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Anesth Analg 2002;95:1037-1041
© 2002 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Endotracheal Epinephrine: A Call for Larger Doses

Yossi Manisterski, MD, Zvi Vaknin, MD, Ron Ben-Abraham, MD, Ori Efrati, MD, Danny Lotan, MD, Mati Berkovitch, MD, Asher Barak, MD, Zohar Barzilay, MD FCCM, and Gideon Paret, MD

Department of Pediatric Intensive Care, The Chaim Sheba Medical Center, Tel Hashomer and the Sackler Faculty of Medicine, Tel Aviv University, Israel

Address correspondence and reprint requests to Gideon Paret, MD, Department of Pediatric Intensive Care, Chaim Sheba Medical Center, Tel Hashomer 5262l, Israel. Address e-mail to gparet{at}post.tau.ac.il


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Endotracheal administration of epinephrine 0.02 mg/kg (twice the IV dose) is recommended when IV access is unavailable during cardiopulmonary resuscitation. The standard IV dose has been considered too small for the endotracheal route by causing a detrimental decrease of arterial blood pressure (BP), presumably mediated by the ß-adrenergic receptor unopposed by {alpha} adrenergic vasoconstriction. We conducted a prospective, randomized, laboratory comparison of increasing doses of endotracheal epinephrine to ascertain the yet undetermined optimal dose of endotracheal epinephrine that would increase BP. After injecting normal saline (control), saline-diluted epinephrine (0.02, 0.035, 0.1, 0.2, and 0.3 mg/kg) was injected into the endotracheal tube of five anesthetized dogs at least 1 wk apart. Arterial blood samples for blood gases were collected before and at 14 time points up to 60 min after the drug administration. Heart rate and arterial BP were continuously monitored with a polygraph recorder. Only the 0.3 mg/kg dose successfully caused an increase in BP, observed 2 min after administration, and lasting for 10 min. An early decrease in BP was obviated only at a dose equivalent to 10-fold the currently recommended one.

IMPLICATIONS: We conducted a prospective, randomized, laboratory comparison of increasing doses of endotracheal epinephrine to ascertain the yet undetermined optimal dose of endotracheal epinephrine that would increase arterial blood pressure (BP). A decrease in BP was obviated only at a dose equivalent to 10-fold the currently recommended one. Clinical studies using larger doses of endotracheal epinephrine and their use as first-line therapy in cardiac arrest are warranted.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The endotracheal route has been suggested by the European Committee for Resuscitation (1) and the American Heart Association (2) as an alternative method for the administration of epinephrine, the most important medication used in advanced cardiac life support, if IV access cannot be attained (1–4). The European Heart Association presently recommends that when the endotracheal route is used, the epinephrine dosage should be twice to three times larger than for the IV route, i.e., 0.02–0.03 mg/kg. However, the optimal dose of endotracheal epinephrine for augmenting aortic diastolic blood pressure (BP) is unknown. Whereas most of the previous investigators who studied endotracheal epinephrine administration have reported favorable results (5–12), the initial decrease of BP associated with endotracheal epinephrine was generally ignored (5–15). In two previous studies, the ß adrenergic-mediated effect of epinephrine accounted for this hypotension (16,17). ß adrenergic stimulation may be counterproductive by causing peripheral vasodilatation, decreasing aortic BP, and reducing myocardial perfusion pressure (18,19). This explains the findings of clinical studies that suggest that the standard IV dose was less than optimal, often ineffective, and even possibly deleterious when endotracheally administered (14,20,21).

In search of an endotracheal dose that would lead to an increase in BP, we compared the hemodynamic effects of endotracheal epinephrine by first administering saline (control), followed by increasing doses of normal saline-diluted epinephrine (0.02, 0.035, 0.1, 0.2, and 0.3 mg/kg) in five dogs. This prospective, randomized, crossover trial was designed to determine the pharmacodynamic variables of heart rate, BP, and oxygenation after endotracheal epinephrine administration at these selected doses.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study was approved by the Animal Care and Users Committee of the Tel Aviv University, Israel, and the animals were maintained in accordance with national and institutional guidelines.

Five adult mongrel dogs of both sexes, weighing 13.6–23.2 kg, were anesthetized with IV pentobarbital (25 mg/kg) and intubated tracheally with a low-pressure cuffed endotracheal tube whose position was verified by bilateral lung inflation. The animals were ventilated (fraction of inspired oxygen = 0.21) at a respiratory rate of 20–24 breaths/min to maintain a PaCO2 of 25–45 mm Hg and a PaO2 of >90 mm Hg. Both femoral arteries were percutaneously cannulated to measure arterial BP and for blood gas sampling. Heart rate (standard lead 2) and arterial BP were continuously recorded, as previously described (11) (79d, Grass Instruments, Quincy, MA). Ringer’s lactate solution at a dose of 6 mL · kg-1 · h-1 was used for infusion therapy.

