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Anesthesiology:
doi: 10.1097/ALN.0b013e31826d3de2
Perioperative Medicine

Electroencephalographic and Hypnotic Recoveries after Brief and Prolonged Infusions of Etomidate and Optimized Soft Etomidate Analogs

Ge, Rile M.D., Ph.D.*; Pejo, Ervin B.S.*; Husain, S. Shaukat Ph.D.; Cotten, Joseph F. M.D., Ph.D.; Raines, Douglas E. M.D.§

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Abstract

Background: Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster – and less context-sensitive – with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate.
Methods: Etomidate, DMMM, and CPMM where infused into rats (n = 6 per group) for either 5 min or 120 min. After infusion termination, electroencephalographic and hypnotic recovery times were measured. The immobilizing ED50 infusion rates were determined using a tail clamp assay.
Results: Upon terminating 5-min infusions, electroencephalographic and hypnotic recovery times were not different among hypnotics. However, upon terminating 120-min infusions, recovery times varied significantly with respective values (mean ± SD) 48 ± 13 min and 31 ± 6.5 min (etomidate), 17 ± 7.0 min and 14 ± 3.4 min (DMMM), and 4.5 ± 1.1 min and 4.2 ± 1.6 min (CPMM). The immobilizing ED50 infusion rates were (mean ± SD) 0.19 ± 0.03 mg−1 · kg−1 · min−1 (etomidate), 0.60 ± 0.12 mg−1 · kg−1 · min−1 (DMMM), and 0.89 ± 0.18 mg−1 · kg−1 · min−1 (CPMM).
Conclusions: Electroencephalographic and hypnotic recoveries following prolonged infusions of DMMM and CPMM are faster than those following methoxycarbonyl etomidate or etomidate. In the case of CPMM infusion, recovery times are 4 min and context-insensitive.
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What We Already Know about This Topic

* Methoxycarbonyl etomidate is a low-potency, high-clearance, soft etomidate analog that produces context-sensitive recovery from hypnosis in rats because its metabolite accumulates in the brain
* Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) have hypnotic potencies and clearances intermediate between those of etomidate and methoxycarbonyl etomidate
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What This Article Tells Us That Is New

* Recovery times after terminating 120-min infusions in rats were prolonged relative to recovery after 5-min infusions for etomidate and, to a lesser extent, for DMMM, but recovery times after terminating CPMM infusions were short and context-insensitive
Fig. 1
Fig. 1
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METHOXYCARBONYL etomidate is the prototypical ultrarapidly metabolized etomidate analog (fig. 1).1 Similar to remifentanil, methoxycarbonyl etomidate is hydrolyzed by esterases to a carboxylic acid metabolite whose potency is orders of magnitude lower than that of the parent compound.1–3 However, unlike remifentanil, methoxycarbonyl etomidate has a duration of action that is markedly context-sensitive, as encephalographic and hypnotic recoveries following prolonged (e.g., 30-min) continuous infusions are 1 or 2 orders of magnitude slower than those following brief (e.g., 5-min) infusions or single boluses.4,5 This context sensitivity likely reflects the accumulation of methoxycarbonyl etomidate’s carboxylic acid metabolite in the central nervous system during prolonged continuous methoxycarbonyl etomidate infusion.4
In the accompanying manuscript, we described the development of a family of methoxycarbonyl etomidate analogs whose members exhibit widely varying pharmacokinetic and pharmacodynamics properties.6 Among the 13 new compounds, dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) had the highest hypnotic potencies and clearances that were intermediate between those of methoxycarbonyl etomidate and etomidate. Based on these properties, we hypothesized that hypnosis could be maintained for prolonged periods of time with DMMM and CPMM using substantially lower infusion rates than with methoxycarbonyl etomidate, and that postinfusion recovery would be relatively rapid and less context-sensitive because less metabolite would be produced.
To test these hypotheses in a rat model, we used a closed-loop infusion system with electroencephalographic feedback to induce and maintain approximately equivalent hypnotic depths for either 5 or 120 min using etomidate, DMMM, and CPMM. We defined the infusion rates necessary to maintain an electroencephalographic burst suppression ratio (BSR) of 80% (in a background of 1% isoflurane) and the times required for the electroencephalogram to recover upon infusion termination. We also measured the times required for rats to regain their righting reflexes following 5 or 120 min infusions of etomidate, DMMM, and CPMM (in the absence of isoflurane) as a behavioral measure of recovery. Finally, we determined ED50 infusion rates of etomidate, DMMM, and CPMM infusion that maintain immobility in the rat to define the relative anesthetic potencies of these agents and assess the anesthetic depths achieved during our experiments.
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Materials and Methods

