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Journal of Tropical Pediatrics Advance Access originally published online on May 15, 2006
Journal of Tropical Pediatrics 2006 52(3):155-157; doi:10.1093/tropej/fml006
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© The Author [2006]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Clinical Review

Evidence behind the WHO Guidelines: Hospital Care for Children: Should s/c Adrenaline, Hydrocortisone or Antihistamines be used as Premedication for Snake Antivenom?

Siang Yong Soh, Primary Reviewer

University of Melbourne, Australia

George Rutherford, Secondary Reviewer

University of California, San Francisco, USA

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources, these can be found at; http://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/PB.htm. This series reviews the scientific evidence behind WHO's recommendations. The WHO guidelines, and more reviews are available at www.ichrc.org.

This review addresses the question: Should s/c adrenaline, hydrocortisone or antihistamines be used as premedication for snake antivenom?

The WHO Pocketbook of Hospital Care for Children recommends that in the event antivenom is given for snakebite then IM epinephrine and IV chlorpheniramine should be prepared in case allergic reaction occurs.


   Introduction
Top
 Notes
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Methodology
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 Discussion
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Managing snake envenomation is challenging throughout the world. Even though antivenom is highly effective in reducing serious complications and mortality [1, 2], its potential for severe anaphylactoid reactions calls for judicious use [3–5]. The frequency of acute reactions to antivenom varies between 2-54% [6, 7] and are responsive to administration of adrenaline [4–6, 8]. The late serum sickness-like reactions can occur in more than 50% of patients [4, 9] and are readily treated with steroids and antihistamines [5].

These hypersensitivity reactions are mainly caused by the foreign animal proteins present in the antivenom and the probability of a reaction depends partly on the type of antivenom [10], its manufacturing and concentrating process, and the dose used [6, 9]. Therefore, studies vary in reported hypersensitivity reaction rates due to different antivenoms used and the quality of the antivenom [7, 11, 12]. In settings where antivenom reaction rates are high, pre-medication to reduce serious reactions seems a sound approach.

Adrenaline, steroids or antihistamines have been used as pre-medication, with varying results. This review investigates the evidence for the effectiveness of such premedications and intends to answer the question: Should s/c adrenaline, hydrocortisone or antihistamines be used as premedication for snake antivenom?


   Methodology
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 Introduction
 Methodology
Results
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The clinical search strategy was (antivenins OR antivenom OR snakebite OR snakebite prophylaxis) AND (hydrocortisone OR steroids OR antihistamines OR adrenaline). Clinical filters used were "therapy" and "broad". 126 articles were found. Using the same search term but restricting to systematic reviews, only one relevant article was found.

Of the 126 articles, 66 articles were selected using titles. Of them, 27 were excluded because there were no abstracts and were published prior to 1980 (13) or because the articles were commentaries or letters (14). A further 23 articles were excluded after examining the abstracts, as they were not relevant to the question. An additional 12 case-series or case-control studies were excluded, leaving one systematic review and three RCTs.

All trials were appraised individually by this review. The systematic review (included two out of the three RCTs) was type 1a and the three RCTs were type 1b evidence (Oxford grading system).


   Results
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 Notes
 Introduction
 Methodology
 Results
Discussion
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Subcutenous adrenaline
An RCT (n = 105) using 0.25ml 1 in 1000 adrenaline showed significant reduction in acute adverse reactions between the adrenaline group (6/56) and the placebo group (21/49) with a relative risk of 0.25 (P value of 0.0002, 95%CI = 0.11–0.57). The differences consistently applied to each category of mild (P = 0.05, 95%CI = 0.05 to 1.15), moderate (P = 0.04, 95%CI = 0.12 to 1.05) and severe reactions (P = 0.04, 95%CI = 0.00 to 1.13) [13]. No severe adverse effects were attributed to adrenaline use.

Hydrocortisone
There is no large RCT using hydrocortisone alone as premedication for snake antivenom treatment. However, in one small RCT, adverse reactions were observed in 80% (12/15) of the treatment group (hydrocortisone only) and 81% (13/16) of the placebo group, a one percentage point reduction, (95% CI = -29% to 27%). The author concluded that "prophylaxis with a parallel hydrocortisone infusion alone is ineffective in reducing the occurrence of acute adverse reaction to antivenom serum" [14].

Antihistamines
In one RCT (n = 101) promethazine (H1 antagonist) was used as pre-medication. Early anaphylatic reactions occurred in 12/49 of the treatment group and 13/52 of the placebo group [15]. RR = 0.98, 95%CI = 0.50 to 1.93 [6]. The study demonstrated that premedication (15–20 min prior to antivenom administration) with intramuscular promethazine was ineffective in preventing early anaphylactic reactions [15].

A smaller RCT showed that combination of hydrocortisone infusion and intravenous bolus chlorpheniramine (H1 antagonist) could significantly reduce the incidence of adverse reactions compared to placebo. 52%(11/21) in combined hydrocortisone and chlorpheniramine group and 81% (13/16) in the placebo group, a 29% reduction, (95% CI 0.2%-58%, P = 0.04). [14]. However, its statistical significance has been questioned by at least two authors [16, 17].


   Discussion
Top
 Notes
 Introduction
 Methodology
 Results
 Discussion
Summary
 References
 
Subcutaneous adrenaline
Even though subcutaneous adrenaline appears to be a potent premedication in reducing acute adverse reactions when given prophylactically, the single trial showing its effectiveness had strict exclusion criteria. In particular, patients below 12 years old were not enrolled [13]. Therefore, the use of s/c adrenaline in children has not been proven and a decision on appropriate dosing and consultation with an experienced clinician would be necessary prior to pre-treatment with adrenaline.

