Intravenous Induction Agents

Introduction

1. Propofol
2. Barbiturates (Thiopentone / Methohexital)
3. Etomidate
4. Ketamine
5. Benzodiazepines (Midazolam - limited use)
6. Dexmedetomidine

1. Propofol (Di-isopropyl Phenol)

• Rapid onset (one arm-brain circulation)
• Short context-sensitive half-time - ensures rapid, clear-headed recovery even after prolonged infusion
• Large volume of distribution (Vd); redistribution drives recovery from a single dose
• Extensively metabolized in the liver; no active metabolites
• T1/2 keo (effect-site equilibration): ~2-3 minutes for hypnosis; ~7 minutes for haemodynamic depression

• Smooth, pleasant induction with low incidence of post-operative nausea and vomiting (PONV)
• Anti-emetic properties
• Bronchodilation - safe in reactive airway disease
• Safe in porphyria and malignant hyperpyrexia
• Can be used for maintenance of anaesthesia (unlike thiopentone), including Total IV Anaesthesia (TIVA) with remifentanil
• Target-controlled infusion (TCI) possible using Marsh or Schneider pharmacokinetic models

• Hypotension on induction: induction dose of 2-2.5 mg/kg produces a 25-40% fall in systolic blood pressure via vasodilation (reduction in central sympathetic tone, direct smooth muscle relaxation, nitric oxide stimulation) and mild myocardial depression
• Pain on injection (into small veins)
• Does not provide analgesia
• Propofol infusion syndrome (PRIS) - rare but fatal complication with prolonged high-dose infusion (metabolic acidosis, rhabdomyolysis, cardiac failure)
• Caution in hypovolaemia, coronary artery disease, elderly patients (dose reduced by ~50% in those >80 years)

2. Thiopentone (Thiopental Sodium) - Barbiturate

• Rapid onset (one arm-brain circulation; onset in 30 seconds)
• Terminated by redistribution after a single dose
• Long context-sensitive half-time compared to propofol and etomidate - not suitable for prolonged infusion
• Hepatic metabolism (slow); active metabolite pentobarbital can accumulate

• Rapid, smooth induction
• Reduces cerebral metabolic rate (CMRO2) and intracranial pressure (ICP) - useful in neuroanaesthesia
• Anticonvulsant properties
• Historically established, inexpensive

• Myocardial depression and hypotension - marked in elderly and hypovolaemic patients
• Contraindicated in porphyria (precipitates acute attack)
• Causes bronchospasm and laryngospasm (no airway protective effect)
• Prolonged sedation/"hangover" after repeated doses due to accumulation
• Highly alkaline solution - extravasation causes tissue necrosis; intra-arterial injection is a serious complication (arterial spasm, gangrene)
• Cannot be used for maintenance
• Supply issues: thiopentone has become unavailable in many countries, further cementing propofol's dominance

3. Etomidate

• Rapid onset (one arm-brain circulation after 0.3 mg/kg)
• Brief duration of action; rapid offset even after infusion
• Hepatic ester hydrolysis to inactive metabolites

• Unrivalled haemodynamic stability - minimal effect on blood pressure, cardiac output, or heart rate - making it the agent of choice in patients with:
  • Cardiovascular disease, cardiac contractile dysfunction
  • Severe hypovolemia / haemodynamic instability
  • Trauma patients with unclear volume status
• Does not cause apnoea
• Reduces ICP and CMRO2 - suitable in neuroanaesthesia
• Bronchodilatory - safe in reactive airway disease
• Does not trigger malignant hyperpyrexia

• Adrenocortical suppression: inhibition of 11β-hydroxylase (major site) and 17α-hydroxylase (minor site) reduces cortisol and aldosterone synthesis. Even a single induction dose causes suppression lasting 6-8 hours; concern remains about mortality in critically ill (ICU) patients
• Pain on injection (propylene glycol vehicle)
• Myoclonus - spontaneous involuntary muscle movements during induction (in up to 70% of patients without premedication)
• High incidence of PONV
• Continuous infusion has been abandoned due to adrenocortical suppression risk
• Independent risk factor for emergence delirium

