Author's Accepted Manuscript

Total Intravenous Anesthesia Versus Inhalation

Anesthesia: A Drug Delivery Perspective
Talmage D. Egan MD

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PII: S1053-0770(15)00047-6
DOI: http://dx.doi.org/10.1053/j.jvca.2015.01.024
Reference: YJCAN3187

To appear in: Journal of Cardiothoracic and Vascular Anesthesia

Cite this article as: Talmage D. Egan MD, Total Intravenous Anesthesia Versus
Inhalation Anesthesia: A Drug Delivery Perspective, Journal of Cardiothoracic and
Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2015.01.024

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Total Intravenous Anesthesia Versus Inhalation Anesthesia: A Drug Delivery Perspective

Talmage D. Egan, MD

From the Departments of Anesthesiology, Pharmaceutics and Bioengineering, University of Utah

School of Medicine, Salt Lake City, Utah

Address reprint requests to

Talmage D. Egan, MD

Departments of Anesthesiology, Pharmaceutics and Bioengineering,

University of Utah School of Medicine,

50 N Medical Dr,

Salt Lake City, Utah 84132

E-mail: Talmage.Egan@hsc.utah.edu

Acknowledgments

Dr. Egan has served as a paid consultant to Mylan.

When formulating an anesthetic plan, the anesthesiologist deliberates over numerous therapeutic

decisions. Perhaps chief among these is whether to proceed with an inhalation or intravenous

anesthetic technique. Although there are many differences between the two approaches, they

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differ most fundamentally in terms of how the anesthesiologist gains access to the circulation for

delivery of the anesthetic. This brief review aims to compare and contrast inhalation anesthesia

with total intravenous anesthesia (TIVA) from a drug delivery perspective, making the case that

advances in TIVA drugs, clinical pharmacology concepts, technologies, and techniques over the

last 25 years have transformed TIVA into an attractive alternative to more traditional inhalation

anesthesia methods.

DRUG DELIVERY: INHALATION VERSUS TIVA

Administering volatile anesthetics through the lung via a calibrated vaporizer affords several

fundamental advantages compared with intravenous delivery as summarized in the upper panel

of Fig 1.1 These advantages are primarily a function of gaining access to the circulation

indirectly through the lung. Because uptake of inhaled anesthetic progressively diminishes as

equilibrium between alveolar and pulmonary capillary partial pressures is approached, the

vaporizer setting is a proportional reflection of the anesthetic concentration in the blood and

therefore at the site of drug action at steady state. This enables accurate administration of the

inhaled drug to a target concentration; the anesthesiologist can set an upper limit above which

the partial pressure cannot rise. Moreover, the expired concentration of inhaled agent can be

measured and confirmed by respiratory gas monitoring, ensuring that the targeted concentration

has been achieved (pharmacokinetic [PK] exactness). Finally, the pharmacodynamic (PD)

significance of the measured concentration is standardized in terms of minimum alveolar

concentration (MAC), a well-developed and widely understood concept, which provides an

increased degree of PD exactness.

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As summarized in the lower panel of Fig 1, at the beginning of the TIVA era, intravenous

anesthesia techniques were associated with significant disadvantages compared with inhalation

anesthesia.1 When access to the circulation for drug delivery is obtained directly as with all

intravenous techniques, there is nothing to prevent indefinite uptake of drug (ie, there is no

equilibration process as with inhalation drug delivery). Therefore, without the aid of a PK model,

the infusion rate of an intravenous anesthetic does not reveal much about the temporal profile of

drug concentration in the blood, preventing administration targeted to a designated

concentration. Moreover, there was not a method to measure continually the concentration of

intravenous anesthetics in real time, preventing equivalent PK exactness. Finally, at the dawn of

the TIVA era, concentration-effect relationships analogous to MAC for intravenous anesthetics

had not yet been firmly established, hindering the achievement of equivalent PD exactness

compared with inhalation anesthesia.

Intravenous anesthesia research over the last 25 years has focused on mitigating these

shortcomings identified in the early days of TIVA practice. Because the fundamental advantage

of inhalation anesthesia (ie, the equilibration process that occurs when gaining access to the

circulation via the lung) is obviously not applicable to intravenous techniques, the disadvantages

of TIVA stemming from this difference in access to the circulation must be addressed in other

ways. As summarized in Table 1, TIVA advances have focused on achieving enhanced drug

delivery and improved PK and PD exactness.2 These advances have come in the form of new

drugs, delivery technologies, and clinical pharmacology concepts.

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 NEW DRUGS: PROPOFOL AND REMIFENTANIL

From a practical perspective, to gain traction over inhalation anesthesia techniques, TIVA

practice required anesthetic agents with certain qualities. Perhaps most importantly, the drugs

needed to be sufficiently short acting that recovery could be achieved reasonably quickly despite

long infusions. Some PD advantages of TIVA compared with inhalation agents, such as less

nausea, would also make TIVA attractive.

