A novel intravenous general anesthetic--- emulsified isoflurane: from bench to bedside

Abstract

Application of volatile anesthetics greatly alters modern medicine. There are obvious advantages of volatile anesthetics such as strong anesthetic potency, rapid onset and elimination through respiration system. Isoflurane is one of the most widely used volatile anesthetics in clinic. Emulsified isoflurane, the emulsion of isoflurane, is a novel intravenous general anesthetic. With the development of emulsified isoflurane in the past fifteen years, its utility has spread from intravenous general anesthesia to various fields including regional anesthesia, organ protection, as well as anesthetic pharmacological study. In this review, we will summarize literatures of emulsified isoflurane about its history, clinical application and future potential utility in the above mentioned fields.

Keywords

emulsified isoflurane (EI) / general anesthesia / regional anesthesia / organ protection / anesthetic pharmacological study

Introduction

Since the application of diethyl ether in 1846, volatile anesthetics have become the most widely used general anesthetics because of their strong anesthetic potency. The use of methoxyflurane and halothane is rare now because they might induce injury to kidney [1] and/or liver [2,3]. For isoflurane and sevoflurane, they are directly eliminated through respiration system with extremely low ratio of biological metabolism. Thus, no obvious toxicity induced by isoflurane and sevoflurane has been observed.

What about volatile anesthetics are intravenously injected? Anesthetic pharmacologists will immediately realize the great potential of this exciting attempt. As the novel entitled “Clothes make the man,” written by the Zurich novelist Gottfried Keller, indicates the great impact of the clothing on social reputation, likewise, encapsulation or formulation of a medication and the route of administration are known to profoundly affect pharmacokinetic and dynamic properties of a drug, to modify the ratio between therapeutic activities versus toxicity, and are even capable of evoking novel biologic effects [4]. Intravenous administration eliminates the requirement for specific ventilator and provides an independence of anesthetic induction to pulmonary function. However, intravenous injection of liquid volatile anesthetics induces serious outcomes, including acute lung edema, injury to important organs, and even lethal consequences [5–8]. Therefore, the development of available vehicle for volatile anesthetics is critical for the idea of injecting volatile anesthetics to systemic circulation.

Intralipid is the most likely candidate to be the vehicle for volatile anesthetics. As early as in 1962, Krantz et al. reported that methoxyflurane emulsion induced general anesthesia in monkeys and dogs [9]. However, the following studies found that methoxyflurane emulsion induced injury such as thrombophlebitis when used in human beings [10]. Eger et al. reported that emulsified isoflurane (EI) could induce general anesthesia with rapid onset, and without significant side effects [11].

Our studies demonstrated that anesthetic induction and recovery produced by EI were more rapid than that by propofol [12]. Firstly, as opposed to inhaled administration, intravenous injection requires significantly less isoflurane (80% less for induction and 20% less for maintenance) to obtain same effects, reducing environmental pollution and tissue toxicity [4]. Secondly, EI with its preconditioning potential could be added to organ-preserving solution. Finally, since volatile anesthetics elicit protection of the endothelium, intravenous administration, would clearly facilitate the use of halogenated ether for organ protection in other clinical fields, and thus promote their administration during diagnostic and interventional procedures in cardiology or endovascular procedures of high risk patients.

The application of EI has been spread from original general anesthesia to many fields of clinical medicine. In this review, we will summarize literatures of EI about its history and future application.

Emulsified isoflurane for general anesthesia

Volatile anesthetics with high vapor pressure and low anesthetic potency might be inappropriate for emulsified preparation. If the agent enjoys a high vapor pressure at body temperature, it is clear that it will be rapidly excreted by the lung. This necessitates large volume of a high concentration of the anesthetic emulsion to be infused rapidly to maintain anesthesia. If the anesthetic is poorly potent, likewise, a relatively high concentration and a large volume of emulsion will be required for anesthesia.

Systemic injection of methoxyflurane emulsion has been found to induce general anesthesia but with slow onset [9]. Other agents producing rapid induction, such as halothane, might be added to achieve more rapid induction [13]. However, previous studies show that halothane undoubtedly causes injury to liver [2,3]. By following studies, potency and vapor pressure of isoflurane are appropriate for emulsified preparation. Application of emulsified isoflurane (EI) in mice induced rapid general anesthesia, first reported by Eger et al. in 1995 [11]. Recently, a novel preparation of emulsified sevoflurane (fluoropolymer-based emulsion) was developed, in which the concentration of sevoflurane (v/v) could be up to 20%–30% [14,15]. This novel preparation is of great potential to delivery volatile anesthetics to systemic circulation.

