Effect-site targeting in clinical TIVA practice

Overview

Target-controlled infusion can be aimed at the predicted plasma concentration or at the predicted effect-site (brain) concentration, and the clinical difference is substantial[4]. Because drug must equilibrate from plasma into the brain, a plasma target lags the clinical effect by minutes; an effect-site target accepts a calculated transient overshoot in plasma to bring the brain to the intended concentration quickly. This single refinement underpins smooth, rapid induction, fine titration to a depth monitor, and the propofol-remifentanil TIVA technique that is now the standard for shared-airway and day-surgery anaesthesia[1][2]. This topic covers the clinical use of effect-site targeting from induction to recovery.

Plasma versus effect-site and the role of ke0

After an intravenous dose the plasma concentration changes immediately but the brain concentration follows only after an equilibration delay, described by the first-order rate constant ke0 (and its time-equivalent, the t-half ke0)[4]. This hysteresis is why a plasma-targeted bolus takes time to work, and why the effect-site model — adding an effect compartment linked to plasma by ke0 — lets the pump predict the brain concentration and target it directly. A drug with a fast ke0 (propofol, remifentanil) equilibrates quickly, giving brisk onset and offset that suit effect-site targeting; a slow ke0 would make the predicted effect-site unreliable[4]. The ke0 is built into each model (Schnider and Eleveld for propofol, Minto for remifentanil) and should not be mixed across models.

Induction by effect-site targeting

Induction is where effect-site targeting earns its keep. A plasma-targeted induction must wait for the brain to catch up; an effect-site target of around four to six micrograms per millilitre of propofol (Schnider) brings the brain to an anaesthetic concentration within a minute or two, with the pump giving a brisk initial bolus then tapering[4]. Loss of consciousness, loss of the eyelash reflex and acceptance of the airway are the clinical endpoints; the depth monitor confirms the predicted effect-site matches the actual brain state. The transient plasma overshoot that drives the brain to target can depress the blood pressure, so in the elderly and the haemodynamically fragile the target is started low and titrated up[4].

The propofol-remifentanil TIVA combination

Modern effect-site TIVA is almost always a two-channel technique: propofol for hypnosis and remifentanil for analgesia, each with its own target[1][4]. Remifentanil reduces the propofol concentration needed for anaesthesia and blunts the response to noxious stimulus, and because remifentanil has a very short context-sensitive half-time, its target can be raised for intense stimulus (intubation, incision) and dropped again immediately. The combination produces a controllable, rapidly adjustable anaesthetic with smooth emergence, and pharmacological adjuvants such as intravenous lidocaine can further smooth emergence and reduce coughing[1].

Target ranges and clinical endpoints

A typical maintenance regime uses a propofol effect-site target of three to six micrograms per millilitre with a remifentanil target of two to six nanograms per millilitre (Minto), adjusted to the stimulus and the patient[4]. The targets are means, not rules: the right target is the lowest that produces an adequate depth (no movement, an acceptable haemodynamic response, a depth index in range) and the highest that avoids hypotension and respiratory depression. Targets are raised briefly for stimulus and lowered for the vulnerable patient, and the anaesthetic is titrated continuously against clinical signs and the depth monitor rather than left at a set number[4].

Titration to the processed-EEG depth monitor

Because the displayed target is a prediction, effect-site TIVA is paired with a processed-EEG depth monitor — a dimensionless index (and its raw trace) that estimates cortical anaesthetic effect[4][5]. The index trends toward the intended range for adequate surgical anaesthesia, and the target is adjusted when the index wanders. The depth monitor is the feedback that closes the gap between the model's prediction and the patient's actual brain state, and it is essential whenever the prediction is unreliable (the elderly, the obese, the critically ill, hypothermia, high-dose or atypical drug)[4].

