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 PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shnayderman, D. Articles by Raines, D. E. Search for Related Content PubMed PubMed Citation Articles by Shnayderman, D. Articles by Raines, D. E. Related Collections Mechanisms Preclinical Pharmacology Pharmacology

---

ANESTHETIC PHARMACOLOGY

Increases in Spinal Cerebrospinal Fluid Potassium Concentration Do Not Increase Isoflurane Minimum Alveolar Concentration in Rats

Dimitry Shnayderman, BS^*, Michael J. Laster, DVM^*, Edmond I. Eger, II, MD^*, Irene Oh, BS^*, Yi Zhang, MD^*, Steven L. Jinks, PhD, Joseph F. Antognini, MD, and Douglas E. Raines, MD

From the *Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; Department of Anesthesiology and Pain Medicine, University of California, Davis, California; and Department of Anesthesia and Critical Care, The Massachusetts General Hospital, Boston, Massachusetts.

Address correspondence and reprint requests to Dr. Eger, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu.

	Abstract

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
BACKGROUND: Previous studies demonstrated that MAC for isoflurane directly correlates with the concentration of Na⁺ in cerebrospinal fluid surrounding the spinal cord, the primary site for mediation of the immobility produced by inhaled anesthetics. If this correlation resulted from increased irritability of the cord, then infusion of increased concentrations of potassium (K⁺) might be predicted to act similarly. However, an absence of effect of K⁺ might be interpreted to indicate that K⁺ channels do not mediate the immobility produced by inhaled anesthetics whereas Na⁺ channels remain as potential mediators. Accordingly, in the present study, we examined the effect of altering intrathecal concentrations of K⁺ on MAC.

METHODS: In rats prepared with chronic indwelling intrathecal catheters, we infused solutions deficient in K⁺ and with an excess of K⁺ into the lumbar space and measured MAC for isoflurane 24 h before, during, and 24 h after infusion. Rats similarly prepared were tested for the effect of altered osmolarity on MAC (accomplished by infusion of mannitol) and for the penetration of Na⁺ into the cord.

RESULTS: MAC of isoflurane never significantly increased with increasing concentrations of K⁺ infused intrathecally. At infused concentrations exceeding 12 times the normal concentration of KCl, i.e., 29 mEq/L, rats moved spontaneously at isoflurane concentrations just below, and sometimes at MAC, but the average MAC in these rats did not exceed their control MAC. At the largest infused concentration (58.1 mEq/L), MAC significantly decreased and did not subsequently return to normal (i.e., such large concentrations produced injury). Infusions of lower concentrations of K⁺ had no effect on MAC. Infusion of osmotically equivalent solutions of mannitol did not affect MAC. Na⁺ infused intrathecally measurably penetrated the spinal cord.

CONCLUSIONS: The results do not support a mediation or modulation of MAC by K⁺ channels.

	Introduction

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
Potassium (K⁺) channels may be important direct or indirect mediators of the capacity of inhaled anesthetics to produce immobility.1 Several studies find that anesthetics enhance K⁺ channel conductance, thereby increasing K⁺ efflux from neuronal cells and causing hyperpolarization.2–4 Such an action provides a plausible explanation for anesthesia. In one study,5 changes in cerebrospinal fluid K⁺ concentrations in dogs did not cause changes in MAC (the minimum alveolar concentration of inhaled anesthetic required to prevent movement in response to a noxious stimulus in 50% of subjects). However, the change in central nervous system K⁺ concentration was not limited to the spinal cord but also affected the brain, which limits the implication of the finding. This is relevant because of the importance of the cord as the primary mediator of the immobility produced by inhaled anesthetics.6 More importantly, the change in cerebrospinal fluid K⁺ was 0.2 mEq/L, only 5% of the normal extracellular K⁺ concentration.

