CLINICAL MANIFESTATION AND MANAGEMENT OF SNAKEBITES IN LITHUANIA (Vipera berus) AND IN ISRAEL (Vipera palaestinae)

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY

FACULTY OF MEDICINE

DEPARTMENT OF DISASTER MEDICINE

TZABAR GUR

CLINICAL MANIFESTATION AND MANAGEMENT OF

SNAKEBITES IN LITHUANIA (Vipera berus) AND IN ISRAEL (Vipera

palaestinae)

A LITERATURE REVIEW MASTER THESIS

Supervisor:

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1 SUMMARY

Master thesis by Tzabar Gur

Title – Clinical manifestation and management of snakebites in Lithuania (Vipera berus) and in Israel (Vipera palastinae).

The aim of the theses To review epidemiology, clinical manifestation, treatment and most common causes of death of patients who were bitten by snakes Vipera palaestinae (in Israel) and Vipera berus (in Lithuania).

Objectives of the study 1.To determine the epidemiology of snakebite by Vipera palaestinae in Israel and

Vipera berus in Lithuania. 2. To find the symptoms, signs and complications of snakebites caused by Vipera palaestinae and Vipera berus. 3. Antivenom and supportive treatment of patients who were bitten by Vipera palaestinae in Israel and Vipera berus in Lithuania. 4. To determine mortality rate and causes of death due

to snakebites caused by Vipera palaestinae in Israel and Vipera berus in Lithuania.

Methodology a literature review was conducted using the electronic medical database PubMed and Google Scholar selecting publications which were relevant to the topic. Combination of the keywords: “snakebite”, ”snake bite”, ”viper”, ”Vipera berus”, ”Vipera palaestinae”, ”envenomation”, ”antivenom”, “antivenin”, ”European adder”, “middle east”, “Lithuania”, “Israel’ were used. As well as filters were applied: language “English”, “Lithuanian”, “Hebrew”; species “human” in order to select the articles and researches for this literature review.

Results and conclusions: In Lithuania the average V. berus snakebites is 34 cases per year. In Israel there are 150-200 snakebites per year, most of them are caused by V. palaestinae. The main local sings of the snakebite are fangs marks, severe pain and edema. Most common systemic signs are CVS manifestation, vomiting, abdominal pain, anaphylactoid reaction. The most common complications are necrosis, compartment syndrome, limb amputation and renal failure. The only specific treatment is antivenin. In Lithuania there is no standardized protocol. In Israel the treatment protocol is 50mL i/v of V. palaestinae antivenom. In Israel there is 1 death after V. palaestinae envenomation every 5 years. In Lithuania there was no death after V. berus envenomation during 2001-2009 period.

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2 CONFLICTS OF INTEREST

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3 PERMISSION ISSUED BY THE ETHICS COMMITTEE

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4 ABBREVIATIONS

AIDS- acquired immunodeficiency syndrome ALT- alanine transaminase

APTT- activated partial thromboplastin time AST- aspartate transaminase

atm- standard atmosphere unit C- Celsius

C. cerastes- Cerastes cerastes

C. purpureomaculatus- Cryptelytrops purpureomaculatus

Cm- centimeters

CVS- cardio vascular system ECG- electrocardiogram

EMA- European Medicines Agency h - hours

HIV- human immunodeficiency virus HSR- hypersensitivity reaction

H1A-histamine H1-receptor antagonist H2A-histamine H2-receptor antagonist IM- intramuscular

IgE- immunoglobulin E IV- intravenous

Mg/kg- milligram per kilogram mL- milliliters

Mm- millimeters

Mm Hg- millimeter of mercury

NSAIDs- non-steroidal anti-inflammatory drugs PLA2- phospholipase A2

PM- post meridiem

PSS- Poisoning Severity Score PT- prothrombin time

Rh- rhesus

SC- subcutaneous Sol.- solution spp.- species

V. berus- Vipera berus (common European viper, common European adder) V. palaestinae- Vipera palaestinae (Daboia palaestinae)

VXP- Vipera xanthine palaestinae WHO- World Health Organization

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5 INTRODUCTION

There are 5,400,000 events of snakebite every year. Snakebite can be caused by nonvenomous and venomous snakes. Venomous snakebites can be classified into “dry” bite and envenomation. “Dry” bite means that no venom enter the victim’s body after the venomous snakebite. Envenomation is the process in which the venom enters the body during venomous snakebite. Envenomation due to snakebite considered as health threatening condition in the whole world, especially in the rustic regions of developing countries. Every year 2,500,000 cases of the snakebites are envenomated, approximately 125,000 result in death, mostly in Asia; 100,000 suffer from severe outcomes [1–3]. Snakebite envenomation is a neglected global health problem, responsible for substantial mortality, disability, anxiety and other psychological morbidity, particularly in rural tropical areas [3]. Venomous snakebite is a medical emergency impacting the site of the bite and potentially can affect the whole body systems [4].

The Viperidae is a family of venomous snakes, which are known in the society as vipers. Vipers are found in most geographical areas of the globe, for instance in Europe - Vipera berus (V. berus), in America - American crotalus durissus, in Africa - Cerastes cerastes (C. cerastes), in Asia - Cryptelytrops

purpureomaculatus (C. purpureomaculatus) [5].