The maximum concentration of isoflurane in 30% intralipid has been demonstrated to be about 8% (v/v, 100ml EI contains pure liquid isoflurane 8 ml). Liu et al. measured the liquid/gas partition coefficients of volatile anesthetics by two step equilibrium methods [16], as well as the factors that affected liquid/gas partition coefficients such as body temperature and age of patients [17,18]. The largest solubility of isoflurane is 5.64 and 8.24 ml/100 ml in 20% and 30% intralipid, respectively [19]. Thus, 8% EI has been demonstrated to be stable for storage as long as 24 months.

As shown in Table 1, EI could produce reliable general anesthesia in many animal models. Zhou et al. found that 8% EI is potent for general anesthesia in rats, with rapid onset (within 5 s) and short anesthetic duration (22±15 s). ED₅₀ of 8% EI to produce loss of righting reflex in rats is 0.70 ml/kg (0.056 ml/kg pure liquid isoflurane) and LD₅₀ is 2.10 ml/kg (0.168 ml/kg pure liquid isoflurane) in rats [20]. In Beagle dogs, the ED₅₀ of 8% EI to induce loss of righting reflex is 0.938 ml/kg (0.075 ml/kg pure liquid isoflurane) and tolerance dose is 1.80 ml/kg (0.144 ml/kg pure liquid isoflurane) [21]. Yang et al. found that EI produced anesthetic induction within 105±24 s, which was significantly shorter than that induced by inhaled isoflurane (378±102 s, P<0.01). The volume of pure liquid isoflurane was 1.8±0.5ml for emulsified preparation to induce general anesthesia, while 9.8±2.0 ml pure liquid isoflurane was needed for inhalation (P<0.01). The end-tidal MAC of isoflurane with intravenous injection was also significantly lower than that by inhalation [22]. In addition, the security of EI was verified by stable hemodynamic state with single bolus and no pathological damage was found in important organs including liver, lung, and heart as well as nervous tissue after injection. For long-term application of EI, no hemolysis was found in Beagle dogs and no pathological injury was observed in important organs after continuous injection of EI as long as 30 days [23,24].

Propofol is a commonly used intravenous general anesthetic. Comparing to propofol (61±9 s), onset time of general anesthesia induced by EI (58±9 s) was not different with single bolus. However, duration of general anesthesia with EI (105±61 s) was significantly shorter than that induced by propofol (292±100 s, P<0.01) [12]. Thus, EI is particularly appropriate for operations that demand rapid tracheal intubation or rapid recovery.

There are some obvious advantages of EI in general anesthesia. More accurate control of the volume for administration might be achieved by intravenous injection of EI than by inhalation of isoflurane. Once a sufficient quantity of anesthetic emulsion has been injected to establish the desired anesthesia, it can be maintained by the rebreathing technique as well as by continuous infusion. For operation about the face this procedure enables the anesthesiologist to administer the agent without the use of the anesthetic mask. It is also apparent that for surgical procedures in cases of mass emergencies, this procedure affords the advantage of simplicity.

Except for intravenous injection, EI has been proven to induce general anesthesia with many administrative approaches. Sun et al. reported that intraperitoneal injection of 8% EI produced general anesthesia with an extensive therapeutic window. The onset time (2.6±1.0 min) and maintenance of general anesthesia (28±11 min) induced by intraperitoneal injection of 8% EI were significantly longer than that induced by intravenous application [25]. Therefore, intraperitoneal injection of 8% EI is appropriate for short-term veterinary surgeon and animal experiments. Lin et al. observed that oral administration of 8% EI could produce hypnosis in rats and its ED₅₀ was 1.72 ml/100 g body weight (0.138 ml pure liquid isoflurane/100 g body weight) [26]. The doses are relatively enormous in term of volume and anesthetic used and that both oral and intraperitoneal delivery will be characterized by slow kinetics as compared to intravenous injection.

