The physiologic responses to epinephrine during cooling and after rewarming in vivo

Guidelines for using inotropic drugs to support cardiovascular function at low core temperatures are not well characterized. Such guidelines are essential for treating patients in acute heart failure, as will be the case during induced therapeutic hypothermia, as well as during rewarming from accidental hypothermia. Detailed knowledge of temperature-dependent changes in pharmacodynamics and pharmacokinetics of such cardioactive drugs is essential for establishing treatment guidelines.

Over the last decade, induced hypothermia is being increasingly used to reduce cerebral damage in patients after resuscitation from sudden cardiac arrest [1, 2]. However, after return of spontaneous circulation (ROSC), these patients often have acute heart failure and need inotropic cardiac support to resume adequate circulatory function [1] after induction of hypothermia in which the core temperature is deliberately lowered to 34°C - 32°C and maintained for 24 to 48 hours.

Rewarming shock is a clinically descriptive term that refers to a pathophysiologic state of cardiovascular collapse taking place during or after rewarming from accidental hypothermia [3]. Rewarming shock is recognized as a progressive reduction of cardiac output (CO) and a sudden decrease in arterial blood pressure. To treat or prevent rewarming shock, cardioactive inotropic drugs are commonly necessary to elevate low CO.

Relatively few studies have explored the pharmacologic effects of epinephrine or norepinephrine treatment during hypothermia. Studies on the effects of epinephrine (Epi) used to convert hypothermic cardiac arrest to ROSC during cardiopulmonary resuscitation (CPR) in pigs show diverse effects. In clinical practice, it is recognized that in the acutely failing heart postoperatively or after resuscitations, only drugs such as Epi and NE provide positive inotropy and perfusion pressure. The American Heart Association (AHA) recommends the following algorithm for the use of Epi during hypothermia; at less than 30°C, i.v. epinephrine should not be given, but at greater than 30°C, epinephrine should be given, if indicated, but at longer than standard intervals [4].

In our laboratory, we found that Epi, if given in doses (1.25 μg/ml) that increased CO, without affecting vascular resistance during normothermia, gave rise to vasoconstriction (increased α-adrenoceptor response) but failed to elevate low CO (decreased β-adrenoceptor response) when given during hypothermia [5, 6]. Thus, in an attempt to elevate CO during cooling to 28°C in our experimental hypothermia model, the effects of two different Epi doses, 0.125 or 1.25 μg/ml, which both exert significant cardiovascular effects during normothermia, were tested during hypothermia.

Sprague-Dawley rats (males, 250 to 300 g), were used in the experiments. Anesthesia was induced by sodium pentobarbital (60 mg/kg body weight, i.p.), followed by a continuous infusion of 7.5 mg/kg/h through an i.v. line in the right jugular vein extended to the right auricle. The animals were monitored for any sign of discomfort during hypothermia and rewarming, so that an additional anesthesia might be provided if necessary.

All animals survived cooling and rewarming. Except for single ectopic ventricular beats, no episodes of other arrhythmias occurred during cooling and rewarming.

The present study showed that a low-dose Epi managed to maintain positive inotropic effects on LV cardiac function during cooling to 30°C, but these effects vanished during cooling to 28°C. Second, a higher dose (×10) Epi did not increase SV or CO at these low temperatures, but induced a significant increase in afterload. Third, the prehypothermic dose-dependent increase in LV function in response to both a low- and a high-dose Epi was reproducible after rewarming in the saline control group after cooling and rewarming, but not so in the Epi-treated group.

The results of the present study showing a lack of cardiac inotropic effects, combined with potentiating vascular vasoconstriction at a higher-dose Epi during cooling to 28°C, are in accordance with results previously reported by others [8, 9]. However, new information in the present study is that a low-dose Epi exerts positive inotropic effects on cardiac function without affecting afterload during cooling to 30°C, a finding of importance for induced hypothermia, as applied to reduce cerebral damage in patients after resuscitation from sudden cardiac arrest. Further, the lack of cardiac effects of Epi, irrespective of dose, at temperatures below 30°C is of importance for resuscitation from accidental hypothermia.