In Lithuania the only venomous snake is V. berus, as well as one of the most common venomous snake in Europe. V. berus is also known as common European viper, common European adder.

In Israel the most common venomous snake is Vipera palaestinae (V. palaestinae), which is endemic viper found in Middle East. V. palaestinae in the literature is also known as Daboia palaestinae, Vipera

xanthina palaestinae [6,7].

Vipers bites can be lethal, therefore they required attention and immediate medical care [8]. The only specific treatment is antivenin. Thus, it is limited by high price, cold storage, snakebite diagnosis and political issues [3].

The purpose of this literature review is to provide summarized information from the newest articles and studies about the most common venomous snakes in Lithuania and Israel. The aim of this master thesis: to review epidemiology, clinical manifestation, treatment and most common causes of death of patients who were bitten by snakes Vipera palaestinae (in Israel) and Vipera berus (in Lithuania).

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6 AIM AND OBJECTIVES

Aim: To review epidemiology, clinical manifestation, treatment and most common causes of death of patients who were bitten by snakes Vipera berus (in Lithuania) and Vipera palaestinae (in Israel).

Objectives:

1. To determine the epidemiology of snakebite by Vipera berus in Lithuania and Vipera palaestinae in Israel.

2. To find the symptoms, signs and complications of snakebites caused by Vipera berus and Vipera

palaestinae.

3. To determine specific and supportive treatment of patients who were bitten by Vipera berus in Lithuania and Vipera palaestinae in Israel.

4. To determine mortality rate and causes of death due to snakebites caused by Vipera berus in Lithuania and Vipera palaestinae in Israel.

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7 RESEARCH METHODOLOGY AND METHODS

Data collection and search strategy:

The literature review was performed by screening different electronic databases including PubMed and Google Scholar. It was conducted following the PRISMA (preferred reporting items for systematic reviews and meta-analysis) statement. Total number of 45 articles and researches were fully reviewed. The 20 most relevant articles were selected. The search was restricted to English and last 10 years articles only (with an exception of 3 articles) [Fig.1].

Information source:

PubMed and Google Scholar

Inclusion criteria:

Phrases used:

snakebite, snake bite, venomous snake, viper, adder, envenomation, manifestation, first aid, antivenom, antivenin, European adder, middle east, Lithuania, Israel, Vipera berus, Vipera palaestinae, Daboia

palaestinae.

Sentences used:

- Snakebite in Europe/ Lithuania - Snakebite in Middle East/ Israel - Epidemiology of snakebite - Manifestation after envenomation

- Antivenin administration in Israel/ in Lithuania - Snake bite management

- Mortality rate after envenomation - Causes of death due to envenomation

Exclusion criteria:

- Older than 10 years publication

- Researches which were not written in English, Lithuanian or Hebrew languages - Irrelevant or less relevant researches (after reading title and abstract)

Types of publication and studies:

This literature review included systematic reviews, case reports and researches published in English, Lithuanian or Hebrew languages during the last 10 years (with an exception of 3 articles).

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Included into literature review

(n=8) Included into literature

review (n=12)

Title and abstract were screened

(n=56)

After adding keywords “Vipera palaestinae”, “Daboia palaestinae”

(n=294)

Title and abstract were screened

(n=24)

Full-text articles assessed for eligibility

(n=25) Full-text articles

assessed for eligibility (n=20) Based on exclusion criteria 238 works excluded 31 result excluded after using filters: - language - species 17 articles and researches were irrelevant to the topic Initial search (n=13022)

After adding keyword “Vipera berus” (n=145) Based on exclusion criteria 121 works excluded 4 result excluded after using filters: - language

8 articles and researches were irrelevant to the topic

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8 RESULTS AND THEIR DISCUSSION

8.1 Epidemiology of snake bites

8.1.1 Epidemiology of snake bites by V. berus in Lithuania

Envenomation due to snakebite is an uncommon event, however it is potentially severe injury in Europe. Envenomation approximately affects 0.4-1.1 people per 100,000 population annually and causes 4 lethal cases per year. In Europe there are 3 snake species of Vipera family (V. berus, V. aspis, and V.

ammodytes) which are responsible for the majority of envenomation [8,9].

In Lithuania there is only one venomous snake species - the common adder (Vipera Berus) which belongs to the Viperidae family [2]. Between the years 2001 to 2009 there were reported 309 cases of snakebites in Lithuania (mean population - 3 250 000). Among the 309 cases 63% were males. 11% of the bitten patients were under the age of 15 years old. In comparison to other European countries the prevalence of snakebites in children under the age of 15 was significantly lower in Lithuania. Average cases of snakebite per year – 34. The average stay in the hospital was 3.6 days and the median stay – 2 days [6].

Adder bites incidents mostly happen in the summer with a peak between the months July and August. The adder bites usually visible as 2 bitten points with distance of 5-12 mm between them. The skin around the punctured wounds usually becomes purplish and vesicles sometimes appears [8]. The most common body parts to be bitten by a snake are the lower limbs distal to the knees and the upper limbs distal to the elbows (90%). Snakebite can even occur by a dead snake due to posthumous reflex which causes the contraction of the oral muscle [2].