The present study tested the effect of intrathecally infused K⁺ at various concentrations on isoflurane MAC in rats. We reasoned that if isoflurane acted by enhancing K⁺ channel conductance, then increasing extracellular K⁺ concentrations (to reduce the magnitudes of the resulting increase in K⁺ efflux and hyperpolarization) would increase MAC. Similarly, we predicted that reducing extracellular K⁺ concentrations would decrease MAC. As controls, we also tested whether changes in intrathecal osmolarity would affect MAC, and whether Na⁺ infused intrathecally would penetrate the spinal cord. We chose to study Na⁺ penetration because we had no capacity to measure K⁺ increases accurately. Although we might produce substantial changes in extracellular K⁺, these would represent only a small fraction of the total (primarily intracellular) K⁺, and thus would not accurately describe the actual changes in extracellular K⁺. We investigated the possibility of using the stable isotope ⁴¹K⁺, but we found it difficult to analyze by mass spectrometry because of an overlapping peak. Cowards that we are, we were not interested in working with the radioisotope of K⁺.

	METHODS

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
Materials
Isoflurane was donated by Baxter Healthcare Corp. (New Providence, NJ).

Studies of MAC in Rats
With approval of the Committee on Animal Research of the University of California, Davis (studies of intrathecal potassium and of altered intrathecal osmolarity), and the Committee on Animal Research of the University of California, San Francisco (studies of diffusion of Na⁺ into the spinal cord), we studied 98 male, 12-15 wk-old, Long-Evans rats weighing 300-450 g obtained from Charles River Laboratories (Hollister, CA). Six rats died during study and two were discarded for logistical reasons, leaving 90 rats for which results are presented. Each animal was caged with up to as many as two additional rats before insertion of catheters, and was housed singly thereafter. All had continuous access to standard rat chow and tap water before study.

Effect of Lumbar Intrathecal Infusions of Solutions Containing Lower and Higher Concentrations of K⁺ (49 Rats)
Figure 1 summarizes the experimental design. On day 1, rats were anesthetized with isoflurane, and a 32-gauge polyurethane catheter (Micor Inc., Allison Park, PA) was placed through the atlanto-occipital membrane using the method described by Yaksh and Rudy.7 The catheter was threaded caudally 6-8 cm towards the lumbar sac, the length depending on the size of the rat. The proximal end of the catheter was drawn through the external auditory meatus and sutured in place, and the wound was infiltrated with 0.25% bupivacaine. Rats recovered from anesthesia and surgery for 24 h before study.

View larger version (20K): [in this window] [in a new window]   Figure 1. A schematic of the Methods used in the present study.

Rats were studied in groups of up to eight placed in individual clear plastic cylinders. Each cylinder received approximately 1 L/min oxygen containing approximately 2% isoflurane. An infusion of artificial cerebrospinal fluid (aCSF) was begun immediately after induction of anesthesia at 4 µL/min via the previously placed intrathecal catheter. The aCSF contained: NaCl 126.6 mM; NaHCO₃ 27.4 mM; KCl 2.4 mM; KH₂PO₄ 0.50 mM; NaSO₄ 0.49 mM; CaCl₂ 1.10 mM; MgCl₂ 0.83 mM; and glucose 5.49 mM. The pH was adjusted to 7.3 by addition of a small amount of NaOH. Total osmolarity was approximately 330 mOsm. A rectal temperature probe was inserted. The isoflurane concentration was decreased to 1.0%-1.2% and sustained at this concentration for 50 min, after which the tail was clamped and moved by rolling the clamp at 1-2 Hz for up to 1 min (less if the rat moved). After certifying that movement had occurred, the isoflurane concentration was increased by approximately 0.15%-0.2% and, after a 30-min period of equilibration, the tail clamp was again applied and movement or lack of movement determined. Isoflurane partial pressures were monitored using an infrared analyzer (Datascope, Helsinki, Finland). Immediately after determination of the response to tail clamp, a sample of gas was obtained from one of the chambers and analyzed for isoflurane by gas chromatography. This process continued until all rats failed to move in response to application of the tail clamp. MAC was calculated as the average of the largest concentration that permitted movement and the smallest concentration that suppressed movement. This value was designated MAC0. Anesthetic administration was then discontinued, and the rats recovered.

The next day, the rats again were anesthetized with isoflurane and MAC redetermined (MAC1). However, on this day, one or two of the rats received an infusion of aCSF (the control group). The other six or seven rats received an infusion of a solution containing a decreased or an increased concentration of KCl (the experimental group). A decreased concentration was produced by removing the 2.4 mM of KCl. An increased concentration was produced by adding 4, 8, 12, 16, and 24 times the normal KCl (the largest K⁺ concentration was 58.1 mEq/L as opposed to the normal of 2.9 mEq/L). When the concentration of K⁺ was increased by eight-fold or more, the aCSF given the control group was altered by addition of sufficient mannitol to produce an osmolarity equal to that produced by the addition of KCl in the experimental group. Anesthetic administration was then discontinued and the rats recovered. The investigator making the determination of MAC was blinded to the contents of the infusions.

