Intravenous Induction Agents – Propofol, Etomidate, Ketamine, and Thiopental

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“Induction” refers to the first major step in general anesthesia where agents are used to confer sedation and ultimately loss of consciousness. For the most part, induction agents modulate the GABA receptor, the chief inhibitory neurotransmitter of the central nervous system (CNS), altering chloride ion conductance and leading to the hyperpolarization of neurons. This edition of the Pre-Op Screen features a brief review on the commonly used induction agents.

Propofol
propofol-structure
Propofol (Image: Wikipedia)

Propofol is one of the most popular induction agents in North America made even more publicized due to the events surrounding Michael Jackson’s death. It decreases the disassociation rate of GABA from its receptor and therefore potentiates its neuroinhibitory effects. Propofol also causes a direct reduction in myocardial contractility, systemic vascular resistance (SVR), and preload resulting in hypotension making it a poor choice in shock. Neurologically, propofol lowers intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral metabolic rate for oxygen (CMRO2) – in patients with high ICP, the lower CPP can result in neurological injury. It can also cause marked respiratory depression, apnea, or airway obstruction (even at smaller sedating doses), so always be ready for airway intervention!

Because of propofol’s poor water solubility, it must be reconstituted in a lipid vehicle (soybean oil, glycerol, egg lecithin), giving it a characteristic milky white appearance and the nickname “milk of amnesia.” The emulsion is like a petri dish for bacteria, so once prepared, the agent must be used within six hours.

Metabolism: Hepatic metabolism and excretion. Rapid redistribution in peripheral tissues.
Dose: 1.5-2.5 mg/kg IV (induction), 50-200 mcg/kg/min IV (maintenance). Propofol can be painful, so try using a larger vein or flushing lidocaine prior to induction (mixed results). The dose will be higher in pediatric patients and lower in the elderly, patients with reduced cardiac reserve, or patients in shock.
Other: Propofol possesses anti-emetic and anti-convulsant properties

Etomidate
etomidate-structure
Etomidate (Image: Wikipedia)

Etomidate, a carboxylated imidazole (‘R’ stereoisomer 5x more potent than the ‘S’), has a claim-to-fame rooted in its favorable cardiovascular profile. This agent depresses the reticular activating system (RAS) but also has disinhibitory effects within the CNS occasionally causing myoclonus after induction. Because of minimal myocardial depression (and a mild reduction in SVR), etomidate is great for patients with very little cardiac reserve; unlike propofol, it’s not likely to cause apnea either! It also decreases cerebral blood flow (CBF), CMR02, and ICP making it suitable for CNS pathologies. Unfortunately, etomidate inhibits enzymes involved with cortisol and aldosterone synthesis (up to 8 hours after a single induction dose!) thereby causing transient adrenal suppression. This is more of an issue in the ICU with patients on infusions or those who undergo multiple etomidate inductions within a relatively short period of time.

Unlike propofol, etomidate is water soluble (still painful on injection from propylene glycol vehicle), but like propofol, it is lipid soluble, works quickly, and is rapidly redistributed into tissue compartments.

Metabolism: Hepatic metabolism, renal excretion
Dose: 0.2-0.3 mg/kg IV
Other: Can cause post-operative nausea and vomiting (PONV)

Ketamine
ketamine-structure
Ketamine (Image: Wikipedia)

In comparison to the aforementioned agents, ketamine is an NMDA receptor antagonist. It’s also a more “complete” anesthetic, providing not only amnesia but pretty remarkable analgesia. It’s more often used as an adjunct to sedation or chronic pain management, but can be used as an induction agent in hemodynamically unstable patients as it (in contrast to the other agents) RAISES blood pressure (BP), heart rate (HR), and the cardiac output (CO); consequently, this increases myocardial oxygen demand making it a poor choice in patients with coronary artery disease. Ketamine also increases CBF, ICP, and CMRO2 making it unfavorable in head trauma causes.

Ketamine has a high incidence of psychotomimetic reactions (often “vivid dreams”) and creates dissociative anesthesia. It’s also very useful in patients with chronic airway conditions (COPD, asthma, etc.) as it bronchodilates and preserves airway reflexes.

Metabolism: Rapid hepatic metabolic, lipid solubility gives it a rapid onset and redistribution
Dose: 1-2 mg/kg IV or 3-5 mg/kg IM (only agent that can be given intramuscularly)

Thiopental

Thiopental (a barbiturate and controlled substance) has seen a decline in its popularity given the widespread availability of propofol and etomidate. Barbiturates exert their effect on the GABA receptor by prolonging the duration of the channels’ opening. Interestingly, thiopental’s highly alkaline nature (pH ~ 9) can cause cutaneous damage in the event of IV infiltration; furthermore, it can precipitate in acidic solutions (ie, do not mix with rocuronium!). It decreases CBF, ICP, and CMRO2 as well as EEG burst suppression making it neuroprotective and favorable in neurosurgery.

Metabolism: Hepatic metabolism, renal excretion. Rapidly absorbed into the CNS with distribution into peripheral compartments. Large doses can saturate the peripheral compartments thereby prolonging the duration of thiopental.
Dose: 3-5 mg/kg IV
Other: Anticonvulsant properties (methohexital is a barbiturate that does not have anti-convulsant properties, often used for electroconvulsive therapy)

Midazolam

Midazolam is a benzodiazepine (BZD), and like all drugs in this class, it increases the efficiency of GABA binding its receptor. All BDZs have anxiolytic, amnestic, sedative, hyponotic, and anticonvulsant properties. They’re routinely used as pre-medication (anxiolytics) prior to surgery. They decrease CBF, ICP, and CMRO2 while having an exaggerated respiratory depression when combined with opioids. Flumazenil is a specific antagonist which is not to be used in patients on chronic BZD therapy. Given its short acting nature, flumazenil may need to be administered multiple times or risk re-sedation with BZD which still has not been metabolized.

Metabolism: Hepatic metabolism, renal excretion
Dose: 0.04-0.08 mg/kg IV (pre-medication), 0.2-0.4 mg/kg IV (induction)

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