European viper bites: clinical management from pre-hospitalisation to follow-up a narrative review

Introduction

Background

Venomous snakebites in Europe are mainly due to Viperidae species of the genus Vipera. There are fourteen species of “true vipers” (subfamily Viperinae) in Europe, eleven of which belong to the genus Vipera. Among them, the main species of medical relevance due to their greater distribution in Europe and the greater number of species the snake bites recorded are six namely, V. berus (Figure 1), Vipera ammodytes (Figure 2), V. aspis, V. latastei, V. seoanei and V. ursinii (1,2). The species widespread in Italy are: Vipera ammodytes, V. aspis, V. berus, and V. ursinii. Since 2016, a new species Vipera walser, has been added, which is morphologically similar to Vipera berus, in both size and general appearance, with full taxonomic classification still in process (3).

Figure 1 Vipera berus.

Figure 2 Vipera ammodytes.

European vipers can be identified by morphological criteria. On the head there are irregularly arranged scales forming three symmetrical shields surrounded by smaller scales, while on the body there are keeled scales. In addition, adders differ in ecological and distributional characteristics. European adders usually reach an average size of 50–70 cm and do not exceed one meter. The pupil of vipers is vertical and in bright lights take on a “slit” shape (4). Vipers have the top of the head covered with small irregularly arranged scales or at most three symmetrically arranged shields, surrounded by smaller scales; they also have dorsal trunk scales that are always keeled. The shape of the head is more or less triangular or sub-oval (1).

In 2009, snakebite was included in the World Health Organization’s (WHO) list of neglected diseases. Each year, snakebites kill between 81,000 and 138,000 people and cause long-term disability in about 400,000 people (Global Burden Project of the World Bank) (5-7). Morbidity and mortality due to snakebites similar that of prostate and cervical cancers. In May 2019, at the World Health Assembly, the WHO launched its roadmap, which aims to halve snakebite mortality and disability by 2030. The WHO strategy focuses on snakebite prevention campaigns and the development of safe and effective treatments. It also highlights the need to accelerate snake antivenom development, stockpile serum supplies, and ensure adequate treatment supplies. Many snakebites often go unreported in Europe because snakebite reporting is not mandatory, so it is difficult to have up-to-date case histories. Considering that Europe has a relatively large number of viper species of medical interest associated with favorable habitat, the number of bites is underestimated, confirming that the incidence of mortality and morbidity is neglected in Europe (8).

Objective

The purpose of this work is to provide medical and paramedical health personnel with appropriate first aid strategies to inform optimal management of viper bites. Our research focuses exclusively on European Vipers, defining the incidence of bites, the composition of the venom and the effects caused by it, for a better clinical-diagnostic framework. The latter is also crucial to prevent long-term sequelae that can dramatically affect prognosis. The article is aimed at all doctors who may encounter patients bitten by European vipers. We present this article in accordance with the Narrative Review reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-81/rc).

Methods

The data for this narrative review were derived from careful search of scientific databases, including PubMed, MedlinePlus, Cochrane Library. We read 484 titles of scientific articles using the keywords: Viper bites: symptoms and treatment. Duplicate articles were excluded and the articles most relevant to our work were selected by reading the study abstracts. Articles with subheadings that were not pertinent to our review were excluded (Table 1). Some articles were discarded because they approached the topic more from a biological, zoological or clinical case report. Studies dealing with vipers not found in Europe were excluded. Some of these papers presented case reports. This type of work was necessary in order to obtain an adequate number of studies to best address the topic of clinical management of the European viper bite, from prehospitalization to follow-up. Ultimately the selected articles deal with European vipers us in the classification of the major European pit vipers and in determining bite incidence, venom composition, occurrence of signs and symptoms, diagnosis, treatment and follow-up.

