Learning Objectives: After reading this article, the physician should be able to:
1. Discuss the indications and contraindications of epinephrine for the treatment of asthma.
2. Explain the methods of injection of epinephrine for the treatment of asthma.
3. Describe the clinical effects of epinephrine for the treatment of asthma.
Most emergency physicians are quite familiar with the EpiPen, but few have seen serious complications from it. It's unclear whether these devices actually save lives despite their popularity and omnipresence. Occasionally a patient will accidentally inject himself, usually in the hand or finger while frantically trying to stave off an allergic reaction. More often, curious children will accidentally discharge the device. Although only 0.3 mg (adult version) or 0.15 mg (EpiPen Junior) of epinephrine is discharged per dose, this small amount of epinephrine in a digit will almost invariably cause acute ischemia. The result is a pale finger and some numbness but minimal pain.
There are scattered case reports detailing the treatment of accidental EpiPen injection into a digit, but there are little data except anecdotal reports. It's unclear whether the ischemia must be treated or whether it will resolve spontaneously. I could find no reports of permanent sequelae from this device. However, the traditional approach has been to inject the same spot where the EpiPen was discharged with the alpha blocker phentolamine. Almost immediately, phentolamine counteracts the alpha adrenergic agonism of epinephrine, resulting in vasodilation.
Some authors suggest a phentolamine/lidocaine digital block, but that does not make physiologic sense to me. Within a few minutes after administering phentolamine (exact procedure outlined last month), the injured digit should return to baseline, and the suspected (but unproven) vascular emergency is corrected.
There are no downsides to phentolamine injection, and attempting other unproven interventions, such as nitroglycerine ointment and warm water, is probably a waste of time given the safety and efficacy of phentolamine. At the end of last month's column, I asked for reader feedback concerning personal experience with the EpiPen. Any responses will be addressed in future columns.
This month's column discusses another use for epinephrine, an intervention for acute asthma with which I am quite familiar — subcutaneous epinephrine. Writing about epinephrine for asthma probably makes me a bit of a dinosaur these days. Before the widespread use of beta adrenergic aerosol treatment for bronchospasm, however, everyone with asthma presenting to the ED received subcutaneous epinephrine for an acute attack. Most received a number of injections, and the epinephrine usually cured the acute attack. The technique was so common and the results so predictable that the nurses often were given the liberty to start the protocol.
Today's house staff have grown up using aggressive nebulizer beta agonists as their mainstay for the treatment of acute asthma, and this, too, has become a nurse-initiated protocol. My residents have little or no experience with epinephrine for asthma. Because its use has been curtailed, many residents and nurses wrongly believe that this is a very dangerous drug, and are afraid to use it. Epinephrine is religiously eschewed in the older asthmatic despite an excellent safety profile in this population.
The following selected articles extol the value of epinephrine in acute asthma. Epinephrine has been around since the early 1900s, and while not always first-line therapy anymore, epinephrine is still a very potent bronchodilator that should remain in one's arsenal of asthma interventions.
The Use of Epinephrine in the Treatment of Older Adult Asthmatics, Cydulka R, et al, Ann Emerg Med, 1988;17(4):322
Because there is some concern that epinephrine may be harmful for older asthmatics or for patients with coexisting heart disease or hypertension, the authors developed a protocol to study these issues. They focused on asthmatics over age 40. The specific concern and investigation focus were the potential adverse cardiovascular effects of epinephrine when administered to patients at risk for hypertension and coronary artery disease. This study from the ED of the Northwestern University Medical School compared the effects of up to four doses of subcutaneous epinephrine (0.3 mg [0.3 ml] of 1:1,000 epinephrine per dose) given at 20-minute intervals. At least half of the subjects received three doses. Aerosol adrenergics were not used during the study period.
The 20-minute interval protocol for subcutaneous epinephrine was at that time a standard approach and universally accepted as an intervention of choice for asthma. Of the 108 episodes of acute asthma, patients were grouped by age of over or under 40. Ages ranged from 15 to an amazing 96 years. If the patient had a history of angina or recent myocardial infarction, they were excluded. Patients with hypertension or other nonactive forms of cardiac disease were eligible for epinephrine for their asthma, however. Criteria for the early termination of the protocol included ventricular tachycardia, three or more PVCs with hypotension, or the precipitation of angina. The authors monitored heart rate, EKG rhythm, blood pressure, respiratory rate, and peak expiratory flow.
