Intravenous induction agents,
as they have actually been examined.

I would reduce the dose substantially — of the order of half a standard dose — give it slowly, and wait considerably longer than usual before assessing the effect. Four separate mechanisms are pushing in the same direction here, and it is worth naming them rather than saying simply that he is elderly and shocked.

First, age: a patient over 80 needs roughly half the propofol dose of a 20-year-old, and that is both a smaller central compartment with lower clearance and a brain more sensitive to a given concentration. Second, hypovolaemia: a fractured neck of femur with a haemoglobin of 78 means a contracted central volume, so the same dose produces a higher peak concentration, and a redistributed cardiac output delivers more of that to the brain. Third, hypoalbuminaemia: at 24 g/L the free fraction of a highly protein-bound drug is meaningfully increased, and only free drug crosses into the brain. Fourth, his circulation time is prolonged by the low cardiac output, so the effect will appear later than I expect — and if I judge the dose by the absence of effect at fifteen seconds, I will give a second dose on top of a first that had not yet arrived.

That last point is the one I would emphasise. The commonest way of overdosing this patient is not choosing the wrong number; it is titrating on a normal timescale.

Likely follow-ups

• You have decided on a reduced dose. How much reduced, and how would you give it?
• Why does his albumin matter to this decision?
• He becomes profoundly hypotensive after induction anyway. What is the mechanism?
• Would your answer differ if you had chosen etomidate instead?

IV Induction Agents 1: Principles and Mechanisms →

The essential difference is clearance. Propofol’s clearance is 1.5 to 2.2 litres per minute, which exceeds hepatic blood flow — so it cannot all be hepatic, and extrahepatic metabolism has been confirmed directly, mainly renal with a pulmonary contribution. That very high clearance means that when the infusion stops, elimination keeps pace with the drug returning from the peripheral compartments, so the plasma concentration still falls quickly. The context-sensitive half-time stays under forty minutes even after eight hours.

Thiopentone is the opposite on both counts. Its clearance is around 3.5 mL/kg/min, an order of magnitude lower, and at high dose it saturates its own metabolism, so handling moves from first-order towards zero-order. Its context-sensitive half-time rises steeply and does not plateau — an infusion has a tail measured in days.

I would add that propofol’s metabolites are of little or no clinical activity, and that its kinetics are predictable enough for a three-compartment model to be built and driven by a pump, which is what makes target-controlled infusion possible on top of the pharmacology. And I would be careful to say that the short distribution half-life is what terminates a bolus, not what makes it suitable for an infusion. Those are different arguments about different phases of the drug’s behaviour, and conflating them is the commonest way this question goes wrong.

Likely follow-ups

• You have said its context-sensitive half-time is short. What determines that?
• Its terminal half-life is 5 to 12 hours. How is that compatible with rapid recovery?
• Would you use it for sedation in a ventilated 14-year-old on the intensive care unit?
• What would make you stop a propofol infusion in an adult on day three?

IV Induction Agents 2: Propofol, TIVA and TCI →

The competing considerations are haemodynamic stability against adrenal suppression, in a patient who has both a compromised circulation and sepsis. I would use ketamine as my first choice here, in a reduced dose, because it supports the circulation actively rather than merely failing to depress it, and it carries no endocrine cost.

Against etomidate specifically: it is the agent with the best haemodynamic profile, and a single dose inhibits 11β-hydroxylase for up to 72 hours, lowering both cortisol and aldosterone. The evidence that this increases mortality after a single dose is not conclusive — a Cochrane review found none — but retrospective analysis of the CORTICUS septic shock population suggested higher 28-day mortality in those who received it. Given that I have an alternative that is haemodynamically acceptable, I would take the option without the unresolved question attached to it.

If I did use thiopentone, I would give a substantially reduced dose, and I can say why in mechanism rather than by rule. At a pH of 7.18 the unionised fraction of a drug with a pKa of 7.6 is considerably higher than at 7.4, so more of the free drug can cross into the brain. At an albumin of 21 g/L the free fraction itself is higher, because the drug is 80% protein bound in health. Those two multiply, and on top of them sit a contracted central volume and a redistributed cardiac output. I would expect to need something closer to half the textbook dose, given slowly, and I would wait longer before judging its effect because his circulation time is prolonged.

On steroid supplementation: I would not give it routinely after a single induction dose. The evidence in the CORTICUS analysis was that steroid supplementation provided no benefit in those patients.

Likely follow-ups

• You have chosen against etomidate. What would change your mind?
• If you use thiopentone, how would the acidosis and the albumin change your dose, and by what mechanism?
• What is the mechanism of the adrenal suppression, and how long does it last?
• Is there any role for steroid supplementation if you do give etomidate?

IV Induction Agents 3: Thiopentone and Etomidate →

I would answer this system by system, and start by noting that the two drugs sedate by completely different mechanisms — propofol through GABA-A receptors, dexmedetomidine through α2 receptors at the locus coeruleus and the endogenous sleep pathway — because most of the differences follow from that.

Cardiovascular. Propofol produces a monophasic fall in blood pressure, driven mainly by a fall in systemic vascular resistance, with venodilatation reducing preload and a smaller direct negative inotropic effect. Crucially the baroreflex is blunted, so there is no compensatory tachycardia and bradycardia is common. Dexmedetomidine’s response is biphasic: an early transient hypertension from peripheral post-synaptic α2-mediated vasoconstriction, followed by hypotension and bradycardia from central sympatholysis. The biphasic response is the hallmark. Both can produce significant bradycardia; only dexmedetomidine can produce hypertension.

Central nervous system. Both reduce cerebral metabolic rate and, with it, cerebral blood flow and intracranial pressure. The differences are in the quality of the sedation and in what comes with it. Propofol produces sedation resembling natural sleep with a dose-related progression to unconsciousness, has antiemetic and anticonvulsant properties, and no analgesia. Dexmedetomidine produces sedation resembling non-REM sleep in which the patient is rousable and cooperative, provides analgesia and is opioid-sparing, and reduces the incidence of delirium.

The respiratory difference is what usually decides it, and I would say so even though the question asks about two other systems: propofol causes dose-dependent respiratory depression and apnoea, and dexmedetomidine causes minimal respiratory depression. For an awake fibreoptic intubation that is decisive, and I would choose dexmedetomidine. Its practical disadvantages there are the slow onset — the loading dose has to be given over ten minutes and must not be rushed — the bradycardia and hypotension, and the absence of any reversal agent.

Likely follow-ups

• You mention a biphasic response. What is the mechanism of each phase?
• Which would you choose for an awake fibreoptic intubation, and why?
• What are the practical disadvantages of dexmedetomidine in that setting?
• How does the quality of sedation differ, and does that matter clinically?

IV Induction Agents 4: Ketamine, Midazolam and Dexmedetomidine →