Combinative use of multiple anesthetics in operation could balance anesthetic effects and toxicities of these agents, increasing anesthetic quality and decreasing side effects. Yang et al. reported that combinative use of EI, fentanyl and midazolam produced strong synergism in rats [27,28].

Recently, the phase I clinical trial of EI has been completed in West China Hospital (Sichuan University, Chengdu, China), and it demonstrated that EI was safe in human with strong anesthetic potency (unpublished data). In brief, single bolus injection of EI led to fast onset of unconsciousness (typically within 40 s after initiation of injection), followed by predictable recovery within little or no residual drug effect. A progressive increase of duration of unconsciousness and depression in BIS (Bispectral Index) was observed following the escalation of injection dose. In addition to sedative effect, responses to noxious stimulus (standard electrical stimulus) were also inhibited in most of the volunteers with the development of unconsciousness. Another feature was that after intravenous injection, isoflurane was still eliminated via lung by expiration, which suggests that modulation of ventilation could remain an effective approach to adjust the anesthetic level. And the end-tidal concentration of isoflurane could still be used to estimate the blood and cerebral concentration of isoflurane.

In summary, single bolus injection of 8% EI is rapid in anesthetic induction and recovery without obvious influence to hemodynamics. Because of the distinct properties of general anesthetics, it is quite possible for EI to get into clinical use with the completion of phase I clinical trial.

Emulsified isoflurane for regional anesthesia

As early as in the 1970s, methoxyflurane was found to produce infiltration regional anesthesia [29–31]. However, direct administration of methoxyflurane to local region could induce tissue injury consequently [29]. Emulsified isoflurane (EI) arouses this challenge because no free pure liquid isoflurane exists in EI. Until now, EI has been demonstrated to produce regional anesthesia in vivo in many animal models and to block nerve conduction in isolated nerve, as well as to inhibit sodium channels in isolated spinal neurons, as shown in Table 2. These regional anesthetic effects include epidural anesthesia in rabbits [32], subarachnoid anesthesia in Beagle dogs [33], intravenous regional anesthesia (IVRA) in tail of rats [34]. For epidural and subarachnoid anesthesia, 8% EI produced regional spinal anesthesia with similar effects as 1% lidocaine, both in onset time and duration. In IVRA, EC₅₀ of EI to produce regional anesthesia was 4.467%±0.375% (v/v) with rapid onset (within 1 min), and its analgesic duration was about 30 min, which was similar to 0.5% lidocaine [34]. In the isolated toad sciatic nerve model, EI blocked nerve conduction in a concentration-dependent manner with IC₅₀ (inhibitory concentration) at 5.46% [35]. Recently, we found that EI could inhibit spinal voltage-gated Na⁺ channel at clinical relevant concentrations (EC₅₀ = 0.69±0.08 mM) [33], and this is the direct evidence to demonstrate the sensitivity of wild type sodium channels in spinal cord to volatile anesthetics, which might account for immobility effect of volatile anesthetics on spinal cord.

Interestingly, EI and lidocaine produced regional anesthesia in a synergistic manner in IVRA by which EI could significantly reduce requirement of lidocaine (EI at concentration of 1.6% could reduce EC₅₀ of lidocaine by 84.7%) [34]. This finding not only promotes EI to a world of regional anesthesia, but also provides a feasible method to explore anesthetic mechanisms that isoflurane could produce both general and regional anesthesia. For the synergism between EI and lidocaine, it is possible that these two drugs produce regional anesthesia with different targets or different sites of the targets.

In addition, besides its regional anesthetic action, our recent study suggested that EI could increase convulsive threshold of lidocaine and suppress lidocaine-induced convulsive seizure and improve cognitive function and injury of hippocampal CA3 pyramid neurons after lidocaine-induced convulsion.

All the studies about regional anesthetic effects of EI provide a potential utility that EI could improve safety of regional anesthesia by reducing requirement of traditional local anesthetics and treating side effects induced by traditional local anesthetics. In addition, the novel administrative approach for isoflurane is a method for studies of anesthetic mechanism, which will be discussed in later part of this review. As the approval of EI into clinical trial, we expect that the use of EI in regional anesthesia might come into practice in the near future.

