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CARDIOVASCULAR ANESTHESIOLOGY

The Electrophysiological Effects of Racemic Ketamine and Etomidate in an In Vitro Model of "Border Zone" Between Normal and Ischemic/Reperfused Guinea Pig Myocardium

Jean-Luc Hanouz, MD, PhD^*, Yohann Repesse, BSc, Lan Zhu, MD, Sandrine Lemoine, BSc, René Rouet, PhD, Laurent Sallé, PhD, Benoît Plaud^*, and Jean-Louis Gérard, MD, PhD^*

From the *Department of Anesthesiology, CHU Caen, France; and Laboratory of Experimental Anesthesiology and Cellular Physiology, UPRES EA, CHU Caen, France.

Address correspondence and reprint requests to Jean-Luc Hanouz, Département d’Anesthésie réanimation, CHU de Caen, Ave. Côte de Nacre, 14033 Caen Cedex, France. Address e-mail to hanouz-jl{at}chu-caen.fr.

Abstract

BACKGROUND: Etomidate and ketamine are used during induction of anesthesia in high-risk patients. However, their effects on action potential (AP) variables and ischemia/reperfusion-induced arrhythmias and conduction blocks are unknown.

Methods: Guinea pig right ventricular muscle strips were mounted in a 5-mL double chamber bath with the strips separated into two zones by an impermeable latex membrane. One-half (normal zone) was exposed to normal perfusate while the other half (altered zone) was exposed to hypoxia, hyperkalemia, acidosis, and lack of glucose. AP variables were recorded continuously in the normal and altered zones. Spontaneous arrhythmias and conduction blocks were noted. Etomidate (10^–7, 10^–6, and 10^–5 M) and ketamine (10^–6, 10^–5, and 10^–4 M) were superfused into the bath throughout the experiment and the electrophysiologic effects compared with the control group.

RESULTS: We found that under control conditions, etomidate and ketamine did not modify resting membrane potential, maximal upstroke velocity, AP amplitude, or AP duration at 90% of repolarization (APD₉₀). Ketamine (10^–4 M), but not weaker concentrations and none of the concentration of etomidate, reversed the ischemia-induced shortening of APD₉₀ and APD dispersion. Etomidate and ketamine did not modify the occurrence of conduction block during simulated ischemia. In contrast, ketamine (25% at 10^–6 M, 13% at 10^–5 M, and 13% at 10^–4 M vs 90% in the control group, P < 0.05) but not etomidate (38% at 10^–7 M, 63% at 10^–6 M, and 63% at 10^–5 M vs 90% in the control group, NS) decreased the incidence of reperfusion-induced spontaneous arrhythmias.

CONCLUSIONS: In guinea pig myocardium, our data suggest that ketamine, in clinically relevant concentrations, decreases ischemia-induced AP shortening and spontaneous reperfusion-induced ventricular arrhythmias. Further study is required to precisely determine the effect of etomidate on reperfusion-induced arrhythmias.

Because their use is associated with few depressant hemodynamic effects, etomidate and ketamine are often used for induction of anesthesia in high-risk patients and in clinical situations associated with cardiovascular instability or hypovolemia.1,2 Such patients may be at high risk for perioperative myocardial ischemia and associated life-threatening ventricular dysrhythmias.3 Despite an extensive literature documenting the effects of IV anesthetics on myocardial contractility and the systemic vasculature, there is little known about the electrophysiological effects of ketamine and etomidate under normal and ischemic conditions. Furthermore, the effects of ketamine and etomidate on myocardial ischemia/reperfusion-induced arrhythmias is unknown. Consequently, we examined the electrophysiological effects of racemic ketamine and etomidate in an in vitro model of the "border zone" between normal and ischemic myocardium.

METHODS

Animal care conformed to the recommendations of the Helsinki Declaration. The study was in accordance with the official edict of the French Ministry of Agriculture and it was performed after receiving approval from the IRB for laboratory animal experimentation of our university.

