Epinephrine

Background: The efficacy of vasopressor therapy during closed-chest resuscitation is limited and decreases over lime. We previously reported that sodium-hydrogen exchanger isoform-1 inhibition during ventricular fibrillation (VF) using cariporide ameliorates ischemic contracture and enhances the efficacy of chest compression. We currently investigated whether cariporide could potentiate pressor responses to epinephrine and vasopressin.

Methods: VF was induced and left untreated for 12 min in two series of 16 rats each. Chest compression was then started and the depth adjusted within the initial 2 min to attain an aortic diastolic pressure between 26 and 28 mm Hg. In one series, rats received boluses of epinephrine (150 [micro]g/kg); in the other series, rats received boluses of vasopressin (0.8 U/kg) to maintain the aortic diastolic pressure > 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide or 0.9% NaCl immediately before starting chest compression. Defibrillation was attempted at 20 min of VF (8 min of chest compression).

Results: Cariporide prompted higher and more sustained coronary perfusion pressures in both the epinephrine group (37 [+ or -] 5 mm Hg vs 29 [+ or -] 7 mm Hg, p < 0.05) and the vasopressin group (36 [+ or -] 5 mm Hg vs 28 [+ or -] 6 mm Hg [+ or -] SD, p < 0.02) even though fewer additional vasopressor doses were required. After resuscitation, cariporide-treated rats had less ventricular ectopic activity, better hemodynamic function, and improved survival scores. In separate experiments, in situ perfusion of the aorta excluded a vascular-mediated effect of cariporide.

Conclusion: Cariporide enhanced the hemodynamic efficacy of vasopressor agents and improved resuscitation outcomes probably as a result of enhanced forward blood flow without effect on the peripheral vasculature.

Key words: cardiopulmonary resuscitation; defibrillation; epinephrine; ischemia; sodium-hydrogen antiporter; vasopressin; ventricular fibrillation

Abbreviations: ANOVA = analysis of variance; NHE-1 = sodium-hydrogen exchanger isoform-1; VF = ventricatlar fibrillation

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Restoration of cardiac activity after prolonged intervals of untreated cardiac arrest is contingent on capability for generating, by external means, coronary blood flows above critical threshold levels. (1) When closed-chest resuscitation is used, coronary blood flow becomes directly proportional to the pressure difference established between the aorta and the right atrium during the so-called compression "diastole" (it, relaxation phase of chest compression). (2,3) This pressure gradient is referred to as the coronary perfusion pressure and is primarily driven by the aortic "diastolic" pressure. The right atrial diastolic pressure varies little and--under most circumstances--has minimal influence. Thus, efforts to increase the coronary perfusion pressure must target determinants of the aortic diastolic pressure; namely, the forward blood flow generated and its downstream vascular resistance.

Because chest compression generates forward blood flows that rarely exceed 20% of normal (4) and typically deteriorate over time, (5) increases in systemic vascular resistance are essential for securing viable coronary perfusion pressures. Although a prominent neuroendocrine vasoconstrictive response to cardiac arrest decreases distal aortic runoff, the magnitude of this response is limited and exogenous vasoconstrictive agents are usually required. The American Heart Association recognizes epinephrine and vasopressin as vasopressor agents with comparable efficacy for the purpose of cardiac resuscitation. (6) However, even exogenous vasopressor agents have limited efficacy. In the case of epinephrine, its pressor effects are transient and of lesser magnitude after subsequent doses. (7) The response to vasopressin tend to be more sustained (8); however, it is not clear that one agent is superior than the other for the purpose of clinical resuscitation, (9) with the possible exception of cardiac arrest caused by asystole. (10) Accordingly, strategies that could enhance the hemodynamic interaction between closed-chest resuscitation and vasopressor agents are warranted.

Previous investigators have suspected that vascular responsiveness to vasopressor agents diminishes during cardiac resuscitation as a result of receptor desensitization (11) and/or down-regulation. (12) However, poor response may also reflect deterioration of forward blood flow. Observations in animal models (13) and in human victims of cardiac arrest (14) suggest that development of ischemic contracture may be a limiting factor for hemodynamically effective closed-chest resuscitation. Ischemic contracture develops as a result of severe myocardial ischemia and causes progressive ventricular wall thickening with reductions in cavity size, limiting the preload required for chest compression to generate forward blood flow. We have recently demonstrated using rat (15) and pig (16) models of ventricular fibrillation (VF) and closed-chest resuscitation that ischemic contracture can be ameliorated by inhibition of the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1) using cariporide, in turn, enabling hemodynamically more effective chest compression.

