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Epinephrine therapy in patients receiving beta blocker treatment

Question:

2/9/2021
I see a 16 year-old on carvedilol. Our pharmacy has a significant drug-drug interaction warning with epi:

• Noncardioselective beta-blockers can significantly enhance the pressor response to epinephrine. The mechanism involves blockade of beta-2 adrenergic receptors in the peripheral vasculature, resulting in unopposed alpha-adrenergic effect of epinephrine that is responsible for vasoconstriction. Severe hypertension accompanied by bradycardia has been reported in patients who were treated with a noncardioselective beta-blocker like propranolol or nadolol prior to receiving epinephrine. In rare cases, cardiac arrest and stroke have occurred.
• Beta-blockers may attenuate the response to epinephrine in the treatment of anaphylactic reactions. Noncardioselective beta-blockers, in particular, can antagonize the bronchodilating effects of epinephrine by blocking beta-2 adrenergic receptors in smooth muscles of the bronchial tree. All beta-blockers can antagonize the cardiostimulatory effects of epinephrine by blocking beta-1 adrenergic receptors in the heart. Some investigators have suggested that the use of beta-blockers in itself is associated with an increased incidence and severity of anaphylaxis due to modulation of adenylate cyclase, which can influence release of anaphylactogenic mediators. However, data are limited and conflicting.
• Extreme caution and close monitoring of cardiovascular status are indicated when epinephrine is administered to patients treated with noncardioselective beta-blockers. A dosage reduction of epinephrine may be necessary.

Our practice parameters state:
If epinephrine is ineffective in treating anaphylaxis in patients taking b-blockers, then glucagon administration might be necessary. Glucagon can reverse refractory bronchospasm and hypotension during anaphylaxis in patients on b-blockers by activating adenyl cyclase directly and bypassing the b-adrenergic receptor.

Question: How should patients on non selective or selective beta blockage be counseled and managed regarding the use of epi?

Answer:

The simple response is that patients with anaphylaxis who are receiving non-selective or selective beta blocker medications should be treated with IM epinephrine (1,2). The only effective therapy for anaphylaxis is epinephrine, and this treatment should be utilized irrespective of beta blocker therapy. The concerns you raise are relative but not prohibitive. Adding nebulized adrenergic bronchodilator with antii-muscarinic therapy may help if bronchospasm is not addressed with epinephrine, and hypertension is generally not a problem in subjects with anaphylaxis, particularly in children. Hypotension is typical but not always noted with anaphylaxis (see archived Ask the Expert question below). The prohibitions raised by the pharmacy warnings are referring to general pharmacology and not pharmacology during life-threatening anaphylaxis. The use of glucagon is a consideration, as this therapy increases cyclic AMP in various cells, including mast cells, without relying on the beta receptor. However, this therapy is associated with nausea and vomiting and requires IV access. Thus, this is not relevant when counseling patients.

In summary, I would recommend counseling patients on beta blocker therapy the same as patients at risk of anaphylaxis who are not receiving beta blocker therapy. Epinephrine should be utilized as an IM injection, preferably in the latter thigh, when the first manifestation of anaphylaxis is recognized. I would prefer that the beta blocker treatment be changed, and I would discuss the need of beta blocker therapy and possible alternatives with the other treating physicians. The risk of severe anaphylaxis is increased with beta blocker therapy; therefore, advising appropriate use of epinephrine rather than caution is even of greater importance in such individuals (1).

I hope this information is of help to you and your practice.
All my best.

Dennis K. Ledford, MD, FAAAAI

1) Coop CA, Schapira RS, Freeman TM. Are ACE Inhibitors and Beta-blockers Dangerous in Patients at Risk for Anaphylaxis? J Allergy Clin Immunol Pract, 2017; 5(5): 1207-11.

2) Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bernstein D, Bernstein J, et al. Anaphylaxis—a practice parameter update 2015. Ann Allergy Asthma Immunol 2015;115:341-84.

10/22/2015: Anaphylaxis with hypertension
I have very few patients who react to some food or some drug with an allergic classical reaction even sometimes with an anaphylactic shock, but the amazing point is that they develop a hypertension instead of hypotension. How to explain this and what would be the place of adrenaline?

Answer:
Anaphylaxis is a syndrome and the manifestations show wide variability during a single episode and among individuals. The source of the allergen, the status of the affected individual prior to the event, the physiologic responses to anaphylaxis, the time course and variability as to which organ systems are most affected add to the range of clinical manifestations.

Your question specifies “anaphylactic shock” but this is not consistent with hypertension by definition. However, during a reaction, patients may initially have hypertension and subsequently develop hypotension. Peripheral vasoconstriction also varies during the course of anaphylaxis such that the hypotension occurring late in anaphylaxis is more likely due to third space loss with reduced vascular volume and myocardial contractility rather than vasodilation. In this situation, epinephrine would have limited or no benefit and the preferred treatment would be vascular volume replacement.

