SQ or IM Epi for Anaphylaxis? ============================= Date sent: Sun, 18 May 1997 18:27:15 +1000 Send reply to: "EMED-L is a list for hospital based emergency medicine practitioners." From: Richard Paoloni & Lisa Horvath Subject: re. IMI vs SQ (or SCI as we say in Sydney) To: Multiple recipients of list EMED-L On 5/15/97 I wrote the following: >Though not necessarily harmful adrenaline given subcutaneously is more >slowly >and poorly absorbed than intramuscular. The reason is that the >subcutaneous >blood vessels have predominantly alpha receptors (which >vasoconstrict, thus >delaying drug absorption, as is well known when it is >used with local anaesthetic) >whilst muscular blood vessels have >relatively more beta receptors (which >vasodilate, as in exercise). In rather a terse reply it was suggested that this statement was completely incorrect (and that more over it was common knowledge that it was incorrect). Following this, our ever helpful pharmacist (hi Tina) provided a middle ground stating that she believed IMI adrenaline was more quickly absorbed but that absorption was more erratic after IMI injection. So, to the references I went to clear this up (medline search from 1983 to present of adrenaline, epinephrine, subcutaneous, intramuscular = 400 articles + their references; the findings from the ones relevant to our discussion are presented below) ................... ---------------------------------------------------------------------------- --------------------------------------- There is no easy answer because the two routes of administration have never been directly compared in the literature. Most of the articles relate specifically to Rx of anaphylaxis. Goodman and Gilman's pharmacological text (1) states "absorption from subcutaneous tissue occurs slowly because of local vasoconstriction. Absorption is more rapid after intramuscular than after subcutaneous injection" Lip & Metcalfe (2) wrote " current recommendations suggest that adrenaline should be given intramuscularly rather than subcutaneously, as in allergic emergencies absorption from the site of the subcutaneous injection may be too slow, especially if the patient is shocked due to severe anaphylaxis. After intramuscular injection absorption is rapid and usually adequate if reasonable circulation is present". Ueda et al (3) agree with this - "when adrenaline is injected locally [subcutaneously in their study], its vasoconstrictive action retards its own absorption" The recommendations Lip & Metcalfe allude to are those of the British National Formulary (4). This sentiment is echoed in an editorial of the BMJ (5) which states "the keystone of effective treatment [of anaphylaxis] is adrenaline .... injected intramuscularly (not subcutaneously because absorption is too slow, especially in the presence of shock). Hedner et al - the authors of the paper being commented upon - then respond (same page as 2) that "In Sweden, though, the recommendation is to give adrenaline ... subcutaneously." They go on to say that "subcutaneous administration of adrenaline was also considered to be preferable in a recent review on anaphylaxis in the NEJM". On finding this article by Bochner & Lichtenstein (6) there is no comment about the difference between intramuscular and subcutaneous routes. It is merely stated in a table that the adrenaline is given subcutaneously. Two other papers (7, 8) also simply imply, without elaboration, that adrenaline was given subcutaneously. The second of these papers makes the very valid point that it is usually delay in administering adrenaline that causes fatalities. The Drug and Therapeutics Bulletin (9) is honest enough to say that "Adrenaline has long been the mainstay of treatment for anaphylaxis, but it is still not clear how best to give it. It can be administered, by intramuscular or subcutaneous injection, intravenous injection or infusion or by inhalation from an aerosol". Costa (10) also avoids the issue in his article by recommending either. Dahlof et al (11) found that "Subcutaneously administered adrenaline caused within 5 min a significant increase of plasma adrenaline level (from 1.0 +/- 0.2 to peak of 6.5 +/- 1.2 nM) which gradually decreased during 2 h". Mellem et al (12) compared aerosol administration with subcutaneous. They found that arterial adrenaline levels after aerosol increased significantly within 1 min whereas it was 4 min after subcutaneous administration. Warren et al (13) document similar times in their study. Heilborn et al (14) found that "the absorption of injected [subcutaneous] epinephrine was variable and in several cases very slow [up to two hours to peak levels].... inhaled epinephrine was rapidly and dose dependently absorbed". They went on to say "it is not surprising that absorption of epinephrine from a subcutaneous depot is low and variable in view of the well established use of epinephrine as a local vasoconstrictor that delays the absorption of local anaesthetics". This study was more interested in prophylactic implications and used 'normal subjects' but makes you think doesn't it - two hours !! This study also quoted interesting research that showed endogenous epinephrine levels in man were 5-10 nM two minutes after anaphylaxis induced by histamine-releasing drugs; in this study the average peak epinephrine level after 