Animals
All studies were conducted in accordance with rules and regulations of the Subcommittee on Research Animal Care at the Massachusetts General Hospital, Boston, Massachusetts. Adult male Sprague-Dawley rats (250–500 g) were purchased from Charles River Laboratories (Wilmington, MA) and housed in the Massachusetts General Hospital Center for Comparative Medicine animal care facility. All intravenous drugs were administered through a femoral venous catheter preimplanted by the vendor before animal delivery to our animal care facility.
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Hypnotic Drugs
Etomidate (2 mg/ml in 35% propylene glycol/water) was from Hospira (Lake Forest, IL). DMMM and CPMM were synthesized (more than 97% purity) by Aberjona Laboratories (Beverly, MA), using the previously described approach and solubilized at 5 mg/ml in 10% propylene glycol/normal saline.6 Isoflurane was purchased from Baxter (Deerfield, IL). Bupivicaine and heparin were from APP Pharmaceuticals (Schaumburg, IL).
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Electroencephalographic Electrode Placement and Recording
Electroencephalographic electrodes were placed in each rat skull during 2 or 3% isoflurane anesthesia, as previously described.7 The electrodes were connected via a cable to a P511 AC preamplifier (Grass Technologies, West Warwick, RI). The electroencephalographic signal was amplified 5,000-fold, filtered (low frequency pass: 0.3 Hz, high frequency pass: 0.03 kHz), digitized at 128 Hz using a USB-6009 data acquisition board (National Instruments, Austin, TX), and the BSR measured in real time with LabView Software (version 8.5 for Macintosh OS X; National Instruments) to provide feedback for a closed-loop infusion system and to monitor BSR recovery after infusion termination.
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BSR Extraction and Closed-loop Infusion of Hypnotic Agents
We used the approach described in Rampil and Laster, Vijn and Sneyd, and Cotten et al. to estimate the BSR during each 6-s time epoch.7–9 Suppression was defined as an interval during which the time-differentiated electroencephalographic signal amplitude stayed within a suppression voltage window for at least 100 ms. This suppression voltage window was defined individually in each rat as previously described.7 Rats were then equilibrated with 1% inhaled isoflurane delivered through a tight-fitting nose cone for at least 45 min until the BSR stabilized before study. Closed-loop hypnotic infusion studies were done in a background of 1% inhaled isoflurane.
A KDS Model 200 Series infusion pump (KD Scientific, Holliston, MA) was used for continuous hypnotic infusion. The pump was controlled remotely via its RS 232 serial port by a Macintosh computer using a Keyspan USB-Serial port adapter (Tripp Lite, Chicago, IL). A LabView 8.5 instrument driver using Virtual Instrument Software Architecture protocols provided computer-to-pump communication. For closed-loop infusions, we used the algorithm described by Vijn and Sneyd in which the hypnotic infusion rate is increased or decreased every 6 s depending upon whether the BSR is below or above, respectively, the target value.9 The magnitude of the change in the infusion rate is dependent upon the difference between the current BSR measured in the rat and the BSR target. For all closed-loop experiments, we used a BSR target of 80%. To prevent overdosing, the algorithm was modified with a maximum infusion rate of 2 mg−1 · kg−1 · min−1 for etomidate and 3 mg−1 · kg−1 · min−1 for DMMM and CPMM. For each hypnotic, these maximal rates deliver a cumulative dose equivalent to four times the ED50 for loss-of-righting reflexes (as determined in single bolus studies) every minute.6 We also employed a minimum infusion rate of 0.1 mg−1 · kg−1 · min−1 for all hypnotics. The BSR was measured for 5 min before beginning closed-loop hypnotic infusion and then until the BSR recovered to the baseline value after infusion termination.
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Fitting and Analysis of Closed-loop Infusion Data to Define the 90% BSR Recovery Time
