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Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, Utah
Address correspondence and reprint requests to Ken B. Johnson, MD, Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT 84132. Address e-mail to kjohnson{at}anesth.med.utah.edu
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Abstract |
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IMPLICATIONS: Hemorrhagic shock produced minimal changes in the pharmacokinetics and no change in the pharmacodynamics of etomidate in swine. These results suggest that, unlike other sedative hypnotics and opioids, minimal adjustment in the dose of etomidate is required to achieve the same drug effect during hemorrhagic shock.
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Introduction |
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Many authors have further quantified the pharmacokinetic changes associated with blood loss by using compartmental models (1,2,4,5,9) and have demonstrated that blood loss results in a decrease in central compartment volume, central compartment clearance, or both (1,2,4,5). These pharmacokinetic changes account for the often large differences observed in plasma or whole blood concentrations after equivalent dosing in bled and unbled animal studies (1,2). A decrease in the cardiac output and blood volume are likely physiologic mechanisms explaining these pharmacokinetic changes.
De Paepe et al. (4), studying the influence of blood loss on the pharmacology of etomidate, have demonstrated that moderate blood loss (18 mL/kg) produced a change in the pharmacokinetics of etomidate (a decrease in the central compartment volume of distribution, steady-state volume of distribution, and systemic clearance) and minimal change in the potency of etomidate in a rat isovolemic hemorrhage model. They concluded that the pharmacokinetic but not the pharmacodynamic changes resulted in a 37% reduction in dose to achieve the same drug effect.
Similar to the work performed by De Paepe et al., in this present study, we explored how hemorrhagic shock influences the pharmacokinetics and pharmacodynamics of etomidate, but implemented a more severe hemorrhage model (30 mL/kg) in swine. Because etomidate has a rapid redistribution with a large volume of distribution after IV injection (10–12) and that drug redistribution is in part a function of cardiac function (13), we hypothesized that hemorrhagic shock would reduce the apparent distribution volumes. Similarly, because etomidate is primarily metabolized in the liver (11), and liver perfusion is known to decrease with blood loss (14), we also hypothesized that hemorrhagic shock would reduce clearance. Because De Paepe et al. found no change in etomidate pharmacodynamics in the presence of moderate hemorrhage, we hypothesized that even with a more severe hemorrhage model implemented in swine, the pharmacodynamic profile of etomidate would be preserved.
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Materials and Methods |
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Animal Preparation
Swine weighing between 23.8 and 42.6 kg (mean weight 33.0 kg) were commercially obtained and quarantined for 6 days in a temperature- and light-controlled environment. Animals had free access to food and water ad libitum. Anesthesia was induced with an IM injection of tiletamine HCl 1.3 mg/kg, zolazepam 1.3 mg/kg, ketamine 1.3 mg/kg, and xylazine 1.3 mg/kg. Intravascular access was obtained from an ear vein.
After induction, each animal’s trachea was intubated and their lungs were mechanically ventilated. Initial ventilator settings were set to a tidal volume of 8–10 mL/kg, a respiratory rate of 20 breaths per minute, a fraction of inspired oxygen of 50%, and no positive end-expiratory pressure. Tissue oxygenation was monitored by using continuous pulse oximetry placed on the tongue or ear. Ventilation was monitored by using an inspired/expired gas analyzer that measured oxygen, carbon dioxide, and potent inhaled anesthetic concentrations. Ventilator settings were adjusted as needed to keep the pulse oximetry (SpO2) >95% and the end-tidal CO2 at 38 ± 4 mm Hg. Once satisfactory ventilator settings were established, a baseline arterial blood gas was obtained. Ventilator settings were adjusted further if needed to maintain the arterial partial pressure of carbon dioxide at 40 ± 4 mm Hg.
A continuous level of anesthesia was achieved with isoflurane and intermittent boluses of pancuronium (0.1 mg/kg). Expired isoflurane levels were monitored and kept at 1.0 minimum alveolar anesthetic concentration equivalent for swine (15). Subcutaneous electrocardiograph electrodes were placed and the electrocardiograph was monitored throughout the study.
The left femoral artery was cannulated with a 16-gauge arterial sheath using sterile technique to monitor arterial blood pressure and heart rate continuously. The right femoral artery was cannulated with a 16-gauge arterial sheath for blood removal and subsequent reinfusion. An internal jugular vein was cannulated with a pulmonary artery catheter for thermodilution estimates of cardiac output. Colonic temperatures were monitored and maintained at 37°C throughout the study with a heating blanket and heating lamps as needed. Once vascular access procedures were completed, each animal was anticoagulated with an IV bolus injection of heparin (100 U per kilogram of body weight).
