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Cardiovascular Research 1998 40(3):546-556; doi:10.1016/S0008-6363(98)00199-0
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Effect of bolus epinephrine on systemic hemodynamics in canine anaphylactic shock

S.N. Mink*, C. Bands, A. Becker, J. Elkin, S. Sharma, H. Unruh and W. Kepron

Department of Internal Medicine, Surgery, Pediatrics, and Immunology, University of Manitoba, Winnipeg, Manitoba, Canada

* Corresponding author. Tel.: +1-204-787-2684; fax: +1-204-787-4826.

Received 7 January 1998; accepted 21 April 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Epinephrine (Epi) is considered to be the drug of choice for anaphylactic shock (AS). However, the benefit of this drug on improving systemic hemodynamics in AS has never been shown. We used a canine ragweed model of AS to determine if an intravenous bolus of Epi hastened the recovery of hemodynamics and modified mediator release (Med) compared with no treatment (NT). Methods: In one protocol (n=8), the effects on hemodynamics of two intravenous doses of Epi (0.01 and 0.025 mg/kg) were examined for 3 h postshock in respective studies approximately three weeks apart under pentobarbital anesthesia in the same animal. In five other dogs, left ventricular (LV) mechanics were additionally determined by sonomicrometric techniques to determine changes in contractility as defined by the preload recruitable stroke–work (SW) relationship. Results: Compared with NT values, Epi treatments produced only transient increases in mean arterial pressure (MAP) and cardiac output (CO) post-challenge. By 20 min postshock, CO in the Epi studies were generally lower (p<0.05) and BP was not different from NT values. With Epi treatment, SW was reduced for a given LV end-diastolic volume compared with the control study. Epi treatments also caused relatively higher plasma thromboxane B2 concentrations postshock. Conclusion: Our findings indicate that, when given immediately postshock, bolus-Epi did not hasten recovery and caused impairment in LV mechanics in canine AS.

KEYWORDS Allergy; Asthma; Mediators; Canine


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
In anaphylactic shock, circulatory collapse is caused by the release of mediators from tissue mast cells and peripheral blood basophils in a sensitized individual. Most cases of anaphylaxis are due to ingestants, hymenopteran stings, radiocontrast media and pharmaceuticals [1–3]. Epinephrine is considered the drug of choice for the treatment of anaphylaxis. {alpha}-Adrenergic effects of epinephrine increase left ventricular preload by reducing venous capacitance, while β-adrenergic effects reverse bronchospasm and increase cardiac inotropy and chronotropic activity [2, 3, 5, 6].

Nevertheless, in human anaphylaxis, studies on the utility of epinephrine in improving hemodynamic recovery have not been totally supportive. Smith et al. [2]found that epinephrine had no apparent benefit on systemic hemodynamics when anaphylactic shock developed in patients investigated for insect-sting hypersensitivity. In other studies, excessive doses of epinephrine have precipitated hypertension and arrhythmias, while epinephrine resistance has also been reported [1–5, 7]. The route of administration and dose in anaphylaxis are furthermore empiric and controversial [4].

Because there is little experimental data demonstrating the efficacy of epinephrine in anaphylaxis, and because human data are difficult to ascertain, we used a canine ragweed model to examine the effect of bolus epinephrine on improving systemic hemodynamics in anaphylactic shock [8–10]. Our primary objective was to determine whether or not epinephrine hastened hemodynamic recovery in this model.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Anaphylaxis model
This study was approved by the Central Animal Committee at the University of Manitoba. The ragweed model used in this study has been described previously [8–11]. Briefly, newborn mongrel dogs received 0.5 mg of ragweed mixed with 30 mg of Al(OH)3 intraperitoneally within 24 h after birth. Injections were repeated weekly for eight weeks, at biweekly intervals for approximately 30 weeks, and then at monthly intervals [8–10]. The animals were examined at approximately one year of age.

