IV administration of halogenated and nonhalogenated ether and nonether alkane (“volatile”) anesthetics has been explored for more than a century.1Of note, the earliest evaluations were in humans.2,,6One immediate and significant challenge was formulation. Early endeavors simply dissolved the anesthetics in aqueous solutions, but low solubility and side effects were problematic. A variety of oil-in-water emulsions were tried, with the first successes described 50 yr ago.2In the current issue of ANESTHESIOLOGY, Jee et al.  describe a novel “fat-free” approach to formulating a volatile anesthetic (sevoflurane) emulsion, and the IV anesthetic delivery which it enabled.7 

“This new emulsion formulation of sevoflurane should facilitate additional investigations evaluating IV volatile anesthetic pharmacology, and the potential clinical application and utility of such a formulation.”

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Volatile anesthetics formulated as emulsions in Intralipid® (Fresenius Kabi AB, Uppsala, Sweden) or other fats have been shown to produce general anesthesia. Anesthesia could be induced with an emulsion, and once achieved, maintained by continuous infusion or by rebreathing.2,,6,8,9Not surprisingly, induction time was shorter with IV compared with inhaled volatile anesthetics.9,10The minimum alveolar concentration of emulsified volatile anesthetics was significantly lower than that of inhaled anesthetics, attributed in part to effects of the IV lipid load on the blood:gas partition coefficient, but measured blood concentrations were equivalent.9,10Recovery time after emulsified volatile anesthetics was also rapid,10,11and emulsion formulation was reported to not affect the time course of isoflurane washout.10 

Volatile anesthetic emulsions have also been shown to elicit other, more “nontraditional” effects caused by inhaled volatile anesthetics. Emulsified isoflurane and sevoflurane in anesthetic and subanesthetic concentrations were cardioprotective against reperfusuion injury when administered intravenously12,,15or in cardioplegia solution.16Volatile anesthetics, encapsulated in lecithin microdroplets and injected intradermally, produced long-duration local anesthesia lasting several days in humans.17,18Volatile anesthetic emulsions have also been reported to produce epidural anesthesia in rabbits,19reversible conduction block in toad sciatic nerve,20and IV regional anesthesia in rats.21 

Nevertheless, as summarized in this issue's ANESTHESIOLOGY article by the research team from the Departments of Anesthesiology and Chemistry and School of Pharmacy at the University of Wisconsin, volatile anesthetic emulsions formulated in Intralipid® or other fats have been limited by solubility, carrying capacity, and stability. In a previously reported effort to improve the amount of sevoflurane stably emulsified, the Wisconsin team created a copolymer (designated F13M5)-based surfactant nanoemulsion that could dissolve up to 20% sevoflurane by volume.22The sevoflurane emulsion, when injected intavenously, induced general anesthesia in rats and dogs with rapid onset and recovery.22,23However, the F13M5-based sevoflurane emulsion was accompanied by significant hypotension in the dogs, because of histamine release.23Moreover, in additional studies reported in this issue of ANESTHESIOLOGY, long-term stability testing of the original F13M5-based emulsion showed it to be unstable, leading to nanoparticle aggregation and formation of unacceptably large particles. The histamine release and formulation stability were significant safety issues necessitating a new formulation approach.

The investigators now report the successful formulation of sevoflurane with a newly developed polymer, forming a nanoemulsion containing 20% sevoflurane by volume.7The new emulsion was stable for more than 1 yr when stored at 4°C, and, when injected intravenously, produced general anesthesia in rats with rapid onset and recovery.

This new emulsion formulation of sevoflurane should facilitate additional investigations evaluating IV volatile anesthetic pharmacology, and the potential clinical application and utility of such a formulation. Existence of a stable formulation may obviate the need for preparing emulsions on a daily or frequent basis. Additional mechanistic investigations, such as those evaluating sites (brain vs.  spinal cord) of anesthetic action,24,25organ protection and modulation of ischemia-reperfusion injury, and neuraxial or regional anesthesia, may be facilitated.

Like many articles, the one by Jee et al.  prompts several obvious and nonobvious questions, and points the way to future investigations by which to seek the answers. For example, what are the fate, effect, and safety of the excipients and coformulation agents in the sevoflurane emulsion? How will the pharmacokinetics and pharmacodynamics of the new IV sevoflurane compare with that of inhaled sevoflurane or other volatile anesthetics? Although emulsions can obviously change the route of volatile anesthetic administration, will they influence the route and kinetics of elimination: pulmonary clearance and exhalation? Can the new sevoflurane emulsion be used for maintenance of anesthesia? How will exhaled IV volatile anesthetics be scavenged? If an anesthetic circuit is needed for scavenging, does this obviate one potential advantage of emulsions of not needing an anesthesia machine? Or can available nonanesthesia machine-based scavenging masks, which can also provide oxygen, be used? What are the relative advantages and disadvantages of IV emulsion versus  inhalation-based administration of volatile anesthetics? Might IV anesthetic emulsions lead to new clinical indications in addition to that for which volatile anesthetics were originally approved? We can hopefully look forward to future investigations addressing these and other questions.