4. Ketamine (Phencyclidine Derivative)

• IV induction: 1-2 mg/kg
• IM: 4-8 mg/kg (useful when IV access unavailable)
• Subanesthetic/analgesic: 0.1-0.5 mg/kg IV

• Rapid onset; relatively rapid offset even after infusion (short context-sensitive half-time)
• Hepatic metabolism by CYP3A4 (N-demethylation) to active metabolite norketamine (20-30% potency of ketamine)
• High lipid solubility

• Only IV induction agent that increases blood pressure and heart rate via sympathetic stimulation (catecholamine release) - ideal in haemodynamic compromise and haemorrhagic shock
• Excellent bronchodilator - agent of choice for induction in status asthmaticus and reactive airway disease
• Minimal respiratory depression; preserves airway reflexes and spontaneous breathing (allowing use without intubation in field anaesthesia)
• Profound analgesia at subanesthetic doses - useful for painful procedures and as adjunct in balanced anaesthesia
• Can be given IM - useful in uncooperative/paediatric patients
• Safe for field anaesthesia, mass casualty, resource-limited settings
• Emerging role as a rapid-acting antidepressant (IV ketamine/intranasal esketamine)

• Emergence delirium / dysphoria / hallucinations - vivid, unpleasant dreams and psychomotor agitation during recovery; attenuated by premedication with a benzodiazepine (midazolam)
• Increases ICP and CBF - classically avoided in raised intracranial pressure (though recent evidence in TBI suggests limited functional impact)
• Increases intraocular pressure - avoid in open globe injuries
• Hypersalivation and secretions - requires anticholinergic premedication (glycopyrrolate/atropine)
• Increases CMRO2
• Causes cardiovascular stimulation - caution in severe coronary artery disease, uncontrolled hypertension

5. Midazolam (Benzodiazepine)

• Provides anxiolysis, amnesia, and sedation - primarily used as premedication or co-induction agent rather than sole induction agent
• Relatively stable haemodynamics
• At large doses (0.25-0.35 mg/kg), can induce anaesthesia
• Prolonged effects and slow, less predictable induction compared to propofol
• Synergistic respiratory depression with opioids - requires close monitoring
• Reversal agent available: flumazenil
• Rarely used as primary induction agent in modern practice given the superiority of propofol and etomidate

6. Methohexital (Methohexitone) - Oxybarbiturate

7. Dexmedetomidine

• Produces sedation, anxiolysis, analgesia, and sympatholysis
• Minimal respiratory depression - key advantage; patients remain rousable and cooperative ("cooperative sedation")
• Approved for ICU sedation (up to 24 hours) and procedural sedation
• May help prevent delirium
• Heart rate and cardiac output decrease in a concentration-dependent manner
• Not typically used as a sole induction agent but increasingly used for awake fibre-optic intubation and as an adjunct

Summary Table

Key Concepts to Remember

• Pharmacokinetic principle: All IV induction agents share high lipid solubility for rapid CNS entry; termination of a single-dose effect is by redistribution, NOT metabolism.
• Choice of agent should be tailored to the patient's clinical status: propofol for healthy elective patients, etomidate for cardiovascular instability, ketamine for shock/asthma/field use, thiopentone for neuroanaesthesia (where available).
• Rapid Sequence Induction (RSI): Uses a predetermined IV induction dose + rapidly acting muscle relaxant (suxamethonium or rocuronium) to secure the airway quickly in patients at high risk of aspiration (e.g., emergency surgery, full stomach).
• TIVA (Total IV Anaesthesia): Propofol + remifentanil infusion; gaining popularity due to propofol's favourable pharmacokinetics and low PONV profile.