Basic & Clinical Pharmacology & Toxicology, 2014, 115, 222–228
Doi: 10.1111/bcpt.12223
Intravenous Lipid Emulsion Improves Recovery Time and Quality from Isoflurane Anaesthesia: A Double-Blind Clinical Trial Qian Li, Di Yang, Jin Liu, Han Zhang and Jingyu Zhang Department of Anesthesiology and Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China (Received 5 January 2014; Accepted 11 February 2014) Abstract: Recovery time and quality after general anaesthesia is important for patient safety. This study aimed to determine whether intravenous lipid emulsion could improve recovery profiles from isoflurane anaesthesia in adult patients undergoing laparoscopic cholecystectomy. Sixty-six patients were enrolled. After anaesthesia induction, inspired isoflurane concentration was adjusted to maintain stable vital signs and the suitable conditions for operation. At the end of the operation, the isoflurane was discontinued, and either 2 ml/kg 30% lipid emulsions or 0.9% saline solution was administered intravenously. The time to eye opening, extubation and exit from the operation room was recorded, and the quality of recovery from anaesthesia was assessed. Sixty patients completed the study. The median time to eye opening and exit from the operation room was significantly shorter in the lipid emulsion group than in the saline group [15.5 (interquartile range 9.0) versus 20.0 (10.0) min., p = 0.01; 19.5 (8.3) versus 23.6 (6.3) min., p = 0.04, respectively], whereas the median time to extubation did not show any noticeable difference. The quality of recovery was better in the lipid emulsion group than that of the saline solution group with respect to drowsiness visual analogue scale score (p < 0.01), Observer’s Assessment of Alertness/Sedation score (p < 0.01), Mini-Mental State Examination score (p = 0.04) and Modified Aldrete Post Anaesthesia Recovery score (p = 0.03). No serious adverse events were observed during the study period. In conclusion, intravenous lipid emulsion may effectively improve the recovery time and quality from isoflurane anaesthesia for laparoscopic cholecystectomy.
Both rapid recovery and quality recovery from general anaesthesia are directly linked to patient safety and efficiency in the operation room and post-anaesthesia care unit (PACU) [1]. To facilitate rapid recovery from anaesthesia, reversal agents are often used to counteract, or reverse, the effects of drugs used in general anaesthesia. There are four kinds of drugs commonly used for general anaesthesia – general anaesthetics, amnesic agents, analgesics and muscle relaxants. With the exception of general anaesthetics, the mechanism of how they work is well understood, and reversal agents were developed accordingly. Currently, reversal effects for amnesic agents, analgesics and muscle relaxants are usually achieved using flumazenil [2], naloxone [3] and neostigmine as well as sugammadex, respectively [4,5]. However, because the site and mechanism of the action of general anaesthetics such as inhaled anaesthetics are still not well understood, effective reversal agents for general anaesthetics remain to be developed. Recent studies, however, offered new evidence that reversal of anaesthetics can function at blood level. Intravenous lipid emulsion (ILE) is presently recognized as an antidote to local anaesthetic systemic toxicity (LAST) [6]. Key factors contributing to the effect of ILE on LAST are the lipophilic quality of local anaesthetics and the ‘lipid sink’ phenomenon, which suggests that free drug levels, and therefore toxicity, are
decreased by expanding the plasma lipid phase after ILE infusion [7,8]. Inhaled anaesthetics are very lipophilic, and our previous study demonstrated that the commonly used inhalation anaesthetic isoflurane has high solubility in 30% lipid emulsion solution [9]. These findings on the reversal of drug action and the lipophilicity of inhaled anaesthetics provide the rationale for the hypothesis that administrating lipid solvents can remove lipophilic inhaled anaesthetics from their effect targets, thus accelerating recovery from anaesthesia. Laparoscopic cholecystectomy (LC) is one of the most common surgeries worldwide. In the U.S. alone, 675,000 laparoscopic cholecystectomies were performed in 2008, and most LC were performed on ambulatory basis [10], which means the rapid and high quality recovery from anaesthesia is of great importance. The purpose of this prospective, randomized, double-blind trial was to test a method to reverse the effects of inhaled anaesthetics in patients undergoing LC. The main hypothesis was that, in relation to the present standard care with no antagonist to reverse general anaesthetics, intravenous lipid solvent administration accelerates the recovery time and quality after general anaesthesia with isoflurane. Another aim of the study was to document patient safety of intravenous lipid solvent administration.
Author for correspondence: Jin Liu, Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China (fax +86 2885423593, e-mail [email protected]).