In addition to the specific implications for anesthesiology research and possibly practice, the manuscript by Jee et al.  also serves to remind us of issues relevant to innovation. Thus this editorial could have easily been titled “Sevoflurane emulsions: Informing nanoscale science and macroscale science policy.” Innovation in pharmaceutical development can be considered radical or incremental, where the former involves development of new molecular entities while the latter includes supplemental indications and new formulations.26Another interesting aspect of the pharmaceutical innovation published by Jee et al.  is that it comes from an academic laboratory.

Should academic anesthesia be engaged in pharmaceutical development? Should academia in general? Indeed, the role of academia in innovation, entrepreneurship, and commercialization is currently controversial. Is this like getting oil and water to mix?“Purists” may argue that academia is the domain of basic, rather than applied, research. Nevertheless, logic and evidence contravene such contentions. Whereas early constructs considered basic and applied research either exclusive and in conflict, or arrayed on either ends of a linear one-dimensional continuum, more informed paradigms consider them dynamic and intertwined.27University innovation and technologies result in the introduction of hundreds of new products to the marketplace and billions of dollars of benefit to the U.S. economy annually, and the creation of more than one new startup company per day.28Indeed, approximately one-third of the scientifically innovative drugs approved by the U.S. Food and Drug Administration from 1998 to 2007 were initially discovered in universities.29Moreover, applied and commercialization research does not detract from traditional academic missions. Research shows that intellectual property creation and commercialization does not make faculty less likely to publish (on the contrary, they are more prolific), shift effort away from fundamental research toward more applied research, significantly delay publication, or replace scholarly output and quality as principal criteria for academic employment and advancement.28The research and the report by Jee et al. , together with the publication record of these investigators, confirm these contentions. Other academic anesthesia laboratories have likewise contributed to radical or incremental pharmaceutical innovation with commercialization potential,30,,32and such endeavors are to be encouraged.

In summary, the report by Jee et al.  describes a new, enabling technology for the formulation of sevoflurane, and perhaps other, volatile anesthetic emulsions, which are stable when stored for up to a year. Such emulsions can be administered intravenously to rapidly achieve general anesthesia. Other potential applications may also be discovered. We look forward to additional investigations of volatile anesthetic emulsions.

