A Perspective to Stinging Nettles from Emergency Department, Snakebites Worldbite

Keywords

Snakebite; Worldwide; Management; Emergency department

Introduction

Epidemiology

Venomous snakes are responsible for approximately 1.5-3 million bites as well as perhaps more than 100.0000 fatalities annually worldwide [1]. Although exist 3000 venomous snake species in a global scale, only 200 of them pose a life threat for humans due to venom properties and tooth pattern. The venomous species include Elapidae, Viperidae, Hydrophiidae, Colubridae, and Antractaspididae families [2].

Progressive urban development and degradation of wild life have not resulted in lower rates of attacks of humans by wild animals. On the contrary, animals like snakes pose public health problems due to their venoms [3]. Humans residing in rural environments are reportedly more prone to snakebites than people living in urban centers [4-6]. Such a disparity may result from larger snake populations in rural areas but also people making a living through agriculture, which is reportedly a risk factor for snakebite [7]. People suffering from snakebite are generally adult males actively taking part in professional life [5,8].

General distribution of venomous snakes

Venomous snakes have a habitat distributed throughout the planet but are especially an important public health problem in the rural tropical areas of sub-Saharan Africa, Asia, and Latin America. They are especially numerous in Africa, Asia and South America [9-11]. WHO guidelines indicate two major categories in relation to the relative risk of each species. Category 1 is the most medically important group and encompasses snakes with a great potential for threatening life or causing major morbidity, disability, of injury. Category 2 is of secondary importance medically but also includes highly venomous snakes that may well cause disability, morbidity, or mortality; the difference of the snakes in this category is that clear epidemiological or clinical information may not exist and/or these snakes are responsible for less snakebite incidents owing either to their activity cycles, behavior, or habitats that are remote from human settlement [9].

Myanmar has the world record for venomous snakebites [12]. Regionally speaking, the leading country in the Central America region is Panama, where 1800 snakebite records occur annually, causing a fatality rate of 0.5/100.000 people [13]. In Asia, Kerala is one of the places that have the lead in this category, along with West Bengal, Tamil Nadu, Maharashtra, and Andhra Pradesh, and hosts about 37 venomous snake species, [14]. In South America, Brazil suffers most from snakebites (approximately 26,000-29,000 cases annually), which is followed by Venezuela (7,000), Colombia (3,000), Ecuador (1,400-1,600), Peru (1,400-1,500), and Bolivia (1,000) [15]. Although snakebite incidences in African continent vary considerably as a result of differing hospitalization rates, Kenya has the most extensive record [8]. In Caribbean, snakebite incidents largely remain unrecorded [16]. Snakebites are less a cause of medical concern in Europe than the other parts of the planet; European snakebite incidents are usually caused by Malpolon monspessulanus and the sub-family of Viperidae [17]. The latter is also the most common snake species in rural Turkey [18].

Mechanisms/Pathophysiology

Venom-antivenom characteristics

Each species has its own venom composition, and snake’s age and geographical region also affects it. Venom composition usually dictates clinical presentation [19,20]. Some components of typical venom act together and form protein complexes; toxin content and composition of venom should be well known to cover the geographical differences of fatality potential of and clinical signs and symptoms associated with various venoms [21,22]. Snake venoms contain abundant amounts of phospholipase A2 (PLA2), B, C and D enzymes, hemorrhaging, transaminase, hyaluronidase, phosphodiesterase, acetyl cholinesterase, cytolytic, necrotic toxins. The major protein families in snake venom with a discussion of their toxic activities can be found below [23,24]:

• Phospholipases A2: local and systemic myotoxicity, pain, damage to lymphatic vessels, edema, neurotoxicity, nephrotoxicity and hemolysis.

• Metalloproteinases: hemorrhage, myonecrosis, extracellular matrix degradation, blistering, pain, edema and cardiovascular shock, nephrotoxicity and coagulopathy.

• Hyaluronidases: extracellular matrix degradation.

• Three-finger toxins: Cytotoxicity, necrosis and neurotoxicity.

• Dendrotoxins: Neurotoxicity.

• Serine proteinases: Coagulopathy, edema and hypotension.

• Vasoactive peptides (for example, bradykinin-potentiating peptides): Hypotension.

• Disintegrins: Inhibition of platelet aggregation.

• C-Type lectin-like proteins: Inhibition or promotion of platelet aggregation and thrombocytopenia.