Organ protection with emulsified isoflurane

Emulsified isoflurane (EI) has been demonstrated to protect many organs including heart, brain, spinal cord, lung, kidney and liver against the injury induced by ischemia or ischemia-reperfusion in animal models [36–40]. Chen et al. reported that intravenous administration of EI protected against ischemia-reperfusion (I/R) injury in heart of rabbits [41]. Rao et al. reported that EI could reduce the concentrations of creatine kinase-MB (CK-MB) and lactate dehygrogenase (LDH) in plasma after I/R injury in a rabbit model, and reduce infarct size of heart as well as suppress damage of mitochondrial ultra-micro structure [42]. The mechanism of protection by EI might be achieved by decreasing mitochondrial DNA segment deletion and apoptosis of myocardium. Other studies has shown that EI protected heart by increasing synthesis of NO to increase anti-oxidation ability of the myocardial cells; at the same time, EI increased activity of superoxide dismutase (SOD), and decreased concentration of malondialdehyde (MDA) [43,44]. Hu et al. found that by preconditioning with EI in rat model of I/R injury, EI could improve function of left ventricle and reduce infarct size against I/R induced injury [45]. This protection of EI may be contributed by its anti-apoptosis potential to increase expression of anti-apoptosis protein Bcl-2, and decrease expression of apoptosis protein Bax and caspase-3 [46,47].

Besides the protection to heart, EI could also provide similar protection to brain, spinal cord, lung and kidney as well as liver both with pre- or post- conditioning. Lv et al. reported that preconditioning with EI could provide a protection to liver against I/R injury [48].Zhang and colleagues reported that preconditioning with EI could provide a protection to liver and lung in rats after shock, increasing survival rates and this protection might contribute to the anti-apoptosis effect of EI and improvement of anti-oxidative ability of mitochondrion [49,50]. Wang et al.reported that 8% EI could decrease infarct size of brain in rats after I/R injury [51,52].

Comparing to isoflurane with inhalation, there are some advantages of EI. Firstly, EI is the fat emulsion of isoflurane, and its ability for regional administration makes it easy to be widely used. I/R injury is quite probably induced by cardiovascular surgery, and early studies showed that volatile anesthetics including isoflurane and sevoflurane could decrease infarct size of heart, increasing survival rates. However, in cardiovascular surgery, with the approach of inhaled way in anesthetic maintenance, it is hard for volatile anesthetics to reach heart, especially in extracorporeal circulation surgery. Our study shows that adding EI to St. Tomas solution could significantly protect I/R or big cardiac operation-induced injury [38,39]. This novel protective method suggests a technique to improve I/R injury or big cardiac operation-induced injury, especially in extracorporeal circulation surgery, and this method cannot be achieved by inhaled isoflurane.

Secondly, EI contains intralipid as its solvent. Many studies have indicated that intralipid could provide some protection to I/R or other causes-induced injury by its effect of energy supplement. Liu et al. reported that postconditioning with 30% intralipid could protect isolated heart in Langendroff model, by decreasing apoptosis of cardiac cells while improving heart function, decreasing releasing of LDH [37]. Huang et al. reported that adding intralipid to St. Thomas solution could reduce infarct size of heart and inhibit releasing of CK-MB, improving function of heart ventricle [39]. Thus, isoflurane and intralipid in EI could protect heart in synergism, at least in additivity.

Thirdly, protection provided by EI is practical because of its ability for intravenous injection or even for oral administration. Our recent study suggests that oral postconditioning of EI also provide similar cardiac protective effect after I/R injury, and this protective method is the most valuable for clinical application.

Is this protection induced by EI a real innovation or just a different administration protocol comparing to inhaled isoflurane? As the article “Emulsified Intravenous versus Evaporated Inhaled Isoflurane for Heart Protection: Old Wine in a New Bottle or True Innovation?” [4] comments that the organ protection of EI is a real innovation, it is not only a novel administrative protocol for isoflurane, but also with some unquestionable advantages. It has been widely admitted that hypoxia and ischemia as well as drug preconditioning induce protection to I/R injury. However, there are few reports about clinic utility of hypoxia and ischemia preconditioning. Why did this happen? The main reason is that both hypoxia and ischemia are of obvious ethical limitations and clinical inconvenience. And drug preconditioning could induce some side effects besides protection. For above reasons, pre- or post- conditioning has been limited in clinic application, and asymmetrical to its scientifically important position. EI could resolve these disadvantages because no obvious side effect has been found for isoflurane after years of use and no obvious side effects have been verified for EI in animal and clinical studies except for anesthetic effects.