Materials
Guinea pigs of either sex weighing 300 to 400 g were anesthetized with ether and their hearts quickly removed as previously described.4 A thin strip of myocardium was carefully dissected from the free wall of the right ventricle and pinned, endocardial surface upward, in a special perfusion chamber (5 mL). The perfusion chamber was bisected by a latex membrane that included a centrally located hole allowing the myocardial strip to be passed through and divided into two compartments called the "normal zone" (NZ) and the "altered zone" (AZ). The two compartments were independently insufflated with carbogen (95% O₂ to 5% CO₂), and perfused at 2 mL/min with Tyrode’s solution containing (mM): 135 Na⁺, 4 K⁺, 1.8 Ca²⁺, 1.8 H₂PO₄^–, 25 HCO^3–, 117.8 Cl^–, and 5.5 glucose. The pH of the Tyrode’s solution was 7.35 ± 0.05, and the temperature was maintained at 36.5°C by a water circulating thermostat-controlled bath (polystat 5HP; Bioblock, Illkirch, France). At the end of each experiment, isolation of the two compartments was confirmed by the injection of methylene blue dye into one compartment.

Data Acquisition and Analysis
Myocardial strips were stimulated at a frequency of 1 Hz using bipolar silicon-coated electrodes positioned in the NZ and in the AZ. Stimuli were rectangular pulses of 1 to 2 V 2 ms of duration, delivered by a programmable stimulator (model SMP 310, Biologic, Grenoble, France) that allowed stimulation of the electrode either in the NZ or in the AZ. During experiments, the NZ was stimulated and action potential (AP) was recorded in the both NZ and AZ. However, the AZ was stimulated to studied conduction blocks after 30 min of simulated ischemia. Preparations needing >5 V pulses to elicit an AP were discarded because there could have been a conduction block at the level of the latex separating membrane. During the protocol, stimulation was stopped whenever sustained spontaneous arrhythmias occurred. AP variables were recorded simultaneously in both the NZ and AZ using glass microelectrodes filled with KCl 3M (tip resistance, 10–30 M) and coupled to a silver-silver chloride microelectrode holder leading to a home-built, high-impedance capacitance neutralizing amplifier. A ball-shaped reference silver-silver chloride electrode was positioned in the superfusate of the compartments.

The following AP variables were automatically measured and stored by an automatic acquisition system and processing device (DATAPAC, Biologic, Grenoble, France): resting membrane potential (RMP), maximal upstroke velocity (V_max), AP amplitude (APA), and AP duration at 90% of full repolarization (APD₉₀).

During both simulated ischemia and reperfusion, conduction blocks and arrhythmias were recorded. Myocardial conduction blocks between the AZ and NZ were defined by the absence of AP detected in one zone after a stimulation applied in the other zone. Blocks were coded as present or absent. Spontaneous sustained arrhythmias (salvos >10 spontaneous AP) were recorded during ischemia and reperfusion periods and coded as present or absent. The ratio of APD₉₀ between the NZ and the AZ was calculated to evaluate ischemia-induced dispersion of APD₉₀ which reflects the dispersion of refractoriness periods.4 When stimulation of the microelectrode was lost, readjustment was attempted. Experiments were continued if the AP after needle readjustment did not vary by 10% from the previous AP.

Experimental Protocol
After a 2-h equilibration period simulated ischemia was induced for 30-min in the AZ by perfusion with a modified Tyrode’s solution while the NZ was maintained under control conditions. The modified Tyrode’s solution contained an elevated K⁺ concentration (from 4 to 12 mM), decreased HCO^3– concentration (from 25 to 9 mM) leading to a decrease in pH (from 7.35 ± 0.05 to 6.90 ± 0.05), decrease Po₂ due to insufflation with 95% N₂ to 5% CO_2, and no glucose. The combined hypoxia, hyperkalemia, acidosis, and lack of glucose reproduced, in vitro, the electrophysiological abnormalities induced in vivo by ischemia.5 At the end of the simulated ischemia, a 30-min reperfusion period was simulated by perfusion of the AZ with normal Tyrode’s solution that included 95% O₂ to 5% CO₂.