Vipera berus used to be present in the outer forests zone and by the swamps more often than it is in

these days. High risk group of people for being bitten by a snake are hunters, agricultural workers, people who work in the zoo, fishermen, tourists. Excessive alcohol consumption diminishes the attention, therefore it may increase the risk for getting bitten by a snake [2].

8.1.2 Epidemiology of snake bites by V. palaestinae in Israel

There are 20,000 snakebites in the middle east; out of them 15,000 are envenomation; 9,000 of those cases end up in the hospital and 100 people die every year [1,2].

Daboia palaestinae is the most common venomous snake in Israel and an important cause of

envenomation in humans and animals [10]. Vipera Palaestinae (Daboia Palaestinae) average length is 70-90 cm and maximum length of 130 cm [7]. Most of V. palaestinae envenomation are mild or moderate [11]. According the study performed in Israel, the lower limb is affected in about 75% of the cases and the upper limb in about 25%. There was no envenomation severity difference detected between the limbs [4].

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manifestation [13]. Vipera palaestinae is responsible for 503 out of 826 events of snakebites which were reported during the years 1998-2001 to the Israel National Poison Information Center [14].

The habitat of V. palaestinae includes most parts of Israel and Lebanon, until the border with Syria [10]. In Israel this snake can be found in the areas from the eastern border with Jorden to the Beersheba city in the south and also in the Golan heights in the north [4,12]. In a study about 1234 snakebites cases which occurred during 8 years period of time: 47% snakebites were reported in the Central, 42% in the Northern and only 11% in the Southern regions of the country [11].

In the same study it was noticed that most of the snakebites (74.2%) occurred at the time 6-9 PM during the hot seasons. The risk of snakebite increased when average day temperature was higher than 23C and the risk of snakebite decreased when the humidity was higher than 40% [11]. In a study of 57 patients, which was done during 6 years period, was noted that most bites (89%) occurred between the months April and October with a significant peak in June (17%) and September (15%) [4].

8.2 Symptoms, signs and complications after snake bite

8.2.1 Clinical manifestation due to V. berus envenomation

It is common to classify symptoms according to envenomation severity into 5 categories using the Poisoning Severity Score (PSS) which was developed in the 1990 in Europe. PSS categories are: 0 - none (no clinical signs of intoxication, only fangs marks, can be also called “dry” bite); 1 - minor (mild local edema and other spontaneously resolving general symptoms); 2 - moderate (spreading of edema, prolonged general symptoms); 3 - severe (severe and life threatening symptoms); 4 – fatal (death) [2,9,15,16].

There are several factors which influence the outcomes of the snakebite. Those factors are: the location of the bite, size of the snake, venom gland status, bite angle, bite duration, snake’s oral microflora and victim’s skin microflora, victim’s health condition (such as systemic chronic diseases: diabetes, hypertension, coagulation disorders), victim’s age and weight, victim’s action after the snakebite that are influencing the spreading of the venom in the body. The localization of snakebite is highly important in the assessment of its outcome, for instance, snakebite to the trunk, neck, face or directly into the blood vessels are more severe than those to the limbs and adipose tissue [2,17].

The venom of V. berus contains proteins (hyaluronidase, proteases and phospholipase) which are enzymes with cytotoxic activity. They damage endothelium, cause edema and hypovolemia after envenomation take place. One of the main enzyme in the venom is phospholipase A2 (PLA2) which causes hemolysis, thrombocytopenia, rhabdomyolysis and acute renal failure [16,18].

In Poland medical documentation of 15 patients who were bitten by V.berus berus were analyzed. At the time of arrival to the hospital all patients had visible fangs marks and complain of severe pain which started immediately after the bite. Major local symptoms were pain, tingling and edema (for 93.3% of patients), redness and subcutaneous blood extravasation appeared together with edema (for 73.3% of

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most common systemic symptoms in this study were: anxiety, nausea, vomiting, diarrhea, abdominal pain and elevated body temperature [16].

In UK 522 cases of snakebite were identified between the years 2004-2010, out of them 52% (271 cases) were caused by adder. In those 271 cases the distribution of clinical manifestation was: 94% - edema was present, 28% - cardiovascular symptoms (hypotension, tachycardia or both), 23% - gastrointestinal symptoms (vomiting and diarrhea), 7% - had anaphylactic reaction (hypotension with orofacial edema, rash or bronchospasm), 13% leukocytosis. ECG changes were obtained in only 2 cases. No severe coagulopathies or death were reported [18].

The venom may affect and cause changes in laboratory tests. Leukocytosis frequently occur and is associated with severe envenomation. Other blood tests may show anemia, thrombocytopenia, metabolic acidosis, prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), increased D-dimer, decreased fibrinogen, increased activity of transaminases ALT and AST, elevated creatinine and creatine kinase. Hemoglobin may remain normal at the beginning, but later anemia may occur. In urine test microscopic hematuria may be detected. The presence or the absence of microhematuria can tell us about the severity of envenomation. In mild envenomation usually there is no hematuria [2,9,19].

In the literature there are only few documented cases where ptosis and blurred vision occurred, most probably it was not a result of neurotoxic venom activity but as a result of the bite in the head area. Moreover, neurotoxin is more common in other subgenus of Vipera berus – V.berus bosniensis [9,16,20].