2.2 Ragweed shock protocol
Eight sensitized dogs were examined on three occasions approximately three weeks apart. The same animal was used to lessen the impact of inter-subject variability; the three-week interval was chosen because challenges are reproducible when performed over this interval ([11]; see Section 3).

The three treatment studies included a low epinephrine study (LO Epi), 0.01 mg/kg body weight; a high epinephrine study (HI Epi), 0.025 mg/kg body weight and a control study (control study) in which an equivalent amount of placebo (1 ml normal saline) was given. The three treatments were randomly administered. The epinephrine doses were based on those of Smith et al [2], adjusted for canine body weight, and were given as boluses over 10 to 15 s as in ref [2](see Section 4). The drug was administered through the right jugular vein.

For each sensitized dog, the dose of allergen to produce shock was known, and the same dose was used in all three treatments. Shock was defined as a reduction in mean arterial pressure (MAP) to approximately 50% of that found pre-allergen challenge. After shock was produced, one of the three treatments was administered at the point of lowest MAP (when a plateau in MAP had occurred). This plateau lasts for {approx}10 to 15 min post challenge [8]. Hemodynamics were obtained before allergen challenge (i.e. at baseline), at the point of maximal hypotensive response (termed Rag), immediately after treatment (i.e {approx} the 10 min interval), at 20, 30, 40, 50 and 60 min posttreatment, and then at 30 min intervals until 3 h posttreatment.

Blood samples to measure mediators of anaphylaxis (see below) and arterial blood samples (PO2, PCO2, pH) were collected before allergen challenge, at maximum shock, at {approx}15 min posttreatment, at 30 min posttreatment, at 30 min intervals until 2 h posttreatment and, finally, at 3 h posttreatment.

In addition, because differences were found between the epinephrine and control studies, a sham shock protocol was subsequently performed in which five of the eight dogs were restudied (the other three animals were enrolled in another study). Its objective was to determine whether the hemodynamic responses to epinephrine observed in the ragweed shock protocol would also occur without anaphylaxis being produced. In the sham shock protocol, the same epinephrine and placebo doses and protocol were used, but allergen was not given (just normal saline solution).

2.3 Animal preparation and procedures
In both protocols, measurements were obtained while the animals were anesthetized with sodium pentobarbital (30 mg/kg, i.v.). Based on previous studies [12, 13], the half-life of pentobarbital anesthesia in dogs was determined to be approximately 8 h. Preshock plasma pentobarbital concentrations would average ≤25 mg/l [13]and, although concentrations would fall slightly, they remain fairly constant over the course of the study (17 to 20 mg/l) [13]. If anesthesia was needed subsequently, 60 mg of pentobarbital was administered over 1 to 2 min at least 10 min prior to obtaining the next measurement, when concentrations would have plateaued.

During the experiment, the animals were placed in the supine position; the trachea was intubated with an endotracheal tube and the lungs were mechanically ventilated at a volume of 20 ml/kg (Harvard Apparatus). The rate of the ventilator was adjusted as needed to maintain the blood pH between 7.3–7.4, since slight metabolic acidosis develops during challenge [8]. Oxygen, at a concentration of 40 to 50%, was inspired to maintain arterial oxygen tension (PO2) above 150 mmHg. Hemodynamic measurements (see below) were obtained at end-expiration with the ventilator turned off for 10 s.

All procedures were performed under sterile conditions. A thermodilution tipped floatation catheter was used to measure mean pulmonary arterial pressure (mPAP), mean pulmonary capillary wedge pressure (mPWP), mean right atrial pressure (mRAP) and to determine thermodilution cardiac output (CO) (Columbus Instruments, OH, USA). A polyethylene catheter was placed into the femoral artery and advanced to the mid descending aorta to measure MAP and to withdraw samples of blood. All catheters were connected to transducers (Cobe Laboratories) and were referenced relative to the left atrium. All transducers were connected to a chart recorder (Astra Med, West Warwick, RI, USA). Stroke volume (SV) was calculated from: SV=CO/HR (heart rate). Systemic vascular resistance (SVR) was calculated from: SVR=[(MAP–RAP)/CO]x80 dynes s/cm5. Pulmonary vascular resistance (PVR) was calculated from: PVR=[(mPAP–mPWP)/CO]x80 dynes s/cm5.