Materials and Methods The research protocol was in accordance with the Helsinki Declaration and approved by the Committee for the Protection of Human Subjects
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
IV LIPID EMULSION IMPROVES ISOFLURANE ANAESTHESIA RECOVERY of West China Hospital (No.13, 01/2011) with Chinese Clinical Trial Registry number: ChiCTR-TRC-11001779. The patients received oral and written information and gave signed copies of informed consent during pre-anaesthesia consultation. We conducted this prospective, randomized, single-centre, doubleblind study at West China Hospital of Sichuan University, which is a large comprehensive hospital (4800 beds) located in Chengdu, Sichuan Province. Patients were selected for the study according to the criteria in table 1. Sixty-six patients were enrolled and were randomly assigned to accept intravenous lipid emulsion (ILE group) or 0.9% saline solution (saline group) according to a computer-generated randomization scheme. The patients and anaesthesiologists administering intraoperative care were both blinded to the group assignment during the entire study. An investigator (H.Z.), who was blinded to the study treatment assignment, assessed the pre-operative baseline data, recovery time, recovery quality and safety during recovery for all of the patients. Detailed medical history, demographic information, history of smoking, motion sickness, as well as previous post-operative nausea and vomiting (PONV) were obtained before anaesthesia for each patient. For baseline data, the patients were evaluated with 10-point drowsiness visual analogue scale (VAS) (0 = none, 10 = maximum), the Observer’s Assessment of Alertness/Sedation (OAA/S, scale of 0– 5) for sedation level, and the Mini-Mental State Examination (MMSE, scale of 0–30) for measurements of cognitions. Routine monitors including electrocardiogram, non-invasive blood pressure and transcutaneous oxyhemoglobin saturation (SpO2) were applied to the patients. An intravenous (IV) cannula was inserted in the basilic or cephalic vein of the forearm. Anaesthesia was induced by intravenous midazolam 0.04 mg/kg, fentanyl 2 lg/kg and propofol 2 mg/kg. Rocuronium 0.6 mg/kg was used to facilitate tracheal intubation. Airway gases were monitored continuously with a gas analyser (M1026B; Philips Medizin Systeme B€oblingen GmbH, B€ oblingen, Germany), and tidal volume was adjusted to maintain an end-tidal carbon dioxide level of 35–40 mmHg. Anaesthesia was maintained with inhaled isoflurane at a fresh gas flow rate of 3 l/min. in combination with continuous intravenous infusion of remifentanil 0.1 lg/kg/min. The end-tidal concentration of isoflurane was adjusted from 0.5% to 2% to maintain blood pressure and heart rate (HR) within 20% change in the pre-operative level. A warm blanket was used to maintain core temperature at 36–37.5°C. Before the end of the operation, granisetron (3 mg) and neostigmine (50 lg/kg) were administered to each patient. After closure of the surgical wound, the isoflurane vaporizer was turned off, other maintained anaesthetics were discontinued, and the fresh gas flow rate was adjusted to 10 l/min. without changing ventilaTable 1. Inclusion and exclusion criteria. Inclusion criteria Age 18–65 years; American Society of Anesthesiologists (ASA) physical status classification score of I or II Scheduled for laparoscopic cholecystectomy Expected duration of anaesthesia not exceeding 120 min. Exclusion criteria Presence of: Obesity (body mass index >30 kg/m2) Lipid metabolism disturbance Sepsis Impaired hepatic or renal function History of neurological disease, cognitive dysfunction and psychiatric disorders Ingestion of any psychotropic drug Chronic alcohol or drug abuse Allergy to soybean, egg or lipoid products Pregnancy or breastfeeding
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tion parameter settings. The study drug, 2 ml/kg 30% ILE [Fat Emulsion Injection (C14–24); Sino-Swed Pharmaceutical Corp. Ltd., Wuxi, China] or 2 ml/kg 0.9% saline solutions, was administered via the IV cannula within 2 min. The recovery time was determined at 1-min. intervals. The time to eye opening was defined as the period between the end of administration of intervention drug and eye opening on verbal command. The time to tracheal extubation was defined as the period between the end of intervention and extubation. The extubation criteria were as follows: patients were conscious and haemodynamically stable; body temperature higher than 36°C; the respiratory rate was maintained 12–30 breaths/min., and there was no clinical residual muscle weakness. Recovery quality was assessed in the operation room and PACU. The time to exit from the operation room was defined as the period between the end of intervention and patients exiting the operation room. Modified Aldrete Post Anaesthesia Recovery Score (MAPARS) was obtained at 5-min. intervals. The time to MAPARS ≥ 9, which indicates that the patient can be safely discharged from the PACU, was defined as the time between the end of administration of intervention drug to the point when MAPARS reached 9. Drowsiness VAS and OAA/S were assessed at 5, 10, 15, 30 and 60 min. after administration of intervention drug. MMSE and MAPARS were assessed at 15, 30 and 60 min. after administration of study drug. The amount of isoflurane used during anaesthesia was determined by MAC hour (MAC9 duration of exposure in hours). The incidences of the following adverse events (AEs) were documented: hypoxia, hypotension, headache, chest pain, allergic reaction to ILE and thrombophlebitis at the site of infusion. Triglyceride, cholesterol levels and coagulation function parameters were obtained 1day post-operatively in each patient. The incidence of post-operative nausea or vomiting and the occurrence of administration of rescue analgesic (5 lg sufentanil IV) for post-operative pain were recorded for 24 hr after surgery. Statistical analysis. Statistical analysis was performed with SAS Version 8.2 (SAS Institute, Cary, NC, USA). The sample size was determined by power analysis according to our pre-test values for the time to eye opening by presuming an allocation ratio of 1, alpha value 0.05 and power of 0.80, yielding an expected sample size of 54. A total of 66 subjects were enrolled under the presumption of a failure rate of approximately 20% so as to allow for unpredictable events such as an anaesthesia procedure exceeding 120 min. or a patient withdrawing consent. Baseline data with normally continuous distribution were analysed by t-test, and categorical data were compared by chi-square or Fisher’s exact test. The time to eye opening and tracheal extubation was analysed by rank-sum test. Generalized estimating equations were used for analysing repeated categorical data, that is, post-operative drowsiness VAS score, OAA/S score, MMSE score and MAPARS. Data are presented as mean S.D., median (interquartile range), n or%. p values of 0.05, table 4). There were no serious AEs reported during the study period. None of the AEs during the entire study process were associated with ILE treatment. There were no instances of hypercoagulability or hyperlipidaemia 1-day post-operatively in any patient. No difference was observed in the incidence of post-operative nausea (16.7% in the ILE group versus 26.7% in the saline group), vomiting (6.7% in the ILE group versus 13.3% in the saline group) or pain requiring rescue medicine (23.3% in the ILE group versus 16.7% in the saline group) between the two groups (table 5). Discussion The main finding of the present study was that ILE, administered after the discontinuation of isoflurane, improved recovery time and quality from anaesthesia. Although modern inhaled anaesthetics such as sevoflurane and desflurane have Table 3. Comparison of recovery time after study drug administration. Saline (n = 30) Time Time Time Time
to to to to
eye opening (min.) tracheal extubation (min.) exit from the OR (min.) MAPARS ≥ 9 min.
20.0 21.0 23.6 33.6
ILE (n = 30)
(10.0) (8.0) (8.3) (14.8)
15.5 17.0 19.5 28.5
p
(9.0) (6.0) (6.3) (12.7)
0.01 0.08 0.04 0.15
Values are presented as median (interquartile range). ILE, intravenous lipid emulsion; OR, operation room; MAPARS, Modified Aldrete Post Anaesthesia Recovery Score. Table 4. ET concentration of isoflurane before and after study drug administration and at time of extubation. Saline
Before study drug 2 min. after study drug 5 min. after study drug 10 min. after study drug 15 min. after study drug 30 min. after study drug 60 min. after study drug Extubation
ILE
n
ET concentration
n
ET concentration
30 30 30 29 17 3 1 30
0.42 0.29 0.24 0.19 0.14 0.13 0.20 0.11
30 30 30 27 12 1 – 30
0.41 0.30 0.24 0.19 0.19 0.25 – 0.12
0.06 0.06 0.08 0.11 0.10 0.12 0.00 0.11
0.07 0.09 0.10 0.13 0.12 0.00 0.12
Values are presented as mean S.D. ILE, intravenous lipid emulsion; n, number of patients with endotracheal tube; ET concentration, endtidal concentration. The ET concentration of isoflurane monitor was discontinued after extubation.