My approach with suspected or definite anaphylaxis with hypertension is to use lower doses of IM epinephrine (e.g. 0.05-0.1 mg for an adult) and closely observe the patient with frequent rechecks of the blood pressure. I do not think you are placing your patient at risk with low dose epinephrine and you are potentially adding risk if you delay treatment of anaphylaxis.

I will share your question with the lead author of the prior and most recent Practice Parameter: Diagnosis and Management of Anaphylaxis (2010 Anaphylaxis Practice Parameter), Dr. Phil Lieberman. Dr. Lieberman has responded. First let me concur with everything Dr. Ledford mentioned in his response to your question, and I would add the following:

First of all, in actuality, it should not be surprising that patients who have classic anaphylactic reactions characterized by skin and respiratory involvement also experience hypertension rather than hypotension. A starting point to understand that would be to review the NIAID/FAAN definition of anaphylaxis (1) which has also been adopted by the FDA in establishing whether or not an anaphylactic event has occurred during the administration of a drug under investigation for approval. For your convenience, I have copied this definition copied.

“Clinical criteria for diagnosing anaphylaxis
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)

2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP**
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's baseline

PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2 × age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.”

As you can see, anaphylaxis can exist without hypotension. The question then becomes how often this occurs, and based on a number of studies (2-9), the vast majority of anaphylactic episodes occur without hypotension. Clinical manifestations of hypotension such as dizziness or documented hypotension occur in probably somewhere around a third of reactions based upon these studies. This means of course that two-thirds occur without hypotension, but it should be clearly stated that does not mean these patients are normotensive. In fact, many are hypertensive during these events. Perhaps the majority experience elevation of blood pressure during non-hypotensive episodes. The reason for this is that during episodes of anaphylaxis, the blood pressure can become elevated because there is compensatory secretion of catecholamines, both norepinephrine and epinephrine (10, 11); activation of the angiotensin system with production of angiotensin I and angiotensin II (12); and production of endothelin-1, a potent vasoconstrictor peptide that is elevated in patients with heart failure, strokes, and hypotension as well (13). “

Unfortunately, we do not know in many cases why a given individual characteristically develops hypotension during anaphylactic episodes whereas other patients do not except for the predisposition to hypotension in patients taking beta-blockers and ACE inhibitors. Nonetheless, many patients do have hypertension accompanying respiratory and cutaneous manifestations, and as noted above, this is probably due to a stress response involving catecholamines, angiotensin, and endothelin.

References:
1. Sampson HA, et al. Second symposium on the definition and management of anaphylaxis: summary report - second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol. 2006; 117(2):391-397.
2. Soreide E, Busrod T, Harber S. Severe anaphylactic reactions outside hospital; etiology, symptoms, and treatment. Acta Anaesthesiologica Scandinavica 1988; 32:339-344.
3. Moro M, Tejedor M, Esteban J, et al. Severity of anaphylaxis according to causes and demographic characteristics. Journal of Allergy and Clinical Immunology 2008; 121(2):S24.
4. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. Journal of Allergy and Clinical Immunology 2001; 107:891-896.
5. Braganza SC, Acworth JP, McKinnon DR, et al. Pediatric emergency department anaphylaxis: different patterns from adults. Archives of Disease in Childhood 2006; 91:159-163.
6. Simons FER, Chad ZH, Gold M. Anaphylaxis in children. Allergy and Clinical Immunology International, Journal of World Allergy Organization 2004; 1 (Supplement):242-244.
7. Simons FER. Anaphylaxis in infants: can recognition and management be improved? Journal of Allergy and Clinical Immunology 2007; 120(3):537-540.
8. Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm. International Journal of Cardiology 2006; 110:7-14.
9. DeSouza RL, Short T, Warman GR, et al. Anaphylaxis associated with fibrinolysis, reversed with tranexamic acid and demonstrated by thromboelastography. Anaesthesia Intensive Care 2004; 32:580-587.
10. Fahmy NR. Hemodynamics, plasma histamine and catecholamine concentrations during an anaphylactoid reaction to morphine. Anesthesiology 1981; 55:329-331.
11. Moss J, Fahmy NR, Sunder N, et al. Hormonal and hemodynamic profile of an anaphylactic reaction in man. Circulation 1981; 63:210-213.
12. Rittweger R, Hermann K, Ring J. Increased urinary excretion of angiotensin during anaphylactoic reactions. International Archives of Allergy and Immunology 1994; 104:255-261.
13. Gawlik R, Rogala E, Jawor B. Endothelin-1 in plasma of patients with hymenoptera venom anaphylaxis. Journal of Allergy and Clinical Immunology 1998; 101 (abstract):S160.

Sincerely,
Phil Lieberman, M.D.

In summary, the combination of the variability of anaphylaxis severity, the variations during anaphylaxis, the vascular volume and vasomotor tone prior to the event, and the anxiety level associated with anaphylaxis contribute to differences in blood pressure. The assessment is further complicated by the fact that often we do not know the blood pressure prior to anaphylaxis, so that an elevated blood pressure reading may nevertheless be a decrease from the affected individual’s basal blood pressure.

I hope this information is of help to you and your practice.

All my best.
Dennis K. Ledford, MD, FAAAAI