In addition, in areas where antivenom adverse reactions rates are low, the benefit of adrenaline needs to weigh against its potential risks. A local study might be needed for such justification [6].

Hydrocortisone
Despite its common use as a prophylaxis against acute adverse reactions of snake antivenins [14], there is no evidence behind such practice. Instead, it was suggested that hydrocortisone is unlikely to help preventing acute adverse reactions [6, 14]. However, there is no large RCT to refute such claims.

The potential benefit of prophylactic hydrocortisone in reducing relapses of acute reactions and incidence of late reaction are yet to be determined [6, 14]. Nevertheless, it is commonly accepted that hydrocortisone be used to treat late reactions [5, 6, 18].

Antihistamines
Previous studies indicated antihistamines are ineffective in preventing acute adverse reactions [6, 15]. A recent underpowered study proposed a synergistic effect of hydrocortisone and antihistamines that might have led to the different results [14]. Therefore, further studies are needed to examine the proposal and to justify the benefits of such combination therapy against its potential side-effects.


   Summary
Top
 Notes
 Introduction
 Methodology
 Results
 Discussion
 Summary
References
 
Premedication with subcutaneous adrenaline is effective in reducing acute adverse reactions due to snake antivenom (Grade A recommendation). However, local factors and patient selection need to be considered carefully. There is no strong evidence to support the use of hydrocortisone as premedication for snake antivenom (Grade B recommendation). Current evidence does not support routine antihistamines use as premedication for snake antivenom (Grade A recommendation). Further studies are needed to verify effectiveness of combination therapy with hydrocortisone and antihistamines. Doses of sub-cutaneous adrenaline as pre-medication for younger children are yet to be evaluated in clinical trials, but fractional doses based on weight may be appropriate.


   Notes
Top
 Notes
Introduction
 Methodology
 Results
 Discussion
 Summary
 References
 
For more information on this project to evaluate the evidence behind the WHO Hospital Care for Children, see J Trop Pediatr 2006; 52: 1–2. If you would like to suggest a topic or contribute a review, please contact Dr Julian Kelly. E-mail <julian.kelly{at}rch.org.au>.


   References
Top
 Notes
 Introduction
 Methodology
 Results
 Discussion
 Summary
 References
 

  1. Ariaratnam CA, et al. A new monospecific ovine Fab fragment antivenom for treatment of envenoming by the Sri Lankan Russell's viper (Daboia Russelii Russelii): a preliminary dose-finding and pharmacokinetic study. Am J Trop Med Hyg 1999;61(2): 259–65.[Abstract]
  2. Brian MJ, Vince JD. Treatment and outcome of venomous snake bite in children Port Moresby General Hospital, Papua New Guinea. Trans R Soc Trop Med Hyg 1987;81(5): 850–2.[CrossRef][Web of Science][Medline]
  3. Arunanthy S, Hertzberg SR. A life-threatening anaphylactoid reaction to polyvalent snake antivenom despite pretreatment. Med J Aust, 1998;169(5): 257–8.[Medline]
  4. Jurkovich GJ, et al. Complications of Crotalidae antivenin therapy. J Trauma 1988;28(7): 1032–7.[Web of Science][Medline]
  5. Otten EJ, McKimm D. Venomous snakebite in a patient allergic to horse serum. Ann Emerg Med, 1983;12(10): 624–7.[CrossRef][Web of Science][Medline]
  6. Nuchpraryoon I, Garner P. Interventions for preventing reactions to snake antivenom. Cochrane Database Syst Rev 2000(2): p. CD002153.
  7. Smalligan R, et al. Crotaline snake bite in the Ecuadorian Amazon: randomised double blind comparative trial of three South American polyspecific antivenoms. Bmj 2004;329(7475): 1129[Abstract/Free Full Text]
  8. Clark RF, et al. Immediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom. Ann Emerg Med 2002;39(6): 671–6.[CrossRef][Web of Science][Medline]
  9. LoVecchio F, et al. Serum sickness following administration of Antivenin (Crotalidae) Polyvalent in 181 cases of presumed rattlesnake envenomation. Wilderness Environ Med 2003;14(4): 220–1.[Medline]
  10. Ariaratnam CA, et al. An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell's viper (Daboia russelii russelii). Trans R Soc Trop Med Hyg 2001;95(1): 74–80.[CrossRef][Web of Science][Medline]
  11. Sutherland SK. Antivenom use in Australia. Premedication, adverse reactions and the use of venom detection kits. Med J Aust 1992;157(11–12): 734–9.[Web of Science][Medline]
  12. Chen JC, et al. Risk of immediate effects from F(ab)2 bivalent antivenin in Taiwan. Wilderness Environ Med 2000;11(3): 163–7.[Medline]
  13. Premawardhena AP, et al. Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial. Bmj 1999;318(7190): 1041–3.[Abstract/Free Full Text]
  14. Gawarammana IB, et al. Parallel infusion of hydrocortisone +/– chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. Med J Aust 2004;180(1): 20–3.[Web of Science][Medline]
  15. Fan HW, et al. Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snake bites. Bmj 1999;318(7196): 1451–2.[Abstract/Free Full Text]
  16. Brown SG. 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; author reply 428–9; discussion 429.[Medline]
  17. Gebski VJ. Parallel infusion of hydrocortisone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. MJA 2004;180(8): 429–9.
  18. Tibballs J. Poisoning and envenomation. In: Paxton G, Munro J, Marks M (eds), Paediatric Handbook, Blackwell Publishing, Melbourne, 2003;16–34.

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This Article
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