Accidents caused by venomous and poisonous animals are extremely complex events. Factors contributing to this complexity include the variety of such animals, differences in the nature of the accident and the course of envenoming/poisoning and the conditions under which the patient is diagnosed and treated. Unfortunately, there is frequently a lack of comprehensive and definitive knowledge on important matters such as the distribution of venomous and poisonous animals, first aid, early recognition of clinically relevant envenoming/poisoning and symptomatic and specific forms of treatment. It is still the case that in most regions of the world, the quality and availability of specific therapeutic agents, in particular the antivenoms, are below the standard that should be achievable nowadays. Strategies for handling accidents with venomous and poisonous animals must take these difficulties and practical limitations into account.

In light of the above, the strategies for the medical care of accidents with venomous and poisonous animals presented in the VAPAGuide were developed on the basis of an analysis of the circumstances in which these accidents occur as well as the conditions under which they are treated. The VAPAGuide provides a systematic approach to the solution of the important problems of clinical toxinology.

General circumstances of accidents with venomous and poisonous animals

Knowledge of the basic conditions under which accidents with venomous and poisonous animals occur is necessary to understand the strategies for medical care presented in the VAPAGuide.

• Many such accidents represent a medical emergency.
• These accidents often occur far from medical care facilities.
• There is no universally applicable first aid method available, not even for accidents within a group of animals, e.g. the terrestrial snakes. The great majority of numerous first aid methods propagated are potentially or even exclusively detrimental. Only a few first aid methods have stood up to critical scrutiny. However, to date there have been no controlled clinical investigations of such methods. The propagation of useful first aid methods usually fails due to the absence of conditions required to implement extensive education programmes or a shortage of suitable materials that may be required for a particular first aid measure.
• The venomous or poisonous animal that caused the accident is generally not available for identification, and in many cases was not even seen by the victim.
• Extensive biological knowledge is also necessary for the optimal care of patients who have been the victim of an accident with a venomous or poisonous animal. This is primarily important in order to be able to identify the animal from morphological characteristics and to narrow down the possible cause with the help of indirect, e.g. ecological, criteria. However, staff at medical facilities do not usually have the necessary training to be able to do this. The great diversity of venomous and poisonous animals is one of the reasons that it is difficult to provide such training.
• Accidents with venomous or poisonous animals, e.g. snakebites, do not always result in clinically relevant envenoming or poisoning. This fact makes it necessary to have a list of criteria with the help of which the onset of envenoming or poisoning can be recognised or, ideally, predicted, in order to be able to employ symptomatic and specific treatment measures in a timely and rational manner.
• With a few exceptions the currently available specific therapeutic agents (antivenoms) have a large range of sometimes severe adverse reactions. This fact alone makes it necessary that there are conclusive indications for the administration of antivenom.
• In many cases, the use of specific therapeutic agents (antivenoms) requires identification of the animal that caused the accident. This is of particular relevance for those regions in which there are no polyspecific antivenoms available that cover all the medically significant animals in a particular group, e.g. snakes.
• The variability of venom composition, which is observed even in individual animals within the same species, is a further factor that makes it difficult to choose the appropriate antivenom. Clinical efficacy studies are required in order to define the scope of application of the various antivenoms. However, these are only available for a very few antivenoms and for narrowly confined regions. 
• Knowledge of the distribution areas of most venomous and poisonous animals as well as the epidemiology of accidents with such animals is not comprehensive. Only a very few diagnostic and therapeutic methods have been investigated in controlled clinical studies. The relevant knowledge necessary to manage accidents with venomous and poisonous animals is scattered throughout various specialist journals.
• Accidents with venomous and poisonous animals are largely a problem of economically disadvantaged regions.

 

Questions important for the medical care of envenoming and poisoning

Is the situation a medical emergency? Does a specific and effective first aid method exist? What level of identification of the animal that caused the accident is necessary? What level of identification of the animal that caused the accident can be achieved if the animal is not available for morphological identification? Which strategy guarantees the best conditions for first aid, diagnosis and treatment if the animal is not available for morphological identification? What level of identification of the animal that caused the accident can be achieved if the animal is available for morphological identification? Which strategy guarantees the best conditions for first aid, diagnosis and treatment if the animal has been conclusively identified taxonomically? How is clinically relevant envenoming or poisoning recognised? How is the appropriate antivenom chosen? When is it administered? What is expected of an ideal antivenom? How reliable is the information regarding first aid, diagnosis and treatment on which the recommendations for managing accidents with venomous or poisonous animals are based? Which venomous or poisonous animal caused the accident?

 

1. Is the situation a medical emergency?

Many accidents with venomous and poisonous animals represent medical emergencies. Information regarding diagnosis and treatment must therefore be systematic and readily accessible. There is a hierarchy of aims:

• Delaying the onset of systemic envenoming or poisoning by means of first aid measures until a medical facility can be reached.
• It is then important to maintain vital functions, in particular respiration and circulation, as well as implementing other forms of symptomatic treatment. 
• Quickly establishing whether a specific therapeutic agent (antivenom) exists and is available should take place either at the same time as or directly after the implementation of immediate life-saving measures.
• If a specific therapeutic agent (antivenom) is available, it should be administered immediately, provided that it is indicated and the necessary precautionary measures have been taken.