In mammals, epinephrine is the prominent catecholamine affecting cardiac contractility, acting through stimulation via sarcolemmal β-adrenoceptors. In the myocyte, Epi stimulates β-adrenoceptors, causing phosphorylation of the sarcolemmal L-type Ca²⁺ channel via cyclic AMP and protein kinase A pathways. This phosphorylation increases the open probability of the channel [10], allowing for greater trans-sarcolemmal Ca²⁺ influx with each depolarization and producing, in part, the positive inotropic effect of Epi. Farrell et al. [11] reported increased adrenergic (Epi) sensitivity in fish cardiomyocytes during acute cooling by showing that sarcolemmal Ca²⁺ flux through the L-type Ca²⁺ channel (I(Ca²⁺)) was significantly more sensitive to adrenergic stimulation during cooling. Thus, although adrenergic stimulation may affect the relative importance of SR Ca²⁺ release in E-C coupling, temperature-induced modulation of β-adrenoceptors may alter the efficacy of adrenergic effects. If cardiomyocytes from fish acclimatized at 14°C were exposed to 7°C, a significant decrease in I(Ca²⁺) was measured, but if Epi were added, I(Ca²⁺) increased by a factor of 7.2, indicating a significant increase in adrenergic sensitivity in response to cooling [12]. As already mentioned, we found in our laboratory that Epi, when given during normothermia in doses that increased CO without affecting vascular resistance, gave rise to vasoconstriction (increased α-adrenoceptor response), but failed to elevate low CO (decreased β-adrenoceptor response) when given during hypothermia [6]. This finding also fit the idea that cooling may induce a transition from β- to α-adrenoceptor properties, as suggested in a study using isolated rat atria [13]. As a result, Epi may not be an ideal inotropic agent for enhancing CO at low core temperature, but based on observations in the present study, the Epi dose applied during hypothermia must be significantly lower than doses normally used at 37°C core temperature. Further, studies on the effects of Epi used to convert hypothermic cardiac arrest to ROSC during CPR in pigs show diverse effects. These studies all show that Epi will increase coronary blood pressure (CPP) below 30°C, which may be seen as a sign of adequate vascular response to Epi at low core temperatures, but cardiac effects (ROSC) are not conclusive [14‐17].

Experimental data from Chernow [18] show that the sympathetic nervous system could be "switched off" at a threshold temperature about 29°C, and hypotensive patients with temperatures below this may benefit from infusions of exogenous catecholamines. In support of this notion, a study on human skin artery responses to tissue cooling showed an increased sensitivity in both α₁- and α₂-adrenoreceptors to norepinephrine at 24°C [19]. In addition, if CO could be elevated pharmacologically, rewarming by any means would become more efficient [20]. Danzl and Pozos [21] recommend infusion of low doses of catecholamines in patients who have lower blood pressure than would be expected for that degree of hypothermia and who are not responding to crystalloids and rewarming. However, in the present experiment, we observed that in animals having received Epi during cooling, the physiologic responses to Epi had vanished after rewarming. This finding indicates that the combined impact of hypothermia and adrenergic stimulation has serious impact on β-adrenoceptor function after normothermia is reestablished. Taken together, the use of cardioactive drugs during hypothermic conditions remains quite contradictory. Therefore, pharmacologic treatment applied during the two clinically challenging modalities outlined, induced and accidental hypothermia, call on written treatment protocols or guidelines which are so far largely missing or at least not properly updated. More research is needed to explore temperature-dependent changes in pharmacodynamics and pharmacokinetics of cardioactive drugs to write these guidelines.

Results from the present study show that a low-dose Epi, in essential contrast to a high-dose Epi, exerts positive inotropic effects during cooling to 30°C. Because of significant hypothermia-induced alterations of cardiac as well as vascular adrenoceptor sensitivity, the use of cardioactive agents not affecting these receptor systems is advised during hypothermic conditions.