The preparations were randomly assigned to the seven following groups: control (n = 10), racemic ketamine 10^–6 M (n = 8), 10^–5 M (n = 8), 10^–4 M (n = 8), and etomidate 10^–7 M (n = 8), 10^–6 M (n = 8), 10^–5 M (n = 8). In the pharmacological groups, one concentration of ketamine and etomidate was superfused in both the NZ and AZ during the simulated ischemia and reperfusion periods. The data were recorded and stored by a student (ZL, RY, and LS) blinded to experimental groups. Ketamine and etomidate were dissolved daily in Tyrode’s solution (Sigma Aldrich, Cergy Pontoise, France). These concentrations were chosen because they encompass the free plasmatic concentrations of ketamine6 (3–30 µg/mL) and etomidate7 (300 ng/mL to 1 µg/mL) measured after induction of anesthesia in adult patients.

Statistical Analysis
Data are expressed as mean ± sd. AP variables at identical time points were compared among groups by an analysis of variance and if significantly different, a Student-Newman-Keuls post hoc test. Repeated-measures analysis of variance was used to test differences over time among groups for AP variables. ² and Fisher’s exact test were used for comparison of categorical data. The Bonferroni adjustment was used to adjust the P value required for statistical significance considering multiple comparisons. All P values were two-tailed, and a P < 0.05 was required to reject the null hypothesis.

RESULTS

Ischemia and Reperfusion Effects on AP Variables
In the NZ of the control group, AP variables recorded were unchanged during the 60 min of perfusion with normal Tyrode’s solution (Table 1). As reported in Table 2, in the AZ of the control group, 30 min simulated ischemia induced a significant membrane depolarization (RMP –38% ± 7% of baseline, P < 0.001), a decrease in V_max (–81% ± 12% of baseline, P < 0.001), a decrease in APA (–37% ± 13% of baseline, P < 0.001), and a shortening of APD₉₀ (–63% ± 10% of baseline, P < 0.001). The 30-min reperfusion period was associated with recovery of these AP variables to values similar to baseline.

Effects of Etomidate and Ketamine on AP Variables
There were no differences in baseline AP variables among the control, etomidate and ketamine groups (Table 1). In the NZ, etomidate 10^–7, 10^–6, and 10^–5 M and ketamine 10^–6, 10^–5, and 10^–4 M did not modify any of the AP variables (Table 1). Etomidate 10^–7, 10^–6, and 10^–5 M did not modify ischemia-induced changes in RMP, V_max, APA, and APD₉₀ (Table 2). Ketamine 10^–6, 10^–5, and 10^–4 M did not modify ischemia-induced changes in RMP, V_max, and APA (Table 2). Ketamine at 10^–4 M, but not 10^–6 and 10^–5 M, significantly decreased ischemia-induced shortening of APD₉₀ after 30 min (–38% ± 17% vs –63% ± 10% for the control group, P = 0.01). At the end of reperfusion (60 min recording), RMP, APA, V_max, and APD₉₀ in the AZ returned to baseline in all groups (Table 2). Ketamine 10^–4 M significantly decreased the ratio of APD₉₀ between the NZ and the AZ (Fig. 1).

View larger version (34K): [in this window] [in a new window]   Figure 1. Effects of etomidate and ketamine on the ratio of action potential duration at 90% of repolarization (APD90) between the normal zone (NZ) and the altered zone (AZ). Data are mean ± sd. *P < 0.05 vs control group.

Effects of Etomidate and Ketamine on Conduction Block
In the control group, 40% of the preparations exhibited conduction blocks between the NZ and AZ during the 30 min of simulated ischemia. As shown in Figure 2, the occurrence of conduction blocks during simulated ischemia was not modified by etomidate 10^–7, 10^–6, 10^–5 M, or ketamine 10^–6, 10^–5, and 10^–4 M.

View larger version (21K): [in this window] [in a new window]   Figure 2. Effects of etomidate and ketamine on the incidence of conduction blocks and spontaneous arrhythmias during the 30-min simulated ischemia and 30-min after reperfusion periods. Data are expressed as percentage of preparations with disturbances. The number at the top of each column indicates the ratio between number of preparations presenting the disturbance and the total number of preparations in each group. Comparisons were made between the control group and pharmacological groups.