 

The VAPAGuide is structured in such a way as to fulfill emergency medical requirements. The most important elements of the VAPAGuide in terms of practical use are the following:

• Key to the animal groups & Animals that cause envenoming and poisoning (picture guide)
• Groups of venomous and poisonous animals (see respective entries in the Emergency & clinical flowcharts, the Diagnosis & treatment section and the Biomedical database)
  • Poisonous animals,
  • Cnidarians (Jellyfish, Corals and Anemones),
  • Venomous fish,
  • Scorpions,
  • Spiders,
  • Hymenopterans (Bees, Wasps and Ants),
  • Sea snakes,
  • Terrestrial snakes:²
    
    • North America,
    • Mexico and Central America,
    • South America and the West Indies,
    • Europe,
    • North Africa, Near and Middle East,
    • Central and Southern Africa,
    • The Far East,
    • Indian Subcontinent and Southeast Asia,
    • Australia and the Pacific Islands,
  • Miscellaneous animals.

• Emergency flowcharts¹ for the various groups of animals²
• Clinical flowcharts¹ for the various groups of animals²
• The problem-oriented sections Diagnosis & Treatment¹ for the various groups of animals²

 

Three important emergency medical requirements are met:

• Rapid narrowing down of the large number of possible animals that could have caused the accident through identification of the relevant group of venomous or poisonous animals² by means of simple critera (see below, 12. Which venomous or poisonous animal caused the accident?).
• Quick orientation with regard to
  • the possible acute symptoms of envenoming/poisoning within a group of animals with the aid of the Emergency and Clinical flowcharts,
  • symptomatic emergency medical treatment measures within a group of animals with the aid of the Emergency flowchart and the Diagnosis & Treatment entries,
  • the choice of an appropriate antivenom.
• Easy location of diagnostic and therapeutic information in the Emergency flowcharts and the Diagnosis & Treatment³ entries for the identified group of animals.

_______

¹ _{As far as possible, we have used a uniform structure for each group of animals, in order to provide the user the advantage of a standardised procedure. Classification of the signs and symptoms of envenoming or poisoning according to 7 primary venom/poison effects aids in providing a systematic approach to the management of envenoming or poisoning. The following primary venom/poison effects, i.e. primary effects of a venom/poison on organs or organ systems, are defined:}

_{– autopharmacological effects,}

_{– local effects,}

_{– haemostatic (haemolytic) effects,}

_{– neurological effects,}

_{– muscular effects,}

_{– cardiac effects,}

_{– renal effects.}

 

² _{The Terrestrial snakes are further divided by region, and for each region there is an Emergency flowchart, a Clinical flowchart and a Diagnosis & Treatment section. The Miscellaneous animals are a very heterogeneous group and thus have only Biomedical database entries for the individual animals.}

 

³ _{The guidelines presented in the Diagnosis & Treatment sections are aided by the fact that each of the three fundamental levels of medical care (First aid / lay people → General practitioner / Health post → Hospital) is dealt with individually and with reference to the available resources. The problem-oriented structure leads the inexperienced doctor through all the problems that must be taken into account when managing such an accident. For the experienced doctor, on the other hand, the VAPAGuide offers quickly accessible answers to specific questions that may arise during treatment of a patient.}

 

 

2. Does a specific and effective first aid method exist?

General first aid techniques, such as cardiopulmonary resuscitation by laypersons, are not described in this guide. Please refer to other sources.

Specific first aid methods are measures applied in an accident caused by a venomous or poisonous animal that prevent or delay the absorption and circulation of toxins or toxin fractions. The aim of such measures is to delay the onset of systemic signs of envenoming or poisoning at least until adequate medical care is available.

The VAPAGuide describes those specific first aid measures for which there is broad agreement among the experts. The limitations of their use are defined. This is necessary because most specific first aid methods only have a limited scope of application, beyond which they may even have harmful consequences. Specific first aid measures are described in the following sections of the VAPAGuide:

• In the section First aid
• In the rspective Diagnosis & Treatment entries for the groups of venomous or poisonous animals
  • Poisonous animals
    • How can the absorption of poison be prevented?
  • Cnidarians
    • Inactivation of the nematocysts
    • How can absorption and circulation of the venom be delayed?
  • Venomous fish 
    • Painful stings
    • Painful, extensive puncture wounds
  • Scorpions
    • How can absorption and circulation of the venom be delayed?
  • Spiders
    • How can absorption and circulation of the venom be delayed?
  • Hymenopterans
    • Emergency treatment of allergic reactions by lay people
  • Sea snakes
    • How can absorption and circulation of the venom be delayed?
  • Terrestrial snakes
    • How can absorption and circulation of the venom be delayed?
      • North America,
      • Mexico and Central America,
      • South America and the West Indies,
      • Europe,
      • North Africa, Near and Middle East,
      • Central and Southern Africa,
      • The Far East,
      • Indian Subcontinent and Southeast Asia,
      • Australia and the Pacific Islands

• In the Biomedical database entries for all groups of venomous and poisonous animals. 

In the Biomedical database entries only those first aid methods are described that have been the subject of clinical studies or for which there is otherwise sufficient documentation.

 

 

3. What level of identification of the animal that caused the accident is necessary?

The most important reason for aiming at a high level of identification of the animal that caused the accident lies in the answer to the question:

Does a specific therapeutic agent (antivenom) exist?

 

Further reasons are related to the following questions:

• Do specific and effective first aid methods exist?
• Was the envenoming or poisoning caused by an animal that can cause clinically relevant acute or chronic harm?
• What course will the envenoming/poisoning take?
• Which diagnostic tests need to be employed (e.g. tests to determine haemostasis)? How often?
• Which symptomatic forms of treatment need to be prepared for (e.g. instruments for endotracheal intubation and artificial respiration)?
• Does the patient need to be observed for a long period because of the risk of long-term damage?

 

The level of identification of an animal is of crucial importance in answering the question of whether a specific therapeutic agent (antivenom) exists and, if indicated, is available. In a few cases this also applies to specific first aid methods, but the other way around, in order to avoid the use of harmful first aid measures.

