Send letter to journal:
Re: Authors response to Kounis & Kounis

Dear Editor

We thank Kounis & Kounis for their interest in our article. Their insights into the link between allergic mechanisms and coronary disease are interesting. However, the level of evidence supporting their extrapolations of this and other animal data to human anaphylaxis is limited.

Different species exhibit different patterns of organ involvement during anaphylaxis [1]. Animal data can only be regarded as hypothesis generating, and unfortunately human data is scarce. Studies of artificially sensitised isolated animal cardiac tissue and small animals have only a limited application to immediately life-threatening multisystem allergic events in intact humans with naturally acquired IgE- mediated allergy.

Although cardiac dysfunction during human anaphylaxis (including ECG changes and global suppression of myocardial function) has been reported, the significance of these above other well-recognised events, seen in the majority of cases and all physiologically antagonised by adrenaline, remains uncertain. An understanding of global issues –upper airway compromise and bronchospasm causing hypoxaemia, distributive shock, hypovolaemic shock, reduced coronary and cerebral perfusion, and reflex mechanisms– are probably more important in terms of emergency management.

Thus, the keys to treating the vast majority of cases continue to be; the supine position, adrenaline, oxygen, and fluid (volume) resuscitation.

In the context of human anaphylaxis, it is incorrect to state that "today it is almost certain that cardiac damage is the primary event". Kounis & Kounis back up this statement with a single piece of original research, which looked at artificially sensitised guinea pigs [2].

As we point out in our paper, there are several mechanisms that may explain our observations of a cardiac effect during severe human anaphylaxis. These include direct mediator actions on the heart, supported by our observation in one case of ECG changes in the absence of hypotension. But, we also observed that diastolic hypotension was an early feature in those experiencing hypotension (as illustrated by case 1), indicating systemic vasodilation to be important. Neurocardiogenic reflex responses to the resulting reduction in venous return may partially explain the association between death and the upright position (which exacerbates venous pooling) observed by Pumphrey [3]. Fisher has also demonstrated the importance of massive fluid loss by extravasation that occurs during anaphylaxis in humans [4].

Kounis & Kounis refer to two deaths following the administration of adrenaline [5]. However, these deaths involved the administration of massive intravenous boluses that can only be interpreted as major errors in management. In our response to previous correspondence we have outlined why the intravenous route (by infusion, not bolus administration) may be the best option in experienced hands [6].

To quote Fisher, "In severe anaphylaxis adrenaline by any route is better than none" [7]. How this is achieved depends on the level of expertise at hand.

References

1. Kemp SF and Lockey RF. Anaphylaxis: a review of causes and mechanisms." J Allergy Clin Immunol 2002; 110(3): 341-8.

2. Felix SB, Baumann G, Berdel WE. Systemic anaphylaxis-separation of cardiac reactions from respiratory and peripheral events. Res Exp Med 1990; 190: 239-252.

3. Pumphrey RS: Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003, 112:451-452.

4. Fisher MM. Clinical observations on the pathophysiology and treatment of anaphylactic cardiovascular collapse. Anaesth Intensive Care 1986; 14(1): 17-21.

5. Pumphrey RSH. Lessons for management of anaphylaxis froma study of fatal reactions. Clin Exp Allergy 200; 30: 1144-1150.

6. Brown SGA, Blackman KE, Heddle RJ. Authors response to Gori et al. [electronic response to eLetter by Gori et al. Risks of Overzelous Adrenalin Administration http://emj.bmjjournals.com/cgi/eletters/21/2/149#277] emjonline.com 2004 http://emj.bmjjournals.com/cgi/eletters/21/2/149#333

Send letter to journal:
Re: Kounis Syndrome, Insect Sting Anaphylaxis and Adrenaline treatment

Dear Editor

In the elegant paper of Brown et al [1] concerning insect sting anaphylaxis and its treatment, two patients developed electrocardiographic changes suggesting acute inferior myocardial ischaemia with normal troponin and cardiac enzymes. These cases are characteristic examples of type II variant of Kounis syndrome [2].