Instrumentation for electroencephalographic (EEG) monitoring was accomplished by preparing the skin over the frontooccipital regions bilaterally and placing four cutaneous low-impedance electrodes (Zipprep; Aspect Medical, Framingham, MA). A ground electrode was placed in the midline between the frontal and occipital regions. Four channels of the EEG were amplified and digitally recorded by using an EEG monitoring machine (Aspect A-1000, software version 3.22; Aspect Medical).
Hemorrhage Protocol
After instrumentation, animals underwent a 30-min stabilization period before initiating the hemorrhage protocol. After the stabilization period, unbled control animals underwent a 30-min sham hemorrhage.
The hemorrhage protocol was designed to ensure that each animal was at an equivalent degree of metabolic compromise from hemorrhagic shock before initiating the etomidate infusion. This was accomplished by using an isobaric hemorrhage model as described by Wiggers (16).
In prior work in our laboratory, the influence of moderate hemorrhagic shock on the pharmacokinetics of fentanyl, remifentanil, and propofol was investigated (1,2,17). With remifentanil, we administered large doses with the goal of eliciting a measurable response in cerebral electrical activity in swine bled to a shed blood volume of 45 mL/kg with a target mean arterial blood pressure of 40 mm Hg (1). When the same approach was taken with propofol, the animals suffered cardiovascular collapse before completing the study protocol. Thus, we had to reduce both the dose of propofol and the severity of the hemorrhage protocol in order for animals to complete the study protocol (17). The severity of the hemorrhage protocol was reduced by increasing the target mean arterial blood pressure to 50 mm Hg and reducing the shed blood volume target to 30 mL/kg. To accommodate comparisons between sedative hypnotics, we used a hemorrhage protocol in this study identical to the one implemented in our propofol work.
A pilot study was performed to identify the dose of etomidate that would allow animals to survive the hemorrhage protocol, yet develop a measurable effect in the Bispectral Index Scale (BIS) from the etomidate infusion. A series of 4 trials was performed over a dosing range of 100–400 µg · kg-1 · min-1 for 10 min in an unbled state with the goal of determining what dose would be required to detect a change in the BIS. With doses of 300 or 400 µg · kg-1 · min-1 for 10 min, the BIS decreased to near 0. A fifth trial with a dose of 300 µg · kg-1 · min-1 for 10 min was administered after the hemorrhage protocol. The pilot animal survived the etomidate infusion and the 3-h study period after drug administration and hemorrhagic shock.
Subsequently, 16 animals were randomly assigned to 2 groups: the experiment shock group and the control group. The arterial blood pressures were measured with a pressure transducer (Utah Medical, Midvale, UT). Blood was removed and stored in a citrated bag at a rate required to achieve a mean arterial blood pressure of 50 mm Hg over 20 min by a servo-controlled peristaltic pump. Blood was then removed until a target shed blood volume of 30 mL/kg had been achieved. With the blood reservoir bag on a scale, shed blood volume was determined from the weight. A computerized data acquisition system recorded the mean arterial blood pressure, systolic and diastolic arterial pressures, heart rate, and shed blood volume every 5 s.
Arterial blood samples for pH, partial pressure of oxygen, partial pressure of carbon dioxide, bicarbonate, glucose, potassium, hematocrit, glucose, and lactate were measured by using blood gas and chemistry analyzers (Stat Profile 1 Analyzer; Nova Biomedical, Waltham, MA and YSI Model 2700 Select Biochemistry Analyzer; Yellow Springs Instrument Co., Yellow Springs, OH) before hemorrhage, after hemorrhage but before the etomidate infusion, and upon completing the etomidate infusion. Metabolic and hemodynamic variables for each group were compared at these time points by using an unpaired two-tailed Student’s t-test. P values < 0.05 were considered significant.
Plasma Etomidate Administration and Assay
Etomidate (300 µg · kg-1 · min-1) was administered IV at a constant rate infusion using a syringe pump (Medfusion 2010i; Medex Inc., Duluth, GA) for 10 min. During and after the infusion, 3-mL arterial blood samples were obtained at preset intervals, with more rapid sampling during the infusion and immediately after termination of the infusion. A baseline sample was collected before the infusion. During and after the infusion, samples were collected at 1, 2, 3, 4, 8, 10, 11, 12, 13, 14, 15, 17.5, 20, 25, 30, 40, 60, and 180 min.
