Overview
- Understanding the adverse effect profiles of induction, sedative and premedicant agents is essential for safe anaesthetic practice.
- These drugs act on multiple organ systems and their adverse effects inform drug selection, dosing strategy and monitoring requirements.
- The two induction agents most thoroughly covered in the source material are propofol and etomidate, and their profiles are compared systematically below.
Propofol
Mechanism of Action (Relevant to Adverse Effects)
- Propofol acts primarily as a $\text{GABA}_A$ receptor agonist, increasing $\text{Cl}^-$ conductance and causing neuronal hyperpolarisation.
- This mechanism underlies both its desired hypnotic effects and many of its systemic adverse effects.
- At sufficient doses, propofol suppresses the EEG and can produce burst suppression.
Cardiovascular Adverse Effects
Propofol produces a dose-dependent decrease in blood pressure that is significantly greater than that produced by thiopental. This hypotension arises through multiple mechanisms:
| Mechanism | Effect |
|---|---|
| Peripheral vasodilation | Reduced systemic vascular resistance |
| Mild myocardial depression | Reduced cardiac contractility |
| Blunted baroreceptor reflex | Impaired compensatory heart rate response |
| Reduced sympathetic nerve activity | Decreased vascular tone and heart rate |
The blunting of the baroreceptor reflex is particularly important: patients cannot mount an appropriate tachycardia to offset the fall in blood pressure, which can precipitate significant haemodynamic compromise, particularly in hypovolaemic patients, those with fixed cardiac output states (e.g. severe aortic stenosis), or the elderly.
Key clinical point: Propofol should be used with caution in patients at risk for, or intolerant of, decreases in blood pressure.
Respiratory Adverse Effects
Propofol produces a slightly greater degree of respiratory depression than thiopental. This manifests as:
- Reduced tidal volume and respiratory rate
- Apnoea at induction doses
- Depression of upper airway reflexes
- Despite this, propofol has a favourable respiratory profile in one important respect: it is less likely than barbiturates to provoke bronchospasm and may be the induction agent of choice in patients with reactive airway disease or asthma.
- The exact mechanism of bronchodilation is not fully characterised, but may relate to inhibition of airway smooth muscle constriction.
Important caveat: The bronchodilator properties of propofol may be attenuated by the metabisulfite preservative present in some propofol formulations. Clinicians should be aware of the specific formulation being used in patients with sulphite sensitivity or asthma.
Neurological Effects
| Effect | Detail |
|---|---|
| EEG suppression | Dose-dependent; burst suppression at high doses |
| Reduced CMRO₂ | Decreased cerebral metabolic rate of O₂ consumption |
| Reduced CBF | Cerebral blood flow reduction |
| Reduced ICP | Intracranial pressure reduction |
| Reduced IOP | Intraocular pressure reduction |
- These effects are broadly comparable in magnitude to thiopental.
- Propofol can be used in patients at risk for cerebral ischaemia, although no human outcome studies have confirmed efficacy as a neuroprotectant.
Other Adverse Effects
Pain on Injection
- Propofol causes pain on injection in a significant proportion of patients.
- This is due to activation of pain receptors (likely bradykinin-mediated) by the aqueous phase of the emulsion.
Strategies to reduce injection pain:
- Pre-treatment or co-administration of lidocaine
- Use of larger arm or antecubital veins (where the drug is more diluted by faster-flowing blood)
Antiemetic Action
- Propofol has a significant antiemetic action, which is considered a beneficial side effect.
- This is particularly useful in patients at high risk of postoperative nausea and vomiting (PONV), and propofol-based TIVA techniques are associated with lower PONV rates compared to volatile anaesthetic techniques.
Propofol Infusion Syndrome (PRIS)
PRIS is a rare but potentially fatal complication associated with prolonged, higher-dose propofol infusions.
| Feature | Detail |
|---|---|
| Risk population | Young patients, head-injured patients |
| Context | Prolonged high-dose infusions |
| Characteristics | Metabolic acidosis, hyperlipidaemia, rhabdomyolysis, liver enlargement |
| Outcome | Can be fatal |
- The precise mechanism of PRIS involves impairment of mitochondrial respiratory chain function and fatty acid oxidation, leading to cellular energy failure in cardiac and skeletal muscle.
- Long-term infusions for ICU sedation carry the highest risk.
Etomidate
Formulation and Context
- Etomidate is a substituted imidazole supplied as the active D-isomer, formulated as a 2 mg/mL solution in 35% propylene glycol due to its poor water solubility.
- It is primarily used for induction in patients at risk for hypotension, reflecting its superior cardiovascular stability compared to propofol and barbiturates.
Cardiovascular Adverse Effects
Etomidate's major cardiovascular advantage, and the reason it is often chosen for haemodynamically compromised patients, is its cardiovascular stability:
| Parameter | Effect of Etomidate |
|---|---|
| Heart rate | Small increase |
| Blood pressure | Little or no decrease |
| Cardiac output | Little or no decrease |
| Coronary perfusion pressure | Minimal effect |
| Myocardial O₂ consumption | Reduced |
This profile compares favourably with both propofol and barbiturates, making etomidate the induction agent of choice in patients with cardiogenic shock, severe cardiac disease or haemodynamic instability.
Respiratory Adverse Effects
- The degree of respiratory depression due to etomidate is less than that due to thiopental.
- Etomidate may induce hiccups (as does methohexital), and does not significantly stimulate histamine release, making it a reasonable choice in patients at risk of histamine-mediated reactions.