Acute tubular necrosis leading acute kidney failure is one of the severe complications of the venomous snakebite. Major tissue necrosis, vasculitis and dissection are the consequences of wrongly treating snakebites by given inadequate dose of antivenin. Late outcome of this mistake is fibrosis which lead to contractures and movement reduction. Other complications include the following: coagulopathies and thrombocytopenia which lead to bleeding diathesis, deep vein thrombosis, compartment syndrome, rhabdomyolysis, pancreatitis, acute paralytic ileus, pulmonary and cerebral edema. Those complications are rare and are more associated with other Viperidae family snakes [2,9,19].

8.2.2 Clinical manifestation due to V. palaestinae envenomation

V. palaestinae is one of the most dangerous snakes among Viperidae spp. and its venom is highly

toxic to humans [1]. The venom of V. palaestinae contain the principle two components: phospholipase A2 and basic proteins. Those two component together are responsible for the venom lethality. Other components are hyaluronidase, esterase, cytolysins, hemorrhagic substances, phosphodiesterase, thrombin, L- amino acid oxidase, proteolytic factor and integrin inhibitors. Those substances make the venom highly neurotoxic, cytotoxic, hemorrhagic, nephrotoxic and cardiotoxic. The way the venom affect the body via endothelial injury, increased capillary permeability, thromboplastin and thrombin inhibition, thrombocytes dysfunction, some level of fibrinolysis and hypofibrinogenemia, histamine and kinins secretion. There was the hypothesis that endogenous substances for instance proteolytic enzymes which are released during envenomation take a part in late consequences [1,7,12,14].

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potency of injected venom, body weight and health status of the victim, the bite location, efficiency of first aid and initial management [4].

The local manifestations of V. palaestinae envenomation are fangs marks, severe pain, edema, ecchymosis, lymphangitis, lymphadenitis and bullae. Snake’s fangs are responsible for the puncture wounds which are usually one or two (rarely more than two). Distance smaller than 8 mm between the punctures signal that the snakebite is caused by a small snake, while a large snake will leave a gap of 15 mm between the punctures. After V. palaestinae bite serous-hemorrhagic fluid and non-coagulated blood is coming out from the punctured wound. Unlike a wound caused by an insect, when there is no blood coming out from the bite wound or the blood is already coagulated. Local edema typically occurs within the first 10 minutes, distributes proximally to the location of the bite and it is able to spread through the entire limb or torso. Generalized edema can appear in children in less than 24 hours. It is important to remember that the size of the edema is not always an accurate measurement to assess the level of the dangerousness of the envenomation. Vipera xantina palaestinae (VXP) is very common in Israel and can be easily recognized. If there was a history of snakebite together with the recognition of the VXP and the geographical region fitted the distribution of VXP and presentation of typical local signs (massive progressive swelling, bullae and ecchymosis) the diagnosis of the VXP was determined as definite. Worsen of deterioration was defined as swelling progression. With the present of swelling there was a need for ecchymosis and bullae to be appear in order to determine a probable diagnosis [2,12,14].

Snakebites affect multiple organ systems such as cardiovascular, gastrointestinal, neurological and hematological systems. The main systemic signs and symptoms are: nausea, vomiting, diarrhea, abdominal pain, diaphoresis, restlessness, tachycardia, hypotension, anaphylactoid reaction (itching, urticaria), thrombocytopenia and leukocytosis [4,12,14].

In one of the study, where 57 cases of children were analyzed, V. palaestinae envenomation leaded to moderate or severe symptoms in 43% of patients and to systemic symptoms (mainly gastrointestinal manifestation) in 35% of patients. In the same study it was noticed that even if there is an absence of visible local or systemic symptoms, the venom can induce an effect to the hematologic system. The interval between the time of the bite and the time of admission ranged from 15 to 120 minutes (60 minutes median). The shortest hospital stay was 12 hours. Clinical manifestations were documented in 55 (96.4%) of victims and 30 (53%) were mild, 19 (33%) moderate and 6 (10%) severe. From this group, 37 (65%) experienced systemic reactions due envenomation with the most common symptoms: tachycardia (35%), vomiting (29%) and abdominal pain (19%). Compartment syndrome were developed in 2 patients and they underwent fasciotomy (surgical decompression). Thrombocytopenia was noted in 1 patient, mild coagulopathy developed for 3 patients and 8 patients suffered from mild myotoxicity. 1 patient suffered from kidney injury. 26 children developed leukocytosis, probably due to systemic inflammatory response [4].

Untreated or severe envenomation may result in serious complications and irreversible outcomes. Envenomation causes impact to the local tissue and may lead to multiple pathologies such as edema, hemorrhage, dermo- and myonecrosis that eventually can end with tissue or function loss and even the

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Delayed compartment syndrome diagnosis may lead to ischemic contractures or amputations of the limbs. Prospective study which included 97 patients showed that in order to prevent late diagnosis it is important strictly observe the bitten extremity using pulse oximeter and if it is necessary to use intra-compartmental pressure monitoring system. Once compartment syndrome is confirmed, fasciotomy should be performed immediately. Swelling at the bite area usually extends to the whole extremity in 6-48 hours. There was a report of the case when compartment syndrome occurred later than 48 hours (3 days) after the bite [17]. Subfascial pressure measurement is known as the best way to detect the occurrence of compartment syndrome. Compartment syndrome can be misdiagnosed in the case when subfascial pressure is not measured and it can lead to unnecessary operations. Possibly confusion might occur between the local reactions to V. palaestinae venom (severe pain and massive swelling) and compartment syndrome due to similar signs and features [4].