To achieve steady-state conditions, 20 min were allowed for stabilization after endotracheal intubation and catheter insertions. The same protocol applied to each experimental dose (see below). Baseline blood samples for arterial blood gases were drawn, after which one dose of normal saline (control) was administered. This was followed by 5 increasing doses (0.02, 0.035, 0.1, 0.2, and 0.3 mg/kg) of epinephrine hydrochloride that were diluted with 10 mL of normal saline and administered into the endotracheal tube of each dog. After the epinephrine administration, five forced manual ventilations were delivered with an Ambu bag.

Each dog underwent each dose regimen in a randomized order, and there was at least a 1-wk interval between trials. Statistical analyses included analysis of variance with repeated measures and Student’s paired t-test. Arterial blood gases at baseline and after the epinephrine administration were compared by Student’s t-tests. A P value <0.05 was considered significant. Data are expressed as mean ± SEM.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Endotracheally-administered epinephrine produced an initial significant decrease in systolic, diastolic, and mean BP in the 5 tested epinephrine doses (0.02, 0.035, 0.1, 0.2, and 0.3 mg/kg) compared with endotracheally-administered normal saline (P < 0.05) (Figs. 1 and 2). The maximum decrease of mean BP occurred at the first minute after the administration, beginning 15 s after epinephrine injection, and decreased to 80% of baseline mean BP. Only the dose of 0.3 mg/kg, which showed an initial decrease of BP, was followed by a subsequent increase, which was observed 2 min after the administration and lasted for 10 min.



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  		Figure 1. Change of diastolic arterial blood pressure (BP) after endotracheal epinephrine (•). Epinephrine or saline administration is indicated by the arrow.

 


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  		Figure 2. Change of mean arterial blood pressure (BP) after endotracheal epinephrine ({blacksquare}). Epinephrine or saline administration is indicated by the arrow.

 
Epinephrine caused significant tachycardia at all doses; it developed immediately after endotracheal administration, reached a maximal level between 0.5–2 min after injection, and lasted until the end of the trial (P < 0.05). There were no significant differences in the arterial blood gases between the study groups.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The use of adrenergic agonists for producing an increase in diastolic BP during cardiopulmonary resuscitation (CPR) improves the success rate of CPR (22). The increase in aortic diastolic BP associated with epinephrine administration is critical for maintaining coronary blood flow and enhancing the success of resuscitation. Epinephrine has been the preferred adrenergic drug for the treatment of patients with cardiac arrest for more than 35 years. Its effectiveness during CPR is a result of its {alpha} and especially its {alpha}2 adrenergic effects by which systemic vascular resistance, coronary perfusion pressure, and myocardial blood flow are increased.

In this study, we showed that only with 10 times the largest recommended dose (i.e., 0.03 mg/kg) of endotracheal epinephrine was there an associated increase of BP that is the prerequisite hemodynamic response for successful resuscitation. The endotracheal administration of epinephrine 0.02, 0.035, 0.1, and 0.2 mg/kg in our dog model produced an early significant decrease in systolic, diastolic, and mean arterial BP that paralleled a long-lasting significant increase in heart rate. This initial decrease of BP associated with endotracheal epinephrine was not addressed in earlier animal studies that had reported favorable results using endotracheal epinephrine (5–7,9,15) (Table 1). In one study comparing plasma epinephrine concentrations after peripheral bronchial versus endotracheal epinephrine delivery in a nonarrest canine model, the mean arterial BP decreased after the epinephrine administration in both groups, a response the authors considered to be the result of using a small dose of epinephrine (10). Our group compared different volumes of dilution in an animal model and showed that endotracheal epinephrine was associated with a decrease in systolic, diastolic, and mean BP (9). Naganobu et al. (13) compared the effects of distilled water and normal saline as diluents for the endobronchial administration of epinephrine in anesthetized dogs; the initial hemodynamic response to endotracheal epinephrine diluted with saline was a decrease of BP. In another canine study in which our group delivered saline-diluted epinephrine endobronchially, the mean arterial BP decreased after the epinephrine administration at a dose of 0.05 mg/kg. Pretreatment with a nonspecific ß blocker (propranolol) abolished these effects (17).


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  		Table 1. Previously Published Studies and Reported Hemodynamic Effects of Endotracheal Adrenaline Administration on Blood Pressure
 
This initial decrease of BP associated with endotracheal epinephrine was generally overlooked in clinical studies as well. Raymondos et al. (14) investigated the effect of endotracheal epinephrine in 34 patients receiving implantable cardioverter defibrillators under general anesthesia and demonstrated an increase in mean arterial BP but did not discuss the decrease in mean arterial BP in the initial phase after the epinephrine administration. In addition, some (unspecified number) of their patients were on ß blockers, and this may have abolished the ß2-mediated decrease of BP (14). Suspicion about the effectiveness and optimality of the standard epinephrine dose administered endotracheally was raised in other clinical investigations. Quinton et al. (20) found that 10 mL of 1:10,000 epinephrine, which is approximately 0.01 mg/kg, was ineffective in 5 patients in asystolic cardiac arrest. McCrirrick and Monk (23) examined the hemodynamic effects of endotracheal epinephrine over a range of doses to a maximum of 10 µg/kg and suggested that these amounts are likely to be ineffective. McCrirrick and Kestin (8) compared systolic BP responses to IV and endotracheal (0.5 µg/kg diluted to 5 mL) epinephrine administration in 12 patients undergoing elective hip replacement. They reported that endotracheal administration of epinephrine failed to produce a clinically important increase in systolic arterial BP in any patient and that arterial BP decreased by 10 mm Hg or more after the endotracheal epinephrine administration in four patients.