These observations prompted us to hypothesize that NHE-1 inhibition could favorably interact with vasopressor agents and enhance the hemodynamic efficacy of closed-chest resuscitation, resulting in higher coronary perfusion pressures, resuscitability, and survival. This hypothesis was investigated in a rat model of prolonged untreated VF and conventional closed-chest resuscitation using epinephrine and vasopressin as vasopressor agents in the presence and absence of the selective NHE-1 inhibitor cariporide. We chose a 12-rain interval of untreated VF to simulate severe arrest conditions under which vasopressor agents are typically required during chest compression to meet the hemodynamic goals for successful resuscitation. (3,7,8) Moreover, the myocardial benefits of cariporide become more evident under conditions of prolonged ischemia when greater myocardial dysfunction is expected. (15) Separate studies were also conducted using an in situ aortic perfusion model to assess whether cariporide could mediate the vascular effect of the vasopressor agents used in the intact model.

MATERIALS AND METHODS

The studies were approved by our Research and Development Committee and were conducted in accordance with institutional guidelines.

Intact Rat Model

Animal Preparation: Thirty-two adult male Sprague-Dawley rats (450 to 565 g) were anesthetized using intraperitoneal injection of sodium pentobarbital (loading dose, 45 mg/kg; maintenance dose, 10 mg/kg every 30 min). Core temperature was maintained between 36.5[degrees]C and 37.5[degrees]C using an infrared heating lamp. A 5F cannula was orally advanced into the trachea and used for positive pressure ventilation during cardiac resuscitation and the postresuscitation interval. Proper placement was verified using an infrared C[O.sub.2] analyzer (C[O.sub.2]SMO model 7100; Novametrix Medical Systems; Wallingford, CT). P[E.sub.50] catheters were advanced into the left ventricle, abdominal aorta, and the right atrium for pressure measurements. A lead II ECG was recorded using subcutaneous needles. A precurved guidewire was advanced through the lumen of a 3F catheter (C-PUM-301J; Cook; Bloomington, IN) and its up positioned into the right ventricle for electrical induction of VF.

VF and Resuscitation Protocols: VF was induced by delivering a 60-Hz alternating current to the right ventricular endocardium (1.0 to 6.0 mA) and left untreated for 12 min. Chest compression was then started using an electronically controlled and pneumatically driven (50 pounds per square inch) chest compressor (CJ-80623; CJ Enterprises; Tarzana, CA) programmed to deliver 200 compressions per minute. The depth of compression was adjusted within the initial 2 min (before administration of vasopressor agents) to attain an aortic diastolic pressure between 26 and 28 mm Hg and thus secure a coronary perfusion pressure greater than the 20-ram Hg threshold for resuscitability in rats. (17) The depth of compression was left unchanged for the remaining interval of chest compression. Positive pressure ventilation was concomitantly provided using an electronically controlled solenoid valve (R-481; Clippard Instrument Laboratory; Cincinnati, OH) programmed to deliver 0.39 mL/100g body weight of 100% oxygen every two compressions. Defibrillation was attempted at 8 min of chest compression by delivering a maximum of two 2-J monophasic transthoracic shocks (Lifepak 9P; Physio-Control; Minneapolis, MN). If VF persisted or an organized rhythm with a mean aortic pressure of [less than or equal to] 25 mm Hg ensued, chest compression was resumed for 30 s. The defibrillation-compression cycle was repeated up to three additional times, increasing the energy of individual shocks (if VF persisted) to 4 J and then to 8 J for the last two cycles. Successful cardiac resuscitation was defined as the return of an organized electrical activity with a mean aortic pressure [greater than or equal to] 60 mm Hg for [greater than or equal to] 5 min. Rats were monitored for a maximum of 120 min after resuscitation.

