Adrenaline in the treatment of anaphylaxis: what is the evidence?
BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7427.1332 (Published 04 December 2003) Cite this as: BMJ 2003;327:1332
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EDITOR, McLean-Tooke et al (1) state that "the benefit of using
appropriate doses of intramuscular adrenaline far exceeds the risk" and
that "intravenous route should be reserved for those with unresponsive
anaphylaxis." However, such claims are inconsistent with the statement
that "As there are no controlled trials there is no way to estimate the
risk in relation to benefit" and readers get a very misleading message.
We would like to emphasize that it is the time of maximum plasma
adrenaline concentrations that affects the outcome. There is now good
clinical and experimental evidence indicating that delay of
administration of adrenaline is associated with both increased risk and
decreased benefit. (2,3) Intravenous administration of adrenaline ensures
rapid delivery to its site of action and avoids the problem of erratic and
variable absorption. In a view of this, the expert use of high dilution
intravenous adrenaline in hospitals with appropriate monitoring may be
more optimal care for a patient with severe anaphylaxis. The evidence for
safety of intravenous adrenaline in a small series of younger adults with
acute life-threatening asthma has recently been documented.(4)
As authors rightly point out, increased risk is associated with
adrenaline overdose, usually caused by inappropriate administration.
This risk is relatively high, because therapeutic and toxic doses are
rather similar. Non-intravenous adrenaline administration is therefore
entirely appropriate in initial pharmacologic management of anaphylaxis in
a setting without monitoring and intensive care facilities. Intramuscular
route seems to be superior to the subcutanous route, because of faster
absorption. Nevertheless, pharmacokinetic data suggest that subcutaneous
route might be safer. We have therefore proposed that for high risk
patients with mild symptoms, subcutanous route would be better option.(5).
In low risk patient with mild reaction, however, the risks of adrenaline
may outweigh the benefits, even if administered by subcutaneous route.
Michal R Pijak, consultant in rheumatology, allergy and clinical
immunology,
Frantisek Gazdik, associate professor of clinical immunology,
Katarina Gazdikova, associate professor of clinical pharmacology,
Slovak Medical University, Institute of Preventive and Clinical
Medicine,
Limbova 12, 833 03 Bratislava, Slovakia
1. McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in
the treatment of anaphylaxis: what is the evidence? BMJ 2003;327:1332-5.
2. Pumphrey RSH. Lessons for management of anaphylaxis from a study
of fatal reactions. Clin Exp Allergy 2000;30:1144-50.
3. Bautista E, Simons FE, Simons KJ, Becker AB, Duke K, Tillett M et
al. Epinephrine fails to hasten hemodynamic recovery in fully developed
canine anaphylactic shock. Int Arch Allergy Immunol. 2002;128:151-64.
4. Smith D, Riel J, Tilles I, Kino R, Lis J, Hoffman JR. Intravenous
epinephrine in life-threatening asthma. Ann Emerg Med. 2003;41:706-11.
5. Pijak MR, Gazdik F, Gazdikova K. Subcutaneous adrenaline for
anaphylaxis: compromise in high risk patient with mild symptoms.
http://bmj.com/cgi/eletters/327/7427/1332#44125, 19 Dec 2003.
Competing interests:
None declared
Competing interests: No competing interests
Subcutaneous adrenaline for anaphylaxis: compromise in high risk
patient with mild symptoms
EDITOR-McLean-Tooke et al state that "mild reactions such as
angioedema and urticaria without airway involvement would not be described
as anaphylaxis." (1) Although this statement is in line with current
guidelines, confusion arises because more than half of the patients may
have mild symptoms for one hour or more before severe respiratory
compromise develop.(2) This may increase the risk of late administration
of adrenaline which is generally associated with poor outcome.
We welcome that history of severe reaction was selected as the main
criterion in the algorithm for identifying patients who may benefit from
an adrenaline auto-injector. However, the authors paradoxically
introduced another source of confusion, by claiming that "the severity of
previous reactions does not determine the severity of future reactions"
Most importantly, they failed to explain under what circumstances
should adrenaline be administered in a high risk patient with mild
symptoms.
