In Dogs With a European Adder Bite, Does the Use of Antivenom With Supportive Treatment Compared to Supportive Treatment Alone Improve Time to Recovery?

a Knowledge Summary by

Lindsay Hodgson BVSc 5 ^1*

Giorgia Brambilla BVSc 5 ¹

¹University of Bristol, Senate House, Tyndall Ave, Bristol BS8 1TH
^*Corresponding Author (lh12819.2012@my.bristol.ac.uk)

Question

In [dogs with European adder bites] does the use of [antivenom and supportive treatment] compared to [supportive treatment only] [improve time to recovery]?

Clinical scenario

A dog has been brought into your practice with a suspected European adder bite. You do not stock antivenom in the practice and you are aware that it can be difficult to access a source. You wish to know if there is any evidence that giving antivenom will improve the dog’s recovery time, compared to supportive treatment alone.

The evidence

The quality of the evidence available to answer the PICO question is limited by the lack of studies directly comparing the addition of antivenom to  supportive treatment alone. At the time of writing no studies were found for the use of antivenom to treat European adder envenomation of dogs with time to recovery used as an outcome. Current studies are limited by bias; the decision to use antivenom is often made on severity of clinical signs, so that only the most severely affected dogs receive it Different sized dogs will also be affected with varying degrees of severity, with some dogs presenting asymptomatically. In addition, different amounts of venom may be injected with some bites injecting no venom (Sutton et al, 2011) so every dog is not subjected to the same amount of venom. These limitations influence the conclusions that can be drawn about the effect of antivenom on time to recovery.

In conclusion, a convincing body of evidence to influence the clinician’s decision whether or not to use antivenom in the dog, in addition to supportive treatment, does not currently exist. Other considerations include difficulty in sourcing antivenom (Sutton et al, 2011), so if clinicians decide its use is warranted, they should begin locating a source as soon as possible. Adverse reactions to antivenom have also been reported and a study conducted on 54 dogs found that 7% of the patients developed at least one side effect after administration of F(ab)2 antivenom. The reactions reported in this paper included facial swelling unrelated to the snake bite, profound panting and non-productive cough (Lund et al, 2013); anaphylaxis (Turkovic et al, 2015)  has also been reported. At the time of writing, the authors were unable to find any reports of death in dogs directly caused by  antivenom administration and Lund et al (2013) state that adverse effects appear to be “relatively mild and self-limiting”. As with any drug, the side effects should be considered as part of the decision making process about whether or not to use antivenom.

Summary of the evidence

Appraisal, application and reflection

The literature search performed by the authors found three papers which partially addressed the PICO question.

The study by Lund et al (2013) reports an improvement in local swelling and mental status in animals that received antivenom within 24 hours of the European adder bite. The group of dogs receiving antivenom also showed decreased proteinuria levels two weeks after the bite. These findings could be considered of interest when answering the PICO question; the study, however, presents some significant limitations which affect the quality of the evidence produced. The dogs recruited for the study had not been randomly assigned to the antivenom or the control group. The choice to administer antivenom was based on the clinician’s subjective assessment of the severity of the clinical signs, the financial situation of the owner and the availability of antivenom. This could have led to the introduction of bias in patient selection. Moreover, the study was not blinded and the subjective improvement noted by the clinicians in swelling and mental status of dogs receiving antivenom cannot be regarded as good quality evidence for the PICO question.

In the Sutton et al (2011) study of cases reported to the VPIS, it was found that in dogs receiving antivenom, oedema lasted an average of 46.8 hours, compared to dogs that did not receive antivenom, where oedema lasted an average of 94.1 hours. This was the most significant finding to the PICO question in this paper but is limited by several factors. Duration of generalised oedema was not reported in all dogs, decreasing the sample size, and objective method of oedema measurement was not given. Statistical analysis of the findings was not reported, so it is not known if the findings are significant. Death occurred in 3% of dogs receiving antivenom and 4.8% of dogs not receiving antivenom, which appears similar, but unfortunately no conclusions can be drawn due to the lack of statistical analysis. The study looked at broad risk factors for envenomation and mortality and the scope of treatment, rather than evaluating the effect of any individual treatment, and this was a common theme among the evidence found.