On the third day, the rats again were anesthetized with isoflurane and the process of MAC determination repeated (MAC2). On this day, all rats received only an infusion of aCSF. The rats again were allowed to recover and were examined for gross abnormalities in hindlimb function.

Thus, these measurements supplied two control assessments. The change in MAC with treatment could be compared with the MAC in the same rat when given aCSF, and the change in MAC with treatment could be compared with the MAC in a comparable group of rats given aCSF. Injury from treatment could be assessed by noting whether a gross abnormality in motor function, particularly of the hindlimbs, was evident after the third anesthetic, and whether MAC2 differed from MAC0 in the experimental group more than in the control group.

Effect of Lumbar Intrathecal Infusions of Hyperosmotic Solutions (23 Rats)
We further studied the issue of the effect of osmolarity on isoflurane MAC by additional studies of rats allocated to receive intrathecal infusions of osmolarity increased by the addition of mannitol (K⁺ normal). These were done to certify that any changes in MAC were not caused by changes in osmolarity rather than changes in K⁺. These added numbers to the rats for whom such studies had already been done as described earlier. Blinding was maintained by studying rats receiving various osmolar concentrations in the same group (i.e., again the person determining MAC1 did not know the contents of the infusate).

Determination of Movement of Sodium into the Spinal Cord (18 Rats)
The preceding studies assume that at least some fraction of K⁺ penetrates the spinal cord. An absence of penetration would explain an absence of an effect of infusion of larger K⁺ concentrations. However, measurement and interpretation of changes in cord K⁺ consequent to infusion of increased K⁺ may be confounded by the fact that most K⁺ is intracellular and the concentration we seek to measure is extracellular. In addition, we might significantly increase extracellular K⁺ but that would represent only a small fraction of the total K⁺, and the difference would be difficult to measure accurately (the difference of two large numbers).

Accordingly, we measured the change in cord Na⁺ (Na⁺ as a surrogate for K⁺). This allowed a more sensitive measure of extracellular penetration, since most Na⁺ is extracellular. Groups of six rats prepared as above with intrathecal catheters received infusions of a low concentration of Na⁺ (28.5 mEq/L), normal aCSF, or a high concentration of Na⁺ (192.5 mEq/L), concentrations used in our previous study of the determination of Na⁺ infusion on isoflurane MAC.8 After 2 h of infusion at 4 µL/min, the lower cord and the brain were removed, briefly dipped in distilled water, blotted, weighed, homogenized in a determined volume of distilled water, and the concentration of Na⁺ measured with a Na⁺-sensitive electrode. The Na⁺ concentration in the cord and brain were calculated, considering the weights and known dilutions.

Gas Chromatographic Analysis
We used a Gow-Mac 580 flame ionization detector gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ) to analyze isoflurane concentrations. The 4.6-m-long, 0.22-cm (ID) column was packed with SF-96. The column temperature was 107°C with the detector maintained at a temperature approximately 50°C higher. The carrier gas flow was nitrogen at a flow of 16 mL/min. The detector received 35 mL/min hydrogen and 250 mL/min air. Primary standards were prepared for isoflurane and the linearity of the response of the chromatograph determined. We commonly used secondary (cylinder) isoflurane standards referenced to the primary standards.

Statistical Analyses
Mean values and standard deviations were determined for the MAC determinations. A one-way analysis of variance with Fisher’s protected least significant difference was done to determine whether infusion of altered K⁺ concentrations significantly affected MAC and whether one or more groups differed significantly. We accepted a value of P < 0.05 as significant.