Venom

The different species found in Europe, and particularly in Italy, account for the wide variability of venom and consequently the breadth of clinical pictures and response to antidotal treatment. Viper venom is characterized by a mixture of components including proteases, metalloproteinases, hyaluronidases, phospholipase A2 (PLA2), and coagulation inhibitory/activating factors. The main neurotoxins found in European viper venom are PLA2s capable of causing paralysis by affecting neuro-muscle transmission predominantly at the pre-synaptic level; PLA2s act peripherally as they are unable to cross the blood-brain barrier. Most pit viperid bite poisonings cause symptoms that can progress and range from local tissue lesions to kidney damage to widespread paralysis (9-13), involving various muscle groups up to hypoxia and multi-organ failure, intracranial hemorrhage and death. From a neurological point of view, the manifestations are affected by many factors: the amount of venom inoculated, the concentration of phospholipase neurotoxic component, and individual response. The variability and change over time of the components of snake venom are the subject of continuous study, and studies are also under way to try to characterize the venom of different viper species. These aspects are relevant for clinical evaluation and for the indication of antidotal treatment with antisera as species-specific as possible (14,15).

Signs and symptoms

Locally, two holes spaced about 6 to 8 mm apart may be observed, associated with intense local pain, hard edema, and ecchymosis that may extend to the entire affected limb with cyanotic patches, lymphangitic streaks, and lymphadenopathy. In dry-bite, that is, bite without venom inoculation, local and systemic manifestations are absent.

At the systemic level, flaccid paralysis characterized by interruption of nerve transmission at the neuromuscular junction is observed, which progresses very rapidly involving first the extra-ocular and facial muscles and then affecting the bulbar, neck, limb muscles, and respiratory muscles, resulting in hypoxia and eventually progressing to multiorgan failure with death. In cases of European viper (Vipera berus) bites, a particular detail is observed, which is paralysis of the frontal muscle (16).

At the respiratory and cardiovascular levels, pulmonary edema, thrombocytopenia, coaugulopathies, respectively, are observed (17-19). Moreover, the venom’s protein nature can act as a true allergen that can induce a type I IgE-mediated hypersensitivity leading to severe vascular problems or respiratory reactions that vary depending on the patient’s response and the nature of the insult (20,21). Other symptoms are appearance of general malaise, headache, and ophthalmoplegia, eyelid ptosis, vomiting, diarrhea, dyspnea (22). In addition, although rare, compartment syndrome (CS), a life and limb-threatening condition that develops due to increased pressure from edema that restricts blood flow, hindering the outflow of blood from the closed anatomical space, may also occur. Early manifestations include pain, due to lack of oxygenated blood and accumulation of waste products, and decreased peripheral sensation secondary to nerve irritation; later, absence of distal pulse, hypoesthesia and paresis of the extremities appear, because increased tissue pressure eventually compromises arterial blood flow.

If untreated or inadequately treated, muscles and nerves within the compartment undergo ischemic necrosis until renal failure and death; only a fasciotomy performed over 6 hours by decompressing restores normal muscle perfusion (23,24). Endocrinologically, acute hypopituitarism, secondary to pituitary infarction due to coagulopathy, may occur, manifesting with hypotension and hypoglycemia and an Addisonian crisis characterized by: weakness, apathy, confusional state, severe hypotension up to hypovolemic shock (drop in blood pressure and loss of consciousness), nausea, vomiting, abdominal pain and fever (21,25-27).

For clinical evaluation of the bite, for prognostic and therapeutic purposes, the Audebert-Boels classification, a scale divided into four classes of severity with respective scores, is used (Table 2).

Diagnosis

Diagnosis is based on a detailed patient history, objective examination, and appropriate laboratory tests. The history includes all data regarding the circumstances of the bite (e.g., geographic area, time of bite, number of bites, site of bite), details regarding the snake (if seen, photographed), clinical manifestations of venom, and previous medical conditions (e.g., comorbidities, allergies, previous snake bites, medications). Laboratory tests include assessment of the coagulation profile by repeated measurements of the international normalized ratio (INR) method of blood coagulation, activated partial thromboplastin time (aPTT), D-dimer, and fibrinogen degradation products. The coagulation test is of fundamental importance especially in rural hospitals where some tests such as thromboelastography (TEG) are missing. In addition, a sharp decrease in hemoglobin levels and hematocrit are suggestive of internal bleeding (28,29). For diagnostic purposes, blood levels of creatine kinase, electrolytes, myoglobin, lactic dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea as well as creatinine, in conjunction with urine examination (hematuria, proteinuria, urea levels, and urinary excretion) allow us to assess possible venom-induced rhabdomyolysis and associated complications, such as acute renal failure that is characterized by myoglobulinemia, polyuria or oliguria, or anuria (30,31).