Because the BSR increased from a preinfusion baseline to the 80% target in an approximately sigmoidal manner when hypnotic infusions were initiated and then decreased to a postinfusion baseline in a sigmoidal manner once hypnotic infusions were terminated, we analyzed the BSR data by fitting this entire infusion time-dependent change in the BSR to a biphasic sigmoidal equation using the analysis software Igor Pro 6.1 (Wavemetrics, Lake Oswego, OR). This biphasic equation was formed by the combination of two monotonic relationships:10
Equation (Uncited)
Equation (Uncited)
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In the equation, t is the time during the infusion experiment, h and h1 approximate the respective midpoints as the BSR rises and falls upon hypnotic infusion initiation and termination, r and r1 are the respective slopes of the rising and falling phases of the BSR, and M, B, and B1 together define the maximal and pre- and postinfusion baseline BSR values. From each fit, we calculated the 90% BSR recovery time, which was defined as the time from infusion termination until the time when the BSR fell 90% toward the postinfusion baseline value.
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Determination of Closed-loop Hypnotic Infusion Protocols
For each 120-min closed-loop infusion experiment, we defined the average infusion rate required to maintain an 80% BSR during each 5-min epoch by recording the infusion rate every 6 s and binning this data into 24 different 5-min periods. For each study group (etomidate, DMMM, and CPMM), we then calculated the within-group average infusion rate during each 5-min period and fit the time-dependent change in infusion rate to an exponential equation using Igor Pro 6.1 in the form:
Equation (Uncited)
Equation (Uncited)
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In the equation, y is the infusion rate at time t, A + y0 is the initial infusion rate, y0 is the steady-state infusion rate after long infusion times, and invTau is the inverse time constant that defines the change in infusion rate over time.
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Recovery of Righting Reflexes after Hypnotic Infusions
In individual rats, loss of righting was produced using a continuous infusion of the desired hypnotic (etomidate, DMMM, or CPMM) for either 5 or 120 min. To achieve approximately equivalent hypnotic depths, we used the infusion protocols defined by equation 2 using values of A, y0, and invTau determined for each hypnotic in the closed-loop experiments. Approximately 3 min after the hypnotic infusion was begun, rats were turned supine. After the infusion was terminated, the recovery time (spontaneous righting onto all four legs) was measured with a stopwatch.
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Determination of Immobilizing ED50s
The immobilizing ED50 for each hypnotic was determined as generally described by Zhang et al.11 We chose an initial infusion rate for each hypnotic that was 30% of the steady-state infusion rate value determined in closed-loop studies (y0 in equation 2). This initial infusion rate was maintained for 40 min, then the tail was clamped with an alligator clip and the clip rotated 180° at 1 to 2 Hz for 1 min or until the rat made a purposeful response. If the rat responded, the infusion rate was increased by 20%, and after another 40-min equilibration period, the tail was clamped as before. This procedure was repeated every 40 min with escalating hypnotic infusion rates until the rat failed to respond. The ED50 infusion rate for immobility was then defined in that rat as the average of the highest rate that produced a response and the subsequent rate that did not.
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Statistical Analysis
All data are reported as mean ± SD. Statistical analyses were done using Prism v5.0 for the Macintosh (GraphPad Software, Inc., LaJolla, CA) or Igor Pro 6.1. Statistical comparisons among the six groups of rats receiving different hypnotics for different durations of time were made using a one-way ANOVA followed by a Tukey post hoc test. P < 0.05 was considered statistically significant.
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Results