Experimental Series: Two series of 16 rats each were conducted. In one series, epinephrine hydrochloride (Abbott Laboratories; North Chicago, IL) was administered in bolus doses of 150 [micro]g/kg; in the other series, vasopressin (American Regent Laboratories; Shirley, NY) was administered in equipressor bolus doses of 0.8 U/kg. The doses were empirically determined in preliminary pilot studies aimed at increasing the aortic diastolic pressure during chest compression > 35 mm Hg. In both series, an initial bolus dose was administered into the right atrium at the end of the second minute of chest compression. Additional boluses (same dose) were administered during chest compression at minimum intervals of 2 min if the aortic diastolic pressure decreased < 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide dissolved in 0.9% NaCl or an equal amount of 0.9% NaCl (control) into the right atrium immediately before starting chest compression. Cariporide, (4-isopropyl-methylsulfonylbenzoyl-guanidine methanesulfonate; Aventis Pharma Deutschland GmbH; Frankfurt, Germany) is a highly selective NHE-1 inhibitor with no apparent effects on the [Na.sup.+]-[Ca.sup.2+] exchanger or fast [Na.sup.+] currents. (18) Cariporide has only negligible biological actions on noninactivating [Na.sup.+] currents, but these effects are observed only at very high concentrations. (18) Because cariporide in the rat model can prompt spontaneous defibrillation, (15) electrical defibrillation was timed in control rats to match the time at which spontaneous defibrillation occurred in cariporide-treated rats.

Aortic Perfusion Model

Sixteen additional rats (440 to 510 g) were instrumented with P[E.sub.50] catheters advanced into the abdominal aorta for pressure measurement and drug infusion. The chest cavity was opened through a midline incision and the heart and lungs removed. The descending thoracic aorta was then isolated and a stainless steel cannula advanced for perfusion with a Krebs-Henseleit solution containing the following: NaCl, 118 mmol/L; KCl, 4.7 mmol/L; Ca[Cl.sub.2], 1.25 mmol/L; MgS[O.sub.4], 1.2 mmol/L; NaHC[O.sub.3], 25 mmol/L; K[H.sub.2]p[o.sub.4], 1.2 mmol/L; glucose, 5 mmol/L; and Na pyruvate, 2 mmol/L; and equilibrated with 95% oxygen and 5% C[O.sub.2]. Start of perfusion was delayed 12 min to parallel the 12-min interval of untreated VF in the intact rat model. Low-flow perfusion (simulating closed-chest resuscitation) was then initiated and maintained for an 8-min interval. The perfusate flow was adjusted within the first minute to attain an aortic pressure between 30 and 35 mm Hg and then left unchanged for the ensuing 7 min.

Experimental Series: Two series of eight experiments each were conducted in which a bolus of either epinephrine (150 [micro]g/kg) in one series or vasopressin (0.8 U/kg) in the other series was administered into the aorta at 2 min of low-flow perfusion. These doses were the same as those used in the intact rat experiments. Within each series, rats were randomized to receive an infusion of cariporide or 0.9% NaCl during the interval of low-flow perfusion. Cariporide was administered as a 100-[micro]mol/L solution prepared in 0.9% NaCl and infused at 10% of the perfusate flow to yield a 10-[micro]mol/L intravascular concentration. A 10-[micro]mol/L concentration has been shown in isolated cell preparations to fully inhibit the exchanger. (18) In a previous study (15) in an isolated rat heart model of VF, a 10-[micro]mol/L concentration of cariporide markedly attenuated the development of ischemic contracture.

Measurements: Signals were processed using signal conditioners (BIOPAC Systems; Santa Barbara, CA), sampled at 250 scans per second, and digitized using a 16-bit data acquisition board (AT-MIO-16XE-50; National Instruments; Austin, TX). Pressures were measured using disposable pressure transducers (Maxxim Medical; Clearwater, FL) zeroed to the mid-chest. The coronary perfusion pressure corresponded to the diastolic pressure difference between the aorta and right atrium. During chest compression, these pressures were measured at the end of chest relaxation. The left ventricular pressure was processed to obtain the maximal rate of pressure rise as an estimate of contractility. The development of ventricular arrhythmias during the initial 5 min after resuscitation was assessed according to the definitions set by the Lambeth conventions. (19) Premature wide QRS complexes were classified as singlets, bigeminy, and salvos. Wide complex tachycardia was defined as more than four consecutive premature wide QRS complexes and classified as nonsustained (< 120 s) or sustained ([greater than or equal to] 120 s). VF was classified as nonsustained (< 120 s) or sustained ([greater than or equal to] 120 s). Resuscitation and survival were analyzed separately and in a combined score in which failure to resuscitate was assigned 0 points; survival < 60 min, 1 point; survival [greater than or equal to] 60 < 120 min, 2 points; and survival [greater than or equal to] 120 min, 3 points.

