    • T _1/2 (beta): 11 hours
  • Long CSHT

PHARMACODYNAMICS

• CNS:
  • Hypnosis
  • Decrease in cerebral metabolic rate of oxygen (CMRO₂)
  • Decrease in cerebral blood flow (CBF)
  • Decrease in intracranial pressure (ICP)
  • Decrease in intraocular pressure
  • Anticonvulsant
  • Antanalgesic in small doses
  • EEG (Alpha –> delta –> burst suppression –> isoelectric)
• CVS
  • Venous vasodilation > arterial vasodilation
  • Direct negative inotropic effect
  • Compensatory tachycardia (due to preserved baroreceptor reflex)
• RESP
  • Respiratory depression
  • Intact upper airway reflexes
  • Bronchospasm (due to histamine release)
  • Decreased ventilatory response to hypoxia and hypercarbia
• GIT
  • Decreased hepatic blood flow
  • Induction of hepatic enzymes
  • Depression of intestinal activity
• GUT
  • Deceased urine output (decreased CO –> decreased RBF // increased ADH release)
• OTHER
  • Anaphylaxis
  • Tissue necrosis in extravasation
  • Accidental arterial injection –> microembolisation / ischaemia
  • More precipitate acute porphyria
  • Immunosuppressive at high doses

TOXICITY / SIDE EFFECTS

• Severe anaphylaxis 1:20 000 incidence
• Extravasation leads to tissue necrosis
• Prolonged infusion:
  • Hypokalaemia / hyponatraemia / increased infection risk
• Sudden cessation can lead to rebound critical hyperkalaemia after prolonged infusion

CONTRAINDICATIONS

• Absolute
  • Allergy to barbiturates
  • Porphyria
  • Constrictive pericarditis
  • Status asthmaticus
  • Severe respiratory compromise
• Relative
  • Severe cardiac dysfunction / shock
  • Hepatic dysfunction
  • Renal dysfunction
  • Myxoedema
  • Addison’s disease
  • Severe anaemia
  • Myasthenia gravis

THIOPENTONE INFUSION

• Used for neuroprotection, e.g. several elevated intracranial pressure, and status epilepticus
• An example of an infusion guideline used at Institution 1 is:
  • Loading dose of 5-20 mg/kg over 1 hour
  • Then commence infusion at 3-4 mg/kg/hr
• Hypokalaemia is known to develop with prolonged infusion, aim to not replace if possible (due to concerns for rebound hyperkalaemia), replace if arrhythmias, ECG changes, or if K⁺ drops below 2 mmol/L
• Titrate infusion dose as guided by BIS or cEEG burst suppression
• Thiopentone is immunosuppressive at high doses and often sepsis is the reason to cease the infusion
• A high dose prolonged infusion may cause vasopressin-resistant diabetes insipidus requiring bursts of DDAVP (4 microgs IV intermittently)

EVIDENCE IN REFRACTORY ICPs

• Look… the evidence isn’t great.
• Currently still recommended for elevated ICP refractory to standard medical and surgical treatment by the Brain Trauma Foundation with IIb level of evidence
• Oh’s 8th Edition of the Intensive Care Manual gives a throwaway line of “Barbituates are not recommended on current evidence” and then lists the BTF guidelines as its reference
• The most important aspect when considering any large sedative bolus is to ensure haemodynamic stability!

References and links

LITFL

• CCC – Increased Intracranial Pressure in TBI
• CCC – Status epilepticus

References

• Australian Injectable Drugs Handbook, 8th Edition. (2022). Retrieved 26 August 2022, from https://aidh.hcn.com.au/
• Australian Medicines Handbook. (2022). Retrieved 26 August 2022, from https://amhonline.amh.net.au/
• Bersten, A. and Soni, N., 2019. Oh’s Intensive Care Manual. 8th ed. Elsevier.
• Brain Trauma Foundation. (2023). Retrieved 10 May 2023, from https://braintrauma.org/coma/guidelines/guidelines-for-the-management-of-severe-tbi-4th-ed
• IBM Micromedex. (2022). Retrieved 13 August 2022, from https://www.micromedexsolutions.com
• Peck, T., & Hill, S. (2014). Pharmacology for Anaesthesia and Intensive Care (4th ed., pp. 97-101). Cambridge: Cambridge University Press.

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