Intravenous Anaesthetic Agents

Overview

IV induction agents target GABA receptors (most common), NMDA receptors, and alpha-2 receptors to cause anaesthesia. Propofol and Barbiturates decrease the rate of dissociation of GABA from its receptors increasing the duration of chloride channel opening. Benzodiazepines facilitate the attachment of GABA to its binding site on the receptor increasing the frequency of chloride channel opening. Ketamine is an antagonist of the NMDA receptors, which are normally excitatory ion channels.

Summary of common IV induction agents

Drug	Induction dose (mg/kg)	Effects	Nota bene
Propofol	1.5-2.5	Decreased CMROW, CBF, ICP, SVR. Dose-dependent respiratory depression	Pain on injection, Antiemetic, Anticonvulsant
Sodium thiopental	3-5	Decreases CMR02, CBF, ICP, SVR. Direct myocardial depressant. Dose-dependent respiratory depression	Anticonvulsant, Precipitates when injected with acidic solutions
Ketamine	1-2	Increases CMR02, CBF, ICP. Cardio-stimulating. Minimal respiratory depression, bronchodilation, maintains airway reflexes	Analgesic effect, intrinsic myocardial depressant that is unmasked with depletion of catecholamines
Etomidate	0.2-0.3	Decreased CMR02, CBF, ICP. Maintains cardiovascular stability. Decreases airway reflexes less than propofol and barbiturates	Pain on injection, high incidence of pONV, myoclonus, inhibits adrenocortical axis

Class	IV Agents
Barbiturates	Methohexital, Phenobarbital, Thiopental
Non-barbiturates	Ketamine, Propofol
Benzodiazepines	Midazolam
Opioids
Neuroleptics

IV induction agents according to speed of induction

Category	IV Agents
Ultra-short rapid induction Agents	Propofol, Thiopental, Methohexital
Rapid induction agent	Etomidate
Intermediate induction agent	Midazolam
Slow induction agents (basal narcotics)	Ketamine, Benzodiazepines, Opioids, Neuroleptics

• Properties of an ideal IV Anaesthetic agent
  • Water soluble and stable in solution
  • No pain on IV injection (but should have pain on arterial injection)
  • High therapeutic ratio
  • No emergence phenomenon
  • No hangover effect
  • Rapid onset
  • Stable when exposed to light

Sedation

Depth of sedation

Depth	Responsiveness	Airway	Spontaneous ventilation	Cardiovascular function
Minimal sedation (Anxiolysis)	Normal response to verbal stimuli	No effect	No effect	No effect
Moderate sedation (Conscious sedation)	Purposeful response to verbal or tactile stimulus	No intervention required	Adequate	Usually maintained
Deep sedation	Purposeful response following repeated or painful stimulus	Intervention may be required	May be adequate	Usually maintained
General anaesthesia	Unarousable	Intervention often required	Frequently inadequate	May be impaired

Pharmacodynamics

All hypnotics affect major organ systems apart from the brain. Profound hemodynamic effects are seen in patients with hypovolemia, with a large depressant effect seen in the elderly and in those with pre-existing cardiovascular disease (these patients need decreased dose requirement)

• Effects on body systems
  • All, except Ketamine, cause dose dependent respiratory depression
  • All cause hypotension and cardiac depression (Etomidate causes the least cardiac depression)

Propofol

Propofol is a rapid-acting induction agent that is produced in egg lecithin emulsion (egg yolk) because of high lipid solubility. It is the mainstay induction agent. Formulations of propofol support bacterial growth, hence good sterile technique and labeling of expiration time (12 hours) is crucial. Prolonged infusion can cause hypertriglyceridemia. Propofol has anti-emetic properties and can be used for TIVA cases and as background infusion to prevent PONV.

Induction dose: 1.5-2.5mg/kg (children need a higher dose, elderly require a lower dose)

• Effects on the cardiovascular system
  • Decreased SVR (arterial and venous)
  • Direct myocardial depressant (dose reduction in patients with shock)
• Effects on the respiratory system
  • Dose-dependent respiratory depression
  • Can cause bronchodilation in patients with COPD
• Effects on the central nervous system
  • Reduces CMRO2, CBF and ICP (CPP may be reduced depending on its effect on SBD)
  • Cerebral vasoconstriction (which is counterintuitive!)
• Adverse effects
  • Pain on injection (32-36%). Can be attenuated with IV lidocaine or administering drug in larger vein (cubital fossa or forearm)
  • Anaphylaxis (since the formulation contains lecithin)
  • Propofol infusion syndrome (PRIS) in critically ill patients receiving high dose of propofol (>4mg/kg/hr) for prolonged periods of time. High mortality, especially in children. Treatment is supportive.
    • Metabolic acidosis
    • Rhabdomyolysis
    • Cardiac failure
    • Renal failure
    • Hypertriglyceridemia

Sodium Thiopental

Sodium thiopental is a very cheap, easily reconstitutable, rapid induction agent. It has a wide therapeutic range and is preferred for induction since it has high potency, high lipid solubility, rapid brain entry, and rapid tissue redistribution. It is highly alkaline (pH ) and can precipitate in acidic solution (should not be mixed with Rocuronium).