 

Within the individual animals groups, the importance of achieving a high level of identification of the animal that caused the accident is evaluated as follows:

0   no importance

+   helpful

++ essential

 

• Poisonous animals

++ with regard to the applicability of a specific therapeutic agent, however, only in respect of scombrotoxic fish poisoning and ciguatera

0   with regard to first aid measures

+   with regard to risk assessment, diagnosis and symptomatic treatment

• Cnidarians (Jellyfish, Corals and Anemones)
  

++ with regard to the applicability of a specific therapeutic agent (antivenom), however, only regionally relevant in respect of Chironex fleckeri stings

 

++ with regard to first aid measures

+   with regard to risk assessment, diagnosis and symptomatic treatment

• Venomous fish
  

++ with regard to the applicability of a specific therapeutic agent (antivenom) in respect of accidents with Stonefishes

+   with regard to first aid measures

+   with regard to risk assessment, diagnosis and symptomatic treatment

• Scorpions

++ (regionally) with regard to the applicability of a specific therapeutic agent (antivenom)

0   with regard to first aid measures

+   with regard to risk assessment, diagnosis and symptomatic treatment

• Spiders

++ (regionally) with regard to the applicability of a specific therapeutic agent (antivenom)

+   (regionally) with regard to first aid measures

+   with regard to risk assessment, diagnosis and symptomatic treatment

• Hymenopterans (Bees, Wasps and Ants)
  

0  with regard to the applicability of a specific therapeutic agent (antivenom)

0  with regard to first aid measures

0  with regard to risk assessment, diagnosis and symptomatic treatment

• Sea snakes
  

0  with regard to the applicability of a specific therapeutic agent (antivenom)

0  with regard to first aid measures

+  with regard to risk assessment, diagnosis and symptomatic treatment

• Terrestrial snakes

++ with regard to the applicability of a specific therapeutic agent (antivenom)

++ (regionally) with regard to first aid measures

+   with regard to risk assessment, diagnosis and symptomatic treatment

 

 

4. What level of identification of the animal that caused the accident can be achieved if the animal is not available for morphological identification?

Only rarely does the victim of an accident with a venomous or poisonous animal bring the animal with them. Descriptions of the animal by patients and companions are often inadequate, and many patients do not even see the animal that caused the accident. This fact is of fundamental importance for strategies for managing envenoming and poisoning.

 

What solutions to this fundamental problem are offered by the VAPAGuide?

First stage: The organising principle, which requires only a few criteria, is the allocation of an accident involving a venomous or poisonous animal to a group of animals. This is possible in most cases and dramatically reduces the possible number of animals that may have caused the accident. In the group terrestrial snakes, additional division of this group into regions achieves a further reduction in the possible number of causative species (see below, 12. Which venomous or poisonous animal caused the accident?).

Second stage: Within a group of animals or a regional group (terrestrial snakes), the level of identification is facilitated as much as possible with the help of indirect criteria (see below, 12. Which venomous or poisonous animal caused the accident?).

Successful identification of an animal within a group of animals is greatly dependent on the diversity of the local venomous and poisonous fauna and familiarity with local conditions.

 

 

5. Which strategy guarantees the best conditions for first aid, diagnosis and treatment if the animal is not available for morphological identification?

As it is generally possible to assign the animal that caused the accident to a group of animals, the VAPAGuide is so conceived that each animal group or regional group (terrestrial snakes) represents the basic unit for diagnosis and treatment.

For each group of animals or regional group (terrestrial snakes) an Emergency flowchart, a Clinical flowchart and Diagnosis & Treatment entries are available, and these provide problem-oriented information on the required diagnostic-therapeutic steps. They guarantee maximum differential diagnostic and differential therapeutic flexibility during the entire process of managing an accident due to a venomous or poisonous animal.

If, during the course of treatment, clinical signs provide sufficient evidence to identify the animal that caused the accident with certainty, the relevant Biomedical database entry can be consulted. These entries contain detailed information at a family, genus, species or subspecies level (see below, 11. How reliable is the information regarding first aid, diagnosis and treatment on which the recommendations for managing accidents with venomous or poisonous animals are based?).

 

 

6. What level of identification of the animal that caused the accident can be achieved if the animal is available for morphological identification?

If the patient brings in the animal that caused the accident, the level of identification that can be achieved depends on the willingness and ability of the treating doctor or other persons present to carry out a morphological identification. In accidents with animals kept in terraria or aquaria, the taxonomic identity of the animal is generally known.

 

There are morphological identification methods available in the VAPAGuide for the medically relevant terrestrial venomous snakes in the following regions (see repective Morphological identification key):

• • North America,
  • Mexico and Central America,
  • South America and the West Indies,
  • Europe,
  • North Africa, Near and Middle East,
  • Central and Southern Africa,
  • The Far East,
  • Indian Subcontinent and Southeast Asia,
    There is no morphological identification key for Australia and the Pacific Islands as it is very difficult to distinguish between the Australian elapids. Such an identification key would be of little use to non-biologists. Moreover, an ELISA test kit (see Therapy phase: hospital) and good polyvalent antivenoms are available that cover the whole of Australia.

 

There are no morphological identification keys in the VAPAGuide for any of the other groups of animals, for the following reasons:

• Identification of the animal that caused the accident beyond assigning it to an animal group has no consequences for treatment (e.g. the hymenopterans); or
• There is only one or a few species within a group of animals for which antivenom is available and thus definitive identification would be of use (e.g. the Stonefishes in the group Venomous fish, and Chironex fleckeri/Chiropsalmus quadrigatus in the group Cnidarians). In this case only a few criteria are needed to distinguish these species from the others in the animal group (e.g. the "ladder-like pattern" on the skin following a Chironex fleckeri sting); or
• The identification criteria for some groups of venomous and poisonous animals cannot be simplified to the extent necessary for their use by doctors and other medical staff (e.g. identification of scorpions and spiders at a genus or species level).