8.3 Vipera berus and Vipera palaestinae snake bite management

8.3.1 First aid after snake bite

Venomous snakebite is a medical emergency impacting the site of the bite and potentially can affect all body systems [4].

First aid of the snakebite is highly important and relevant topic because often people are making mistakes while providing first aid to the victim, for instance: sucking out the venom from a snake bite, making wound incision, applying heat or ice to the site of snakebite [2,16].

First step of the first aid is to calm down and to secure the victim. It is required to calm down the bitten person because hyperdynamic state can trigger the development of shock and aggravate the status of the patient due to rapidly spreading of the venom. Bracelets, rings and other body attaching accessories should be removed in order to prevent tissue mechanical constriction of the swelling extremity. Make sure airways are open and breathing is free and sufficient. Washing and cleaning the punctured wound should be avoided. Incision, excisions, mouth suction on the venom must not be used. While mouth suction, microflora can enter the victim’s body through the punctured wound, so it should not be performed. Even in a case of performing perfectly incision and suction, only 20% of the venom is eliminated. Moreover, the snake fangs are curved, the venom is not accumulated right under the bite marks; thus only a really deep incision would reach the venom collection. This type of incision performed by not experienced person can cause tendon or nerve injury. For venom suction - commercial extractors can be used, they are creating a negative pressure of 1 atm in order to suck the venom. One more important step of the first aid is to immobilized the bitten limb and to keep it lower than the heart level in order to avoid venom distribution and systematic spreading. The reason of doing it is to prevent any movements that can speed up the venom distribution and absorption into the blood stream and lymphatic system. Edema may be reduced by elevation of the bitten limb, but it should be done only if the patient’s condition is stable. Pressure bandage usage is questionable due to the fact that in many cases it is applied incorrectly. In cases of bites from other family snakes (for example

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for the right equipment, which is mostly not available in the field, thus, should not be performed. Nowadays the tourniquet is not in a usage. Ice should not be applied as well. Although ice helps to relief the pain and to decrease the lymph drainage, it also has a negative effect as ischemia which increases the damage [2,16].

8.3.2 Supportive treatment after snake bite envenomation

Respiratory function and airway passage should be monitored and ensured. Heart rate, blood pressure, ECG, kidney function, fluid balance and coagulation status should be monitored as well. Vasopressors and crystalloids are used to correct hypotension. NSAIDs are given as pain management. Calcium gluconate is given for relieved muscle spasms and seizures. Injection of tetanus prophylaxis should be given because the spores can enter the body during the bite. Broad spectrum antibiotics prophylaxis is given in a case where wound incision or mouth suction was performed. If the punctured wound becomes infected, cultured flora is taken from the wound secretions and antibiotics are given accordingly.

Enterobacter spp., pseudomonas spp. and Clostridium perfringens are found in 90% of the infected wound

cases. Routine use of antibiotics or corticosteroids are not recommended. Antiemetics and antihistamines are given for symptomatic treatment. Blood group and Rh should be determined. Fresh plasma, cryoprecipitate and thrombocytes can be used for hemorrhages. No stimulants or alcohol to be given. The bitten limb circumference should be measured every 15 minutes in order to estimate the dynamics of swellings and to prevent the occurrence of compartment syndrome [1,2,4,12].

8.3.3 Specific treatment after snake bite envenomation in Lithuania (Vipera berus) and in Israel (Vipera palaestinae)

Until today, the only specific treatment for snakebite envenomation is antivenin. Specific antivenin is a serum containing antibodies against snake’s venom antigens [1].

In Europe there are 8 available antivenoms for treating Vipera spp. envenomation. Only 3 of them are raised against V. berus venom: Biomed Viper venom antitoxin (F(ab’)2), ViperaTAb(Fab), ViperFAV (F(ab’)2). Two of them are monovalent (Biomed Viper venom antitoxin and ViperaTAb) used against

V.berus. ViperFAV antivenom is polyvalent, it includes antibodies against venom of 3 main venomous

snakes in Europe: V. berus, V. aspis and V. ammodytes [9,21].

The polyvalent antiserum against common adder can be used for local and systemic symptoms. Antivenin may not correct thrombocytopenia and rhabdomyolysis, as well there is no evidence of protection from local tissue damage. However, antivenin is able to correct clinical signs and laboratory abnormalities [2]. The bigger dose of venom may lead to more intense swelling. The power and speed of the augmentation of the swelling may be explained by the endothelial damage, increased capillary permeability and by the possible activation of endogenous processes. The process should be ceased by administration of antivenom therapy. Antivenom therapy should also decrease the hospitalization time and prevent complication even if it is given many hours after envenomation [14]. Antivenom administration is able to reduce most symptoms of compartment syndrome. If compartment syndrome progress and pressure reach more than 30 mm Hg

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The European Medicine Agency (EMA) on 9 October 2015 approved to MicroPharm Limited UK, for the ovine specific immunoglobulin (Fab) fragments raised against V. berus venom [22]. However, in Europe there is no standardized protocol for antivenom administration [9].