Induction dose: 3-5 mg/kg in adults, 5-6 mg/kg in children, 6-8 mg/kg in infants

• Effects on the cardiovascular system
  • Decreased SVR
  • Direct myocardial depressant
• Effects on the respiratory system
  • Dose-dependent respiratory depression
• Effects on the central nervous system
  • Decreased CMRO2, CBF, ICP (causes EEG burst suppression in larger doses and is commonly used for neurosurgical procedures)
  • Anticonvulsant properties (typical for barbiturates…except Methohexital)
• Side effects
  • Intra-arterial injection can cause intense vasoconstriction, thrombosis and tissue necrosis
    • Treated with Papaverine and Lidocaine or regional anaesthesia-induced sympathectomy and heparinization
• Contraindications
  • Porphyria
  • Myasthenia gravis

Methohexital

Methohexital is a epileptogenic barbiturate that is commonly used for induction during Electroconvulsive therapy (it reduces seizure threshold and prolongs seizure duration). It is very short-acting and can be administered IV, IM, or PR.

• Contraindications
  • Pregnancy (causes neurodevelopmental delay)
  • Asthma (causes bronchospasm)

Ketamine

Ketamine is the closest “complete anaesthetic”. It produces a dissociative anaesthetic state (with profound analgesia and amnesia despite maintenance of consciousness). Good to use for patients with hypovolemia and hypotension, and can be used with Oxygen supplementation.

Induction dose: 1-2mg/kg.

Intra-operative dose: 0.5-1mg/kg before incision (after intubation, unless used for induction) and 0.25mg/kg each hour (infusion or bolus)

• Effects on the cardiovascular system
  • Cardio-stimulatory effect due to direct sympathetic stimulation (increased BP, HR, CO)
  • Direct myocardial depression (revealed when catecholamines are depleted)
• Effects on the respiratory system
  • Bronchodilation
  • Minimal respiratory depression (preserves airway reflexes)
  • Causes increased oral secretions (attenuated with co-administration of Glycopyrrolate or atropine)
• Effects on the central nervous system
  • Increases CMR02, CBF, ICP
• Side effects
  • High incidence of psychomimetic reactions (can be attenuated by co-administering Midazolam)
  • Nystagmus
  • Unpleasant emergence reactions e.g. Delirium, hallucination

Midazolam

Midazolam is a benzodiazepine that has anxiolytic, anticonvulsant, amnestic, sedative, and hypnotic effects. It is preferred for sedation and pre-medication since it produces retrograde amnesia. It has a long shelf life and is safe to use. Comes in liquid formulations of 3mg/ml, 1mg/ml, and 0.5mg/ml.

Premedication dose: 0.02-0.05 mg/kg IV/IM (typically 1-2 mg)

Induction dose: 0.1-0.2 mg/kg IV

• Effects on the cardiovascular system
  • Generally hemodynamically stable
  • SVR and BP depression when used in larger doses
• Effects on the respiratory system
  • Dose-dependent respiratory depression (exaggerated when combined with opioids for patients with chronic respiratory disease)
• Effects on the central nervous system
  • Decreased CMRO2 and CBF
  • Does not produce EEG burst suppression
• Flumazenil
  • Flumazenil is a specific antagonist to benzodiazepines.
  • It is very short-acting and has a duration of 45-90 minutes following a 1-3 mg dose.
  • Complication- status epilepticus→ treated by administering more midazolam

Etomidate

Etomidate is a rapid-induction agent preferred for patients with high dependency (maintains cardiovascular stability, “cardiac drug”). Its rapid onset is due to its high lipid solubility and large non-ionized fraction at physiologic pH. It is rather expensive and rare to find in our setting.

• Effects on the cardiovascular system
  • Maintains hemodynamic stability even in the presence of pre-existing disease (does not induce histamine release)
• Effects on the respiratory system
  • Dose-dependent respiratory depression
• Effects on the central nervous system
  • Decreases CMR02, CBF, ICP and CPP (since it causes minimal decrease in SBP)
  • Anticonvulsant properties (but minimal effect on the duration of ECT-induced seizure activity)
• Effects on the endocrine system
  • Inhibits adrenocortical axis (by inhibiting 11-beta hydroxylase)
• Side effects
  • Burns on injection since its solution contains propylene glycol (attenuated with lidocaine)
  • Increased incidence of PONV
  • Myoclonus (50%)
  • Hiccups
  • Thrombophlebitis