 

 

7. Which strategy guarantees the best conditions for first aid, diagnosis and treatment if the animal has been conclusively identified taxonomically?

If the animal has been conclusively identified, the user can immediately go to the relevant Biomedical database entry for that animal. There he/she will find verified data on first aid, diagnosis and treatment of the envenoming or poisoning caused by this animal (see below, 11. How reliable is the information regarding first aid, diagnosis and treatment on which the recommendations for managing accidents with venomous or poisonous animals are based?). Whether or not the Biomedical database entry will contain the information necessary for the treatment of a patient depends on how much is known and has been documented with regard to accidents involving this animal. For this reason, the central resource should always be the Diagnosis & Treatment entries for the animal group or regional group (terrestrial snakes), even if the animal that caused the accident has been conclusively identified.

Emergency and Clinical flowcharts as well as Diagnosis & Treatment entries are available for each of the animal groups or regional groups (terrestrial snakes) and provide problem-oriented information regarding the required diagnostic-therapeutic steps. The taxonomic units within an animal group, i.e. families, genera, species and subspecies, or geographic variants, are referred to whenever there is information available (see Diagnosis & Treatment entries for the individual animal groups).

 

 

8. How is clinically relevant envenoming or poisoning recognised?

In order to assess the clinical relevance of an accident with a venomous or poisonous animal, the following factors must be taken into consideration:

 

The "dangerousness" of venomous/ poisonous animals, as assessed by the risk of mortality and morbidity, varies within broad limits

If the animal can be identified, it is possible to estimate these risks (see below, 12. Which venomous or poisonous animal caused the accident?).

 

The amount of venom/poison that can be delivered by a specific species varies within broad limits

In the case of defensive bites by venomous snakes, for example, often only a small amount of venom or none at all is injected. For some species it has been shown that in over 50% of cases no venom at all is injected (dry bites). However, the same species may also inject a volume of venom that exceeds the amount fatal for humans many times over.

The following is necessary to assess the amount of venom/poison that has been delivered:

• Clinical investigation to determine any venom/poison effects (see "Is it likely that a clinically relevant injection of venom has taken place?" in the Diagnosis & Treatment entries for the individual animal groups). 
• Observation of the patient for a sufficiently long period in order to exclude with certainty the possibility that a clinically relevant application of venom has taken place (see "Exclusion of clinically relevant envenoming" in the Diagnosis & Treatment entries for the individual animal groups).

 

The time between the application of venom/poison and the onset of symptoms of envenoming/poisoning identifiable either clinically or by laboratory methods varies within broad limits

This is the case not only between individual species of venomous or poisonous animals but also within a single species with regard to the effects of different toxin components. The interval between the application of toxin and manifestation of envenoming/poisoning is determined by numerous factors. The most important are the absorption and circulation properties of individual toxin components, which are primarily determined by their molecular weight. Toxin components with a low molecular weight (e.g. postsynaptically active neurotoxins from snakes, toxins from certain jellyfish) are rapidly absorbed and transported by the venous system and thus quickly exert their corresponding systemic effects. In contrast, toxin components with a high molecular weight, e.g. haemostatically active venom components from snakes, are absorbed slowly and transported by the lymphatic system. The effects caused by these toxin components may therefore occur only after a long delay. A crucial factor in this (desired) delay are efficient first aid methods.

The following is necessary for evaluation:

• Repeated clinical and laboratory investigations to determine any venom/poison effects (see "Is it likely that a clinically relevant injection of venom has taken place?" and "Monitoring of the patient if there is no indication for antivenom treatment following the initial investigation" in the Diagnosis & Treatment entries for the individual animal groups).
• Observation of the patient for a sufficiently long period in order to exclude with certainty the possibility of delayed onset of clinically relevant envenoming/poisoning (see "Exclusion of clinically relevant envenoming" in the Diagnosis & Treatment entries for the individual animal groups).

 

The sensitivity and specificity of most clinical and laboratory methods are not high enough to be able to predict the development of clinically relevant envenoming/poisoning with sufficient certainty

For example, clinical signs of a haemostatic defect following certain snakebites may be only mild or even absent even though haemostasis is so severely impaired that clotting tests show abnormal results. On the other hand, haemostatic tests, in particular global tests (clotting time, PT, aPTT), may not be sensitive enough to answer certain questions. For example, disseminated intravascular coagulation may already be present even though the results of the global tests are still within the normal range. External, easily recognisable signs of envenoming/poisoning, such as local swelling following a snakebite, have a limited positive predictive value with regard to the development of systemic envenoming/poisoning. Moreover, some species of snakes have venoms that are systemically active without causing local effects.  

The following is necessary for evaluation:

• Observation of the patient for a sufficiently long period in order to exclude with certainty the possibility of envenoming/poisoning that is not initially detected by the investigations conducted due to low sensitivity (see "Exclusion of clinically relevant envenoming" in the Diagnosis & Treatment entries for the individual animal groups).
• Taking into account the sensitivity of the investigation methods used when excluding systemic envenoming/poisoning (see Biomedical database entries; however, there are verified data on this subject for only a few species of animals).
• The use of investigation methods that take into account the entire range of possible venom/poison effects that may be caused by the members of a group of animals or regional group (terrestrial snakes), if the identity of the animal that caused the accident cannot be determined with sufficient certainty (see the Diagnosis & Treatment entries for the individual animal groups).

 

Sensitive and specific methods for early recognition and prediction of clinically relevant systemic envenoming/poisoning are under development

Immunological methods, in particular enzyme-linked immunosorbent assays (ELISAs), for this purpose are very promising and have already been tested in several studies. However, they are not yet standardised and not yet suitable for routine clinical use.