In Israel there is a treatment protocol for the progressive local signs and systemic symptoms that occur after V. palaestinae envenomation. According the protocol, 50mL of V. palaestinae antivenom should be administrated intravenously (IV). The antivenom is diluted in 250-500mL of 0.9% sodium chloride solution and should be administrated over 1-2 hours. Patients with cardiovascular collapse or other severe toxicities should be treated more aggressively with starting dose of 80-120 mL antivenom. If local or systemic signs are progressing additional 30 mL dose should be administrated. Antivenom administration for pediatric patients should follow the same guidelines as adults. The amount of antivenin should be calculated more according clinical view and laboratory findings rather than weight of the patient. In children total volume of fluid in which antivenom is diluted can be decreased if necessary. In a case when the patient did not notice, recognize the type of snake and the patient cannot even provide any morphological features of the snake, the geographical region can give a hint which snake caused the envenomation. V. palaestinae envenomation must be suspected in any case of a child that arrived to the ER with a snakebite from typical geographic area [4].

Antivenin adverse effects are: acute type I HSR anaphylactic reaction due to IgE antibodies which circulate and reacting with horse proteins; anaphylactoid reactions is caused by direct mast cells degranulation caused by horse proteins; serum sickness (is a late phase allergic reaction caused by immune complexes, combined of the person’s antibodies against the horse proteins – antigens). Serum sickness manifestation is fever, hives, myalgia, arthralgia, kidney dysfunction and neuropathy which appears in 7-14 days after antivenom administration. It is treated with oral prednisolone 1-2 mg/kg daily until the symptoms are gone. Oral antihistamine therapy can also ease the symptoms. In order to facilitate the possible acute hypersensitivity reaction to antivenin, the administration of standard dosage of H1 and H2 blocking antihistamines as pretreatment should be considered. For those who had received horse proteins in the past and did not develop allergic reactions, the initial dose of 0.2 mL antiserum is subcutaneously (SC) administrated and if no allergic reaction developed in 30 minutes, the remaining dose is given intramuscular (IM) (mostly in the gluteal muscle). Starting dose of antivenom should be diluted in 1000 ml of saline. Antivenom should be given intravenously slowly with epinephrine. If the patient tolerate, after 10 minutes the infusion rate should be increased in order to give the complete dose in 1-2 hours [2].

In Israel since 2012 a monovalent immunoglobulin is used, which is more purified and less immunogenic than the original antivenom. High incidence rate of anaphylaxis (4%) and serum sickness (4%) due to previous antivenin were reduced by usage of monovalent immunoglobulin. In retrospective review of 57 patients which was mentioned earlier, antivenom was given to 25 (42%) patients, all children which were graded in moderate - severe condition by definition. Median time from envenomation to antivenom administration was 1 hour. Antivenom was given to 1 patient 24 hours after envenomation for severe tachycardia. Prior exposure to antivenin did not occur to any of the children and none of them developed serum sickness or other adverse reactions. Medications for hypersensitivity were no given to any

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passed since the snakebite until the antivenom administration in her case was 120 minutes. There was no incident of death [4].

In one of the articles there were reported 3 cases of V. palaestinae snakebite in the distal limbs. 36-48 hours after the event massive swelling progressed to the trunk. In 2 patients the swelling reached the neck and was serious enough to cause dysphagia and to imply forthcoming upper respiratory tract obstruction. Tense swelling which caused urinary retention occurred and the insertion of urinary catheter was necessary. The result of antivenom administration was diminished swelling. The antivenom is highly effective when given within the first hours after envenomation as well it was efficient in patients with late (24h) progressive local complications, particularly if they were also represented with systemic signs [14].

The specific antivenin is effective against systemic and local signs when administrated within hours after envenomation but it is indistinct how long after envenomation it can still be efficient. In a research, which was done about delayed administration of antivenin, 10 patients 5-46 years old were collected consecutively from all reported patients to the National Poison Information Center in Haifa. All the patients received the antivenin more than 24 hours after envenomation. The study included the patients with confirmed VXP snakebite and that continued to deteriorate after 24 hours after the event despite the treatment. On the time of arrival to the hospital 8 patients represented with local signs and 7 represented with mild to severe systemic symptoms and signs. The late systemic signs were hypotension, pulmonary edema, thrombocytopenia, anemia and abnormal liver function. After delayed antivenin administration progression of local signs resolved in all patients and swelling regressed within 24 hours. The limitations of the study are small heterogenous patients group, circumstantial VXP bite identification in 3 patients, antibiotics and early antivenin administration in some patients, lack of long term follow up and the absence of control group. VXP antivenin administration to be considered for patients after envenomation complicated by late (>24 hours), progressive local manifestations, especially if accompanied by systemic manifestations. More studies needed to be done in order to understand the efficacy of delayed antivenin administration, clarify the initial antivenin dose [12].