Baseline measurements were made after 30 min of stabilization. Initial mPWP was at {approx}5 mmHg and, if needed, 6% hetastarch in 0.9% NaCl solution was used to elevate mPWP to this value. No further fluid was administered. Following completion of the experiment, the animals were given prophylactic antibiotics (cloxacillin, 10 mg/kg i.v. and gentamicin, 2 mg/kg) and were returned to their cages.

2.4 Mediators of anaphylaxis
At the designated periods, 30 ml of blood were withdrawn from the femoral artery catheter with a syringe that contained 3 ml of EDTA and 0.5 ml of indomethacin. This blood was centrifuged and stored at –70°C until analyzed for mediators. Plasma concentrations of histamine, PGF1{alpha}, and TXB2 (breakdown products of prostacyclin and thromboxane, respectively), and leukotrienes (LTE4) were measured by radioimmunoassay techniques [Immunotech International, AMAC Inc., Westbrook, ME, USA [15], NEN Res Products, Boston, MA; NEK-008, NEK 007, and NEK-043 [16], respectively]. In the leukotriene assay, since in vitro conversion of LTC4 and LTD4 to LTE4 occurs spontaneously, measurements of all leukotrienes were obtained after enzymatic conversion (by {gamma}-glutamyl transpeptidase and microsomal leucine aminopeptidase) to LTE4, as described by Heavey et al. [14]. The average values of two samples were reported.

2.5 Left ventricular (LV) mechanics protocol
Since epinephrine treatment seemed to impair CO in anaphylaxis, a LV mechanics protocol was performed in five other sensitized dogs, to assess whether treatment caused LV systolic or diastolic impairment in this model. An epinephrine study (0.01 mg/kg, i.v.) and a control study were performed in randomized design approximately three weeks apart, in which LV mechanics were determined by sonomicrometric techniques [13, 17, 18]. Shock was produced as described in the ragweed protocol.

In this chronically instrumented preparation, three pairs of subendocardial hemispheric ultrasonic crystal transducers (Channel Industries, Santa Barbara, CA, USA) were implanted into the LV two months prior to the study, as previously described [13, 17, 18]. Pairs of ultrasonic crystal transducers were placed along the anterior–posterior (AP) and septal–lateral (SL) minor axes, and along the apex to base (AB) major axis of the LV, respectively. In this preparation, the pericardium was loosely reapproximated. The wires were tunnelled subcutaneously and brought out at the back of the neck.

In the LV mechanics study, in addition to the other procedures previously described, a high fidelity pressure-tipped catheter (Millar Instruments, Houston, TX, USA) was advanced from the carotid artery into the LV. LV end-diastolic pressure (LVEDP) was defined as the pressure at which +dP/dt increased by 150 mmHg/s, with the increase sustained for >50 ms [17, 18]. LVEDP was related to simultaneous LV dimension tracing to define end-diastolic dimension (LVEDD) (Triton Technology, San Diego, CA, USA). LV end-ejection dimension (LVEED) and volume (LVEDV) (see below) were defined by the maximum negative LV pressure decline (–dP/dtmax) [17–19].

A Fogarty catheter was advanced into the inferior vena cava through a femoral vein puncture. When the balloon on the Fogarty catheter was inflated, venous return was reduced, so that multiple pressure–dimension coordinates could be obtained. An esophageal balloon was placed into the lower esophagus to measure pleural surface pressure (Ppl), as previously described [17]. In this essentially open pericardial preparation, this allowed us to determine transmural LVEDP (LVEDPtm)=(LVEDP–Ppl) [17].