 

 

9. How is the appropriate antivenom chosen? When is it administered?

Specific therapeutic agent: In the treatment of accidents with venomous or poisonous animals, a specific therapeutic agent is a substance that neutralises or antagonises one or more of the toxin components of a taxonomically, ontogenetically and geographically characterised animal. Such agents are almost exclusively antivenoms.

Antivenom: An antivenom is a specific therapeutic agent that neutralises certain components of animal toxins. It consists of antibodies that are obtained from immunisation of animals. Traditionally, horses have been used for this purpose, but recently it has been recognised that sheep are also suitable for obtaining antibodies. Antivenoms vary greatly with regard to their efficacy and rate of adverse reactions, depending on the manufacturing process used. Some determining factors are the species of animal that is immunised, the immunisation technique, the choice of venom used for immunisation and its preparation, and how the obtained antibodies are prepared as well as the techniques used for their purification and concentration. There are monospecific and polyspecific antivenoms. Monospecific antivenoms are produced against the venom of a single species or subspecies, while polyspecific antivenoms are produced against the venoms of various species.

In any accident with a venomous or poisonous animal it is necessary to determine whether a suitable, effective specific therapeutic agent (antivenom) is available and if its use is indicated.

Antivenoms are available for the treatment of envenoming caused by some snakes, scorpions, spiders, cnidarians (only Chironex fleckeri/Chiropsalmus quadrigatus), venomous fish (primarily Stonefishes) and ticks (only Ixodes holocyclus).

However, in numerous countries antivenoms are not produced at all or in insufficient quantities, or distribution of antivenoms within these countries is inadequate. Apart from that, they are often of doubtful quality, and controlled clinical studies of their efficacy exist in only a very few cases. Measured against what is currently technologically achievable in the sector of antivenom production, antivenoms count among the neglected therapeutic agents.

 

The following questions must be answered in each individual case:

 

a) Does a specific therapeutic agent (antivenom) exist? b) Against which venom effects is the antivenom expected to be effective? c) Has efficacy been proven? d) When is antivenom use indicated? e) When is antivenom use contra-indicated? f) How is antivenom administered and at what dose? g) What adverse reactions can be expected, and how are they treated?

 

a) Does a specific therapeutic agent (antivenom) exist?

In order to answer this question, identification of the animal that caused the accident is crucial (see above, 3. What level of identification of the animal that caused the accident is necessary?

If only antivenoms with a taxonomically narrow range of efficacy (monospecific antivenoms) are available for the region in which the accident occurred, a significantly higher level of identification is necessary than when antivenoms with a taxonomically broad range of efficacy are available (polyspecific antivenoms).

If the identification of the animal has been established to such a level that the appropriate antivenom can be chosen according to taxonomic criteria, the question of efficacy nonetheless remains open. Apart from questions of quality, this is justified by the fact that the variability of venom composition is subject to factors that go beyond taxonomic criteria, e.g. geographical and ontogenetic factors. In this way an antivenom may demonstrate suboptimal neutralisation properties even if it was correctly chosen according to taxonomic criteria, e.g. at the species level. This difficulty gives rise to the recommendation to choose an antivenom that is suitable according to taxonomic criteria and for the production of which venoms from regional populations were used. This applies to the most common situation, i.e. that there are no regional clinical antivenom efficacy studies available.

In the VAPAGuide, the Emergency flowcharts assist in showing the path to the choice of appropriate antivenom(s).

In the Diagnosis & Treatment entries for the animal groups or regional groups (terrestrial snakes) the problem of antivenom availability is discussed in the section "How is the appropriate antivenom chosen?".

 

b) Against which venom effects is the antivenom expected to be effective?

From well-documented clinical antivenom studies it is known that that antivenoms have extremely variable efficacy against individual venom components (Warrell 1990b, 1992a).

Autopharmacological effects: As far as well-documented treatment histories demonstrate, prolonged and recurrent autopharmacological effects, such as arterial hypotension, appear to be treatable by antivenom. Clinical improvement can be expected within 10–20 min. However, it is important not to miss often concurrent hypovolaemia, which can be treated by fluid replacement.

Local effects: In most cases, local venom effects caused by snakes and spiders are not at all or only slightly affected by antivenom administration. A crucial factor is time, as even under optimal conditions the time between venom application and antivenom administration is too long to neutralise the venom components responsible for the development of local tissue damage sufficiently early. A certain effect on the progression of oedema seems to be attainable. In contrast, Chironex antivenom appears to have a very favourable effect with regard to pain and the disfiguring effects of the venom on the skin. However, to date there have only been case reports regarding this effect. 

Haemostatic effects: Controlled clinical studies of haemostatic defects following snakebites have shown that neutralisation of procoagulative and anticoagulative venom components can be achieved with a number of commercially available antivenoms in various regions of the world. As long as a sufficient dose of an effective antivenom is administered, spontaneous systemic bleeding ceases within 15–30 min and coagulability of the blood is restored within 6 h. Antivenoms are even effective when, for example, defibrinogenation has already been present for days or weeks. It is necessary to keep in mind that even after initially successful antivenom treatment, the haemostatic defect may recur and require further doses of antivenom. This is explained by continued absorption of venom from the region of the bite. 

Neurological effects: In cases of envenoming in which presynaptically active venom components are dominant, the currently available antivenoms are evidently fairly ineffective. In fact, it is often observed that signs of paralysis actually progress after antivenom administration. Following envenoming with postsynaptically active venom components, a rapid improvement in neurological signs of envenoming was observed in some cases following antivenom administration.