Why would a small endotracheal dose, but not a 10-fold larger dose, cause a decrease in BP? The answer to this question may lie in the interaction between epinephrine and its receptors. Studies in animal models indicate that epinephrine produces a dose-dependent vasopressor response through distinct {alpha} and ß subsets of end-organ receptors (24). Epinephrine is the final product of catecholamine synthesis stimulating both {alpha}- and ß-adrenergic receptors in a dose-dependent fashion. At very small concentrations (0.05–0.1 µkg/min), the ß-adrenergic receptors are preferentially activated, resulting in positive inotropic and chronotropic effects (19). At larger doses (0.2–1 µkg/min), it is a vigorous vasoconstrictor (19). This is associated with arteriolar vasoconstriction causing increased systemic vascular resistance and thus increased aortic BP leading to improved coronary perfusion pressure and myocardial blood flow (25). The increase in aortic diastolic BP associated with epinephrine during CPR is critical for maintaining coronary perfusion pressure and myocardial blood flow and is the key to its effectiveness in successful resuscitation. However, in contrast to the importance of {alpha} stimulation during resuscitation, ß stimulation may be counterproductive by causing peripheral vasodilatation, decreasing aortic BP, and reducing myocardial perfusion pressure. Furthermore, in humans undergoing CPR, cardiac output decreases to <30% of normal values (26). This may limit blood flow and the transport of drugs from the alveoli to the central circulation, thereby further decreasing epinephrine blood concentration to the ß adrenergic dose range, and this may account for the failure of endotracheal administration of epinephrine during CPR, a feature that was noted in recent clinical reports (12–15). These effects were abolished in the current study when the dogs were treated with a larger endotracheal dose.

Several limitations of the present study must be considered. This investigation does not address other factors that could affect the absorption of an endotracheal drug such as the drug’s plasma levels and effectiveness (including technique or method of administration), the use of a diluent, the properties of the diluent, particle size, or the total volume of the given solution that had been previously investigated in studies that dealt specifically with these issues (5–8,10,11,20,23).

Cross-species catecholamine pharmacokinetics and pharmacodynamics are not well established. The underlying pharmacologic processes are similar in humans and other mammals, but direct application of catecholamine doses from animals to humans is not necessarily appropriate. Nevertheless, the reasoning behind the suggestion that the recommended dose may be deleterious to animals pertains to humans as well (27).

There is an extremely large individual variation in response to catecholamines administered during CPR (27). Wide interpatient variability in catecholamine pharmacokinetics and pharmacodynamics is well established for critically ill and normal humans. It is likely that there is similar intersubject variability during resuscitation from cardiac arrest (28). Furthermore, the individual’s response to catecholamines most likely relates to more factors other than plasma catecholamine levels, including the density, number, and location of {alpha}-adrenergic receptors (29). This suggests that absolute levels of catecholamines alone cannot guarantee successful resuscitation. Thus, our results may not necessarily apply to other hemodynamic scenarios, such as cardiac arrest or ventricular fibrillation models. However, other studies described indications for endobronchial drug administration with (still) stable circulation (8,11,13,17,30).

Another issue to be considered is that tracheal absorption of epinephrine at any given dose may be less effective during cardiac arrest than it was in our study and may cause predominantly ß2-mediated effects (8). Nevertheless, we believe that the accumulated data on animal and clinical studies are more and more convincing that the recommended doses of endotracheal epinephrine of 0.02–0.03 mg/kg pose a possible hazard. Goetting and Paradis (31) proposed that larger IV doses of epinephrine than the ones currently recommended may improve resuscitation rates, but there are no equivalent clinical studies on large dose endotracheal doses. Large dose epinephrine may improve coronary perfusion and increase vascular resistance to promote initial return of spontaneous circulation during CPR, but these same effects may exacerbate postresuscitation myocardial dysfunction (2). Insofar as our findings on a canine model clearly demonstrated the benefit of larger endotracheal epinephrine doses on systolic, diastolic, and mean BP, the incorporation of larger endotracheal doses in humans with cardiac arrest as first-line therapy warrants additional studies.


   Acknowledgments
 
This study was a part of the requirements for graduation from the Medical School of Tel Aviv University, Tel Aviv, Israel (YM). We thank Esther Eshkol for editorial assistance.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication June 14, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press