The older patients had significantly higher baseline systolic blood pressure than the younger patients (147 vs. 131 mmHg). This was statistically significant (P<0.05). The mean systolic pressure decreased (by about 10 mmHg) in patients over 40 after they were treated with epinephrine. The mean diastolic pressure and heart rate decreased in patients over 40 following all doses of epinephrine. Patients in both groups demonstrated a decrease in respiratory rate and an increase in peak flow rates. Both groups demonstrated nonsignificant PACs and PVCs. As the bronchospasm was relieved and pulmonary function improved, blood pressure and pulse rate invariably declined. No patients in the older group developed serious ventricular arrhythmias.
Although the authors cautioned against the use of epinephrine in older asthmatics with coronary artery disease, their findings supported the use of subcutaneous epinephrine for all patients with acute asthma, regardless of age.
Comment: Before the advent of albuterol, epinephrine was standard of care for all asthmatics, and even the older patients tolerated it just fine. Today, most asthmatics who walk into the ED do just fine with inhaled albuterol and atrovent. Inhaled beta agonists/anticholinergics are now used in all age groups, and albuterol is even given continuously. However, when albuterol was first introduced, it was medical heresy to use it more than every four hours. Even though epinephrine was supported by everyone, when we started using albuterol every hour in the ED, our pulmonologist accused us of practicing dangerous medicine. “Imagine the hubris of those ER docs” was one quote I heard in a P&T committee meeting. Go figure.
The patient arriving by ambulance in extremis is another story. I personally use subcutaneous epinephrine as my first-line treatment in most seriously ill asthmatics. It's easy to administer, it works, and the blood pressure and heart rate invariably decline despite the puzzled look of the house staff and young nurses. In fact, I often have to give the drug myself because a nurse will not give it to someone who has a pulse rate of 160 or a blood pressure of 180 systolic. The hypertension and tachycardia are due to hypoxia, anxiety, and the work of breathing, and these only get better with the relief of bronchospasm. I realize this is a difficult concept to understand unless you have personal experience with it, but I am certain that this technique has saved many an asthmatic from intubation and periods of prolonged hypoxia.
Epinephrine will cause some tremors, chills, anxiety, and occasionally nausea, but most patients can tolerate 0.3 mg (0.3 ml) of 1:1,000 subcutaneous epinephrine every 20 to 30 minutes. In the old days, I frequently used 0.5 ml in a similar fashion, but I was never certain whether the increased dose was beneficial. Although patients who are given epinephrine commonly will experience tremors, a similar effect is seen with beta agonists. Of course, you don't always have to give 0.3 mg. If you are concerned about the patient's cardiovascular status, 0.1 mg injections are one way of hedging your bet. While the albuterol is being set up or during the initial stages of treatment, even minor doses of epinephrine may turn the tide in your favor. You should certainly respect epinephrine's potential cardiovascular effects, so a cautious approach is warranted in the elderly or someone with serious heart disease. Age itself, however, is not a contraindication. One patient in this study was 96 years old!
Other specific benefits of epinephrine include the intubated asthmatic, children (0.01 mg/kg), or other individuals who cannot readily use inhaled medications. One old-fashioned way to differentiate bronchiolitis/bronchitis from asthma in a child was to assess the response to subcutaneous epinephrine. I'm not sure I ever believed that dogma, but many small children with tachypnea and wheezing tolerated a shot of epinephrine in the ED.
The patient who may benefit most from subcutaneous epinephrine is the one in severe enough bronchospasm to be unable to move any air or not be able to hold the nebulizer. These are the patients who rip off the face mask. Some patients with severe long-standing asthma know better than the doctor when they need to be intubated. Some even ask for the ET tube. These are patients who are standing hunched over the bed, refuse to sit down, are gasping for breath, and are about as diaphoretic as the treating physicians. This patient is about to have a respiratory arrest on the ED floor, and these are the patients most likely to receive epinephrine when I am their doctor. It's prudent, of course, merely to intubate these really sick asthmatics, but that's easier said than done.