Considering that benign allergic reactions should not be treated
with adrenaline(3) and that the potential for misdiagnosis in high risk
patient with mild symptoms is not known, we suggest compromise solution:
to administer adrenaline subcutaneously instead of intramuscularly. The
potential for harm following subcutaneous adrenaline administration is
extremely small,(4) and its efficacy for prevention of anaphylaxis has
recently been documented.(5)
Finally, we would like to stress that the use of adrenaline with
milder symptoms will depend on patient´s history. Several factors
mentioned by authors seem to predispose individuals to more severe
anaphylaxis, including a history of previous severe reaction, asthma,
reaction to trace allergen and lack of access to emergency medical care.
A number of other factors may lower the threshold for when to administer
adrenaline eg, if the reaction is provoked by peanut, tree nuts, or
seafood, personal history of atopy, adolescence (especially late teens),
failure to identify the responsible allergen in the meal.
Michal R Pijak, consultant in rheumatology, allergy and clinical
immunology
Frantisek Gazdik, associate professor of clinical immunology
Katarina Gazdikova, associate professor of clinical pharmacology
Slovak Medical University, Institute of Preventive and Clinical
Medicine,
Limbova 12, 833 03 Bratislava, Slovakia
1. McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in
the treatment of anaphylaxis: what is the evidence? BMJ 2003;327:1332-5.
2. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal
anaphylactic reactions to food in children and adolescents. N Engl J Med
1992;327:380-4.
3. Hourihane JO'B, Warner JO. Benign allergic reactions should not
be treated with adrenaline. BMJ 1995;311:1434.
4. Cone DC; National Association of EMS Physicians Standards and
Clinical Practice Committee. Subcutaneous epinephrine for out-of-hospital
treatment of anaphylaxis. National Association of EMS Physicians Standards
and Clinical Practice Committee. Prehosp Emerg Care 2002;6:67-8.
5. Premawardhena AP, de Silva CE, Fonseka MM, Gunatilake SB, de Silva
HJ. Low dose subcutaneous adrenaline to prevent acute adverse reactions to
antivenom serum in people bitten by snakes: randomised, placebo controlled
trial. BMJ 1999;318:1041-3.
Competing interests:
None declared
Competing interests: No competing interests
EDITOR – As emergency physicians, we would have liked to see the
informative review by McLean-Tooke et al. [1] completed by a discussion
of the need for hospital observation following the use of adrenaline for
anaphylaxis.
In accordance with current guidelines, [2,3] many patients attending
emergency departments (ED) in the UK with an allergic reaction will be
admitted for a period of observation if they have required adrenaline.
The rationale for this is the risk of a secondary event after resolution
of
initial symptoms (the so-called biphasic reaction). The reported
incidence of such reactions varies between 3 and 20%. [4,5] The mean
time to onset of the secondary event is reported to be 10 hours, but they
may occur as late as 24-36 hours after the initial reaction. [5]
The available evidence in this area is limited to small case series.
Most of
those studies provide neither information about patient disposition nor
duration of observation following resolution of symptoms. While
secondary reactions are said to be potentially equally or more severe
than the first one, most are probably mild. [4] There are no published
reports about adverse outcomes from secondary reactions in patients
discharged from the ED.
The study by Gold and Sainsbury quoted by McLean-Tooke et al. found a
reduced need for hospital admission in children treated with a correct
dose of adrenaline by auto-injector in the community. This implies that
admission may not be mandatory.
Further evidence is needed to guide decisions about the place and
duration of observation necessary following the use of adrenaline for
anaphylaxis. At present, however, there is no indication for admission of
all patients treated.
1. McLean-Tooke APC, Bethune CA, Fay AC et al. Adrenaline in the
treatment of anaphylaxis: what is the evidence? BMJ 2003;327:1332-5
2. Gavalas M, Sadana A, Metcalf S. Guidelines for the management of
anaphylaxis in the emergency department. J Accid Emerg Med 1998; 15:
96-8.
3. Project Team of the Resuscitation Council (UK). The emergency
medical treatment of anaphylactic reactions for first medical responders
and for community nurses. Revised Jan 2002. www.resus.org.uk/pages/
reaction.htm
4. Brady WJ Jr, Luber S, Carter CT et al. Multiphasic anaphylaxis: an
uncommon event in the emergency department. Acad Emerg Med 1997;
4:193-7.