	RESULTS

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
No group of rats demonstrated a significantly increased MAC associated with an alteration in infused K⁺ (Table 1, Fig. 2; P < 0.0004). MAC1/MAC0 did not correlate with the concentration of K⁺ in the intrathecal infusate (Table 1, Fig. 2), except that the results for the infusion of the highest concentration (24 times control KCl, or 58.1 mEq/L) showed a significant decrease in MAC (P < 0.005 for all comparisons), and rats given 16 times the control KCl had MAC decreases that significantly exceeded those for rats given aCSF (P < 0.02) and 8 times control KCl (P < 0.01). The results for MAC2/MAC0 also differed significantly among groups (P < 0.005). Most of the significance resulted from the groups given 24 times control [significantly different (P < 0.05) from rats given 0, aCSF, 8, and 16 times control KCl], a finding indicative of residual injury at the largest infused concentration. We also found that intrathecal infusion of hyperosmotic solutions did not change MAC1/MAC0 (P = 0.46) or MAC2/MAC0 (P = 0.53), suggesting that the changes seen at the largest concentrations of infused KCl were not due to an increase in osmolarity (Fig. 3).

View larger version (18K): [in this window] [in a new window]   Figure 2. Intrathecal infusion of K+ did not increase isoflurane MAC. MAC0 is the control MAC obtained during intrathecal infusion of normal artificial cerebrospinal fluid (aCSF). MAC1 is the MAC obtained during intrathecal infusion of aCSF containing the indicated concentrations of K+. Thus, MAC1/MAC0 indicates the fractional change in MAC produced by the altered K+ concentration. The largest concentration infused (58.1 mEq/L) significantly (P < 0.001) decreased MAC, but this decrease also was associated with injury to the cord as reflected in the failure of a subsequently determined MAC (MAC2) to return to normal.

View larger version (15K): [in this window] [in a new window]   Figure 3. Separate control groups of rats received artificial cerebrospinal fluid (aCSF) containing a normal concentration of K+, but various concentrations of mannitol, concentrations that changed osmolarity as much as the studies in which K+ had been altered. No significant changes in MAC were associated with changes in osmolarity.

Intrathecal 2-h infusions of solutions with a decreased Na⁺ concentration decreased Na⁺ concentrations in the spinal cord and infusions of increased concentrations increased cord concentrations (Fig. 4). Such intrathecal infusions had no effect on brain concentrations.

View larger version (20K): [in this window] [in a new window]   Figure 4. Intrathecal infusion of artificial cerebrospinal fluid (aCSF) containing decreased and increased concentrations of Na+, respectively, decreased and increased cord concentrations of Na+ (P < 0.002 for the difference in cord concentrations for the infusion of increased versus decreased Na+ concentrations) without altering cerebral Na+ concentrations (difference not significant. Values are given as the fraction of the average value during infusion of normal aCSF. N = 6 for all groups.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
The data pictured in Figures 2 and 3 confirm previous observations8 that repeated measurements of MAC over days do not affect MAC. More importantly, the results do not support our hypothesis that intrathecal infusion of increased concentrations of K⁺ would increase MAC. Instead, we found no change in MAC at any infused concentration of K⁺ except that the largest infused concentration produced a significant decrease and injury to the cord as reflected in the failure of MAC to return to control values.

Why did no increase in MAC occur? Perhaps K⁺ failed to penetrate the cord. Several observations suggest that this was not the case. First, we observed that rats receiving infusions of largest concentrations of K⁺ displayed evidence of stimulation (e.g., spontaneous movement at concentrations less than MAC and pain if awakened soon after cessation of the infusion). Perhaps this reflected stimulation of nerve roots, rather than penetration of the cord, but similar observations were not made during our previous study of infusion of high and low concentrations of Na⁺8 which also might have affected such nerves.

Second, intrathecal infusions of decreased and increased concentrations of Na⁺ produced parallel shifts in cord concentrations of Na⁺ (Fig. 4). If K⁺ and Na⁺ have similar capacities to diffuse into the cord, these findings for Na⁺ suggest that K⁺ also penetrated the cord. The counterargument might be that Na⁺ primarily resides in the extracellular space, a smaller (and thus more readily filled) space than the intracellular space occupied by K⁺. That is, the intracellular space in glia and neurons provides a buffer to the infused K⁺. However, the amount of neural tissue is smaller than the volume infused. The average weight of 11 spinal cords (total cord) equaled 0.233 ± 0.085 g and the lumbar portion of the cord would be still less. In 2 h of intrathecal infusion at 4 µL/min, we supplied 0.480 mL. Thus, it would appear likely that what we infused might overwhelm any buffering by neurons and glia, particularly at higher K⁺ concentrations.