Muscular effects: Only early administration of antivenom appears to have an effect on the course of envenoming. If damage to the musculature is already established (rhabdomyolysis), antivenom will no longer be effective and it is necessary to wait for spontaneous regeneration of the musculature.

Cardiac effects: In the literature, cases of envenoming with primary cardiac effects are not very well documented. Thus it is not possible to make many claims about the ability of antivenom to influence these effects. However, in general effects on the cardiovascular system appear to respond well to antivenoms. However, cardiovascular problems may also be secondary, for example due to autopharmacologically active venom components.

Renal effects: On the basis of experience to date, antivenom administration has no influence on the development of acute renal failure, even if the antivenom is already administered shortly after the application of venom.

 

c) Has efficacy been proven?

Numerous factors determine the efficacy of an antivenom. Along with other aspects of the production process, the choice of venoms used for immunisation plays an important role.

Only in the case of a few antivenoms has efficacy been proven by controlled clinical studies.

In the VAPAGuide, the results of the available antivenom studies are presented in the relevant Biomedical database entries. If an antivenom is selected, the Biomedical database should be consulted to see if there is any information regarding the efficacy of the antivenom in the entry for the relevant animal.

 

d) When is antivenom use indicated?

In general the administration of antivenom is always indicated if systemic venom effects are observed. With regard to the likelihood of success, it is necessary to consider clinical efficacy studies (if available) and to take into account the fact that antivenoms have variable efficacy with regard to different venom effects. Local effects may also represent an indication for the administration of antivenom (see above). The preferable basis on which to make the decision to administer antivenom is the presence of clinical signs and symptoms with a high predictive value for the occurrence of systemic envenoming. However, in this regard clinical signs are either not applicable or only so to a limited extent. The same is true for the results of laboratory investigations. Immunological methods are being developed that could in future assist in making the decision whether or not to administer antivenom.

In the VAPAGuide, indications for the administration of antivenom are discussed in the Diagnosis & Treatment entry for a group of animals or a regional group (terrestrial snakes) under the question "Who requires antivenom?".

 

 

e) When is antivenom use contra-indicated?

In the case of life-threatening envenoming, there are no absolute contra-indications to the administration of antivenom. The section "Antivenom treatment" discusses how to proceed under difficult conditions, such as in atopic subjects.

 

f) How is antivenom administered and at what dose?

Antivenoms are most effective when administered intravenously. The antivenoms that are currently coming onto the market and which consist of Fab fragments will probably also be suitable for subcutaneous and intramuscular administration, due to their low molecular weight and thus improved absorption behaviour (see below, 10. What is expected of an ideal antivenom?). However, the intramuscular administration of antivenom is problematic and can be dangerous in the case of envenoming in which haemostasis is impaired.

The antivenom doses specified by antivenom manufacturers are often based on the results of mouse assays, from which it is not possible to reliably extrapolate the doses required in humans. Dosage information that is based on systematic clinical observations exists only for a few antivenoms. Children are given the same dose as adults or a larger dose.

It is extremely important to continue to observe a patient even after successful administration of antivenom. Continued absorption of venom from a depot in the region in which the venom was injected, and which is not accessible to the administered antivenom, can cause deterioration of the patient's condition and make further antivenom doses necessary. In extreme cases, such absorption processes can continue for several days.

 

In the VAPAGuide, the practical approach to antivenom administration is discussed in the section "Antivenom treatment". If verified dosage information is available for a specific antivenom, this is given in the relevant Biomedical database entry. In the Diagnosis & Treatment entries for the different groups of animals, the section "Monitoring of the patient: After administration of antivenom (assessment of success of antivenom or indication for continued antivenom treatment)" lists the investigations that need to be carried out following antivenom administration.

 

g) What adverse reactions can be expected, and how are they treated?

During and following antivenom treatment, the following reactions are possible (Warrell 1990b):

• Early reactions, almost exclusively so-called anaphylactoid reactions, which generally occur within 10–60 min after starting intravenous antivenom administration. In isolated cases, an early reaction might be an anaphylactic reaction in the true sense, i.e. an immediate-type hypersensitivity reaction (type I). This type of reaction can be expected in patients with a pre-existing sensitivity to horse serum.
• Pyrogenic reactions caused by endotoxin-like substances. These occur 1–2 h after starting antivenom treatment.
• Delayed-type hypersensitivity, so-called serum sickness, which on average occurs 7 days (range 5–24 days) after antivenom administration.

Early anaphylactoid reactions and delayed-type hypersensitivity, which constitute by far the greatest proportion of adverse reactions to antivenom, cannot be predicted with the aid of sensitivity tests, such as intradermal or intraconjunctival test doses of antivenom. Such tests should no longer be utilised (Malasit et al. 1986).

Treatment of adverse reactions to antivenom is discussed in the section "Antivenom treatment".

The technological requirements necessary for the production of effective and safe antivenoms have been in place for a long time. An example are therapeutic antibodies, such as are used for the treatment of digitalis poisoning.

 

 

10. What is expected of an ideal antivenom?

An ideal antivenom should

• be specially tailored to the needs of a specific region.
  The medically significant species and the geographical and ontogenetic variants within a group of venomous animals in a specific region should be covered by a polyspecific or various monospecific antivenoms. If taxonomic differentiation within a region is difficult, the preference should be for a polyspecific antivenom.
• possess a high degree of efficacy.
  This is dependent on the concentration or the properties of the specific antibodies. The properties of Fab fragments make them highly advantageous, and they also have a significantly more favourable adverse reaction profile. Due to their low molecular weight, they have very favourable absorption and distribution properties. Their absorption behaviour could allow i.m. or s.c. administration. This would have great advantages, as antivenoms could then be administered in basic medical facilities. The distribution properties of Fab fragments allow them to access compartments that would be inaccessible to larger molecules. In this way certain venom components would still be neutralisable after they had already disappeared from the circulation and had been sequestered in the extravascular spaces of certain tissues.
• cause as few adverse reactions as possible (no severe adverse reactions at all).
  Fab fragments processed in a certain way do fulfill this requirement. As is known from therapeutic antibodies used to treat digitalis poisoning, the rate of allergic reactions to such preparations is under 1%, none of them severe (Kirkpatrick et al. 1991, Smith et al. 1992).
• be available at a reasonable price.
  Most of the countries in which the majority of accidents with venomous and poisonous animals occur have limited economic resources. Antivenoms will only reach the patients who need them if they can be made available at a reasonable price (Russell et al. 1985, Smith et al. 1992, Sullivan 1987).

