2009B02 What are the potential side effects of propofol and its formulations?

Ingredient

mg/mL

Function

Side effect

Soybean oil

100

Solvent: oil in water emulsion

·   Bacterial contamination:

o Discard if open >6 hours

o Finish infusion by 12 hours

·   Lipotoxicity

·   Propofol infusion syndrome

o Mitochondrial dysfunction

o Lactic acidosis, bradycardia arrest

o Rare

o Mainly in unwell children)

(Alternative solvents: liposomes, medium chain TAG, cyclodextrins)

Glycerol

22.5

Tonicity

Egg lecithin

12

Emulsifier

·   Very low risk anaphylaxis (protein deplete)

Disodium edetate

0.5

Antimicrobial

NaOH

Tiny

Adjust pH

Unknown

·   Pain on injection: ? cause

Absorption

·   IV cf inhaled: risk of indefinite accumulation

Distribution

·   Large V_DSS -> slow offset after long infusion

·   Small, lipid soluble, unionized -> rapid placental transfer

Metabolism / excretion

·   Quinol metabolite -> green hair and urine

Modelling

·   Unable to measure plasma concentration clinically

·   Unable to measure effect site concentration

Narrow therapeutic index

i.e. sedation <-> general anaesthesia

·   Risk of airway obstruction, apnoea

·   Inappropriate for untrained staff to administer propofol sedation

Excitatory phenomena

·   Myoclonus/hiccough occurs in 10%

o ? Differential effect on excitatory and inhibitory neurons

o ? Loss of cortical inhibition

o ? Disrupted dopaminergic/cholinergic signalling in subcortex

·   Note: no EEG evidence of seizure

·   Note: propofol is intrinsically anticonvulsant

Cerebral hypoperfusion

CPP = mAP – (CVP or ICP)

·   ↓mAP may be greater than ↓ICP or ↓CVP

·   Problem partly offset by ↓CMRO₂

Euphoria

·   ↑Dopamine discharge at subanaesthetic dose

·   Risk of addiction, dependence

Delirium

·   Higher risk in the elderly

·   ? Cause

Other

·   No antidote available

Mechanisms

·   Inhibit L-Ca2+ channel (↓L-Ca²⁺)

·   ↑Nitric oxide release (↑NO)

·   ↓SNS output from medulla due to ↑GABA activity (↓SNS)

Clinical effects

·   ↓Venous tone, ↓venous return, ↓preload (major effect)

·   ↓Heart rate, ↓contractility

·   ↓SVR, ↓afterload (most important effect)

·   ↓Cardiac output

·   ↓mAP

·   ↓Organ perfusion (e.g. oliguria)

At risk organs:

·   Below autoregulatory threshold mAP (e.g. <70mmHg for kidney)

·   Pressure-passive organ (e.g. placenta)

·   Poorly tolerates ischaemia (e.g. brain)

At risk patients:

·   Poor autoregulation

o Elderly

o Atherosclerosis

·   Minimal reserve

o Shock

o LV failure

Respiratory depression: mechanism

·   ↑GABA -> suppress medulla resp centre and spinal motor neurons

Respiratory depression: clinical effects

·   ↓RR, ↓V_T

·   Risk apnoea at induction

·   ↓Response to ↑PaCO₂ and ↓PaO₂

·   Synergistic resp depression with BDZ and opioids

↓Airway reflexes

·   ↑Risk aspiration if unprotected airway

↓Pharyngeal dilator tone

·   ↑Risk obstruction

·   Very common if OSA

↓HPV

·   Vasodilatation -> universal ↓PVR -> worse V/Q matching

·   Relatively preserved cf. volatile anaesthetics