The advent of propofol ushered in the TIVA era. Propofol has PK and PD properties that are well

suited to the implementation of a TIVA paradigm. The reasonably rapid decline in concentration

despite long infusions3 and the clear headed, often nausea-free recovery contributed to making

propofol the pharmacologic foundation of TIVA practice.4-7 Prior to propofol’s availability, the

existing sedative-hypnotic agents were either too long active (eg, sodium thiopental) or were

associated with unacceptable adverse effects with prolonged administration (eg, etomidate).

Remifentanil, an esterase-metabolized opioid, was designed with the priorities of a modern, often

outpatient anesthesia practice in mind. Utilizing a “soft-drug” paradigm wherein the drug is

designed to be metabolically labile and thus have a very high clearance,8 remifentanil’s effects

dissipate quickly after an infusion is terminated.9 The high clearance is also the kinetic attribute

partly responsible for the rapid achievement of a steady state after beginning a remifentanil

infusion; that is, both the “front-end” and “back-end” kinetics of remifentanil are well suited to

the establishment, maintenance, and recovery from TIVA.10 Given these pharmacologic

properties, remifentanil is frequently combined with propofol for the provision of TIVA.

The pharmaceutical industry, in collaboration with clinical experts, is actively developing a

variety of new agents that may enhance TIVA practice in the future.11 Capitalizing on the

advantages of the “soft-drug” approach applied to anesthesia, these research efforts are in large

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part focused on esterase-metabolized benzodiazepines (eg, remimazolam) and other sedative

hypnotics (eg, etomidate and propanidid analogues).12-14 Novel propofol formulations, typically

in nonlipid excipients, are also an area of active interest.15

ADVANCES IN DRUG DELIVERY: TARGET-CONTROLLED INFUSION, ADVISORY

SYSTEMS, AND EXPIRED PROPOFOL

Enabling drug administration in the concentration domain was an obvious early goal of

intravenous anesthesia research efforts. By coding a PK model into a computer program and

linking it to an electronic pump, delivery according to a drug’s specific kinetic profile was

achieved.16 This concept was first applied to propofol17; commercial embodiments of the idea are

now available for many commonly used intravenous anesthetics (although sadly not in the

United States).18 Called target-controlled infusion (TCI) systems, the user of a TCI system

designates a target concentration to achieve rather than specifying an infusion rate as with a

traditional calculator pump. Using a PK-model-based BET (bolus, elimination, and transfer”)

algorithm, the TCI system then calculates the necessary infusion rates to achieve the targeted

concentration.19,20 Use of TCI requires knowledge of PK models, the biophase concept, PD

models, and the concept of covariate effects for special populations (eg, age, body weight). TCI

systems approximate the concept of a vaporizer for IV anesthetics, although the analogy is not

fully applicable because a vaporizer utilizes the principles of physics, whereas TCI systems rely

on the predictions of PK models.

A natural augmentation of PK-based TCI technology was to extend the concept into the PD

domain. Clinical pharmacology advisory systems are now available to support clinical decision-

making by informing the anesthesiologist of predictions about both the temporal profile of drug

5
concentrations and the likelihood of certain anesthetic effects.21,22 Based on high-resolution

PK/PD models, including a model of the synergistic PD interaction between propofol and

opioids,23,24 this technology automatically acquires from pumps the drug doses administered by

the clinician and then presents the drug dosing history (bolus doses, infusion rates), the predicted

drug concentrations in the effect-site (past, present and future), and the predicted drug effects,

including sedation, analgesia, and neuromuscular blockade. Although in their infancy, these

kinds of advisory systems bring sophisticated clinical pharmacology information from the

literature to the point of care and may eventually prove to be useful to clinicians.25,26

Anesthesiologists have always viewed the ability to measure in real time the concentration of

volatile anesthetics in the expired gas of anesthetized patients as a significant advantage of the

inhalation approach because it improves the PK exactness of drug administration in the

concentration domain (see Fig 1). Recent work by several laboratories has shown that it might be

feasible to commercialize a device that measures the concentration of propofol in expired gas.

The feasibility of the concept was first demonstrated using a variation of mass spectrometry

known as proton transfer reaction mass spectrometry that can detect propofol in minute amounts

(parts per billion by volume) in the expired breath of anesthetized patients.27 More recently,

several groups have further refined the technology using similar techniques.28-30 Preliminary

results suggest that the overall concept and technique are indeed promising and could have far

reaching implications in TIVA research and practice.31 Of course, there are many obstacles (eg,

miniaturization, validation, cost barriers) to be overcome before the technology could move into

mainstream clinical practice.