BSR Recovery Following 5- and 120-min Closed-loop Infusions
Fig. 2
Fig. 2
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In closed-loop experiments using rats preequilibrated with 1% isoflurane, the BSR reached the target value of 80% 3 or 4 min after initiating the infusion. Once the infusion was terminated, the BSR decreased to a postinfusion value that was similar to the preinfusion value. Figures 2A and 2B show the results of typical experiments in which a rat was infused with etomidate for either 5 min or 120 min, respectively. The respective 90% BSR recovery times for these experiments, calculated from the biphasic sigmoidal fit, were 9.0 min and 50.3 min. Figures 2C and 2D show the results of analogous experiments in which DMMM was infused. In this case, the calculated 90% BSR recovery times were 8.8 min and 15.7 min for infusion durations of 5 min and 120 min, respectively. Figures 2E and 2F show typical results of experiments in which CPMM was infused. The calculated 90% BSR recovery times following the 5-min and 120-min CPMM infusions were 6.3 min and 3.3 min, respectively.
Fig. 3
Fig. 3
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Figure 3 summarizes the results of all closed-loop experiments to define the 90% BSR recovery times after infusing etomidate, DMMM, or CPMM. Upon terminating 5-min infusions, the 90% BSR recovery times did not vary significantly with the identity of the administered hypnotic and averaged 11.1 ± 3.9 min (etomidate), 10.0 ± 3.9 min (DMMM), and 6.2 ± 1.7 min (CPMM). However upon terminating 120-min infusions, recovery times varied significantly with average values of 48 ± 13 min (etomidate) 17 ± 7.0 min (DMMM), and 4.5 ± 1.1 (CPMM). For etomidate, recovery times after 120-min infusions were significantly longer than that after 5-min infusions (P < 0.001) whereas for both DMMM and CPMM, recovery times did not vary significantly with infusion duration.
Fig. 4
Fig. 4
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Figure 4 shows the cumulative hypnotic doses received by rats during closed-loop infusions of the three hypnotics. With 5-min infusions, the cumulative doses administered by the closed-loop system were not significantly different among the three hypnotics and averaged 6.2 ± 2.3 mg/kg (etomidate), 8.6 ± 1.2 mg/kg (DMMM), and 7.7 ± 3.4 mg/kg (CPMM). However, with 120-min infusions, the cumulative doses varied significantly with average values of 36 ± 12 mg/kg (etomidate), 107 ± 18 mg/kg (DMMM), and 143 ± 38 mg/kg (CPMM).
Fig. 5
Fig. 5
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Figure 5 shows the average infusion rate for each 5-min period during 120-min closed-loop infusions of etomidate, DMMM, and CPMM. For all hypnotics, the infusion rates determined by the closed-loop system were highest during the first 5-min epoch before declining to steady-state values of 0.25 ± 0.01 mg−1 · kg−1 · min−1 (etomidate), 0.86 ± 0.01 mg−1 · kg−1 · min−1 (DMMM), and 1.14 ± 0.02 mg−1 · kg−1 · min−1 (CPMM). For each hypnotic, the curve in figure 5 is an exponential fit of the data set. This fit defined the infusion protocol used subsequently to assess the rate of hypnotic recovery (i.e., recovery of righting reflexes) in the absence of isoflurane.
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Hypnotic Recovery Following 5- and 120-min Infusions
Fig. 6
Fig. 6
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To assess hypnotic recovery rates using a behavioral endpoint, we infused each hypnotic for either 5 or 120 min in the absence of isoflurane. We used the infusion rates that we had previously defined during the closed-loop studies (i.e., the exponential fit of the data shown in fig. 5) to induce and maintain approximately equivalent hypnotic depths. We then measured the time required for rats to recover their righting reflexes after the infusion was stopped (fig. 6). We found that all rats lost their righting reflexes approximately 3 min after initiating the hypnotic infusion. Upon terminating 5-min infusions, the recovery times did not vary significantly with the identity of the administered hypnotic and averaged 4.0 ± 0.8 min (etomidate), 3.3 ± 0.7 min (DMMM), and 4.2 ± 1.3 min (CPMM). However, upon terminating 120-min infusions, these recovery times varied significantly (P < 0.001) with average values of 31 ± 6 min (etomidate), 14 ± 3 min (DMMM), and 4.2 ± 1.6 min (CPMM). For etomidate and DMMM, recovery times after 120-min infusions were significantly (P < 0.001) longer than after 5-min infusions. However, for CPMM, recovery times following 5-min and 120-min infusions were identical.
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Etomidate, DMMM, and CPMM Immobilizing ED50s
Continuous infusion of all three hypnotics produced immobilization at sufficiently high infusion rates. The average immobilizing ED50 (n = 5 rats/hypnotic) were 0.19 ± 0.03 mg−1 · kg−1 · min−1 (etomidate), 0.60 ± 0.12 (DMMM), and 0.89 ± 0.18 (CPMMM).
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Discussion