Statistical Analysis: Differences between groups for continuous variables were analyzed using one-way analysis of variance (ANOVA). Alternative nonparametric tests were used if the data failed tests of normality or equal variance. Categorical variables were analyzed using Fisher exact test. The data are presented as mean [+ or -] SD. A value of p < 0.05 was considered significant.

RESULTS

Intact Rat Model

Baseline hemodynamic variables were comparable among and within groups. During chest compression, the target aortic diastolic pressure and the corresponding coronary perfusion pressure were attained at 2 min using comparable depths of compression in both series (Table 1). Very small changes in the diastolic right atrial pressure--typically within approximately 1 mm Hg--were observed among and within groups during the interval of chest compression. This pressure, averaged over the interval of chest compression, was essentially identical between cariporide- and NaCl-treated rats (3.5 [+ or -] 0.9 mm Hg and 3.6 [+ or -] 1.1 mm Hg). Thus changes in coronary perfusion pressure could be attributed almost exclusively to changes in the aortic diastolic pressure. The highest aortic diastolic pressure observed after the initial and the subsequent doses of epinephrine and vasopressin are shown in Figure 1. In the absence of cariporide, both vasopressor agents elicited comparable pressure increases. In the presence of cariporide, a more prominent response occurred in the vasopressin series. Subsequent doses promoted pressure increases of lesser magnitude corresponding to approximately 70% of the initial response (Fig 1). These additional doses were required in > 50% of the control rats but in only one cariporide-treated rat in the epinephrine series. Despite fewer additional vasopressor doses, a higher and more sustained coronary perfusion pressure was documented in both series when cariporide was present (Fig 2). Likewise, the coronary perfusion pressure averaged from minute 3 until the last minute of chest compression was significantly higher when cariporide was present in both the epinephrine series (37 [+ or -] 5 mm Hg vs 29 [+ or -] 7 mm Hg, p < 0.05) and the vasopressin series (36 [+ or -] 5 mm Hg vs 28 [+ or -] 6 mm Hg, p < 0.02).

[FIGURES 1-2 OMITTED]

As previously reported, (15) cariporide prompted spontaneous defibrillation and reestablished cardiac activity between minutes 4 and 8 of chest compression in six epinephrine-treated rats and in three vasopressin-treated rats. However, because we matched defibrillation times, the duration of VF was comparable within series (Table 1). This resulted in significantly fewer electrical shocks and less cumulative energy required for successful defibrillation in the epinephrine series when cariporide was present. Cariporide also reduced postresuscitation singlets and bigeminy in both vasopressor series (p < 0.05) and episodes of ventricular tachycardia in the epinephrine series (p < 0.01, data not shown). The mean aortic pressure at 5 min and 10 min after resuscitation was significantly higher in the vasopressin series when cariporide was present (Fig 3). Moreover, the survival score favored cariporide with statistically significant differences in the epinephrine series.

[FIGURE 3 OMITTED]

Analysis of both series combined demonstrated higher averaged coronary perfusion pressures (36.4 [+ or -] 5.0 mm Hg vs 28.5 [+ or -] 6.2 mm Hg, p < 0.0005), greater resuscitability (16 of 16 animals vs 11 of 16 animals, p < 0.05), and a trend toward better survival scores (2.3 [+ or -] 0.9 vs 1.5 [+ or -] 1.3, p = 0.056) when cariporide was present despite administration of fewer vasopressor doses (1.1 [+ or -] 0.5 vs 1.8 [+ or -] 0.8, p < 0.005).

Aortic Perfusion Model

The target aortic pressure of 30 to 35 mm Hg was attained within 1 min using a perfusion flow that was similar in all four groups (19.7 [+ or -] 2.3 mL/min). A prominent pressure response with a peak effect after approximately 1 min occurred after administration of epinephrine and vasopressin (Fig 4). There were no statistically significant differences in the pressure effects observed in the presence or absence of cariporide, although there was a numerically lower pressor response in the vasopressin series when cariporide was present (Fig 4).

[FIGURE 4 OMITTED]

DISCUSSION

The present study demonstrates that cariporide may potentiate the hemodynamic effects of epinephrine and vasopressin during closed-chest resuscitation without evidence that such an effect results from an enhanced vascular pressor response.

Effects During Chest Compression

We designed the experiments to investigate whether cariporide (by maintaining a greater forward blood flow) could potentiate the effects of epinephrine and vasopressin during closed-chest resuscitation, and used the aortic diastolic and the coronary perfusion pressure as surrogate measures of this effect. We confirmed that changes in coronary perfusion pressure were largely determined by changes in the aortic pressure because the right atrial pressure was essentially unchanged throughout chest compression. As planned, the depth of compression was gradually increased during the initial 2 min of chest compression attaining the target aortic diastolic pressure of 26 to 28 mm Hg with similar compression depths in all groups. Although cariporide--by attenuating ischemic contracture--allows generation of forward blood flow and coronary perfusion pressure with less depth of compression, (20) such effect becomes evident typically after the second minute of chest compression. Thus, the hemodynamic conditions at 2 min of chest compression and immediately before administration of the vasopressor agents were comparable in all four groups. The depth of compression was then maintained constant allowing the aortic diastolic (and hence the coronary perfusion) pressure to vary in relation to the pharmacologic interventions.

The vasopressor agents were administered in doses that would predictably increase the coronary perfusion pressure above resuscitability thresholds. However, these doses elicited effects that were transient in control rats requiring the administration of additional doses to secure that the coronary perfusion pressure remained above resuscitability thresholds. The relatively short-lived pressor effects of epinephrine (8) and to a lesser extent that of vasopressin (21) have been documented, and is in part explained by their distribution and metabolism. The subsequent doses promoted lesser pressor responses, which have been previously documented in the ease of epinephrine (7) and attributed to diminished vascular responsiveness. (12)

The presence of cariporide modified this response. First, it prompted greater increases in the aortic diastolic pressure following the initial dose of the vasopressor agent, with statistically significant differences in the vasopressin group. Second, it prolonged the pressor effect in both groups obviating the need for additional doses in all but one epinephrine-treated rat. Although we cannot completely exclude the possibility that cariporide potentiated the vascular effect of epinephrine and vasopressin, the present evidence argue otherwise. A previous study (22) failed to demonstrate direct or indirect vasoconstrictive effects of cariporide. In a study (20) in which we measured the distribution of systemic and regional blood flow with fluorescent microspheres, cariporide had no effects on peripheral vascular resistance under the very same conditions of VF and closed-chest resuscitation. In the current in vivo aortic perfusion experiments--designed to mimic the experimental conditions present during closed-chest resuscitation--cariporide did not enhance the pressor responses to either epinephrine or vasopressin. To the contrary, there was a numerically lower response in the case of vasopressin (Fig 4, not statistically significant), an observation that might be related to the numerical decline in the coronary perfusion pressure over time observed in the vasopressin but not in the epinephrine group (Fig 2).

Thus, the effects of cariporide stemmed most likely from its myocardial effects preventing (or attenuating) the development of ischemic contracture, and therefore preserving the left ventricular volumes (preload) required to enable more sustained and effective chest compression. The data suggest a novel and nonvascular mechanism by which NHE-1 inhibition could enhance the hemodynamic response to vasopressor agents during closed-chest resuscitation.

Effects After Restoration of Spontaneous Circulation

The presence of cariporide reduced the intensity of ventricular ectopic activity during the initial 5 min after resuscitation. Similar effects have been re ported by others in animal models of regional and global myocardial ischemia (23) and by us in similar models of VF and closed-chest resuscitation. (15,16) Interestingly, suppression of postresuscitation ventricular ectopic activity by cariporide occurred with comparable effectiveness in the presence or absence of epinephrine. Epinephrine is known to accentuate ventricular ectopic activity. (24,25) This effect in part involves activation of [[alpha].sub.1]-adrenoceptors and can be suppressed by NHE-1 inhibition. (26) Irrespective of the mechanisms, postresuscitation electrical stability may be important considering the high proportion of patients who die early after return of spontaneous circulation as a result of recurrent fatal arrests. (27)

Cariporide was also associated with higher postresuscitation aortic pressures in the vasopressin group. In previous studies, using isolated rat heart models of VF, (15,28) intact rats, (15) and intact pigs, (16) we have documented amelioration of postresuscitation diastolic and systolic dysfunction leading to better postresuscitation hemodynamic function. The mechanisms are probably related to direct myocardial protective effects of cariporide along with improved myocardial perfusion, fewer electrical shocks, and fewer cumulative doses of epinephrine and vasopressin, which are known to have detrimental effects on postresuscitation myocardial function. (29,30)

Mechanisms of Action

The prominent intracellular acidosis that accompanies myocardial ischemia activates the sarcolemmal NHE-1 prompting in isoelectric exchange of [H.sup.+] (efflux) for [Na.sup.+] (influx). Inability of the [Na.sup.+]-[K.sup.+] pump to extrude [Na.sup.+] during ischemia leads to progressive intracellular accumulation of [Na.sup.+], (31-33) becoming a "substrate" for reperfusion injury. (34) Although [Na.sup.+] may also enter the cell through the [Na.sup.+]-HC[O.sup.-.sub.3] cotransporter, the [Na.sup.+]-[Mg.sup.2+] exchanger, the [Na.sup.+]-[K.sup.+]/2[Cl.sup.-] cotransporter, and [Na.sup.+] channels, NHE-1 seems to be the predominant route during ischemia and reperfusion. Injury associated with [Na.sup.+] overload is predominantly caused by sarcolemmal [Ca.sup.2+] entry through the [Na.sup.+]-[Ca.sup.2+] exchanger acting in reverse mode. (35,36) This leads to intracellular [Ca.sup.2+] overload and adverse effects on cell function and cell viability. [Ca.sup.2+] overload in conjunction with adenosine tryphosphate depletion and oxidative stress has been associated with opening of a nonspecific high-conductance pore in the inner mitochondrial membrane prompting mitochondrial swelling, depolarization, and uncoupling. (37) [Na.sup.+] overload may also act through [Ca.sup.2+]-independent detrimental effects on mitochondrial function (38) and facilitate reperfusion arrhythmias by maintaining re-entry as a result of decreased phase 0 (conduction velocity) of the action potential. (39)

The conditions that develop during cardiac arrest are uniquely poised to trigger maximal and sustained NHE-1 activity. The intense intracellular acidosis that develops rapidly after the onset of cardiac arrest is the initial trigger for NHE-1 activation. The subsequent resuscitation attempt, using dosed-chest techniques, promotes reperfusion with coronary flows that rarely exceed 20% of normal. (4) These flow levels are not sufficient to reverse ischemia (40) but are sufficient to supply the coronary circuit with normoacidic blood, washing out the excess of extracellular protons but without reversing ischemia. These conditions would favor NHE-1 to remain active throughout the resuscitation effort and probably the initial minutes after the return of spontaneous circulation. Moreover, stress mediators such as angiotensin II, (41) [alpha]-adrenergic agonists, (26,42) and endothelin 1 (43) also increase the sensitivity of the exchanger, (44) prompting an increased exchange rate for the same intracellular pH level. NHE-1 inhibition, using the selective and potent inhibitor cariporide, limits sarcolemmal [Na.sup.+] entry and ameliorates the associated detrimental effects that manifests as ischemic contracture, reperfusion arrhythmias, and postresuscitation myocardial dysfunction. (16)

CONCLUSIONS

These studies demonstrate the capability of cariporide to potentiate the hemodynamic effects of epinephrine and vasopressin during closed-chest resuscitation and to improve resuscitation from VF. Our review of the literature and the in situ aortic perfusion experiments failed to produce evidence in favor of a vascular effect of cariporide. Thus, we propose that the favorable hemodynamic effects observed when cariporide was present resulted from the previously reported myocardial effects of cariporide enabling hemodynamically more effective chest compression by preventing ischemic contracture. The effects herein described could conceivably apply to other interventions targeting the injury prompted by ischemia and reperfusion and represent a novel therapeutic approach for enhancing the hemodynamic efficacy of vasopressor agents during closed-chest resuscitation.

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* From the Medical Service (Dr. Gazmuri), Section of Critical Care Medicine Medical Service, and CPR Research Laboratories (Drs. Kolarova, Yi, and Ayoub), North Chicago VA Medical Center and Rosalind Franklin University of Medicine and Science, North Chicago, IL.

Part of this work received the 2003 Emergency Medicine Specialty Award at the 32nd Critical Care Congress of the Society of Critical Care Medicine, February 1, 2003; San Antonio, TX.

This work was supported by a VA Merit Review Grant entitled "Myocardial Protection During Ventricular Fibrillation," a National Institutes of Health grant R01 HL71728-01 "Myocardial Protection by NHE-1 Inhibition," and a grant from Aventis Pharma Deutschland GmbH, Frankfurt, Germany.

Manuscript received April 6, 2004; revision accepted October 8, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Raul J. Gazmuri, MD, PhD, Medical Service (111F), North Chicago VA Medical Center, 3001 Green Bay Rd, North Chicago, IL 60064; e-mail: Raul.Gazmuri@med.va.gov

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