Burkhardt L: Die intravenose narkose mit aether and chloroform. Muenchen Med Wschr 1909; 56:2365
Krantz JC Jr, Cascorbi HF, Helrich M, Burgison RM, Gold MI, Rudo F: A note on the intravenous use of anesthetic emulsions in animals and man with special reference to methoxyflurane. ANESTHESIOLOGY 1961; 22:491–2
Krantz JC Jr, Cascorbi HF, Rudo FG: Anesthesia. 64. The intravenous administration of methoxyflurane (Penthrane) emulsions in animals and man. Anesth Analg 1962; 41:257–62
Eger EI 2nd, Johnson EA, Larson CP Jr, Severinghaus JW: The uptake and distribution of intravenous ether. ANESTHESIOLOGY 1962; 23:647–50
Cascorbi HF, Helrich M, Krantz JC Jr, Baker LR, Rozman RS, Rudo FG: Hazards of methoxyflurane emulsions in man. Anesth Analg 1968; 47:557–9
Biber B, Johannesson G, Lennander O, Martner J, Sonander H, Werner O: Intravenous infusion of halothane dissolved in fat. Haemodynamic effects in dogs. Acta Anaesthesiol Scand 1984; 28:385–9
Jee J-P, Parlato MC, Perkins MG, Mecozzi S, Pearce RA: Exceptionally stable fluorous emulsions for the intravenous delivery of volatile general anesthetics. ANESTHESIOLOGY 2012; 116:580–5
Eger RP, MacLeod BA: Anaesthesia by intravenous emulsified isoflurane in mice. Can J Anaesth 1995; 42:173–6
Musser JB, Fontana JL, Mongan PD: The anesthetic and physiologic effects of an intravenous administration of a halothane lipid emulsion (5% vol/vol). Anesth Analg 1999; 88:671–5
Yang XL, Ma HX, Yang ZB, Liu AJ, Luo NF, Zhang WS, Wang L, Jiang XH, Li J, Liu J: Comparison of minimum alveolar concentration between intravenous isoflurane lipid emulsion and inhaled isoflurane in dogs. ANESTHESIOLOGY 2006; 104:482–7
Zhou JX, Luo NF, Liang XM, Liu J: The efficacy and safety of intravenous emulsified isoflurane in rats. Anesth Analg 2006; 102:129–34
Chiari PC, Pagel PS, Tanaka K, Krolikowski JG, Ludwig LM, Trillo RA Jr, Puri N, Kersten JR, Warltier DC: Intravenous emulsified halogenated anesthetics produce acute and delayed preconditioning against myocardial infarction in rabbits. ANESTHESIOLOGY 2004; 101:1160–6
Rao Y, Wang YL, Zhang WS, Liu J: Emulsified isoflurane produces cardiac protection after ischemia-reperfusion injury in rabbits. Anesth Analg 2008; 106:1353–9
Lucchinetti E, Schaub MC, Zaugg M: Emulsified intravenous versus  evaporated inhaled isoflurane for heart protection: Old wine in a new bottle or true innovation? Anesth Analg 2008; 106:1346–9
Hu ZY, Luo NF, Liu J: The protective effects of emulsified isoflurane on myocardial ischemia and reperfusion injury in rats. Can J Anaesth 2009; 56:115–25
Huang H, Zhang W, Liu S, Yanfang C, Li T, Liu J: Cardioprotection afforded by St Thomas solution is enhanced by emulsified isoflurane in an isolated heart ischemia reperfusion injury model in rats. J Cardiothorac Vasc Anesth 2010; 24:99–103
Haynes DH, Kirkpatrick AF: Ultra-long-duration local anesthesia produced by injection of lecithin-coated methoxyflurane microdroplets. ANESTHESIOLOGY 1985; 63:490–9
Haynes DH, Kirkpatrick AF: Long duration local anesthesia with lecithin-coated microdroplets of methoxyflurane: Studies with human skin. Reg Anesth 1991; 16:173–80
Chai YF, Yang J, Liu J, Song HB, Yang JW, Liu SL, Zhang WS, Wang QW: Epidural anaesthetic effect of the 8% emulsified isoflurane: A study in rabbits. Br J Anaesth 2008; 100:109–15
Li Z, Yang J, Liu J, Gong CY, Gan J, Zhang X, Luo WJ, Li GH: Reversible conduction block in isolated toad sciatic nerve by emulsified isoflurane. Anesth Analg 2010; 110:1024–9
Zhou C, Gan J, Liu J, Luo WJ, Zhang WS, Chai YF: The interaction between emulsified isoflurane and lidocaine is synergism in intravenous regional anesthesia in rats. Anesth Analg 2011; 113:245–50
Fast JP, Perkins MG, Pearce RA, Mecozzi S: Fluoropolymer-based emulsions for the intravenous delivery of sevoflurane. ANESTHESIOLOGY 2008; 109:651–6
Johnson RA, Simmons KT, Fast JP, Schroeder CA, Pearce RA, Albrecht RM, Mecozzi S: Histamine release associated with intravenous delivery of a fluorocarbon-based sevoflurane emulsion in canines. J Pharm Sci 2011; 100:2685–92
Antognini JF, Carstens E: Macroscopic sites of anesthetic action: Brain versus  spinal cord. Toxicol Lett 1998; 100–101:51–8
Yang J, Li Z, Gong CY, Chai YF, Li T, Li GH, Luo N, Luo NF, Zhu L, Liu J: A model for the preferential delivery of isoflurane to the spinal cord of the goat. Vet J 2011; 187:239–44
Berndt E: The impact of incremental innovation on biopharmaeuticals. Pharmacoeconomics 2006; 24(Suppl 2):69–86
Stokes DE: Pasteur's quadrant: Basic science and technical innovation. Washington, D.C., Brookings Institution Press, 1997
Managing university intellectual property in the public interest. Washington, D.C., National Academies Press, 2010
Kneller R: The importance of new companies for drug discovery: Origins of a decade of new drugs. Nat Rev Drug Discov 2010; 9:867–82
Morey TE, Modell JH, Shekhawat D, Shah DO, Klatt B, Thomas GP, Kero FA, Booth MM, Dennis DM: Anesthetic properties of a propofol microemulsion in dogs. Anesth Analg 2006; 103:882–7
Cotten JF, Husain SS, Forman SA, Miller KW, Kelly EW, Nguyen HH, Raines DE: Methoxycarbonyl-etomidate: A novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression. ANESTHESIOLOGY 2009; 111:240–9
Baker MT: The anticonvulsant effects of propofol and a propofol analog, 2,6-diisopropyl-4-(1-hydroxy-2,2,2-trifluoroethyl)phenol, in a 6 Hz partial seizure model. Anesth Analg 2011; 112:340–4