Etomidate plasma concentrations were measured by using a gas chromatography mass spectrometer technique with a quantitation limit of 300 ng/mL.
Pharmacokinetic Analysis
The concentration-versus-time data for both groups were compared by using a repeated-measures analysis of variance. If the repeated-measures analysis of variance demonstrated significance, further analysis was done at each sampling time by using a Scheffé post hoc test to determine which sample times in the shock group varied from the control group. The concentration-versus-time data were also compared estimating pharmacokinetic variables for a three-compartment model. A "two-stage" approach implemented in pharmacokinetic modeling software (WinNonLin; Pharsight Corp., Chelsea, MI) was performed to estimate a three-compartment mamillary model from the etomidate concentration-versus-time data for each animal. The triexponential equation was parameterized in terms of central compartment volume, exponents, and micro rate constants. The second stage of the "two-stage" approach was to calculate the mean of the pharmacokinetic variables for each group. The shock and control groups were compared with an unpaired two-tailed Student’s t-test. P values < 0.05 were considered significant.
Pharmacodynamic Analysis
BIS Analysis.
The pharmacologic effect of etomidate was characterized by examining the influence of etomidate on the BIS. One concern is that shock itself, in the absence of etomidate, may alter the BIS. In a prior study in our laboratory, BIS data using an identical hemorrhage protocol and isoflurane anesthetic in the absence of a sedative hypnotic infusion after the isobaric hemorrhage, elicited no significant change in the BIS when compared with normotensive animals under identical anesthetic conditions (17).
Pharmacodynamic Modeling of the Concentration-Effect Relationship.
The concentration-effect relationship was characterized by using an effect compartment model (18). Because plots of the concentration-effect relationship were sigmoid in shape, an inhibitory "sigmoid Emax" equation (i.e., Hill equation) and a first-order rate constant characterizing the effect site equilibration kinetics were used to model the relationship. Pharmacokinetic variables for each individual animal were estimated by using pharmacokinetic modeling software (WinNonLin; Pharsight Corp.). With the pharmacokinetic variables fixed, pharmacodynamic variables for each animal were estimated in WinNonLin according to the equation: equation
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where E is the predicted effect, E0 is the baseline effect level, Emax is the maximal effect, Ce is the effect site concentration, 
is a measure of curve steepness, and ECe50 is the effect site concentration that produces 50% of maximal effect. This pharmacodynamic model was fit to the apparent effect site concentration-versus-drug effect data. A concentration-effect curve was plotted for each individual animal and for each group based on the mean of each pharmacodynamic variable.
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Results |
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Pharmacokinetic Analysis
The etomidate infusion administered in this protocol resulted in time-versus-concentration curves characteristic of brief IV infusion of a sedative hypnotic exhibiting a rapid distribution phase followed by a slower elimination phase. Individual etomidate concentrations in the shock and control groups are presented in Figure 2. Visual inspection of the raw data reveals that both the shock and control groups developed similar plasma etomidate levels throughout the experiment, although a few of the animals in the shock group seem to have slightly higher plasma etomidate concentrations during the infusion when compared with controls. The peak concentration achieved after the etomidate infusion was 4.6 ± 0.3 and 6.2 ± 0.7 µg/mL for the control and shock groups, respectively (mean ± SEM). A repeated-measures analysis of variance comparing the etomidate plasma concentration levels over time between groups revealed a significant difference between groups. A post hoc analysis with a Scheffé test revealed that the etomidate plasma concentrations at the end of the infusion (the 10-min sample) were significantly different.
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Discussion |
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The Influence of Hemorrhagic Shock and Etomidate on Cardiovascular Performance
Animals in the shock group developed hemodynamic and metabolic changes consistent with hemorrhagic shock. The hemorrhage protocol produced an estimated 43% decrease in blood volume assuming a vascular volume of 70 mL/kg for swine. As shown with other IV anesthetics (13,19), we expected that these changes in cardiovascular function would be large enough to alter the pharmacokinetic profile of etomidate.
We found that a brief continuous infusion of etomidate altered cardiovascular performance in our control group in a similar manner to that reported by Prakash et al. (20) in swine and Price et al. (21) in humans, namely, a decrease in mean arterial blood pressure and an increase in systemic vascular resistance. These authors also reported a decrease in cardiac index with etomidate (20,21), but in our study, we found no change in cardiac index with either group. Several authors have studied the influence of etomidate on myocardial contractility and concluded that etomidate decreases contractility in a dose-dependent manner (22,23) but that myocardial depression typically does not occur after doses that are used in clinical practice.