5. Ellis AK, Day JH. Diagnosis and management of anaphylaxis. CMAJ
2003;169:307-11.
Competing interests:
None declared
Competing interests: No competing interests
We read with much interest the article by McLean-Tooke et al (1).
They mentioned that published reports of fatal cardiac arrhythmias and
myocardial infarction associated to intravenous adrenaline often fail to
state clearly that other factors including hypoxia, acidosis, or the
direct action of inflammatory mediators, maybe, at least in part,
responsible for the cardiovascular complications.
Here we describe a case in which a clear relationship between the
administration of intravenous adrenaline and cardiovascular complications
was found:
A 29 year-old woman current smoker with a medical history of
hypercholesterolemia. She was being studied for recurrent idiopathic angio
-oedema. She was under treatment with topic acyclovir for herpes simplex
labialis 48 hours before arriving to our emergency room. She came 20
minutes after the last acyclovir application presenting lip and laryngeal
angio-oedema and hypotension and showing evident signs of anaphylactic
shock. Hydrocortisone (200 mg intravenous) was administrated and an
intramuscular adrenaline 1 mg preparation (1:1000) was administered
intravenously in error. The patient developed central chest pain and the
electrocardiogram showed ischemic changes followed by auto-limited
ventricular tachycardia and acute pulmonary edema. Hypoxia and acidosis
were not presented with normal acid-base values. She required noninvasive
positive pressure ventilation followed by furosemide and dobutamine
administration. The patient improved with a complete recovery. A complete
cardiac study performed showed no evidence of myocardial disease.
In this case due to an error in the route of administration, a clear
link was found between adrenaline intravenous administration and
myocardial ischemia and ventricular tachycardia. We can exclude other
causes of acute coronary syndrome like hypoxia, acidosis or myocardial
disease, and so we can conclude that intravenous adrenaline was the main
cause. We agree that major adverse effects may occur when adrenaline is
given too rapidly, inadequately diluted, or in excessive dose.
Our case shows that intravenous adrenaline administration may lead to
severe cardiovascular effects.
1. McLean-Tooke A, Bethune CA, Fay AC, Spickett GP. Adrenaline in the
treatment of anaphylaxis: what is the evidence?. BMJ 2003;3
Competing interests:
None declared
Competing interests: No competing interests
In response to 'algorithm illogical', the presence of a systemic
reaction i.e. a reaction away from the site of contact would warrant
consideration about the need for an adrenaline autoinjector. The reaction
does not have to be severe to be systemic - thus a child with widespread
urticaria following peanut ingestion should be followed on the protocol
and risk assessed. As stated ' patients at high risk are those with
asthma; reaction to trace allergen only; repeated exposure to allergen
likely and lack of access to emergency medical care'.
In reply to Prof. Sivagnanams comments I would agree the clear
message here is that IM is the preferred route for adrenaline
administration in anaphylaxis. As for cocaine or uncontrolled
hyperthyroidism and concurrent use of adrenaline I would still consider
its use RELATIVELY contraindicated. If the reaction is severe and failing
to respond to other interventions including fluid administration,
antihistamine and steroids then the use of adrenaline may be appropriate.
The dosage is not clear but I would certainly recommend a reduced dose. As
such I would not recommend administration of adrenaline without
electrocardiographic monitoring or in the presence of appropriately
trained staff, and I would certainly not give these patients an adrenaline
auto-injector.
Lastly, in reply to 'Need for working definition' whilst a the
working definition of anaphylaxis given involves either respiratory
difficulty or hypotension this will need to be in the context of an
allergic history and is a clinical diagnosis. An episode of hypotension
following a vaso-vagal episode does not therefore come under the umbrella
of anaphylaxis. In some cases it may not be clear whether a hypotensive
episode is a vaso-vagal reaction versus anaphylaxis, and I would suggest
if there is a realistic possibility that this could be anaphylaxis then I
would treat for such.