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several advantages, isoflurane is still commonly used during clinical practice and research [11]. Furthermore, our previous study had demonstrated high solubility of isoflurane in 30% lipid emulsion [9]; then, in this study, we further investigated whether intravenous lipid emulsion could improve recovery profiles from general anaesthesia induced base on isoflurane. To our best knowledge, this is the first study to evaluate the efficacy and safety of 30% ILE in the recovery profiles from isoflurane anaesthesia. In the present study, we found that patients in the ILE group showed faster time to eye opening on verbal command compared with the saline group (p = 0.01), suggesting that administration of intravenous lipid emulsion could accelerate the emergence from isoflurane-induced hypnosis. A shorter time to exit from the operation room was also observed in the ILE group (p = 0.04). Although without being statistically significant, the ILE group did show a 4-min. reduction in the time to extubation and a 5-min. reduction in the time to reach a MAPARS of 9 compared with the saline group. The differences in these results were seemingly only a few minutes shorter with ILE. However, a previous study showed that each 1-min. reduction per case in the operation room may result in a larger economic value than 1 min. [12]. Especially in a busy ambulatory setting or a large hospital that serves high-volume surgical patients and with more than 8 hr of surgeries and turnovers in the operation room (e.g. on average, West China Hospital performs over 250 surgeries and has about 10 hr of surgeries in the operation room per workday), these modest changes may allow the surgeon to perform an additional surgery per operation room block or to reduce the need for overtime personnel, and the hospital to save scheduled labour costs in the operation room and PACU [13]. Compared with previous reports using isoflurane in laparoscopic surgery, our study showed time to eye opening and extubation 6–7 min. and 7–8 min. slower, respectively [14,15]. However, these previous studies used local anaesthetics to reduce the maintenance dose of isoflurane or discontinued other anaesthetics before the end of endoscopic performance, while in the present study, local anaesthetics were not adopted. Furthermore, to minimize variability, other maintained anaesthetics were discontinued upon completion of the skin closure rather than at variable times before the end of the surgery. These could be the possible explanations for the slower emergence in our patients. With respect to recovery quality, ILE application produced better recovery quality from isoflurane anaesthesia. Our results showed a lower drowsiness level (p < 0.01) and an earlier recovery from sedation (p < 0.01) during the 60 min. after study drug administration with ILE compared with saline solution. In addition, a greater recovery of cognitive function was demonstrated in the ILE group compared with the saline group (p = 0.04). All of these factors contributed to a greater overall MAPARS value (p = 0.03) in the ILE group than that in the saline group within the 60 min. after study drug administration. The data suggest that intravenous lipid emulsion provides for a desirable outcome of earlier assessment of neurological and cognitive function, and a faster resumption of a normal state after isoflurane anaesthesia.
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
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A
B
C
D
Fig. 2. Drowsiness VAS scores, OAA/S scores, MMSE scores and MAPARS versus time between the two groups after study drug administration. The drowsiness VAS score was less for the ILE group than the saline group (p < 0.01; Panel A). Compared with the saline group, the OAA/S score was higher in the ILE group (p < 0.01; Panel B). The MMSE score was greater for the ILE group than for the saline group (p = 0.04; Panel C). The MAPARS was higher for the ILE group than for the saline group (p = 0.03; Panel D). ILE, intravenous lipid emulsion; VAS, visual analogue scale; OAA/S, Observer Assessment of Alertness and Sedation; MMSE, Mini-Mental State Examination; MAPARS, Modified Aldrete Post Anaesthesia Recovery Score. Table 5. Comparison PONV and post-operative pain requiring rescue medicine in the two study groups.
Post-operative nausea Post-operative vomiting Pain requiring rescue medicine
Saline (n = 30)
ILE (n = 30)
p
8 (26.7%) 4 (13.3%) 5 (16.7%)
5 (16.7%) 2 (6.7%) 7 (23.3%)
0.53 0.42 0.75
Values are presented as n (%) or mean S.D. ILE, intravenous lipid emulsion.