Neurological Effects
| Effect | Detail |
|---|---|
| Hypnosis | Produced reliably |
| Analgesia | None, etomidate has no analgesic properties |
| CBF, CMRO₂, ICP, IOP | Reduced similarly to thiopental |
| EEG | Increased activity in epileptogenic foci |
| Seizure risk | Has been associated with seizures |
The lack of analgesic effect is an important clinical consideration: etomidate must always be supplemented with opioids or other analgesic agents.
The increase in EEG activity in epileptogenic foci means etomidate should be used with caution in patients with a known seizure disorder, although this property has also been exploited (off-label) to facilitate epileptic focus mapping.
Injection Site and Movement Adverse Effects
| Adverse Effect | Incidence | Management |
|---|---|---|
| Pain on injection | High | Lidocaine pre-treatment |
| Myoclonic movements | High | Pre-medication with benzodiazepines or opioids |
- Myoclonic movements occur in a significant proportion of patients and can be mistaken for seizure activity.
- They are thought to result from disinhibition of subcortical structures and are not true epileptic events.
Adrenocortical Suppression, The Key Adverse Effect
- Etomidate inhibits adrenal biosynthetic enzymes required for the production of cortisol and other steroids.
- Specifically, it inhibits 11β-hydroxylase (and to a lesser extent other enzymes in the steroidogenic pathway), causing dose-dependent suppression of the hypothalamic-pituitary-adrenal (HPA) axis.
| Feature | Detail |
|---|---|
| Enzyme inhibited | 11β-hydroxylase (primarily) |
| Duration after single dose | Up to 24 hours of cortisol suppression |
| Clinical concern | Critical illness, trauma, sepsis |
| Risk of infusion | Prolonged adrenocortical suppression, long-term infusions not recommended |
- Although a single induction dose causes transient adrenocortical suppression, this is of particular concern in trauma and critically ill patients who may depend on intact cortisol responses for haemodynamic stability and immune function.
- This has led to controversy about the use of etomidate as the routine induction agent in septic patients.
Gastrointestinal Adverse Effects
- Etomidate is associated with nausea and vomiting, which is more prominent than with propofol.
- This should be considered when selecting an induction agent in patients at high risk for PONV or pulmonary aspiration.
Comparative Summary Table
| Adverse Effect | Propofol | Etomidate |
|---|---|---|
| Cardiovascular depression | Significant (dose-dependent ↓ BP) | Minimal (preferred in haemodynamic instability) |
| Baroreceptor reflex blunting | Yes | No |
| Respiratory depression | Greater than thiopental | Less than thiopental |
| Bronchospasm risk | Low (bronchodilator) | Low (no histamine release) |
| Pain on injection | Yes | Yes (high incidence) |
| Myoclonic movements | No | Yes (high incidence) |
| Hiccups | No | Yes |
| Nausea and vomiting | Low (antiemetic) | Yes |
| Seizure activity/EEG | Suppressive | May activate epileptogenic foci |
| Adrenocortical suppression | No | Yes (significant) |
| Propofol infusion syndrome | Yes (high dose, prolonged) | No |
| ICP/CBF/CMRO₂ | Reduced | Reduced |
| Analgesic effect | None | None |
Clinical Relevance
Propofol
- Haemodynamically compromised patients: Propofol's dose-dependent hypotension is exacerbated in hypovolaemia, cardiac failure or elderly patients. Slow titration, dose reduction, and fluid pre-loading are important mitigation strategies.
- Asthmatic patients: Propofol is the preferred induction agent. However, the anaesthetist should check the formulation to confirm whether metabisulfite is present, particularly in sulphite-sensitive patients.
- PONV-high-risk patients: Propofol-based TIVA is advantageous due to its antiemetic properties.
- Raised ICP: Propofol reduces CMRO₂, CBF and ICP, making it suitable for neurosurgical patients, though the associated hypotension may compromise cerebral perfusion pressure, careful blood pressure management is essential.
- PRIS prevention: In ICU patients requiring prolonged sedation, propofol infusion rates should be kept as low as effective, duration minimised, and patients monitored for early signs of PRIS (unexplained metabolic acidosis, elevated triglycerides, elevated CK).
Etomidate
- Emergency/haemodynamic instability: Etomidate is the induction agent of choice when cardiovascular compromise is present (e.g. trauma, septic shock, severe cardiac disease) due to its minimal haemodynamic effect.
- Sepsis and critical illness: The adrenocortical suppression caused by even a single induction dose of etomidate is controversial in septic patients who may require a normal cortisol stress response. Many clinicians avoid etomidate in sepsis or supplement with stress-dose hydrocortisone.
- Seizure disorders: Use with caution given EEG activation in epileptogenic foci. Pre-treatment with benzodiazepines may mitigate this risk and will also reduce myoclonic movements.
- Prevention of myoclonus: Pre-treatment with a benzodiazepine or opioid significantly reduces the incidence of myoclonic movements and pain on injection.
- No analgesia: Etomidate must be combined with an opioid analgesic component in all anaesthetic induction sequences.
- Long-term infusion: Not recommended due to adrenocortical suppression. The propylene glycol vehicle also raises concerns regarding accumulation toxicity with prolonged infusion.
Summary
- Both propofol and etomidate are valuable induction agents with distinct adverse effect profiles that guide their clinical application.
- Propofol's primary adverse effects centre on cardiovascular depression and respiratory depression, with the rare but serious risk of PRIS with prolonged infusion, offset by its antiemetic properties and bronchodilation.
- Etomidate's primary clinical advantage is cardiovascular stability, but this is tempered by its significant adverse effects of adrenocortical suppression, myoclonic movements, pain on injection, and nausea.
- Selecting the appropriate agent requires careful consideration of the individual patient's physiological state, comorbidities, and the clinical context of the anaesthetic.