Together with our previous studies, the current studies show that DMMM and CPMM maintain hypnosis with doses that are 1 or 2 orders of magnitude lower than methoxycarbonyl etomidate.4 They also show that following prolonged hypnotic infusion, encephalographic and hypnotic recovery times range from several minutes to several hours with CPMM less than DMMM less than etomidate less than methoxycarbonyl etomidate. In the case of CPMM, recovery times were independent of infusion duration.
Methoxycarbonyl etomidate, DMMM, and CPMM are members of a structurally related family of hypnotics that we have termed “spacer-linked etomidate esters” because each has a metabolically labile ester moiety that is linked to the etomidate backbone via a carbon spacer.6 Methoxycarbonyl etomidate is the prototypical member of this family, and its metabolically labile ester is linked to the etomidate backbone via a simple two-carbon spacer. When designing methoxycarbonyl etomidate, our objective was to minimize any steric hindrance that might inhibit esterase-catalyzed hydrolysis of the labile ester and thus slow recovery.1 In vitro studies demonstrated that the methoxycarbonyl etomidate half-life in rat blood is very short (20 s) and its in vivo duration of hypnotic action in rats following single bolus administration is extremely brief (1 or 2 min), even when given at several multiples of its hypnotic ED50 dose.1,12
In subsequent infusion studies, it became apparent that methoxycarbonyl etomidate dosing requirements were high and electroencephalographic and hypnotic recoveries upon infusion termination were remarkably context-sensitive.4 For example, electroencephalographic recovery following a single methoxycarbonyl etomidate bolus occurred within several minutes, whereas recovery following a 30-min methoxycarbonyl etomidate infusion occurred on the time-scale of hours.4,7 Analysis of metabolite levels in the cerebrospinal fluid revealed that with prolonged methoxycarbonyl etomidate infusion, the carboxylic acid metabolite of methoxycarbonyl etomidate reached millimolar concentrations.4 These are concentrations that produce significant hypnotic effects, which strongly suggested that the high context-sensitivity was the result of accumulated metabolite in the brain.4,13 Such high metabolite concentrations can logically be attributed to the large quantity of methoxycarbonyl etomidate that must be infused to maintain hypnosis for prolonged periods of time.
DMMM and CPMM are analogs of methoxycarbonyl etomidate that contain aliphatic groups (two methyl groups and a cyclopropyl group, respectively) designed to sterically protect the labile ester from enzymatic attack and increase metabolic stability relative to methoxycarbonyl etomidate. We hypothesized that this increased stability would reduce the DMMM and CPMM infusion rates necessary to maintain hypnosis (and thus the quantity of metabolite generated), resulting in less context-sensitivity than we had observed with methoxycarbonyl etomidate.4 During the initial characterization of DMMM and CPMM, we unexpectedly found that these agents also had hypnotic potencies that were nearly 8-fold higher than methoxycarbonyl etomidate, a property that would further reduce dosing requirements.