Competing interests:
None declared
Competing interests: No competing interests
We read with interest the excellent review by McLean-Tooke et al on
adrenaline in the treatment of anaphylaxis [1] and we would like to add
our experience. This review, along with 2 other recent publications
[2,3], failed to recommend the use of a pure alpha agonist in severe
anaphylactic reactions unresponsive to epinephrine. The successful use of
this treatment was described in a series of case reports by ourselves in
2001 [4] and by Higgins and Gayatri in 1999 [5].
There is no doubt that repeated administration of intramuscular
epinephrine is the treatment indicated for life threatening out of
hospital anaphylaxis, as discussed by McLean-Tooke et al [1]. However,
the in-hospital management of severe anaphylaxis which results in cardiac
arrest, especially under anaesthesia, includes the use of intravenous
epinephrine at 1:10,000 dilution as a first line treatment.
Anaphylaxis under anaesthesia has been reported with an incidence of
1:13,000 [6] and between 1:10,000 to 1:20,000 [7] anaesthetics
administered. Although this is uncommon, our hospital, with around 30,000
anaesthetic episodes per year, may see 2 or 3 severe cases annually. Our
experience is that epinephrine resistant anaphylaxis does occur with
electomechanical dissociation persisting despite the repeated
administration of epinephrine in 1mg boluses.
Severe anaphylaxis under anaesthesia probably represents the extreme
edge of the spectrum of anaphylactic reactions, perhaps due to the
concomitant administration of many drugs and the exposure of patients to
rapid boluses of intravenous antigens. The severity of the reactions is
reflected in the profound reduction in systemic vascular resistance that
occurs due to the release of histamine and other vasoactive substances
associated with mast cell degranulation and may lead to cardiac arrest
secondary to electromechanical dissociation.
Epinephrine has agonist activity at both alpha 1 receptors, causing
vasoconstriction, and beta 1 receptors, causing increased inotropy and
chronotropy of the heart. However, stimulation of beta 2 receptors in the
smooth muscle wall of blood vessels in skeletal muscle and the liver
causes these vessels to dilate. In normal subjects, it has been shown
that an intravenous infusion of epinephrine may lead to a reduction in
total peripheral resistance via this effect on beta 2 receptors [8]. In
contrast, pure alpha 1 agonists, such as phenylephrine, produce unopposed
vasoconstriction in peripheral vessels leading to an increase in
peripheral vascular resistance.
The primary effect of adrenaline during cardiopulmonary arrest is
thought to be systemic vasoconstriction, due to alpha 1 receptor
stimulation, elevating aortic diastolic pressure and thus increasing
coronary perfusion pressure [9, 10]. One possible reason for a lack of
response to epinephrine in cases of electromechanical dissociation
secondary to reduced systemic vascular resistance may be that the drug’s
effects on alpha 1 receptors (vasoconstriction) and beta 2 receptors
(vasodilatation) do not correct the imbalance. A net effect of
vasodilatation may persist no matter how much epinephrine is administered.
In contrast, the vasoconstriction produced by pure alpha 1 agonists may
lead to a more predictable increase in systemic vascular resistance in
circumstances where excessive systemic vasodilatation already exists.
Compensation for a profound falls in systemic vascular resistance may also
be achieved by the administration of intravenous fluids, as described by
Waldhausen et al [11], when epinephrine does not produce sustained
cardiovascular improvement
The risk of fatal cardiac arrythmias and myocardial infarction
following the administration of intravenous epinephrine, as discussed by
McLean-Tooke [1], are related to the beta 1 effects of the drug. Repeated
boluses of epinephrine in pursuit of vasoconstriction in anaphylactic
shock makes such adverse events more likely. However, by switching to
pure alpha agonists in the treatment of epinephrine resistant
cardiovascular collapse associated with anaphylaxis, the progression to
such cardiac irritability, associated arrythmias and myocardial ischaemia
may be avoided.
The case reports by ourselves [4] and Higgins and Gayatri [5] would
suggest that resuscitation from a suspected anaphylactic reaction should
not be discontinued without the administration of a significant
intravenous bolus of a pure alpha agonist following repeated intravenous
boluses of epinephrine. Higgins and Gayatri proposed that the use of a
pure alpha agonist should be considered before resorting to a third 1mg
dose of epinephrine [5]. We would endorse this recommendation and
encourage its adoption into future recommendations for the treatment of
severe anaphylactic reactions.
References:
1. McLean-Tooke APC, Bethune CA, Fay AC, Spickett GP. Adrenaline in
the treatment of anaphylaxis: what is the evidence? BMJ 2003;327:1332-35.
2. Hepner DL, Castells MC. Anaphylaxis during the perioperative period.
Anesth Analg 2003;97:1381-95.
3. Association of Anaesthetists of Great Britain and Ireland. Suspected
anaphylactic reactions associated with anaesthesia. London : Association
of Anaesthetists of Great Britain and Ireland, 2003.
4. McBrien ME, Breslin DS, Atkinson S, Johnston JR. Use of methoxamine in
the resuscitation of epinephrine-resistant electromechanical dissociation.
Anaesthesia 2001;56:1085-89.
5. Higgins DJ, Gayatri P. Methoxamine in the management of severe
anaphylaxis. Anaesthesia 1999;54:1126.
6. Laxenaire MC. Epidemiological survey of anaphylactoid reactions
occurring during anaesthesia. Fourth French multicentre survey (July 1994
-December 1996). Ann Fr Anesth Reanim 1999;18:796-809.
7. Fisher MM, Baldo BA. Anaphylaxis during anaesthesia; current aspects
of diagnosis and prevention. Eur J Anaesthesiol 1994;11:263-84.
8. Ganong WF. The Adrenal Medulla and Adrenal Cortex. In: Ganong WF ed.
Review of Medical Physiology. London: Prentice-Hall International,
1989;301-24.
9 Yakaitis RW, Otto CW, Blitt CD. Relative importance of and
adrenergic receptors during resuscitation. Crit Care Med
1979;7:293- 6.
10. Turner LM, Parsons M, Luetkemeyer RC, Ruthman JC, Anderson RJ, Aldag
JC. A comparison of epinephrine and methoxamine for resuscitation from
electromechanical dissociation in human beings. Ann Emer Med 1988;17:443-
9.
11. Waldhausen E, Keser G, Marquaradt B. Anaphylactic shock.
Anaesthetist 1987;36: 150-8.
Competing interests:
None declared
Competing interests: No competing interests
In their review of adrenaline for the treatment of anaphylaxis,
McLean-Tooke and colleagues state that "the severity of previous reactions
does not determine the severity of future reactions" [1]. In the setting
of insect venom anaphylaxis, this is incorrect. A large prospective study
of venom allergic individuals found no person went on to experience a
reaction more severe than the worst prior reaction [2]. Another large
sting challenge study and our prospective study of accidental field stings
had similar findings, although a few individuals went on to experience
more severe reactions [3,4]. Older age also predicts a higher risk of a
Mueller grade IV (hypotensive) reaction [4].
Inaccurate patient recollection, incomplete medical records,
fluctuations in sensitivity, and variation in the amount of venom
delivered probably explain our observation that people with a history of
Mueller grade III (respiratory) reactions frequently go on to experience a
Grade IV reaction [5]. Therefore it is common practice to focus the
provision of venom immunotherapy (VIT) and adrenaline autoinjectors
(Epipens) on people with a history of respiratory or hypotensive
reactions. However, because people with a history of milder reactions
occasionally go on to experience a more severe reaction, VIT and/or
Epipens should probably be offered if a person is frequently exposed in
areas that are isolated with limited access to emergency medical care,
even if they have history of only mild reactions.
It is often not appreciated that adrenaline must be injected into the
anterior thigh to achieve maximum absorption- injection into arm muscles
is no better than the subcutaneous route [6]. It is good to see the
recommendation the provision of two Epipens. In our sting challenge study,
the median total dose of adrenaline (administered by intravenous infusion
titrated to the lowest effective rate) was 762 mcg in patients
experiencing hypotensive reactions, more than double the standard Epipen
dose, and several required substantially more [7]. These results emphasise
the importance of patients being instructed to: (1) not hesitate injecting
themselves with adrenaline into the anterior thigh; (2) immediately call
for ambulance assistance using the national emergency telephone number,
and (3) use their second Epipen if they do not improve or continue to
deteriorate. In a severe reaction, an Epipen simply "borrows time" until
help arrives.