Effects of Etomidate and Ketamine on the Occurrence of Spontaneous Arrhythmias During Simulated Ischemia and Reperfusion
As illustrated in Figure 2, during simulated ischemia the number of preparations exhibiting spontaneous repetitive responses was not modified by etomidate 10^–7, 10^–6, and 10^–5 M, or ketamine 10^–6, 10^–5, and 10^–4 M. During the reperfusion period, the occurrence of spontaneous repetitive responses was not significantly decreased by etomidate 10^–7, 10^–6, and 10^–5 M. In contrast, ketamine 10^–6, 10^–5, and 10^–4 M significantly decreased the occurrence of spontaneous repetitive responses (Fig. 2).

DISCUSSION

The results of this study were that 1) etomidate and ketamine in clinically relevant concentrations did not modify AP variables of isolated guinea pig myocardium under control conditions, 2) etomidate did not modify the ischemia-induced change in AP variables whereas ketamine at 10^–4 M, but not 10^–6 and 10^–5 M, attenuated ischemia-induced APD₉₀ shortening and dispersion of refractoriness periods, and 3) ketamine, but not etomidate, significantly decreased the incidence of spontaneous reperfusion-induced arrhythmias.

Despite their wide clinical use in patients at high risk for perioperative cardiac complications, there are little data examining the effects of etomidate and ketamine on myocardial AP variables. While, to our knowledge, the electrophysiological effects of etomidate have not been reported, ketamine 3 x 10^–4 M, was found to decrease RMP, V_max, APA, and to increase APD₉₀ in guinea pig myocardium.8 However, the decrease in AP variables reported did not exceed 10%. Other studies have reported no change in APD₉₀ in guinea pig hearts exposed to ketamine at clinically relevant concentrations.9 The free plasmatic concentrations of etomidate7 and ketamine6 measured in adult patients during anesthesia correspond to 10^–6 M and 10^–5 M, respectively. However, higher concentrations may result from accidental injection and pharmacokinetics changes related to aging, liver failure, and hypoalbuminemia.10

Myocardial AP reflects the sequential activation and inactivation of ion channels conducting depolarizing inward (Na⁺ and Ca²⁺), and repolarizing outward (K⁺) currents. Ketamine has been shown to elicit a tonic conduction block, but not a use-dependent block, of the inward Na⁺ and Ca²⁺ currents in guinea pig ventricular myocytes.11 Voltage clamp studies on isolated ventricular myocytes have shown that ketamine and etomidate, at clinically relevant concentrations, have no effect or a small effect on the L-type Ca²⁺ current (I_Ca,L).12,13 Etomidate 6 x 10^–5 M has been shown to induce a 20% and 10% decrease I_K1 and I_Kto, respectively.12 On the other hand, ketamine 10^–6 and 10^–5 M has been shown to have no effect on I_K1 but to decrease it at higher concentrations.13–15 Taken together, these data indicate that etomidate and ketamine, at clinically relevant concentrations, have a small to no effect on the inward and outward currents responsible for the myocardial AP variables under non-ischemic conditions.

Our results confirm that ischemia induces a decrease in RMP and AP as previously reported.4,16 Additionally, etomidate did not modify the ischemia-induced decrease in AP variables whereas ketamine at 10^–4 M significantly reduced the APD₉₀ shortening after 30 min of simulated ischemia (Table 2). Because the ischemia-induced shortening of APD has been related to the activation of an ATP-sensitive potassium (K_ATP) conductance,17 our results suggest that ketamine could inhibit K_ATP conductance. This is in accordance with previous results showing that ketamine inhibited, in a concentration-dependent manner, pinacidil-induced AP shortening and sarcolemmal K_ATP channels in ventricular myocytes.18,19

Ischemia dramatically shortens the repolarization phase, but also induces heterogeneity of the repolarization in the border zone between ischemic and nonischemic myocardium. Ketamine at 10^–4 M decreased the ratio of APD₉₀ between the NZ and the AZ (Fig. 1). This ratio may be used as an index of APD₉₀ dispersion between the NZ and ischemic zone.4,20 The APD dispersion reflects regional differences in repolarization which are associated with a greater susceptibility to re-entry and thus to cardiac arrhythmias. Consequently, the decrease in APD₉₀ dispersion induced by ketamine at 10^–4 M should result in an antiarrhythmic effect. However, further studies are required to precisely determine the concentration response relation of etomidate and ketamine on APD dispersion.