Authors have also reported a preservation of, or increase in, sympathetic tone and vascular resistance after the administration of etomidate (24). An increase in sympathetic tone may offer an explanation for why the systemic vascular resistance increased after the etomidate infusion in the control group.
The increase in mean arterial blood pressure with the etomidate infusion in the shock group was somewhat surprising and not consistent with what was previously reported under hemorrhagic hypotensive conditions. De Paepe et al. (4) administered an etomidate infusion in a rodent hemorrhage model and reported a decrease in mean arterial blood pressure after an etomidate infusion.
A possible explanation for this difference is a function of the hemorrhage protocol used in this study. After reaching the target shed blood volume, the computer-controlled roller pump that removed or reinfused blood to maintain the target mean arterial blood pressure was turned off. This was done to minimize the impact of blood removal or reinfusion on etomidate drug concentration. In a prior study using the identical hemorrhage model (17), we observed changes in mean arterial blood pressure in bled animals over time once the computer-controlled roller pump had been turned off. In the absence of a sedative hypnotic infusion, the mean arterial blood pressure increased as part of a compensatory mechanism after hemorrhage. This may include an increase in vascular tone from increasing catecholamine levels (25) or recruitment of extravascular fluid to the vascular compartment to augment the circulating blood volume as has been previously demonstrated by decreasing hematocrit levels in isobaric hemorrhage models (26). This may be an explanation for the small decrease in hematocrit after the etomidate infusion in the shock group.
We suggest that these compensatory mechanisms may have dominated over the moderate cardiovascular depression associated with etomidate and that etomidate itself may have contributed to the adrenergic response that developed during hemorrhagic shock. For example, despite a 30 mL/kg hemorrhage, bled swine maintained their cardiac index and systemic vascular resistance in the presence of an etomidate infusion. These hemodynamic findings underscore the potential advantage of etomidate over other induction drugs as suggested by many authors (27–29) and support the rationale for using etomidate in certain clinical settings where adverse hemodynamic side effects associated with other induction drugs may prove harmful.
The Influence of Hemorrhagic Shock on Etomidate Pharmacokinetics
Based on our prior work estimating pharmacokinetic parameters for fentanyl, remifentanil, and propofol after moderate-to-severe hemorrhage, we anticipated etomidate plasma levels would be higher in animals subjected to hemorrhagic shock. Inspection of the raw data revealed that in shocked animals, etomidate plasma levels were near equivalent to controls throughout the study period except for an increase in plasma concentrations in the shock group at the end of the infusion.
Our pharmacokinetic parameters for etomidate in the control group are similar to those reported for humans (11). No pharmacokinetic analyses of etomidate administered to swine are available for comparison. The difference in the peak plasma concentrations was small and the results from the two-stage pharmacokinetic analysis revealed that the rapidly equilibrating peripheral compartment volume (V2) and to a lesser extent the slowly equilibrating peripheral compartment (V3) and volume at steady state were reduced in bled animals. A potential explanation for this decrease may be that as the cardiac output is reduced, etomidate redistribution to peripheral tissues is also reduced. We reported a 34% decrease in cardiac index between the shock and control animals. As Upton et al. (13) demonstrated with propofol, a reduction in cardiac output can significantly alter the pharmacokinetic profile of IV anesthetics.
These findings are somewhat similar to our findings with fentanyl (2), remifentanil (1), and propofol (17). In our prior work, hemorrhagic shock considerably altered central and/or the peripheral compartment clearances and volumes in swine leading to markedly increased plasma or whole blood concentrations after equivalent dosing regimens. These earlier results with other IV anesthetics are consistent with what others have reported for propofol (5), etomidate (4), and lidocaine (9) in other animal hemorrhagic shock models. The most interesting difference between the results presented herein and this prior work is that hemorrhagic shock did not reduce the clearance of etomidate as it has other IV anesthetics.