Emulsified isoflurane as pharmacological tool drug

The exact mechanism of anesthetics to induce unconscious state is still unclear. Although many hypotheses and theories of anesthetic mechanism have been purposed, none of them are perfect.

Because emulsified volatile anesthetics could be intravenously and regionally injected, they will be the useful tool drugs for studies of anesthetic mechanisms, especially for the studies about regional actions of volatile anesthetics. Many studies have demonstrated the main targets for various endpoints of general anesthesia and it has been verified that spinal cord is the critical target for volatile anesthetics, particularly accounts for immobility. Yang et al. reported that spinal cord was the most likely site for immobility action of isoflurane by selective delivery of EI to spinal cord or brain [53,54]. The minimum partial pressure to induce immobility in carotid versus femoral arterial blood (9.56±1.86 mmHg vs. 9.68±1.90 mmHg) did not differ. But the minimum partial pressure in carotid arterial blood was half that in femoral arterial blood (5.35±1.45 mmHg vs. 10.97±3.04 mmHg, P<0.05). This result indicates that the spinal cord is the primary mediator of immobility and that the brain plays little or no role [53]. With epidural and subarachnoid administration of EI, typical regional anesthesia was introduced, without any influence to consciousness [32,33]. In addition, our recent study found that emulsified volatile anesthetics including emulsified halothane, emulsified isoflurane, emulsified enflurane as well as emulsified sevoflurane produced regional spinal anesthesia with similar potency and duration in rats, when they were intrathecally administrated, although their general effect was different. This might suggest that sensitivity of brain and spinal cord is different to volatile anesthetics and the general and regional effect of volatile anesthetics might be different.

In previous studies, we found that EI and lidocaine produced IVRA in a synergistic manner [34]. Generally, synergism is achieved by two drugs with similar pharmacological effect but with different mechanisms. The synergism between isoflurane and lidocaine indicates that the two anesthetics may produce regional anesthesia with different targets or different sites of target at least. The voltage-gated Na⁺ channel is widely regarded as the main target of conventional local anesthetics, such as lidocaine. The synergism between EI and lidocaine can be achieved by the effect of isoflurane and lidocaine on different sites of the voltage-gated Na⁺ channel; therefore, the involvement of the voltage-gated Na⁺ channel cannot be totally excluded for the IVRA effect of EI. Interestingly, our recent study showed that EI could inhibit sodium channel in isolated spinal neurons at clinically relevant concentrations (EC₅₀ = 0.69±0.08 mM) which indicated the effect of isoflurane on voltage-gated Na⁺ channels [33]. Thus, the results of the two studies indicate that isoflurane could inhibit voltage-gated Na⁺ channels, and this effect is different to the effect of lidocaine. Besides IVRA, EI blocked nerve conduction in a concentration-dependent manner in the isolated toad sciatic nerve (IC₅₀ = 5.46%), indicating the peripheral nervous effect of isoflurane [35].

Other studies found that emulsified volatile anesthetics have been used to determine analgesic and hypnotic effect of volatile anesthetics on various receptors, including spinalalpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, spinal N-methyl-D-methyl-D-aspartate receptors as well as strychnine-sensitive glycine receptors [55–57].

Summary

EI has been demonstrated to be potent in general anesthesia by previous studies, with rapid onset and recovery. Thus, there are reliable advantages of EI in clinic utility such as rapid induction and operations that demand rapid tracheal intubation or rapid recovery. Except for general anesthesia, EI could be a candidate local anesthetic or local anesthetic adjuvant at least, by which the safety of regional anesthesia could be significantly improved. In addition, the application of EI might bring pre- or post- conditioning into practice. As a pharmacological tool drug, increasing knowledge about anesthetic mechanism might be revealed by EI in future studies.