• Cysteine-rich secretary proteins: smooth muscle paralysis.

• Small basic myotoxic peptides: Muscle contracture.

• Natriuretic peptides: Hypotension.

• Sarafotoxins: Cardiotoxicity.

In 1984 Albert Calmette, with the collaboration of Pierre Paul Émile Roux, readied antisera production on rabbits against venominduced death. At the same time, Physalix and Bertrand showed hyperimmune serum-induced effective neutralization of snake venoms. The first human use of an antivenom was carried out by Lépinay, a colleague of Calmette. The first anti-venom against Indian Cobra was introduced in 1895 [25,26].

In order to guarantee neutralization of venoms by antivenoms, a preclinical test should be conducted in compliance with internationally-accepted protocols and guidelines; of these, neutralization of venom potency, also known as ED50, is the major preclinical test. It refers to an effective antivenom dose that makes 50% of test animals survive a 3×to 5×LD50 challenge dose (where the LD50=lethal dose of venom that results in killing 50% of test animals in a given interval) [26,27].

Nevertheless, antivenoms differ with respect to the rate of adverse reactions, which range from early anaphylactic reactions to later serum sickness type reactions; furthermore, no antivenom has been proven safe in this sense when adverse reactions are carefully scrutinized after their use [28]. Antivenoms also carry some major disadvantages including access problems in rural regions where they are needed the most; geographical and taxonomic differences between snake species resulting in a diverse venom composition and antigenic reactivity; and potential allergic reactions associated with antivenoms [29]. Nevertheless, people in rural and remote places still perform folk medicine using herbal products for most of their medical problems including snakebites. Medicinal herbs are used to extract a wide range of bioactive medicines that can be either directly utilized for the treatment if snakebites or, as vital supplements, for production of anti-venoms. These compounds can thus be make of use as efficacious alternative agents in two main areas, namely as the sole therapy when antivenom immunotherapy is not urgently available, or in supplement form on top of existing therapy [30]. Alkaloids, acids, steroids, flavonoids, coumestans, pterocarpans, terpenoids and some miscellaneous compounds can be mentioned as herbal compounds used to treat snakebite victims [23].

Pathophysiology

Pharmacologically, snake venom incorporates various pharmacologically active proteins and peptides with pivotal roles in the pathophysiology of snakebite [31]. The venomous snake superfamily Colubroidae is the largest venomous animal family. Vipers (family Viperidae) and elapids (family Elapidae) are responsible for the majority of envenomations and fatal cases from snakebite among Homo Sapiens and domestic animals [32].

A venomous snake injects its venom through its fangs, modified teeth that are connected to a venom gland through a duct [24]. The size of the fangs determines whether a snake’s venom is released into subcutaneous or intramuscular compartments. Some components of a venom act locally in the immediate vicinity of the area it has been released while others are transported to distant body sites via lymphatics or blood vessels and act systemically [33].

Snake venom is a highly complex and biochemically diverse compound with a wide range of toxicological effects that result in highly diverse clinical signs and symptoms. Some compounds in venoms inflict local tissue injury with resulting long-term sequelae but others act systemically resulting in signs of neurotoxicity (e.g. respiratory paralysis), hemorrhage, acute renal injury, rhabdomyolysis (that is, diffuse muscle breakdown), cardiovascular effects, autonomic hyperactivity or thrombus formation [34].

Local tissue injury mainly occurs through the effects of myotoxic phospholipases A2 (PLA2s), which are connected to and damage the cellular membrane of muscle fibers; this event leads to calcium influx to the cytosol, resulting in myofilament hypercontraction, mitochondrial dysfunction and other degenerative consequences, irreversibly injuring muscle cell [35-37]. This mechanism leads to chronic musculoskeletal sequelae as long-term health complications of snakebites [38]. Metalloproteinases in Snake Venom (SVMPs) cause degradation of important components of capillary basement membrane, which gives rise to reduced mechanical stability of micro vessels and dermal injury due to injury to dermal–epidermal interface, which eventually form blisters [39,40].

Neurotoxicity occurs by the actions of two major neurotoxins: a-neurotoxins and β-neurotoxins, which cause descending flaccid neuromuscular paralysis, and can induce a fatal blockade of bulbar (oral and laryngeal muscles responsible for speech and swallowing) and respiratory muscles [24]. a-Neurotoxins are connected to cholinergic receptors at the motor end plate of muscle fibers; these inhibit acetylcholine binding and provoke flaccid paralysis. In contrast, βequent clinical checks [-neurotoxins are PLA2s that affect presynaptic nerve terminal of neuromuscular junctions and cause enzymatic hydrolysis of phospholipids [41,42].