Parenthetically, I know of two Munchausen's patients who faked asthma just to get intubated. They could look extremely distressed and even wheeze on command, quite a talent, except they could never master the art of fooling the pulse oximeter. One even carried a counterfeit letter from a nonexistent doctor stating that this patient should be intubated (spelled incorrectly) early because he had severe refractory asthma.
Although theoretically dangerous, epinephrine has never been demonstrated to be contraindicated in acute asthma, regardless of age. I usually have to pull out this particular article a few times a year to buttress my intervention to the neophyte intern or to the recent nursing school graduate. (Thanks for doing this study, Rita). Most of the older nurses merely smile in approval when they hear me ask them for epinephrine; meanwhile, the house staff try to figure out the dose of magnesium or solumederol, interventions which may help asthma but rarely make the difference between intubation or provide a rapid relief of bronchospasm.
Although one should be cognizant of the potent cardiovascular effects of epinephrine, tachycardia, the work of breathing, and hypoxia are probably more detrimental to patients with coronary artery disease than the epinephrine. Although I would not use it in a patient who had chest pain, ST segment elevation, or just had been released from the hospital following bypass surgery or stenting, such patients are few and far between. In my experience, the older patient who seems to have severe asthma is more likely suffering from pulmonary edema or an exacerbation of COPD than straightforward status asthmaticus.
Subcutaneous Adrenaline versus Terbutaline for the Treatment of Acute Severe Asthma, Spiteri MA, et al, Thorax, 1988;43(1):19
This article is a prospective double-blind study comparing the effects of subcutaneous epinephrine versus subcutaneous terbutaline in a small cohort of patients presenting with severe asthma. The patients' ages range from 16 to 65, so a number of older individuals with potential cardiovascular problems were included. In the mid-1980s, there was a trend to use subcutaneous terbutaline, a pure beta agonist, for acute asthma because of the notion that it was as effective but less toxic than epinephrine. Terbutaline's isolated beta agonism theoretically was better than the combined alpha and beta effects of epinephrine.
Following baseline evaluation, the patients were given either 0.5 mg of subcutaneous epinephrine, or terbutaline. Note that the dose of epinephrine was 0.5 mg, a rather hefty dose compared with the standard 0.3 mg protocols. In addition to the study drugs, patients also were given nebulized albuterol, IV hydrocortisone, and aminophylline. A number of pulmonary function parameters were measured in both groups at 5 and 15 minutes after the injection. There were no significant increases in blood pressure or heart rate with either the epinephrine or terbutaline treatment groups, and no treatment-related EKG abnormalities were observed. There was no significant difference between the two drugs, leading the authors to conclude that subcutaneous epinephrine and terbutaline yielded comparable improvements in patients presenting with acute asthma. They also concluded that neither had adverse cardiovascular effects.
Comment: A number of articles have demonstrated the benefit of subcutaneous terbutaline for the treatment of acute asthma, but it has never been proven to be any better or safer than epinephrine. Both drugs will give significant tremor and anxiety, but subcutaneous terbutaline has fallen out of favor. Its main use today is for the treatment of premature labor. I note that the dose of epinephrine in this study was on the high side (0.5 mg), and I refer to my previous comment that 0.3 mg would be a reasonable starting dose for most adults. As noted in all other studies, the treatment of acute bronchospasm with the potent alpha and beta agonist epinephrine decreased blood pressure and pulse rate because of improved pulmonary parameters.