Measurements were obtained at baseline, shock, and at 1 and 2 h postshock, since most changes occurred at these intervals in the hemodynamics study. In the individual dogs, LVEDP was maintained constant between conditions with a range of 7 to 12 mmHg. Intravenous volume (6% hetastarch in normal saline solution) was given as needed to maintain a constant LVEDPtm. Following the procedure, vascular accesses were surgically closed.

From the three LV dimensions (D), ventricular volume was calculated as described by Sodums et al [18]: volume={pi}/6 DAPxDSLxDAB, where D is EED or EDD. SV was calculated from LVEDV–LVEED. Stroke–work (SW) was calculated from SVx(mean LV systolic pressure–LVEDP) [20, 21]. LV contractile function was assessed by the preload recruitable stroke work (PRSWR) relationship [20, 21]. For each dog, multiple SW vs. LVEDV coordinates (at least four) were obtained for each condition. The slope of this relationship was determined by linear regression analysis.

2.6 Statistical analysis
In each protocol, the different treatments were compared at individual time periods following shock by means of a two-way analysis of variance (ANOVA) for two repeated measures [i.e. factor A (treatments) and factor B (time periods)] in which the interaction between the two factors was assessed (Northwest Analytical, Portland, OR, USA). In this analysis, significance in the interaction term controls for experiment wise error and repeated measurements [22]. If a significant interaction were present, then the treatments behaved differently over time. In that case, a Student Newman Keuls' Multiple-Range Test (SNK) was used to determine at which specific time periods a difference among the three treatments occurred. A SAS program (SAS Institute, Cary, NC, USA) (Proc Univariate) was used to test for normality and the results indicated that the data did not violate this assumption for the variables analyzed [23].

In addition, a one-way ANOVA for repeated measures and SNK were used to ascertain differences between parameters for a given treatment and to determine whether there were differences among the three treatments at the baseline and Rag intervals. Because we were mainly interested in differences among treatments, we did not report all the statistics for a given treatment over the 3 h course of the study. Results are reported as mean±SEM.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Ragweed shock protocol
For each dog, the same dose of ragweed [range, 0.1 to 85 mg; mean (±SEM), 25±9 mg] was used in each of the three treatments, and MAP fell to similar extents during ragweed challenge (see Rag in Fig. 1). At the time of maximum hypotension, either high or low epinephrine treatments or normal saline solution was randomly administered. In the HI and LO Epi, epinephrine treatment caused an immediate increase in MAP, but this effect was short-lived and, thereafter, MAP were similar among the treatments. In all studies, MAP returned to preshock values at approximately 50 min postshock.


Figure 1
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  		Fig. 1 In the ragweed shock protocol, mean systemic blood pressure, cardiac output, stroke–volume and mean pulmonary wedge pressure were followed over a 3-h period in the control study and in the high dose (HI Epi) and low dose epinephrine (LO Epi) studies. RAG is ragweed antigen. Statistics were by two-way repeated measures ANOVA and SNK.

 
The CO values found at baseline were not different among the treatments (Fig. 1, lower left panel). Compared with the baseline value, CO fell precipitously during allergen challenge to similar extents in all three studies. In the HI and LO Epi, epinephrine caused a rise in CO at the 10-min period, but after this transient rise, CO in the epinephrine studies fell relative to control values. Between 20 to 90 min postshock, CO gradually increased in the control study, and at many intervals, CO values in the control study were higher than those found in the epinephrine studies. Similar results were observed in SV (Fig. 1, upper right hand panel).

Compared with the control study, the lower CO and SV found after the 10 min period in the epinephrine studies were not due to lower mPWP (see Fig. 1, lower right hand panel). Epinephrine treatment caused an increase in mPWP at the 10 min interval compared with the control value, but after the 10-min period, Pwp were similar among the treatments.