Interpreting the depth trace and paradoxical excitation

The depth monitor is imperfect and must be read with judgement. Paradoxical excitation — an increase in the index or beta activity at light or, paradoxically, at deepening planes of propofol anaesthesia — can mislead an operator into thinking the patient is light when they are not, and the literature emphasises reading the complexity of the raw trace rather than the number alone[5]. Electromyographic activity from the frontalis, electrocautery and vasoconstrictive artefact all distort the index, so a sudden change is checked against the clinical picture (movement, tearing, the surgical stimulus, the blood pressure) before the target is changed[5].

TIVA for the shared and unsecured airway

Effect-site TIVA is the technique of choice where the airway is shared with a surgeon or an endoscopist, or where it is unsecured[2]. In robotic-assisted bronchoscopy, for example, anaesthesia is maintained by propofol-remifentanil TIVA while the bronchoscopist occupies the airway, often with jet ventilation or spontaneous ventilation preserved, and the absence of an inhalational agent avoids pollution and the problem of delivering a gas through an open, shared circuit[2]. The same logic applies to ENT microlaryngoscopy, dental and maxillofacial surgery, and radiation therapy under anaesthesia — settings where TIVA's controllability and airway-independence are decisive[2].

Avoiding opioid-induced respiratory depression

The depth and the drive to breathe are separate, and the synergy between a remifentanil (or any opioid) effect-site target and a sedative is a leading cause of perioperative respiratory depression[6]. A high remifentanil target combined with a benzodiazepine or another sedative can produce apnoea and chest-wall rigidity; the case literature of remimazolam with remifentanil describes exactly this interaction, and it is the reason remifentanil target is titrated to the stimulus and reduced as soon as the stimulus ends, with ventilation supported throughout[6].

Closed-loop effect-site delivery

The natural extension of effect-site titration to the depth monitor is closed-loop anaesthesia, in which the depth signal feeds back to the pump to adjust the target automatically[3]. Closed-loop systems reduce variability, avoid under- and over-shoot, and free the anaesthetist's attention, and reviews confirm their feasibility for automated hypnotic delivery during general anaesthesia[3]. They are not yet routine because their performance depends entirely on a reliable depth signal: artefact or a misleading index drives the pump to overdose or underdose, so the human remains in supervision, intervening when the signal is unreliable[3][5].

Special situations and recovery

In the elderly and frail, effect-site targets are reduced and titrated slowly because of pharmacodynamic sensitivity and reduced clearance; in the obese, the model's handling of weight (Schnider's lean-body-mass cap, Eleveld's allometric scaling) determines whether the prediction is sound[4]. For day surgery, the rapid offset of propofol and remifentanil effect-site targeting supports fast, clear-headed emergence and a low rate of postoperative nausea, which is part of the technique's appeal. Recovery is governed by the context-sensitive half-time: a high target sustained to the end of a long case accumulates peripherally and delays emergence, so the target is weaned as the stimulus recedes rather than held to the last moment[4].

[1] [1]

Red flags

References

1. [1]He ZY, et al. Comparison of propofol-remifentanil target-controlled infusion with lidocaine versus neuromuscular blockade for laryngoscopy Minerva Anestesiol, 2026.PMID 42267885
2. [2]Stretch B, et al. Peri-operative care of patients undergoing robotic-assisted bronchoscopy under general anaesthesia - a single-centre retrospective cohort study Anaesth Rep, 2026.PMID 42283065
3. [3]Felippe VA, et al. Closed-loop systems for automated hypnotic drug delivery during general anaesthesia: a systematic review and meta-analysis Br J Anaesth, 2026.PMID 42014224
4. [4]Stojanovic M, et al. What's new in intravenous anaesthesia? Curr Opin Anaesthesiol, 2026.PMID 41677226
5. [5]Newman D, et al. Reframing paradoxical excitation: disentangling electroencephalogram complexity and entropy reveals resting-state dynamics associated with propofol susceptibility in healthy adults Br J Anaesth, 2026.PMID 42225443
6. [6]Kim HY, et al. Respiratory Depression Following Concomitant Infusion of Remimazolam and Remifentanil Using Targeted Effect-Site Concentrations: A Randomized Controlled Trial Medicina (Kaunas), 2026.PMID 42195193