Intravenous Epinephrine in Life-Threatening Asthma, Smith D, et al, Ann Emerg Med, 2003;41(5):706
This is a recent and relatively small retrospective study investigating the use of intravenous rather than subcutaneous epinephrine for treating patients with life-threatening asthma. It was an explicit retrospective chart review of 27 emergency department patients, ranging in age from 19 to 58 (mean age 25). It took 10 years for the UCLA Department of Emergency Medicine to gather these patients, but apparently IV epinephrine was an option to the clinicians at that institution. While the authors do not support the routine use of epinephrine for mild to moderate asthma, they believe it may have a role in life-threatening asthma. Epinephrine by the IV route has never been meaningfully evaluated, however. The intravenous route offers a rapid onset of action, and reliable delivery of a titrateable drug, and the option to immediately discontinue the medication if adverse effects occur. This defines an ideal drug for a volatile, life-threatening, and potentially unstable situation. Eight of the 27 patients had been previously intubated for asthma. Ten of the patients were hypertensive (BP greater than 160 systolic) prior to treatment with epinephrine, and none had an increase of greater than 10% in systolic BP from the epinephrine.
In addition to the aggressive use of inhaled beta agonist and adjunctive steroids and other therapies, the attending physician had the discretion to use intravenous epinephrine in severe respiratory distress. As one would expect, all patients provided this therapy were treated in the ICU, but it is not clear if the drip was started in the ED. Also, I could not determine how many patients were intubated.
A number of cardiovascular and respiratory parameters were analyzed. Explicit criteria for adverse outcomes included development of a new arrhythmia (other than sinus tachycardia) within 60 minutes of intravenous epinephrine; cardiac ischemia as manifested by new ischemic EKG changes; development of a new focal neurological finding believed to be possibly caused by cerebral ischemia; new or worsening hypotension; or new or worsening hypertension related to the epinephrine infusion.
Most patients received a small loading dose of IV epinephrine prior to a continuous infusion. The loading dose ranged between a minimal 0.05 mg to a rather impressive 1 mg. The mean loading dose was 0.2 mg. The continuous infusion rate peaked at 0.02 mg/min. I calculate this to be 0.4 mg over 20 minutes so it was closely equivalent to the standard subcutaneous dosing regimen. Most patients received about 1 mg epinephrine from the infusion over an hour. The actual procedure for mixing or infusing the drip was not detailed. The intervention was not driven by a strict protocol so the technique varied. Altered mental status and decreased respiratory effort (usually defining respiratory failure) were the seeming indications for IV epinephrine.
There were no documented major adverse effects of intravenous epinephrine, and there were no deaths among the study patients. Only one patient complained of chest pain that was not attributed to the epinephrine use. Not a single patient had an arrhythmia other than sinus tachycardia during the administration of the intravenous epinephrine. About a third of the patients demonstrated an increase in pulse rate. There were no adverse EKG changes consistent with ischemia, no increase in cardiac enzymes, no strokes, and no significant hypertension.
Despite an intensive and specific effort, the authors were unable to find any major adverse effects of intravenous epinephrine in these critically ill patients. There were not even any adverse perturbations in vital signs despite the intravenous infusion of this powerful alpha and beta agonist. The authors note that most patients were young and that their study size was small. They did, however, conclude that their study demonstrated the safety of intravenous epinephrine in patients with acute life-threatening asthma, and they did suggest a future trial to further identify the particular aspects of this therapy.
Comment: I like this article, but intravenous epinephrine is a potent intervention that should be reserved for critically ill patients and even then used with caution. (See the insightful accompanying editorial by Steve Green, MD, in the same issue.) Few physicians would ever consider an intravenous infusion of epinephrine for treating an asthmatic, particularly when he is critically ill. Personally, I have never used this intervention. This protocol would certainly get the attention of my medical staff, and likely a few questions and criticism would shortly arise. The nurses would not likely hang the drip because it's not in their protocol manual. I don't suggest using it on your next asthmatic without a buy-in of the consultants.
This study further substantiates the benefits of epinephrine versus the adverse effects in critically ill asthmatics. In a similar protocol, I do recall using intravenous isoproterenol for the last-ditch treatment of severe intubated asthmatics, and those patients clearly developed significant tachycardia and hypotension, and some had cardiac enzyme changes. Isoproterenol is the world's most potent beta agonist, but most of my current residents have never heard of it. Isoproterenol inhalers were commonly prescribed, but were withdrawn from the market years ago because of a suspected increased risk for sudden death. An isoproterenol infusion was considered a last-ditch effort for asthma, one undertaken only in very controlled circumstances. IV isoproterenol is certainly a clinical dinosaur today, and although it is a potent beta agonist and great bronchodilator, it is best left out of asthma protocols.