References

[1] Mazze RI. Methoxyflurane revisited: tale of an anesthetic from cradle to grave. Anesthesiology2006; 105(4): 843–846

[2] Habibollahi P, Mahboobi N, Esmaeili S, Safari S, Dabbagh A, Alavian SM. Halothane-induced hepatitis: a forgotten issue in developing countries. Hepat Mon2011; 11(1): 3–6

[3] Brasil LJ, San-Miguel B, Kretzmann NA, Amaral JL, Zettler CG, Marroni N, González-Gallego J, Tuñón MJ. Halothane induces oxidative stress and NF-kappaB activation in rat liver: protective effect of propofol. Toxicology2006; 227(1–2): 53–61

[4] 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 Analg2008; 106(5): 1346–1349

[5] Spencer JA, Green NM. Suicide by ingestion of halothane. JAMA1968; 205(10): 702–703

[6] Sutton J, Harrison GA, Hickie JB. Intravenous halothane. Lancet1971; 297(7694): 345–346

[7] Sandison JW, Sivapragasam S, Hayes JA, Woo-Ming MO. An experimental study of pulmonary damage associated with intravenous injection of halothane in dogs. Br J Anaesth1970; 42(5): 419–424

[8] Sutton J, Harrison GA, Hickie JB. Accidental intravenous injection of halothane. Case report. Br J Anaesth1971; 43(5): 513–520

[9] Krantz JC Jr, Cascorbi HF, Rudo FG. Anesthesia. 64. The intravenous administration of methoxyflurane (Penthrane) emulsions in animals and man. Anesth Analg1962; 41: 257–262

[10] Cascorbi HF, Helrich M, Krantz JC Jr, Baker LR, Rozman RS, Rudo FG. Hazards of methoxyflurane emulsions in man. Anesth Analg1968; 47(5): 557–559

[11] Eger RP, MacLeod BA. Anaesthesia by intravenous emulsified isoflurane in mice. Can J Anaesth1995; 42(2): 173–176

[12] Ma HX, Li J, Yang ZB, Yang XL, Liu AJ, Yang JW, Rao Y, Luo NF, Zhang WS, Liu J. Comparison of emulsified isoflurane and propofol with intravenous injection in Beagle dogs. Chin J Anesthesiol (Zhonghua Ma Zui Xue Za Zhi) 2006; 26(9): 862–863 (in Chinese)

[13] Johannesson G, Alm P, Biber B, Lennander O, Werner O. Halothane dissolved in fat as an intravenous anaesthetic to rats. Acta Anaesthesiol Scand1984; 28(4): 381–384

[14] Fast JP, Perkins MG, Pearce RA, Mecozzi S. Fluoropolymer-based emulsions for the intravenous delivery of sevoflurane. Anesthesiology2008; 109(4): 651–656

[15] Jee JP, Parlato MC, Perkins MG, Mecozzi S, Pearce RA. Exceptionally stable fluorous emulsions for the intravenous delivery of volatile general anesthetics. Anesthesiology2012; 116(3): 580–585

[16] Jia MX, Luo NF, Zhang WS, Zhou JX, Liu J. Partition coefficients of volatile anesthetics in lipid emulsion and its components. West China J Pharm Sci (Hua Xi Yao Xue Za Zhi) 2004; 19(6): 422–425 (in Chinese)

[17] Zhou JX, Liu J. The effect of temperature on solubility of volatile anesthetics in human tissues. Anesth Analg2001; 93(1): 234–238

[18] Zhou JX, Liu YQ, Liu J. Combined effect of hypothermia and crystalloid hemodilution on the solubility of volatile anesthetics in human blood. Chin Med J (Engl)2002; 115(7): 1014–1019

[19] Zhou JX, Luo NF, Liu J. Saturated concentration of emulsified isoflurane at 20°C and its anesthetic potency for intravenous injection in rats. J Beijing Med (Bei Jing Yi Xue) 2004; 26(6): 376–378 (in Chinese)

[20] Zhou JX, Luo NF, Liang XM, Liu J. The efficacy and safety of intravenous emulsified isoflurane in rats. Anesth Analg2006; 102(1): 129–134

[21] Ma HX, Yang ZB, Yang XL, Liu AJ, Yang JW, Rao Y, Luo NF, Zhang WS, Liu J. Determination of intravenous emulsified isoflurane MAC and its circulatory effects in Beagle dogs. J Clin Anesthesiol (Lin Chuang Ma Zui Xue) 2007; 23(10): 836–838 (in Chinese)

[22] 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. Anesthesiology2006; 104(3): 482–487