Cardiovascular and hemostatic disturbances mainly occur through SVMPs impairing the coagulation cascade or hydrolyze fibrinogen and fibrin [39, 43, 44]. Venom-induced systemic bleeding represents a major pathway leading to hemodynamic disturbances and may culminate in to cardiovascular shock [33].

Acute renal injury occurs due to renal ischemia secondary to reduced renal blood flow, and results from hemodynamic alterations caused by systemic bleeding and vascular leakage; proteolytic degradation of the glomerular basement membrane by SVMPs; deposition of microthrombi in the renal microvasculature, direct cytotoxic action of venom components, inducing systemic myotoxicity (that is, rhabdomyolysis), accumulation of large amounts of myoglobin in renal tubules, with consequent toxicity [45,46].

Rhabdomyolysis is due to the action of myotoxic PLA2s at the systemic level as a result of the binding of these toxins to receptors in muscle fibers [37].

Clinic

Snakebite envenomation manifests with local and systemic symptoms [47]. The former is pain, swelling, hemorrhagic blistering, bruising, and regional lymphadenopathy while the latter are headache, nausea, vomiting, and abdominal pain [14]. Snakebites may sometimes cause minimal or no symptoms and called as ‘dry bites’ (that is, transcutaneous bites without envenoming) [48]. Specific snakebites may result in specific symptoms. To conclude, pathophysiology and the toxins are the determinants of the clinical presentation.

Diagnosis

Bite site should be definitely well examined; time of envenomation, prehospital treatments if any, culprit snake species and other relevant questions about snakebite should be thoroughly questioned and recorded [24]. Patients’ clinical condition should be assessed using complete blood cell count, biochemistry parameters including renal and hepatic functions, coagulation parameters, serum electrolytes, and myocardial enzymes. Electrocardiography and imaging tests including computed tomography and magnetic resonance should be performed as necessary [1]. Although venom antigens can be detected and quantified in body fluids with enzyme immunoassays, kits utilizing the latter are not widespread on a global scale [24].

Management

Treatment is based on the severity of envenomation; it is divided into field care and hospital management.

Field care

The therapeutic goals include total body immobilization, with particular care to immobilize the affected limb to prevent the venom from disseminating through veins and lymph vessels, airway management, checking breathing and circulation, eliminating any ring or tight object from around the affected limb, and putting a pressure pad or pressure bandage over the bite site [7,44]. Incision of the bite site, suction of the venom, and applying tourniquets are ineffective, potentially harmful, and should thus be discouraged [7]. First aid should delay systemic dissemination of a venom, prevent fatal complications, and transport a patient to a healthcare facility [49].

Hospital management

The initial assessment in the emergency department should include an examination of the airway, respiration, circulation, and level of consciousness. Patients in shock due to cardiovascular compromise should be urgently resuscitated, as those with respiratory failure due to neurotoxicity and cardiac arrest secondary to hypoxia, cardiac toxicity, or rhabdomyolysis-induced hyperkalemia [49,50]. Clinical severity of envenomation determinates the therapy. Table 1 provides the grading of system of signs indicative of severity. Observation should be done at least 24 hours with frequent clinical checks [24]. A “dry bite” that lacks signs of envenomation requires a watchful observation in the emergency service for a period of 8-10 hours against the possibility of the progression of symptoms [50].

  

    
0
    
no envenomation 
    
Fang marks, minimal pain,    swelling and erythema around the fang marks <2.5cm, no systemic symptoms. 
  
  

    
I
    
Minimal envenomation
    
Fang marks, immediate    pain, swelling and erythema of 2.5-15 cm during the first 12 hours, no    systemic signs. 
  
  

    
II
    
Moderate envenomation
    
Fang marks, immediate    severe pain, swelling and erythema of 15-40 cm during the first 12 hours,    mild systemic signs. 
  
  

    
III
    
Severe envenomation
    
Fang marks, immediate    severe pain, swelling and erythema >40 cm in the first 12 hours with    systemic signs. 
  
  

    
IV
    
Very severe envenomation
    
Fang marks, immediate    severe pain, severe systemic signs including shock and coma. 
  

Table 1: Grading the severity of envenomation.