IV epinephrine is not the same as subcutaneous epinephrine. Although subcutaneous epinephrine is quite safe, I caution the reader to be very respectful and generally eschew even very small doses of intravenous epinephrine when the subcutaneous route is reasonable. In the intact vascular system, IV doses of epinephrine as low as 0.1 mg can have potent cardiovascular effects, producing severe hypertension, tachycardia, headache, and chest pain. Even in the presence of anaphylaxis, the subcutaneous route for epinephrine is generally preferable and adequate. If the blood pressure is greater than 60 to 70 mmHg in acute anaphylaxis, I will usually first opt for subcutaneous epinephrine, reserving the IV route for more seriously ill patients or those not rapidly responding. If I am going to use IV epinephrine for anaphylaxis, my preference is to mix 1 mg in 500 ml of saline, and slowly titrate the intravenous drip. In a life-threatening situation of anaphylaxis, small aliquots of IV epinephrine (such as 0.1 mg) can be supported.
Note that the crash cart epinephrine (1:10,000) and asthma type epinephrine (1:1000) are very different preparations. While 1 ml of crash cart epinephrine (0.1 mg) is a common initial intravenous titrating dose for this preparation, giving 1 ml of the asthma type preparation delivers a full 1 mg.
A procedural note about the mechanics of delivering subcutaneous epinephrine is in order. Most nurses know how to administer small doses of epinephrine with a 1 ml syringe and a short 25 gauge needle into the deltoid region. This is essentially a subcutaneous injection, but the short needle allows one to insert the full length of needle perpendicularly into the skin. Some authors and anecdotal experience have suggested that intramuscular epinephrine may be absorbed slightly more quickly in the emergent situation. Studies have found, however, that subcutaneous epinephrine will reach the systemic circulation in a few minutes. The deltoid is a very vascular area, and one sees an effect of epinephrine injected in the general vicinity of the deltoid muscle quite quickly. I see no reason to use a deep intramuscular injection except into an extremely obese individual.
One benefit of epinephrine that has been largely lost on current day house staff is the drug's remarkable ability to treat acute urticaria (hives). A small aliquot of subcutaneous epinephrine, such as 0.1 or 0.2 mg, will cure most cases of acute hives within a few minutes. Although IV diphenhydramine (Benadryl) is a standard treatment for hives, epinephrine works better and faster. There is no reason that both can't be used at the same time. The next time you see a patient who is going crazy with itching and severe urticaria, consider a small dose of subcutaneous epinephrine as your first-line intervention.
In the old days, the standard subcutaneous epinephrine protocol for acute asthma was followed by a shot of susphrine, a long-acting aqueous epinephrine preparation that is no longer available (J Natl Med Assoc 1953;45:120), a MedLine reference I could not find. Most physicians erroneously believed the susphrine was epinephrine in oil, but this is not the case. Susphrine was, in fact, a depot subcutaneous injection of epinephrine, delivering both immediate effects and bronchodilation that continued for four to six hours. I have been unable to find susphrine in our pharmacy over the past years when I wanted to use it for acute uriticaria or allergic reactions. The ampoules were cloudy and smelled like sulfur, and often the nursing staff threw them out when they observed these properties, believing them to be out of date.
Despite my labeling it a clinical dinosaur that should be resurrected in select cases, current protocols for the treatment of severe asthma still consider epinephrine. See the recent review on severe asthma by Papiris et al. (Crit Care 2002;6:30.)
Reader Feedback: Readers are invited to ask questions and offer personal experiences, comments, or observations on InFocus topics. Dr. Roberts requests feedback on issues raised by this month's discussion, particularly answers to his questions below. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send questions and comments to JRoberts@MercyHealth.org.
1. Do you use epinephrine for acute asthma, and what are the parameters for use?
2. Do you have experience with IV epinephrine, good or bad?
3. Do you know of adverse events from epinephrine used for asthma (such as cardiovascular events)?