The lipid sink phenomenon may also contribute to our findings. It is well known that the lipid sink phenomenon is widely accepted as the dominant mechanistic theory for the resuscitation using ILE against LAST and overdose of some lipophilic drugs [16,17]. An animal experiment indicated that radiolabelled bupivacaine administered to the mixture
consisted of equal volume 30% intralipid and plasma moved to the lipid phase with a partition coefficient of 12 and further showed that ILE could speed removal of bupivacaine from aorta plasma [7]. Isoflurane is quite lipophilic. 30% ILE/gas partition coefficient of isoflurane at 37°C is 31.6 [16], which is approximately 22.6 times higher than its blood/gas partition coefficient of 1.4 [17] at the same temperature. According to the lipid sink mechanism [8], when 2 ml/kg of 30% ILE is injected into the vascular compartment in an adult with blood volume about 70 ml/kg, isoflurane would then be drawn into the lipid sink, and its concentration in the blood phase will decrease to about 60.8% [70 / (2 9 22.6 + 70) 9 100% = 60.8%] after equilibrium between injected ILE and blood if considering that they are in a closed system. As isoflurane concentration in the blood-phase drops, a concentration gradient would develop between the action site of isoflurane and blood, with isoflurane moving away from its site of action and towards the lipid sink, as the same happens as successful
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
IV LIPID EMULSION IMPROVES ISOFLURANE ANAESTHESIA RECOVERY
application of ILE for the reversal of other lipophiles toxicity [7,18,19]. This results in a faster decreasing isoflurane concentration to a threshold level for the eye opening at the site of action of isoflurane and a shorter time to eye opening in the ILE group compared with the saline group in this study. The ET isoflurane concentrations at all time-points before and 60 min. after study drug administration in the two groups were similar (table 4, p > 0.05), suggesting that the mechanism for faster eye opening in the ILE group is not located between the blood and the lungs, but between the blood and the brain. Because the site and mechanism of action of inhaled anaesthetics are still unknown, choosing an antagonist acting in the blood level is more feasible than trying to find an antagonist that acts in the action site level today. The lipid sink effect of ILE might not be limited to isoflurane in this study. Midazolam and fentanyl are both highly lipophilic [20,21]. Midazolam produces sedation, increases drowsiness VAS score and decreases MMSE and OAA/S scores [22,23]. In the present study, with the similar doses of midazolam (p = 0.11) and duration of anaesthesia (p = 0.92) for the two groups, the lower drowsiness VAS, greater OAA/ S and MMSE scores were observed in the ILE group. Similarly, intravenous fentanyl increases incidence of PONV [24] and decreases post-operative pain. With similar doses of fentanyl used for the two groups (p = 1.00) in this study, even though statistical significances were not reached, the incidences of post-operative nausea (16.7% versus 26.7%) and vomiting (6.7% versus 13.3%) were lower, and the incidence of pain requiring rescue medicine (23.3% versus 16.7%) was higher in the ILE group than in the saline group (table 5). The above data suggest that ILE might also have the lipid sink effects on lipophilic midazolam and fentanyl. Few data are available regarding the upper safety limit for total intravenous injection dose of ILE. Our previous study demonstrated that 30% ILE/gas partition coefficient of isoflurane was 1.5 times that of 20% ILE/gas partition coefficient [9]. Therefore, 30% ILE was chosen to the present study for the efficiency consideration. The dose used in this study, 2 ml/kg of 30% ILE, is much lower than the LD50 of highvolume lipid infusion obtained with rat models (67.7 ml/kg) [25], and the dose used in rescue for overdose of bupivacaine (12 ml/kg 30% lipid) [26] or calcium channel blocker (18 ml/ kg 20% lipid) in rodent models [27]. Furthermore, case reports that used ILE to reverse LAST with higher bolus dose (4.16 and 3.33 ml/kg) [28,29] than the present study did not report any complication related to lipid therapy. More importantly, none of the AEs associated with ILE treatment were noted during the entire study process. And we did not find any serious adverse events in this study during the anaesthesia recovery phase and the 1-day post-operative follow-up in the ILE group compared with the saline group. Therefore, the dose used in this study, 2 ml/kg of 30% ILE, is safe and effective. There are several limitations in the present study. The main limitation is that we did not monitor changes in blood concentration, partial pressure and blood/gas partition of isoflurane, which could provide stronger evidence for lipid sink theory to ILE effects on recovery from isoflurane anaesthesia. Secondly,
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we calculated the sample size (27 subjects in each group) before the study according to the pre-test data of time to eye opening on command because it is a typical sign of recovery from hypnosis induced by general anaesthetics, and we found a significant difference in time to eye opening with a sample size of 30 in each group in this study. However, according to a power analysis based on the results from this study, we found that the sample size in each group to reach a significant difference would be 114 subjects for time to extubation, 128 for time to MAPARS ≥ 9, 266 for incidence of post-operative nausea and 323 for incidence of vomiting, respectively. Thirdly, we did not test dose-effective relationship between ILE dose and its effects on recovery from isoflurane anaesthesia; the dose and concentration of ILE used in this study might not represent optimal values. Besides, this was a singlecentre study with a small sample size. To translate the present findings into clinical practice, further multi-centre studies focusing on effectiveness, safety and best dosage are needed. Nonetheless, the effect of ILE on improving recovery profiles of isoflurane anaesthesia has been demonstrated in the present study. In conclusion, 2 ml/kg of 30% intravenous lipid emulsion facilitates recovery time and quality from isoflurane anaesthesia for laparoscopic cholecystectomy in adults. The underlying mechanism might be related to the ‘lipid sink’ phenomenon. Source of Funding National Natural Science Foundation of China (81300110). References 1 Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 2003;362:1921–8. 2 Saxon L, Hjemdahl P, Hiltunen AJ, Borg S. Effects of flumazenil in the treatment of benzodiazepine withdrawal–a double-blind pilot study. Psychopharmacology 1997;131:153–60. 3 Takahashi M, Sugiyama K, Hori M, Chiba S, Kusaka K. Naloxone reversal of opioid anesthesia revisited: clinical evaluation and plasma concentration analysis of continuous naloxone infusion after anesthesia with high-dose fentanyl. J Anesth 2004;18:1–8. 4 Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL. (ed.). Miller’s Anesthesia, 7th edn. Churchill Livingstone, Elsevier, PA, 2010;2440–4. 5 Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology 2008;109:816–24. 6 Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W. Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity. Anaesthesia 2009;64:122–5. 7 Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998;88:1071–5. 8 Heinonen JA, Litonius E, Backman JT, Neuvonen PJ, Rosenberg PH. Intravenous lipid emulsion entraps amitriptyline into plasma and can lower its brain concentration–an experimental intoxication study in pigs. Basic Clin Pharmacol Toxicol 2013;113:193–200. 9 Zhou JX, Luo NF, Liang XM, Liu J. The efficacy and safety of intravenous emulsified isoflurane in rats. Anesth Analg 2006;102:129–34.