Treatment

The out-of-hospital approach to the patient with an adder bite is based on dos and don’ts.

In the area of things to do:

• Keep calm;
• Remove rings, bracelets, and watches if the bite is on the hand or upper limb;
• Cleanse and disinfect the wound;
• Apply compressive bandaging to delay venom spread;
• Call emergency services.

Don’ts:

• Do not incise the bite area;
• Do not suck the venom;
• Do not apply a tourniquet;
• Do not administer stimulant drinks;
• Do not use alcohol containing substances for disinfection (Table 3) (32).

Regardless of the species involved, one must be prepared to intervene to treat both local and systemic signs by closely monitoring the patient for at least 12 to 24 hours after the bite.

Local treatment involves checking edema every hour, measuring limb circumference, presence and extent of local ecchymosis (using a marker), and circulation status.

Indications for surgery are not well established because they are based on the clinical judgment and experience of the practitioner who assesses necrotic and infectious complications at the level of the wound; in addition, in the presence of signs and symptoms of infection, broad-spectrum antibiotic therapy is required. Tetanus prophylaxis is always necessary where there is no vaccine coverage (33).

As for systemic treatment, airway patency must be ensured, with the use of oxygen and assisted ventilation. The presence of severe coagulopathy involves the administration of fresh or frozen plasma and serum; while hypotension should be treated with crystalloids and rhabdomyolysis with fluids and sodium bicarbonate.

In the case of certain and documented poisoning, the specific antidotal therapy should be administered, which consists of administering exclusively intravenously a 10 mL vial of snake antivenom diluted in 100 mL of slowly infused saline. This amount is usually needed to neutralize about 500 IU of venom (the initial dose of antivenom is typically 1–2 vials, 10 mL each, administered intravenously, depending on the severity of the infection. If symptoms persist or worsen, additional doses may be required, with careful monitoring of the patient’s response). Prompt administration of antivenom, when indicated, rarely leads to complications. However, there are various snake antivenom formulations on the market that may differ in composition and timing of infusion. The relevant data sheet should be consulted each time. It is produced through a process of hyperimmunization of equine species with a mixture of venoms from Vipera berus, Vipera ursinii, Vipera aspis and Vipera ammodytes. The lyophilized protein produced by equine sera is a combination of different antibodies against venom constituents and serum residues. Once the immunoglobulin fragments contained in the preparation are administered, it is distributed throughout the body specifically neutralizing the viper toxins; in addition, one must always consider the possibility of either a life-threatening anaphylactic reaction, (even when skin tests are negative), or a delayed hypersensitivity reaction, i.e., serum sickness (34-36).

Follow-up

Acute pathological effects of poisoning, adequately treated, tend to resolve completely within a few days of the bite; other pathological effects or their consequences may last for about six months although this period is subject to interindividual variability (37). From a musculoskeletal perspective, persistent contractures, muscle atrophy to joint stiffness with reduced and impaired range of motion may remain; clearly manifest in patients who have not had a course of physiotherapy. When scars are extensive, they may result in both abnormal skin desquamation and discoloration at the site of the bite sometimes turning into squamous cells.