8.4 Causes of death and mortality rate due to snake bite envenomation

8.4.1 Causes of death due to Vipera berus and Vipera palaestinae envenomation

Comorbidities such as cardiovascular diseases, hypertension, diabetes mellitus and coagulopathy worsen the outcomes of envenomation. Patients in age groups of old and very young age also have worse prognosis comparing to healthy adults. Anticoagulants usage, coagulopathies, peptic ulcer, endometriosis and menstruations increasing the risk of bleeding. Beta blockers usage increase the chance of anaphylactic reaction to antivenin. Venomous snakebite for a pregnant women is highly dangerous also to the fetus because it can lead to uterus arterial hypotension, hypoxia, hemorrhagic complication, placental abruption [2].

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Causes of death after envenomation include: cardiovascular shock, respiratory depression, renal tubular necrosis, coagulopathy, intracranial hemorrhage into pituitary gland, gastrointestinal hemorrhage or multiple organ system failure (respiratory, cardiovascular, neurologic, renal, hepatic and hematologic) [1,8,9]. The major cause of death after envenomation is inadequately managed hypotension [2].

8.4.2 Mortality rate after Vipera berus and Vipera palaestinae envenomation

The snakebite was neglected problem for many years by governments and international health agencies around the world. In comparison snakebite mortality rate is equal to 1/5 of deaths caused by malaria worldwide and half of deaths due to HIV/AIDS in India. The WHO recognized in 2009 the snake bite as neglected tropical disease [3].

Since the entry of the specific antivenom therapy in 1950s the mortality due to V.palaestinae envenoming had lessened drastically from 6-10% to 0.5-2% [4,10,12]. The Israel National Poison Center confirms that roughly there is 1 case of envenomation which ends in death every 5 years. In the 1970s and earlier the mortality rate was much higher most probably due to the different in the critical care level, late use of antivenom and long evacuation time [4].

In Lithuania during 2001-2009 period of time there were not death associated with envenomation. In Europe the annual average of deaths was 1.2 per year, annual mortality 0.0005 per 100 000 population [6]. Even if European adder can lead to death, mortality rate might be reduced in case when sufficient treatment is provided [19]. Mortality has dramatically decreased in Europe during 20th century. In Sweden the average annual mortality per 100,000 population in the years 1911-1949 fell from 0.02 to 0.003 in 1950-1979 and between the years 1980-2009 it dropped to 0.0008 per 100,000. The dramatically decreased in mortality is related to the development of intensive care intervention, reanimation and the use of purified antivenom since 1995 [21].

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9 CONCLUSIONS

1. In Lithuania the average number of V. berus snakebites is 34 cases per year.

In Israel there are 150-200 documented snakebites per year, most of them are caused by V.

palaestinae.

2. The major local signs after V. berus snakebite are fangs marks, severe pain, tingling, edema, a bit less common are redness and subcutaneous blood extravasation. Most common systemic signs are hypotension, tachycardia, nausea, vomiting, abdominal pain, elevated body temperature and anxiety. Complications due to V. berus envenomation are rare and more common in other Viperadae spp. snakes.

Specific signs associated with V. palaestinae envenomation are massive progressive swelling, bullae and ecchymosis. Most common systemic signs are tachycardia, vomiting, abdominal pain, hypotension, nausea and anaphylactoid reaction. Main complications associated with V.palaestinae envenomation are dermo - myonecrosis, compartment syndrome, limb amputation and renal failure.

3. The only specific treatment is antivenin. In Lithuania there is no standardized protocol for its administration. In Israel the treatment protocol for the progressive local signs and systemic symptoms is 50mL i/v of V. palaestinae antivenom which is diluted in 250-500mL of 0.9% sodium chloride solution and should be administrated over 1-2 hours.

Supportive treatment include respiratory function, heart rate, blood pressure, kidney function, fluid balance monitoring and correction. Hypotension is corrected by crystalloid infusion. Painkillers should be administrated. In order to prevent delayed compartment syndrome circumference of the limb and pressure should be measured.

4. Mortality rate in Europe between the years 1980-2009 is 0.0008 per 100,000 people. In Lithuania there was no death after V. berus envenomation during 2001-2009 period. In Israel there is 1 death after V. palaestinae envenomation every 5 years.

The main cause of death is uncontrolled hypotension. The other causes of death are cardiovascular shock, respiratory depression, kidney failure, coagulopathy, intracranial hemorrhage into pituitary gland, gastrointestinal hemorrhage or multiple organ system failure.

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10 REFERENCES

[1] Nusair SD, Ahmad MI. Toxicity of Vipera palaestinae venom and antagonistic effects of methanolic leaf extract of Eryngium creticum lam. Toxicon 2019;166:1–8.

https://doi.org/10.1016/j.toxicon.2019.05.006.

[2] Adukauskienė D, Varanauskienė E, Adukauskaitė A . Venomous snakebites. Medicina (B Aires) 2011;8:461.

[3] Xiao H, Pan H, Liao K, Yang M, Huang C. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development. Biomed Res Int 2017;2017.

https://doi.org/10.1155/2017/6592820.