In each treatment study, mPWP measured at the 180 min interval was slightly lower compared with the preshock value. After the 180 min measurement, intravascular volume was given to return the mPWP to the baseline value, and CO was again measured. At comparable mPWP, CO values were still lower than the baseline value, but particularly in the epinephrine studies (5.3±1.8 l/min in the control study, p<0.01; 4.5±1.6 l/min in the LO Epi, p<0.01; 2.9±1 l/min in the HI Epi, p<0.01).

Compared with the control study, HR did not change in the epinephrine studies, while there was a transient decrease in PVR at the 10-min interval with treatment (see Table 1). Compared with the preshock value, SVR (Table 1) increased to a similar extent during shock in all studies. At the 10-min interval, SVR measured in the LO Epi was higher compared with the other studies, while over the later measurement intervals, SVR in the HI Epi tended to be higher.


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  		Table 1 Hemodynamics in the ragweed shock protocol

 
Mediators showed a variable response with treatment. Histamine concentrations (Fig. 2) measured over the intervals were not different among the treatments. However, epinephrine treatments caused significant increases postshock in PGF1{alpha} at 15 min and in TXB2 and LTE4 at 15 to 30 min compared with the control study.


Figure 2
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  		Fig. 2 In the ragweed shock protocol, mediators of anaphylaxis (histamine, prostaglandins, thromboxane and leukotrienes, respectively) are shown over the 3-h period in the three studies. See legend to Fig. 1 for statistics.

 
In all studies, arterial PO2 remained >150 mmHg over the course of the experiment and the pH was maintained between 7.3 to 7.4.

3.2 Sham shock protocol
In the HI and LO Epi, epinephrine treatments (see Fig. 3) caused large immediate increases in MAP compared with the control study, but these increases were short-lived and, by 20 min post-treatment, MAP were similar among the treatments.


Figure 3
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  		Fig. 3 In the sham shock protocol, mean systemic blood pressure, cardiac output, mean pulmonary wedge pressure and systemic vascular resistance are shown over the 3-h period in the three studies. PLAC is placebo. VOL is volume infusion to return Pwp to preshock values. See legend to Fig. 1 for statistics.

 
In contrast to results obtained in the ragweed-shock protocol, in the sham shock protocol, CO did not initially increase when epinephrine was given in either the LO or HI Epi (see Fig. 3, lower left hand panel). In the sham-shock protocol, CO fell over the course of the 3-h post-treatment period in all studies, but fell to a greater extent in the HI Epi.

Compared with the control study, the greater declines in CO observed posttreatment in the epinephrine studies were not due to lower mPWP. As shown in Fig. 3 (upper right hand panel), HI and LO Epi caused large transient increases in mPWP, which, by 20 min posttreatment, were similar between studies. HRs were not different among the three studies (see Table 2).


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  		Table 2 Hemodynamics in the sham shock protocol

 
In both the HI and LO Epi, SVR (see Fig. 3, lower right hand panel) increased immediately after epinephrine treatment, but returned to the value found in the control study by 20 min posttreatment. In each study, SVR returned to the baseline value after volume infusion.

For the most part, mediators remained near baseline values, except for TXB2, which, at 15 and 30 min in the HI (400±86 and 296±57 pg/0.1 ml) and LO Epi (376±87 and 289±57 pg/0.1 ml), were greater (p<0.05) than the corresponding control values (152±77 and 117±33 pg/0.1 ml).

3.3 LV mechanics protocol
In the LV mechanics protocol, LVEDPtm (see Table 3) were unchanged between pre- and postshock conditions as per protocol. Ppl also remained unchanged between conditions, since there was little airtrapping produced during intravenous allergen challenge in this model. The MAP found under the different conditions are shown in Table 3 and were not different between the control and epinephrine studies. By the time measurements were obtained during the shock condition, MAP measured in the epinephrine study had returned to the control study value.