The current studies confirm our hypothesis, because hypnotic dosing requirements are significantly lower for DMMM and CPMM than previously shown for methoxycarbonyl etomidate; the total (cumulative) doses of DMMM and CPMM required to maintain an 80% BSR for 120 min (107 ± 18 mg/kg and 143 ± 38 mg/kg, respectively) approximated the total dose of methoxycarbonyl etomidate that maintained an 80% BSR for just 2 or 3 min (all in a background of 1% isoflurane).4 In addition, electroencephalographic recovery upon terminating DMMM or CPMM infusions did not show the marked context-sensitivity previously observed with methoxycarbonyl etomidate.4 With DMMM and CPMM (and etomidate), we also failed to see the slow phase of electroencephalographic recovery that was apparent after even brief methoxycarbonyl etomidate infusions and which was attributed to the slow clearance of metabolite from the brain.4 Although we did not measure metabolite concentrations in the present study, our results imply that metabolite failed to reach concentrations sufficient to significantly affect the BSR even after 120 min, because electroencephalographic recovery occurred over minutes, not hours.
The results of the righting reflexes studies closely paralleled those of the electroencephalographic studies. However, in the former studies, the difference in the recovery times following 120-min versus 5-min DMMM infusions reached statistical significance.
Our electroencephalographic studies utilized a high (80%) target BSR to more easily quantify recovery upon termination of hypnotic infusions. Although this degree of burst suppression is indicative of a relatively deep level of anesthesia, it was achieved in a background of 1% isoflurane.14,15 This background allowed us to measure the full time-course of burst suppression induction and recovery without motion artifact. It was also expected to reduce the hypnotic infusion rates necessary to achieve such burst suppression toward a more clinically relevant range. This expectation was met as our immobility studies indicate that the steady-state infusion rates used in the electroencephalographic and hypnotic studies correspond to immobilizing ED50 multiples of only 1.3, 1.4, and 1.3 for etomidate, DMMM, and CPMM, respectively.
In conclusion, DMMM and CPMM are sterically hindered analogs of methoxycarbonyl etomidate that maintain equivalent levels of hypnosis with significantly lower infusion rates than methoxycarbonyl etomidate. Encephalographic and hypnotic recoveries following DMMM and CPMM infusion occur without the marked context-sensitivity characteristic of methoxycarbonyl etomidate, which is attributed to metabolite accumulation in the brain. In the case of CPMM, encephalographic and hypnotic recoveries occur in approximately 4 min, independent of infusion duration.
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References

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6. Husain SS, Pejo E, Ge R, Raines DE. Modifying methoxycarbonyl etomidate interester spacer optimizes in vitro metabolic atability and in vivo hypnotic potency and duration of action. Anesthesiology. 2012;117:1027–36

7. Cotten JF, Le Ge R, Banacos N, Pejo E, Husain SS, Williams JH, Raines DE. Closed-loop continuous infusions of etomidate and etomidate analogs in rats: A comparative study of dosing and the impact on adrenocortical function. Anesthesiology. 2011;115:764–73

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12. Pejo E, Cotten JF, Kelly EW, Le Ge R, Cuny GD, Laha JK, Liu J, Jie Lin X, Raines DE. In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate. Anesth Analg. 2011;115:297–304

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14. Bruhn J, Bouillon TW, Shafer SL. Bispectral index (BIS) and burst suppression: Revealing a part of the BIS algorithm. J Clin Monit Comput. 2000;16:593–6

15. van den Broek PL, van Rijn CM, van Egmond J, Coenen AM, Booij LH. An effective correlation dimension and burst suppression ratio of the EEG in rat. Correlation with sevoflurane induced anaesthetic depth. Eur J Anaesthesiol. 2006;23:391–402

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