Third, intrathecal, but not intraventricular, infusion of Na⁺ produces a concentration-dependent increase in MAC.8 Increases in central nervous system Na⁺ produced by systemic alterations in Na⁺ (where the changes in Na⁺ must occur throughout the central nervous system) produce similar changes in MAC.5

Fourth, we have demonstrated that some anesthetic drugs [e.g., etomidate]9 penetrate the brain in the time frame of the present experiment. A report on intrathecal Mg⁺⁺ injections suggests that, in rabbits, injected Mg⁺⁺ acts on ventral horn neurons in less than an hour.10 The larger cord of the rabbit makes the diffusion distances greater than in our experimental animal, the rat.

Could the negative results be the product of a K⁺-induced increase in MAC counteracted by another effect of increased extracellular K⁺, such as reduction of action potential amplitude due to a larger proportion of Na⁺ channels being in the inactivated state? This hypothesis suggests a fortuitously exact counterbalancing between excitation and depression, an unlikely result, especially over a wide range of K⁺ concentrations. That is, the increase in excitation at every point would have to be matched by an exactly equal decrease at every K⁺ concentration: The curves for excitation and depression would have to be quantitative mirror images of each other. Qualitative mirror images would be insufficient to explain the results. Furthermore, K⁺ changes must be greater at the surface of the cord as opposed to deeper within the cord. Thus, if increasing K⁺ concentrations acted on two sites (one inhibitory and one excitatory), the more superficial site would be acted on at lower infused concentrations than the deeper one. With increasing concentrations, the more superficial site might approach a maximum response at a lower concentration than the deeper site. This, too, would make unlikely a precise counterbalancing of effects at all infused concentrations of K⁺. Thus, this possible explanation seems unlikely to provide a significant criticism.

The argument of counterbalancing effects also could be leveled at the effects of inhaled anesthetics on K⁺ channels. If compensation occurs with K⁺ infusion, why can it not occur in response to the increased K⁺ conductance produced by inhaled anesthetics? Obviously, such a criticism might lead to the absurd conclusion that nothing inhaled anesthetics do can explain anesthesia.

Perhaps the failure of increasing K⁺ to alter MAC in the absence of injury to the cord indicates that K⁺ channels do not mediate the immobility produced by inhaled anesthetics. Despite the plausibility of the argument for K⁺ channels playing some role, the evidence against such a role is considerable. For example, although knockout of the TREK1 potassium channel increases the MAC of chloroform, desflurane, halothane, and sevoflurane,11 the increase is usually small and, more importantly, it is inconsistent, varying from 7% (desflurane) to 48% (halothane), and these changes do not correlate with the in vitro effects of these anesthetics on the TREK1 potassium channel.4 Mice lacking KNCK5 or Kir3.2 potassium channels do not have an increased MAC.12 Administration of the K⁺ channel blocker 4-aminopyridine does not decrease halothane MAC in rats.13 Administration of the TASK-1 or TASK-3 potassium channel blocker doxapram to mice does not increase MAC.14 An increase in body temperature activates (opens) some potassium channels15 and thus should decrease MAC, but an increase in body temperature increases MAC in diverse mammals.16–19 Increases in pH can increase the opening of some potassium channels,20 but decreases in Paco₂, and thus increases in pH, do not decrease MAC.21 Increasing Paco₂ decreases MAC rectilinearly.22 Perhaps K⁺ channels are not relevant to MAC.

	Footnotes

 
Accepted for publication May 19, 2008.

Supported by NIH grant 1P01GM47818 and RO1 grant (GM 078167 to S.L.J.).