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  		Table 3 Parameters in the left ventricular mechanics protocol

 
In Fig. 4, the pooled data for the five dogs are shown, with SW plotted as a function of LVEDV. At baseline, the slopes of PRSWR were similar in the epinephrine and control studies. Immediately after allergen challenge, the slopes significantly diverged postshock and, with epinephrine treatment, mean slopes obtained postshock were significantly reduced compared with the control study (see Table 3). This divergence appeared to narrow between shock and 2 h postshock. In the calculation of the slope, the square of the correlation coefficient R2 was >0.95 under all conditions. On the other hand, diastolic function, as determined by LVEDV for a given LVEDPtm, was unchanged during anaphylaxis with and without epinephrine treatment (see Table 3).


Figure 4
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  		Fig. 4 Pooled data for the five dogs in the LV mechanics protocol in which the preload recruitable stroke–work (SW) relationship was measured in different studies during control and with epinephrine treatment. SW is plotted on the ordinate as a function of left ventricular end-diastolic volume (LVEDV). During the epinephrine study, the slope of the relationship for the postshock conditions was shifted downward and to the right compared with the control study.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The purpose of this study was to determine if epinephrine treatment would hasten the recovery and improve systemic hemodynamics in a canine model of anaphylactic shock. In the ragweed shock protocol, epinephrine treatment caused an initial increase in MAP, which was accompanied by simultaneous increases in CO and mPWP, compared with the control study. This beneficial finding of epinephrine was caused by a transient {alpha}-adrenergic effect on venous capacitance, which resulted in a higher LV preload and, hence, CO, while SVR did not change very much. However, by 20 min postshock, MAP and mPWP in the epinephrine treatment conditions were not different from control values, while CO values were lower over many of the study intervals. Any positive inotropic effect of epinephrine on the heart must have been very transient (or nonexistent), since, in the LV mechanics protocol, by the time measurements were obtained (i.e. 10 to 15 min post bolus), LV systolic function was depressed, such that SW was reduced for a given LVEDV. In all of the studies, regardless of whether or not epinephrine was administered, MAP reached the preshock value about 50 min postshock.

The lower SW found with epinephrine treatment may be related to catecholamine-mediated myocardial damage, to the consequences of acute pressure overload or to myocardial ischemia, which, in turn, may be a component of both of the latter mechanisms. High circulating catecholamines, leading to acute cardiotoxicity, may be due to an impairment in intracellular calcium handling, a reduction in coronary blood flow and to the formation of high cytotoxic free radicals derived from catecholamine auto-oxidation [24, 25]. The dose of epinephrine required to produce catecholamine toxicity in in-vitro preparations is reported to be higher (6.5 mg/kg) than the amounts given in the present study [24, 25], but, conceivably, under conditions of anaphylaxis, toxicity could be caused by lower doses.

Epinephrine treatment also caused a sudden increase in LV pressure, which may have resulted in myocardial dysfunction. Bishop and Melsen [29]showed that, after three days of aortic banding in rabbits, the myocardium showed fibrosis and necrosis, which may have represented relative oxygen deficiency. In the present study, although the duration of acute pressure overload found with epinephrine treatment lasted for a few minutes, the reduction in CO that followed could be related to cellular necrosis caused by myocardial supply–demand imbalance. In addition, the LV depression observed with epinephrine may be related to an increase in thromboxane. Epinephrine has been shown to increase plasma concentrations of thromboxane and prostacyclin, which may be related to interaction between platelets and the endothelium [26, 27]. Thromboxane has been shown to produce myocardial depression in other experimental models [28]. Whatever the mechanism of LV depression, however, our results show that cardiac function recovered over a three-week period.

In the present study, we gave epinephrine over a 15-s period in a manner similar to that described by Smith et al. [2]. The suggested doses in the literature vary widely [4, 30]. Smith et al. [2]gave repeated doses of epinephrine (0.5 and 1 mg, i.v.) when subjects developed shock in response to venom challenge. This latter study was unique in its ability to follow the hemodynamic time course of anaphylaxis in human subjects. In the present study, we gave the approximate doses given by Smith et al. [2], adjusted for canine body weight. Although it is recognized that other approaches could be used, these doses approximated to 0.01 and 0.025 mg/kg, respectively.