REFERENCES
1. McLean-Tooke APC, Bethune CA, Fay AC, Spickett GP. Adrenaline in
the treatment of anaphylaxis: what is the evidence? BMJ
2003;327(7427):1332-1335.
2. van der Linden PW, Hack CE, Struyvenberg A, van der Zwan JK.
Insect-sting challenge in 324 subjects with a previous anaphylactic
reaction: current criteria for insect-venom hypersensitivity do not
predict the occurrence and the severity of anaphylaxis. J Allergy Clin
Immunol 1994;94(2 Pt 1):151-9.
3. Blaauw, P.J., O.L. Smithuis, and A.R. Elbers, The value of an in-
hospital insect sting challenge as a criterion for application or omission
of venom immunotherapy. J Allergy Clin Immunol, 1996. 98(1): p. 39-47.
4. Brown SGA, Franks RW, Baldo BA, Heddle RJ. Prevalence, severity,
and natural history of jack jumper ant venom allergy in Tasmania. J
Allergy Clin Immunol 2003;111(1):187-92.
5. Brown SGA, Wiese MD, Blackman KE, Heddle RJ. Ant venom
immunotherapy: a double-blind, placebo-controlled, crossover trial. Lancet
2003;361(9362):1001-6.
6. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults:
intramuscular versus subcutaneous injection. J Allergy Clin Immunol
2001;108(5):871-3.
7. Brown SGA, Blackman KE, Stenlake V, Heddle RJ. Insect sting
anaphylaxis; prospective evaluation of treatment with intravenous
adrenaline and volume resuscitation. Emerg Med J 2004;(In Press).
Competing interests:
None declared
Competing interests: No competing interests
Sir,
The clinical review ‘ADRENALINE IN THE TREATMENT OF ANAPPYLAXIS’ was
excellent, but for the ‘working definition’ of anaphylaxis mentioned
therein.
A good working definition is that an anaphylactic reaction involves one or
both of the two severe features: respiratory difficulty (which may be due
to laryngeal oedema or asthma) and hypotension (which may present as
fainting, collapse, or loss of consciousness).
Very commonly in clinical practice we come across patients more often
females fainting after a painful prick, usually due to pain, precipitating
a vaso- vagal episode with blood pressure measurements < 90/60 mm of
hg.
Applying the above mentioned working definition all these syncopes also
will come into the purview of anaphylaxis. Thus, a review of this working
definition is required in near future.
Asif RAHEEM.MD
Emergency physician
Abha general hospital.
Abha
Saudi Arabia.
Competing interests:
None declared
Competing interests: No competing interests
The following few points are in connection to the article entitled
“Adrenaline in the treatment of anaphylaxis: what is the evidence? 1
What is the best route for administering adrenaline?
It is pertinent to note that for the following reasons adrenaline
serves better if it is given by intramuscular rather than subcutaneous
route.
a. Absorption of epinephrine after subcutaneous injection is slow due to
local vasoconstrictor action2. (However the same source indicates that
adrenaline be given subcutaneously or intravenously with due caution for
management of acute hypersensitivity).
b. In general the rate of absorption of a drug by subcutaneous route is
slower than that of intramuscular route. Upon sympathetic stimulation (as
in shock) blood vessels supplying skeletal muscles bearing ?2 receptors
dilate. The same effect can be expected with exogenously administered
adrenaline and this is only partly counterbalanced by the vasoconstrictor
action on the ? receptors that are also present in the vascular bed2.
c. In shock there is already intense compensatory vasoconstriction in the
skin hence absorption of drugs administered by subcutaneous route is slow
and erratic.
All these boils down to the fact that intramuscular route is best (or
cautious intravenous) rather than subcutaneous.
Does adrenaline have any important drug interactions?
“Cocaine sensitises the heart to catecholamines (as does uncontrolled
hyperthyroidism), and adrenaline is therefore relatively contraindicated
(grade C)”1
However no alternative for such cases has been advocated by the authors.
Whatever may be the coexisting factor, in a case of anaphylactic shock,
theoretically speaking there seems to be no better alternative
(physiological antagonist) than adrenaline (may be with half the dose as
mentioned for patients on drugs like beta blockers, tricyclic
antidepressants etc.).