Dr. Eger is a paid consultant to Baxter Healthcare Corp, who donated the isoflurane used in these studies.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

1. Yost CS. Tandem pore domain K channels: an important site of volatile anesthetic action? Curr Drug Targets 2000;1:207–17[Medline]
2. Franks NP, Lieb WR. Volatile general anaesthetics activate a novel neuronal K⁺ current. Nature 1988;333:662–4[Web of Science][Medline]
3. Franks NP, Lieb WR. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science 1991;254:427–30[Abstract/Free Full Text]
4. Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K⁺ channels. Nat Neurosci 1999;2:422–6[Web of Science][Medline]
5. Tanifuji Y, Eger EI II. Brain sodium, potassium, and osmolality: Effects on anesthetic requirement. Anesth Analg 1978;57:404–10[Abstract/Free Full Text]
6. Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993;79:1244–9[Web of Science][Medline]
7. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031–6[Medline]
8. Laster MJ, Zhang Y, Eger EI II, Shnayderman D, Sonner JM. Alterations in spinal, but not cerebral, cerebrospinal fluid Na⁺ concentrations affect the isoflurane minimum alveolar concentration in rats. Anesth Analg 2007;105:661–5[Abstract/Free Full Text]
9. Benkwitz C, Liao M, Laster MJ, Sonner JM, Eger EI II, Pearce RA. Determination of the EC50 amnesic concentration of etomidate and its diffusion profile in brain tissue: implications for in vitro studies. Anesthesiology 2007;106:114–23[Web of Science][Medline]
10. Jellish WS, Zhang X, Langen KE, Spector MS, Scalfani MT, White FA. Intrathecal magnesium sulfate administration at the time of experimental ischemia improves neurological functioning by reducing acute and delayed loss of motor neurons in the spinal cord. Anesthesiology 2008;108:78–86[Web of Science][Medline]
11. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G, Lazdunski M. TREK-1, a K(+) channel involved in neuroprotection and general anesthesia. EMBO J 2004;23:2684–95[Web of Science][Medline]
12. Gerstin KM, Gong DH, Abdallah M, Winegar BD, Eger EI II, Gray AT. Mutation of KCNK5 or Kir3.2 potassium channels in mice does not change MAC. Anesth Analg 2003;96:1345–9[Abstract/Free Full Text]
13. Ma HC, Wang YF, Feng CS, Zhao H, Dohi S. Effects of adenosine agonist R-phenylisopropyl-adenosine on halothane anesthesia and antinociception in rats. Acta Pharmacol Sin 2005;26:181–5[Web of Science][Medline]
14. Cotten JF, Keshavaprasad B, Laster MJ, Eger EI II, Yost CS. The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration. Anesth Analg 2006;102:779–85[Abstract/Free Full Text]
15. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honore E. TREK-1 is a heat-activated background K(+) channel. EMBO J 2000;19:2483–91[Web of Science][Medline]
16. Eger EI II, Saidman LJ, Brandstater B. Temperature dependence of halothane and cyclopropane anesthesia in dogs: Correlation with some theories of anesthetic action. Anesthesiology 1965;26:764–70[Web of Science][Medline]
17. Eger EI II, Johnson BH. MAC of I-653 in rats, including a test of the effect of body temperature and anesthetic duration. Anesth Analg 1987;66:974–6[Abstract/Free Full Text]
18. Antognini JG. Hypothermia eliminates isoflurane requirements at 20 degrees C. Anesthesiology 1993;78:1152–6[Web of Science][Medline]
19. Liu M, Hu X, Liu J. The effect of hypothermia on isoflurane MAC in children. Anesthesiology 2001;94:429–32[Web of Science][Medline]
20. Leonoudakis D, Gray AT, Winegar BD, Kindler CH, Harada M, Taylor DM, Chavez RA, Forsayeth JR, Yost CS. An open rectifier potassium channel with two pore domains in tandem cloned from rat cerebellum. J Neurosci 1998;18:868–77[Abstract/Free Full Text]
21. Eisele JH, Eger EI II, Muallem M. Narcotic properties of carbon dioxide in the dog. Anesthesiology 1967;28:856–65[Web of Science][Medline]
22. Brosnan RJ, Eger EI II, Laster MJ, Sonner JM. Anesthetic properties of carbon dioxide in the rat. Anesth Analg 2007;105:103–6[Abstract/Free Full Text]

This article has been cited by other articles:

				E. I. Eger II, D. E. Raines, S. L. Shafer, H. C. Hemmings Jr, and J. M. Sonner Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility? Anesth. Analg., September 1, 2008; 107(3): 832 - 848. [Abstract] [Full Text] [PDF]

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 PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shnayderman, D. Articles by Raines, D. E. Search for Related Content PubMed PubMed Citation Articles by Shnayderman, D. Articles by Raines, D. E. Related Collections Mechanisms Preclinical Pharmacology Pharmacology