Chronic ulcers at the bite site can aggravate tissue injury and prolong recovery, leading to amputation in 6.9% of cases (8,38). Swelling, allodynia, and hyperalgesia persist for many weeks. The renal insult consists of acute interstitial nephritis, renal damage that progresses to chronic renal failure. Central retinal artery occlusion can result in optic atrophy, and neuritis is secondary to hemorrhage. Later changes have been observed in the sense of smell (including loss of smell-anosmia) and taste, which in most patients is reported as a horrible taste sensation persists for months or years. At the endocrinological level, there is late chronic hypopituitarism with deficiency of certain hormones such as cortisol, growth hormone, thyroxine, and testosterone. Finally, in these patients, it is possible to observe over a long period of 12–48 months, anxiety, post-traumatic depression, and the whole symptomatological set of somatization (18,19).

Discussion

In our single-institution case series, the viper bite is second in frequency only to the bite of Loxosceles rufescens (39).

This article described the most common vipers in Europe and particularly in Italy, the incidence of bites, and the correct therapeutic approach to take. It consists of a thorough history collection combined with an initial laboratory and clinical evaluation using the Audebert-Boels classification (Table 2), which is a severity scale with a score from 0 to 3 describing the severity of the bite. A score of 0 indicative of no poisoning, i.e., dry-bite without venom inoculation. Dry-bites are characterized by the absence of the classic symptomatology associated with venom injected into the victim. In this case, a diagnosis is reached only after a long period of observation 12–24 h and associated with various laboratory investigations; therefore, treatment consists of local therapy with cleansing and disinfection combined with systemic antibiotic therapy and tetanus prophylaxis (40). A score of 1 indicates minimal poisoning characterized by the presence of edema confined to the bite area.

Moderate poisoning, on the other hand, is associated with a score of 2, which in turn is subdivided into 2a when there is positivity to one or both of the following symptoms such as, regional edema with hematoma and 2b when the symptoms of 2a are associated with systemic symptoms. Finally, severe poisoning with a score of 3, presents with signs of hemodynamic instability and diffuse trunk edema. In bites in which venom has been injected, associated with marked symptomatology, antidotal therapy is administered, due to which the mortality is 0.9% (8). The therapy should be preceded by appropriate premedication based on the use of an antihistamine and a corticosteroid, as the serum could result in an anaphylactic reaction, although such a reaction could also occur at the time of venom inoculation itself. However, administration of the snake antivenom in turn could result in the development of so-called serum sickness, which is an observable clinical occurrence in some patients. Globally, reports of serum sickness following antivenom therapy range from 5% to 56%, with 40% for serum anaphylaxis (41). Serum sickness is an adverse drug reaction that occurs 5 to 20 days after administration of heterologous protein or foreign serum, such as antivenin (42).

In affected patients, the host immune system produces antibodies against these heterologous proteins, resulting in the formation of circulating antigen-antibody immune complexes and causing a type III hypersensitivity reaction. Mononuclear phagocytic cells, which are normally involved in their elimination, in some cases, fail to remove them from the circulation, thus resulting in their deposition in various tissues such as vascular endothelium, synovial tissues, and renal glomeruli. In addition, complement activation results in the stimulation of histamine secretion resulting in increased vascular permeability. The result is the development of typical signs and symptoms of antiophytic serum sickness characterized by: fever, chills, urticaria, rash, arthralgia, myalgia, abdominal pain, nausea, vomiting, headache, and lymphadenopathy (43-46). However, greater reporting of viper bites is hoped for. When you are not near hospitals, the correct behavior is to stabilize the patient and transport him to the nearest hospital.

Conclusions

It is important that the patient is hospitalized as soon as possible and that prehospitalization maneuvers are correct. Snake antivenom administration should not be practiced in all patients but only in severity classes 2 and 3. Subjects who have been administered snake antivenom should follow up clinically/with laboratory tests. It is essential to put in place practices to reduce direct contact with viper; prevention remains the main therapy and is implemented: wearing appropriate clothing, boots, socks and/or long pants so as to protect the parts most in contact with the ground. However, much remains to be done both in the area of prevention and correct behaviors to be adopted, and in the out-of-hospital and hospital clinical approach in case of an established bite, so further future research on this issue is hoped for.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-81/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-81/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-81/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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