Turkovic et al (2015) found that antivenom administration did not significantly clinically affect local swelling 24 hours after envenomation, which appears to contrast to the finding from the Lund paper (2013). This paper was another case series studying risk factors, treatments and outcomes, with a very small study size and data relevant to the PICO question was incomplete. Duration of hospitalisation was recorded for dogs receiving and not receiving antivenom but the results were unfortunately not analysed for significance. The use of heparin and antihistamines in treating envenomation were highlighted as future areas of research.

The majority of the studies found by the authors examine risk factors for envenomation, adverse effects of antivenom administration and common treatment choices. Furthermore, most studies were retrospective, considered envenomation by other species or studied the effects of other elements of the treatment regime, such as glucocorticoids. There is wide variation in the combinations of supportive treatment given in the literature; combinations of intravenous fluid therapy (IVFT) with crystalloids, colloids or blood products, analgesia, antibacterial agents, glucocorticoids, antihistamines and heparin (Sutton et al, 2011, Turkovic et al, 2015 and Lund et al, 2013). This lack of a standardised treatment protocol makes direct comparison of the effect of antivenom more difficult to assess. These variations affect the analysis of the impact of antivenom on time to recovery. The best study design to answer this PICO question would directly compare the outcomes when the use of antivenom is the only variable imposed by the study authors.  

The PICO question could be best answered by a prospective, randomised, double-blinded controlled trial, comparing the effects of the addition of antivenom to supportive treatment alone. This could be considered as a research prospect; although a lack of antivenom licensed in dogs and the need to envenomate dogs would render such a study unlikely to pass ethics approval. The relatively small number of dogs envenomated each year in the UK could potentially render such a study financially unviable for antivenom manufacturers. Objective judgement of the clinical effects of antivenom, such as reduction of oedema, also generates difficulties. As such, the proposed clinical trial using ViperaVet may be of interest in revisiting this clinical question in the future; although at the time of writing the study was postponed (VPIS, 2017).

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on OVID Platform 1973 - Week 7 2017 Thomson Reuters Web of Science 1900-2017 PubMed (any date)
Search terms:	Dog* OR cani* OR bitch* OR pup* ‘Viper* berus’ OR ‘European adder*’ OR ‘European viper*’ OR adder Antiven* OR antiser* OR anti-ven* OR anti-ser* 1 and 2 1 and 2 and 3 Please note the terms “adder bite*” and “envenomation” were also included in the search strategy, but yielded fewer results than the terms used above and yielded no additional papers.
Dates searches performed:	23/03/2017

Exclusion / Inclusion Criteria
Exclusion:	Reviews of available treatments Expert opinion Letters Book chapters Papers studying envenomation by species other than the European adder or envenomation of humans Papers in a foreign language (that could not reasonably be translated) Papers that could not be accessed by authors or library staff
Inclusion:	Studies regarding the use of antivenom for treatment of envenomation of dogs by the European adder, Vipera berus.

Search Outcome
Database	Number of results	Excluded – Species other than the European adder	Excluded – Did not meet PICO question	Excluded – Cannot access paper	Excluded – Foreign language	Excluded – Book chapter	Excluded – Duplicate paper	Total relevant papers
CAB Abstracts	18	3	6	0	5	1	0	3
Web of Science	32	2	17	2	0	0	11	0
Pub Med	13	0	2	0	0	0	11	0
Total relevant papers when duplicates removed								3

The authors declare no conflicts of interest.

The authors wish to thank Clare Boulton for her assistance with the literature search and Emma Place for her assistance with locating papers.

1. Lund, H., Kristiansen, V., Eggertsdóttir, A. et al . (2013). Adverse reactions to equine-derived F(ab’)2-antivenin in 54 dogs envenomated by Vipera berus berus. Journal of Veterinary Emergency and Critical Care. 23 (5), 532–537. 2013. 1111/vec.12099
2. Sutton, N., Bates, N. and Campbell, A. (2011). Canine adder bites in the UK: a retrospective study of cases reported to the Veterinary Poisons Information Service. Veterinary Record. 169 (23), 607. 2011. http://dx.doi.org/10.1136/vr.d4695
3. Turkovic, V., Teichmann, S. and Doerfelt, R. (2015). European Adder bites in dogs in southern Germany. A retrospective study over a 6.5-year period. Tieraerztliche Praxis Ausgabe Kleintiere Heimtiere . 43 (4), 221-230. 2015. https://doi.org/10.15654/TPK-140364
4. Veterinary Poisons Information Service. (2017). Clinical trial for veterinary adder antivenom – invitation to take part. Available: https://vpisglobal.com/adder-antivenom/ Last accessed 26th July 2017.