Rapid Responses published:
Algorithm illogical
Yoav Ben-Shlomo (5 December 2003)
Adrenaline in anaphylaxis
G Sivagnanam (5 December 2003)
need for a more refined working definiton
Asif Raheem (7 December 2003)
Identifying people most at risk of severe anaphylaxis, and provision of
adrenaline autoinjectors.
Simon G. A. Brown (9 December 2003)
Successful use of pure alpha agonists in epinephrine resistant anaphylaxis
Michael E McBrien, Dara S Breslin (10 December 2003)
Authors response
Andrew P C McLean-Tooke, Claire A Bethune, Gavin P Spickett (10 December 2003)
A clear link between adrenaline intravenous administration and severe
cardiovascular effects
Sergio Abanades, Joan Buch. Clinical Hematology Resident. Hospital del Mar (11
December 2003)
Observation after adrenaline: what is the evidence?
Martin F Wiese, Catherine Johnson, senior house officer and John A. Henry, professor
(11 December 2003)
Subcutaneous adrenaline for anaphylaxis: compromise in high risk patient
with mild symptoms
Michal R Pijak, Frantisek Gazdik, Katarina Gazdikova (19 December 2003)
Adrenaline in the treatment of anaphylaxis: what is the risk and benefit?
Michal R Pijak, Frantisek Gazdik, Katarina Gazdikova (21 December 2003)
Does adrenaline have an important drug interaction with alpha adrenergic
receptor blocking drugs?
Alan Watson (22 December 2003)
Algorithm illogical
Yoav Ben-Shlomo,
Senior Lecturer in
Clinical Epidemiology
Dept. of Social
Medicine, University of
Bristol
Send response to
journal:
Re: Algorithm illogical
5 December 2003
The review of adrenaline for anaphylaxis by McLean-Tooke and
colleagues is a most helpful piece of work. However, their
recommended algorithm (fig 3) for identifying patients that may
benefit from an adrenaline auto-injector seemed to be inconsistent
with their own review of the evidence.
Whilst there is clearly limited epidemiological evidence, they state that
(1) the severity of a past reaction does not predict a future reaction.
Hence a child with an urticarial response to nuts may on subsequent
challenge have a life threatening response. (2) Asthma co-morbidity
appears to increase the risk of a fatal reaction.
However, their suggested algorithm ignores the presence/absence of
asthma unless you have had a severe reaction and recommends that
asthmatic children with only a local reaction not be provided with an
auto-injector even though they are candidates for a future life
threatening reaction. It also ignores other factors such as accessibility
to emergency room facilities e.g. a child who lives in a rural area is
clearly at greater risk of death without an Epipen as it will take more
time for an ambulance to arrive. Given the modest cost of an Epipen
and its relative safety, this makes little sense to me.
How can this be justified? I would welcome their comments.
Competing interests: None declared
Adrenaline in anaphylaxis
G Sivagnanam,
Additional Professor of
Pharmacology
Chengalpattu Medical
College, Chengalpattu
603 001 Tamilnadu,
India
Send response to
journal:
Re: Adrenaline in
anaphylaxis
5 December 2003
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
need for a more refined working definiton
Asif Raheem,
emergency physician
Abha genreal hospital,
abha saudi arabia
Send response to
journal:
Re: need for a more
refined working
definiton
7 December 2003
Sir, The clinical review ADRENALINE IN THE TREATMENT OF
ANAPHYLAXIS 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
Identifying people most at risk of severe
anaphylaxis, and provision of adrenaline
autoinjectors.
Simon G. A. Brown,
Consultant Emergency
Physician and Senior
Clinical Lecturer
Fremantle Hospital
and University of
Western Australia,
Fremantle, WA 6160,
Australia
Send response to
journal:
Re: Identifying people
most at risk of severe
anaphylaxis, and
provision of adrenaline
autoinjectors.
9 December
2003
In their review of adrenaline for the treatment of anaphylaxis, McLeanTooke 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 inhospital insect sting challenge as a criterion for application or omission
of venom immunotherapy. J Allergy Clin Immunol, 1996. 98(1): p. 3947.
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
Successful use of pure alpha agonists in
epinephrine resistant anaphylaxis
Michael E McBrien,
Consultant
Anaesthetist
Royal Victoria
Hospital, Belfast BT12
6BA,
Dara S Breslin
Send response to
journal:
Re: Successful use of
pure alpha agonists in
10 December
2003
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 resistant
anaphylaxis
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;11:26384.
8. Ganong WF. The Adrenal Medulla and Adrenal Cortex. In: Ganong
WF ed. Review of Medical Physiology. London: Prentice-Hall
International, 1989;301-24.
adrenergic and 9 Yakaitis RW, Otto CW, Blitt CD. Relative
importance of 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
Authors response
Andrew P C McLeanTooke,
SpR in Immunology
Royal victoria
Infirmary, NewcastleUpon-Tyne, NE2 2TB.,
Claire A Bethune,
Gavin P Spickett
Send response to
journal:
Re: Authors response
10 December 2003
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 vasovagal 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
A clear link between adrenaline intravenous
administration and severe cardiovascular effects
Sergio Abanades,
Clinical Pharmacology
Resident
Institut Municipal
d'Investigació Mèdica.
Barcelona 08003.
Spain,
Joan Buch. Clinical
Hematology Resident.
Hospital del Mar
Send response to
journal:
Re: A clear link
11 December
2003
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
between adrenaline
intravenous
administration and
severe cardiovascular
effects
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
Observation after adrenaline: what is the
evidence?
Martin F Wiese,
lecturer
Emergency
Department, St.
Mary's Hospital, Praed
St, London WC1N 3RA,
Catherine Johnson,
senior house officer
and John A. Henry,
professor
Send response to
journal:
Re: Observation after
adrenaline: what is the
evidence?
11 December
2003
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
Subcutaneous adrenaline for anaphylaxis:
compromise in high risk patient with mild
symptoms
Michal R Pijak,
consultant in
rheumatology, allergy
and clinical
immunology
Slovak Medical
University, Institute of
Preventive and Clinical
Medicine,,
Frantisek Gazdik,
Katarina Gazdikova
Send response to
journal:
Re: Subcutaneous
adrenaline for
anaphylaxis:
compromise in high
risk patient with mild
symptoms
19 December
2003
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-ofhospital 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
Adrenaline in the treatment of anaphylaxis:
21 December
what is the risk and benefit?
Michal R Pijak,
consultant in
rheumatology, allergy
and clinical
immunology
Slovak Medical
University, Institute of
Preventive and Clinical
Medicine,,
Frantisek Gazdik,
Katarina Gazdikova
Send response to
journal:
Re: Adrenaline in the
treatment of
anaphylaxis: what is
the risk and benefit?
2003
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;41:70611.
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
Does adrenaline have an important drug
interaction with alpha adrenergic receptor
blocking drugs?
Alan Watson,
General Practitioner
Tranmere South
Australia 5073
Send response to
journal:
Re: Does adrenaline
have an important
drug interaction with
alpha adrenergic
receptor blocking
drugs?
22 December
2003
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 714715.
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