Kounis syndrome [3][4][5] is the concurrence of allergic or hypersensitivity reactions with acute coronary syndromes. Kounis syndrome is caused by conditions such as angioedema, bronchial asthma, exercise- induced anaphylaxis, food allergy, idiopathic anaphylaxis, serum sickness, urticaria, and mastocytosis; drugs such as antibiotics, antineoplastics, contrast media, corticosteroids, intravenous anaesthetics, nonsteroidal antiinflammatory drugs, skin disinfectants,thrombolytics and others; certain environmental exposures, poisons, and venoms. This occurs via inflammatory mediators such as histamine, tryptase, chymase, and arachidonic acid products such as thromboxane and leucotrienes. These mediators are released from mast cells during an allergic insult. However, these mediators have been found in blood or urine of patients suffering from acute coronary episodes of non allergic aetiology [3].

Histamine exerts its action via H1-, H2-, and H3- histamine receptors. H1-receptors mediate constriction of coronary smooth muscle and initiate rhythmic phasic activity,H2-receptors mediate a minor degree of relaxation, and H3-receptors inhibit endogenous norepinephrine release from sympathetic nerves and accentuate the degree of shock observed during antigen challenge since they block neural adrenergic stimulation [6]. Tryptase and chymase effectively activate the zymogen forms of metalloproteinases such as interstitial collagenase,and stromelysin found in atheromatous plaques and may play an important role in atheromatous plaque erosion or rupture [7]. Chymase converts angiotensin I into angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries. Thus, angiotensin II generated by the chymase released from mast cells could act synergetically with histamine and could aggravate the local spasm of the infarcted coronary artery [8]. Today, it is almost certain that the majority of cases of unstable angina and acute myocardial infarction are the result of combined coronary artery spasm and atheromatous erosion or rupture followed by thrombus formation.

In contrary to what is generally believed, that anaphylactic cardiac damage is due to peripheral vasodilatation and hypotension, today it is almost certain that cardiac damage is the primary event during anaphylaxis [9], followed by hypotension. Experimental studies have proven that anaphylactic reactions can induce rapid decline in coronary blood flow rates due to marked coronary vasoconstriction followed by clinical events and electrocardiographic changes [10].

Adrelaline reverses the immediate symptoms of anaphylaxis by its effects on á and â adrenoceptors and by counteracting the histamine effects through the H3- receptors.It reverses perirheral vasodilatation, reduces oedema, induces bronchodilatation, has positive inotropic and chronotropic action on the myocardium and suppresses further mediator release [11]. Although careful titrated intravenous adrenaline is an effective strategy in treating anaphylaxis, its use is not without risk, especially in patients with cardiovascular comorbidity. In a recent report [12] two deaths occurred from myocardial infarction after adrenaline administration for mild iatrogenic reactions. Recent experimental studies [13] have shown that when adrenaline is administered during maximum anaphylactic shock and after the mediators have been released it may have limited utility in the treatment of cardiovasculal collapse. Earlier administration, before maximal hypotension occurs, adrenaline may produce a more beneficial effect.

Therefore, intravenous adrenaline should be reserved for extreme emergencies when there is doubt about the adequacy of the circulation [11].

References

(1) Brown SGA, Blackman KE, Stenlake V , et al. Insect sing anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004; 21: 149-154.

(2) Nikolaidis LA, Kounis NG, Grandman AH. Allergic angina and allergic myocardial infarction: A new twist on an old syndrome. Can J Cardiol 2002; 18: 508-511.

(3) Zavras GM, Papadaki PJ, Kokkinis CE, et al. Kounis syndrome secondary to allergic reaction following shellfish ingestion. Int J Clin Pract 2003; 57: 622-624.

(4) Koutsojannis CM, Kounis NG. Lepirudin anaphylaxis and Kounis syndrome. Circulation 2004; 109: e315.

(5) Koutsojannis CM, Mallioris CN, Kounis NG. Corticosteroids, Kounis syndrome and the treatment of refractory vasospastic angina. Circulation J 2004: 68: 806-807.

(6) Chrusch C, Sharma S, Unruh H, et al. Histamine H3 receptor bockade improves cardiac function in canine anaphylaxis. Am J Respir Care Med 1999; 160: 1142-1149.

(7) Johnson JC, Jackson CL, Angelini GD, et al.Activation of matrx-degrating metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 1998; 18: 1707-1715.

(8) Laine P, Kaartinen M, Penttila A, et al. Association between myocardial infarction and mast cells in adventitia of the infart-related coronary artery. Circulation 1999; 99: 361-369.

(9) Felix SB, Baumann G, Berdel WE. Systemic anaphylaxis-separation of cardiac reactions from respiratory and peripheral events. Res Exp Med 1990; 190: 239-252.