In terms of our study, many aspects need to be addressed relative to the relationship of our anaphylaxis model to the human condition. In our model, after shock is produced, MAP gradually rises and recovers to preshock values in approximately 50 min, even without treatment. Whereas spontaneous recovery might be different from what is traditionally thought to occur in human anaphylaxis, Smith et al. [2]showed spontaneous hemodynamic recovery over 60 to 90 min in subjects who developed anaphylaxis in their study of insect-sting hypersensitivity. Thus, there is little evidence to indicate that epinephrine hastens hemodynamic recovery in either canine or human anaphylactic shock.

In our ragweed model, we also found that SVR increased during shock, while most data on human anaphylaxis have reported that a decrease in SVR is found [31]. Nevertheless, most hemodynamic data in human anaphylaxis have been reported post fluid resuscitation, and a low SVR was obtained when fluid was infused in our canine model in a previous study [8]. In the present study, we were also only concerned with the hemodynamic consequences of anaphylaxis, since respiratory changes are minor when intravenous allergen is given in this model [8]. We maintained PO2150 mmHg and pH within the normal range, to prevent hemodynamic deterioration due to respiratory consequences. In the clinical condition, bronchospasm and laryngospasm may benefit from epinephrine treatment.

In the present study, hemodynamics were examined while the animals were anesthetized, since it would not be possible to study these animals in the conscious condition. Of the anesthetic agents available, all would affect some aspect of the anaphylactic response in our model, i.e. histamine release and/or bradycardia by narcotic agents [32]and vasodilation by inhalational agents [33]. Since pentobarbital anesthesia is often used for investigating hemodynamics in allergic models [34, 35], we administered this anesthesia in the present study.

Furthermore, although some investigators have indicated that pentobarbital anesthesia may impair cardiac contractility [36, 37], we previously found that when pentobarbital plasma concentrations in dogs were maintained ≤25 mg/l, LV contractility was similar to that observed in the awake condition [13]. We also showed that serum pentobarbital concentrations remain within a relatively narrow range between 1 and 4 h of administration. Nevertheless, pentobarbital anesthesia is known to increase HR and blood pressure, which may be related to the vagolytic effect of the agent, although baroreceptor reflex effects cannot be excluded [36, 37]. In the ragweed shock protocol, there were no differences in the HR responses between the epinephrine and control studies when epinephrine was administered (see Table 1). Whereas this failure of HR to increase with epinephrine treatment may have been related to the anesthesia used, Smith et al. [2]also found that epinephrine had little, if any, effect on HR in anaphylaxis. Since it is not possible to exclude an effect of anesthesia on our results, it is recognized that our conclusions must be cautiously applied to the human condition.

Epinephrine is considered the drug of choice in anaphylactic shock. This is primarily based on work performed in isolated preparations. β-Adrenergic agonists, such as epinephrine, cause an increase in intracellular cyclic AMP, which, in turn, attenuates mediator release during immunological challenge [38]. However, there are few studies that have evaluated the use of epinephrine in anaphylaxis once shock has been attained. In the present study, it is important to note that other therapies administered in anaphylaxis, such as steroids, antihistamines and intravenous fluids, were not given. However, Smith et al. [2]showed that fluids had little beneficial effect on hemodynamics in human anaphylaxis. Most of the guidelines for the treatment of anaphylactic shock are empiric and anecdotal and, therefore, each therapy administered in anaphylaxis should be evaluated individually. Our results would support the conclusion of Smith et al. [2]that bolus-epinephrine does not hasten the time to recovery of systemic hemodynamics in anaphylactic shock.

Time for primary review 26 days.


   Acknowledgements
 
Supported by the Heart and Stroke Foundation of Manitoba.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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