[23] Rao Y, Wang YL, Zhang WS, Yang XL, Ma HX, Yang JW, Liu AJ, Yang ZB, Liu J. The hemolytic effect of emulsified isoflurane after single bolus in Beagle dogs. Chin J Anesthesiol (Zhonghua Ma Zui Xue Za Zhi)2006; 7(26): 666–667 (in Chinese)

[24] Yang ZB, Yang XL, Zhang WS, Ma HX, Liu AJ, Rao Y, Yang JW, Liu J. Toxicity study on long-term intravenous administration of emulsified isoflurane in rats. J Clin Anesthesiol (Lin Chuang Ma Zui Xue)2008; 24(9): 112–115 (in Chinese)

[25] Sun HF, Wang QY, Liang XM, Zhang ZX, Liu J. The efficacy and safety of emulsified isoflurane after intraperitoneal injection in rats. Chin J Anesthesiol (Zhonghua Ma Zui Xue Za Zhi)2004; 24(1): 51–53(in Chinese)

[26] Lin HX, Luo NF, Liu J, Yang J, Li Q. The sedative and hypnotic effects and safety of oral emulsified isoflurane in rats. J Sichuan Univ (Med Sci Ed) (Sichuan Da Xue Xue Bao Yi Xue Ban)2010; 41(5): 862–864, 887 (in Chinese)

[27] Yang JW, Yi ML, Chai YF, Zhang WS, Liu J. Fentanyl hypnotic interaction with emulsified isoflurane. J Sichuan Univ (Med Sci Ed) (Sichuan Da Xue Xue Bao Yi Xue Ban)2007; 38(6): 973–976 (in Chinese)

[28] Yang JW, Chen Y, Gao AL, Zhang WS, Liu J. Interaction between fentanyl with emulsified isoflurane. West China J Pharm Sci (Hua Xi Yao Xue Za Zhi)2007; 22(5): 529–532 (in Chinese)

[29] Haynes DH, Kirkpatrick AF. Long duration local anesthesia with lecithin-coated microdroplets of methoxyflurane: studies with human skin. Reg Anesth1991; 16(3): 173–180

[30] Kirkpatrick AF, Lavallee-Grey M, Haynes DH. Long duration local anesthesia with lecithin-coated microdroplets of methoxyflurane: studies with rat skin. Reg Anesth1991; 16(3): 164–172

[31] Haynes DH, Kirkpatrick AF. Ultra-long-duration local anesthesia produced by injection of lecithin-coated methoxyflurane microdroplets. Anesthesiology1985; 63(5): 490–499

[32] 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 Anaesth2008; 100(1): 109–115

[33] Zhou C, Wu W, Liu J, Liao DQ, Kang Y, Chen XD. Inhibition of voltage-gated sodium channels by emulsified isoflurane may contribute to its subarachnoid anesthetic effect in beagle dogs. Reg Anesth Pain Med2011; 36(6): 553–559

[34] 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 Analg2011; 113(2): 245–250

[35] 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 Analg2010; 110(4): 1024–1029

[36] 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. Anesthesiology2004; 101(5): 1160–1166

[37] Liu XL, Liu J. Effects of emulsified isoflurane and intralipid on ischemia-reperfusion injury in isolated rat heart. West China J Pharm Sci (Hua Xi Yao Xue Za Zhi)2007; 22(5): 525–527(in Chinese)

[38] Hu Q, Wang J, Chang X, Long C. Cardioprotective effects of emulsified isoflurane strengthened cardioplegia on ischemia-reperfusion injury in isolated rat hearts. J Clin Med Pract (Shi Yong Lin Chuang Yi Yao Za Zhi)2009; 13(1): 5–8 (in Chinese)

[39] 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 Anesth2010; 24(1): 99–103

[40] Liu SL, Liu J. Apoptosis mechanism of intralipid postconditioning to reduce ischemia reperfusion injury of isolated rat hearts. J Sichuan Univ (Med Sci Ed) (Sichuan Da Xue Xue Bao Yi Xue Ban)2007; 38(4): 663–666 (in Chinese)

[41] Chen YQ, Jin XJ, Dai ZP, Zhang WS, Liu J. Effects of emulsified isoflurane induced preconditioning on cardiac hemodynamic during myocardiac ischemia-reperfusion injury in rabbits. J Anesthesiol Resusc (Guo Ji Ma Zui Xue Yu Fu Su Za Zhi)2006; 27(4): 224–226 (in Chinese)