1. McLean-Tooke APC, Bethune CA, Fay AC, Spickett GP. Adrenaline in
the treatment of anaphylaxis: what is the evidence? BMJ 2003; 327:1332–5
2. Hoffman BB In: Goodman & Gilman’s The pharmacological basis of
therapeutics. 10th Ed. New York: McGraw Hill; 2001. pp 215-268
Competing interests:
None declared
Competing interests: No competing interests
Does adrenaline have an important drug interaction with alpha adrenergic receptor blocking drugs?
Dr McLean - Tooke and colleagues list systemic and topical beta
adrenergic blockers, tricyclic antidepressants, monoamine oxidase
inhibitors and cocaine as having important drug interactions with
adrenaline. I suggest that any drug with alpha adrenergic receptor
blocking activity should be included.
In 1995 I managed a patient with an anaphylactic collapse following a
bee sting who was taking the alpha 1 receptor blocker prazosin for
hypertension. He appeared to have resistant hypotension following self
administered adrenaline by auto-injector and general practitioner
administered adrenaline (1).
In 1998 a patient from my practice who was on long term thioridazine and
amitriptyline had a sudden collapse presumed to be anaphylactic in nature
where there was prolonged hypotension. Both of these drugs have a major
alpha 1 adrenergic receptor blocking action. The hypotension failed to
respond to adrenaline infusions but there was an eventual response to
infusion with a pure alpha 1 receptor agonist (2). Prior to publishing
this article I carried out a literature search and found that the only
published studies of the reverse adrenaline effect related to animal
studies.
The reverse adrenaline effect has been described in standard
pharmacology texts for years. The expectation is that parenteral
adrenaline will increase blood pressure in the recipient. In patients on
drugs with alpha 1 adrenergic receptor blocking activity however the
adrenaline is unable to cause vasoconstriction in the skin and viscera
because the alpha receptors on the smooth muscle of the arterioles of
those organs are blocked. The adrenaline is free to act on the beta 2
receptors on the smooth muscle of the arterioles of skeletal muscle to
cause vasodilatation to prepare for “fight or flight” The net result is
vasodilatation and exacerbation of hypotension.
There are several cases published reviewing the speculative
mechanisms of the sudden death of youths who were on drugs with alpha 1
adrenergic receptor blocking activity; either on tricyclic antidepressants
alone or in combination with phenothiazines (3,4). There are likewise many
unexplained deaths described in adults on thioridazine and other
phenothiazines. These deaths are attributed usually to ventricular
fibrillation related to prolongation of the QT interval. I suggest from
pharmacology of the alpha adrenergic receptor blocking drugs that a
reverse adrenaline effect (from endogenous or parenteral adrenaline) may
exacerbate hypotension leading to a terminal arrhythmia secondary to
electromechanical dissociation from profound hypotension.
I would be interested to hear if other colleagues have had problems
with resistant hypotension when using adrenaline for anaphylaxis in
patients on alpha 1 receptor blockers.
At the very least there are theoretical reasons for advising against
the use of drugs with alpha 1 adrenergic receptor blocking activity in
patients with a history of anaphylaxis. In anaphylaxis the drug history
will rarely be available. Doctors should be aware that if hypotension is
resistant to repeated doses of adrenaline the reverse adrenaline effect
may need to be considered.
References:
1. Watson A. Don’t get stung with the adrenergic blockers (beta or
alpha). Australian Family Physician Vol. 24, No. 10, October 1995 1879
2. Watson A. Alpha adrenergic blockers and adrenaline- a mysterious
collapse. Australian Family Physician Vol. 27 No. 8, August 1998 714-715.
3. Popper CW, Zimnitzky B. Sudden death putatively related to
desipramine treatment in youth: a fifth case and a review of speculative
mechanisms. Journal Of Child And Adolescent Psychopharmacology Vol.5, No.
4, 1995 283-300.
4. Varley CK, McLennan J. Case study: two additional sudden deaths
with tricyclic antidepressants. J.Am. Acad. Child Adolesc. Psychiatry
36:3, March 1997 390-394.
Competing interests:
None declared
Competing interests: No competing interests