 

 

Table 2.1 Antivenoms: types, characteristics, reactions

 

Antibodies/antibody fragments		Characteristics	Reactions / problems	Examples
ab		high non-specific protein content   highly immunogenic   immune complex formation	early (anaphylactoid) reactions and serum sickness (~30%) (Theakston 1991)   early (anaphylactoid) reactions after i.v. administration (3–54%) (Malasit et al. 1986)	Thai Red Cross (TRC) antivenom
F(ab’)2		immunogenic immune complex formation	early (anaphylactoid) reactions and serum sickness (~10%) (Reid 1968)   anti-complement activity (Sutherland 1977)	Zagreb antivenom (European vipers)
Fab		less immunogenic than intact IgG or F(ab’)2   greater distribution capacity   no immune complex formation	Recurrent envenoming*
Fabspecific	affinity chromatography	greater efficacy   no non-specific Fab	immunological reactions comparable to those with therapeutic antibodies used for the treatment of digitalis poisoning, i.e. <1%, none of them severe (Kirkpatrick et al. 1991)   Recurrent envenoming*	TAb antivenoms (e.g. European vipers)

 

* Recurrent envenoming was common when rapidly cleared Fab antivenoms were introduced: EchiFab, Micropharm, London, UK for envenoming by Nigerian saw-scaled viper, ProlongaTab, Micropharm for envenoming by Sri Lankan Russell's viper (D. russelli), and CroFab, BTG, London, UK for envenoming by American rattlesnakes. Possible mechanisims: (a) continued absorption of antivenom from the bite site after antivenom has been cleared or has complexed with venom and (b) redistribution of venom after dissociation of the venom-antivenom complexes (Warrell 2010).

 

11. How reliable is the information regarding first aid, diagnosis and treatment on which the recommendations for managing accidents with venomous or poisonous animals are based?

The range of envenoming/poisoning symptoms and the results of (controlled) clinical studies on first aid methods, diagnosis and treatment are well documented for a number of venomous and poisonous animals down to the species and subspecies level. In contrast, for other animals there are practically no data on envenoming/poisoning available that meet the necessary standards. The most important requirement that a study on envenoming/poisoning must meet is the unequivocal identification of the animals that caused the accidents. Numerous published studies do not meet this requirement. Case reports often suffer from the same problem. Moreover, generalisation from case reports is problematic because of the wide variability of envenoming/poisoning symptoms even within narrowly defined taxonomic units. In addition, the published data are scattered among numerous journals.

The VAPAGuide deals with this problem by presenting the available verified data on first aid, diagnosis and treatment in the Biomedical database entries for each animal group for the most narrowly defined taxonomic units possible, i.e. at the family, species and subspecies level, as well as for geographic variants. This guarantees that these data can be accessed rapidly, in order to be able to assess the possible course of envenoming/poisoning and to take advantage of diagnostic and therapeutic experience.

However, the available data are not sufficiently comprehensive to be able to consistently provide therapeutic recommendations at this level.

The difficulties discussed above with regard to identification of the animal that caused the accident (see 4. What level of identification of the animal that caused the accident can be achieved if the animal is not available for morphological identification?) are naturally also relevant to the availability of data for narrowly defined taxonomic units. The solution adopted by the VAPAGuide is the same for both problems: Strategies for the management of envenoming and poisoning are formulated at the more general level of a group of animals or a regional group (terrestrial snakes).

 

 

Diagnostic and therapeutic recommendations are presented in a systematic and problem-oriented manner in the Emergency flowchart, Clinical flowchart and Diagnosis & Treatment entries for each group of animals or regional group (terrestrial snakes). Wherever possible, the most narrowly defined taxonomic units within the respective group of animals, i.e. families, species and subspecies, and geographical variants are referred to, with cross-reference to the Biomedical database. In this manner, the Emergency flowchart, Clinical flowchart and Diagnosis & Treatment entries on the one hand are linked to the Biomedical database entries on the other, and as much detailed information as is available can be called upon in the practical management of a case of envenoming/poisoning.

Apart from the fact that in most cases the available literature and the difficulties in identifying the animal that caused an accident require that for the practical management of such an accident it must be handled at the level of the animal group or regional group (terrestrial snakes), this level is actually sufficient for many purposes (see above, 3. What level of identification of the animal that caused the accident is necessary?).

The ability to translate insights from animal experiments into clinical toxinology is greatly limited due to the very high species specificity of most venom/poison effects. In contrast, the value of well-planned clinical field work to aid the development of first aid methods, diagnosis and treatment as well as our understanding of envenoming/poisoning is undisputed.

 

 

12. Which venomous or poisonous animal caused the accident?

If the name of the venomous or poisonous animal that caused the accident is known, then naturally the relevant information can be found by performing a direct search in the VAPAGuide.

If the name of the animal is not known, the important question is:

What level of identification of the animal that caused the accident is necessary? (3. above).

In order to answer this question, it is necessary to proceed as shown below.