(10) Levi R. Cardiac anaphylaxis: models, mediators, mechanisms, and clinical considerations. In: Maronne G, Lichtenstein LM, Condorelli M, Fauci AS (Eds) Human inflammatory disease, vol1: Clinical immunology. Decker, Toronto, pp 93-105.

(11) Johnston SL, Unsworth J, Gompels MM. Adrenaline given outside the context of life threatening allergic reactions. BMJ 2003; 326: 589-590.

(12) Pumphrey RSH. Lessons for management of anaphylaxis froma study of fatal reactions. Clin Exp Allergy 200; 30: 1144-1150.

Send letter to journal:
Re: Authors response to Gori et al

Dear Editor

Dr Gori, Cinotti and Papagallo's concerns [1] reflect the inexperience of many medical staff in the use of adrenaline to treat anaphylaxis, a misunderstanding of the ethical issues relating to our trial, and perhaps over-reliance on invasive measures of severity that are a sign of sustained and untreated cardiorespiratory collapse. To deal with each comment in turn:

- Even Mueller Grade I reactions can be extremely uncomfortable; in many patients these are florid, cause significant discomfort, and are associated with unbearable itching, severe malaise and marked anxiety. In our experience these symptoms respond immediately to adrenaline, but respond slowly (and unreliably) when treatment is limited to antihistamines and steroids.

- Ethically we were required to offer patients the opportunity to withdraw from the study at any time. This included the use of adrenaline to treat extremely uncomfortable and distressing symptoms. Nevertheless, no patient requested the use of adrenaline prior to our objective criteria for intervention being met.

- Intravenous adrenaline infusion, regulated by an electronic infusion pump and supervised by experienced doctors as in our study, is a safe method of giving adrenaline. Because there is no absorption phase and a very short half-life, the effect of any infusion rate change is almost immediate and adverse effects can be stopped immediately by ceasing or reducing the rate of infusion. Conversely, intravenous, large intramuscular, and even subcutaneous boluses of adrenaline can result in significant adverse reactions [2].

- Gori et al claim that "late side effects due to adrenaline intravenous (may occur in) cardiopathic patients". We are unaware of any evidence or anecdotal experiences for this occuring in the absence of earlier signs such as ECG changes, ischaemic chest pain and cardiovascular instability.

- So-called "biphasic" reactions are a poorly understood phenomenon. In our experience many such reactions are actually due to an ongoing (rather than biphasic) reaction, unmasked as an intramuscular bolus of adrenline slowly wears off. An advantage of using an intravenous infusion of adrenaline is that when turned off, ongoing reactions are immediately unmasked. In our study this occured in 7/11 (64%) of people with Grade III/IV reactions [3]. After discharge according to our criteria, no patient suffered a biphasic reaction. True biphasic reactions are exceedingly rare (and generally mild) in the setting of ant sting anaphylaxis [4]. Prolonged &/or biphasic reactions may be more frequent in severe reactions due to ingested allergen [5]. Therefore, the discharge criteria used in our very select study group was appropriate, but of course should not be extrapolated to the general management of anaphylaxis.

- The measurement of arterial pH and pO2 were not performed because firstly, the invasiveness (and risk) of arterial puncture/line insertion was not justifiable for a condition almost always manageable without this intervention. Secondly, significant changes in PaO2 (<60 mmHg) are reliably detected by an SpO2 below 92% (this was continually monitored). Thirdly, a fall in pH would be a late feature due to tissue hypoxia- we did not feel it ethical to wait so long before treating with adrenaline!

Finally, we must emphasise that our study was performed in an idealised setting on a select group of patients treated by experienced consultant emergency physicians. Further studies are required in the general emergency department setting. In the meantime we encourage doctors not to use treatments with which they are unfamiliar, and to instead consider established consensus guidelines. That is, intramuscular adrenaline (0.3-0.5 mg in adults) as first line treatment, repeated if necessary after 5 minutes.

References

(1) Gori L, Cinotti S, Pappagallo S. Risks of Overzelous Adrenalin Administration [electronic response to Brown et al. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation] emjonline.com 2004 http://emj.bmjjournals.com/cgi/eletters/21/2/149#277

(2) Horowitz BZ, Jadallah S, Derlet RW. Fatal intracranial bleeding associated with prehospital use of epinephrine. Ann Emerg Med 1996;28:725- 7.