[42] Rao Y, Wang YL, Zhang WS, Liu J. Emulsified isoflurane produces cardiac protection after ischemia-reperfusion injury in rabbits. Anesth Analg2008; 106(5): 1353–1359

[43] Rao Y, Wang YL, Chen YQ, Zhang WS, Liu J. Protective effects of emulsified isoflurane after myocardial ischemia-reperfusion injury and its mechanism in rabbits. Chin J Traumatol2009; 12(1): 18–21

[44] Yang MC, Chen YP, Cao DJ, Qian X, Li P. The optimal concentration for the protective effect of emulsified isoflurane on the neonatal rat cardiac myocytes hypoxia/reoxygenation injury of primary culture. J Sichuan Univ (Med Sci Ed) (Sichuan Da Xue Xue Bao Yi Xue Ban)2009; 40(6): 1075–1077, 1090 (in Chinese)

[45] Hu ZY, Luo NF, Liu J. The protective effects of emulsified isoflurane on myocardial ischemia and reperfusion injury in rats. Can J Anaesth2009; 56(2): 115–125

[46] Tan XQ, Chen YP, Zhang WS, Liu J. Effect of emulsified isoflurane on myocardial apoptosis and expressions of bcl-2 and bax induced by hypoxia-reoxygenation. J Third Mil Med Univ (Di San Jun Yi Da Xue Xue Bao) 2008; 30(17): 1611–1614 (in Chinese)

[47] Tan XQ, Chen YP. Emulsified isoflurane protects hypoxia/reoxgenation injury in cultured neonatal rat myocardial cells by suppressing caspase-3 expression. J Third Mil Medical Univ (Di San Jun Yi Da Xue Xue Bao)2009; 31(14): 1341–1344 (in Chinese)

[48] Lv H, Yang LQ, Yu WF, Li Q, Ren HM, Zhu M, Xu LY. Protection of liver against ischemia/reperfusion injury by Kupffer cell mediated emulsified isoflurane preconditioning: experiment with rats. Natl Med J China (Zhonghua Yi Xue Za Zhi)2007; 35(87): 2468–2471(in Chinese)

[49] Zhang L, Luo N, Liu J, Duan Z, Du G, Cheng J, Lin H, Li Z. Emulsified isoflurane preconditioning protects against liver and lung injury in rat model of hemorrhagic shock. J Surg Res2011; 171(2): 783–790

[50] Lv X, Wang ZM, Huang SD, Song SH, Wu FX, Yu WF. Emulsified isoflurane preconditioning reduces lung injury induced by hepatic ischemia/reperfusion in rats. Int J Med Sci2011; 8(5): 353–361

[51] Wang Y, Zhang WS, Deng L, Liu J. Protective effect of 8% emulsified isoflurane against focal cerebral ischemia-reperfusion injury in rats. West China J Pharm Sci (Hua Xi Yao Xue Za Zhi)2008; 23(2): 140–142(in Chinese)

[52] Wang YL, Wang ZP, Zhu W. Effect of preconditioning with different doses of emulsified isoflurane on focal cerebral ischemia-reperfusion injury in rats. Chin J Anesthesiol (Zhonghua Ma Zui Xue Za Zhi)2010; 30(10): 1243–1246 (in Chinese)

[53] Yang J, Chai YF, Gong CY, Li GH, Luo N, Luo NF, Liu J. Further proof that the spinal cord, and not the brain, mediates the immobility produced by inhaled anesthetics. Anesthesiology2009; 110(3): 591–595

[54] 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 J2011; 187(2): 239–244

[55] Hang LH, Shao DH, Yang YH, Dai TJ, Zeng YM. Spinal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors may mediate the analgesic effects of emulsified halogenated anaesthetics. Clin Exp Pharmacol Physiol 2007; 34(11): 1121–1125

[56] Hang LH, Dai TJ, Zeng YM. Spinal N-methyl-D-aspartate receptors may mediate the analgesic effects of emulsified halogenated anesthetics. Pharmacology2006; 76(3): 105–109

[57] Chen Y, Dai TJ, Zeng YM. Strychnine-sensitive glycine receptors mediate the analgesic but not hypnotic effects of emulsified volatile anesthetics. Pharmacology2007; 80(2-3): 151–157

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg