Introduction

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We have recently demonstrated a reversible myocardial dysfunction after successful resuscitation from prolonged ventricular fibrillation (VF) (Tang et al., 1993; Gazmuri et al., 1996). Observations on experimental animals and anecdotal reports on human victims support the concept that this marked but reversible form of systolic and diastolic myocardial dysfunction together with life-threatening ventricular ectopic dysrhythmias compromises postresuscitation survival (DeAntonio et al., 1990; Tang et al., 1993; Gazmuri et al., 1996). The high fatality rate in the early hours and days after successful resuscitation may therefore be related in part to the myocardial dysfunction after global myocardial ischemic injury of cardiac arrest and resuscitation (Brown et al., 1992; Callaham et al., 1992; Stiell et al., 1992). The extent to which pharmacological interventions and specifically buffer agents administered during cardiopulmonary resuscitation (CPR) effect such postresuscitation myocardial dysfunction was investigated in the experimental studies herein reported.

We had demonstrated earlier that epinephrine, when administered during CPR, significantly increased the severity of postresuscitation myocardial dysfunction and resulted in early postresuscitation death. However, when the ₁ effects of epinephrine were blocked, postresuscitation myocardial function and survival were significantly increased (Tang et al., 1995). A comparison of the effects of the administration of "CO₂-generating" buffer, sodium bicarbonate, and the "CO₂-consuming" buffer, tromethamine, in doses that produced approximately equal increases in arterial blood pH, demonstrated differences in outcomes of initial resuscitation. The CO₂-consuming buffer minimized the severity of postresuscitation myocardial dysfunction when compared with sodium bicarbonate (Sun et al., 1996).

As yet largely unexplored are the combined effects of the adrenergic and the buffer agents. Redding and Pearson (1967) held that infusion of the alkaline buffer increased the pressor response of epinephrine during CPR and thereby improved resuscitation and postresuscitation survival. This contrasted with the studies of Paradis et al. (1990) on human victims in which sodium bicarbonate decreased the pressor response to epinephrine during CPR.

The present study was therefore designed to examine the effects of CO₂-consuming and CO₂-generating buffer agents in combination with an adrenergic vasopressor agent. The objective measurements included the success of initial resuscitation, postresuscitation myocardial function, and postresuscitation survival. Our hypothesis was that the success of resuscitation, postresuscitation myocardial function, and duration of survival will be adversely effected by buffer agents, independently of the effects of the adrenergic vasopressor and more so after the inorganic buffer, sodium bicarbonate.

	Materials and Methods

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The protocol was approved by the Institutional Animal Care and Use Committee. All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-32, revised 1985).

Animal Preparation. Thirty male Sprague-Dawley rats weighing from 450 to 550 g were fasted overnight except for free access to water. The animals were anesthetized by an i.p. injection of 45 mg/kg pentobarbital sodium supplemented with additional doses of 10 mg/kg at hourly intervals, except that no anesthetic agents were administered for 30 min before inducing cardiac arrest. The trachea was orally intubated with a 14-gauge cannula mounted on a blunt needle (Abbocath-T; Abbott Hospital Inc., North Chicago, IL) with a 145° angled tip as described previously (Tang et al., 1995; Sun et al., 1996; Xie et al., 1997).

Experimental Procedure. Experiments were performed in two phases. In phase 1, the buffer agents were administered before the adrenergic vasopressor. In phase 2, the adrenergic vasopressor was administered before buffer agents. The studies were randomized within each phase by the sealed envelope method as described previously (Xie et al., 1997). The investigators were blinded to each intervention until immediately before inducing VF.

1

Measurements. A 1.5-ml bolus of arterial blood from a donor rat of the same colony was transfused into the inferior vena cava immediately after withdrawal of a total of 1.5-ml aliquots of blood from the aorta and the right atrium. PO₂, PCO₂, and lactic acid were measured on these samples by techniques described previously (Tang et al., 1995; Sun et al., 1996; Xie et al., 1997). At 1 and 6 min after start of precordial compression and at 30, 60, 120, 180, and 240 min after successful resuscitation, this panel of measurements was repeated. Aortic, left ventricular, and right atrial pressures, EKG, and P_ETCO₂ were continuously recorded on a PC-based data acquisition system supported by CODAS software (DATAQ Inc., Akron, OH). Coronary perfusion pressure was calculated as the difference between decompression diastolic aortic and time-coincident right atrial pressure measured at the end of each minute of precordial compression.

Statistical Analyses. For measurements between groups, ANOVA and Scheffe's multicomparison techniques were used. Comparisons between time-based measurements within each group were performed with ANOVA repeated measurements. The outcome differences were analyzed with Fisher's exact test. Measurements are reported as mean ± S.D. A value of p < .05 was considered significant.

	Results

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Baseline hemodynamic and blood analytical measurements did not differ significantly among the six groups. Buffer agents administered during CPR before adrenergic vasopressor increased arterial pH from 7.17 to 7.47 (Table 1). However, as in earlier studies (Kette et al., 1991), coronary perfusion pressure was decreased after both buffer agents but not with saline placebo (Fig. 1A). When buffer agents were administered after adrenergic vasopressor, no decrease in coronary perfusion pressure was observed (Fig. 1B). All animals were successfully resuscitated after one or more transthoracic countershocks.

View larger version (28K): [in this window] [in a new window]   Fig. 1.   Comparison of coronary perfusion pressure during precordial compression. *p < .01 versus tromethamine and NaHCO3. A, buffer agents or saline placebo were administered before adrenergic vasopressor. B, adrenergic vasopressor was administered before buffer agents or saline placebo.

The cardiac index dP/dt₄₀ and negative dP/dt were each decreased and left ventricular diastolic pressure was increased after successful resuscitation when the buffer agent preceded the adrenergic vasopressor (Fig. 2). When injection of buffer agents preceded the adrenergic vasopressor (Fig. 2), the severity of myocardial dysfunction was increased (Fig. 3).

View larger version (44K): [in this window] [in a new window]   Fig. 2.   Comparison of cardiac index, dP/dt40, negative dP/dt, and left ventricular end-diastolic pressure (LVDP) among the three groups. Buffer agents or saline placebo were administered before the adrenergic vasopressor. *p < .05; **p < .01 versus control. BL, baseline; VF, ventricular fibrillation; PC, precordial compression; DF, defibrillation.

View larger version (43K): [in this window] [in a new window]   Fig. 3.   Adrenergic vasopressor was administered before buffer agents or saline placebo. Abbreviations are the same as in Fig. 2.

The duration of postresuscitation survival was decreased when adrenergic vasopressor was combined with buffer agents. The decrease was greatest when administration of the buffer agents preceded the adrenergic vasopressor drug (Table 2).

	Discussion

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The present study demonstrated that in this model, both CO₂-consuming and CO₂-generating buffer agents significantly increased the severity of postresuscitation myocardial dysfunction and decreased the duration of postresuscitation survival.

In 1961, Jude et al. proposed that blood pH would best be maintained within normal range during CPR and therefore advised administration of sodium bicarbonate. This was intended to augment systemic vascular responsiveness to vasopressor agents. This practice was reinforced in anecdotal reports and adapted in the early Standards and Guidelines of the American Heart Association (Harden et al., 1963; Stewart, 1964; Fillmore et al., 1970; AHA Guidelines, 1974).

The evidence supporting the assumption that buffer agents increase systemic vascular responsiveness to vasopressor agents (the  adrenergic effects) during CPR is insecure. Bleske et al. (1993) investigated the effects of sodium bicarbonate (1 mEq/kg) or normal saline on the vasopressor effect of epinephrine in pigs after 10 min of untreated VF. After start of precordial compression, these investigators observed no significant differences in aortic systolic, diastolic, and coronary perfusion pressure or in the success of resuscitation between animals treated with sodium bicarbonate and saline placebo. No hemodynamic benefit followed increases in the dose of sodium bicarbonate to 3 mEq/kg, (Bleske et al., 1995). In studies from our laboratory, increases in systemic blood pH during CPR failed to alter either myocardial tissue pH or PCO₂ (von Planta et al., 1989; Kette et al., 1990). The observations on 87 human victims by Paradis et al. (1990) were even more persuasive. Patients with acidemia had a significantly greater pressor response to epinephrine than patients with alkalemia. Alkalemia rather than acidemia decreased the pressor response to epinephrine. The use of buffer agents was therefore viewed as counterproductive and the present studies further documented that buffer agents in combination with adrenergic vasopressor failed to increase the pressor response to epinephrine and improve outcomes. To the contrary, it compromised postresuscitation myocardial function and survival.

We previously demonstrated that hypertonic buffer solutions produce systemic arterial vasodilation during CPR independently of their effect on blood pH. Arterial vasodilation, in turn, accounted for decreases in coronary perfusion pressure and the success of CPR with evidence of intensified global myocardial ischemia (von Planta et al., 1988; Kette et al., 1991). However, when the adrenergic vasopressor agent was administered before the buffer agents, arterial vasodilation was no longer in evidence. Yet, there was comparable postresuscitation myocardial dysfunction and reduced postresuscitation survival. Accordingly, the reduction in coronary perfusion pressure that followed injection of hypertonic buffer alone does not explain the increases in the severity of postresuscitation myocardial dysfunction and foreshortening of postresuscitation survival attributable to buffer agents in this experimental setting. In contrast to earlier experimental observations, CO₂-generating and CO₂-consuming buffers had approximately the same effect on postresuscitation myocardial dysfunction (Sun et al., 1996).

Epinephrine was combined with esmolol to block ₁-adrenergic effects, which were shown to be detrimental in settings of VF. Inotropic ₁-adrenergic actions of epinephrine increased myocardial oxygen consumption of the fibrillating heart and thereby increased the severity of ischemic injury. In earlier studies, esmolol produced no additional hemodynamic changes when administered with epinephrine during VF and CPR (Tang et al., 1995).

One rationale for the use of buffer agents was to augment the vasoconstriction produced by the adrenergic agonists (Cingolani et al., 1970; Gonzalez and Clancy, 1975; Steenbergen et al., 1977). This concept is unsupported by the present studies. In addition, other myocardial effects were theoretically viewed as beneficial. Myocardial intracellular ATP production, the entry of calcium into the cells, and the capability of calcium binding to troponin within cardiac myocytes are reduced during acidosis (Poole-Wilson and Langer, 1979; Chapman, 1983; Langer, 1985; Mehta and Kloner, 1987). As a consequence, myocardial oxygen consumption is reduced (Marsh et al., 1988; Santala et al., 1990). To this extent, acidemia would theoretically be protective. Our interpretation of current knowledge would therefore implicate increases in myocardial oxygen consumption after administration of the buffers. In fact, such has been demonstrated in isolated perfused hearts by our group (Tang et al., 1991). Increases in blood pH are more likely to further increase myocardial oxygen requirements of the fibrillated heart and increase the severity of global ischemic myocardial injury (Ditchey and Lindenfeld, 1988). In the present study, buffer agents increased postresuscitation myocardial impairment, a finding consistent with earlier observations during which increases in arterial pH further increased myocardial oxygen requirements and intensified myocardial ischemia.