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Total Intravenous Anesthesia Versus Inhalation Anesthesia: A Drug Delivery Perspective Talmage D. Egan MD

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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, This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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: [email protected]

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 1

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.


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.


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 4

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 decisionmaking 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.


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 effectsite 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


technique internationally and compares very favorably with traditional inhalation anesthesia approaches.

REFERENCES 1. Egan TD: Intravenous drug delivery systems: toward an intravenous "vaporizer". J Clin Anesth 8: 8S-14S, 1996 2. Egan TD: Target-controlled drug delivery: progress toward an intravenous "vaporizer" and automated anesthetic administration. Anesthesiology 99:1214-1219, 2003 3. Schnider TW, Minto CF, Gambus PL, et al: The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 88:11701182, 1998 4. Apfel CC, Heidrich FM, Jukar-Rao S, et al: Evidence-based analysis of risk factors for postoperative nausea and vomiting. Br J Anaesth 109:742-753, 2012 5. Apfel CC, Korttila K, Abdalla M, et al: A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 350:2441-2451, 2004 6. Sebel PS, Lowdon JD: Propofol: a new intravenous anesthetic. Anesthesiology 71:260-277, 1989 7. Valanne J: Recovery and discharge of patients after long propofol infusion vs isoflurane anaesthesia for ambulatory surgery. Acta Anaesthesiol Scand 36:530-533, 1992


8. Egan TD: Is anesthesiology going soft?: trends in fragile pharmacology. Anesthesiology 111:229-230, 2009 9. Egan TD, Lemmens HJ, Fiset P, et al: The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers [see comments]. Anesthesiology 79:881-892, 1993 10. Egan TD, Minto CF, Hermann DJ, et al: Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers [published erratum appears in Anesthesiology 85:695, 1996]. Anesthesiology 84:821-833, 1996 11. Sneyd JR, Rigby-Jones AE: New drugs and technologies, intravenous anaesthesia is on the move (again). Br J Anaesth 105:246-254, 2010 12. Antonik LJ, Goldwater DR, Kilpatrick GJ, et al: A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg 115:274-283, 2012 13. Egan TD, Obara S, Jenkins TE, et al: AZD-3043: a novel, metabolically labile sedativehypnotic agent with rapid and predictable emergence from hypnosis. Anesthesiology 116:12671277, 2012 14. Pejo E, Santer P, Jeffrey S, et al: Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology. Anesthesiology 121:290-301, 2014 15. Egan TD: Exploring the frontiers of propofol formulation strategy: is there life beyond the Milky Way? Br J Anaesth 104:533-535, 2010 10

16. Glen JB: The development and future of target controlled infusion. Adv Exp Med Biol 523:123-133, 2003 17. Kenny GN: Target-controlled anaesthesia: concepts and first clinical experiences. Eur J Anaesthesiol Suppl 15:29-31, 1997 18. Egan TD, Shafer SL: Target-controlled infusions for intravenous anesthetics: surfing USA not! Anesthesiology 99:1039-1041, 2003 19. Kruger-Thiemer E: Continuous intravenous infusion and multicompartment accumulation. Eur J Pharmacol 4:317-324, 1968 20. Schwilden H: A general method for calculating the dosage scheme in linear pharmacokinetics. Eur J Clin Pharmacol 20:379-386, 1981 21. Gin T: Clinical pharmacology on display. Anesth Analg 111:256-258, 2010 22. Kennedy RR: Seeing the future of anesthesia drug dosing: moving the art of anesthesia from impressionism to realism. Anesth Analg 111:252-255, 2010 23. Bouillon TW, Bruhn J, Radulescu L, et al: Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology 100:1353-1372, 2004 24. Kern SE, Xie G, White JL, et al: A response surface analysis of propofol-remifentanil pharmacodynamic interaction in volunteers. Anesthesiology 100:1373-1381, 2004 25. Short TG: Using response surfaces to expand the utility of MAC. Anesth Analg 111:249251, 2010


26. Struys MM, De Smet T, Mortier EP: Simulated drug administration: an emerging tool for teaching clinical pharmacology during anesthesiology training. Clin Pharmacol Ther 84:170-174, 2008 27. Harrison GR, Critchley AD, Mayhew CA, et al: Real-time breath monitoring of propofol and its volatile metabolites during surgery using a novel mass spectrometric technique: a feasibility study. Br J Anaesth 91:797-799, 2003 28. Hornuss C, Praun S, Villinger J, et al: Real-time monitoring of propofol in expired air in humans undergoing total intravenous anesthesia. Anesthesiology 106:665-674, 2007 29. Takita A, Masui K, Kazama T: On-line monitoring of end-tidal propofol concentration in anesthetized patients. Anesthesiology 106:659-664, 2007 30. Grossherr M, Hengstenberg A, Meier T, et al: Propofol concentration in exhaled air and arterial plasma in mechanically ventilated patients undergoing cardiac surgery. Br J Anaesth; 102:608-613, 2009 31. Kharasch ED: Every breath you take, we'll be watching you. Anesthesiology 106:652-654, 2007 32. Fisher DM: (Almost) everything you learned about pharmacokinetics was (somewhat) wrong! Anesth Analg 83:901-903, 1996 33. Minto CF, Schnider TW: Contributions of PK/PD modeling to intravenous anesthesia. Clin Pharmacol Ther 84:27-38, 2008 34. Hughes MA, Glass PS, Jacobs JR: Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 76:334-341, 1992


35. Shafer SL, Varvel JR: Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology 74:53-63, 1991 36. Shafer SL, Stanski DR: Improving the clinical utility of anesthetic drug pharmacokinetics. Anesthesiology 76:327-330, 1992 37. Youngs EJ, Shafer SL: Pharmacokinetic parameters relevant to recovery from opioids. Anesthesiology 81:833-842, 1994 38. Minto CF, Schnider TW, Short TG, et al: Response surface model for anesthetic drug interactions. Anesthesiology 92:1603-1616, 2000

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)


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.


Fig 1


Total intravenous anesthesia versus inhalation anesthesia: a drug delivery perspective.

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