Slowing of conduction velocity, occurrence of conduction blocks, and dispersion of refractoriness period between an ischemic zone and a non-ischemic zone (border zone) favor the emergence of re-entry arrhythmias.5,20 The present results show that the occurrence of conduction blocks in the border zone during simulated myocardial ischemia was not modified by ketamine and etomidate. In contrast, ketamine has been shown to slow conduction velocity and atrioventricular nodal conduction in left atrial tissue,21 and papillary muscles8 obtained from guinea pig heart. However, ketamine was the less potent negative dromotropic drug, and there are important electrophysiological differences between nodal conduction and ventricular tissue. Finally, these studies did not assess conduction blocks related to ischemia.

Importantly, our results show that ketamine significantly decreased the incidence of reperfusion-induced repetitive responses around the border zone (Fig. 1). This should be interpreted in the context of a report of ketamine-induced preconditioning showing that ketamine enhanced the recovery of isometric force developed by isolated human myocardium after hypoxia reoxygenation.22 However, in the present study ketamine was administered throughout the duration of ischemia and reperfusion and not only before the ischemic period. Consequently, we could not exclude that ketamine may have exerted a protective effect during simulated ischemia or reperfusion periods. Our study did not determine the mechanisms involved in the antiarrhythmic effect of ketamine observed on reperfusion-induced arrhythmias in our experimental model. However, the attenuation of ischemia-induced APD₉₀ shortening and the decrease in APD dispersion in the border zone should decrease re-entry and thus arrhythmias. Finally, further studies are needed to understand the precise mechanism involved in the antiarrhythmic effect of ketamine in ischemic-reperfused myocardium and to precisely determine the magnitude of etomidate’s effect.

Several limitations to this study need to be acknowledged. First, in the present study, etomidate tended towards, but did not significantly decrease, the incidence of reperfusion-induced repetitive response. This may have resulted from a type II error due to the small number of experiments according to the moderate difference observed. Thus, the present study did not have the power to exclude the possibility that etomidate may also decrease the incidence of reperfusion-induced arrhythmias. Second, we simulated ischemia using a modified Tyrode’s solution mimicking ischemic conditions. As previously described,5,16 these conditions accurately reproduced the electrical alterations of cardiac APs observed in vivo during experimental myocardial ischemia.23 Additionally, the reliability of the double-bath technique is demonstrated by the constancy of the AP variables in the NZ, despite the adjacent AZ. The present border zone model reproduces arrhythmias similar to those observed, in vivo, during experimental transient coronary artery occlusion,5,23 or in humans during coronary transluminal angioplasty and after thrombolytic therapy.24 Third, the study was performed on guinea pig myocardium, which differs from human myocardium, although the main ionic currents involved in the studied phenomenas are qualitatively similar between species. Finally, an in vitro model, no matter how complex, cannot reproduce exactly in vivo situations but may provide important information for clinicians.25

In conclusion, our study using guinea pig ventricular myocardium suggests that clinically relevant concentrations of ketamine decrease the incidence of spontaneous reperfusion-induced arrhythmias at least in part through attenuation of ischemia-induced APD₉₀ shortening and dispersion of refractoriness periods.

Footnotes

Accepted for publication October 3, 2007.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hanouz, J.-L. Articles by Gérard, J.-L. Search for Related Content PubMed PubMed Citation Articles by Hanouz, J.-L. Articles by Gérard, J.-L. Related Collections Cardiovascular Mechanisms Preclinical Pharmacology Pharmacology