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21 Andresen T, Upton RN, Foster DJ, Christrup LL, Arendt-Nielsen L, Drewes AM. Pharmacokinetic/pharmacodynamic relationships of transdermal buprenorphine and fentanyl in experimental human pain models. Basic Clin Pharmacol Toxicol 2011;108:274–84. 22 Suzuki M, Tsueda K, Lansing PS, Tolan MM, Fuhrman TM, Sheppard RA, et al. Midazolam attenuates ketamine-induced abnormal perception and thought process but not mood changes. Can J Anaesth 2000;47:866–74. 23 Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51. 24 Rama-Maceiras P, Ferreira TA, Molins N, Sanduende Y, Bautista AP, Rey T. Less postoperative nausea and vomiting after propofol + remifentanil versus propofol + fentanyl anaesthesia during plastic surgery. Acta Anaesthesiol Scand 2005;49:305–11. 25 Hiller DB, Di Gregorio G, Kelly K, Ripper R, Edelman L, Boumendjel R, et al. Safety of high volume lipid emulsion infusion: a first approximation of LD50 in rats. Reg Anesth Pain Med 2010;35:140–4. 26 Di Gregorio G, Schwartz D, Ripper R, Kelly K, Feinstein DL, Minshall RD, et al. Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest. Crit Care Med 2009;37:993–9. 27 Perez E, Bania TC, Medlej K, Chu J. Determining the optimal dose of intravenous fat emulsion for the treatment of severe verapamil toxicity in a rodent model. Acad Emerg Med 2008;15:1284– 9. 28 Calenda E, Dinescu SA. Failure of lipid emulsion to reverse neurotoxicity after an ultrasound-guided axillary block with ropivacaine and mepivacaine. J Anesth 2009;23:472–3. 29 Smith HM, Jacob AK, Segura LG, Dilger JA, Torsher LC. Simulation education in anesthesia training: a case report of successful resuscitation of bupivacaine-induced cardiac arrest linked to recent simulation training. Anesth Analg 2008;106:1581–4.
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Doi: 10.1111/bcpt.12223
Intravenous Lipid Emulsion Improves Recovery Time and Quality from Isoflurane Anaesthesia: A Double-Blind Clinical Trial Qian Li, Di Yang, Jin Liu, Han Zhang and Jingyu Zhang Department of Anesthesiology and Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China (Received 5 January 2014; Accepted 11 February 2014) Abstract: Recovery time and quality after general anaesthesia is important for patient safety. This study aimed to determine whether intravenous lipid emulsion could improve recovery profiles from isoflurane anaesthesia in adult patients undergoing laparoscopic cholecystectomy. Sixty-six patients were enrolled. After anaesthesia induction, inspired isoflurane concentration was adjusted to maintain stable vital signs and the suitable conditions for operation. At the end of the operation, the isoflurane was discontinued, and either 2 ml/kg 30% lipid emulsions or 0.9% saline solution was administered intravenously. The time to eye opening, extubation and exit from the operation room was recorded, and the quality of recovery from anaesthesia was assessed. Sixty patients completed the study. The median time to eye opening and exit from the operation room was significantly shorter in the lipid emulsion group than in the saline group [15.5 (interquartile range 9.0) versus 20.0 (10.0) min., p = 0.01; 19.5 (8.3) versus 23.6 (6.3) min., p = 0.04, respectively], whereas the median time to extubation did not show any noticeable difference. The quality of recovery was better in the lipid emulsion group than that of the saline solution group with respect to drowsiness visual analogue scale score (p < 0.01), Observer’s Assessment of Alertness/Sedation score (p < 0.01), Mini-Mental State Examination score (p = 0.04) and Modified Aldrete Post Anaesthesia Recovery score (p = 0.03). No serious adverse events were observed during the study period. In conclusion, intravenous lipid emulsion may effectively improve the recovery time and quality from isoflurane anaesthesia for laparoscopic cholecystectomy.
Both rapid recovery and quality recovery from general anaesthesia are directly linked to patient safety and efficiency in the operation room and post-anaesthesia care unit (PACU) [1]. To facilitate rapid recovery from anaesthesia, reversal agents are often used to counteract, or reverse, the effects of drugs used in general anaesthesia. There are four kinds of drugs commonly used for general anaesthesia – general anaesthetics, amnesic agents, analgesics and muscle relaxants. With the exception of general anaesthetics, the mechanism of how they work is well understood, and reversal agents were developed accordingly. Currently, reversal effects for amnesic agents, analgesics and muscle relaxants are usually achieved using flumazenil [2], naloxone [3] and neostigmine as well as sugammadex, respectively [4,5]. However, because the site and mechanism of the action of general anaesthetics such as inhaled anaesthetics are still not well understood, effective reversal agents for general anaesthetics remain to be developed. Recent studies, however, offered new evidence that reversal of anaesthetics can function at blood level. Intravenous lipid emulsion (ILE) is presently recognized as an antidote to local anaesthetic systemic toxicity (LAST) [6]. Key factors contributing to the effect of ILE on LAST are the lipophilic quality of local anaesthetics and the ‘lipid sink’ phenomenon, which suggests that free drug levels, and therefore toxicity, are
decreased by expanding the plasma lipid phase after ILE infusion [7,8]. Inhaled anaesthetics are very lipophilic, and our previous study demonstrated that the commonly used inhalation anaesthetic isoflurane has high solubility in 30% lipid emulsion solution [9]. These findings on the reversal of drug action and the lipophilicity of inhaled anaesthetics provide the rationale for the hypothesis that administrating lipid solvents can remove lipophilic inhaled anaesthetics from their effect targets, thus accelerating recovery from anaesthesia. Laparoscopic cholecystectomy (LC) is one of the most common surgeries worldwide. In the U.S. alone, 675,000 laparoscopic cholecystectomies were performed in 2008, and most LC were performed on ambulatory basis [10], which means the rapid and high quality recovery from anaesthesia is of great importance. The purpose of this prospective, randomized, double-blind trial was to test a method to reverse the effects of inhaled anaesthetics in patients undergoing LC. The main hypothesis was that, in relation to the present standard care with no antagonist to reverse general anaesthetics, intravenous lipid solvent administration accelerates the recovery time and quality after general anaesthesia with isoflurane. Another aim of the study was to document patient safety of intravenous lipid solvent administration.
Author for correspondence: Jin Liu, Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu 610041, China (fax +86 2885423593, e-mail [email protected]).