 

Step 1: Assignment of the animal that caused the accident to an animal group

→  Key to the animal groups and Animals that cause envenoming and poisoning (picture guide).

 

In total, 8 groups of animals are defined (an additional group, Miscellaneous animals, includes all those venomous or poisonous animals that do not belong to any of the other 8 groups and that have only slight epidemiological significance).

• Poisonous animals
• Cnidarians (Jellyfish, Corals and Anemones)
• Venomous fish
• Scorpions
• Spiders
• Hymenopterans (Bees, Wasps and Ants)
• Sea snakes
• Terrestrial snakes
  
  • North America
  • Mexico and Central America
  • South America and the West Indies
  • Europe
  • North Africa, Near and Middle East
  • Central and Southern Africa
  • The Far East
  • Indian Subcontinent and Southeast Asia
  • Australia and the Pacific Islands

In the great majority of cases, assignment of the animal that caused the accident to one of these 8 groups can be easily achieved with the aid of the few simple criteria given in the section Key to the animal groups. The information necessary for this process can be easily ascertained from the patient history or from symptoms that are already obvious upon initial clinical examination of the patient. Exceptions: bites from snakes that have only small fangs (elapids, Australian elapids) and whose venom causes only minor local reactions or none at all may go wholly unnoticed. In the case of a tick bite, the tick might have already fallen off by the time the patient is examined, and thus local signs may be absent.

Assignment of a case to a specific animal group makes it possible by simple means to rapidly reduce the large number of possible animals that might have caused the accident.

 

Step 2: Identification of the animal that caused the accident within the animal group

Definition: Identification is used in the sense of morphological identification of an animal and in the sense of narrowing down the identity of an animal by indirect means, e.g. geographical criteria (Distribution tables), biological criteria (Biological tables) and clinical criteria (Emergency flowcharts, Clinical flowcharts). Criteria for the identification of the animal that caused the accident within a group of animals are offered if there are consequences with regard to first aid measures or diagnosis and treatment (see above, 4. What level of identification of the animal that caused the accident can be achieved if the animal is not available for morphological identification?).

 

Below is a summary for each animal group of the strategies offered by the VAPAGuide for identification of the animal that caused an accident, and where they can be found:

 

 

→ Identification of the animal that caused the accident within the group Poisonous animals:

• Emergency flowchart
• Clinical flowchart
• Diagnosis & Treatment
  • Taxonomic differentiation of poisoning due to poisonous animals
    
  • Clinical differentiation of poisoning due to poisonous animals
  • Immunological-chemical differentiation of poisoning due to poisonous animals
• Table 4.1: Poisonous fish (arranged according to classes, orders and families) with regard to the possible types of poisoning they cause
• Biomedical database 

 

 

→ Identification of the animal that caused the accident within the group Cnidarians (Jellyfish, Corals and Anemones):

• Emergency flowchart
• Clinical flowchart 
• Diagnosis & Treatment
  • Chironex fleckeri/Chiropsalmus quadrigatus stings
    
  • Physalia sp. stings 
  • Carukia barnesi stings ("Irukandji syndrome")
• Fig. 4.11: Ecological, morphological and medical characteristics of dangerous jellyfish in the Indo-Australian region.
• Biomedical database

 

→ Identification of the animal that caused the accident within the group Venomous fish:

• Emergency flowchart
• Clinical flowchart
• Diagnosis & Treatment 
  • How can the species that caused the acutely dangerous accident be identified?
    
• Biomedical database

 

→ Identification of the animal that caused the accident within the group Scorpions:

• Emergency flowchart
• Clinical flowchart 
• Fig. 4.33: Morphology of scorpions (morphological criteria to distinguish between families)
• Biomedical database

 

→ Identification of the animal that caused the accident within the group Spiders:

• Emergency flowchart
• Clinical flowchart 
• Fig. 4.38: Morphology of spiders (morphological criteria to distinguish between mygalomorph and labidognath spiders)
• Biomedical database

 

→ Identification of the animal that caused the accident within the group Hymenopterans (Bees, Wasps and Ants):

• Biomedical database

 

→ Identification of the animal that caused the accident within the group Sea snakes:

• Emergency flowchart 

• Biomedical database 

 

→ Identification of the animal that caused the accident within the group Terrestrial snakes:

• Morphological identification key (general and regional)
  If the snake that caused the accident is available for identification, it can be identified to the genus level with the aid of the regional morphological identification key. The identification keys are conceived in such a way that it should be possible for a lay person (with regard to biology) to classify a snake taxonomically by observing a few easily identifiable characteristics. Further differentiation to the species level can then be undertaken using the Distribution tables and the biological information in the relevant Biomedical database entries.

 

• Distribution tables
  If the snake that caused the accident is not available for morphological identification, the number of possible snakes in a particular region that might have caused the snakebite can be dramatically reduced with the aid of the Distribution tables. With these tables, it is possible to identify which species of venomous snakes occur in a particular region as well as in particular countries within a region.

 

• Biological tables
  Again if the snake that caused the accident is not available for morphological identification, these tables are intended to expedite identification of the cause as much as possible. This involves the use of various biological and epidemiological criteria. Some snakebites can be connected with specific habitats and certain human occupations.

 

• Regional Emergency flowcharts, Clinical flowcharts  and Diagnosis & Treatment entries
  Although signs and symptom complexes are insufficient on a global level as criteria to identify the cause of a snakebite, they can be successfully employed at a regional level. However, envenoming must be very severe or already relatively far advanced for signs and symptom complexes to be sufficiently distinct to be useful as differentiation criteria. Therefore this method is of very limited value in the early phase of envenoming, and thus unsuitable as the basis for important clinical decisions, such as the precautionary choice of a specific antivenom.