Etomidate is similar to other sedative hypnotics (e.g., propofol) in terms of volume of distribution and drug redistribution. It exhibits a rapid redistribution to peripheral tissues after IV injection. Once at steady state, etomidate reaches a volume of distribution that can be as large as 4 L/kg, whereas only a small percentage (e.g., 7%) of the drug remains in the central compartment (11). Prior work has established that hepatic biotransformation is the likely primary source of etomidate clearance. Etomidate has a hepatic extraction ratio near 0.5 (11) and a protein binding level of near 80% (4). According to Blaschke’s triangle (30), which maps out the hepatic extraction ratio and plasma protein binding (%) across hepatic blood flow, etomidate clearance should be sensitive to protein binding but not particularly sensitive to changes in hepatic blood flow. We did not measure the plasma protein content or the percentage of etomidate bound to plasma proteins. However, in a study by De Paepe et al. (4) examining the influence of moderate hemorrhagic shock on etomidate pharmacokinetics in rodents, the authors measured protein levels and the percent of bound drug before and after hemorrhage. They found that protein content and percent protein binding of etomidate did not significantly change or contribute to observed pharmacokinetic changes (4). We hypothesized that hemorrhagic shock would reduce clearance as a consequence of impaired hepatic perfusion. In our shock model, we did not measure hepatic blood flow. We measured no difference in drug clearance. We can only speculate that hepatic blood flow, although likely decreased, was not severe enough to slow etomidate metabolism and elimination.
The Influence of Hemorrhagic Shock on Etomidate Pharmacodynamics
We used the BIS as a surrogate measure of etomidate effect and found that a 10-minute continuous infusion of etomidate produced a similar decrease in the BIS in both the control and shock groups. The two-stage pharmacodynamic analysis corroborated the similarity between groups observed in the BIS versus time data. Plots of the effect site concentration versus drug effect visually demonstrate that our hemorrhagic shock model did not influence the potency of etomidate in swine.
Our pharmacodynamic results are similar to those reported by De Paepe et al. (4) in a rodent hemorrhage model in which etomidate was infused to achieve an end point in the amplitude of the 2.5- to 7.5-Hz frequency band of the EEG signal. They found that etomidate produced only small changes in some of their nonparametric descriptors used to describe their observed pharmacodynamic effect and concluded that the influence of hemorrhagic shock contributes little to increasing the potency of etomidate.
Limitations of the Study
There are several limitations to this line of investigation that have been discussed in prior work (1,2,5). Some of these include: (i) controlled unresuscitated hemorrhagic shock is not typical of clinical practice where resuscitation is usually underway and hemorrhage may not be controlled before the administration of an IV anesthetic, and (ii) differences among species in how they exhibit their response to hemorrhagic shock such as differences in splenic red cell reserve and dissimilar hemoglobin p50s.
In our shock model, we administered etomidate during the compensatory phase of isobaric hemorrhagic shock, a point in the hemorrhage protocol in which blood had to be removed to maintain the target pressure. At this point in the hemorrhage process, we observed a favorable pharmacologic response to a brief continuous infusion of etomidate. One limitation of our work is that we did not explore the pharmacokinetic and pharmacodynamic profile of etomidate when administered in a more severe setting, i.e., the decompensatory phase of isobaric hemorrhage (the point in isobaric hemorrhage in which blood is reinfused to maintain the target blood pressure). At this point, with high-energy phosphate stores depleted (31) and continuing cardiovascular collapse (32), the known cardiodepressant effects of etomidate may prove to be harmful.
An additional limitation to this study was that we administered etomidate in the presence of isoflurane. One concern is that isoflurane would alter the concentration-effect relationship of etomidate as measured by the BIS and should be acknowledged when interpreting our pharmacodynamic profile of etomidate in bled and unbled swine. No studies have investigated the dose response of isoflurane on the BIS in swine. However, the dose response of isoflurane on the BIS has been well established for humans (33) and has been used as a measure of isoflurane effect with variable success in goats (34) and horses (35). As noted previously, we performed a series of pilot studies in our prior work with propofol that demonstrated no significant effect from isoflurane on the BIS over the time course of the hemorrhage protocol used in this study.
The BIS has been established as a surrogate measure of etomidate’s hypnotic effect in humans (36) and was used in this study to detect etomidate’s effect in swine. A limitation of this approach is that the BIS has not been well established as a measure of cerebral activity in swine, and the scale (0–100) is difficult to interpret in this animal model. Despite these limitations, we did observe a significant change in the BIS over time with the administration of a brief etomidate infusion that was similar to that reported with etomidate administration to humans (36).
In summary, we evaluated the influence of moderate hemorrhage (30 mL/kg) on the pharmacokinetics and pharmacodynamics of etomidate. We found that hemorrhagic shock produced small changes in the pharmacokinetics and no changes in the pharmacodynamics of this sedative hypnotic. These results illustrate the potential advantages of using etomidate over other sedative hypnotics in settings of intravascular volume depletion.
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Acknowledgments |
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The authors are grateful for the etomidate assay work performed by Sang Park, PhD, at the Analytical Facility in the Department of Anesthesiology at the University of Washington.
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