Materials and Methods The research protocol was in accordance with the Helsinki Declaration and approved by the Committee for the Protection of Human Subjects
© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
IV LIPID EMULSION IMPROVES ISOFLURANE ANAESTHESIA RECOVERY of West China Hospital (No.13, 01/2011) with Chinese Clinical Trial Registry number: ChiCTR-TRC-11001779. The patients received oral and written information and gave signed copies of informed consent during pre-anaesthesia consultation. We conducted this prospective, randomized, single-centre, doubleblind study at West China Hospital of Sichuan University, which is a large comprehensive hospital (4800 beds) located in Chengdu, Sichuan Province. Patients were selected for the study according to the criteria in table 1. Sixty-six patients were enrolled and were randomly assigned to accept intravenous lipid emulsion (ILE group) or 0.9% saline solution (saline group) according to a computer-generated randomization scheme. The patients and anaesthesiologists administering intraoperative care were both blinded to the group assignment during the entire study. An investigator (H.Z.), who was blinded to the study treatment assignment, assessed the pre-operative baseline data, recovery time, recovery quality and safety during recovery for all of the patients. Detailed medical history, demographic information, history of smoking, motion sickness, as well as previous post-operative nausea and vomiting (PONV) were obtained before anaesthesia for each patient. For baseline data, the patients were evaluated with 10-point drowsiness visual analogue scale (VAS) (0 = none, 10 = maximum), the Observer’s Assessment of Alertness/Sedation (OAA/S, scale of 0– 5) for sedation level, and the Mini-Mental State Examination (MMSE, scale of 0–30) for measurements of cognitions. Routine monitors including electrocardiogram, non-invasive blood pressure and transcutaneous oxyhemoglobin saturation (SpO2) were applied to the patients. An intravenous (IV) cannula was inserted in the basilic or cephalic vein of the forearm. Anaesthesia was induced by intravenous midazolam 0.04 mg/kg, fentanyl 2 lg/kg and propofol 2 mg/kg. Rocuronium 0.6 mg/kg was used to facilitate tracheal intubation. Airway gases were monitored continuously with a gas analyser (M1026B; Philips Medizin Systeme B€oblingen GmbH, B€ oblingen, Germany), and tidal volume was adjusted to maintain an end-tidal carbon dioxide level of 35–40 mmHg. Anaesthesia was maintained with inhaled isoflurane at a fresh gas flow rate of 3 l/min. in combination with continuous intravenous infusion of remifentanil 0.1 lg/kg/min. The end-tidal concentration of isoflurane was adjusted from 0.5% to 2% to maintain blood pressure and heart rate (HR) within 20% change in the pre-operative level. A warm blanket was used to maintain core temperature at 36–37.5°C. Before the end of the operation, granisetron (3 mg) and neostigmine (50 lg/kg) were administered to each patient. After closure of the surgical wound, the isoflurane vaporizer was turned off, other maintained anaesthetics were discontinued, and the fresh gas flow rate was adjusted to 10 l/min. without changing ventilaTable 1. Inclusion and exclusion criteria. Inclusion criteria Age 18–65 years; American Society of Anesthesiologists (ASA) physical status classification score of I or II Scheduled for laparoscopic cholecystectomy Expected duration of anaesthesia not exceeding 120 min. Exclusion criteria Presence of: Obesity (body mass index >30 kg/m2) Lipid metabolism disturbance Sepsis Impaired hepatic or renal function History of neurological disease, cognitive dysfunction and psychiatric disorders Ingestion of any psychotropic drug Chronic alcohol or drug abuse Allergy to soybean, egg or lipoid products Pregnancy or breastfeeding
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tion parameter settings. The study drug, 2 ml/kg 30% ILE [Fat Emulsion Injection (C14–24); Sino-Swed Pharmaceutical Corp. Ltd., Wuxi, China] or 2 ml/kg 0.9% saline solutions, was administered via the IV cannula within 2 min. The recovery time was determined at 1-min. intervals. The time to eye opening was defined as the period between the end of administration of intervention drug and eye opening on verbal command. The time to tracheal extubation was defined as the period between the end of intervention and extubation. The extubation criteria were as follows: patients were conscious and haemodynamically stable; body temperature higher than 36°C; the respiratory rate was maintained 12–30 breaths/min., and there was no clinical residual muscle weakness. Recovery quality was assessed in the operation room and PACU. The time to exit from the operation room was defined as the period between the end of intervention and patients exiting the operation room. Modified Aldrete Post Anaesthesia Recovery Score (MAPARS) was obtained at 5-min. intervals. The time to MAPARS ≥ 9, which indicates that the patient can be safely discharged from the PACU, was defined as the time between the end of administration of intervention drug to the point when MAPARS reached 9. Drowsiness VAS and OAA/S were assessed at 5, 10, 15, 30 and 60 min. after administration of intervention drug. MMSE and MAPARS were assessed at 15, 30 and 60 min. after administration of study drug. The amount of isoflurane used during anaesthesia was determined by MAC hour (MAC9 duration of exposure in hours). The incidences of the following adverse events (AEs) were documented: hypoxia, hypotension, headache, chest pain, allergic reaction to ILE and thrombophlebitis at the site of infusion. Triglyceride, cholesterol levels and coagulation function parameters were obtained 1day post-operatively in each patient. The incidence of post-operative nausea or vomiting and the occurrence of administration of rescue analgesic (5 lg sufentanil IV) for post-operative pain were recorded for 24 hr after surgery. Statistical analysis. Statistical analysis was performed with SAS Version 8.2 (SAS Institute, Cary, NC, USA). The sample size was determined by power analysis according to our pre-test values for the time to eye opening by presuming an allocation ratio of 1, alpha value 0.05 and power of 0.80, yielding an expected sample size of 54. A total of 66 subjects were enrolled under the presumption of a failure rate of approximately 20% so as to allow for unpredictable events such as an anaesthesia procedure exceeding 120 min. or a patient withdrawing consent. Baseline data with normally continuous distribution were analysed by t-test, and categorical data were compared by chi-square or Fisher’s exact test. The time to eye opening and tracheal extubation was analysed by rank-sum test. Generalized estimating equations were used for analysing repeated categorical data, that is, post-operative drowsiness VAS score, OAA/S score, MMSE score and MAPARS. Data are presented as mean S.D., median (interquartile range), n or%. p values of 0.05, table 4). There were no serious AEs reported during the study period. None of the AEs during the entire study process were associated with ILE treatment. There were no instances of hypercoagulability or hyperlipidaemia 1-day post-operatively in any patient. No difference was observed in the incidence of post-operative nausea (16.7% in the ILE group versus 26.7% in the saline group), vomiting (6.7% in the ILE group versus 13.3% in the saline group) or pain requiring rescue medicine (23.3% in the ILE group versus 16.7% in the saline group) between the two groups (table 5). Discussion The main finding of the present study was that ILE, administered after the discontinuation of isoflurane, improved recovery time and quality from anaesthesia. Although modern inhaled anaesthetics such as sevoflurane and desflurane have Table 3. Comparison of recovery time after study drug administration. Saline (n = 30) Time Time Time Time
to to to to
eye opening (min.) tracheal extubation (min.) exit from the OR (min.) MAPARS ≥ 9 min.