(3) SGA Brown, KE Blackman, V Stenlake, and R J Heddlel.: Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004; 21: 149-154.

(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;111:187-92.

Send letter to journal:
Re: Risks of Overzelous Adrenalin Administration

Dear Editor

In the paper of SGA Brown [1] adrenaline was administered to 19 patients of 21, 3 of which in stage II and 5 in stage I of Muller's grading of systemic allergic reactions, we think that adrenaline administrationat at this stage is excessive and potentially hazardous in respect to signs and symptoms, although the patients were continuously monitored. We think adrenaline administration should be avoided or carefully tritated especially in older and cardiopatic patients in stage I and II of Muller's classification; and reserved only for severe cases of anaphylactic reactions presenting with stridor, wheezing, respiratory distress and clinical signs of shock.[2] Besides, discharge home after a symptom free interval of only two hours is probably not safe, both for the risk of biphasic anaphylactic reaction (3) and possibility of late side effects due to adrenaline intravenous administration, especially in cardiopatic patiens. Moreover one of the indications for starting the protocol was also , as stated at point 6, only the request of a trial partecipant. We think this is not a reliable way for assessing the clinical status of a patient on the base of which to decide administration of adrenaline. Besides could be more useful and safe to know data about hypoxia and acidosis trough haematic serial samples, rather than performing spirometry.

References

1.SGA Brown, KE Blackman, V Stenlake, and R J Heddlel.: Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004; 21: 149-154.

2. Montanaro A, Bardana EJ Jr.: The mechanism, causes and the treatment of anaphylaxis. J Invest Clin Immunol 2002;2:2-11.

3. Brazil E, MacNamara AF.: “Not so immediate” hypersensitivity- the danger of biphasic anaphylactic reactions. J Accid Emerg Med 1998; 15: 252 -3.

Send letter to journal:
Re: Authors' response to Heywood and Fatovich

Dear Editor

Dr Fatovich asks about initial reaction severity in three participants who were prescribed steroids and antihistamines for large local reactions or persistent urticaria.[1]

Two initially had severe (hypotensive) reactions whereas the other had no systemic reaction. Although frequently used, it is difficult to determine the benefit of steroids and antihistamines to manage large local reactions and allergic urticaria. One of us has recently outlined why these agents are probably of little use in severe allergic reactions.[2] We agree that they are over-emphasised in many texts despite the absence of convincing evidence for therapeutic efficacy.

Our decision to give adrenaline by intravenous infusion was based on an ethical requirement to provide optimal resuscitation. This approach prevented both the inadequate response to treatment that might result from delayed absorption after IM administration, and the adverse reactions seen with IV boluses.

Heywood’s first question[3] is better answered by another (larger) sting challenge study that found a clear inverse relationship between the challenge-to-reaction interval and subsequent reaction severity.[4] We found no such relationship, but because of our small sample size this analysis was underpowered. Practically such knowledge is of limited use, as demonstrated by case 3 where symptoms did not occur until 20 minutes after the sting, compared to the overall median of 8 minutes.

Our consent process and ethical considerations, reviewed by two respected university hospital ethics committees, have already been outlined both in the EMJ and Lancet.[5] In accordance with good ethical practice the risks of participation (including the small risk of death) were clearly outlined both verbally and in writing.

To understand the ethical justification for this trial it must be appreciated that:

1) Patients may die if they erroneously believe treatment to be effective.[6] Thus, it is unethical to conduct a poorly designed trial.

2) Efficacy can only be proven if a control group demonstrates that severe reactions can be precipitated by the challenge procedure. The alternative –waiting for an accidental sting away from medical care– is not ethical.

3) Large studies have demonstrated the safety of sting challenge using strict exclusion criteria,[4,7] even if adrenaline is withheld during hypotensive reactions.[8] We gave adrenaline immediately when objective features of respiratory or cardiovascular compromise were identified. This approach is consistent with published consensus indications for the use of adrenaline.[9,10]

4) The small short-term risk from the trial needs to be balanced against the far greater reduction in long-term risk from providing an effective immunotherapy.

5) There can be little doubt as to the informed nature of the consent process if it is remembered that participants had previously experienced reactions in the field, away from emergency medical care.