[4] Pivko-Levy D, Munchnak I, Rimon A, Balla U, Scolnik D, Hoyte C, et al. Evaluation of antivenom therapy for Vipera palaestinae bites in children: experience of two large, tertiary care pediatric hospitals. Clin Toxicol 2017;55:235–40. https://doi.org/10.1080/15563650.2016.1277233. [5] Ozverel CS, Damm M, Hempel BF, Göçmen B, Sroka R, Süssmuth RD, et al. Investigating the

cytotoxic effects of the venom proteome of two species of the Viperidae family (Cerastes cerastes and Cryptelytrops purpureomaculatus) from various habitats. Comp Biochem Physiol Part - C Toxicol Pharmacol 2019;220:20–30. https://doi.org/10.1016/j.cbpc.2019.02.013.

[6] Chippaux JP, Saz-Parkinson Z, Amate Blanco JM. Epidemiology of snakebite in Europe: Comparison of data from the literature and case reporting. Toxicon 2013;76:206–13. https://doi.org/10.1016/j.toxicon.2013.10.004.

[7] Rima M, Naini SMA, Karam M, Sadek R, Sabatier JM, Fajloun Z. Vipers of the Middle East: A rich source of bioactive molecules. Molecules 2018;23:1–17.

https://doi.org/10.3390/molecules23102721.

[8] Tranca S, Cocis M, Antal O. Lethal case of vipera bersus bite. Clujul Med 2016;89:435–7. https://doi.org/10.15386/cjmed-581.

[9] Lamb T, de Haro L, Lonati D, Brvar M, Eddleston M. Antivenom for European Vipera species envenoming. Clin Toxicol 2017;55:557–68. https://doi.org/10.1080/15563650.2017.1300261. [10] Tirosh-Levy S, Solomovich R, Comte J, Sutton GA, Steinman A. Daboia (Vipera) palaestinae

envenomation in horses: Clinical and hematological signs, risk factors for mortality and construction of a novel severity scoring system. Toxicon 2017;137:58–64.

https://doi.org/10.1016/j.toxicon.2017.07.007.

[11] Shashar S, Yitshak-Sade M, Sonkin R, Novack V, Jaffe E. The Association Between Heat Waves and Other Meteorological Parameters and Snakebites: Israel National Study. J Emerg Med

2018;54:819–26. https://doi.org/10.1016/j.jemermed.2018.02.002.

[12] Bentur Y, Zveibel F, Adler M, Raikhlin B. Delayed administration of Vipera xanthina palaestinae antivenin. J Toxicol - Clin Toxicol 1997;35:257–61. https://doi.org/10.3109/15563659709001209. [13] Bentur Y, Lurie Y, Cahana A, Kovler N, Bloom-Krasik A, Gurevych B, et al. Poisoning in Israel:

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[15] Persson H, Sjöberg G, Haines J, Pronczuk de Garbino J. Poisoning Severity Score ( Pss ) Ipcs / Eapcct. Clin Toxicol 1998;36:205–13.

[16] Garkowski A, Czupryna P, Zajkowska A, Pancewicz Sł, Moniuszko A, Kondrusik M, et al. Vipera berus bites in eastern poland - a retrospective analysis of 15 case studies. Ann Agric Environ Med 2012;19:793–7.

[17] Türkmen A, Temel M. Algorithmic approach to the prevention of unnecessary fasciotomy in extremity snake bite. Injury 2016;47:2822–7. https://doi.org/10.1016/j.injury.2016.10.023.

[18] Coulson JM, Cooper G, Krishna C, Thompson JP. Snakebite enquiries to the UK National Poisons Information Service: 2004-2010. Emerg Med J 2013;30:932–4. https://doi.org/10.1136/emermed-2012-201587.

[19] Hønge BL, Hedegaard SK, Cederstrøm S, Nielsen H. Hospital contacts after bite by the European adder (Vipera berus). Dan Med J 2015;62:1–6.

[20] Varga C, Malina T, Alföldi V, Bilics G, Nagy F, Oláh T. Extending knowledge of the clinical picture of Balkan adder (Vipera berus bosniensis) envenoming: The first photographically-documented neurotoxic case from South-Western Hungary. Toxicon 2018;143:29–35. https://doi.org/10.1016/j.toxicon.2017.12.053.

[21] Al-Shekhadat RI, Lopushanskaya KS, Segura Á, Gutiérrez JM, Calvete JJ, Pla D. Vipera berus berus venom from Russia: Venomics, bioactivities and preclinical assessment of microgen antivenom. Toxins (Basel) 2019;11:1–14. https://doi.org/10.3390/toxins11020090.

[22] Agency EM. Public summary of opinion on orphan designation Ovine specific immunoglobulin (Fab) fragments raised against Vipera berus venom for the treatment of snakebite envenomation 2015;000.

CLINICAL MANIFESTATION AND MANAGEMENT OF SNAKEBITES IN LITHUANIA (Vipera berus) AND IN ISRAEL (Vipera palaestinae)

CLINICAL MANIFESTATION AND MANAGEMENT OF

SNAKEBITES IN LITHUANIA (Vipera berus) AND IN ISRAEL (Vipera

palaestinae)

TABLE OF CONTENTS

1 SUMMARY

2 CONFLICTS OF INTEREST

3 PERMISSION ISSUED BY THE ETHICS COMMITTEE

4 ABBREVIATIONS

5 INTRODUCTION

6 AIM AND OBJECTIVES

7 RESEARCH METHODOLOGY AND METHODS

8 RESULTS AND THEIR DISCUSSION

9 CONCLUSIONS

10 REFERENCES