20.0 21.0 23.6 33.6
ILE (n = 30)
(10.0) (8.0) (8.3) (14.8)
15.5 17.0 19.5 28.5
p
(9.0) (6.0) (6.3) (12.7)
0.01 0.08 0.04 0.15
Values are presented as median (interquartile range). ILE, intravenous lipid emulsion; OR, operation room; MAPARS, Modified Aldrete Post Anaesthesia Recovery Score. Table 4. ET concentration of isoflurane before and after study drug administration and at time of extubation. Saline
Before study drug 2 min. after study drug 5 min. after study drug 10 min. after study drug 15 min. after study drug 30 min. after study drug 60 min. after study drug Extubation
ILE
n
ET concentration
n
ET concentration
30 30 30 29 17 3 1 30
0.42 0.29 0.24 0.19 0.14 0.13 0.20 0.11
30 30 30 27 12 1 – 30
0.41 0.30 0.24 0.19 0.19 0.25 – 0.12
0.06 0.06 0.08 0.11 0.10 0.12 0.00 0.11
0.07 0.09 0.10 0.13 0.12 0.00 0.12
Values are presented as mean S.D. ILE, intravenous lipid emulsion; n, number of patients with endotracheal tube; ET concentration, endtidal concentration. The ET concentration of isoflurane monitor was discontinued after extubation.
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several advantages, isoflurane is still commonly used during clinical practice and research [11]. Furthermore, our previous study had demonstrated high solubility of isoflurane in 30% lipid emulsion [9]; then, in this study, we further investigated whether intravenous lipid emulsion could improve recovery profiles from general anaesthesia induced base on isoflurane. To our best knowledge, this is the first study to evaluate the efficacy and safety of 30% ILE in the recovery profiles from isoflurane anaesthesia. In the present study, we found that patients in the ILE group showed faster time to eye opening on verbal command compared with the saline group (p = 0.01), suggesting that administration of intravenous lipid emulsion could accelerate the emergence from isoflurane-induced hypnosis. A shorter time to exit from the operation room was also observed in the ILE group (p = 0.04). Although without being statistically significant, the ILE group did show a 4-min. reduction in the time to extubation and a 5-min. reduction in the time to reach a MAPARS of 9 compared with the saline group. The differences in these results were seemingly only a few minutes shorter with ILE. However, a previous study showed that each 1-min. reduction per case in the operation room may result in a larger economic value than 1 min. [12]. Especially in a busy ambulatory setting or a large hospital that serves high-volume surgical patients and with more than 8 hr of surgeries and turnovers in the operation room (e.g. on average, West China Hospital performs over 250 surgeries and has about 10 hr of surgeries in the operation room per workday), these modest changes may allow the surgeon to perform an additional surgery per operation room block or to reduce the need for overtime personnel, and the hospital to save scheduled labour costs in the operation room and PACU [13]. Compared with previous reports using isoflurane in laparoscopic surgery, our study showed time to eye opening and extubation 6–7 min. and 7–8 min. slower, respectively [14,15]. However, these previous studies used local anaesthetics to reduce the maintenance dose of isoflurane or discontinued other anaesthetics before the end of endoscopic performance, while in the present study, local anaesthetics were not adopted. Furthermore, to minimize variability, other maintained anaesthetics were discontinued upon completion of the skin closure rather than at variable times before the end of the surgery. These could be the possible explanations for the slower emergence in our patients. With respect to recovery quality, ILE application produced better recovery quality from isoflurane anaesthesia. Our results showed a lower drowsiness level (p < 0.01) and an earlier recovery from sedation (p < 0.01) during the 60 min. after study drug administration with ILE compared with saline solution. In addition, a greater recovery of cognitive function was demonstrated in the ILE group compared with the saline group (p = 0.04). All of these factors contributed to a greater overall MAPARS value (p = 0.03) in the ILE group than that in the saline group within the 60 min. after study drug administration. The data suggest that intravenous lipid emulsion provides for a desirable outcome of earlier assessment of neurological and cognitive function, and a faster resumption of a normal state after isoflurane anaesthesia.
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A
B
C
D
Fig. 2. Drowsiness VAS scores, OAA/S scores, MMSE scores and MAPARS versus time between the two groups after study drug administration. The drowsiness VAS score was less for the ILE group than the saline group (p < 0.01; Panel A). Compared with the saline group, the OAA/S score was higher in the ILE group (p < 0.01; Panel B). The MMSE score was greater for the ILE group than for the saline group (p = 0.04; Panel C). The MAPARS was higher for the ILE group than for the saline group (p = 0.03; Panel D). ILE, intravenous lipid emulsion; VAS, visual analogue scale; OAA/S, Observer Assessment of Alertness and Sedation; MMSE, Mini-Mental State Examination; MAPARS, Modified Aldrete Post Anaesthesia Recovery Score. Table 5. Comparison PONV and post-operative pain requiring rescue medicine in the two study groups.
Post-operative nausea Post-operative vomiting Pain requiring rescue medicine
Saline (n = 30)
ILE (n = 30)
p
8 (26.7%) 4 (13.3%) 5 (16.7%)
5 (16.7%) 2 (6.7%) 7 (23.3%)
0.53 0.42 0.75
Values are presented as n (%) or mean S.D. ILE, intravenous lipid emulsion.