We hope that ethics committees in the UK would not deny people the opportunity to participate in the rigorous assessment of a treatment that could provide them with dramatic quality of life benefits, [11] as well as protection from potentially lethal reactions in the setting of a community where one in every eight people receives an accidental sting every year.[12]

There can be little doubt as to the commitment and altruism of trial participants, many of whom considered this to be important research that would benefit others. However, implications that the trial was ill considered, reckless, or unethical do not stand up to careful scrutiny.

References

1. Fatovich DM. Limited use of corticosteroids for insect sting anaphylaxis [electronic response to Brown et al. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation] emjonline.com 2004 http://emj.bmjjournals.com/cgi/eletters/21/2/149#230

2. Brown SGA. Parallel infusion of hydrocortisone with/without chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. Med J Aust 2004;180(8):428-9.

3. Heywood M. Questions raised by this study [electronic response to Brown et al. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation] emjonline.com 2004 http://emj.bmjjournals.com/cgi/eletters/21/2/149#238

4. 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.

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. Brown SGA, Wu QX, Kelsall GR, Heddle RJ, Baldo BA. Fatal anaphylaxis following jack jumper ant sting in southern Tasmania. Med J Aust 2001;175(11-12):644-7.

7. Blaauw PJ, Smithuis OL, Elbers AR. 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):39-47.

8. van der Linden PW, Hack CE, Poortman J, Vivie-Kipp YC, Struyvenberg A, van der Zwan JK. Insect-sting challenge in 138 patients: relation between clinical severity of anaphylaxis and mast cell activation. J Allergy Clin Immunol 1992;90(1):110-8.

9. Emergency medical treatment of anaphylactic reactions. Project Team of The Resuscitation Council (UK). Resuscitation 1999;41(2):93-9.

10. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 3: special challenges in ECC. Anaphylaxis. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000;102(8 Suppl):I241-3.

11. Oude Elberink JN, De Monchy JG, Van Der Heide S, Guyatt GH, Dubois AE. Venom immunotherapy improves health-related quality of life in patients allergic to yellow jacket venom. J Allergy Clin Immunol 2002;110(1):174-82.

12. 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.

Send letter to journal:
Re: Questions raised by this study

Dear Editor

Brown et al's [1] study provoked lively debate amongst the staff at Ipswich Hospital.

I would like to pose two questions:

1) What was the interval between sting challenge and onset of symptoms? Was this related to severity of reaction?

2) What were the details of ethical approval, and what was the consent process and documentation?

I wonder if such a study would receive ethical approval in the UK. Were any estimations of risk given to participants before their recruitment?

This study reinforces the need for early and aggressive treatment of anaphylaxis with adrenaline and large-volume fluid resuscitation. For this, the bravery of both investigators and participants is to be applauded.

Reference

1. S G A Brown, K E Blackman, V Stenlake, and R J Heddle Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation Emerg Med J 2004; 21: 149-154.

Send letter to journal:
Re: Limited use of corticosteroids for insect sting anaphylaxis

Dear Editor

I congratulate Dr Brown and his colleagues on conducting the first prospective trial of a management protocol for anaphylaxis.[1]

Perhaps one of the most telling results was that corticosteroids and antihistamines were prescribed for only three of the 21 patients. In my experience, corticosteroids and antihistamines are frequently overprescribed and overemphasised for the management of allergic reactions. It would be useful to know the initial reaction severity in these three patients, and the authors’ perception of the usefulness or otherwise of the prescribed corticosteroid and antihistamine therapy.

Previous reports have found that corticosteroid agents are used or recommended too frequently; sometimes as the sole therapeutic agent.[2] There is, however, no evidence of a therapeutic benefit for corticosteroids in anaphylactic shock.[3] Yet many emergency medicine textbooks recommend corticosteroids for all cases of anaphylaxis. In severe reactions, often associated with bronchospasm, resuscitation may be protracted and corticosteroids could play a role, but expert opinion suggests that they are not the drugs of first choice.[4]

I would be interested in the authors’ views on this subject, in particular the rationale behind their treatment protocol.

References

1. Brown SG, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004;21(2):149-54.

2. Gupta S, O'Donnell J, Kupa A, Heddle R, Skowronski G, Roberts-Thomson P. Management of bee-sting anaphylaxis. Med J Aust 1988;149(11-12):602-4.

3. Fisher M. Anaphylaxis. Dis Mon 1987;33(8):433-79.

4. Fisher MM, Baldo BA. Acute anaphylactic reactions. Med J Aust 1988;149(1):34-8.