0.5 mg SQ epi was 4.65 nM. In a review article on Rx of Contrast Reactions in AJR (15) the authors do not discriminate - "although there is some disagreement, most researchers recommend that epinephrine be administered via intramuscular [4 references] or subcutaneous [3 references; 2 of which were the same] injection rather than IV to any patient who is not markedly hypotensive. We prefer the subcutaneous route because intramuscular absorption occasionally can be unpredictable". Unfortunately none of the references to this article were available in my medical library on the weekend - sorry ! Both intramuscular and subcutaneous injections of adrenaline have been associated with serious Clostridial infections (one case report each) (16,17) Finally some interesting articles about adrenaline in bronchiolitis. Lowell et al (18) gave 0.01 mg/kg subcutaneous epinephrine (vs placebo) in a randomised double-blind fashion. 15 minutes later 45% had improved and 34% had failed to improve (?what happened to the rest); unfortunately we do not know what would have happened if followed further as those that had not improved were given further epinephrine at 15 minutes. Reijonen et al (19) used 0.01 mg/kg intramuscular epinephrine as rescue therapy in their study of nebulised epinephrine vs albuterol. "Significant improvement in symptom scores" occured in 15 minutes. ---------------------------------------------------------------------------- --------------------------------- Conclusions: Rapidity of Absorption No-one feels that subcutaneous is faster than intramuscular. Several studies show delayed absorption of adrenaline from subcutaneous sites (with peak plasma levels up to two hours after absorption) In terms of prophylaxis the evidence appears to be with aerosol administration both in terms of rapidity and reliability of absorption. No studies about Rx of attacks. Variability of Absorption One comment about 'occasional' unreliability of intramuscular Several studies finding significant intersubject variability with SQ Complications No significant differences reported ---------------------------------------------------------------------------- ------------------------------- My Final Word Much less research done on IMI adrenaline. The national recommendations vary between countries. No direct comparisons between IM and SQ available. I will keep using IMI adrenaline because of my continuing belief that it is more rapidly absorbed (and speed IS important in anphylaxis). I would not be critical of anyone who wished to use SQ adrenaline after they have considered the above information because these studies are nowhere near conclusive. Happy to reconsider my position in the light of new evidence. Please send to me directly or to the list. The take home message, however, is not to delay giving the adrenaline because you are arguing the pros and cons of IM vs SCI ---------------------------------------------------------------------------- ---------------------------------- Congratulations if you managed to read this far. Hope it is clear as mud !! Pao References: 1. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 8th Ed, p197 2. Lip & Metcalfe "Adrenaline in Allergic Emergencies" (Letter) BMJ, 304, p1443 3. Ueda et al "Adrenline absorption: effect of pH in mepivicaine and bupivicaine solutions" Acta-Anaesthesiol-Scand 1992 Oct, 36(7); p660-3 4. BMA, Royal Pharmaceutical Society of Great Britain "British National Formulary, No 22" London: BMA and Pharmaceutical Press, 1991 5. "Treatment of Anaphylactic Shock" Editorial in BMJ, 1981, 282, p1011 6. Bochner & Lichtenstein "Anaphylaxis" NEJM; 1991; 324; 1785-90 7. Corren & Schocket "Anaphylaxis. A preventable emergency" Postgrad Med 1990 Apr, 87(5), 167-8, 171-8 8. AAAI Board of Directors "The use of epinephrine in the treatment of anaphylaxis" J-Allergy-Clin-Immunol 1994 Oct; 94(4); 666-8 9. "Adrenaline for anaphylaxis" Drug Ther Bull 1994 Mar 17; 32(3); 19-21 10. Costa, AJ "Anaphylactic Shock. Guidelines for immediate diagnosis and treatment" Postgrad Med 1988 Mar; 83(4); 368-9, 372-3 11. Dahlof et al "Systemic absorption of adrenaline after aerosol, eye-drop and subcutaneous administration to healthy volunteers" Allergy 1987 Apr; 42(3); 215-21 12. Mellem et al "Faster and more reliable absorption of adrenaline by aerosol inhalation than by subcutaneous injection" Br-J-Clin-Pharmacol 1991 Jun; 31(6); 677-81 13. Warren et al "Systemic absorption of inhaled epinephrine" Clin-Pharmacol-Ther 1986 Dec; 40(6); 673-8 14. Heilborn et al "Comparison of Subcutaneous injection and high-dose inhalation of epinephrine - implications for self-treatment to prevent anaphylaxis" J-Allergy-Clin-Immunol 1986 Dec; 78(6); 1174-9 15. Cohan et al "Treatment of reactions to radiographic contrast material" AJR 1988 Aug; 151; 263-70 16. Teo & Balasubramaniam "Gas gangrene after intramuscular injection of adrenaline" Clin-Orthop 1983 Apr (174); 206-7 17. Hallagan et al "Clostridial myonecrosis resulting from subcutaneous epinephrine suspension injection" Ann-Emerg-Med 1992 Apr; 21(4); 434-6 18. Lowell et al "Wheezing in Infants: The response to epinephrine" Pediatrics 1987 Jun; 79(6); 939 19. Reijonen et al "The clinical efficacy of nebulised racemic epinephrine and albuterol in acute bronchiolitis" Arch-Pediatr-Adolesc-Med 1995 Jun; 149(6);686-92