The lipid sink phenomenon may also contribute to our findings. It is well known that the lipid sink phenomenon is widely accepted as the dominant mechanistic theory for the resuscitation using ILE against LAST and overdose of some lipophilic drugs [16,17]. An animal experiment indicated that radiolabelled bupivacaine administered to the mixture
consisted of equal volume 30% intralipid and plasma moved to the lipid phase with a partition coefficient of 12 and further showed that ILE could speed removal of bupivacaine from aorta plasma [7]. Isoflurane is quite lipophilic. 30% ILE/gas partition coefficient of isoflurane at 37°C is 31.6 [16], which is approximately 22.6 times higher than its blood/gas partition coefficient of 1.4 [17] at the same temperature. According to the lipid sink mechanism [8], when 2 ml/kg of 30% ILE is injected into the vascular compartment in an adult with blood volume about 70 ml/kg, isoflurane would then be drawn into the lipid sink, and its concentration in the blood phase will decrease to about 60.8% [70 / (2 9 22.6 + 70) 9 100% = 60.8%] after equilibrium between injected ILE and blood if considering that they are in a closed system. As isoflurane concentration in the blood-phase drops, a concentration gradient would develop between the action site of isoflurane and blood, with isoflurane moving away from its site of action and towards the lipid sink, as the same happens as successful
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IV LIPID EMULSION IMPROVES ISOFLURANE ANAESTHESIA RECOVERY
application of ILE for the reversal of other lipophiles toxicity [7,18,19]. This results in a faster decreasing isoflurane concentration to a threshold level for the eye opening at the site of action of isoflurane and a shorter time to eye opening in the ILE group compared with the saline group in this study. The ET isoflurane concentrations at all time-points before and 60 min. after study drug administration in the two groups were similar (table 4, p > 0.05), suggesting that the mechanism for faster eye opening in the ILE group is not located between the blood and the lungs, but between the blood and the brain. Because the site and mechanism of action of inhaled anaesthetics are still unknown, choosing an antagonist acting in the blood level is more feasible than trying to find an antagonist that acts in the action site level today. The lipid sink effect of ILE might not be limited to isoflurane in this study. Midazolam and fentanyl are both highly lipophilic [20,21]. Midazolam produces sedation, increases drowsiness VAS score and decreases MMSE and OAA/S scores [22,23]. In the present study, with the similar doses of midazolam (p = 0.11) and duration of anaesthesia (p = 0.92) for the two groups, the lower drowsiness VAS, greater OAA/ S and MMSE scores were observed in the ILE group. Similarly, intravenous fentanyl increases incidence of PONV [24] and decreases post-operative pain. With similar doses of fentanyl used for the two groups (p = 1.00) in this study, even though statistical significances were not reached, the incidences of post-operative nausea (16.7% versus 26.7%) and vomiting (6.7% versus 13.3%) were lower, and the incidence of pain requiring rescue medicine (23.3% versus 16.7%) was higher in the ILE group than in the saline group (table 5). The above data suggest that ILE might also have the lipid sink effects on lipophilic midazolam and fentanyl. Few data are available regarding the upper safety limit for total intravenous injection dose of ILE. Our previous study demonstrated that 30% ILE/gas partition coefficient of isoflurane was 1.5 times that of 20% ILE/gas partition coefficient [9]. Therefore, 30% ILE was chosen to the present study for the efficiency consideration. The dose used in this study, 2 ml/kg of 30% ILE, is much lower than the LD50 of highvolume lipid infusion obtained with rat models (67.7 ml/kg) [25], and the dose used in rescue for overdose of bupivacaine (12 ml/kg 30% lipid) [26] or calcium channel blocker (18 ml/ kg 20% lipid) in rodent models [27]. Furthermore, case reports that used ILE to reverse LAST with higher bolus dose (4.16 and 3.33 ml/kg) [28,29] than the present study did not report any complication related to lipid therapy. More importantly, none of the AEs associated with ILE treatment were noted during the entire study process. And we did not find any serious adverse events in this study during the anaesthesia recovery phase and the 1-day post-operative follow-up in the ILE group compared with the saline group. Therefore, the dose used in this study, 2 ml/kg of 30% ILE, is safe and effective. There are several limitations in the present study. The main limitation is that we did not monitor changes in blood concentration, partial pressure and blood/gas partition of isoflurane, which could provide stronger evidence for lipid sink theory to ILE effects on recovery from isoflurane anaesthesia. Secondly,
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we calculated the sample size (27 subjects in each group) before the study according to the pre-test data of time to eye opening on command because it is a typical sign of recovery from hypnosis induced by general anaesthetics, and we found a significant difference in time to eye opening with a sample size of 30 in each group in this study. However, according to a power analysis based on the results from this study, we found that the sample size in each group to reach a significant difference would be 114 subjects for time to extubation, 128 for time to MAPARS ≥ 9, 266 for incidence of post-operative nausea and 323 for incidence of vomiting, respectively. Thirdly, we did not test dose-effective relationship between ILE dose and its effects on recovery from isoflurane anaesthesia; the dose and concentration of ILE used in this study might not represent optimal values. Besides, this was a singlecentre study with a small sample size. To translate the present findings into clinical practice, further multi-centre studies focusing on effectiveness, safety and best dosage are needed. Nonetheless, the effect of ILE on improving recovery profiles of isoflurane anaesthesia has been demonstrated in the present study. In conclusion, 2 ml/kg of 30% intravenous lipid emulsion facilitates recovery time and quality from isoflurane anaesthesia for laparoscopic cholecystectomy in adults. The underlying mechanism might be related to the ‘lipid sink’ phenomenon. Source of Funding National Natural Science Foundation of China (81300110). References 1 Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 2003;362:1921–8. 2 Saxon L, Hjemdahl P, Hiltunen AJ, Borg S. Effects of flumazenil in the treatment of benzodiazepine withdrawal–a double-blind pilot study. Psychopharmacology 1997;131:153–60. 3 Takahashi M, Sugiyama K, Hori M, Chiba S, Kusaka K. Naloxone reversal of opioid anesthesia revisited: clinical evaluation and plasma concentration analysis of continuous naloxone infusion after anesthesia with high-dose fentanyl. J Anesth 2004;18:1–8. 4 Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL. (ed.). Miller’s Anesthesia, 7th edn. Churchill Livingstone, Elsevier, PA, 2010;2440–4. 5 Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology 2008;109:816–24. 6 Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W. Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity. Anaesthesia 2009;64:122–5. 7 Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998;88:1071–5. 8 Heinonen JA, Litonius E, Backman JT, Neuvonen PJ, Rosenberg PH. Intravenous lipid emulsion entraps amitriptyline into plasma and can lower its brain concentration–an experimental intoxication study in pigs. Basic Clin Pharmacol Toxicol 2013;113:193–200. 9 Zhou JX, Luo NF, Liang XM, Liu J. The efficacy and safety of intravenous emulsified isoflurane in rats. Anesth Analg 2006;102:129–34.
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