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 ADVANCES IN PHARMACOKINETIC AND PHARMACODYNAMIC CONCEPTS

Enhanced understanding of intravenous anesthetic agent PK and PD behavior was critical to

provide the scientific foundation upon which TIVA practice could be based. Some PK/PD

concepts (eg, terminal half-life) developed for other therapeutic areas proved almost useless

when applied in anesthesia practice.32 Thus, the early days of TIVA research were marked by

numerous important advances in PK/PD concepts.33

One such concept tailored for anesthesia practice is the context-sensitive half-time (CSHT). The

CSHT is a simulation that predicts the time necessary to achieve a 50% decrease in drug

concentration in the plasma after termination of a variable length, continuous infusion to a steady

state drug level.34 The "context” is the duration of a continuous infusion, a context that is

obviously relevant to TIVA. Drawing upon ideas developed earlier,35 these CSHT simulations

are an attempt to provide information about drug offset time that is not reflected in the terminal

elimination half-life or other PK parameters (eg, clearances, distribution volumes) considered in

isolation.36 The CSHT has also been referred to as the 50% decrement time (when using effect-

site concentrations instead of plasma).37 Of course, the simulations can be conducted for other

degrees of concentration decline depending on the clinical context (eg, 20% or 80% decrement

times, etc.). The CSHT and decrement time are important conceptual tools in comparing the

kinetic behavior of intravenous sedatives and opioids and have become a fundamental

consideration in the rational selection and administration of intravenous anesthetics.

Because in anesthesia practice the key drugs are rarely administered in isolation, the

advancement of TIVA also required improved understanding of intravenous drug interactions.

Anesthesiologists take advantage of the PD synergy that results when two drugs with different

mechanisms of action but similar therapeutic effects (eg, an opioid and a sedative) are combined.

7
These synergistic combinations can be advantageous because the therapeutic goals of the

anesthetic often can be achieved with less toxicity and faster recovery than when the individual

drugs are used alone in higher doses.

The synergistic interaction between propofol and opioids (eg, propofol-remifentanil as

prototypes)23,34 has now been characterized using sophisticated response-surface methodology.38

By creating a three-dimensional plot of the sedative and opioid concentrations versus drug effect,

response-surface methods describe the PD interaction of the two drugs for any degree of drug

effect. Combined with PK information, the response-surface interaction approach can be used to

identify target concentrations of the two drugs that optimize the recovery process.33 The clinical

application of these drug interaction models through the use of computer simulation constitutes a

revolutionary advance in our understanding of intravenous anesthetic clinical behavior and

further solidifies the scientific foundation of TIVA practice.25

CONCLUSION

The introduction of propofol marked the beginning of the TIVA revolution, but compared with

the inhalation approach to anesthesia there were significant disadvantages associated with TIVA

in its early days. These disadvantages stemmed largely from gaining access to the circulation

directly; exploiting the equilibration process that occurs when delivering a drug through the lung

is a fundamental advantage of inhalation anesthesia.

Theoretical and practical scientific advances related to intravenous anesthetics have now

addressed most of the early shortcomings associated with TIVA. Chief among these advances are

more suitable drugs, TCI technology, and sophisticated PK/PD concepts. TIVA is now a popular

8
technique internationally and compares very favorably with traditional inhalation anesthesia

approaches.

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FIGURE LEGEND

Fig 1. A comparison of anesthetic delivery by inhalation (upper panel) or intravenous infusion

(lower panel) at the beginning of the TIVA era. Inhalational anesthetic delivery benefits from the

fundamental advantage of gaining access to the circulation indirectly. The equilibration process

that takes place across the lung vasculature enables drug delivery to well defined anesthetic

targets (ie, MAC) in the concentration domain using a calibrated vaporizer. See text for detailed

explanation. TIVA, total intravenous anesthesia; MAC, minimum alveolar concentration.

(Adapted with permission from Egan.1)

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Table 1. Advances in TIVA addressing disadvantages compared to inhalation anesthesia

categorized according to the paradigm introduced in Fig 1.

Access to the Circulation

None

Drug Delivery

Target controlled infusion

Clinical pharmacology guidance systems

Pharmacokinetic/Pharmacodynamic Exactness

Kinetically responsive drugs (eg, propofol, remifentanil, and other “soft drugs” in

development)

Measurement of propofol in expired gas (ie, “end-tidal” propofol)

Advanced kinetic concepts (eg, CSHT)

Advanced dynamic concepts (eg, response-surface drug interactions, the effect-site

concept)

Abbreviations: CSHT, context-sensitive half-time; TIVA, total intravenous anesthesia.

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Fig 1

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