Information for healthcare professionals in Sweden only.
by Rafael Ferrandiz, Ph.D. on April 27, 2016.
Summary: Many teenagers and adults are undertreated with 300 mcg adrenaline pens and need a higher, 500 mcg, dose.
Traditionally, adrenaline auto-injectors (AAI) have been available in 150 and 300 mcg doses. However, dose recommendations and recent guidelines indicate that the prescription of 300 mcg dose may be too low for many adolescents and adults.
The World Allergy Organization Anaphylaxis Guidelines recommends adrenaline be injected promptly by the intramuscular route (IM) in a dose of 10 mcg/kg with a maximum dose of 500 mcg. This is effective and safe in the initial treatment of anaphylaxis .
Similar recommendations are found in the European Guidelines of Anaphylaxis , in the United States Guidelines for the Diagnosis and Management of Food Allergy , the American Heart Association in collaboration with the International Liaison Committee on Resuscitation , as well as in almost all national guidelines.
A review in the U.S. of anaphylaxis and its treatment reported the use of adrenaline in doses between 300-500 mcg .
If no clinical improvement, the IM dose of 300 to 500 mcg may be repeated after 5 to 10 minutes .
The Guidelines to health care providers from both the European and the UK Resuscitation Councils [7, 8] recommend doses of intramuscular adrenaline on an age basis:
Adrenaline should be given by IM injection into the mid-outer thigh and the safety profile of the IM adrenaline is excellent, although patients may experience transient pallor, palpitations and headache .
In the Nordic countries, the Swedish Association for Allergology (SFFA) , the Finnish National Guidelines , and the Norwegian Society of Allergology and Immunopathology  recommend also the dose of adrenaline to be 10 mcg/kg body weight, with a maximum of 500 mcg.
Moreover, the SFFA recommends that patients over 60 kg should use an adrenaline auto-injector with 500 mcg .
More recently in the UK, the National Institute for Health Care Excellence (NICE) and the British National Formulary (2014) recommend Emerade 500 micrograms (delivering a single dose of adrenaline 500 mcg) for adult and child over 12 years at risk of severe anaphylaxis, repeated after 5-15 minutes as necessary.
One of the limitations of most adrenaline pens is that they are only provided in two strengths, 150 and 300 mcg.
The limited range of higher doses presents a dilemma for physicians prescribing adrenaline for adolescents and adults with a normal and large body weight.
Patients who weigh more than 30 kg are likely to be under-dosed when receiving an injection with their 300 mcg AAIs. The 300 mcg dose is too low for some children and for teens and adults, especially those who are overweight or obese [12-15].
According to the dose recommendation of 10 mcg/kg, a teenager or an adult weighing 50 kg will need a 500 mcg dose.
While the Finnish national guidelines  recommend the dose of adrenaline for intramuscular administration to be 10 mcg/kg body weight with a maximum of 500 mcg, the National Institute for Health and Welfare (THL) recommends that patients above 50 kg body weight may consider using two 300 mcg AAI:s at once to treat an anaphylactic shock .
The lack of response to adrenaline in the emergency first-aid treatment of anaphylaxis observed in clinical practice has been attributed, among other potential risks, to a low initial dose of adrenaline .
Even though there are only few dose-response studies, the optimal dose is mainly based on tradition: 300 mcg is used for adults in many countries although the addition of a 500 mcg dose is used in some countries [15, 17, 18].
Repeated doses of adrenaline during the treatment of anaphylaxis are common and well documented in clinical practice:
Similar results were published by Manivannan, who reported this occurrence in 13% of patients .
Among the children who needed adrenaline because food-induced anaphylaxis, 13% required 2 doses of adrenaline and 6% required 3 doses. The administration of a second and a third dose of adrenaline occurred shortly after the administration of the first dose, usually within 30 minutes.
This observation supports the view that, in the majority of the reactions, the requirement for multiple doses of adrenaline is not a result of the biphasic nature of the reactions but the lack of response to the initial dose .
It is therefore recommended that patients should carry 2 auto-injectors with them and, if the symptoms persist, inject a second dose after 5-15 minutes with an additional injector.
Clinical experience and demand of many allergists have resulted in the market approval of AAIs in double-packs.
There are no absolute contraindications to the use of adrenaline in a life-threatening anaphylaxis. However, the life-saving pharmacologic effects of adrenaline, including vasoconstriction, decreased mucosal edema, bronchodilation, and decreased release of histamine, tryptase, and other mediators of inflammation, cannot be divorced from pharmacological adverse effects.
Adrenaline is characterized by concentration-dependent, bidirectional effects and a narrow therapeutic index (benefit-to-risk ratio) and the therapeutic range of plasma concentrations associated with successful anaphylaxis treatment is unknown .
The recommended adrenaline dose in acute anaphylaxis is 10 mcg/kg, to a maximum adult dose of 500 mcg, is lower than the initial adrenaline dose used in cardiopulmonary resuscitation .
The life-saving benefits of prompt adrenaline injection in anaphylaxis outweigh the risk of pharmacologic adverse effects.
The adverse effects of adrenaline in therapeutic dose ranges including pallor, tremor, anxiety, palpitations, headache, and nausea, are true pharmacologic effects and might be unavoidable in some patients because of the narrow toxic-therapeutic ratio of the drug. They are also dose-related  and are generally not a cause for concern, are usually mild and confirm that a therapeutic adrenaline dose has been given .
There are at least two factors involving a risk for high doses in patients carrying their AAIs: by repeated injections within a short period of time and by the availability of higher doses in multiple packing.
Patients are instructed to repeat the injection of adrenaline after 5 minutes, if the symptoms persist. This means that in an interval of a few minutes, usually before the 8 minutes required for adrenaline to reach the highest level in the blood [30, 31], the patient can receive a total dose of 600 mcg or 1000 mcg.
In terms of dose accessibility, and because most of the AAIs actually marketed are supplied as double pack, patients have access to inject doses higher than the individual dose, i.e. 300 mcg (2x150 mcg) 600 mcg (2x 300 mcg) and 1000 mcg (2x 500 mcg).
The 500 mcg dose is within the recommended dose of adrenaline for initial treatment of an ongoing anaphylaxis. There are no further risks by administration of this dose than the risks inherent of the therapeutic action of the drug, which has been well reported elsewhere.
In conclusion, the 300 mcg dose may be too low for many teenagers and adults, and according to the current therapeutic guidelines, those patients need a 500 mcg dose.
Emerade adrenaline auto-injector is available in 150, 300 and 500 mcg adrenaline.
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